Title: TRICYCLIC BENZAZEPINE VASOPRESSIN

ANTAGONISTS

This application is a continuation-in-part of co- pending Application Serial No. 08/639,014, filed April 24, 1996, which is a continuation-in-part of U.S. Application Serial No. 08/254,823, filed June 13, 1994, now U.S. Patent No. 5,512,563, which is a continuation-in-part of

Application Serial No. 08/100,003, filed July 29, 1993, now abandoned.

1 ■ Field of the Invention

This invention relates to new tricyclic non- peptide vasopressin antagonists which are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction .

2. Background of the Invention

Vasopressin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain osmoreceptors or decreased blood volume and blood pressure sensed by low-pressure volume receptors and arterial baroreceptors . The hormone exerts its action through two well defined receptor subtypes: vascular Vi and renal epithelial V2 receptors. Vasopressin-induced antidiuresis, mediated by renal epithelial V2 receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased. Vi antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induce increases in total peripheral resistance and altered local blood flow, Vi-antagonists may be therapeutic agents.

V. antagonists may decrease blood pressure, induce hypotensive effects and thus be therapeutically useful in treatment of some types of hypertension.

The blockade of V, receptors is useful in treating diseases characterized by excess renal re- absorption of free water. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific receptors on renal collecting tubule cells. This binding stimulates adenylyl cyclase and promotes the cAMP-mediated incor¬ poration of water pores into the luminal surface of these cells. V_ antagonists may correct the fluid re¬ tention in congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in conges¬ tive heart failure which is more common in older patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopressin levels, a V_ antagonist may be beneficial in promoting free water excretion by antagonizing the action of antiduretic hormone. On the basis of bio¬ chemical and pharmacological effects of the hormone, antagonists of vasopressin are expected to be thera¬ peutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vaso- spasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephrotic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding and abnormal states of water rentention.

The following prior art references describe peptide vasopressin antagonists: M. Manning et al., J. Med. Chem.. 35. 382(1992); M. Manning et al., J Med. Chem., 3_5_, 3895(1992); H. Gavras and B. Lammek, U.S. Patent 5,070,187 (1991); M. Manning and W.H. Sawyer, U.S. Patent 5,055,448(1991); F.E. Ali, U.S. Patent

4,766,108(1988); R.R. Ruffolo et al., Drug News and Perspective. 1(4), 217, (May) (1991) . P.D. Williams et al., have reported on potent hexapeptide oxytocin anta¬ gonists [J. Med. Chem.. 35. 3905(1992)] which also ex¬ hibit weak vasopressin antagonist activity in binding to V and V_ receptors. Peptide vasopressin antago¬ nists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they

10 also exhibit partial agonist activity.

Non-peptide vasopressin antagonists have re¬ cently been disclosed, Y. Yamamura et al., Science. 252. 579(1991); Y. Yamamura et al., Br. J. Pharmacol. 105. 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.)

15 EP 0514667-A1; JP 04154765-A; EPO 382185-A2; and W09105549. Ogawa et al, (Otsuka Pharm. Co.) EP 470514A disclose carbostyril derivatives and pharmaceutical compositions containing the same. Non-peptide oxytocin and vasopressin antagonist have been disclosed by Merck

20 and Co.; M.G. Bock and P.D. Williams, EP 0533242A; M.G. Bock et al., EP 0533244A; J.M. Erb, D.F. Verber, P.D. Williams, EP 0533240A; K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a key mediator in the έz> mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the preven¬ tion of preterm labor, B.E. Evans et al., J. Med. Chem. 3_5, 3919 (1992), J. Med. Chem.. 16, 3993 (1993) and

30 references therein. The compounds of this invention are antagonists of the peptide hormone oxytocin and are useful in the control of premature birth.

The present invention relates to novel tricyclic derivatives which exhibit antagonist activity at V- and/or V_ receptors and exhibit in vivo

vasopressin antagonist activity. The compounds also exhibit antagonist activity at oxytocin receptors. SUMMARY OF THE INVENTION This invention relates to new compounds selected from those of the general formula I:

Fo rmu I α

wherein Y is (CH ₂ ) _n , O, S, NH, NCOCH ₃ , N-lower alkyl CHNH-lower alkyl (C^C^, CHNH ₂ , CHN[lower alkyl (C ₁ -C ₃ )] ₂ , CHO-lower alkyl(C ₁ -C ₃ ) , CHS-lower alkyl(C ₁ -C ₃ ) , or the moiety:

wherein n is an integer from 0-2; A-B is

wherein m is an integer from 1-2, provided that when Y is "(CHo^n" ^{and n~2} ' ^{m ma} y ^{also be} zero and when n is zero, m may also be three, provided also that when Y is -(CH.) - and n is 2, m may not also be two. R. is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C ₁ -C ₃ ) , -SH, -SO lower alkyl(C ₁ -C ₃ ) , -S0 ₂ -lower alkyl(C ₁ -C ₃ ) , -CO-lower alkyl(C ₁ -C ₃ ) , -CF ₃ ; lower alkyl(C ₁ -C ₃ ) ; O-lower alkyl(C ₁ -C ₃ ), -N0 _2# -NH ₂ , -NHCO lower alkyl(C ₁ -C ₃ ) , -N-[lower alkyl(C ₁ -C ₃ ) ] ₂ , -S0 ₂ NH ₂ ; -S0 ₂ NH lower alkyl (C ₁ -C ₃ ) or -S0 ₂ N[lower alkyl (C ₁ -C ₃ )] ₂ ;

R is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C ₁ -C ₃ ) , O-lower alkyl(C.-C_) , or R. and R_ taken together are methylenedioxy or ethylenedioxy;

R ₃ is the moiety:

-CAr wherein Ar is a moiety selected from the group

10

and X is 0, S, -NCH ₃ , or -N-COCH..;

R ₄ is hydrogen, lower alkyl(C -C ); -CO-lower alkyl (C ₁ -C ₃ ); phenylCO, phenylS0 ₂ ; tolylS0 ₂ ; SO lower alkyl

20 (C -C ₃ ) ; or moieties of the formulae:

R ₅ is hydrogen, -CH ₃ , ~C ₂ H ₅ , Cl, Br, F, -0-CH ₃ , or

-0-C ₂ H ₅ ;

R _g is selected from (a) moieties of the formula:

30

-35

wherein cycloalkyl is defined as C to C cycloalkyl, cyclohexenyl or cyclopentenyl; R ₌ is hydrogen, CH_ , a 3

C_K _C , moieties of the formulae:

2. D

-(CH ₂ ) ₂ 0-lower alkyl (C ₁ ~C ₃ ) or -CH ₂ CH ₂ 0H; g is one or two; R. is hydrogen, CH_ or -C_H ;

(b) a moiety of the formula:

where R_ is as hereinbefore defined; (c) a moiety of the formula:

-N-C0 J wherein J is Ra„, lower alkyl(C ±.-C a _D ) branched or unbranched, lower alkenyl(C -C ) branched or unbranch¬ ed, 0-lower alkyl(C -C_) branched or unbranched, -O-lower alkenyl(C -C_) branched or unbranched, tetra- hydrofuran, tetrahydrothiophene, or -CH_-K wherein K is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

D

\ _ / G—F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C.-C )lower alkyl, hydroxy, -CO-lower alkyl(C.-C ₃ ) , CHO, (C.-C )lower alkoxy, -C0_-lower alkyl(C.-C ₃ ) , and R and R. are as hereinbefore defined; (d) a moiety selected from those of the formulae:

wherein R is selected from halogen, (C.-C )lower alkyl, -O-lower alkyl(C,-C ₃ ) and OH, R. is as hereinbefore defined; Ar' is a moiety selected from the group

R ₇ is hydrogen, -CH ₃ , -C ₂ H5, Cl, Br, F, -OCH ₃ , -OC ₂ H ₅ , or -CF ₃ ;

R ₈ and R are independently hydrogen, lower alkyl (C ₁ -C ₃ ); O-lower alkyl(C ₁ -C ₃ ) ; S-lower alkyl(C ₁ -C ₃ ) ,

-CF ₃ , -CN, -OH, -SCF ₃ , -OCF , halogen, NO , amino or NH lower alkyl(C ₁ -C ₃ ) ;

R. is halogen, hydrogen or lower alkyl(C -C ₃ ); W' is

0, S, NH, N-lower alkyl(C ₁ -C ₃ ) , NCO-lower alkyl(C ₁ -C ₃ ) or NS0 ₂ -lower alkyl(C ₁ -C ₃ ) .

represents: (1) fused phenyl or fused substituted phenyl optionally substituted by one or two substi¬ tuents selected from ( ^C -, ~ ^C ₂ ^ lower alkyl, halogen, amino, (C -C ) lower alkoxy, or (^-C ) lower alkyl- amino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C -C ) lower alkyl, formyl, (Cι-C ₃ )lower alkoxycarbonyl, -C0 ₂ H; a moiety of the formula:

halogen or (C,-C ) lower alkoxy. For example, the fused heterocyclic ring may be represented by furan, pyrrole, pyrazole, thiophene, thiazole, oxazole, imidazole, pyrimidine or pyridine ring which may be substituted or unsubstituted.

DETAILED DESCRIPTION OF THE INVENTION Within the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R _~ is a moiety:

and Ar is selected from the moiet-v;

wherein R ₅ , R _g and R_ are as hereinbefore defined.

Especially preferred are compounds wherein R. is the moiety:

and Ar is selected from the moiety:

R _g is NHCOAr' and Ar' is

wherein R _g , R ₉ and W' are as hereinbefore defined.

Also especially broadly preferred are compounds wherein Y in Formula I is -(CH *_*) - and n is zero or one; A-B is

and R ₄ , R _g , Rg, R _? , R _g , R _g and R _1Q are as hereinbefore defined; and m is an integer from 1-2.

The most broadly preferred of the compounds of Formula I are those wherein Y is -(CH_) - and n is

2 n one; A-B is

R ₃ is the moiety:

Ar is

IS

and Ar' is a moiety:

Cycloalkyl and W' are as previously defined and R _D and

O

R ₉ are preferably ortho CF ₃ , Cl, OCH ₃ , CH , SCH or 0CF ₃ substituents or Ar' is a disubstituted derivative wherein R„ and R are independently Cl, OCH_, CH_ .

The most highly broadly preferred of the com¬ pounds of Formula I are those wherein Y is -(CH ) -. n

2'n ' is zero or one and

represents a fused phenyl, substituted phenyl, thio- phene, furan, pyrrole or pyridine ring; A-B is

10

m is one when n is one and m is two when n is zero;

15 R ₃ is the moiety: o

- ICIAr wherein Ar is

20

and R is selected from the group

-NCOAr ' , -NC0CH ₂ Ar ' where Ar' is selected from the group

and R _a , R _b , R^ R ₂ , R ₄ , R ₅ , Rg, R _? , R _g , R _g and W' are as previously defined.

Most particularly preferred are compounds of the formulae:

wherein m is an integer one or two; R and R are as previously defined; R_ is the moiety:

wherein Ar is selected from moieties of the formulae:

R ₆ is

wherein cycloalkyl is defined as C ₃ -C ₆ cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:

Rcl is independently selected from hydrogen, CHJ_ or

10 -C ₂ H ₅ ; and R _e *7 ^< R_, R.- and W' are as herein¬ before defined.

Compounds of this invention may be prepared as shown in Scheme I by reaction of tricyclic deriva¬ tives of Formula 3_a. and 3_b with a substituted or un¬

15 substituted 4-nitrobenzoyl chloride 4. to give the intermediates 5_a and 5b. Reduction of the nitro group in intermediates 5a and 5b gives the 4-aminobenzoyl derivatives ,6a and 6b. The reduction of the nitro group in intermediates 5a. and 5_b may be carried out

20 under catalytic reduction conditions (hydrogen-Pd/C; Pd/C- hydrazine-ethanol) or under chemical reduction conditions (SnCl_-ethanol; Zn-acetic acid; TiCl ) and related reduction conditions known in the art for con¬ verting a nitro group to an amino group. The condi¬

25 tions for conversion of the nitro group to the amino group are chosen on the basis of compatibility with the preservation of other functional groups in the mole¬ cule.

Reaction of compounds of Formula 6a. and .6b

30 with aroyl chloride or related activated aryl car¬ boxylic acids in solvents such as chloroform, dichloro¬ methane, dioxane, tetrahydrofuran, toluewe and the like in the presence of a tertiary base such as triethyl¬ amine and diisopropylethylamine or pyridine and the like, affords the compounds M and £b which are vaso¬

^■ 35 pressin antagonists.

Scheme 1

Scheme 1 (Cont'd)

6o

Reaction of tricyclic derivatives of Formula 6a and .6b with either a carbamoyl derivative j? or a isocyanate derivative iO gives compounds (Scheme 2) of Formula 11a and lib which are vasopressin antagonists of Formula I wherein R _g is

and R, is H, CH ₃ or CLH...

Scheme 2

Reaction of tricyclic derivatives of Formula 6a and 6b with arylacetic acids, activated as the acid chlorides 12,, anhydrides, mixed anhydrides or activated with known activating reagents, gives compounds 13a and 13b (Scheme 3) .

Scheme 3

6α 6b

13c 13b

The compounds of Formula I wherein Y, A-B, 2, R., R ₂ and R are as defined and the aryl of R ₃ (-COAr) is

^R 4 may be prepared, as shown in Scheme 4, by reacting an activated ester of the indole-5-carboxylic acids 14. with tricyclic derivatives 3_a and 3_b. The indole-5- carboxylic acids 14. may be activated by preparing the anhydride, a mixed anhydride or reacting with diethyl cyanophosphonate, N,N_-carbonyldiimidazole or related peptide coupling reagents. As an example, the deriva¬ tive 15_ may be prepared by the reaction of acid 14 and H _/ N-carbonyldiimidazole i _n tetrahydrofuran; the solvent is removed and the derivative reacted with 3a or 3b at

100oC to 120oC wi.thout a solvent. Alternatively, 3a. and 3_b may be reacted with 15. in a solvent such as toluene or xylene at reflux temperatures. The activating reagent for the indole acids 14. is chosen on the basis of its compatibility with the R group and its reactivity with the tricyclic derivatives 3_a and lb to give the vasopressin antagonists 16a and 16b.

Scheme 4

3α 3b

16α 16b

The compounds of Formula I wherein Y, A-B, Z, R., R ₂ and R ₃ are as defined and the R ₃ (-COAr) aryl group is

wherein R o- is

may be prepared as shown in Scheme 5 by first reacting the derivatives 8a. and .8b with sodium hydride or similar reagents to form the amide anion and then reacting the anion with a dialkoxyphosphoryl chloride to give the intermediates 17a and 17b. Reaction of these intermediates with sodium or lithium azide gives the products 18a and 18b.

Alternatively, the products 18a and 18b may be prepared by coupling tetrazole derivatives of the Formula l£ with tricyclic derivatives la and lb (Scheme 6) . The tetrazole carboxylic acids are activated for coupling to the tricyclic compounds 3_a and lb by reaction with peptide coupling reagents, by conver¬ sion to the acid chlorides, anhydrides or mixed anhydrides.

Scheme 6

18α 19 18b

As an alternative method for synthesis of compounds of this invention as depicted in Formula I wherein Y, A-B, R_, R , and Z are as previously defined and R_ is o

- ICIAr is the coupling of aryl carboxylic acids 20a with the tricyclic derivatives 3_a and lb as shown in Scheme 7.

The aryl carboxylic acids are activated for coupling by conversion to an acid chloride, bromide or anhydride or by first reacting with an activating re¬ agent such as N,N-dicyclocarbodiimide, diethyl cyano- phosphonate and related "peptide type" activating re¬ agents. The method of activating the acids 20a for coupling to the tricyclic derivatives 3_a and 3Jb is chosen on the basis of compatibility with other sub- stituent groups in the molecule. The method of choice is the conversion of the aryl carboxylic acids 20a to the corresponding aroyl chloride.. The aryl acid chlorides 2J) may be prepared by standard procedures known in the art, such as reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydrofuran dioxane in the presence of pyridine or tertiary bases such as triethylamine and the like. Alternatively, the aroyl chlorides, prepared from the aryl carboxylic acids 20, may be reacted with derivatives 3_a and lb in pyridine with or without 4-(dimethylamino)pyridine to give derivatives 21a and 21b.

In general, when the aryl carboxylic acids are activated with E,N-carbonyldiimidazole and other "peptide type" activating reagents, higher temperatures are required than when the aroyl chlorides are used. The reaction may be carried out in a higher boiling solvent xylene or without a solvent (100°C to 150°C) .

Scheme 7

The starting materials la. and lb in Scheme 1 can be made by literature methods. For example, inter¬ mediate 6,ll-dihydro-5H-dibenz[b,e]azepines and substituted derivatives are prepared according to literature procedures: L. H. Werner, et al., J. Med. Chem.. 8., 74-80 (1965); A.W.H. Wardrop et al., J. Chem. Soc. Perkins Trans I, 1279-1285 (1976).

Substituted 5,11-dihydrodibenz[b,e]azepin-6- 0 one are prepared by literature procedures: J. Schmutz et al., Helv. Chim. Acta.. 48. 336 (1965); and reduced to substituted 6,ll-dihydro-5H-dibenz[b,e]azepines with lithium aluminum hydride, diborane, diborane-dimethyl- sulfide and agents known to reduce an amide carbonyl to

-l> a methylene group. Intermediate 10,ll-dihydrodibenz[b, f] [l,4]thiazepines are prepared by literature proce¬ dures - for example, see K. Brewster et al., J. Chem. Soc. Perkin I, 1286 (1976) . Reduction of either dibenz[b,f] [l,4]oxazepines [A.W.H. Wardrop et al., J. 0 Chem. Soc. Perkin Trans. I, 1279 (1976)] and dibenz[b,f] [1,4]oxazepin-ll(lOH)-ones and dibenz- [b,f] [1,4]thiazepin-ll(lOH)-ones - J. Schmutz et al., Helv. Chim. Acta. 48. 336 (1965) ; may be carried out with lithium aluminum hydride in inert solvents such as => dioxane and the like. The tricyclic 6,7-dihydro-5H-di- benz[b,d]azepine intermediates of Formula 3_0 may be prepared by the literature procedures: T. Ohta et al., Tetrahedron Lett.. 26. 5811 (1985); Wiesner et al., J. Amer. Chem. Soc. , T7, 675 (1955) ; or derivatives may be 0 prepared by coupling procedures illustrated in Scheme 8. The reduction of nitro compounds of structure type 31 followed by ring closure, affords lactams 22. which are reduced to give tricyclic azepines of Formula 33.

5,ll-Dihydro-6H.-pyrido[3,2-c] [1]benzazepines are prepared by literature procedures - J. Firl et. al.. Liebiσs Ann. Chem. 469, (1989). Tricyclic l,2,3,4-tetrahydropyrazolo[4,3-cJ [l]benzazepines are synthesized as described in the literature - G.

Palazpino et. al,. , J. Heterocyclic Chem.. 26. 71 (1989) .

Scheme 8

Scheme 8 (cont'd)

(

Tricyclic intermediates 42. for the synthesis of selected vasopressin antagonists of this invention wherein Y in Formula I is -CH_- and m is one, may be prepared as shown in Scheme 9. Suitable l-nitro-2- chloro or l-nitro-2-bromo heterocycles 15. undergo halogen exchange when reacted with an alkyllithium reagent such as t-butyllithium, ≤-butyllithium or n-butyllithium to give intermediates 12 which react with anhydrides of Formula 3_8. R.. is tert-butyl _r secondary butyl, n-butyl, 2,6-dimethylpiperidine or a hindered non-nucleophilic dialkylamine. The nitro products 19. are reduced with hydrogen and a suitable catalyst or chemically reduced (Zn-acetic acid, TiCl 3 etc.) to the amino intermediates 4j0. Ring closure to the cyclic lactams 4_1 is conveniently carried out by heating in xylene or an inert solvent at 100°C to

200 C. The cyclic lactams of structure type 41 are readily reduced by diborane in tetrahydrofuran, diborane-dimethylsulfide in tetrahydrofuran or lithium aluminum hydride in a suitable solvent such as dioxane to give the tricyclic compounds 42.

Scheme 9

Alternatively, as shown in Scheme 10, some of the tricyclic derivatives of structural type 4_2 may be prepared by "palladium" type coupling or "copper" induced coupling of halogenated derivatives 4_3 to give tricyclic lactams 4_4. Reduction of the lactam carbonyl group gives the intermediates 4_2_. Coupling of halogen derivatives 4_5_ to effect ring closure with activated copper or "palladium" type reagents which induce aryl coupling gives lactams 4J3. Diborane reduction of lactams ΛjS gives derivatives 47. Ullmann cross- couplings of halogenated heterocycles and 2-bromo- nitrobenzenes and related cross-couplings by low valent palladium species such as [Pd(PPh ₃ ).] and PdCl_(PPh ) are known synthetic procedures; N. Shimizu et al., Tetrahedron Lett. 34. 3421 (1993) and references therein; N. M. Ali et al., Tetrahedron. 37. 8117 (1992) and references therein; J. Stavenuiter et al., Hetero¬ cycles, 2JS, 2711 (1987) and references therein.

Scheme 10

Tetrahydro-lH-l-benzazepin-5-ones 5_1 and the tetrahydro-lH-l-benzazepin-2,5-diones 52. are useful compounds for the synthesis of intermediate tricyclic heterocyclic structures 51 and 5£ (Scheme 11) . The tetrahydrobenzazepin-5-ones 5_1 and 52. may be formylated to give hydroxymethylene derivatives or reacted with either the Vilsmeier reagent or the N,N-dimethylform- amide dimethyl acetal to give the dimethylamino- 0 methylene derivatives. The construction of hetero¬ cyclic rings from α-hydroxymethyleneketones by reactions with hydrazine N-methylhydrazine, hydroxyl- amine or formamidine to give pyrazoles, N-methyl- pyrazoles, oxazoles or pyrimidines respectively, is a standard literature procedure. See Vilsmeier formyla- tion - Tetrahedron, 49. 4015-4034 (1993) and references therein and ring formations - J. Heterocyclic Chem. , 29. 1214 (1992) and references therein.

Substituted and unsubstituted tetrahydro- benzazepin-2-ones are known compounds which are pre¬ pared by reaction of α-tetralones with sodium azide under acidic conditions. [J. Chem. Soc. 456 (1937) ; Tetrahedron 4_9_, 1807 (1993) ] (Schmidt reaction) . Re¬ duction of tetrahydro-lH-benzazepin-2-ones gives the tetrahydro-lH-benzazepines 4J3 which on acylation gives compounds 4_9_. Oxidation of N-acyl tetrahydro-lH- benzapines of type 4J? to give the 5-one derivatives is a known oxidative procedure; R. L. Augustine and W. G. Pierson, J. Pro. Chem.. 34. 1070 (1969) .

J O

The synthesis of 3,4-dihydro-lH,-l-benzaze- pine-2,5-diones (52,:R ₁₅ =H) has been reported as well as the conversion of 3,4-dihydro-lH.-l-benzazepine-2,5- diones to 4-[(dimethylamino)methylene]-3,4-dihydro-lH.- l-benzazepine-2,5-diones with N_,N.-dimethylformamide, dimethylacetal: [W.-Y. Chen and N.W. Gilman, J. Hetero- cyclic Chem.. 20, 663 (1983)]. The preceding reference describes the synthesis of 2-methyl-5,7-dihydropyrimi- do[5,4-d][l]benzazepin-6(6H)-ones which may be reduced

to remove the lactam carbonyl group to give tricyclic derivatives of structural type £54. wherein Z is a pyrimidine ring.

Scheme 11

The synthesis of compounds of Formula I wherein R_ is o

- ICIAr _; the Ar group is

^R 6 ^iS

-CON-Ar '

and where Ar' is as previously defined is carried out according to Scheme 12. The tricyclic compounds la. and 3b are reacted with mono-methyl terephythalyl chloride 55 (prepared from mono-methyl terephthalate and thionyl chloride) in the presence of a tertiary base such as triethylamine in solvents such as dichloromethane, tetrahydrofuran, dioxane, toluene and the like to give derivatives 56a and 56b. These ester intermediates (56a and 56b) are hydrolyzed with two to ten equiva¬ lents of an alkaline hydroxide such as potassium or sodium hydroxide in aqueous methanol or ethanol to give the corresponding acids after acidification and workup. The free acids are converted to the acid chlorides with thionyl chloride and these acid chloride intermediates, 57a and 57b. reacted with aminoaryl derivatives of formula:

Ar '-N-H

R, (R _β " H, CH ₃ , C ₂ H ₅ )

wherein Ar' is as previously defined to give compounds 59a and 59b.

Scheme 12

Scheme 12 (cont'd)

5

As described in reaction Scheme l, the following specific tricyclic ring systems of the generic formula la. and lb are illustrated to show one of the synthetic methods for the synthesis of the compounds of this invention. These derivatives 60. 61, 66, 6£, 22./ 2≥/ 23., £1/ M, 12/ 10/ and £1 when subjected to the reaction conditions in Scheme 1 which is the acylation of the tricyclic compounds (R. =H) with 4-nitrobenzoyl chloride or a substituted 4-nitrobenzoyl chloride in the presence of a trialkyl- amine such as triethylamine in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like give the intermediates 6_1, 64, 67. 2P_, 21 _/ 2i, 29, 82., 85., 88, 11, 94.- These 4-nitro- benzoyl and substituted 4-nitro-benzoyl derivatives are reduced with hydrogen in the presence of a catalyst such as Pd/C in solvents such as ethanol, ethanol-ethyl acetate, acetic acid or N,N-dimethylformamide to give the 4-aminobenzyl or substituted 4-aminobenzoyl derivatives 6>2., jJ5_, 6JL, 21 _/ 21 _/ 21 _/ ϋP_, 83_, f3j6, 8_9_, 92. 95. Alternatively, the 4-nitrobenzoyl and substituted 4-nitrobenzoyl derivatives £1, £4., 62, 2P_, 21 _/ IA, 79. 82. 85 _f 88. 91. 94 are reduced with Pd/C and hydrazine in refluxing ethanol.

The 4-aminobenzoyl and substituted 4-amino- benzoyl derivatives £2., ££, £8, 21/ 24., 22, £!/ £1/ ££/ 89, 92. 95 are reacted with acid chlorides of the formula: Ar'COCl,

cycloalkyl (CH_) C0C1, Ar'CH ₂ C0Cl, to give products as shown in Scheme 1 wherein R _β is as defined.

As described in Scheme 2, the tricyclic 4- aminobenzoyl or substituted 4-aminobenzoyl derivatives £1, £5, £8, 21/ IA, 22/ JLP_, £1/ ££/ £1/ 12, and 95 are reacted with carbamoyl derivatives

or arylisocyanates

A r ' - N = C = 0 to give specific derivatives wherein R _fi is

and R, is independently selected from H, CH or -C_H ₅ .

As described in Scheme 7, the tricyclic derivatives £0, £1, ££, £9_, 7_2, 25, 2£, ϋl, £1/ £2, 90. and £3. are reacted in one step with a previously synthesized ArCOCl compound wherein Ar is as previously defined. For example, reaction of the specific tricyclic derivatives £0, £3., £6, £9, 12., 25, 2£, £1,

84, £7, 12, 12. with aroyl chlorides of the following structural types:

gives in one step derivatives of these delineated tri¬ cyclic compounds wherein the Ar group of the moiety:

in formula I is

and R,. is

wherein cycloalkyl, R _a , R.^, R _χ , R , R ₅ , R _? and Ar' are as hereinbefore described.

Among the more preferred compounds of this invention are those selected from Formula I:

Formula I wherein; Y is a bond; A-B is

-<CH ₂ ) ₂ - (CH ₂ ) ₂ -

R _l is H, halogen (chlorine, fluorine, bromine, iodine) , OH, -S-lower alkyl (C ₁ -C ₃ ), -SH, -SO lower alkyl (C ₁ -C ₃ ) , -S0 ₂ lower alkyl (C ₁ -C ₃ ) , -CO lower alkyl (C ₁ -C ₃ ) , -CF ₃ , lower alkyl (C ₁ -C ₃ ) , -0 lower alkyl (C ₁ -C ₃ ) , -N0 ₂ , -NH ₂ , -NHCO lower alkyl <Cι- C3), -N- [ lower alkyl (Cι-C ₃ )] ₂ , S0 ₂ NH ₂ , -S0 ₂ NH lower alkyl (C ₁ -C ₃ ), or -S0 ₂ N [lower alkyl (Cι~ c ₃ ⁾ l ₂ ;

R ₂ is H, Cl, Br, I, F, -OH, lower alkyl (Ci- C ₃ ), -0 lower alkyl (C ₁ -C ₃ ); or

R _l and R ₂ taken together are methylenedioxy or ethylenedioxy;

R ₃ is the moiety

O

-CAr

herein Ar is a moiety selected from the group

and X is selected from 0, S, -NCH ₃ , or -N-COCH ₃ ; R ₄ is selected from H, lower alkyl (C ₁ -C ₃ ), -CO-lower alkyl (C ₁ -C ₃ ), S0 ₂ lower alkyl (C ₁ -C ₃ ), and the moieties of the formulae:

R5 is H, -CH ₃ , -C2H5, Cl, Br, F, -0-CH3 , or -0-C ₂ H ₅ ;

R6 is selected from:

(a) moieties of the formula:

wherein cycloalkyl is defined as C ₃ -C ₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

R ₂ is as hereinbefore defined; n is 0-2;

R ₇ is H, -CH ₃ , -CH ₂ H ₅ , Cl, Br, F, -OCH ₃ , -OC ₂ H ₅ , or -CF ₃ ;

R _a is hydrogen, CH3 , C2H5, moieties of the formulae :

or

(CH ₂ ) ₂ -0-lower alkyl (C1-C3) or -CH ₂ CH ₂ OH; q is one or two;

R _b is hydrogen, -CH ₃ or -C ₂ Hs;

Ar' is selected from the group:

wherein

R ₄ , R ₅ are as hereinbefore defined;

Rs and R ₉ are independently hydrogen, lower alkyl (C ₁ -C ₃ ), O-lower alkyl (C ₁ -C ₃ ) , S-lower alkyl (C ₁ -C ₃ ), -CF ₃ , -CN, -OH, -SCF ₃ , -OCF ₃ , halogen, N0 ₂ , amino, or -NH-lower alkyl (C ₁ -C ₃ );

Rio is selected from halogen, hydrogen, or lower alkyl (C ₁ -C ₃ );

W is selected from O, S, NH, N-lower alkyl (C ₁ -C ₃ ), -NCO-lower alkyl (C ₁ -C ₃ ), or NS0 ₂ -lower alkyl (C ₁ -C ₃ ); and

(b) a moiety of the formula:

where R ₂ is as hereinbefore defined;

(c) a moiety of the formula:

R _b

-N I — COJ

wherein J is R _a , lower alkyl (Ci-Cs) branched or unbranched, lower alkenyl (C ₂ -Cs) branched or unbranched, -O-lower alkyl (Ci-Cs) branched or unbranched, -O-lower alkenyl (C ₂ -Cs) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or -CH ₂ -K wherein K is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C ₁ -C ₃ ) lower alkyl, hydroxy, -CO-lower alkyl (Cι-C ₃ ), CHO, (Cι-C ₃ )lower alkoxy, or -C0 ₂ -lower alkyl (C ₁ -C ₃ ), and R _a and R _b are as hereinbefore defined;

(d) a moiety selected from those of the formulae:

wherein

R _c is selected from halogen, (C ₁ -C ₃ ) lower alkyl, -O-lower alkyl (C ₁ -C ₃ ) or OH;

R _b is as hereinbefore defined; q is 1 or 2; wherein Ar' is selected from the group:

R ₇ is hydrogen, -CH ₃ , -C ₂ H ₅ , Cl, Br, F, -OCH ₃ , -OC ₂ H ₅ , or -CF ₃ ;

R _θ and R9 are independently hydrogen, lower alkyl (C ₁ -C ₃ ), O-lower alkyl (C ₁ -C ₃ ), S-lower alkyl (C ₁ -C ₃ ), -CF ₃ , -CN, -OH, -SCF ₃ , -OCF _3/ halogen, N0 ₂ , amino, or -NH-lower alkyl (C _! -C ₃ );

RlO is selected from the group of halogen, hydrogen, or lower alkyl (C ₁ -C ₃ );

W is selected from O, Ξ, NH, N-lower alkyl (Ci- C ₃ ), -NCO-lower alkyl (C ₁ -C ₃ ), or NS0 ₂ -lower alkyl (C ₁ -C ₃ ); the moiety

represents a fused thiophene ring or fused substituted thiophene ring optionally substituted by one or two substituents selected from (C ₁ -C ₃ ) lower alkyl, halogen, formyl, (C ₁ -C ₃ ) lower alkoxy, (C ₁ -C ₃ ) lower alkoxycarbonyl, -CO2H, a moiety of the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof. Within the group above are the following preferred sub-groups 1 and 2 of compounds: 1. wherein R ³ is the moiety

O

II

—CAr wherein Ar is a moiety selected from the group

Rs is selected from the group

W is 0 or S;

A-B, R _a , Rb, Ri, R2, R4, R5, R7, R8, R ₉ , and cycloalkyl are as defined in Claim 1; or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. compounds of the formula:

wherein; Y is a bond; A-B is

-<CH ₂ ) ₂ -N or N- (CH ₂ ) ₂ - R ₃ R ₃

R _l is H, halogen (Cl, F, Br, I), OH, -S-lower alkyl (C ₁ -C ₃ ), -SH, -SO lower alkyl (C ₁ -C ₃ ), -S0 ₂ lower alkyl (C ₁ -C ₃ ), -CO lower alkyl (C ₁ -C ₃ ), -CF ₃ , lower alkyl (C ₁ -C3), -O lower alkyl (C ₁ -C ₃ ), -N0 ₂ , -NH ₂ , -NHCO lower alkyl (C ₁ -C ₃ ), -N- [ lower alkyl (C1-C3H2, S0 ₂ NH ₂ , -S0 ₂ NH lower alkyl (C1-C3), or -S0 ₂ N [lower alkyl (Cι~C ₃ )] ₂ ;

R ₂ is selected from H, Cl, Br, I, F, -OH, lower alkyl (C ₁ -C ₃ ), or -0 lower alkyl (C ₁ -C ₃ ) ; or

R _l and R ₂ taken together are methylenedioxy or ethylenedioxy;

R ₃ is the moiety

O

II

-CAr wherein Ar is a moiety selected from the group

R5 is H, -CH3, -C ₂ Hs, Cl, Br, F, -O-CH3 , or -0-C ₂ H ₅ ;

Rβis selected from:

wherein cycloalkyl is defined as C ₃ -C ₆ cycloalkyl, cyclohexenyl or cyclopentenyl; n is 0-2; and wherein Ar ' is selected from the moieties :

R, wherein R _a and R _b are independently selected from H, -CH3, or -C ₂ H ₅ ;

R ₇ is H, -CH ₃ , -C ₂ H ₅ , Cl, Br, F, -O-CH ₃ , -0-C ₂ Hs or -CF3;

Rθ and Rg are independently selected from hydrogen, lower alkyl {C ₁ -C ₃ ), O-lower alkyl (C ₁ -C ₃ ), S-lower alkyl (C ₁ -C ₃ ), -CF ₃ , -CN, -OH, -SCF ₃ , -OCF ₃ , halogen, N0 ₂ , amino, or -NH-lower alkyl (C ₁ -C ₃ );

W is selected from O, S, NH, N-lower alkyl (Cι~ C ₃ ), -NCO-lower alkyl (C ₁ -C ₃ ) , or

NS0 ₂ -lower alkyl (C1 -C3 ) ; the moiety

represents a fused thiophene ring or fused substituted thiophene ring optionally substituted by one or two substituents selected from (C ₁ -C ₃ ) lower alkyl, halogen, formyl, (C ₁ -C ₃ ) lower alkoxy, (C ₁ -C ₃ ) lower alkoxycarbonyl, -CO2H, a moiety of the formula:

- (CH ₂ ) N

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Among the more preferred compounds of this invention are those selected from:

N- [4-[ (4, 5-dihydro-6H-thieno[3 ,2-d] [1]benzazepin-6- yl)phenyl] -2-methyl-3-fluorobenzamide . N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl)phenyl] -2-methylbenzamide.

N- [4- [ (4, 5-dihydro-6H-thieno[3 , 2-d] [1]benzazepin-6- yl)phenyl] -2-methy1-5-fluorobenzamide.

N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-chlorophenyl] -2-methyl-3-fluorobenzamide.

N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1] benzazepin-6- yl)carbonyl] -3-chlorophenyl] -2-methylbenzamide.

N- [4- [ (4, 5-dihydro-6H-thieno[3 , 2-d] [1]benzazepin-6- yl) carbonyl] -3-chlorophenyl] -2-methyl-5-fluorobenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl)carbonyl] -3-chlorophenyl] -2-chloro-5-fluorobenzamide.

N-[4- [ (4, 5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6-yl) - 3-chloro-phenyl] -2- (methylthio) -5-fluorobenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl)phenyl] -2-chloro-5-fluorobenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-chlorophenyl] -2-methyl-3-chlorobenzamide. N- [4- [ (4, 5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-chlorophenyl] -2-chlorobenzamide. N- [4- [ (4, 5-dihydro-6H-thieno[3 , 2-d] [1]benzazepin-6- yl)carbonyl] -3-chlorophenyl] -2-methoxy-5-fluoro¬ benzamide.

N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-chlorophenyl] -2-chloro-4-fluorobenzamide. N- [4- [ (4, 5-dihydro-6H-thieno[3, 2-d] [1]benzazepin-6-yl) - 3-methyl-phenyl] -2-methyl-3-fluorobenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6-yl) - 3-methoxy-phenyl] -2-methylbenzamide.

N-[4-[ (4,5-dihydro-6H-thieno[3, 2-d] [1]benzazepin-6-yl) - 3-methyl-phenyl] -2-methyl-5-fluorobenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3, 2-d] [1]benzazepin-6- yl)carbonyl] -3-methoxyphenyl] -2-methyl-3-fluoro¬ benzamide.

N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-fluorophenyl] -2-methylbenzamide. N-[4-[ (4,5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl) carbonyl] -3-methoxyphenyl] -2-methyl-5-fluoro¬ benzamide.

N-[4-[ (4, 5-dihydro-6H-thieno[3,2-d] [1]benzazepin-6- yl)carbonyl] -3-methylphenyl] -2-chloro-5-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-chlorophenyl] -2-methyl-5-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3-chlorophenyl] -2-methyl-3-fluorobenzamide. N-(4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3-chlorophenyl] -2-chloro-5-fluorobenzamide.

N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-chlorophenyl] -2, 5-dichlorobenzamide . N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -phenyl] -2-methyl-5-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl]-phenyl] -2-methyl-3-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3-methylphenyl] -2-methyl-5-fluorobenzamide, N- [4-[ (5, 6-dihydro-4H-thieno[2,3-a] [3]benzazepin-4- yl)carbonyl] -3-methylphenyl] -2-methyl-3-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-methylphenyl] -2-chloro-5-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3 ]benzazepin-4- yl)carbonyl] -3-methylphenyl] -2, 5-dichlorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-methoxyphenyl] -2-methyl-5-fluoro¬ benzamide.

N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-methoxyphenyl] -2-methyl-3-fluoro¬ benzamide.

N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3, 6-dimethylphenyl] -2-methyl-5-fluoro¬ benzamide.

N-[4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3 , 6-dimethylphenyl] -2-methyl-3-fluoro¬ benzamide.

N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -3-chlorophenyl] -2-chloro-4-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -3-chlorophenyl] -2-chloro-6-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl)carbonyl] -phenyl] -2-methoxy-5-fluorobenzamide. N- [4- [ (5, 6-dihydro-4H-thieno[2, 3-a] [3]benzazepin-4- yl) carbonyl] -phenyl] -2- (methylthio) -5-fluorobenzamide.

The subject compounds of the present inven¬ tion are tested for biological activity as follows:

Binding Assay to Rat Hepatic V Receptors

Rat liver plasma membranes expressing the vasopressin V. receptor subtypes are isolated by sucrose density gradient according to the method de- scribed by Lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at -70°C until used in subsequent binding experiments. For binding experiments, the following is added to the wells of a ninety-six well format microtiter plate: 100 μl of 100.0 mM Tris.HCl buffer containing 10.0 mM MgCl_, 0.2% heat inactivated BSA and a mixture of pro¬ tease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 ^m 9 %' 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor,

10.0 mg % and 0.1 mM PMSF, 20.0 μl of [phenyl-

₃ alanyl-3,4,5,- H] vasopressin (S.A. 45.1 Ci/mmole) at

0.8 nM, and the reaction initiated by the addition of

80 μl of tissue membranes containing 20 μg of tissue protein. The plates are kept undisturbed on the bench top at room temperature for 120 min. to reach equili¬ brium. Non-specific samples are assayed in the pre¬ sence of 0.1 μM. of the unlabeled antagonist phenyl- alanylvasopressin, added in 20.0 μl volume. For test compounds, these are solubilized in

50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel ^® cell Harvester (Gaithersburg, MD) . The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC _5n values by the LUNDON-2

program for competition (LUNDON SOFTWARE, OH) and displayed in Table I.

5

Binding Assay to Rat Kidney Medullary V Receptors

Medullary tissues from rat kidneys are dis¬ sected out, cut into small pieces and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM ₀ EDTA with many changes of the liquid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate is filtered through 5 several layers (4 layers) of cheese cloth. The fil¬ trate is rehomogenized using a dounce homogenizer, with a tight fitting pestle. The final homogenate is cen- trifuged at 1500 x g for 15 min. The nuclear pellet is discarded and the supernatant fluid recentrifuged at o 40,000 x g for 30 min. The resulting pellet formed contains a dark inner part with the exterior, slightly pink. The pink outer part is suspended in a small amount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry's method (Lowry et 5 al., J. Biol. Chem., 1953). The membrane suspension is stored at -70°C, in 50.0 mM Tris.HCl, containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0 mg protein per ml of suspension until use in subsequent binding experiments. 0 ^For binding experiments, the following is added in μl volume to wells of a 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl, and a mixture of protease inhibitors: leupeptin, 1.0 mg %;

,c; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 μl of [ 3H] Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at

0.8 nM and the reaction initiated by the addition of

80.0 μl of tissue membranes (200.0 μg tissue protein).

The plates are left undisturbed on the bench top for 120 min to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μl volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel ^® cell Harvester (Gaithersburg, MD) . The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Coun¬ ter, with an efficiency of 65% for tritium. The data are analyzed for IC ₅₀ values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and displayed in Table I.

Radioliσand Binding Experiments with Human Platelet

Membranes

(a) Platelet Membrane Preparation:

Frozen platelet rich plasma (PRP) , received from the Hudson Valley Blood Services, are thawed to room temperature. (Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY) . The tubes containing the PRP are centrifuged at 16,000 x g for 10 min. at 4°C and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 mM Tris.HCl, pH 7.5 containing 120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000 x g for 10 min. This washing step is repeated one more time. The wash discarded and the lysed pellets homogenized in low ionic strength buffer of Tris.HCl, 5.0 mM, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000 x g for 10 min. The resulting pellet is resuspended in Tris.HCl buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g for 10 min. The final pellet is resuspended in 50.0 mM Tris.HCl buffer pH 7.4 containing 120 mM NaCl and

5.0 mM KC1 to give 1.0-2.0 mg protein per ml of suspension.

(b) Binding to Vasopressin V. receptor subtype in Human

5 ά

Platelet Membranes:

In wells of a 96 well format microtiter plate, add 100 μl of 50.0 mM Tris.HCl buffer contain¬ ing 0.2% BSA and a mixture of protease inhibitors ₀ (aprotinin, leupeptin etc.). Then add 20 μl of

[ 3H]Ligand (Manning or Arg8Vasopressin) , to give final concentrations ranging from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 μl of platelet suspension

(approx. 100 μg protein) . Mix all reagents by 5 pipetting the mixture up and down a few times. Non specific binding is measured in the presence of 1.0 μM p of unlabeled ligand (Manning or Arg Vasopressin) . Let the mixture stand undisturbed at room temperature for ninety (90) min. Upon this time, rapidly filter off 0 ^tne incubate under vacuum suction over GF/B filters, using a Brandel Harvester. The radioactivity caught on the filter disks is determined by the addition of liquid scintillant and counting in a liquid scintillator. 5

Binding to Membranes of Mouse Fibroblast Cell Line fLV-2> Transfected with the cDNA Expressing the Human

V_ Vasopressin Receptor

(a) Membrane Preparation 0 Flasks of 175 ml capacity, containing attached cells grown to confluence, are cleared of culture medium by aspiration. The flasks containing the attached cells are rinsed with 2x5 ml of phosphate buffered saline (PBS) and the liquid aspirated off each "5 time. Finally, 5 ml of an enzyme free dissociation Hank's based solution (Specialty Media, Inc., Lafayette, NJ) is added and the flasks are left undisturbed for 2 min. The content of all flasks is

poured into a centrifuge tube and the cells pelleted at 300 x g for 15 min. The Hank's based solution is aspirated off and the cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500 x g for 10 min to remove ghost membranes. The supernatant fluid is cen¬ trifuged at 100,000 x g for 60 min to pellet the receptor protein. Upon completion, the pellet is re¬ suspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM phenylmethylsul- fonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml of suspension, (b) Receptor Binding

For binding experiments, the following is added in μl volume to wells of a 96 well format of a micrσtiter plate: 100.0 μl of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl., and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF., 20.0 μl of [ 3H] Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at

0.8 nM and the reaction initiated by the addition of

80.0 μl of tissue membranes (200.0 μg tissue protein).

The plates are left undisturbed on the bench top for

120 min to reach equilibrium. Non specific binding is assessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μl volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel ^® cell Harvester

(Gaithersburg, MD) . The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed

by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC _gQ values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and the data is displayed in Table I.

Tob I o I (con t ' d)

U)

Tob I » I ( _c o π » ' d )

Tab le I (cont 'd)

-86

Tob I e I (con t ' d)

Tab I e I (con t *d)

Tab I e 1 (cont 'd)

Tαb I e I (con t ' d )

Tαbl e I (cont 'd)

Table I (cont'd)

μM

Vasopressin V Antagonist Activity in Conscious

Hvdrated Rats: 5 Conscious hydrated rats are treated with com¬ pounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound. One hour later, arginine vasopressin (AVP, antidiuretic hormore, ADH) dissolved in peanut oil is administered ₀ at 0.4 μg/kg intraperitoneally. Two rats in each test would not receive arginine vasopressin but only the vehicle (peanut oil) to serve as water-loading control. Twenty minutes later each rat is given 30 mL/kg of deionized water orally by gavage and is placed indi- 5 vidually in a metabolic cage equipped with a funnel and a graduated glass cylinder to collect urine for four hours. Urine volume is measured and osmolality analyz¬ ed by use of a Fiske One-Ten osmometer (Fiske Assoc, Norwood, MA, USA) . Urinary sodium, potassium, and _Q chloride are analyzed by use of ion-specific electrodes in a Beckman E3 (Electrolyte 3) Analyzer. In the fol¬ lowing results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity. The results are displayed in Table II.

0

Table II Diuretic Effect of CL Compounds (V Antagonism) in Normal Sprague-Dawley Rats

Ex. No. Dose N Urine Volume Osmolality (mg/kg) (ml/4 hrs.) (mOsm/kg)

Water-Load Control 78 13.3 + 0. .3 229 ± ⁶

Water-Load Control+DMSO(10%) 6 12.1 + 1 497 + 53 (20%) 4 12.4 + 0. .8 361 + 30

AVP-Control 76 2 + 0. .2 1226 + 58

2 30 6 18.9 + 1. ,7 401 + 49

10 6 15.2 + 2. ,4 408 + 34

3 6 2.9 + 0.,5 1235 + 162

5 10 2 2 1137

10 10 2 7.1 1023

11 30 4 9.7 + 0. 6 1114 + 55

14 30 2 13.1 739

16 30 2 7.2 1257

22 30 2 10.2 738

61 10 2 9.3 975

62 10 2 7.7 1034

92 10 2 13.5 679

121 10 2 5 1064

123 10 2 5.8 1125

124 10 2 5.5 1172

136 30 2 19 306

137 30 2 15.8 358

138 30 2 13.8 380

167 30 2 2 1544

Table II (cont'd)

Diuretic Effect of CL Compounds (V Antagonism) in Normal Sprague-Dawley Rats

Ex. No. Dose N Urine Volume Osmolality (mg/kg) (ml/4 hrs.) (mOsm/kg)

250 30 2 6.5 1378

251 10 2 7.5 835 0 252 10 2 7.5 790

253 10 2 6 837

255 30 2 2.3 1456

257 10 2 11.8 434 5 259 10 2 6 1080

260 10 4 13.8+2.1 498+25

261 10 2 3.8 1337

262 10 2 6.8 899 0

264 10 2 12 682

266 10 2 4.3 1186

267 10 2 7.5 517

268 30 2 7.4 831 :i

379 20 2 7 483

416 10 2 4.3 1156

448 30 2 4.8 1084

O 451 10 2 5.3 989

452 10 2 7.8 584

453 10 2 9.4 776

454 10 2 4 1255

455 10 2 13.5 420

456 10 2 4.8 1209

Table II (cont'd)

Diuretic Effect of CL Compounds (V Antagonism) in Normal Sprague-Dawley Rats

Ex. No. Dose N Urine Volume Osmolality (mg/kg) (ml/4 hrs.) (mOsm/kg)

457 10 2 5.8 1036

458 10 2 13.5 537

534 10 2 10.6 695

Vasopressin V.1 Antagonist Activity in Conscious Rats.•

Conscious rats are restrained in a supine ₅ position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous in¬ filtration with 2% procaine (0.2 ml) . Using aseptic technique the ventral caudal tail artery is isolated and a cannula made of PE 10 and 20 (heat-fused) tubing ₀ is passed into the lower abdominal aorta. The cannula is secured, heparinized (1000 i.u./cc) , sealed and the wound closed with one or two stitches of Dexon 4-0. The caudal vein is also cannulated in the same manner for intravenous drug administration. The duration of 5 the surgery is approximately 5 minutes. Additional local anesthesia (2% procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an upright position. The cannula is attached o ^{to a} Statham P23Db pressure transducer and pulsatile blood pressure is recorded. Increase of systolic blood pressure responses to arginine vasopressin 0.01 and 0.2 international unit (I.U.)(350 I.U.=1 mg) injections are recorded prior to any drug (compound) administration, ₅ after which each rat is dosed orally with compounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,180,240 and 300 min. later. Per¬ centage of antagonism by the compound is calculated ₀ using the pre-drug vasopressin vasopressor response as 100%.

The results of this test on representative compounds of this invention are shown in Table III. The results of this test on representative ₅ compounds of this invention in which the dose, the maximum % inhibition and the time in minutes, are shown in Table IV.

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

Dose VAS Dose Min Post Control Response Average (mg/kg) i.u./kg Dose Before VAS After VAS Change Change Inhibition

230 255 25

0.1 230 285 55 45

235 270 35

EX.No. 5 10 i.v. 0.05 30 225 260 35 30 - 9

235 260 25

0.1 230 265 35 35 22

225 260 35

Ex.No. 5 20 i.v. 0.05 60 245 250 5 10 64

225 240 15

0.1 245 260 15 17.5 61

235 255 20 O

0.05 90 225 240 15 10 64

220 225 5

0.1 230 250 20 56

225 245 20

0.05 120 225 245 20 15 45

225 235 10

0.1 230 245 15 17.5 61

225 245 20

0.05 180 225 245 20 12.5 55

230 235 5

0.1 225 255 30 20 56

240 250 10

0.05 240 215 235 20 17.5 36

220 235 15

0.1 215 250 35 25 44

230 245 15

0.05 300 210 245 35 22.5 18

245 255 10

0.1 200 235 35 30 33

235 260 25

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Dody weiigghhtt((ss)) MOO, 400 grams

Table III (cont'd)

VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

Dose VAS Dose Min Post Control Response Average % (mg/kg) i . u . /leg Dose Before VAS After VAS Change Change Inhibitio LL

CONTROL 0.01 0 139 182 43 29.5

128 144 16

0.02 142 182 40 33

162 188 26

EX.No. 16 30 p.O. 0.01 30 133 166 33 25 15

148 165 17

0.02 136 163 27 27.5 17

154 182 28

0.01 60 131 168 37 30.5 - 3

154 178 24

0.02 134 163 29 29 12

162 191 29

0.02 137 172 35 40.5 -23

149 195 46

0.01 120 146 163 17 23.5 20

148 178 30

0.02 142 166 24 29.5 11

161 196 35

0.01 180 142 169 27 30.5 - 3

140 174 34

0.02 138 169 31 26 21

153 174 21

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body we :iigghhtt((εε)) :420,460 grams

Table III (cont'd)

VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

Dose VAS Dose Min Post Control Response Average % (mg/kg) i.u./kg Dose Before VAS After VAS Change Change Inhibition LL

CONTROL 0.01 0 161 191 30 28.5

143 170 27 0.02 157 217 60 51.5

145 108 43

EX.No. 61 10 i.V. 0.01 30 158 182 24 21 26

146 164 18 0.02 158 196 38 32.5 37

146 173 27

EX.No. 61 20 i.V. 0.01 60 163 180 17 13 54

147 156 9 0.02 159 179 20 14.5 72 ,

146 155 9 O 0.01 90 153 165 12 8 72

150 154 4 0.02 154 173 19 16.5 68

144 158 14 0.01 120 151 165 14 12 58

145 155 10 0.02 151 176 25 20 61

143 158 15 0.01 180 142 165 23 15.5 46

143 151 8 0.02 148 172 24 17.5 66

145 156 11 0.01 240 144 156 12 12 58

144 156 12 0.02 150 179 29 23 55

147 164 17 0.01 300 142 161 19 15.5 46

144 156 12 0.02 140 167 27 24 53

153 174 21

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body wesiigghhtt((εs)) :570,460 grams

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

150 189 39 0.02 143 204 61 60.5 156 216 60

Ex.No. 62 10 i.V. 0.01 30 144 196 52 57 -44 141 203 62 0.02 158 217 59 61.5 - 2 163 227 64

Ex.No. 62 20 i.v. 0.01 60 131 148 17 13 67 135 144 9 0.02 135 173 38 29.5 51 134 155 21 o 00 0.01 90 132 156 24 23 42 127 149 22 0.02 140 195 55 54 11 136 189 53 0.01 120 137 160 23 23.5 41 138 162 24 0.02 143 189 46 50 17 139 193 54 0.01 180 131 155 24 24.5 38 133 158 25 0.02 139 155 16 15 75 144 158 14 0.01 240 126 153 27 30 24 133 166 33 0.02 134 167 33 40.5 33 142 190 48 0.01 300 128 152 24 25 37 138 164 26 0.02 140 167 27 38 37 146 195 49

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body weight(s) 500,450 grams

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

CONTROL 0.01 0 140 162 22 17.5 147 160 13 0.02 138 169 31 33 141 176 35

EX.No. 123 10 i.v. 0.01 30 139 151 12 17.5 0 154 177 23 0.02 139 177 38 20 39 154 156 2

EX.No. 123 20 i.v. 0.01 60 137 140 3 6 66 147 156 9 0.02 132 139 7 6 82 146 151 5 0.01 90 137 141 4 6 66 149 157 8 0.02 135 138 3 7 79 149 160 11 0.01 120 136 139 3 5 71 147 154 7 0.02 138 141 3 4.5 86 150 156 6 0.01 180 138 141 3 4 77 150 155 5 0.02 138 142 4 6.5 80 148 157 9 0.01 240 137 145 8 8 54 146 154 8 0.02 140 146 6 6.5 80 148 155 7 0.01 300 138 144 6 8 54 144 154 10 0.02 140 148 8 8 76 146 154 8

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body weight(ε) 500,480 grams

-11:

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

Dose VAS Dose Min Post Control Response Average % (mg/kg) i.u./kg Dose Before VAS After VAS Change Change Inhibition

- ^' . LJL

0.01 300 144 166 22 24.5 18 151 178 27 0.02 135 170 35 34 33 145 178 33

CONTROL 0.01 135 152 17 22.5 132 160 28 0.02 149 216 67 52 137 174 37

Ex.No.14 10 i.v. 0.01 30 131 142 11 11 51 143 154 11 0.02 151 173 22 23 56 136 160 24 0.01 60 151 163 12 12 47 139 151 12 0.02 153 171 18 22 58 140 166 26 0.01 90 135 142 7 13.5 40 140 160 20 0.02 135 173 38 29.5 43 145 166 21 0.01 120 137 155 18 16 29 137 151 14 0.02 143 168 25 23.5 55 139 161 22 0.01 180 131 153 22 21.5 4 134 155 21 0.02 140 170 30 30.5 41 131 162 31 0.01 240 146 170 24 26.5 -18 141 166 29 0.02 140 171 30 32 38 141 175 34

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body weight(s) 480,420 grams

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

Dose VAS Dose Min Post Control Response Average % (mg/kg) i.u./kg Dose Before VAS After VAS Change Change Inhibition I.V.

CONTRO' 0.01 0 147 169 22 21.5

138 159 21

0.02 151 198 47 42

145 182 37

EX.No.22 10 i.v. 0.01 30 152 164 12 8.5 60

146 151 5

0.02 152 177 25 18.5 56

148 160 12

0.01 60 151 166 15 11 49

144 151 7

0.02 121 144 23 25 40

141 168 27

0.01 90 149 166 17 14 35

140 151 11

0.02 151 166 15 13 69

140 151 11

0.01 120 138 155 17 17.5 19

129 147 18

0.02 148 183 35 30 29

141 166 25

0.01 180 142 168 26 20 7

141 155 14

0.02 150 185 35 36 14

132 169 37

0.01 240 134 169 35 28 -30

150 185 35

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body weiigghhtt((ss)) :450,495 grams

Table III (cont'd) VASOPRESSIN (VAS)VASOPRESSOR RESPONSE

150 189 39 0.02 143 204 61 60.5 156 216 60

Ex.No.62 10 i.v. 0.01 30 144 196 52 57 -44 141 203 62 0.02 158 217 59 61.5 -2 163 227 64

20 i.v. 0.01 60 131 148 17 13 67 135 144 9 0.02 135 173 38 29.5 51 134 155 21 0.01 90 132 156 24 23 42 127 149 22 0.02 140 195 55 54 11 136 189 53 0.01 120 137 160 23 23.5 41 138 162 24 0.02 143 189 46 50 17 139 193 54 0.01 180 131 155 24 24.5 38 133 158 25 0.02 139 155 16 15 75 144 158 14 0.01 240 126 153 27 30 24 133 166 33 0.02 134 167 33 40.5 33 142 190 48 0.01 300 128 152 24 25 37 138 164 26 0.02 140 167 27 38 37 146 195 49

SPONTANEOUSLY HYPERTENSIVE RATS n=2 Body weight(s) 500,450 grams

Table IV

VASOPRESSIN (VAS) VASOPRESSOR RESPONSE

E:c. No. Dose mα/kα MAX % Inhibit :ion Time(Min)

2 10 p.o. 65 180

136 10 i.v. 81 30

137 10 i.v. 52 30

138 10 i.v. 88 60

167 10 i.v. 70 180

251 30 i.v. 41 60

252 30 i.v. 75 120

253 30 i.v. 57 180

254 30 i.v. 74 60

255 10 i.v. 65 60

257 10 i.v. 71 60

258 30 i.v. 61 60 59 30 i.v. 29 90 60 30 i.v. 79 120 61 10 i.v. 74 60 63 10 i.v. 55 90 66 30 i.v. 21 120 67 10 i.v. 74 120 68 10 i.v. 85 90 79 10 i.v. 75 300 16 30 i.v. 44 90 48 30 i.v. 60 90 49 10 i.v. 45 90 55 30 i.v. 46 120 57 10 i.v. 61 300 58 10 i.v. 77 180

Oxytocin Receptor Binding (Ξ) Membrane Preparation

Female Sprague-Dawley rats weighing approxi¬ mately 200-250 g are injected intramuscularly (i.m.) with 0.3 mg/kg of body weight of diethylstilbestrol (DES) . The rats are sacrificed 18 hours later under pentobarbital anesthesia. The uteri are dissected out, cleaned of fat and connective tissues and rinsed in 50 ml of normal saline. The tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.HCl, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 with three passes of 10 sec each. The homogenate is passed through two (2) layers of cheesecloth and the filtrate centrifuged at 1000 x g for 10 min. The clear supernatant is removed and recentrifuged at 165,000 x g for 30 min. The re¬ sulting pellet containing the oxytocin receptors is re¬ suspended in 50.0 mM Tris.HCl containing 5.0 mM MgCl at pH 7.4, to give a protein concentration of 2.5 mg/ml of tissue suspension. This preparation is used in sub¬ sequent binding assays with [ H]Oxytocin. (b) Radioligand Binding

Binding of 3,5-[ ³ H]Oxytocin ([ ³ H]0T) to its

3 receptors is done in microtiter plates using [ H]0T, at various concentrations, in an assay buffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl , and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg; 1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml of buffer solution. Non¬ specific binding is determined in the presence of 1.0 uM unlabeled OT. The binding reaction is terminated after 60 min., at 22°C, by rapid filtration through class fiber filters using a Brandel ^® cell harvester (Biomedical Research and Development Laboratories, Inc. , Gaithersburg, MD) . Competition experiments are conducted at equilibrium using 1.0 nM [ 3H]0T and

varying the concentration of the displacing agents. The concentrations of agent displacing 50% of [ 3H]0T at its sites (IC_ ) are calculated by a computer assisted

LUND0N-2 program (LUNDON SOFTWARE INC., Ohio, USA).

The results of this assay on representative examples are shown in Table V.

Table V

Oxvtocin

Dose % Inhibition

^IC 50

Ex. No. .(μW) at 10 uM

2 10 73 2.9

5 10 90 2

11 10 71 4.4

249 10 38

250 10 15

251 10 77

253 10 77 3.1

254 10 95 1.9

255 10 99 0.46

256 10 47 6.5

257 10 97 0.189

258 10 18

259 10 7

260 10 44

261 10 97 0.21

262 10 55 6.2

263 10 94 0.26

264 1 34

266 10 15

267 10 89 1.1

268 10 89 2.4

345 10 2

379 10 96 0.81

416 10 19

448 10 39

450 10 33

451 1 0

Tabl<Ξ V

Oxvtocin

Dose % Inhibition IC 50

Ex. No. ( (uμMM)) aatt 1100 uuMM μM

452 1 1 2 222

453 5 5 5 533 3.3

454 1 100 7 788 2.5

455 1 100 8 888 1.1 0 534 1 100 8 866 0.94

582 2.8

583 10 58

585 0.32

5 The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, 0 εulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium 5 or with organic bases. The compounds can also be used in the form of esters, carbamates and other convention¬ al "pro-drug" forms, which, when administered in such form, convert to the active moiety _in vivo.

0

_>-}

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, gran¬ ules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups contain¬ ing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable car¬ rier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigen¬ cies of the therapeutic situation.

These active compounds may be administered orally as well as by intravenous, intramuscular, or

subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellu¬ lose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfac¬ tants and edible oiβls such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the prepa¬ ration of pharmaceutical compositions may be advanta¬ geously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for exam¬ ple, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and adminis¬ tration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral admin¬ istration of the compounds is preferred.

These active compounds may also be adminis¬ tered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for inject- able use include sterile aqueous solutions or disper¬ sions and sterile powders for the extemporaneous pre¬ paration of sterile injectable solutions or disper¬ sions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contam¬ inating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion

medium containing, for example, water, ethanol, polyol(e.g., glycerol, propylene glycol and liquid polyethylene glycol) , suitable mixtures thereof, and vegetable oils.

Reference Example 1 6,ll-Dihydro-5H-dibenz[b,e]azepine

A mixture of 48.52 g (0.20 mol) of 2-amino- benzophenone-2'-carboxylic acid and 500 ml of xylene is refluxed for 67 hours, cooled to room temperature and filtered. The solid is washed with xylene to give 43.3 g (97.8%) of 5H-dibenz[b,e]azepine-6,11-dione as light tan crystals, m.p. 245-248°C. To 4.46 g (0.020 mol) of the preceding compound in 25 ml of tetrahydro¬ furan is added 12 ml (0.12 mol) of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran. An addi¬ tional 10 ml of tetrahydrofuran is added and the mix¬ ture is stirred overnight and then is refluxed (solids dissolve) for 4 hours. The solution is cooled and 15 ml of methanol added dropwise. The mixture is concen¬ trated under vacuum, 50 ml of 2N sodium hydroxide is added and the mixture refluxed for 2 hours. The solid is filtered, washed with water, air dried and extracted with dichloromethane. The extract is dried (Na 2_SO4„) and the solvent removed to give 3.25 g (83%) of crys¬ tals, m.p. 117-122°C.

Reference Example 2 4-r (2-Methylbenzσyl)aminolbenzoic acid A mixture of 43.42 g (0.26 mol) of ethyl 4-aminobenzoate and 40.8 g (0.26 mol) of 2-methyl- benzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g (0.26 mol) of triethylamine is added dropwise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into water and the organic layer separated. The organic layer is washed with water, IN HCl, 1M NaHCO_ and dried (Na~SO ) . The solvent is removed and the solid slurried with ethyl acetate and filtered to give 57 g of ethyl 4-[ (2-methylbenzoyl)aminojbenzoate as crystals, m.p. 110-115°C.

A mixture of 50.7 g (0.20 mol) of the preced¬ ing compound, 280 ml of ethanol and 55 ml of ION NaOH is refluxed for 5 minutes. The mixture is cooled to room temperature, diluted with 200 ml of water and acidified with concentrated hydrochloric acid (pH 1-2) . The mixture is filtered and the solid washed with water and dried to give 51 g of product as white crystals, m.p. 270-275°C.

10

Reference Example 3

4-r (2-Methylbenzoyl)amino1benzoyl chloride

A mixture of 10.3 g of 4-[ (2-methylbenzoyl)- amino]benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated

15 under vacuum. Toluene is added and the solvent removed under vacuum. Toluene is added and the mixture chilled and filtered to give a yellow solid, m.p. 135-141°C.

Reference Example 4

4-r (2■6-Dimethoxybenzoyl)aminoIbenzσic acid

^" : o

A mixture of 2 g (10 mmol) of 2,6-dimethoxy- benzoyl chloride, 1.65 g (10 mmol) of ethyl 4-aminoben- zoate, 1.11 g of triethylamine and 61 mg of 4-dimethyl- aminopyridine in 10 ml of dichloromethane is refluxed for 20 hours. The mixture is diluted with water and the organic layer separate. The organic layer is washed with water, IN HCl, IN Na.CO-, brine and dried (Na SO ) . The solvent is removed to give a solid which is crystallized from ethyl acetate to give 1.22 g of ethyl 4-[ (2,6-dimethoxybenzoyl)amino]benzoate as crys¬ tals, m.p. 183-185°C.

A mixture of 3.88 g (11.79 mmol) of the pre¬ ceding compound, 17.3 ml of 2N NaOH and 20 ml of methanol is stirred at room temperature overnight. Methanol (30 ml) and water (10 ml) are added and the solution refluxed for 1/2 hour. The solvents are re¬ moved under vacuum and the residual solid triturated with ether and the ether decanted. The solid is dis¬ solved in 30 ml of water and acidified with 2N HCl (pH

3) . The mixture is filtered, the solid washed with water and dried at 60°C under vacuum to give 3.0 g of solid, m.p. 236-240°C.

Reference Example 5 4-r (4-pyridinylcarbonyllaminolbenzoic acid

To a cooled mixture of 1.78 g (0.01 mol) of isoniconinoyl chloride hydrochloride in 5 ml of di¬ chloromethane is added 2.52 g (0.025 mol) of triethyl¬ amine. To the solution is added a solution of 1.65 g of ethyl 4-aminobenzoate in 5 ml of dichloromethane. After stirring at room temperature overnight, 50 mg of 4-dimethylaminopyridine is added and the mixture is refluxed for 24 hours. The mixture is poured into water and filtered to give 3.4 g of brown solid. A 0.50 g sample is triturated with ethyl acetate to give 0.37 g of ethyl 4-[ (4-pyridinylcarbonyl)amino]benzoate as yellow crystals, m.p. 143-145°C.

Anal. Calc'd for ^C ₁₅ ^H ₁₄ ^N 2 ⁰ ₃ ^: C,66.7; H,5.2; N,10.4 Found: C,66.4; H,5.1; N,10.3.

A solution of 8.15 g (30 mmol) of the preced¬ ing compound and 22 ml of 2N NaOH in 60 ml of methanol is heated on a steam bath for 1 hour. The mixture is cooled and filtered to the solid in water is added 2N citric acid. Stirring and filtering gives 4.24 g of crystals, m.p. 362-365°C.

Anal ^, calc'd for ^c ₁₃ ^H ₁₀ ^N ₂ ^O ₃ ¹ / ^{2 H} 2° ^c » ⁶ 2-l? H,4.4;

N,ll.l

Found: 62.6; H,4.3; N,11.0.

Reference Example 6 4-r (3-Pyridinylcarbonyl)aminolbenzoic acid

A mixture of 1.83 g (0.01 mol) of nicotinoyl chloride hydrochloride (97%), 1.65 g of (0.01 mol) of ethyl 4-aminobenzoate, 2.22 g (0.022 mol) of triethyl¬ amine and 61 mg of 4-dimethylaminopyridine in 33 ml of dichloromethane is refluxed 24 hours. The solution is washed with water, 2N citric acid and NaHCO- solution. The solvent is removed and the residue triturated with

methanol to give 2.3 g of ethyl 4-[ (3-pyridinylcar- bonyl)aminojbenzoate as yellow crystals, m.p. 125-127°C

A mixture of 12.0 g (0.044 mol) of ethyl 4-[ (3-pyridinylcarbonyl)amino]benzoic acid, 65 ml of 2N sodium hydroxide and 120 ml of methanol is refluxed for 0.75 hour. The solvent is removed and the residue ex¬ tracted with diethyl ether. The residue is diluted with water and solid citric acid is added until the pH is 4-5. The mixture is filtered and the solid washed with water and air dried to give crystals, m.p. 307-310°C.

Reference Example 7 5,6-Dihvdro-5-(4-nitrobenzoyl)phenanthridine

To a suspension of 7.5 g of 5,6-dihydrophen- anthridine in 40 ml of warm pyridine under nitrogen is added 3.6 g of 4-nitrobenzoyl chloride. The mixture is stirred overnight, filtered and the solid washed twice with 5 ml of pyridine. To the filtrate is added 250 ml of 2N HCl and the mixture stirred and then filtered to give 6.6 g of solid. This solid is heated with 25 ml of ethyl acetate and filtered. The filtrate is diluted with 25 ml of hexane and filtered. The filtrate is chromatographed HPLC on a Waters-Prep 500 instrument with two silica gel columns and hexane-ethyl acetate (4:1) as solvent. Cuts containing product are combined to give 2.3 g of yellow crystals, m.p. 153° to 154°C.

Anal. Calc'd for ^c ₂ o ^H 14 ^N ₂ ° ₃ ^{: C} ' ⁷² * ⁷ '" H,4.3 ^; N,8.5 Found: 72.0; H,4.3; N,8.3.

Reference Example 8 5-(4-Aminobenzoyl^-5.6-dihvdroρhenanthridine

A solution of 2.15 g of 5,6-dihydro-5-(4- nitrobenzoyl)phenanthridine in 50 ml of ethyl acetate and 0.5 g of 10% palladium-on-carbon is hydrogenated in a Parr apparatus under an atmosphere of hydrogen for three hours. The mixture is filtered through

diatomaceous earth and the solvent removed to give

1.7 g of the product as a yellow foam.

Reference Example 9 5

6,ll-Dihydro-5-(4-nitrobenzoyl)-5H-dibenz[b,e]- azepine A mixture of 2.34 g (12 mmol) of 6,11-di- hydro-5H-dibenz[b,e]azepine, 2.23 g (12 mmol) of

1 ₀ 4-nitrobenzoyl chloride, 1.94 g (15 mmol) of diiso- propylethylamine and 70.5 mg of 4-(dimethylamino)pyri¬ dine in 25 ml of dichloromethane is stirred at room temperature for 2 hours, refluxed for 3 hours and al¬ lowed to stand at room temperature for 2 days. The

1 ₅ mixture is washed with water, IN sodium bicarbonate, water, IN HCl, brine and dried (Na_SO ) . The solvent is removed to give 4.0 g of solid. Trituration with ethyl acetate and filtering gives 2.85 g of off-white crystals, m.p. 185-188°C.

- _" •o ^u Anal. Calc'd for C2_1.H1.6,N2_03_ 0.5 H2_0: C,71.4; H,4.7;

N,7.9. Found: C,71.5; H,4.5; N,7.9.

Reference Example 10 5-(4-Aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine

To a solution of 4.5 g of 6,ll-dihydro-5-(4-

"' ^ nitrobenzoyl)-5H-dibenz[b,e]azepine in 230 ml of gla¬ cial acetic acid is added 0.58 g of 10% palladium-on- carbon and the mixture under hydrogen (38 psi) shaken in a Parr hydrogenator for 6.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to give 4.0 g of solid. The solid is ex¬ tracted with 100 ml of dichloromethane and the extract washed with water, dried (Na_S0 ₄ ). The solvent is re¬ moved to give 4.0 g of yellow crystals, m.p. 168-175°C. A sample chromatographed on a thick layer silica gel

JD plate with hexane-ethyl acetate (8:7) as solvent gives yellow crystals, m.p. 173-175°C.

Anal. Calc'd for ^c ₂ ι ^H _i8 ^N 2 ^{0: C} ' ⁸⁰ * ^2; H,5.8; N,8.9. Found: C,79.2; H,6.0; N,8.8.

Reference Example 11 2-Chloro-5H-dibenz[b,e]azepine-6,11-dione Chlorine gas is bubbled into a mixture (par¬ tial suspension) of 1.0 g (450 mmol) of 5H-dibenz[b_,e]- azepine-6,ll-dione in 50 ml of glacial acetic acid. The temperature of the mixture rises to 38°C. On standing, as the temperature of the solutions decreas- es, a white solid precipitates. The mixture is fil¬ tered to give 0.40 g of solid (mixture of starting material and product in ratio of 1:8). The filtrate on standing gives 0.10 g of product as crystals, m.p. 289-293°C. Reference Example 12

10,11-Dihydro-N.N-dimethyldibenzrb.f1 r1,4loxazepine-

2-sulfonamide To 5.88 g of 10,ll-dihydro-N,N-dimethyl-ll- oxodibenz[b,f] [l,4]oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred overnight and then refluxed for 2 hours. The mixture is chilled, diluted with 10 ml of methanol and then concentrated, methanol added again and the mixture concentrated. To the mixture is added 20 ml of 2N NaOH and the mixture refluxed for 2 hours. The mix¬ ture is extracted with dichloromethane, the extract dried (MgSO ) and filtered. The filtrate is passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give 4.8 g of crystals, m.p. 99-102°C. Recrystallization from diisopropylether-dichloro- methane gives 3.96 g of crystals, m.p. 109-110°C. Mass Spectrum (FAB) 305(M+H). Anal. Calc'd for C,59.2; H,5.3; N,9.2; S,10.6. Found: C,57.6; H,5.2;

N,8.9; S,10.1.

Reference Example 13 10.ll-Dihydro-N.N-dimethyl-10-(4-nitrobenzoyl)- dibenzrb,f] r1.41oxazepine-2-sulfonamide

A mixture of 0.9 g of 10,ll-dihydro-N,N-di- methyldibenz[b,f] [1,4]oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3 ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with 5 ml of 2N HCl and three times with 5 ml of 2N Na CO . The extract is dried (MgSO.) and filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and the filtrate concentrated to give 1.1 g of a yellow solid. Crystallization from dichloromethane-diisopropylether gives 0.62 g of crys¬ tals, m.p. 177-178°C.

Reference Example 14

2-Chloro-5.6-dihydrophenanthridine

To a hot (70°C) solution of 2.62 g (17 mmol) of 6(5H)-phenanthridinone in 120 ml of acetic acid is added chlorine gas for 10 minutes. The solution is allowed to cool to room temperature and the mixture filtered. The crystals are filtered to give 1.35 g of crystals, m.p. 310-318°C.

To the preceding compound (1.57 g) in 25 ml of tetrahydrofuran is added 12 ml of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 18 hours, cooled and 15 ml of methanol is added. The mixture is concentrated under vacuum and 50 ml of 2 N sodium hydroxide added. The mixture is refluxed for 2 hours and tne solid filtered off and washed with water and air dried to give the product as a solid.

Reference Example 15 9-Chloro-5g-dibenz[b,e)azepin-6,ll-dione

A mixture of 11.15 g of 5H-dibenz[b,e]aze- pin-6,ll-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70°C) is added chlorine gas. chlorine is bubbled through the solution until a precipitate begins

10 to form. The mixture is allowed to cool to room tem¬ perature and is filtered to give 7.3 g of product, m.p. 290°C to 295°C.

Reference Example 16 9-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepine

¹⁵ To a mixture of 7.28 g of 9-chloro-5H _. -dibenz-

[b,e]azepin-6,ll-dione in 25 ml of tetrahydrofuran under argon is added 8.5 ml of 10 molar boron-dimethyl- sulfide in tetrahydrofuran. The mixture is stirred 18 hours at room temperature, 30 ml of tetrahydrofuran

20 added and the mixture refluxed for 3 hours (solids dissolved) . The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2 N NaOH. The mixture is refluxed overnight and

25 filtered. The solid is extracted with dichloromethane and the extract is washed with 2 N citric acid, water and dried (Na-SO.) . The solvent is removed to give 4.2 g of solid which is triturated with ethyl acetate-hexane (1:2) to give crystals, m.p. 137°C to

30 141°C.

Reference Example 17 10.ll-Dihvdrodibenzrb.fi n.41thiazepine

To a mixture of 3.3 g of 10,11-dihydro-ll- oxodibenz[b,f] [l,4]thiazepine in 25 ml of tetrahydro- ^■ 35 furan is added 4.0 ml of 10 molar borane-dimethylsul- fide in tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional

30 ml of methanol is added and the solvent removed to give white crystals. A sample is purified by chromato¬ graphy on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give white crystals, m.p. 145-148°C.

The following compounds are prepared as described in Reference Example 17.

Reference Example 18 4-Methyl-10.ll-dihydrodibenzrb.f1 r1,41thiazepine

Reference Example 19 4-Chlσro-10.ll-dihydrodibenzfb.f1rl,41thiazepine

Reference Example 20 2-Methyl-10.ll-dihvdrodibenzrb,fin,41thiazepine

Reference Example 21 2-Chloro-10.ll-dihydrodibenzfb.f1 \ 1 ,41thiazepine

Reference Example 22 2-Methoxy-10.ll-dihydrodibenzTb, f\ [ l .41thiazepine

Reference Example 23

8-Chloro-10.ll-dihydrodibenzfb.f) f1,41thiazepine

Reference Example 24

4 ,8-Dich,loro-10.ll-dihvdrodibenzrb.f1 r1.41thiazepine

Reference Example 25 8-Chloro-4-methyl-10.ll-dihvdrodibenzrb.f1 r1.41- thiazepine Reference Example 26 8-Methoxy-10.ll-dihvdrodibenzrb.f1 r1.41thiazepine

Reference Example 27 7-chloro-4-methyl-10.ll-dihvdrodibenzrb.f1 r1.41- thiazepine The following compounds are prepared as described in Reference Example 12.

Reference Example 28 2-Chloro-10.ll-dihvdrodibenzrb.f1 r1.41-oxazepine

Reference Example 29 2-Methyl-10.ll-dihydrodibenzrb.f1 r1.41-oxazepine

Reference Example 30 4-Chloro-10.ll-dihydrodibenzrb.flri,4"|-oxazepine

Reference Example 31 3-Methyl-10.ll-dihydrodibenzrb.f1 ri,41-oxazepine

Reference Example 32 7-Chloro-10.ll-dihvdrodibenzrb.f1 Tl.41-oxazepine

Reference Example 33

8-Chloro-10.ll-dihvdrodibenzrb.f1 r1.41-oxazepine

Reference Example 34

2,4-Dichloro-10.ll-dihydrodibenzrb.fl (1.41-oxazepine

Reference Example 35 4,8-Dichloro-10.ll-dihydrodibenzrb.f1 r1.41-oxazepine

Reference Example 36 4-Chloro-8-methyl-10.ll-dihvdrodibenzrb.f1 r1.41- oxazepine Reference Example 37 4-Methyl-7-chloro-10.ll-dihvdrodibenzrb.f1 r1.41- oxazepine Reference Example 38 l-Chloro-4-methyl-10.ll-dihvdrodibenzrb.f1 r1.41- oxazepine

Reference Example 39

2-Fluoro-10.ll-dihvdrodibenzrb.f1 r1.41-oxazepine

Reference Example 40

N-(2-Iodophenyl)-2-iodophenylacetamide

A solution of 13.32 g (0.05 mol) of 2-iodo- phenylacetic acid in 75 ml thionyl chloride is reflux¬ ed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2-iodophenyl- acetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture of 100 ml of toluene-dichloro- methane (1:1) is added 11 g (0.05 mol) of 2-iodoaniline and (0.10 mol) of diisopropylethylamine. The mixture is stirred at room temperature overnight and the sol¬ vent removed. The residue is dissolved in dichloro¬ methane and the solution washed with IN HCl, saturated sodium bicarbonate, brine and dried (Na S0 ₄ ) . The sol¬ vent is removed and the residue recrystallized from

methanol-ether to give 16.0 g of light brown crystals, m.p. 160°-163°C.

Reference Example 41 2-Iodo-N-(2-iodophenyl)benzeneethanamine

To a suspension of 1.39 g (3 mmol) of 2-iodo-N-(2-iodophenyl)benzeneacetamide in 30 ml of tetrahydrofuran-dichloromethane (1:1) is added 3.75 ml

₁₀ of 2.0 molar borane-dimethylsulfide in tetrahydro¬ furan. The solution is stirred 1 hr at room temperature and then refluxed for 16 hours. The mixture is cooled and water slowly added dropwise until gas evolution ceases. The volatiles are removed under

₁₅ vacuum and the aqueous residue made alkaline with 2N sodium hydroxide. The mixture is extracted with ether (50 ml) and the extract is washed with brine and dried (Na_SO ) . The solution is filtered through a thin pad hydrous magnesium silicate and the filter pad is washed

„ ₀ with ether and the filtrate evaporated. The residual solid is washed with isooctane to give 1.20 g of white solid. Recrystallization from diethylether/hexane gives white crystals.

Reference Example 42 _{n r} N-(4-Nitrobenzoyl-N-(2-iodophenyl)-2-iodobenzeneethyl- amine To a solution of 0.90 g of 2-iodo-N-(2-iodo- phenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitro-

30 benzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-di- chloromethane (5:1) and the solution washed with IN HCl, saturated NaHCO., brine and dried (Na_S0 ) . The

:;5 solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.

Reference Example 43 5-(4-Nitrobenzoyl )-6.7-dihvdro-5H-dibenz(b.d1azepine To a solution of 0.90 g of N-(4-nitroben- zoyl)-N-(2-iodophenyl)-2-iodobenzeneethylamine in 10 ml of N,N-dimethylpropyleneurea (DMPU) is added 1.91 g of "activated" copper bronze. The mixture is stirred and heated at 195° for 2 days, cooled and slowly dropped into 100 ml of 0.5 N HCl with stirring. The precipi¬ tate is filtered, washed with H_0 and air dried (1.0 g of solid) . The solid is extracted with ethyl acetate to give 0.50 g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-hexane (1:2) as solvent gives 0.15 g of yellow solid.

Reference Example 44 5-(4-Aminobenzoyl)-6.7-dihvdro-5H-dibenzrb.diazepine A solution of 0.15 g .of 5-(4-nitrobenzoyl)- 6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanol- ethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydro¬ gen for 8 hr. The mixture is filtered through diato- maceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.

Reference Example 45 5-(4-Nitro-3-methylbenzoyl )-6.ll-dihvdro-5H-dibenz-

Tb.elazepine A mixture of 1.17 g of 6,ll-dihydro-5H-di- benz[b,e]azepine, 1.20 g of 3-methyl-4-nitrobenzoyl chloride, 0.80 ml of diisopropylethylamine in 25 ml of dichloromethane is stirred 18 hours at room tempera¬ ture. The mixture is washed with water and dried (Na_S0.) . The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is con¬ centrated and diluted while hot with hexane to give 1.40 g of crystals. Recrystallization from dichloro- methane-hexane gives 1.26 g of crystals, m.p. 179°-180°C.

Reference Example 46 5-(4-Amino-3-methylbenzoyl)-6.ll-dihvdro-5H-dibenz- rb.elazepine

A mixture of l.ll g of 5-(4-nitro-3-methyl- benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 50 ml of ethanol, 0.30 g of anhydrous hydrazine and 0.27 g palladium-on-carbon is refluxed 1 hour, and then filtered through diatomaceous earth. The filtrate is

10 evaporated and the residue recrystallized from di- chloromethane-hexane to give 0.80 g of crystals, m.p. 203°-204°C.

Reference Example 47 4-r (6.ll-Dihvdro-5H-dibenzrb,elazepin-5-yHcarbonyl]-

15 benzoic acid

A mixture of 0.975 g of 6,ll-dihydro-5H- dibenz[b,e]azepine and 0.20 g of NaH (60% in oil) in 20 ml of tetrahydrofuran is stirred at room temperature for 0.5 hr. Then 1.1 g of mono-methyl terephthalyl 0 chloride (prepared from mono-methyl terephthalate and thionyl chloride) is added and the mixture refluxed 18 hours. The mixture is cooled, poured into ice water and filtered. The solid is triturated with dichloro- methane-hexane to give 1.0 g of crystals, m.p. 182°-185°C. The preceding compound, methyl 4-[(6,ll- dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoate (2.11 g) , 20 ml of 2N NaOH and 20 ml of methanol is stirred overnight and then heated on a steam bath for 1 hr. The solvent is removed to give a solid. The solid 0 is extracted with ether (discarded) . The solid is dissolved in water and the solution acidified with citric acid to give a solid. The solid is filtered and washed with water to give 1.84 g of crystals, m.p.

220°-225°C.

-in

Reference Example 48 2-Methylfurane-3-carbonyl chloride A mixture of 4.0 g of methyl-2-methylfurane- 3-carboxylate, 30 ml of 2N NaOH and 15 ml methanol is refluxed for 1.5 hours. The solvent is removed under vacuum to give a solid. The solid is extracted with dichloromethane (discarded) . The solid is dissolved in water and the solution acidified with 2N citric acid to give a solid. The solid is washed with water and dried to give crystals 1.05 g of crystals of 2-methylfuran-3- carboxylic acid. The preceding compound (0.95 g) and 3 ml of thionyl chloride is refluxed for l hr. The sol¬ vent is removed, toluene added (20 ml, three times) and the solvent removed to give the product as an oil.

Reference Example 49 2-Chloro-5-(4-nitrobenzoyl)-6,ll-dihydro-5H-dibenz fb.ejazepine A mixture of 2.05 g of 2-chloro-6,11-dihydro-

5H-dibenz[b,e]azepine, 2.15 g of 4-nitrobenzoyl chloride, 1.50 g of N,N-diisopropylethylamine, 54 mg of 4-(dimethylamino)pyridine in 15 ml of dichloromethane is refluxed for 18 hours. The mixture is cooled and washed with H ₂ 0, IN HCl, 1M NaHC0 ₃ , brine and dried

(Na_S0 ) . The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue recrystallized from dichloromethane-hexane to give 2.33 g of crystals, m.p. 198°-201°C.

Reference Example 50 2-Chloro-5-(4-aminobenzoyl)-6,ll-dihydro-5H- dibenzrb.e]azepine A solution of 2.1 g of 2-chloro-5-(4-nitro¬ benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine in 400 ml of ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon is hydrogenated in a Parr hydro- genator under 38 pounds per square inch of hydrogen.

The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness. The solid (1.94 g) is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane and the filtrate concentrated. The residue is crystallized from dichloromethane-hexane to give 1.43 g of crystals, m.p. 211°-214 C.

10

Reference Example 51 1,2,3,4-Tetrahydro-l-(4-nitrobenzoyl)-5H-1- benzazepjne To a solution of 5.0 g of 1,2,3,4-tetrahydro-

₁ 5 5g-l-benzazepine and 5.91 ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath, is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml of dichloromethane. The mixture is stirred at 0°C for 1.5 hr and then at room temperature for 18 hours. The

₂₀ mixture is washed with H_0, 2M HCl, 1M NaOH and dried (Na SO ) . The solvent is removed and the residue re- crystallized from ethanol with the aid of activated carbon to give 7.75 g of light yellow crystals, m.p. 148.5°-150.5°C.

^D Reference Example 52 1,2,3,4-Tetrahydro-l-(4-nitrobenzoyl)-5H-1- benzapin-5-one A sample (3.0 g) of l,2,3,4-tetrahydro-l-(4- nitrobenzoyl)-5H-l-benzazepine is dissolved in 200 ml 30 of tert-butanol (with heat) . To the solution is added 8 ml of H_0 and 6.72 g of anhydrous MgSO. and then a solution of 3.3^ g of KMnO. in 100 ml of H.O is added and the mixture heated at 65oC for 20 hours. The mixture is filtered through diatomaceous earth and the

25 filter pad washed with tert-butanol. The combined filtrate is concentrated (t-butanol removed) under vacuum. The solid is filtered and washed well with water to give (after drying) 2.7 g of crystals. Chro-

matography on silica gel with hexane-ethyl acetate (2:1) gives 1.72 g of recovered starting material and 0.81 g of product as crystals, m.p. 135 -137°c.

Reference Example 53 3,4-Dihydro-lH-l-benzazepine-2,5-dione

To a solution of 225 ml of glacial acid and 8.5 ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated) . The mixture is heated at 100 C 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloromethane-hexane to give 20.1 g of 3-(2-nitro- benzoyl)acrylic acid as white crystals, m.p. 153-158°C. A solution of the preceding compound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon is hydro- genated in a Parr hydrogenator under 30 pounds per square inch of hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 g of 3-(2-aminobenzoyl)acrylic acid as an orange solid, m.p. 103°-107°C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml of diethoxyphosphinyl cyanide in 20 ml of dichloro¬ methane is stirred at room temperature for 5 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2 N citric acid, 1M NaHCO , brine and dried (Na_S0.). The solvent is removed and the residue purified by chromatography over silica gel with ethyl acetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals, m.p. 168°-170°C.

Reference Example 54

(4-nitrobenzoyl)-5H-l-benzazepin-5-one

A mixture of 0.780 g of 1,2,3,4-tetrahydro-1- (4-nitrobenzoyl)-5H.-l-benzazepin-5-one and 10 ml of tert-butoxv bis(dimethylamino)methane (Bredereck's Reagent) is heated on a steam bath while stirring for 0 1.5 hours (solid dissolved). Cooling gives a solid and the mixture is diluted with ethyl acetate and filtered. The solid is dissolved in dichloromethane-ethyl acetate (7:3) and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed ₅ with dichloromethane-ethyl acetate (7:3) and the com¬ bined filtrate evaporated to give 0.43 g of yellow crystals, Mass Spec (Cl) MH ⁺ =366, m.p. 180°-183°C.

Reference Example 55 6,7-Dihydro-7-(4-nitrobenzoy1)-5H-pyrimido- 0 [5,4-d] [l]benzazepine

To a solution of 0.152 g (1.89 mmol) of formamidine hydrochloride in 10 ml of methanol under argon is added 0.102 g (1.89 mmol) of sodium methoxide. After stirring 5 min., a solution of 0.46 g (1.26 mmol) 5 of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-l- (4-nitrobenzoyl)-5H-l-benzazepine-5-one in 5 ml of methanol is added and the mixture stirred 18 hours. The solvent is removed, dichloromethane added, and the mixture filtered. The solid is washed with dichloro¬ Ό methane. The combined filtrate is concentrated to dryness to give 0.47 g of tan foam. The preceding solid is purified by chromatography on silica gel. The compound is dissolved in ethyl acetate-dichloromethane and applied to the column. The column is then eluted

.5 with ethyl acetate to give 0.25 g of product as pale yellow crystals.

Reference Example 56 4-r (Dimethylamino)methylene1-3,4-dihvdro-lH-l- benzazepine-2.5-dione A mixture of 0.250 g (1.43 mmol) of 3,4-dihydro-lH-l-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N_,N-dimethylformamide, di- methylacetal is heated at 90°C for 1.5 hour. The mixture is cooled, diluted with diethylether and filtered. The solid is washed well with diethylether and dried to give 0.26 g of tan crystals, m.p. 203°-205°C.

Reference Example 57 2-Methyl-6,7-dihydro-5H _/ -pyrimido[5,4-d] [l]benzazepine

To a solution of 0.308 g (3.26 mmol) of acetamidine hydrochloride in 15 ml of methanol under argon is added 0.176 g of (3.26 mmol) of sodium methoxide and the mixture stirred for 5 min. To the mixture is added 0.50 g (2.17 mmol) of 4-[ (dimethyl¬ amino)methylene]-1,2,3,4-tetrahydro-5H-l-benzazepine- 2,5-dione and the mixture stirred at room temperature overnight. The mixture (containing thick precipitate) is diluted with 3 ml of methanol, chilled and fil- tered. The filtrate is concentrated to dryness. The residue and original solid are combined and chloroform added. The mixture is washed with water, the organic layer is treated with activated carbon and then filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated to give 0.41 g of crystals, m.p. 257°-258°C.

The preceding compound is heated with 5 pqui- valents of lithium hydride in dioxane for 24 hours to give the product as a solid.

Reference Example 58 10.ll-Dihvdro-10-(4-nitrobenzoyl)dibenzTb.f1 r1.41- thiazepine To a solution of 1.6 g of 10,ll-dihydrodi¬ benz[b,f] [1,4]thiazepine in 30 ml of dichloromethane is added 0.1 g of 4-(N,N-dimethylamino)pyridine, 4 ml of triethylamine and 1.0 g of 4-nitrobenzoyl chloride and the mixture is stirred for 16 hours. The mixture is poured into ice-water and extracted with 3x150 ml of dichloromethane. The combined organic extract is washed with water, 2N HCl, 2N Na_C0_, water and dried (MgSO ) . The solvent is removed in vacuo and the product (2.6 g) purified by chromatography on silica gel with hexane-ethyl acetate (4:1) as eluent to give 2.2 g of crystals, m.p. 147°-149°C.

Reference Example 59 10.ll-Dihvdro-10--(4-aminobenzoyl)dibenzrb,f1 ri,41- thiazepine A mixture of 2.2 g of 10,ll-dihydro-10-(4- nitrobenzoyl)dibenz[b,f] [1,4]thiazepine in 150 ml of methanol is shaken in a Parr hydrogenator under 50 pounds per square inch of hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue is re- crystallized from chloroform-hexane to give 1.8 g of crystals, m.p. 52 -55 C.

Reference Example 60 4-rN-Methyl-N-(2-methylbenzoyl)amino1benzoic acid

A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexane under argon to remove the oil. To the washed sodium hydride is added 5 ml of N,N-dimethylformamide. To this mixture is added drop¬ wise a solution of 8.69 g of ethyl 4-[ (2-methylbenzo- yl)amino]benzoate in 20 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours.

The mixture is diluted with water and extracted with dichloromethane. The extract is dried (Na_SO ) , con¬ centrated to reduce the volume and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 11 g of an oil (1:1 mixture of product and N,N- dimethylformamide) . The preceding product, ethyl 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (ll g) is dissolved in 30 ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2 hours and the solovent removed. The residue is extracted with ether (discard) and the remaining residue dissolved in 50 ml of water. The basic solution is acidified with 2N citric acid and the solid filtered off and washed with water. The product is air dried to give 6.72 g of crystals, m.p. 187°-190°C.

Reference Example 61 4-rN-Methyl-N-(2-methylbenzoylamino1benzoyl chloride A solution of 6.72 g of 4-[N-methyl-N-(2- methylbenzoyl)amino]benzoic acid in 20 ml of thionyl chloride is refluxed for one hour. The volatiles are removed in vacuo. Toluene is added to the residue and then the toluene removed in vacuo (repeated several times) to give the 7.3 g of product as a brown oil.

As described for Reference Example 60, but substituting the appropriate ethyl 4-[ (N-aroyl)amino]- benzoate, the folowing compounds are prepared.

Reference Example 62 4-rN-Methyl-N-(2-chlorobenzoyl)amino1benzoic acid Reference Example 63 N-TN-Methyl-N-(2.5-dichlorobenzoyl)amino]benzoic acid

Reference Example 64

N-rN-Methyl-N-(2.4-dichlorobenzoyl)amino1- benzoic acid

Reference Example 65

4-rN-methyl-N-(2-chloro-4-methylbenzoyl)aminol- benzoic acid

Reference Example 66 4-rN-methyl-N-(2-methyl-4-chlorobenzoyl)aminol- benzoic acid

Reference Example 67

4-[N-Methyl-N-(2.4-dimethylbenzoyl)amino1- benzoic acid

Reference Example 68

4-TN-Methyl-N-(2.3-dimethylbenzoyl)aminol- benzoic acid

Reference Example 69

4-rN-Methyl-N-(2-methoxybenzoyl)amino]benzoic acid

Reference Example 70

4-TN-Methyl-N-(2-trifluoromethoxybenzoyl)amino1- benzoic acid

Reference Example 71

4-rN-Methyl-N-(2.4-dimethoxybenzoyl)aminol- benzoic acid

Reference Example 72

4-rN-Methy1-N-(2-methoxy-4-chlorobenzoy1)amino1- benzoic acid

Reference Example 73

4-TN-Methyl-N-(2-methylthiobenzoyl)amino]- benzoic acid

Reference Example 74 -rN-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino]- benzoic acid Reference Example 75 -TN-Methyl-N-(3-methylthiophene-2-ylcarbonyl)aminol- benzoic acid Reference Example 76 4-rN-Methvl-N-(2-methvlfuran-3-vlcarbonyl)amino1- benzoic acid Reference Example 77 4-(N-Methyl-N-(3-methylfuran-2-ylcarbonyl1aminol- benzoic acid

Reference Example 78

4-(N-Methyl-N-(phenylacetyl)aminolbenzoic acid

Reference Example 79

4-rN-Methyl-N-(2-chlorophenylacetyl)amino]- benzoic acid

Reference Example 80

4-rN-Methyl-N-(2-methσxyphenylacetyl)aminol- benzoic acid

10

Reference Example 81

4-TN-Methyl-N-(2-methylphenylacetyl)amino1- benzoic acid

Reference Example 82

4-rN-Methyl-N-(cvclohexylcarbonyl)amino]-

15 benzoic acid

Reference Example 83

4-rN-Methyl-N-(3-cyclohexenecarbonyl)amino]- benzoic acid

Reference Example 84

20

4-rN-Methyl-N-(cyclohexylacetyl)aminolbenzoic acid

Reference Example 85

5.6-Dihydropyridor2.3-b1 ri.41benzothiazepine

To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 ml of ethanol and 11 ml of

25 water is added portionwise 12.72 g of solid sodium bi¬ carbonate. After the complete addition, the mixture is stirred for 15 minutes and 10.0 g of 2-chloro-3-nitro- pyridine added portionwise. The mixture is refluxed for 2 hours, cooled and then concentrated in vacuo.

30 The residual aqueous solution is diluted with 15 ml of water, acidified with 2N HCl and extracted twice with 250 ml of ethyl acetate. The extract is concentrated under vacuum to give a yellow solid residue. The residue is dissolved in a minimum of ethyl acetate by

- 35 heating on a steam bath. The solution is cooled overnight and filtered. (2.5 g of starting material). The filtrate is concentrated, chilled and filtered to give 12.5 g of 2-(3-nitro-2-pyridinylthio)benzoic acid

as a yellow solid. The preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml of ethanol is shaken in a Parr hydrogenator under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatmoaceous earth and the filter cake washed with 200 ml of dichloromethane. The combined filtrate is evaporated in vacuo to give a solid. The solid is triturated with ethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g) is again hydrogenated with Pd/c (0.50 g) in 50 ml of ethanol and 30 ml of acetic acid under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with methanol. The combined filtrate is concentrated in vacuo to give 1.6 g of solid. This solid in 25 ml of N,N-dimethylformamide is again reduced with 0.80 g of Pd/C under 45 psi of hydrogen to give 0.57 g of solid. Recrystalization from ethyl acetate gives 0.28 g of 2-(3-amino-2-pyridinylthio)benzoic acid. The preced¬ ing compound (0.20 g) is heated in 2-hydroxypyridine at 170°C to give 5,6-dihydropyrido[2,3-b] [l,4]benzothia- zepine as a yellow solid. The preceding compound is reacted with borane-dimethylsulfide as described for Reference Example 17 to give the product as a solid.

Reference Example 86 5,6-Dihydro-5-(4-aminobenzoyl)pyrido[2,3-b] [1,4]- benzothiazepine To a mixture of 10 mmol of 5,6-dihydropyrido- [2,3-b_] [l,4]benzothiazepine and 11 mmol of 4-nitro- benzoyl in 25 ml of dichloromethane chilled to 0°C is added 15 mmol of triethylamine. The mixture is stirred at room temperature for 5 hours and then diluted with 75 ml of dichloromethane. The mixture is washed with ^H ₂ ^{0/ 2N c} i ^tr: *- ^c acid, NaHC0_, brine and dried (Na SO ) . The solvent is removed to give 5,6-dihydro-5-(4-nitro- benzoy1)pyrido[2,3-b] [1,4]benzothiazepine as a solid. A mixture of the preceding compound (5 mmol), 0.3 g of

Pd/C and 3 mmol of hydrazine in 25 ml of ethanol is refluxed for 3 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated jin vacuo to give a solid. The solid is purified by chromato¬ graphy on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.

Reference Example 87 5,ll-Dihydro-6-(4-aminobenzoyl)-6H-pyrido[2,3-e] [1]- benzazepine To a mixture of 10 mmol of 5,ll-dihydro-6H- pyrido[2,3-e] [l]benzazepine, and 11 mmol of 4-nitro- benzoyl chloride in 25 ml of dichloromethane, chilled to 0°C, is added 15 mmol of triethylamine. The mix¬ ture is stirred at room temperature for 5 hours and diluted with 75 ml of dichloromethane. The mixture is washed with H_0, 2N citric acid, NaHCO , brine and dried (Na^SO.) . The solvent is removed in vacuo to give 5,ll-dihydro-6-(4-nitrobenzoyl)-6H-pyrido-

[3,2-£] [l]benzazepine as a solid. A mixture of the preceding compound (5 mmol) 0.3 g of Pd/C and 3 mmol of hydrazine in 25 ml of ethanol is refluxed 3 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo to a solid. The solid is purified by chromatography on silica gel to give the product as a solid.

Reference Example 88 2-Nitro-2'-carboxy-diphenylamine A stirred solid mixture of 13.7 g of anthra- nilic acid, 20.2 g of o-bromonitrobenzene, 13.8 g of anhydrous potassium carbonate and 0.1 g of copper metal is heated 200°C oil bath. The reaction mixture is heated for 2 hours, cooled and the solid washed with ether (3x100 ml) . The solid is dissolved in hot water and filtered. The filtrate is acidified with 40 ml of HCl and the resulting solid is collected and dried to

give 20.5 g of the desired product as a solid, m.p. 262-265°C.

Reference Example 89 2-Amino-2'-carboxy-diphenylamine A solution of 7.3 g of 2-nitro-2'-carboxy- diphenylamine in 50 ml of methanol containing 10% palladium-on-carbon is hydrogenated under 42 pounds of pressure for 24 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated to dryness in vacuo to give 6.6 g of the desired product as a solid, m.p. 72-75 C.

Reference Example 90 5,ll-Dihydro-10fi-dibenz[b,e] [1,4]diazepine-11-one

A mixture of 6.6 g of 2-amino-2'-carboxy- diphenylamine in 300 ml of xylene is heated at reflux for 20 hours. The xylene is evaporated in vacuo to a residue which is evaporated from 210 ml of toluene in vacuo to a residue which is evaporated from 50 ml of chloroform to give a residue. The residue is dissolved in 10 ml of tetrahydrofuran and added to 400 ml of ice-cold hexane. The resulting solid is collected, to give 4.3 g of the desired product as a solid, m.p. 121-123°C.

Reference Example 91 5,ll-Dihydro-10H.-dibenz[b,e] [l,4]diazepine

To a stirred solution of 4.3 g of 5,11-di- hydro-10H-dibenz[b,e] [l,4]diazepin-ll-one in 50 ml of tetrahydrofuran, under nitrogen and cooled to 0°C is added 4.0 ml of 10 N methyl sulfide-borane complex. The ice bath is removed after 30 minutes and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture is cooled in an ice bath and 30 ml of anhydrous methanol added dropwise and evaporated to dryness in. vacuo. Another 30 ml of methanol is added and evaporated to a residue. The residue is quenched with 30 ml of 40% sodium hydroxide

followed by heating at 110°C for 45 minutes and cooling to room temperature. The reaction mixture is diluted with 200 ml of water and extracted with methylene chloride (3x100 ml) . The combined extracts are washed with 1 N HCl, water and 0.5 N NaOH. The organic layer is dried and evaporated in vacuo to give 3.2 g of the desired product, m.p. 114-116 C.

Reference Example 92 5H.-Dibenz[b,e]azepine-6,ll-dione

A mixture of 2.50 g of 2-aminobenzophenone- 2'-carboxylic acid in 50 ml of xylene is stirred at reflux for 23 hours. The mixture is filtered to give 1.82 g of the desired product as a solid.

Reference Example 93 2-Chloro-5H-dibenz[b,e]azepine-6,ll-dione

A mixture of 1.0 g of 5H-dibenz[b,e]azepine- 6,11-dione in 50 ml of acetic acid is stirred while chlorine is bubbled into the reaction mixture until saturated. The temperature increases to 38°C. After standing, a precipitate forms and is filtered, washed with hexane and air dried to give 0.62 g of solid which is purified by chromatography to give the desired product as a solid, m.p. 289-293 C.

Reference Example 94 2-Chloro-6,ll-Dihydro-5H-dibenz[b,e]azepine

To a mixture of 7.28 g of 2-chloro-5H-dibenz- [b,e]azepine-6,ll-dione in 25 ml of anhydrous tetra¬ hydrofuran, under argon, is added dropwise 8.5 ml of (10 M) boron-dimethyl sulfide. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is heated at reflux for 3 hours and cooled to room temperature. While stirring, 25 ml of methyl alcohol is carefully added, followed by 100 ml of 2 N NaOH. The reaction mixture is heated at reflux for 24 hours and the solid collected. The solid is dissolved in methylene chloride and washed with 2 N citric acid,

water and dried (Na SO ) . The volatiles are evaporated in vacuo to give 4.16 g of a residue which is crystal¬ lized from ethyl acetate-hexane to give 2.05 g of the desired product as a crystalline solid, m.p. 137-141°C.

Reference Example 95 5,6-Dihydro-6-(4-nitrobenzoyl)-4H-isoxazolo[4,5-d]-

[llbenzazepine A solution of 0.250 g of 1,2,3,4-tetrahydro-

4-[ (dimethylamino)methylene-l-(4-nitrobenzoyl)-5H-1- benzazepin-5-one and 95.2 mg of hydroxylamine hydro¬ chloride in 8 ml of methyl alcohol is heated at reflux under argon for 4 hours. The methanol is evaporated in vacuo to a residue which is dissolved in 10% ethyl acetate in methylene chloride and the solution passed through a pad of silica gel. The filtrate is evapora¬ ted in vacuo to give the desired product as a solid. CIMS:MH ⁺ =336. Reference Example 96

5,6-Dihydro-6-(4-aminobenzoyl)-4H-isoxazolo[4,5-d]- rilbenzazepine A mixture of 0.050 g of 5,6-dihydro-6-(4- nitrobenzoyl)-4H-isoxazolo[4,5-d] [1]benzazepine and 0.169 g of SnCl_ 2H_0 in 2 ml of ethyl alcohol is heated at reflux under argon for 1 hour. Water and 10% NaHCO- is added until basic. The volatiles are eva¬ porated in vacuo to a residue which is stirred with 1:1 chloroform-methanol and filtered. The filtrate is eva- porated in vacuo to a residue which is dissolved in methyl alcohol, treated with activated carbon, filtered through diatomaceous earth and concentrated in vacuo to give 100 mg of the desired product as a white crystal¬ line solid. CIMS(CH ₄ ) :MH ⁺ =306.

Reference Example 97 6,7-Dihydro-2-methyl-7-(4-nitrobenzoyl)-5H-pyrimido- r5,4-d_l rUbenzazepine

To a stirred solution of 0.233 g of acetami- dine hydrochloride in 36 ml of methyl alcohol under argon is added 0.133 g of NaOCH-. After 5 minutes, 0.600 g of 4-[ (dimethylamino)methylene]-1,2, 3,4-tetra- hydro-1-(4-nitrobenzoyl)-5H-l-benzazepin-5-one is added and stirring continued for 18 hours. The volatiles are evaporated to a residue which is dissolved in ethyl acetate and passed through a pad of silica gel. The filtrate is evaporated in vacuo to give 590 mg of the desired product as tan crystals, m.p. 211-212°C. HR FABMS: Exact mass (M+H) :361.1295.

Reference Example 98 6,7-Dihydro-2-methyl-7-(4-aminobenzoyl) -5H-pyrimido-

[5,4-d] [l]benzazepine

A mixture of 400 mg of 6,7-dihydro-2-methyl- 7-(4-nitrobenzoyl)-5H-pyrimido[5,4-d] [l]benzazepine, 87 μl of anhydrous hydrazine and 40 mg of 10% Pd/C in 22 ml of ethyl alcohol is heated at reflux for 1.25 hours, filtered through diatomaceous earth and the pad washed well with methyl alcohol. The combined filtrates are evaporated in vacuo to a residue which is dissolved in ethyl acetate and filtered through a pad of hydrous magnesium silicate and the filtrate concentrated in vacuo to a residue which is dissolved in methyl alcohol and evaporated again to give 330 mg of the desired product as a yellow foam. HR FABMS: Exact mass (M+H) : 331.1555.

Reference Example 99 4-r (Dimethylamino^methylenel-1,2.3 ,4-tetrahvdro-l- (4-nitrobenzoyl)-5H-l-benzazepin-5-one

A mixture of 1.35 g of 1,2,3,4-tetrahydro-l- (4-nitrobenzoyl)-5H-l-benzazepin-5-one and 15 ml of

tert-butoxy-bis(dimethylamino)methane is heated for on a steam bath for 2 hours. The volatiles are evaporated in vacuo to a residue which is stirred with ether and filtered. The cake is washed with ether and the combined filtrates evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue to give 1.60 g of yellow crystalline product, m.p. 180-183°C.

Reference Example 100

2,4.5.6-Tetrahydro-2-methyl-6-(4-nitrobenzoyl)- pyrazolo[4,3-d] [l]benzazepine

A solution of 0.150 g of 4-[ (dimethylamino)- methylene]-1,2,3,4-tetrahydro-l-(4-nitrobenzoyl)-5H÷- l-benzazepin-5-one and 44 μl of methylhydrazine in 5 ml of methyl alcohol is heated at reflux for 18 hours. A precipitate forms on standing. The volatiles are eva¬ porated to a residue which is purified by column chro- matography on silica gel by elution with 5% ethyl acetate-methylene chloride. The product fractions are combined and the volatiles evaporated to a residue which is dissolved in chloroform-methanol, filtered through glass wool and the filtrate evaporated in vacuo to give 0.110 g of the desired product as pale yellow crystals.

Reference Example 101

2.4 ,5.6-Tetrahγdro-2-methyl-6-(4-aminp benzoyl)- pyrazolo[4,3-d.] [l]benzazepine A mixture of 0.520 g of 2,4,5,6-tetrahydro-2- methyl-6-(4-nitrobenzoyl)pyrazolo[4,3-d.] [l]benzazepine, 118 μl of anhydrous hydrazine and 52 mg of 10% palladium-on-carbon in 30 ml of absolute ethyl alcohol

is heated at reflux for 1 hour. The reaction mixture is filtered through diatomaceous earth and the cake washed with 100 ml of methyl alcohol and 1:1 chloro- form-methyl alcohol to give 430 mg of the desired pro¬ duct as off-white crystals. CIMS(CH ₄ )MH ⁺ =319.

Reference Example 102 5-(2-Chloro-4-aminobenzoyl)-6,ll-dihydro-5H- dibenzfb.elazepine

A mixture of 1.40 g of 5-(2-chloro-4-nitro- benzoyl)-6,ll-dihydro-5H.-dibenz[b,e]azepine, 0.20 g of 10% palladium-on-carbon, 0.25 g of anhydrous hydrazine in 25 ml of absolute ethanol is heated at reflux for 1 hour. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo to a residue which is dissolved in methylene chloride and hexane added at the boil to give 0.60 g of the desired pro¬ duct as a crystalline solid, m.p. 158-161°C.

Reference Example 103 2-f2-(Tributylstannyl)-3-thienyl1-1.3-dioxolane

To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-l,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48 N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78°C and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, giving 34.16 g (77%) of the desired product.

Reference Example 104 2-r2-r (2-Nitrophenyl)methyl1-3-thienyl1-1.3-dioxolane A mixture of 2-[2-(tributylstannyl) -3- thienyl]-l,3-dioxolane (8.8 gms, 20 mmols) , 2-nitro- benzyl bromide (4.5 gms, 22 mmol) and tetrakis (tri- phenylphosphine)-palladium (0) (200 mg) is refluxed in degassed toluene for 16 hours under nitrogen atmosphere. At the end, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth. The toluene is removed by concentrating at reduced pressure and the product isolated by silica gel column chromatography by elution with 30% ethyl acetate:hexane to give 4.5 gms. of the desired product . . . + as a viscous liquid. Mass Spectrum; M 292.

Reference Example 105

4,lO-Dihydro-5H.-thieno[3,2-c] [1]benzazepine

A stirred solution of 4 gms of 2-[2-[(2- nitrophenyl)methyl]-3-thienyl]-l,3-dioxolane in acetone (50 ml) and acetic acid (90% 50 ml) is heated to 60°C. Zinc dust (10 gms) is slowly added and after the addi¬ tion, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water. The organic layer is dried (Na SO ) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate:hexane to give 2.0 g of the desired product as a pale yellow crystalline solid, m.p. 86°C. Mass Spectrum; M 202.

Reference Example 106 4.5-Dihvdro-4.4-dimethyl-2-r3-r(2-nitrophenyl)methyl1-

2-thienyl1oxazole To a solution of 4,5-dihydro-4,4-dimethyl-2- (2-thienyl)-oxazole (4.5 gms 25 mmol) in anhydrous ether at -70°C, n-butyl-lithium (2.5 molar solution in hexane, 11 ml) is added drop by drop under N_ atmos¬ phere. The reaction mixture is stirred at -78°C for 45 minutes and tri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed well with water, dried and concen¬ trated. The product obtain is pure enough for further transformation. The oil product, 4,5-dihydro-4,4-di- methyl-2-[3-(tributyistannyl)-2-thienyl]-oxazole is mixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis (tri- phenylphosphine)-palladium (0) (200 mg) for 16 hours. At the end, reaction mixture is cooled to room tempera¬ ture and filtered. Toluene is removed under reduced pressure and the product is isolated as brown oil by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 5.7 g of the desired product. Mass Spectrum; M 316.

Reference Example 107 9,10-Dihydro-4H-thieno[3,2-cJ[1]benzazepin-10-one

A solution of 4,5-dihydro-4,4-dimethyl-2- [3-[ (2-nitrophenyl)methyl]-2-thienyl)oxazole 5 gms is refluxed in acetone/water (3:1 100 ml) containing 1 N HCl (30 ml) for 24 hours. The reaction mixture is concentrated and the residue is dissolved in glacial acetic acid (100 ml) . The acetic acid is stirred at 70°C and zinc dust (10 gm) is slowly added. Stirring is continued at 70 C for 6 hours. At the end, the reaction mixture is cooled to room temperature and filtered. Acetic acid is removed under reduced

pressure and the residue is extracted with chloroform. The chloroform layer is dried and concentrated to give 2.9 gms of the desired product as a brown solid. Mass Spectrum; M 215.

Reference Example 108 9,10-Dihydro-4H-thieno[3,2-c] [1]benzazepine

A stirred solution of 2.0 g of 9,10-dihydro- 4H.-thieno[2,3-c.] [l]benzazepin-10-one and lithium aluminum hydride (500 mg) in tetrahydrofuran is re¬ fluxed for 4 hours. At the end, reaction mixture is carefully quenched with ice cold water and extracted with chloroform. The organic layer is washed well with water and dried over anhydrous Na_S0 , filtered and concentrated. The product is purified by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 1.2 g of the desired product as a bright yellow solid. Mass Spectrum; M 202. Reference Example 109

4-Bromo-l,2,3,4-tetrahydro-l-(4-nitrobenzoyl)-5H- l-benzazepin-5-one A mixture of 0.200 g of 1,2,3,4-tetrahydro-1- (4-nitrobenzoyl)-5H-l-benzazepin-5-one in 2.5 ml of acetic acid is warmed until solution then allowed to cool to room temperature. While stirring, a solution of 0.103 g of bromine in 0.5 ml of acetic acid is added dropwise. After rapid decolorization, the reaction mixture is stirred for 1.5 hours and poured into water. The solid is collected, washed with water and air dried to give 220 mg of the desired product as a crystalline solid, Mass Spectrum; MH =389,391.

Reference Example 110 5,6-Dihydro-2-methyl-6-(4-nitrobenzoyl)-4H-

5 thiazolo[5,4-d] [l]benzazepine

A mixture of 1.19 g of 4-bromo-l,2,3,4- tetrahydro-1-(4-nitrobenzoyl)-5β-l-benzazepin-5-one and 0.230 g of thioacetamide in 4 ml of ethyl alcohol is refluxed under argon for 18 hours. The volatiles are

1° evaporated in vacuo to a residue which is partitioned between CHC1_ and 10% NaHCO . The organic layer is separated and washed twice with water. The organic layer is separated, dried (MgSO.) and evaporated in vacuo to give 1.08 g of yellow foam which is purified

I ⁵ by flash chromatography on silica by elution with 4% ethyl acetate in methylene chloride to give 560 mg of the desired product as pale yellow foam.

20

25

30

35

Reference Example 111 5,6-Dihydro-2-methyl-6-(4-aminobenzoyl)-4H- thiazolo[5,4-d] [l]benzazepine

A mixture of 0.080 g of 5,6-dihydro-2- methyl-6-(4-aminobenzoyl)-4H-thiazolo[5,4-d] [1]benz- azepine and 0.248 g of SnCl dihydrate in 3.5 ml of ethyl alcohol is refluxed under argon for 1 hour. The reaction mixture is diluted with ice water and the pH adjusted to 8 with 10% NaHC0_. After stirring for 3 hours, the mixture is extracted with CHC1 (3x) . The combined organic layers are treated with activated carbon, filtered through a pad of MgSO and the filtrate evaporated in vacuo to a residue. The residue is chromatographed on silica gel by elution with 30% ethyl acetate in methylene chloride to give 60 mg of the desired product as a tan solid, CIMS(CH ):MH =336.

Reference Example 112 Methyl 4-r2-(2-chlorophenyl)-2-cyano-2-(4- morpholinyl)ethyl]benzoate A 0.876 g sample of 60% sodium hydride in oil is washed with hexane followed by the addition of 60 ml of dry N,N-dimethylformamide. The reaction mixture is stirred for 1 hour under argon at room temperature after the addition of 4.73 g of α-(2-chlorophenyl)-4- morpholineacetonitrile. To the reaction mixture is added 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continued for 3 hours. Several drops of acetic acid is added to ice water and the reaction quenched. The pH is 3-4 and saturated NaHCO- added to adjust the pH to 6-7. Upon cooling a solid forms which is filtered, washed with water and dried to give 5.92 g of yellow solid. Crystallization from methylene chloride-hexane gives 2.10 g of the desired product as a crystalline solid, m.p. 116-118°C.

Reference Example 113 Methyl 4-r2-(2-chlorophenyl)-2-oxoethyllbenzoate

A mixture of 1.0 g of methyl [4-(2-chloro- phenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate and 14 ml of acetic acid and 6 ml of water is heated at reflux for 20 minutes then poured over crushed ice. After stirring for 15 minutes the resulting solid is collected, washed with water and air dried to give 0.63 g of tan solid, m.p. 40-42°C.

Reference Example 114 4-r2-(2-chlorophenyl)-2-oxoethyl]benzoic acid

A mixture of 18.78 g of methyl 4-[2-(2- chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of CH_0H, 72.2 ml of water and 5.2 g of NaOH is refluxed for 3 hours then acidified with 2 N citric acid. The reaction mixture is evaporated in vacuo to remove the CH_OH. The aqueous phase is extracted with CH_C1 and acidified with 1 N HCl. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172°C.

Example 1 N-r4-r (10.ll-dihvdro-5H-dibenzrb.f1azepin-5-yl ) - carbonvnphenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2- methylbenzoyl)amino]benzoyl chloride and 0.061 g of 4- (dimethylamino)pyridine in 4 ml of pyridine is added 0.975 g (5 mmol) of 10,ll-dihydro-5H-dibenz[b,f]aze¬ pine. The mixture is heated at 80°C for 18 hours and then 0.2 g of sodium hydride (60% in oil) (5 mmol) is added. The mixture is refluxed for 2 hours, diluted with dichloromethane and water and then filtered. To the filtrate is added IN HCl and the mixture filtered. The filtrate is dried (Na_S0 ₄ ) and the solvent removed to give a solid. The solid (1.1 g) is chromatographed on thick layer silica gel plates to give 70 mg of yel¬ low solid, m.p. 112-118°C. Anal. Calc'd for ^C ₂₉ ^H 24 ^N 2 ^{0: c} ' ⁸⁰ * ⁵ ' ^* H,5.6 ^; N,6.5.

Found : C , 78 .7 ; H , 5. 8 ; N , 6. 7 .

Example 2 N-f4-r (6.ll-Dihvdro-5H-dibenzrb,e1azepin-5-yl)- carbonyl1phenyl1-2-methylbenzamide To a solution of 0.27 g (l mmol) of 4-[(2- methylbenzoyl)amino]benzoyl chloride in 2 ml of tetra¬ hydrofuran is added 0.20 g (1 mmol) of 6,11-dihydro- 5H-dibenz[b,e]azepine and 0.20 g of triethylamine. The

10 mixture is stirred at room temperature for 3 hours and the solvent removed under vacuum. To the residue is added IN HCl and the mixture extracted with ethyl ace¬ tate (20 ml) and the extract washed with saturated NaHCO-, brine and dried (Na SO.) . The solution is fil¬

15 tered through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is triturated with ether-hexane and filtered to give 0.47 g of a white solid: Mass Spectrum; El 433 (M+l) ; El-high reso¬ lution 432.1842.

20

Anal. Calc'd for ^C ₂₉ ^H ₂₄ ^N ₂ ° ₂ ^{: C} ' ⁸⁰ ' ^5? H,5.6 ^; N,6.5. Found: C,79.0; H,6.0; N,6.1.

A sample crystallized from ethyl acetate-hexane gives crystals, m.p. 198-203°C.

Example 3

25 3-Methyl-N-r4-r (5(6H)-phenanthridinyl)carbonyl1- phenyl1-2-thiophenecarboxamide To 0.193 g (1.2 mmol) of 3-methylthiophene- 2-carbonyl chloride in 3 ml of dichloromethane, cooled to 0°C, is added 209 μl of triethylamine. The mixture

" c is stirred and 0.30 g (1 mmol) of 5-(4-aminobenzoyl)- 5,6-dihydrophenanthridine is added. The mixture is stirred at room temperature overnight and then concen¬ trated under vacuum. To the residue is added 30 ml of ethyl acetate and the mixture washed with 2 ml each of water, 2N citric acid, IM sodium bicarbonate and brine. The organic layer is dried (Na ₂ S0 ₄ ) and the solvent removed to give 0.30 g of solid. The solid is chromatographed on thick layer silica gel plates with

ethyl acetate-hexane (1:1) as solvent to give 150 mg of product as a yellow foam.

Anal. Calc'd for C ₂₆ H ₂₀ N ₂ O ₂ S: 0,71.3; H,6.0; N,6.9; Ξ,7.9. Found: C,71.0; H,5.8; N,6.8; S,7.8.

Example 4 N-r4-r (2-Chlorodibenzrb.f1 r1.41oxazepin-10(11H) -yl) - carbonyl1phenyl1-2-methylbenzamide To a mixture of 0.229 g (1.0 mmol) of 2-

10 chloro-10,ll-dihydrodibenz[b, f] [1,4]oxazepine in 1.0 ml of pyridine under nitrogen is added 0.30 g (1.1 mmol) of 4-[ (2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred at room temperature for 1 hour, heated on a steam bath for 5 minutes and 8 ml of 2N HCl

ID added. The mixture is extracted with ethyl acetate and the extract washed three times with 1 ml of IN sodium bicarbonate. The organic layer is dried (MgSO ) and the solvent removed. The residue is crystallized from ethyl acetate-hexane to give 0.24 g of crystals, m.p. ²⁰ 207-208°C. Anal. Calc'd for C _g H ₂ N ₂ 0 ₃ Cl: C,71.9;

H,4.5; N,6.0; Cl,7.6. Found: C,71.6; H,4.6; N,5.9; Cl,7.4.

Example 5 2-Methyl-N-r4-r (5(6H)-phenanthridinyl) carbonyl1-

25 phenyl1benzamide To a solution of 0.181 g (1.0 mmol) of 5,6-dihydrophenanthridine in 2 ml of warm pyridine is added 0.273 g (1.0 mmol) of 4-[ (2-methylbenzoyl)amino]- benzoyl chloride. The mixture is stirred overnight at

30 room temperature, 1.2 ml of 2N HCl added. The solid which separates is filtered and washed with water. The solid is dissolved in dichloromethane and the solution washed with 2M sodium carbonate. The organic layer is concentrated and the residue chromatographed twice on

JD silica gel with ethyl acetate-hexane as solvent to give

7799 mmgg ιof crystals, m.p. 190-194 C. Mass Spec-FAB 419 (M+H) .

Anal. Calc'd for C ₂₈ H _2Q N ₂ 0 ₂ H ₂ 0: C,77.4; H,5.1; N,6.4. Found: C,77.5; H,5.1; N,6.4.

Example 6 N-r4-r (11.12-Dihvdrodibenzrb.f1azocin-5-(6H)-yl)- carbonyl1phenyl1-2-methylbenzamide To a mixture of 0.245 g (1 mmol) of 5,6,11,- 12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane

10 is added a solution of 0.281 g (1.1 mmol) of 4-[(2- methylbenzoyl)amino]benzoyl chloride in 4 ml of di¬ chloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3x2 ml) and IN sodium bicarbonate (3x2 ml) . The organic layer is

ID dried (MgS0 ₄ ) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH_C1_) . The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H).

Anal. Calc'd for ^C ₃₀ ^H 26 ^N 2°2 ^{: C} ' ⁸⁰ - ^7; H,5.9 ^; N,6.3.

20 Found: C,79.1; H,5.7; N,6.1.

Example 7 2 ,6-Dichloro-N-r4-r (5(6H)-phenanthridinyl)carbonyll- phenyl1benzamide A mixture of 300 mg (0.5 mmol) of 5-(4-amino-

25 benzoyl)-5,6-dihydrophenanthridine and 230 mg of (0.55 mmol) of 2,6-dichlorobenzoyl chloride in 1.2 ml of pyridine is heated (100 C) for 3 hr and then stirred at room temperature for 6 days. To the mixture is added 10 mg of 4-(dimethylamino)pyridine and the mixture

30 stirred for 22 days. To the mixture is added 6 ml of 2N HCl and the solid filtered and washed with 2N HCl, IN NaOH, H ₂ 0 to give 0.57 g of solid. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) to give 110 mg of solid. Recrystallization from CH ₂ Cl ₂ -diisopropyl ether to give 73 mg of white crystals, m.p. 230-235°C. Anal. Calc'd for C ₂₇ H ₁₈ C1 ₂ N ₂ 0 ₂ H ₂ 0: C,66.0; H,4.1; N,5.7; Cl,14.4. Found: C,65.5; H,4.1; N,5.6; Cl,14.6.

Example 8 3,4-Dichloro-N-r4-r (5(6H)-phenanthridinyl)carbonyll- phenyl1benzamide A mixture of 150 mg (0.5 mmol) of 5-(4-amino¬ benzoyl)-5,6-dihydrophenanthridine and 115 mg (0.55 mmol) of 3,4-dichlorobenzoyl chloride in l ml of pyri¬ dine is stirred at room temperature for 6 hours. To the mixture is added 6 ml of 2N HCl and the mixture stirred and filtered to give a solid. The solid is washed with water, 2N sodium carbonate and water to give 254 mg of crystals, m.p. 94-95°C. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) as solvent to give 107 mg of solid. Mass Spec (FAB) 473 (M+H).

Example 9 N-T4-r (6.ll-Dihydro-5H-dibenzrb.elazepin-5-yl)- carbonyllphenyl]-2.5-dichlorobenzamide

A mixture of 0.625 g (2 mmol) of 5-(4-amino- benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0,629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room tempera¬ ture for 3 hours. The mixture is washed with water, IN HCl, H ₂ 0, IM NaHC0 ₃ , brine and dried (Na ₂ S0 ₄ ) . The solvent is removed to give crystals. Recrystallization from hexane-CH-Cl- gives 0.16 g of white crystals, m.p. 203-231°C.

Anal. Calc'd for C ₂₈ H _2CJ C1 ₂ N ₂ 0 ₂ : C,69.0; H,4.1; N,5.8; Cl,14.6. Found: C,69.0; H,3.8; N,5.6; Cl,14.8.

Example 10 N-r4-r (6.11-Dihvdro-5H-dibenzrb,e1azepin-5-yl)- carbonyllphenyl1-2 ,4-dichlorobenzamide As described for Example 9, 0.111 g (1.1 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine in 8 ml of dichloromethane is reacted with 0.230 g of (1.1 mmol) of 2,4-dichlorobenzoyl chloride. The product is recrystallized from hexane-dichloro¬

10 methane to give 0.24 g of crystals, m.p. 212-215°C.

Anal. Calc'd for ^c ι ₈ ^H ₂ o ^Cl 2 ^N 2°2 ^H 2 ^{0: C} ' ⁶⁶ * ^{5; H} / ⁴ - ^4" N,5.5. Found: C,66.8; H,4.0; N,5.5.

Example 11 N-T4-r (6. ll-Dihvdro-5H-dibenzrb.e1azepin-5-yl)- 5 carbonyl]phenyl1-2.3-dimethylbenzamide

As described for Example 9, 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.506 g (3.0 mmol) of 2,3-di- methylbenzoyl chloride in dichloromethane. The product 0 is recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 138-142°C. Anal. Calc'd for C _3Q H ₂₆ N ₂ 0 ₂ : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.

Example 12 5 N-T4-T (6. ll-Dihvdro-5H-dibenzrb.e]azepin-5-yl) - carbonyl1phenyl1-2.5-dimethylbenzamide As described for Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,5-dimethylbenzoyl chloride in 10 ml of dichloro¬ methane. The product is recrystallized from dichloro- methane-hexane to give 0.43 g of crystals, m.p. 2 21133--221166°°CC.. AAnnaall.. CCaallcc''dd ffoorr C ^C ₃₃₍₀₎ H ^H ₂ 26N ^N 2. °2 ^{: C} ' ⁸⁰ * ^7? H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.

-3D

Example 13 N-r4-r (6.ll-Dihvdro-5H-dibenzTb.elazepin-5-yl)- carbonyl1phenyl]-2.4-dimethγlbenzamide

As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.303 g (1.8 mmol) of 2,4-di- methylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from hexane-dichloro¬ methane to give 0.38 g of crystals, m.p. 197-199°C. Anal. Calc'd for C _3(} H ₂₆ N ₂ 0 ₂ 1/2 H ₂ 0: C,79.1; H,6.0; N,6.2. Found: C,79.0; H,5.8; N,6.2.

Example 14 N-r4-r (6.11-Dihvdro-5H-dibenzrb.e1azepin-5-yl)- carbonyllphenyl1-2-chlorobenzamide As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.315 g (1.8 mmol) of 2-chloro- benzoyl chloride in dichloromethane. The product is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give a solid. Recrystallization from hexane-dichloromethane gives 100 mg of crystals, m.p. 110-115°C. Anal. Calc'd for

^C ₂₈ ^H 21 ^C1N 2°2 ^1/ ' ^{2 H} 2° ^{: C} ' ⁷² - ⁸ '" H, ⁴ . ^{8; N} , ⁶ . ^{1; C} l, ⁷ . ⁷ . Found: C,72.6; H,4.5; N,5.8; Cl,8.7.

Example 15 N-r4-r (6.ll-Dihvdro-5H-dibenzTb.e1azepin-5-yl)- carbonyl]phenyl]-2-methylbenzamide As described for Example 9, 0.942 g (3 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.52 g (3.3 mmol) of 2-methyl- benzoyl chloride in 20 ml of dichloromethane. The pro¬ duct is triturated with hexane-ethyl acetate to give 1.0 g of yellow crystals, m.p. 198-203°C.

Example 16 2-Chloro-N-r4-r(6.ll-dihvdro-5H-dibenzrb,e]azepin- 5-yl)carbonyl1phenyl1benzeneacetamide A mixture of 0.471 g (1.5 mmol) of 5-(4- aminobenzoy1)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0.340 g (1.8 mmol) of 2-chlorσphenylacetyl chloride, 0.20 g of triethylamine and 9 mg of 4-(dimethylamino)- pyridine in 10 ml of dichloromethane is stirred at room

10 temperature for 48 hours. An additional 0.27 g of 2- chlorophenylacetyl chloride is added and the mixture stirred at room temperature for 2.5 hr. The mixture is washed with IN HCl, H ₂ 0, IM NaHC0 ₃ , brine and dried (Na_SO ) . The solvent is removed and the solid re¬ 5 crystallized from dichloromethane to give 0.27 g of crystals, m.p. 191-194°C. Anal. Calc'd for

^C 2 ₉ ^H ₂₃ ^C1N 2° ₂ ^{: c} - ⁷⁴ ' ⁶ ' ^* H,5.0 ^; N,6.0 ^; Cl,7.6. Found: C,74.4; H,4.9; N,5.9; Cl,7.8.

Example 17 0 N-f4-r (6. ll-Dihvdro-5H-dibenzfb,e1azepin-5-yl>- carbonyllPhenvπ-3-pyridinecarboxamide

A mixture of 0.628 g (2 mmol) of 5-(4-amino- benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0.551 g (3 mmol) of nicotinoyl chloride, hydrochloride, 0.606 g (6 5 mmol) of triethylamine and 15 mg of 4-(dimethylamino)- pyridine in 17 ml of dichloromethane is refluxed for 7 hours. The mixture is washed with H-O, 2N citric acid, H ₂ 0, IN NaHC0 ₃ , brine and dried (Na ₂ S0 ₄ ) . The solvent is removed and the solid recrystallized from hexane-di¬ 0 chloromethane to give 0.12 g of crystals, m.p. 217-220°C. Anal Calc'd for C _2? H ₂₁ N ₃ 0 ₂ H ₂ 0: C,74.1; H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.

Example 18 N-T4-r (6.ll-Dihvdro-5H-dibenzTb.elazepin-5-yl)-

--o carbonyl]phenyl]-3-methyl-2-thiophenecarboxamide

As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.177 g (1.1 mmol) of 3-methyl-2-

thiophenecarbonyl chloride in 5 ml of dichloromethane and 0.111 g of triethylamine for 2 hours at room tem¬ perature to give crystals. Recrystallization from di- chloromethane-hexane gives 0.235 g of crystals, m.p. 201-204°C.

Example 19 N-f4-f(6.ll-Dihydro-5H-dibenzTb.e1azepine-5-yl)- carbonyl1phenyl1-3-(trifluoromethyl)benzamide

As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]aze¬ pine is reacted with 0.302 g (1.4 mmol) of 3-(tri¬ fluoromethyl)benzoyl chloride in 9 ml and 0.145 g (1.4 mmol) of triethylamine for 1.5 hour at room tempera¬ ture. The product is recrystallized from ethyl ace¬ tate-hexane to give 0.14 g of crystals, m.p. 190-191 C.

Example 20 N-(4-r(6.11-Dihydro-5H-dibenzrb.e1azepin-5-yl)- carbonyl]phenyl1-4-(trifluoromethyl)benzamide

As described for Example 9, 0.314 g of 5-(4- aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine is reacted with 0.269 g (1.29 mmol) of 4-trifluoromethyl- benzoyl chloride and 0.130 g (1.29 mmol) of triethyl¬ amine in 9 ml of dichloromethane for 1.5 hours at room temperature. The product is triturated with ethyl ace¬ tate-hexane to give 0.43 g of crystals, m.p. 205-207°C.

Example 21 N-r4-r(6.ll-Dihvdro-5H-dibenzrb.e1azepin-5-yl)- carbonyllphenvπ-2.4-difluorobenzamide As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine is reacted with 0.194 g (1.1 mmol) of 2,4-difluorobenzoyl chloride and 0.111 g (l.l mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.37 g of crystals, m.p. 215-217°C.

Example 22 N-r4-r6. ll-Dihydro-ll-methyl-5H-dibenz rb,e1azepin-5- yl)carbonyl1phenyl]-2-methylbenzamide A sample of 6,ll-dihydro-ll-methyl-5H-dibenz-

[b,e]azepine is synthesized as described in J. Chem. Soc. Perkin I, 1279 (1976). A 0.210 g (1 mmol) sample is added to a stirred and cooled mixture of 0.328 g

(1.2 mmol) of 4-[ (2-methylbenzoyl)amino]benzoyl chlo¬

10 ride, 279 mL (2.0 mmol) of triethylamine and 26 mg of 4-(dimethylamino)pyridine in 4 ml of dichloromethane. The solution is stirred at room temperature overnight. An additional 0.328 g of 4-[ (2-methylbenzoyl) amino]ben¬ zoyl chloride and 150 μl of triethylamine is added and 5 the mixture stirred at room temperature for 6 hours. The volatiles are removed and 30 ml of ethyl acetate is added. The mixture is washed with 12 ml each of 2N citric acid, H_0, IM NaHCO , brine and dried (Na SO ) . The solvent is removed and the residue chromatographed 0 on thick layer silica gel plates with hexane-ethyl ace¬ tate (2:1) as solvent to give 0.13 g of product as a white solid. Anal. Calc'd for C_-H- _c N_0_ 1/4 H.O: C,79.9; H,5.9; N,6.2. Found: C,79.4; H,5.5; N,5.9.

Example 23 5 N-r4-r r2-r (Dimethylamino) sulfonyl1dibenzTb. f1 r1.41- oxazepin-10(11H)-yl1carbonyl]phenyl]-2-methylbenzamide

A solution of 0.22 g of 10,ll-dihydro-N,N-di- methyl-10-(4-nitrobenzoyl)dibenz[b,f] [1, 4]oxazepine-2- sulfonamide, 50 mg of 10% Pd/C under an atmosphere of 0 H_ is shaken in a Parr hydrogenator for 5 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with ethyl acetate. The filtrate is concentrated to 5_a, 6 ml and 0.83 μl of triethylamine added followed by the addition of 0.773 g of o-tolyl

-JO chloride. The mixture is stirred overnight and then washed with H ₂ 0, 2N HCl, IM Na ₂ C0 ₃ and brine. The fil¬ trate is filtered through a thin pad of hydrous magne¬ sium silicate and the pad washed with three volumes of

ethyl acetate. The filtrate is concentrated under vac¬ uum and the residual oil chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) to give 83 mg of a foam. Mass Spectrum (FAB) 540(M+H).

Example 24 N-f4-f (6.ll-Dihydro-5H-dibenzrb,elazepjn-5-yl)- carbonyl1phenyl1benzamide As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine is reacted with 0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) of triethyl¬ amine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from di- chloromethane-hexane to give 0.19 g of crystals, m.p.

219-221°C. Anal. Calc'd for ^C ₂₈ ^H 2 ₂ ^N ₂ ° ₂ ^{: C} ' ⁸⁰ - ^{4; H} ' ⁵ - ³ ' ^* N,6.7. Found: C,79.6; H,5.5; N,6.7.

Example 25 N-f4-r (6.ll-Dihvdro-5H-dibenzfb,e1azepin-5-yl)- carbonyl1phenyl1-2-(trifluoromethoxy)benzamide As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine is reacted with 0.247 g (l.l mmol) of 2-(trifluoromethoxy)benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane at room temperature for 1.5 hours. The product is tri¬ turated with dichloromethane-hexane to give 0.35 g of crystals, m.p. 232-235°C.

The following compounds are prepared as des¬ cribed for in Example 6.

Example 26

N-r4-r(11.12-Dihvdrodibenzrb.f1azocin-5(6rf)-yl>- carbonyl1phenyl]-2-chlorobenzamide

Example 27

N-r4-r (11.12-Dihvdrodibenzrb. f1azocin-5(6H)-yl)- carbonyllphenyll-2-fluorobenzamide

Example 28

N-T4-T (11.12-Dihvdrodibenzrb,f1azocin-5(6H)-yl)- carbonyl]phenyl1-2-methoxybenzamide

Example 29

N-r4-r (11.12-Dihvdrodibenz(b.f1azocin-5(6H)-yl)- carbonyl]phenyl1-2.3-dimethylbenzamide

Exanple 30

N-r4-r (11.12-Dihvdrodibenzrb,f1azocin-5(6H)-yl)- carbonyllphenyl1-2.5-dimethylbenzamide

Example 31

N-r4-r (11.12-Dihvdrodibenzrb.f1azocin-5(6H)-yl)- carbonyl]phenyl1-2,4-dichlorobenzamide

Example 32

N-T4-r (11.12-Dihvdrodibenzrb.f1azocin-5(6H)-yl)- carbonyl]phenyl1-2.3-dichlorobenzamide

Example 33

N-T4-r (11.12-Dihvdrodibenzrb.f1azocin-5(6H)-yl)- carbonyl]phenyl1-2-methyl-5-fluorobenzamide

Example 34 N-r4-r (11.12-Dihvdrodibenzrb■f1azocin-5(6H)-yl)- carbonyllPhenyl1-2-chlorophenylacetamide The following compounds are prepared as described in Example 3.

Example 35 N-r4-r(5(6H)-Phenanthridinyl)carbonyl1phenyl1-2- chlorobenzamide Example 36 N-r4-r(5(6H)-Phenanthridinyl)carbonyl]phenyl]-2- fluorobenzamide Example 37 N-r4-r (5(6H)-Phenanthridinyl)carbonyl]phenyl1-2- methoxybenzamide

Example 38

N-r4-r (5(6H)-Phenanthridinyl)carbonyl1phenyl1-2.3- dimethylbenzamide

Example 39 N-r4-r (5(6H)-Phenanthridinyl)carbonyl1phenyl1-2,5- dimethylbenzamide Example 40 N-[4-[ (5(6H)-Phenanthridinyl)carbonyl1phenyl1-2,4- dichlorobenzamide Example 41 N-(4-r (5(6H)-Phenanthridinyl)carbonyllphenyl1-2.3- dichlorobenzamide

Example 42

N-[4-r (5(6H)-Phenanthridinyl)carbonyl]pheny11-2- methyl-5-fluorobenzamide

Example 43

N-r4-f(5(6H)-Phenanthridinyl)carbonyl1phenyl]-2- chlorophenylacetamide

Example 44

N-r4-r(5(6H)-Phenanthridinyl)carbonyllphenyll-2- methylphenylacetamide

Example 45

N-r4-f (5(6H)-Phenanthridinyl)carbonyllphenyl1-2- methyl-4-chlorobenzamide

Example 46

N-f4-r(5(6H)-Phenanthridinyl)carbonyl]phenyl1-2- chloro-4-methylbenzamide

Example 47

N-r4-r (5(6H)-Phenanthridinyl)carbonyl1phenyl1-2.6- dimethylbenzamide Example 48 N-r4-r (5(6H)-Phenanthridinyl)carbonyl]phenyl1-2- (methylthio)benzamide Example 49 N-r4-r(5(6H)-Phenanthridinyl)carbonyl1phenyl]-2- methyl-3-furanecarboxamide The following compounds are prepared as described in Example 4.

Example 50

N-r4-r (2-Chlorodibenzrb.firi.41oxazepin-lθ(llH)-yl) carbonyl1Phenyl1-2-chlorobenzamide

Example 51

N-T4-r (2-Chlorodibenzrb.fl Tl,41oxazepin-lθ(HH)-yl)■ carbonyl1phenyl1-2-fluorobenzamide

Example 52

N-r4-r (2-Chlorodibenzrb.f1 r1.41oxazepin-10(IIH)-yl) ^■ carbonyl1phenyl1-2-methoxybenzamide

Example 53

N-r4-r(2-Chlorodibenzrb.firi.41oxazepin-lθfllH)-yl)- carbonyllphenyl1-2.3-dimethylbenzamide

Example 54

N-T4-T (2-Chlorodibenzrb.fl ri,41oxazepin-10(IIH) -yl)- carbonyl]phenyl]-2.5-dimethylbenzamide

Example 55

N-r4-r (2-Chlorodibenzrb.f1 r1.41oxazepin-lθ(HH)-yl)- carbonyl]phenyl]-2.4-dichlorobenzamide

Example 56

N-T4-r (Dibenzrb.fl ri.41oxazepin-10(llH) -yl) - carbonyl1phenyl1-2.3-dichlorobenzamide

Example 57

N-T4-T (Dibenzrb.fi ri.41oxazepin-10(llH) -yl)- carbonyl1phenyl1-2-chlorophenylacetamide

Example 58

N-T4-r (Dibenzrb.fi Tl.41oxazepin-10(llH)-yl)- carbonyllphenyl1-2-methyl-3-thiophenecarboxamide

Example 59

N-T4-T (Dibenzrb.fi ri.41oxazepin-10(llH)-yl)- carbonyl]phenyl1-2-methylphenylacetamide

Example 60

N-r4-r (Dibenzrb.f1 Tl.41oxazepin-10(IIH)-yl)- carbonyl1phenyl1-2-methyl-4-chlorobenzamide

Example 61 N-T4-r (6. ll-Dihvdro-5H-dibenzrb.elazepin-5-yl)- carbonyl]phenyl1-2-(methylthio)benzamide

As described for Example 9, a mixture of 0.242 g of 2-(methylthio)benzoyl chloride (m.p. 6l-64°C) , 0.134 g of triethylamine and 0.314 g of 5- (4-aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine in 10 ml of dichloromethane is stirred for 2.5 hours and worked up to give a solid. Trituration with ethyl acetate-hexane gives 0.150 g of crystals, m.p. 222-225°C.

Example 62 N-r4-r (Dibenzrb.fi ri.41thiazepin-10(HH)yl)carbonyl1- phenyl1-2-methylbenzamide

As described for in Reference Example 12, a mixture of 3.3 g of 10,ll-dihydro-ll-oxodibenz[b,f] [1,4]thiazepine, 25 ml of tetrahydrofuran, 4.0 ml of 10 molar borane-dimethylsulfide (2.67 equivalents) in tetrahydrofuran is stirred at room temperature 18 hours to give, after work-up, 10,ll-dihydrodibenz[b,f] [1,4] thiazepine as white crystals, m.p. 145-148°C. The pre¬ ceding compound (3.5 g) is suspended in 25 ml of dichloromethane and a solution of 1.8 g of 4-[(2- methylbenzoyl)amino]benzoyl chloride in 50 ml of di¬ chloromethane added. To the stirred mixture is added 4 ml of triethylamine and 0.2 g of 4-(dimethylamino) pyridine. The mixture is stirred at room temperature for 20 hours. The mixture is filtered and the filtrate concentrated. The residue is purified by chromato¬ graphy on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give 2.2 g of yellow crystals. A sample (0.80 g) is further purified by thick layer chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give 0.50 g of crystals, 76°-78°C.

The following compounds are prepared as described in Example 62.

Example 63 N-r4-r (Dibenzrb.fi ri.41thiazepin-10(llH)yl)carbonyll- phenvn-2-chlσrobenzamide. m.p. 116°-119°C

Example 64 N-T4-r (Dibenzrb.f1 r1.41thiazepin-lO(IIH)yl)carbonyl1- phenyl1-2.5-dichlorobenzamide Example 65 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2,4-dichlorobenzamide. m.p. 112°-115°C

Example 66 N-T4-r (Dibenzrb.fi ri.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2-fluorobenzamide Example 67 N-r4-r (Dibenzrb.fi fl.41thiazepin-10(HH)yl)carbonyl1- phenyl]-2-chloro-4-methylbenzamide Example 68 N-r4-r (Dibenzrb.f1 r1■41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-methyl-4-chlorobenzamide Example 69 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2.4-dimethylbenzamide Example 70 N-r4-r (Dibenzrb.f1 T1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2.3-dimethylbenzamide Example 71 N-r4-( (DibenzTb.fin.41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-methoxybenzamide Example 72 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2-(trifluoromethoxy)benzamide Example 73 N-r4-r(Dibenzrb.firi.41thiazepin-10(llH)yl)carbonyl]- phenyl1-2.4-dimethoxybenzamide Example 74 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2.6-dimethoxybenzamide Example 75 N-T4-r (Dibenzrb.fi ri.41thiazepin-10(ilH)yl)carbonyll- phenγl1-benzamide

Example 76 N-r4-r (DibenzTb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1 ^■ phenyl]-2.6-dichlorobenzamide Example 77 N-T4-r(Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1■ phenyl]-2.6-dimethylbenzamide Example 78 N-r4-r (DibenzTb.fi ri,41thiazepin-10(IIH)yl)carbonyll- phenyl1-2-methylthiobenzamide Example 79 N-T4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-2-methyl-3-thiophenecarboxamide Example 80 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-3-methyl-2-thiophenecarboxamide Example 81 N-r4-r (Dibenzrb,f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-methyl-3-furanecarboxamide Example 82 N-(4-r (Dibenzrb.f1 f1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-3-methyl-2-furanecarboxamide Example 83 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl1-phenylacetamide Example 84 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-chlorophenylacetamide Example 85 N-r4-r(Dibenzrb.f1 r1,41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-methylphenylacetamide Example 86 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl]- phenyl1-2-thiopheneacetamide Example 87 N-T4-r (Dibenzrb.fi ri,41thiazepin-10(HH)yl)carbonyll- phenyl1-2-furaneacetamide

Example 88 N-T4-r (Dibenzrb.f1 Tl.41thiazepin-10(IIH)yl)carbonyl1- phenyl]-2-methyl-3-thiopheneacetamide Example 89 N-r4-r (Dibenzrb.f1 r1.41thiazepin-10(IIH)yl)carbonyl1- 3-chlorophenyl1-2-methylbenzamide Example 90 N-T4-r (Dibenzrb.fi Tl,41thiazepin-10(IIH)yl)carbonyl1- 2-methylphenyl]-2-methylbenzamide Example 91 N-T4-r (6,7-Dihvdro-5H-dibenzrb,dlazepin-5-yl)- carbonyl1phenyl1-2-methylbenzamide As described for Example 2, 1 mmol of 4- [(2-methylbenzoyl)amino]benzoyl chloride, 1 mmol of 5H-dibenz[b,d]azepine and 2 mmol of triethylamine are stirred at room temperature for 5 hours to give the product as a pale yellow solid.

Example 92 N-r4-T(6,7-Dihvdrσ-5H-dibenzTb.diazepin-5-yl)- carbonyl]phenyl]-2-methylbenzamide A mixture of 0.10 g of 5-(4-aminobenzoyl)- 6,7-dihydro-5H-dibenz[b,d]azepine, 0.10 g of triethyl¬ amine in 1 ml of dichloromethane is stirred at room temperature for 6 hours. The mixture is diluted with 6 ml of ethyl acetate and the solution washed with IN HCl, IN NaOH, brine and dried (Na,S0 ₄ ) . The solvent is removed and the solid purified by chromatography on thick layer silica gel plates with the solvent ethyl acetate-hexane (1:1) to give 90 mg of a pale yellow solid.

The following compounds are prepared as described in Example 92.

Example 93

N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyllphenyl1-2-chlorobenzamide

Example 94

N-r4-[ (6.7-Dihvdro-5H-dibenzTb,d1azepin-5-yl) - carbonyl1phenyl1-2.5-dichlorobenzamide

Example 95

N-r4-r (6.7-Dihvdro-5H-dibenz rb.d1azepin-5-yl) - carbonyl1Phenyl1-2.4-dichlorobenzamide

Example 96

N-r4-r (6.7-Dihvdro-5H-dibenz Tb.di azepin-5-yl) - carbonyl]phenyl]-2-fluorobenzamide

Example 97

N-r4-r (6.7-Dihvdro-5H-dibenzTb,dlazepjn-5-yl) - carbonyllphenyl1-2-chloro-4-methylbenzamide

Example 98 N-r4-r (6.7-Dihvdro-5H-dibenz rb,diazepin-5-yl) - carbonyl1phenyl1-2-methyl-4-chlorobenzamide

Example 99 N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl) - carbonyllphenyl1-2.4-diroethylbenzamide Example 100 N-r4-r (6.7-Dihvdro-5H-dibenz rb.d1azepin-5-yl ) - carbonyl]phenyl1-2.3-dimethylbenzamide Example 101 N-T4-r (6.7-Dihvdro-5H-dibenzrb.dlazepin-5-yl) - carbonyl]phenyl1-2-methoxybenzamide Example 102 N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl) - carbonyl]phenyl]-2-(trifluoromethoxy)benzamide

Example 103 N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl) - carbonyl1phenyl1-2.4-dimethoxybenzamide Example 104 N-r4-r (6.7-Dihvdro-5H-dibenzrb.dlazepin-5-yl) - carbonyl]phenyl]-2.6-dimethoxybenzamide Example 105 N-r4-r (6, 7-Dihvdro-5H-dibenzrb.d1azepin-5-yl ) - carbonyl]Phenyl1benzamide

Example 106 N-r4-f (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyllPhenyl1-2,6-dichlσrobenzamide Example 107 N-r4-r(6.7-Dihvdro-5H-dibenzrb.dlazepin-5-yl)- carbonyl1Phenyl1-2.6-dimethylbenzamide Example 108 N-r4-r (6.7-Dihvdro-5H-dibenz(b.d1azepin-5-yl)- carbonyllphenyll-2-methylthiobenzamide Example 109 N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyl]phenyl]-2-methyl-3-thiophenecarboxamide

Example 110 N-r4-f (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyllphenyl)-3-methyl-2-thiophenecarboxamide

Example 111 N-r4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyl]phenyl1-2-methyl-3-furanecarboxamide

Example 112 N-T4-r (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyllPhenyπ-3-methvI-2-furanecarboxamide

Example 113 N-r4-r (6.7-Dihvdro-5H-dibeπzTb.dlazepin-5-yl)- carbonyllphenyl]phenylacetamide Example 114 N-r4-T (6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyllPhenyπ-2-chlorophenylacetamide Example 115 N-r4-r(6.7-Dihvdro-5H-dibenzTb.dlazepin-5-yl)- carbonyl1phenyl1-2-methylphenylacetamide Example 116 N-f4-T (6.7-Dihydro-5H-dibenzTb.d]azepin-5-yl)- carbonyl1phenyl1thiophene-2-carboxamide Example Ul N-r4-T(6.7-Dihvdro-5H-dibenzrb.dlazepin-5-yl)- carbonyl]phenyl1-2-methyl-3-thiopheneacetamide

Example 118 N-r4-r(6.7-Dihvdro-5H-dibenzrb.d1azepin-5-yl)- carbonyl1phenyl1-2-methyl-3-furaneacetamide

Example 119 N-f4-r (6.ll-Dihvdro-5H-dibenzrb,e1azepin-5-yl)- carbonyl]phenyl1-2-methyl-3-furanecarboxamide As described for Example 9, 2-methyl-3- furanecarbonyl chloride is reacted with 5-(4-amino¬ benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane- hexane gives crystals, m.p. 202 -204 C

Example 120

N-(4-f(6. ll-Dihvdro-5H-dibenzrb,e]azepin-5-yl)- carbonyl1Phenyl1-3-chlorobenzo \b1thiophene-2- carboxamide As described for Example 9, 3-chlorobenzo[b]- thiophene-2-carbonyl chloride is reacted with 5-(4- aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloro- methane-hexane gives crystals, m.p. 252°-254°c.

N-r4-f(6.ll-Dihydro-5H-dibenzrb.e]azepin-5-yl)- carbonyl1-3-methylphenyl1-2-methylbenzamide

As described for Example 9, 2-methylbenzoyl chloride is reacted with 5-(4-amino-3-methylbenzoyl)- 6,ll-dihydro-5H-dibenz[b,e]azepine to give the product as crystals, m.p. 112°-114°C.

Example 122 6,ll-Dihydro-5-r4-rrr (2-methylPhenyl)aminolcarbonyl]- amino1benzoyl1-5H-dibenz(b.e1azepine A mixture of 0.314 g of 5-(4-aminobenzoyl)- 6,ll-dihydro-5H-dibenz[b,e]azepine and 0.173 g of o- tolylisocyanate in 15 ml of tetrahydrofuran is refluxed overnight. An additional 84 mg of o-tolylisocyanate is added and the mixture refluxed for three hours. The solvent is removed, water added to the residue and the residue extracted with dichloromethane. The extract is washed with IN HCl, H ₂ 0, IM NaHC0 ₃ , brine and dried

(Na SO ) . The solution is filtered through a thin pad of hydrous magnesium silicate. The pad is washed with dichloromethane. The filtrate (140 ml) is discarded. The filter pad is washed with acetone to give 0.370 g of product. Trituration with dichloromethane-hexane gives 0.186 g of crystals, m.p. 188°-190°C

Example 123 4-r (6.ll-Dihvdro-5H-dibenzrb,e]azepin-5-yl) - carbonyl1-N-f2-methylphenyl)benzamide To a mixture of 0.362 g of 4-[ (6,11-dihydro- 5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride and 0.101 g of triethylamine in 5 ml of dichloromethane is added a solution of 0.129 g of 2-methylaniline in 3 ml of dichloromethane. The mixture is stirred 1.5 hr at room temperature and then washed with H_0 IN HCl, IM NaHCO_, brine and dried (Na SO ). The solvent is removed to give a solid. The solid is dissolved in dichloromethane and filtered through a thin pad of hydrous magnesium silicate with dichloromethane as eluent to give 0.025 g of crystals, m.p. 214°-216°C.

Example 124 4-r (6.ll-Dihvdro-5H-dibenzrb,e1azepin-5-yl) - carbonyl]-N-(2.3-dimethylphenyl)benzamide

As described for Example 123, a mixture of 0.361 g of 4-[ (6,ll-dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl]benzoyl chloride, 0.101 g of triethylamine and 0.145 g of 2,3-dimethylaniline is stirred for 1.5 hr. and worked up to give 0.44 g of crystals, m.p.

248°-251°C.

The following compounds are prepared as described in Example 123.

Example 125 4-[ (6, ll-Dihydro-5H-dibenz[b,e]azepin-5-y1)carbonyl]-

N-(2-chlorophenyl)benzamide

Example 126 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl] N-(2.4-dichlorophenyl)benzamide

Example 127 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-y1)carbonyl]■

N-(2.5-dichlorophenyl)benzamide Example 128 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-

N-(2.4-dimethylphenyl)benzamide

Example 129

4-[ (6,ll-Dihydro-52-dibenz[b,e]azepin-5-yl)carbonyl]- N-(2.5-dimethylphenyl)benzamide

Example 130 4-[ (6,ll-Dihydro-5fi-dibenz[b,e]azepin-5-yl)carbonyl]-

N-(2-methoxyphenyl)benzamide Example 131 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-

N-(2.4-dimethoxyphenyl)benzamide Example 132 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]- N-(3-chloro-4-methoxyphenyl)benzamide

Example 133 4-[ (6,ll-Dihydro-5H.-dibenz[b,e]azepin-5-yl)carbonyl]-

N-(5-chloro-2-methoxyphenyl)benzamide Example 134 4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-

N-(3-chlorophenyl)benzamide

Example 135

4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]- N-(2-chloro-5-methoxyphenyl)benzamide

Example 136 N- [ 4- [ (2-Chloro-6 , ll-dihydro-5H-dibenz [b, e] azepin-5- yl)carbonyllphenyl-2-methylbenzamide

A mixture of 0.349 g of 2-chloro-5-(4-amino- benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.201 g of 2-methylbenzoyl chloride in 13 ml of dichloromethane is stirred at room tem- perature for 3 hours. The mixture is poured into water and the organic layer separated. The organic layer is washed with IN HCl, H ₂ 0, IN NaHC0 ₃ , brine and dried (Na_SO ) . The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the solid crystallized from dichloromethane-hexane to give 0.32 g of crystals, m.p. 187°-189°C.

Example 137 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl12,4-dichlorobenzamide

As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro- 5H-dibenz[b,e)azepine, 0.131 g of triethylamine and 0.272 g of 2,4-dichlorobenzoyl chloride in 13 ml of di- chloromethane is stirred at room temperature for 3 hours. Work-up gives a solid which is crystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 199°-201°C.

Example 138 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]2,3-dimethylbenzamide

As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,ll-dihydro-

5H-dibenz[b,e]azepine, 0.131 g of triethylamine and

0.219 g of 2,3-dιmethylbenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 18 hours. Work-up gives a solid which is recrystallized

from dichloromethane-hexane to give 0.38 g of crystals

191°-193°C.

Example 139 5

2-Chloro-6. ll-dihvdro-5-r4-r r r (2-methylphenyl)aminol- carbonyl]amino]benzoyl]-5H-dibenz[b,e]azepine

As described for Example 122, a mixture of 0.348 g of 2-chloro-5-(4-aminobenzoyl)-6, 11-dihydro- o 5H-dibenz[b,e]azepine and 0.175 g of o-tolylisocyanate in 15 ml of tetrahydrofuran is refluxed overnight and worked-up to give the product as a solid.

The following compounds are prepared as described in Example 136. Example 140

N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-2-chlorobenzamide Example 141 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- ; ; yl)carbonyllphenyl1-2.5-dιchlorobenzamide Example 142 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl) carbonyl1phenyl1-2-chloro-4-methylbenzamide Example 143

N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-2-methyl-4-chlorobenzamide

Example 144 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2.4-dimethylbenzamide Example 145 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2.5-dimethylbenzamide Example 146

N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-methoxybenzamide

Example 147 N-[4-[(2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-trifluoromethoxybenzamide

Example 148 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-2.4-dimethoxybenzamide

Example 14? N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e)azepin-5- yl)carbonyl1phenyl1-2,6-dimethoxybenzamide

Example 150 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-2,6-dichlorobenzamide

Example 151 N-[4-[ (2-Chloro-6,ll-dihydro-5H _. -dibenz[b,e]azepin-5- yl)carbonyllphenvπ-2.6-dimethylbenzamide Example 152 N-[4-[(2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllPhenyll-2-methylthiobenzamide Example 153 N-[4-[ (2-Chloro-6,ll-dihydro-5H.-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-2-methylthiophene-3-carboxamide

Example 154 N-[4-[ (2-Chloro-6,ll-dihydro-5H,-dibenz[b,e]azepin-5- y1)carbonyl1phenyl1-3-methylthiophene-2-carboxamide

Example 155 N-[4-[ (2-Chloro-6,ll-dihydro-5H.-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-2-methylfurane-3-carboxamide

Example 156 N-[4-[(2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1Phenyl]-3-methylfurane-2-carboxamide

Example 157 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllPhenyl]-2-chlorophenylacetamide

Example 158 N-[4-[(2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-methylphenylacetamide

Example 159 N-[4-[ (2-Chloro-6,ll-dihydro-5H.-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-methoxy-4-chlorobenzamide

Example 160 N-[4-[ (2-Chloro-6,ll-dihydro-5H,-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-2-trifluorobenzamide Example 161 N-[4-[ (2-Chlσro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-methoxyphenylacetaτnide

Example 162 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1cyclohexylcarboxamide Example 163 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-3-cvclohexenecarboxamide

Example 164 N-[4-[ (2-Chloro-6,ll-dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1cvclohexylacetamide

Example 165 N-[4-[(6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-2-methoxy-4-chlorobenzamide As described for Example 9, a mixture of 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,ll-dihydro-5H- dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chloro- benzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chloro- benzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product

(crystallized from dichloromethane-hexane) m.p. 237°-239°C.

Example 166 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]-2-trifluoromethylbenzamide As described for Example 9, a mixture of 0.377 g (1.44 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro- o 5H-dibenz[b,e]azepine, 0.15 g of triethylamine and 0.300 g (1.44 mmol) of 2-trifluoromethylbenzoyl chloride is stirred at room temperature for 2 hours and then washed with IN HCl IM NaHCO , brine and dried (Na SO ) . The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give a solid. Crystallization from dichloromethane- hexane gives 0.41 g of crystals, m.p. 191°-193°C.

Example 167 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-N-methyl-2-methylbenzamide

A mixture of 0.291 g of 6,ll-dihydro-5H-di- benz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methyl- benzoyl)amino]benzoyl chloride and 0.182 g of tri¬ ethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1 N HCl water, IM NaHCO , brine and dried (Na ₂ S0 ₄ ) . The solution is passed through a thin pad of hydrous 0 magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170°C. As described for Example 167, but substi¬ tuting the appropriate aroyl chloride, the following compounds are prepared. 5

Example 168 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonylIphenyl1-N-methyl-2-chlorobenzamide

Example 169 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methyl-2.5-dichlorobenzamide

Example 170 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl]-N-methyl-2.4-dichlorobenzamide

Example 171 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]-N-methyl-2-fluorobenzamide

Example 172 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methyl-2-chloro-4-methylbenzamide

Example 173 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]-N-methyl-2-methyl-4-chlorobenzamide

Example 174 N-[4-[ (6,ll-Dihydro-5H.-dibenz[b,e]azepin-5- yl)carbonylIphenyl1-N-methyl-2.4-dimethylbenzamide

Example 175 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methvi-2.3-diroethylbenzaroide

Example 176 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methyl-2-methoxybenzamide

Example 177 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-N-methyl-2-trifluoromethoxy- benzamide

Example 178 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methyl-2,4-dimethoxybenzamide

Example 179 N-[4-[(6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl ) carbonvπphenyl 1 -N-methyl-2-methoxy-4-chloro- benzamide Example 180

N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]-N-methyl-2-methylthiobenzamide

Example 181 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl1phenyl1-N-methyl-2-methylthiophene-3- carboxamide

Example 182

N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-N-methyl-3-methyl-2-thiophene- carboxamide

Example 183

N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl]-N-methyl-2-methyl-3-furane- carboxamide

Example 184

N-[4-[(6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyllphenyl1-N-methyl-3-methyl-2-furane- carboxamide

Example 185

N-[4-[(6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-N-methylphenylacetamide

Example 186 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e)azepin-5- yl ) carbonyl ] ^p henvn -N-methyl-2-chlorophenylacetamide

Example 187 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl) carbonylIphenyl1-N-methyl-2-methoxyphenylacetamide

Example 188 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-N-methyl-2-methyIphenylacetamide

Example 189 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonylIphenyl1-N-methyl-2-methyl-3-thiophene- acetamide Example 190

N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- y1)carbonyl]phenyl]-N-methyl-2-trifluoromethylacetamide

Example 191 N-[4-[ (6,ll-Dihydro-5H.-dibenz[b,e]azepin-5- yl)carbonyl1phenyl]-N-methylσvclohexanecarboxamide Example 192

N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5- yl)carbonyl]phenyl1-N-methyl-3-cvclohexanecarboxamide

Example 193

N-[4-[ (5,6-Dihydro-7H.-pyrim.ido[5,4-d] [1]benzazepin-7- vl)carbonvl1phenvl1-2-methylbenzamide

As described for Example 1, 5 mmol of

4-[ (2-methylbenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H.-pyrimido[5,4-d] [l]benz- azepine in pyridine to give the product as a solid.

Example 194

N-[4-[ (5,6-Dihydro-7H.-pyrimido[5,4-d] [l]benzazepin-7- yl)carbonyl]phenyl1-2.4-dichlorobenzamide As described for Example 1, 5 mmol of 4-[ (2,4-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d]- [l]benzazepine in pyridine to give the product as a solid.

Example 195 N-[4-[ (5,6-Dihydro-7H-pyrimido[5,4-d] [1]benzazepin-7- yl)carbonyl1phenyl1-2.5-dichlorobenzamide As described for Example 1, 5 mmol of 4-[ (2,5-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido- [5,4-d] [l]benzazepine in pyridine to give the product as a solid.

Example 196 N-[4-[ (5,6-Dihydro-7H-pyrimido[5,4-d] [l]benzazepin-7- yl)carbonyl]phenyl1-2-chlorobenzamide As described for Example 1, 5 mmol of 4-[(2- chlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H.-pyrimido[5,4-d] [l]benzazepine in pyridine to give the product as a solid.

Example 197 N-[4-[ (5,6-Dihydro-7H _. -pyrimido[5,4-d] [1]benzazepin-7- yl)carbonyl1phenyl]-2-chlorophenylacetamιde

Example 198 N-[4-[ (5,ll-Dihydro-6H.-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl]phenyl1-2-methylbenzamide A mixture of 5 mmol of 5,ll-dihydro-6-(4- aminobenzoyl)-6g-pyrido[3,2-e][l]benzazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol of triethyl¬ amine in 15 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and solution washed with 20 ml each of H ₂ 0, IM citric acid, NaHC0 ₃ , brine and dried

(Na_SO ) . The solvent is evaporated in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the product as a solid. The following compounds are prepared as described for in Example 198.

Example 199 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [1]benzazepin-6- yl)carbonylIphenyl1-2-chlorobenzamide

Example 200 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [1]benzazepin-6- yl)carbonyl]phenyl]-2.5-dichlorobenzamide Example 201 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]beπzazepin-6- yl)carbonyl]phenyl1-2.4-dichlorobenzamide Example 202 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl) carbonyllphenyl]-2-chloro-4-methylbenzamide

Example 203 N-[4-[ (5,ll-Dihydro-6H.-pyrido[3,2-e] [l]benzazepin-6- yl) carbonyllphenyll-2-methyl-4-chlorobenzamide

Example 204 N-[4-[ (5,ll-Dihydro-6H.-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl]phenyl]-2 ,4-dimethylbenzamide Example 205 N-[4-[ (5,ll-Dihydro-6H.-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2.3-dimethylbenzamide

Example 206 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2-methoxybenzamide Example 207 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazeρin-6- yl)carbonyllphenyl]-2-trifluoromethoxybenzamide

Example 208 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonylIphenyl1-2,4-dimethoxybenzamide

Example 209 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2-methoxy-4-chlorobenzamide

Example 210 N-[4-[(5,ll-Dihydro-6H-pyrido[3,2-e] [1)benzazepin-6- yl)carbonyllPhenyl1-2-trifluoromethylbenzamide

Example 211 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyllPhenyl1-2-methyIthiobenzamide Example 212 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [1]benzazepin-6- yl)carbonyl1phenyl1-2-methyl-3-thiophenecarboxamide

Example 213 N-[4-[ (5,ll-Dihydro-6H.-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyllphenyl1-3-roethyl-2-thiophenecarboxamide

Example 214 N-[4-[ (5,ll-Dihydro-6ϋ-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl]phenyl1-2-methyl-3-furanecarboxamide

Example 215 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e][l]benzazepin-6- yl)carbonyl]phenyl1-3-methyl-2-furanecarboxamide

Example 216

N-[4-[(5,ll-Dihydro-6H _/ -pyrido[3,2-e][l]benzazepin-6- yl)carbonyl1Phenyl1-2-methoxyphenylacetamide

Example 217 N-[4-[(5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2-chlorophenylacetamide

Example 218 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2-methylphenylacetamide

Example 219 N-[4-[(5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyl1phenyl1-2-methyl-3-thiopheneacetamide

Example 220 N-[4-[ (5,ll-Dihydro-62-pyrido[3,2-e] [1]benzazepin-6- yl)carbonyl1phenyl1cvclohexanecarboxamide Example 221 N-[4-[ (5,ll-Dihydro-6H-pyrido[3,2-e] [l]benzazepin-6- yl)carbonyllphenyl1-3-cvclohexanecarboxamide

Example 222 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-methylbenzamide

A mixture of 5 mmol of 5,6-dihydro-5-(4- aminobenzoyl)pyrido[2,3-b] [l,4]benzothiazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol of tri¬ ethylamine in 15 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of HLO, IM citric acid, NaHC0 ₃ , brine and dried (Na ₂ ≤0 ₄ ) . The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.

The following compounds are prepared as described for in Example 222.

Example 223 N-[4-(Pyrido[2,3-b_] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-chlorobenzamide Example 224 N-[4-(Pyrido[2,3-bj [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2,5-dichlorobenzamide

Example 225 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2.4-dichlorobenzamide

Example 226 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-chloro-4-methylbenzamide

Example 227 N-[4-(Pyrido[2,3-b_] [l,4]benzothiazepin-5(6HJ- ylcarbonyl)phenyl]-2-methyl-4-chlorobenzamide

Example 228 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2.4-dimethylbenzamide

Example 229 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2.3-dimethylbenzamide Example 230 N-[4-(Pyrido[2,3-b] [1,4]benzothiazeρin-5(6H)- ylcarbonyl)pheny!1-2-methoxybenzamide

Example 231

N-[4-(Pyrido[2,3-b_] [l,4]benzothiazepin-5(6H)~ ylcarbonyl)phenyl1-2-trifluoromethoxybenzamide

Example 232 N-[4-(Pyrido[2,3-b_][l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2.4-dimethoxybenzamide Example 233 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyll-2-methoxy-4-chlorobenzamide

Example 234 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-trifluoromethylbenzamide

Example 235 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl]-2-methylthiobenzamide

Example 236 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-methyl-3-thiophenecarboxamide

Example 237 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-3-methyl-2-thiophenecarboxamide

Example 238 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-methyl-3-furanecarboxamide

Example 239 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-3-methyl-2-furanecarboxamide

Example 240 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenylIphenylacetamide

Example 241

N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-chlorophenylacetamide

Example 242 N-[4-(Pyrido[2,3-b_] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-methoxyphenylacetamide

Example 243 N-[4-(Pyrido[2,3-b] [l,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1-2-methylphenylacetamide

Example 244 N-[4-(Pyrido[2,3-b] [1,4)benzothiazepin-5(62)- ylcarbonyl)phenyl1-2-methyl-3-thiopheneacetamide

Example 245 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1cvclohexanecarboxamide

Example 246 N-[4-(Pyrido[2,3-b_] [1,4]benzothiazepin-5(6H)- ylcarbonyl)phenyl1cvclopentanecarboxamide Example 247 N-[4-(Pyrido[2,3-b] [1,4]benzothiazepin-5 (6H) - ylcarbonyl)phenyl1cvclohexaneacetamide Example 248 N-[4-(Pyrido[2,3-b_] [1,4]benzothiazepin-5(6H _. ) - ylcarbonyl)phenyl1-3-cvclohexenecarboxamide

Example 249 N-[4-[ (6, ll-Dihydro-5g-dibenz[b,e]azepin-5-yl) - carbonyl1phenyl1-2.3.5-trichlorobenzamide

A mixture of 366 mg of 2,3,5-trichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4- aminobenzoyl) -6,ll-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 1.5 hours. The reaction mixture is partitioned with water and the organic layer is washed with IN HCl, water, 0.5 N NaOH and brine. The organic layer is dried with Na ₂ S0 ₄ and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.52 g of white solid residue which is purified by column chromatography on silica gel by elution with 2:1 hexane-ethyl acetate to give 120 mg of the desired product as a crystalline solid, m.p. 225-230 C.

Example 250 N- [ 4- [ ( 6 , ll-Dihydro-5H-dibenz [b , e ] azepin-5-y 1 ) - carbonvπphenvπ -3 .4-dichlorobenzamide

A mixture of 314 mg of 3 , 4-dichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of

methylene chloride is stirred while 314 mg of 5-(4- aminobenzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 2 hours. The reaction mixture is parti¬ tioned with water and the organic layer is washed IN HCl, water, 0.5 N NaOH and brine. The organic layer is dried with Na ₂ S0 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.35 g of off-white crystalline solid, m.p. 238-241 C.

Example 251 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonylIphenyl1-3.5-dichlorobenzamide

A mixture of 301.6 mg of 3,5-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred in 2 ml of methylene chloride while 314 mg of 5-(4-amino- benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. The reaction mixture is stirred at room temperature for 2 hours and 100 mg of 3,5-dichlorobenzoyl chloride added. The reactants are heated at reflux for 36 hours. The cooled reaction mixture layer washed with 1 N HCl, water, 1 N NaOH, water and brine. The organic layer is dried with Na SO and passed through a short pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 242 mg of the desired product as a crystalline solid, m.p. 263-265°C.

Example 252 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl1phenyl1-2.6-dichlorobenzamide

A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg of N,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of 5-(4-amino- benzoyl)-6, ll-dihydro-5H-dibenz[b,e]azepine is added. The reactants are refluxed in an oil bath at lio°C for 18 hours. The xylene is evaporated in vacuo to a

residue which is partitioned between methylene chloride and water. The organic layer is separated, washed with 1 N HCl, 1 M NaHC0 ₃ , and brine. The organic layer is dried with Na_SO and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 370 mg of the desired product as a crystalline solid, m.p. 257-259°C.

Example 253 N-[4-[(6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyllphenyl]-2.3-dichlorobenzamide

A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,ll-dihydro-5H-dibenz- [b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1 N HCl, water, 1 M NaHC0 ₃ and water then dried over Na ₂ SO . The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225-230°C.

Example 254 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl1phenyl]-2-methyl-3-fluorobenzamide

A mixture of 248.5 mg of l-methyl-2-fluoro- benzoyl chloride and 145 mg of triethylamine is stirred while 376.8 mg of 5-(4-aminobenzoyl)-6,ll-dihydro-5H- dibenz[b,e]azepine is added. Stirring is continued for 3 hours. Water is added and the organic layer washed with l N HCl, water, 1 M NaHC0 ₃ and water then dried over Na ₂ S0 ₄ . The organic layer is passed through a pad of hydrous magnesium silicate. The desired product crystallizes from methylene chloride to give 0.417 g of the desired product, m.p. 167-170°C.

Example 255 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl1phenyl1-3-cvclohexene-1-carboxamide

A mixture of 208 mg of 3-cyclohexene-l-car- bonyl chloride (prepared from 3-cyclohexene-l-carboxy- lic acid and thionyl chloride) and 145 mg of triethyl¬ amine in 3 ml of methylene chloride is added to a solution of 377 mg of 5-(4-aminobenzoyl)-6,11-dihydro- 5g-dibenz[b,e]azepine in 7 ml of methylene chloride. The mixture is stirred for 18 hours, washed with water, 1 N HCl, water, 1 M NaHC0 ₃ and brine then dried with Na SO . The organic layer is passed through a short column of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 340 mg of the desired product as a crystalline solid, m.p. 234-236°C.

Example 256 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azeρin-5-yl)- carbonyl1-3-chlorophenyl1-2.4-dichlorobenzamide

A mixture of 0.50 g of 5-(2-chloro-4-amino¬ benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0.28 g of N,N-diisopropylethylamine and 0.45 g of 2,4-dichloro- benzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO , dried (Na ₂ S0 ₄ ) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give the desired product as a solid residue, m.p., 150-165°C.

Example 257 N-[4-[(6,ll-Dihydro-5g-dibenz[b,e]azepin-5-yl)- carbonyl1-2-methoxyphenyl1-2-methylbenzamide

A mixture of 1.0 g of 5-(3-methoxy-4-amino- benzoyl)-6,ll-dihydro-5g-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methyl- benzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction

mixture is washed with water and saturated NaHC0 ₃ , dried (Na SO ) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209-210 C.

Example 258 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl1-2.6-dimethylphenyl]-2-methylbenzamide

A mixture of 1.42 g of 4-[ (benzoyl)amino]- 3,5-dimethylbenzoic acid in 20 ml of thionyl chloride is heated on a steam bath under argon for 1 hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give 1.40 g of the desired product as a residue which is dissolved in 50 ml of methylene chloride and treated with 0.75 g of N,N- diisopropylethylamine and 0.88 g of 10,ll-dihydro-5H- dibenz[b,e]azepine. The reactants are stirred at room temperature for 18 hours and washed with water, saturated NaHC0 ₃ , dried (Na ₂ S0 ₄ ), passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.90 g of the desired product as a glass. Example 259

N-[4-[(6,ll-Dihydro-5g-dibenz[b,e]azepin-5-yl)- carbonyl1-2,6-dimethylphenyl1-2,4-dichlorobenzamide A mixture of 1.69 g of 4-[ (2,4-dichloro- benzoyl)amino]-3,5-dimethylbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under argon for 1 hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give a residue. A solution of the residue in 25 ml of methylene chloride is treated with 0.75 g of N,N-di- isopropylethylamine and 0.98 g of 10,ll-dihydro-5H- dibenz[b,e]azepine is stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaHC0 ₃ , dried (Na ₂ S0 ₄ ) and passed through a

pad of hydrous magnesium silicate. The filtrate is evaporated to a glass which is dissolved in methylene chloride dried (Na SO ) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated to give 1.89 g of the desired product as an amorphorous solid.

Example 260 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl) - carbonyl1-3-chlorophenyl]-2-methylbenzamide

A mixture of 0.31 g of 5-(2-chloro-4-amino¬ benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooled in an ice bath while 0.18 g of 2- methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1 N HCl, water, 1 M NaHC0 ₃ , brine and dried (Na ₂ S0 ₄ ) . The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p.

138-150°C. M ⁺ =467.

Example 261 N-[4-[ (6,ll-Dihydro-5g-dibenz[b,e]azepin-5-yl) - carbonyl1-2-methoxyphenyl1-2-methyl-5-fluorobenzamide

A mixture of 0.79 g of 5-(3-methoxy-4-amino¬ benzoyl)-6,ll-dihydro-5H-dibenz[b,e]azepine, 0.40 g of N,N-diisopropylethylamine and 0.55 g of 2-methyl-5- fluorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO , dried (Na ₂ S0 ₄ ) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to the filtrate to give 1.05 g of the desired product as a solid.

Example 262 N- [ 4- [ ( 6 , ll-Dihydro-5H-dibenz [b , e ] azepin-5-yl ) - carbonyl1-2-chlorophenyll-2-methyl-3-fluorobenzamide

A mixture of 1.0 g of 6,ll-dihydro-5H-dibenz- [b,e]azepine, 0.80 g of N,N-diisopropylethylamine and 2.01 g of 4-[ (2-methyl-3-fluorobenzoyl)amino]-3-chloro- benzoyl chloride in 100 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHC0_, dried (Na_SO ) and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 1.79 g of the desired product as a crystalline solid, m.p. 254-256°C.

Example 263 N-[4-[ (6,ll-Dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl1-2-methoxyphenyl1-2.4-dichlorobenzamide

A mixture of 1.0 g of 5-(3-methoxy-4-amino- benzoyl)-6,ll-dihydro-5g-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.76 g of 2,4-dichloro- benzσyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO , dried (Na SO.) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.39 g of the desired product as a crystalline solid, m.p. 212-214°C.

Example 264 N-[4-[ (6,ll-Dihydro-5g-dibenz[b,e]azepin-5-yl)- carbonyl]-3-chlorophenyl1-2-methyl-3-fluorobenzamide

A mixture of 1.85 g of 4-[(2-methyl-3-fluoro- benzoyl)amino]-2-chlorobenzoic acid in 30 ml of thionyl chloride under argon is heated at reflux for l hour. The thionyl chloride is evaporated in vauco to a residue which is stirred with hexane and collected to give 1.94 g of 4-[ (2-methyl-3-fluorobenzoyl)amino]-2- chlorobenzoyl chloride which is dissolved in 25 ml of

methylene chloride and 0.49 g of N,N-diisopropylethyl- amine added, followed by 0.65 g of 6,ll-dihydro-5H- dibenz[b,e]azepine. The reactants are stirred at room temperature for 18 hours and washed with water, saturated NaHCO , dried (Na ₂ S0 ₄ ) and passed through a short pad of hydrous magnesium silicate to give 1.19 g of the desired product as a glass.

Example 265 N-[4-[ (6,ll-Dihydro-ll-oxo-5g-dibenz[b,e]azepin-5-yl)- carbonylIphenyl1-2-methylbenzamide

A mixture of 1.08 g of N-[4-[ (6,11-dihydro-

5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methyl- benzamide in 50 ml of t-butanol is heated, 2 ml of water is added followed by 1.18 g of MgS0 ₄ , and 2.6 g of KMnO4,. An additional 0.84 g of KMnO4. in 25 ml of water is added followed by heating at 65°C for 18 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to give 1.2 g of a residue which is purified by column chromatography on silica gel by elution with ethyl acetate and 9:1 ethyl acetate-methanol to give 160 mg of the desired product as a solid, m.p. 115-119°C. Example 266

(2-Methylphenyl)methyl 4-[ (6,ll-dihydro-5H-dibenz[b,e] azepin-5-yl)carbonyl)benzoate To a mixture of 248 mg of 2-methylbenzyl alcohol in 4 ml of anhydrous tetrahydrofuran is added 80 mg of sodium hydride (60% in mineral oil) and the mixture stirred for 1 hour. To the mixture is added 430 mg of 4-[ (6,ll-dihydro-5H-dibenz[b,e]azepin-5-yl)- carbonyl]benzoyl chloride and the mixture is stirred for 18 hours. The tetrahydrofuran is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated and washed with 1 N HCl, water, 1 M NaHCO , and brine. The organic layer is dried (Na ₂ SO ) and

passed through a short pad of hydrous magnesium silicate and hexane added at the boil to give 170 mg of the desired product, m.p. 140-142 C.

Example 267 N-[4-[ (6,ll-Dihydro-52-dibenz[b,e]azepin-5-yl)- carbonyl]phenyl]-N-[ (dimethylamino)methyl]-2- methylbenzamide To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[ (6,ll-dihydro-5H-dibenz[b,e)azepin- 5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethyl- methylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131-133°C.

Example 268 N-[4-[ (5,ll-dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-2-methylbenzamide A mixture of 1.0 g of 5,ll-dihydro-10H-dibenz [b,e] [l,4]diazepine 1.9 g of 4-[ (2-methylbenzoyl) amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2 N HCl, water, saturated NaHCO- and water. The organic layer is dried (Na ₂ S0 ₄ ) and the solvent re¬ moved to give a residue. The residue is chromato¬ graphed on a silica gel column using 1:4 ethyl acetate- hexane to give 1.8 g of the desired product as a solid, m.p. 68-7l°C

The following compounds are prepared as described for Example 268.

Example 269 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1phenyl1-2-chlorobenzamide

Example 270

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]phenyl1-2.4-dichlorobenzamide

Example 271 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]Phenyl1-2.5-dichlorobenzamide

Example 272

N-[4-[(5,ll-Dihydro-lθg-dibenz[b,e] [l,4]diazepin-5- yl)carbonylIphenyl1-3.5-dichlorobenzamide

Example 273

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyllphenyl1-2-fluorobenzamide

Example 274 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl) carbonyl1phenyl1-3-fluorobenzamide

Example 275

N-[4-[(5,ll-Dihydro-10H-dibenz[b,e][l,4]diazepin-5- yl)carbonyl1phenyl1-2-methyl-4-chlorobenzamide

Example 276 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- y1)carbonyl]phenyl1-2.3-dimethylbenzamide

Example 277 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl]-2-methoxybenzamide Example 278 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-2-(trifluoromethoxy)benzamide

Example 279 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonylIphenyl1-2.4-dimethoxybenzamide

Example 280 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-2.6-dimethoxybenzamide

Example 281 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-2-methoxy-4-chlorobenzamide

Example 282 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]phenyl1-2-(trifluoromethyl)benzamide

Example 283 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazeρin-5- yl)carbonyl]phenyl1-3-(trifluoromethyl)benzamide

Example 284 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl]phenv!1-2.6-dichlorobenzamide

Example 285

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl) carbonylIphenyl1-2-(methylthio)benzamide

Example 286 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- vl)carbonvllPhenvl1-4-fluoro-2-(trifluoromethyl) benzamide Example 287

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl) carbonyl1phenyl1-4-fluoro-3-(trifluoromethyl) benzamide

Example 288

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonvlIphenvl1-2-fluoro-3-(trifluoromethyl) benzamide

Example 289 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonylIphenyl1-3.5-dimethylbenzamide

Example 290 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1phenyl1-2.3.5-trichlorobenzamide

Example 300 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]phenyl1-2.5-difluorobenzamide

Example 301

N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1phenyl1-3-fluoro-2-methylbenzamide

Example 302 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonylIphenyll -2.3-dichlorobenzamide Example 303 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyllphenyl]-4-fluoro-2-methylbenzamide

Example 304 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-5-fluoro-2-methylbenzamide

Example 305 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]phenyl1-2-fluoro-5-(trifluoromethyl) benzamide Example 306

N-[4-[ (5,11-Dihydro-lOg-dibenz[b,e] [1,4]diazepin-5- yl)carbonylIphenyl1-2-fluoro-6-(trifluoromethyl) benzamide

Example 307

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1phenyl1-3-fluoro-5-(trifluoromethyl) benzamide

Example 308 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyllphenyl1-2-methyl-3-thiophenecarboxamide

Example 309 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyllphenyl1-3-methyl-2-thiophenecarboxamide

Example 310 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl]phenyl1-2-methyl-3-furanecarboxamide

Example 3U N- [ 4- [ (5 , ll-Dihydro-10H-dibenz [b , e] [ 1 , 4 ] diazepin-5- yl) carbonyl l phenvπ -3-methyl-2-furanecarboxamide

Example 312 N-[4-[(5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyllphenyl1-2-chlorobenzeneacetamide

Example 313 N-[4-[(5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1phenyl1-2-methylbenzeneacetamide

Example 314 N-[4-[ (5,11-Dihydro-lOg-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1phenyl]-2-methoxybenzeneacetamide

Example 315 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyllPhenvπ-2-methyl-3-thiopheneacetamide

Example 316 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e][l,4]diazepin-5- yl)carbonyl]phenyl]-3-methyl-2-thiopheneacetamide

Example 317 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]phenyl1-2-methyl-3-furaneacetamide

Example 318 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-2-methoxyphenyl1-3-fluoro-2- methylbenzamide

Example 319

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-2-methoxyphenyl1-5-fluoro-2- methylbenzamide

Example 320 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-2-methoxyphenyl1-2-chloro-4- fluorobenzamide

Example 321

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-2-methoxyphenyl1-2.6-dichlorobenzaroide

Example 322 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyll-2-methoxyphenyll-2-methylbenzamide

Example 323 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl) carbonyl]-2-methoxyphenyl1-2.5-dichlorobenzamide

Example 324 N-[4-[ (5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-3-chlorophenyl1-2-methylbenzamide

Example 325 N-[4-[ (5, ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-3-chlorophenyl1-2-chlorobenzamide

Example 326 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-3-chlorσphenyl1-2.3-dimethylbenzamide

Example 327 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl]-3-chlorophenyl1-2.3-dichlorobenzamide

Example 328 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl]-3-chlorophenyl1-2-chloro-4-fluoro¬ benzamide Example 329

N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-3-chlorophenyl]-3-fluoro-2-methylbenzamide

Example 330

N-[4-[(5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-3-chlorophenyl1-5-fluoro-2-methylbenzamide

Example 331 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-3-chlorophenyl1-2.4-dichlorobenzamide Example 332

N-[4-[(5,ll-Dihydro-10g-dibenz[b,e][l,4]diazepin-5- vl)carbonvl1-3-chlorophenyl1-4-fluoro-2-(trifluoro¬ methyl)benzamide Example 333 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e][l,4]diazepin-5- yl)carbonyl1-3-chlorophenyl]-2-(methylthio)benzamide

Example 334 N-[4-[ (5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-3-chlorophenyl1-2-(trifluoromethoxy) benzamide

Example 335

N-[4-[(5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl ) carbonyl ] -3 -chlorophenyl 1 -2 , 6-dichlorobenzamide

Example 336 N-[4-[(5,ll-Dihydro-10H-dibenz[b,e] [l,4]diazepin-5- yl)carbonyl1-3-chlorophenyl]-2-fluoro-6-(trifluoro¬ methyl)benzamide Example 337 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e][l,4]diazepin-5- yl)carbonyl1-3-methylphenyl1-2.6-dichlorobenzamide Example 338

N-[4-[(5,ll-Dihydro-10H-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-3-methylphenyl1-2-fluoro-6-(trifluoro¬ methyl)benzamide Example 339 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl]-3-methylphenyl1-5-fluoro-2-methylbenzamide

Example 340 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e][l,4]diazepin-5- yl)carbonyl1-3-methylphenyl1-2.4-dichlorobenzamide

Example 341 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e] [1,4]diazepin-5- yl)carbonyl1-3-methylphenyl1-4-fluoro-2-chlorobenzamide

Example 342 N-[4-[(5,ll-Dihydro-10H-dibenz[b,e][l,4]diazepin-5- yl)carbonyl1-3-methylphenyl1-3-fluoro-2-methylbenzamide

Example 343 N-[4-[(5,ll-Dihydro-10g-dibenz[b,e][l,4]diazepin-5- yl) carbonyl1-3-methyIphenyl1-2.3-dimethylbenzamide

Example 344 N-[4-[(5,ll-Dihydro-10g-dibenz[b.e] [1,4]diazepin-5- vl)carbonvl1-3-methvlphenvl1-2-methvlbenzamide

Example 345 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin- 6-yl)carbonyllPhenyll-2-methylbenzamide

A partial solution of 0.250 g of 5,6-dihydro- 6-(4-aminobenzoyl)-4g-isoxazolo[4,5-d][l]benzazepine in 4 ml of tetrahydrofuran-dioxane (1:3) under argon is treated with 160 μl of 2-methylbenzoyl chloride in 1.5 ml of dioxane followed by 114 μl of triethylamine and stirring continued for 4.5 hours at room temperature. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride containing methanol, washed with 10% NaHC0 ₃ and brine, then treated with activated carbon. The mixture is filter¬ ed through MgS0 ₄ and the filtrate filtered through silica gel with 15% ethylacetate in methylene chloride. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, filtered through glass wool, evaporated to a residue which is dissolved in ethyl acetate by warming to give 0.25 g of the desired product as tan crystals, m.p. 257-260°C. HR FABMS: (M+H)=424.1657.

The following compounds are prepared as described in Example 345.

Example 346 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1phenyl1-2-methyl-4-chlorobenzamide

Example 347 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl]phenyl1-2.3-dimethylbenzamide

Example 348 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-dj [l]benzazepin- 6-yl)carbonyl]phenyl1-2-methoχvbenzamide

Example 349 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-dJ [1]benzazepin-

6-yl)carbonvl1phenvl1-2-(trifluoromethoxy)benzamjdo

Example 350 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin- 6-yl)carbonyl1phenyl]-2-(trifluoromethyl)benzamide

Example 351 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonyl1phenyl1-2-(methylthio)benzamide

Example 352 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonylIphenyl1-2.3-dichlorobenzamide

Example 353 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin- 6-yl)carbonyllPhenyll-3-fluoro-2-methylbenzamide

Example 354 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonylIphenyl1-5-fluoro-2-roethylbenzamide

Example 355 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1phenyl1-2-chloro-4-fluorobenzamide

Example 356 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1phenyl]-4-fluoro-2-(trifluoromethyl) benzamide Example 357 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1phenyl]-4-fluoro-3-(trifluoromethyl) benzamide

Example 358 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonyllphenyl1-4-fluoro-2-methylbenzamide

Example 359 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonylIphenyl1-2-fluoro-5-(trifluoromethyl) benzamide

Example 360 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin- 6-yl)carbonyl1phenyl1-2-fluoro-6-(trifluoromethyl) benzamide Example 361 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-chlorophenyl1-3-fluoro-2-methyl- benzamide

Example 362 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonyl1-3-chlorophenyl1-2-methylbenzamide

Example 363 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-chlorophenyl]-2.3-dimethylbenzamide

Example 364 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin- 6-yl)carbonyl1-3-chlorophenyl1-5-fluoro-2-methyl- benzamide Example 365 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-chlorophenyl1-2-chloro-4-fluoro¬ benzamide Example 366 • N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-dJ [l]benzazepin-

6-yl)carbonyl1-3-chlorophenyl1-2.3-dichlorobenzamide Example 367

N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-vl)carbonvl1-3-methvlPhenvl1-2-methylbenzamide

Example 368 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-methylphenyl1-2,3-dimethylbenzamide

Example 369 N-[4-[(4,5-Dihydro-6g-isoxazolo[4,5-d] [1]benzazepin- 6-yl)carbonyl1-3-methylphenyl1-3-fluoro-2-methyl- benzamide Example 370 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonyl1-3-methyIphenyl1-5-fluoro-2-methyl- benzamide

Example 371 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-dj [1]benzazepin-

6-yl)carbonyl1-3-methyIphenyl1-4-fluoro-2-methyl- benzamide Example 372 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl]-3-methylphenyl1-2-methylthiobenzamide

Example 373 N-[4-[(4,5-Dihydro-6g-isoxazolo[4,5-d][l]benzazepin-

6-yl)carbonyl1-3-methylphenyl1-2-(trifluoro¬ methoxy)benzamide Example 374 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl]-3-methylPhenyl1-3-fluoro-2- methylbenzamide Example 375 N-[4-[ (4,5-Dihydro-6g-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-methoχyphenyl1-5-fluoro-2- methylbenzamide Example 376 N-[4-[(4,5-Dihydro-6H-isoxazolo[4,5-d] [1]benzazepin-

6-yl)carbonyl1-3-methoxyphenyl1-2-methylbenzamide

Example 377 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin- 6-yl)carbonyl1-3-methoxyphenyl]-2-chloro-4-fluoro¬ benzamide Example 378 N-[4-[ (4,5-Dihydro-6H-isoxazolo[4,5-d] [l]benzazepin-

6-yl)carbonyl1-3-methoxyphenyl1-2.3-dichlorobenzamide Example 379

N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4, 3-d] [1]- benzazepin-6(2H)-yl)carbonyl1phenyl]-2-methylbenzamide

To a mixture of 0.420 g of 2,4,5,6-tetra- hydro-2-methyl-6-(4-aminobenzoyl)pyrazolo[4,3-d] [1]- benzazepine and 275 μl of triethylamine in 6 ml of methylene chloride and 2 ml of dioxane is added a solution of 215 μl of 2-methylbenzoyl chloride in 1.5 ml of dioxane. The reactants are stirred under argon for 4.5 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and washed with 10% NaHCO and brine. The organic layer is treated with activated carbon, dried with MgS0 ₄ and evaporated in vacuo to give 660 mg of a tan foam residue. The residue is purified by column chromatography on silica gel by elution with 30% ethyl acetate-methylene chloride to give 590 mg of the desired product as white crystalline solid, m.p. 246-248°C; HR FABMS: (M+H)=437.1972.

The following examples are prepared as described for Example 379.

Example 380 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H.)-yl)carbonyl]phenyl]-2-chlorobenzamide

Example 381 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2,4-dichloro- benzamide Example 382 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2,3-dichloro- benzamide Example 383 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2-methyl-4- chlorobenzamide Example 384 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2,3-dimethyl- benzamide

Example 385 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-methoxybenzamide

Example 386 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2-(trifluoro- methoxy)benzamide Example 387 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2,4-dimethoxy- benzamide Example 388 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-methoxy-4- chlorobenzamide

Example 389 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-(trifluoro- methyl)benzamide Example 390 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2g)-yl)carbonyl]phenyl]-3-(trifluoro- methyl)benzamide Example 391 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-(methylthio)- benzamide Example 392 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonylJphenyl]-4-fluoro-2-(tri- fluoromethyl)benzamide

Example 393 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-fluoro-3-

(trifluoromethyl)benzamide Example 394 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-chloro-4- fluorobenzamide Example 395 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-3-fluoro-2- methylbenzamide

Example 396 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-5-fluoro-2- methylbenzamide Example 397 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-3-fluoro-5-

(trifluoromethyl)benzamide Example 398 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-chloro-5-

(methylthio)benzamide Example 399 N-[4-[ (4,5-Dihydro-2-methylpyrazolb[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2-methyl-3- thiophenecarboxamide

Example 400 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]phenyl]-2-methyl-3- furanecarboxamide Example 401 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-chloro- benzeneacetamide Example 402 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]phenyl]-2-methyl- benzeneacetamide

Example 403 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d][l]- benzazepin-6(2g)-yl)carbonyl]-3-chlorophenyl]-2- methylbenzamide

Example 404

N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]-3-chlorophenyl]-2,3- dimethylbenzamide Example 405 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2H)-yl)carbonyl]-3-chlorophenyl]-2,3- dichlorobenzamide Example 406 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-dJ [1]- benzazepin-6(2g)-yl)carbonyl]-3-chlorophenyl]-2,4- dichlorobenzamide

Example 407 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]-3-chlorophenyl]-3- fluoro-2-methylbenzamide Example 408 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2H)-yl)carbonyl]-3-chlorophenyl]-5- fluoro-2-methylbenzamide Example 409 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2g)-yl)carbonyl]-3-chlorophenylJ -2- chloro-4-fluorobenzamide

Example 410 N-[4-[ (4,5-Dihydro-2-methylpyrazolo[4,3-d] [l]- benzazepin-6(2H)-yl)carbonyl]-3-methylphenyl]-2- methylbenzamide Example 411 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]-3-methylphenyl]-2,3- dimethylbenzamide Example 412 N-[4-[ (4,5-Dihydro-2-methylρyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]-3-methylphenyl]-2- chloro-4-fluorobenzamide Example 413 N-[4-[(4,5-Dihyd ^' ro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]-3-methylphenyl]-3- fluoro-2-methylbenzamide

Example 414 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2H)-yl)carbonyl]-3-methylphenyl]-5- fluoro-2-methylbenzamide

Example 415 N-[4-[(4,5-Dihydro-2-methylpyrazolo[4,3-d] [1]- benzazepin-6(2g)-yl)carbonyl]-3-methylphenyl]-2,4- dichlorobenzamide Example 416 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [l]- benzazepin-7-yl)carbonyl]phenyl1-2-methylbenzamide To a solution of 0.216 mg of 6,7-dihydro-2- methyl-7-(4-aminobenzoyl)-5g-pyrimido[5,4-d] [l]benz- azepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 94 μl of 2-methylbenzoyl chloride in 1.5 ml of methyl-

ene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO- and the separated organic layer treated with activated carbon and filtered through MgSO . The fil¬ trate is evaporated to a residue which is dissolved in ethyl acetate and evaporated jLn vacuo to give 300 mg of the desired product as a pale yellow foam. HR FABMS: Exact Mass (M+H) :449.1974.

The following compounds are prepared as described in Example 416.

Example 417 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [l]- benzazepin-7-yl)carbonylIphenyl1-2.3-dimethylbenzamide

Example 418 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [l]- benzazepin-7-yl)carbonyl]phenyl]-2-chloro-4- fluorobenzamide Example 419

N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [l]- benzazepin-7-yl)carbonyl]phenyl1-2.4-dichlorobenzamide

Example 420 N-[4-[(6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyllphenyl]-2.3-dichlorobenzamide

Example 421 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [l]- benzazepin-7-yl)carbonyllphenyl1-3-fluoro-2- methylbenzamide

Example 422 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyllphenyl1-2-methoxybenzamide

Example 423 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-vl)carbonvliPhenvll-5-fluoro-2- methylbenzamide

Example 424 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1Phenyl1-2-(trifluoro¬ methoxy)benzamide Example 425 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-dj [1]- benzazepin-7-yl)carbonyllphenyl1-2-methoxy-4- chlorobenzamide

Example 426 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonylIphenyll-2-chloro-5- fluorobenzamide Example 427 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-dJ [1]- benzazepin-7-yl)carbonylIphenyl1-2-(trifluoromethyl) benzamide Example 428

N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyllphenyl1-2-(methylthio)- benzamide Example 429 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d][l]- benzazepin-7-yl)carbonyllPhenyl1-4-fluoro-2- methylbenzamide Example 430 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl]-3-chlorophenyl1-2- methylbenzamide Example 431 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-chlorophenyl1-2.3- dimethylbenzamide

Example 432 N- [ 4- [ ( 6 , 7-Dihydro-2-methyl-5H-pyrimido [ 5 , 4-d] [ 1 ] - benzazepin-7-yl)carbonyl1-3-chlorophenyl1-3-fluoro-2- methylbenzamide Example 433 N-[4-[(6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-chlorophenyl1-5-fluoro-2- methylbenzamide

Example 434 N-[4-[(6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyll-3-chlorophenyl1-2-chloro-4- fluorobenzamide Example 435 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-chlorophenyl1-2-chloro-5- fluorobenzamide Example 436 N-[4-[ (6,7-Dihydro-2-methyl-5g-ρyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl]-3-chlorophenyl1-2.3- dichlorobenzamide Example 437 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-chlorophenyl1-2-

(trifluoromethoxy)benzamide

Example 438

N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-methoχyphenyl1-3-fluoro-2- methylbenzamide

Example 439

N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl]-3-methoxyphenyl1-5-fluoro-2- methylbenzamide

Example 440 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5, 4-d] [1]- benzazepin-7-yl)carbonyl1-3-methylphenyl1-3-fluoro-2- methylbenzamide Example 441 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-methylphenyl1-5-fluoro-2- methylbenzamide

Example 442 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-methylphenyl]-2.3- dichlorobenzamide Example 443 N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-methylphenyl1-2-chloro-5- fluorobenzamide Example 444 N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyl1-3-methylphenyl1-2-chloro-4- fluorobenzamide Example 445 N-[4-[(6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-yl)carbonyll-3-methylphenyl1-2.3- dimethylbenzamide

Example 446

N-[4-[ (6,7-Dihydro-2-methyl-5g-pyrimido[5,4-d] [1]- benzazepin-7-vl)carbonyl1-3-methylphenyl1-2-

(trifluoromethyl)benzamide

Example 447

N-[4-[ (6,7-Dihydro-2-methyl-5H-pyrimido[5,4-d] [1]- benzazepin-7-yl) carbonyl1-3-methylphenyl1-2-

(trifluoromethoxy)benzamide

Example 448 N-[4-[ (Dibenz[b,f] [l,4]thiazepin-10(HH)yl)-

5 carbonyllphenyl]-2-chlorobenzamide

To a solution of 385 mg of 2-chloro-benzoyl chloride in 6 ml of methylene chloride at 0 C is added 0.6 g of 10-(4-aminobenzoyl)-10,ll-dihydrodibenz[b,f]- [1,4]thiazepine followed by 0.375 ml of triethylamine. o The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1 N HCl, 1 N Na ₂ C0 ₃ , water and dried over MgSO . The filtrate is evaporated in vacuo to give 0.7 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.3 g of the desired product, m.p. 116-119°C.

Example 449 N-[4-[(Dibenz[b,f] [l,4]thiazepin-10(IIH)-yl)- carbonyl1phenyl1-2.4-dichlorobenzamide

To a solution of 452 mg of 2,4-dichloro- benzoyl chloride in 6 ml of methylene chloride is added 0.6 g of l0-(4-aminobenzoyl)-10,ll-dihydrodibenz[b,f]- [1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1 N HCl, 1 N Na ₂ C0 ₃ , water and dried over MgSO . The filtrate is evaporated in vacuo to give 0.72 g of yellowish solid which is purified by silica gel chro- 0 matography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.254 g of the desired product as ivory crystals, m.p. 112-115°c.

Example 450 5—r4—rr(2-Chlorophenyl)sulfonyllaminoIbenzoyl1-6.ll- 5 dihydro-5g-dibenz[b,e]azepine

A mixture of 0.13 g of 5-(4-aminobenzoyl)- 6,ll-dihydro-5H-dibenz[b,e]azepine, 0.21 g of 2- chlorobenzenesulfonyl chloride, 0.12 g of triethylamine

and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylene chloride is stirred at room temperature for 18 hours. The mixture is partitioned between 1 N NaOH and ethyl acetate. The organic layer is washed with 50% NH ₄ C1 and brine, dried over Na ₂ SO and evaporated to give 0.26 g of the desired product as a yellow solid. MS(CI) :663(M+H; C ³⁵ ) .

A solution of 0.22 g of the preceding compound in 5 ml of tetrahydrofuran is treated with 2 ml of 1 N NaOH and 2 ml of methanol and stirred at room temperature for 1 hour. The organic solvents are removed in vacuo and the residue diluted with 15 ml of ethyl acetate and 5 ml of water. The organic extract is washed with 5 ml of 1 N NaOH, brine and dried (Na_SO ) and evaporated in vacuo to give 0.19 g of yellow solid which is washed with diethylether- isopropyl ether to give 0.17 g of beige solid. MS(CI) :489(M+H, Cl ³⁵ ) .

Example 451

6-(4-[ (2.4-Dichlorobenzoyl)amino]benzoyl]-5,6-dihydro- pyrazolo[4,3-d.] [l]benzazepine-2(4g)-acetic acid

To a stirred slurry of 0.477 g of 6-[4-[(2,4- dichlorobenzoyl)amino]benzoyl]-5,6-dihydropyrazolo- [4,3-d] [l]benzazepine-2(4g)-acetic acid, ethyl ester in 15 ml of ethyl alcohol is added 5 ml of tetrahydro¬ furan followed by 1.30 ml of 1 M NaOH. The reaction mixture is stirred at room temperature for 6 hours followed by the addition of 0.750 ml of 2 M HCl. The acidic reaction mixture is evaporated in vacuo, tri¬ turated with CHC1 ₃ , combined, treated with activated carbon, filtered through MgSO and evaporated in vacuo to give 0.380 mg of the desired product as a clear foam.

Example 452 Ethyl 6-r4-r(2.4-dichlorobenzoyl)amino]benzoyl]-5,6- dihydropyrazolo[4,3-dj [l]benzazpeine-2(4H)-acetate

To a stirred solution of 0.940 g of ethyl 6-(4-aminobenzoyl)-5,6-dihydropyrazolo[4,3-d] [l]benz- azepine-2(4H)-acetate in 25 ml of methylene chloride is added 369 μl of triethylamine followed by the dropwise addition of 373 μl of 2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO , brine and the organic layer treated with activated carbon, and filtered through MgSO . The filtrate is concentrated in vacuo to a residue which is purified by flash chromatography on silica gel using 25% ethyl acetate in methylene chloride to give 380 mg of the desired product as white crystals, m.p. 164-167°C. The mother liquors are combined, evaporated in vacuo to a residue which is dissolved in 25% ethyl acetate in chloroform to give 535 mg of off-white solid, m.p. 160-163.5°C.

Example 453 N-[4-[ (6,ll-Dihydro-5g-dibenz[b,e]azepin-5-yl)- carbonyllphenyll-2-(2-methylpropoxy)benzamide

To a mixture of 0.62 g of 2-chloro-5-nitro- benzoic acid and 0.61 g of triethylamine in 5 ml of methylene chloride is added 0.42 g of isobutylchloro- formate at 0 C. The mixture is warmed to room tem- perature for 30 minutes. A solution of 0.31 g of 5-

(4-aminobenzoyl)-6,7-dihydro-5g-dibenz[b,d]azepine in 1 ml of methylene chloride is added followed by 10 mg of N,N-dimethylaminopyridine and 1.0 ml of toluene is added. The mixture is heated at 100°C for 48 hours. The room temperature reaction mixture is diluted with 15 ml of ethyl acetate and washed with 1 N HCl, l N NaOH, brine and dried (Na ₂ S0 ₄ ) and evaporated in vacuo to a residue. The residue is purified by column chro-

matography on silica gel by elution with 1:2 ethyl acetate-hexane to give 0.28 g of the desired product as a yellow solid. MS(CI) :536(M+H) .

Example 454

N-[4-[ (6,ll-Dihydro-5g-dibenz[b,e]azepin-5-y1)- carbonyl1phenyl1-2-(dimethylamino)acetamide To a solution of 0.31 g of 5-(4-amino- benzoyl)-6,7-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added 0.53 g of Na CO. followed by 0.31 g of N,N-dimethylglycyl chloride. The mixture is stirred at room temperature for 20 hours. The mixture is quenched with water, extracted with ethyl acetate and the organic layer dried (Na ₂ SO ) and con¬ centrated in vacuo to give 0.39 g of yellow foam. The yellow foam is treated with 15 ml of hydrochloric acid and the suspension washed with ethyl acetate. The aqueous suspension is made alkaline with 5 N NaOH and extracted with 30 ml of ethyl acetate. .The organic layer is washed with brine, dried (Na ₂ S0 ) and eva¬ porated to give 0.32 g of the desired product as an off-white solid. MS(CI): 400(M+H). A sample is treated with anhydrous HCl to give the hydrochloride salt. MS(CI): 400(M+H-HC1) .

Example 455 N-[4-(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonylIphenyl1-2,4-dichlσrobenzamide To a stirred solution of 0.235 g of 5,6- dihydro-2-methyl-6-(4-aminobenzoyl)-4H-thiazolo[5,4-d]- [l]benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the dropwise addition of 109 μl of 2,4-dichlorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H- 2O, saturated NaHCO3, and brine. The organic layer is treated with activated carbon, filtered through MgS0 ₄ and the filtrate eva-

porated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ehtyl acetate in methylene chloride to give 330 mg of the desired product as a tan glass.

Example 456 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl]phenyl1-2-methylbenzamide A mixture of 400 mg of 4,10-dihydro-5H- thieno[3,2-c] [l]benzazepine and 700 mg of 4-[(2- methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between chloroform and water. The organic layer is dried (Na ₂ SO ) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 543 mg of the desired product. M+l=439.

Example 457 N-[4-[ (4,10-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyllphenyl]-2.3-dichlorσbenzamide A mixture of 200 mg of 9,10-dihydro-4H- thieno[2,3-cj[1] and 350 mg of 4-[(2-methylbenzoyl)- amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 2 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na ₂ SO ) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 266 mg of the desired product. M+1=494.

Example 458 N-[4-[(4,10-Dihydro-9g-thieno[2,3-cJ [l]benzazepin-9- yl)carbonyl1phenyl1-2-methylbenzamide A mixture of 400 mg of 9,10-dihydro-4H- thieno[2,3-c] [l]benzazepine and 600 mg of 4-[(2- methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na ₂ S0 ) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+l=439.

The following examples are prepared using conditions of Example 456.

Example 459 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2.3-dimethylbenzamide

Example 460 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2.5-dimethylbenzamide

Example 461 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlσrophenyl1-2-methoxybenzamide

Example 462 N-[4-[(4,10-Dihydro-5g-thieno[3,2-£] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-(trifluoromethoxy)- benzamide Example 463 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl]-3-chlorophenyl]-2-methoxy-4- chlorobenzamide

Exammle 464 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-(methylthio)- benzamide Example 465 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2.3-dichlorobenzamide Example 466

N-[4-[(4,10-Dihydro-5g-thieno[3,2-cJ [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-methyl-3-thiophene- carboxamide Example 467 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl]-3-methyl-2-thiophene- carboxamide Example 468 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl]-3-chlorophenyl]-2-chlorobenzeneacetamide

Example 469 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-3-fluoro-2-methylbenzamide Example 470

N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-5-fluoro-2-methylbenzamide

Example 473, N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2.3-difluorobenzamide

Example 472 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-4-fluoro-2-methylbenzamide Example 473

N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyll-2.3.5-trichlorobenzamide

Example 474 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-fluoro-5-(trifluoro¬ methyl)benzamide Example 475 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c][l]benzazepin-5- yl)carbonyl1-3-chlorophenyl]-2-fluoro-6-(trifluoro- methyl)benzamide

Example 476 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-3-fluoro-5-(trifluoro¬ methyl)benzamide Example 477 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2,6-dichlorobenzamide

Example 478 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl]-3-chlorophenyl1-2-(trifluoromethyl)- benzamide Example 479 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-chloro-4-fluoro¬ benzamide Example 480 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-chlorophenyl1-2-chloro-5-fluoro¬ benzamide Example 481 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-fluorophenyl1-3-fluoro-2-methyl- benzamide

_Λ , O 9 /

-242 -

Example 482 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-fluorophenyl]-5-fluoro-2-methyl- benzamide Example 483 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-fluorophenyl]-2-chloro-4-fluoro- benzamide

Example 484 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-methylphenyl1-2-methylbenzamide

Example 485 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyll-3-methylphenyl1-3-fluoro-2-methyl¬ benzamide Example 486 N-[4-[(4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-methylphenyl1-5-fluoro-2-methyl- benzamide Example 487 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-methylpnenyl1-2-chloro-4-fluoro¬ benzamide Example 488 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c][1]benzazepin-5- yl)carbonyl]-3-methylphenyl1-2-chloro-5-fluoro¬ benzamide Example 489 N-[4-[ (4,10-Dihydro-5g-thieno[3,2-≤] [l]benzazepin-5- yl)carbonyl]-3-methylphenyl1-2.3-dichlorobenzamide

Example 490 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-methylphenyl]-2-chloro-4-fluorobenzamide

Example 491 N-[4-[ (4,10-Dihydro-5H-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl1-3-methylPhenyl1-2.3-dimethylbenzamide

Example 492 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [l]benzazepin-5- yl)carbonyl1-3-methylPhenyl1-2,4-dichlorobenzamide

Example 493 N-[4-[(4,10-Dihydro-5g-thieno[3,2-c] [1]benzazepin-5- yl)carbonyl]-3-methylphenyl1-2-(methylthio)- benzamide The following examples are prepared using conditions of Example 458.

Example 494 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [1]benzazepin-9- yl)carbonyl]-3-chlorophenyl]-2-chlorobenzamide

Example 495 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl]-3-chlorophenyl]-2-methylbenzamide

Example 496 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c.] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2.3-dichlorobenzamide

Example 497 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2.3-dimethylbenzamide

Example 498 N-[4-[ (4,10-Dihydro-9H-thieno[2,3-£] [l]benzazepin-9- yl)carbonyl]-3-chlorophenyl1-2.4-dichlorobenzamide

Examole 499 N-[4-[(4,l0-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-methoxybenzamide

Example 500 N-[4-[(4,10-Dihydro-9g-thieno[2,3-cJ [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-(trifluoromethoxy)- benzamide Example 501

N-[4-[(4,10-Dihydro-9H-thieno[2,3-c][l]benzazepin-9- vl)carbonvl1-3-chlorophenvl1-2-methoxv)-4- chlorobenzamide Example 502 N-[4-[(4,10-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl]-3-chlorophenyl]-2.6-dichlorobenzamide

Example 503 N-[4-[(4,10-Dihydro-9g-thieno[2,3-cJ [1]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-(trifluoromethyl)- benzamide Example 504 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl)-2-(methylthio)- benzamide Example 505 N-[4-[(4,10-Dihydro-9H-thieno[2,3-≤] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl]-3-methyl-2-thioρhene- carboxamide Example 506 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c][l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-methyl-3-thiophene- carboxamide Example 507

N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- vl)carbonvl1-3-chlorophenvl1-2-methvlbenzeneacetamide

Example 508 N-[4-[ (4,10-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl]-2-(trifluoromethyl)-4- fluorobenzamide Example 509 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [1]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2.5-dimethylbenzamide Example 510

N-[4-[ (4,10-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-3-fluoro-2-methylbenzamide

Example 511

N-[4-[ (4,10-Dihydro-9H-thieno[2,3-c_] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl]-5-fluoro-2-methylbenzamide

Example 512 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-chloro-4-fluorobenzamide Ex^Ple 513

N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-2-chloro-5-fluorobenzamide

Example 514

N-[4-[(4,10-Dihydro-9g-tτhieno[2,3-c][l]benzazepin-9- yl)carbonyl]-3-chlorophenyl1-2-fluoro-5-(trifluoro¬ methyl)benzamide Example 515 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-chlorophenyl1-3-fluoro-5-(trifluoro¬ methyl)benzamide Example 516 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-fluorophenyl1-2-methylbenzamide

Example 517 N-[4-[ (4,10-Dihydro-9H-thieno[2,3-c][l]benzazepin-9- yl)carbonyl]-3-fluorophenyl1-3-fluoro-2-methylbenzamide

Example 518 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-fluorophenyl]-5-fluoro-2-methylbenzamide

Example 519 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c][l]benzazepin-9- yl)carbonyl1-3-methylphenyl1-2-methylbenzamide

Example 520 N-[4-[(4,10-Dihydro-9g-thieno[2,3-cj[l]benzazepin-9- yl)carbonyl1-3-methylphenyl]-2,3-dimethylbenzamide

Example 521 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c][l]benzazepin-9- yl)carbonyl]-3-methylphenyl1-2.5-dimethylbenzamide

Example 522 N-[4-[(4,10-Dihydro-9g-thieno[2,3-cJ [l]benzazepin-9- yl)carbonyl]-3-methylphenyl]-3-fluoro-2-methylbenzamide

Example 523 N-[4-[ (4,10-Dihydro-9fi-thieno[2,3-cJ[l]benzazepin-9- yl)carbonyl1-3-methylphenyl1-5-fluoro-2-methylbenzamide

Example 524 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl]-3-methylphenyl1-2.3-dichlorobenzamide

Example 525 N-[4-[(4,l0-Dihydro-9g-thieno[2,3-c][l]benzazepin-9- yl)carbonyl]-3-methylphenyl]-2.4-dichlorobenzamide

Example 526 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-methylphenyl]-2-chloro-4-fluorobenzamide

Example 527 N-[4-[(4,10-Dihydro-9H-thieno[2,3-c] [1]benzazepin-9- yl)carbonyl]-3-methylPhenyl]-2-chloro-5-fluorobenzamide

Example 528 N-[4-[(4,10-Dihydro-9H-thieno[2,3-cJ [l]benzazepin-9- yl)carbonyl]-3-methylPhenyl]-2-fluoro-5-(trifluoro¬ methyl)benzamide Example 529

N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [1]benzazepin-9- yl)carbonyl1-3-methylphenyl]-2-methyl-4-chloro¬ benzamide Example 530 N-[4-[(4,10-Dihydro-9H-thieno[2,3-c] [1]benzazepin-9- yl)carbonyl1-3-methylphenyl1-2-methoxybenzamide

Example 531 N-[4-[ (4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-methylphenyl1-2-(trifluoromethoxy)- benzamide Example 532 N-[4-[(4,10-Dihydro-9g-thieno[2,3-c] [l]benzazepin-9- vl)carbonvl1-3-methylPhenyl1-2-(trifluoromethyl)- benzamide

Example 533 N-[4-[(4,10-Dihydro-9H-thieno[2,3-c] [l]benzazepin-9- yl)carbonyl1-3-methylphenyl1-2-(thiomethyl)- benzamide Example 534 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1phenyll-5-fluoro-2- methylbenzamide To a stirred solution of 0.235 g of 5,6-di- hydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo[5,4-d] [l]■ benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the drop-

wise addition of 2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H ₂ 0, saturated NaHCO- and brine. The organic layer is treated with activated carbon, filtered through MgSO and the filtrate evaporated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ethyl acetate in methylene chloride to give 300 mg of the desired product as a white solid; Anal. Calc'd for C ₂₇ H ₂₂ FN ₃ 0 ₂ S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7; H,4.6; N,8.5; F,3.7; S,6.4.

The following examples are prepared using the conditions of Example 534 with the appropriately substituted aroyl chloride.

Example 535 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2.3- dichlorobenzamide Example 536 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2- methy1-4-chlorobenzamide

Example 537 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2- methoxybenzamide Example 538 N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl]-3-chlorophenyl1-2- methoxy-4-chlorobenzamide

Example 539 N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl]-3-chlorophenyl]-2-

(trifluoromethoxy)benzamide Example 540 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d.] [l]- benzazepin-6-yl)carbonyll-3-chlorophenyl1-2- (trifluoromethyl)benzamide

Example 541 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2,6- dichlorobenzamide Example 542 N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyll-3-chlorophenyll-2.3- dimethylbenzamide Example 543

N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d][l]' benzazepin-6-yl)carbonyl1-3-chlorophenyl]-2.5- dimethylbenzamide Example 544 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl]-3-chlorophenyl1-3- (trifluoromethyl)benzamide Example 545 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d][1]• benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2- (methylthio)benzamide Example 546 N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]■ benzazepin-6-yl)carbonyll-3-chlorophenyl1-2- methyl-3-thiophenecarboxamide

Examole 547 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1] benzazepin-6-yl)carbonyl1-3-chlorophenyl1-3- methyl-2-thiophenecarboxamide Example 548 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl]-3-chlorophenyl]-3- methyl-2-furanecarboxamide

Example 549 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2- methylbenzeneacetamide Example 550 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-3- fluoro-2-methylbenzamide Example 551 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-5- fluoro-2-methylbenzamide Example 55? N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl]-4- fluoro-2-methylbenzamide Example 553 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] ^■ benzazepin-6-yl)carbonyl1-3-chlorophenyl]-2- fluoro-4-(trifluoromethyl)benzamide Example 554 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1)• benzazepin-6-yl)carbonyl]-3-chlorophenyl1-3- fluoro-5-ftrifluoromethyl)benzamide

Example 555 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl]-2- chloro-4-fluorobenzamide Example 556 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-chlorophenyl1-2- chloro-5-fluorobenzamide

Example 557 N-[4-[(4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl1-3-chlorophenyl]-4- fluoro-2-(trifluoromethyl)benzamide Example 558 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]' benzazepin-6-yl)carbonyll-3-fluorophenyl1-2- chloro-4-fluorobenzamide Example 559 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-fluorophenyl1-3- fluoro-2-methylbenzamide Example 560 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1] benzazepin-6-yl)carbonyl1-3-fluorophenyl1-5- fluoro-2-methylbenzamide Example 561 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] benzazepin-6-yl)carbonyll-3-fluorophenyl1-2- chloro-4-fluorobenzamide Example 562 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]' benzazepin-6-yl)carbonyl1-3-methylphenyl1-3- fluoro-2-methylbenzamide

Example 563 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1] ^• benzazepin-6-vl)carbonvl1-3-methvlphenvl1-2- methvlbβnzamide

Example 564 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] ^■ benzazepin-6-vl)carbonvll-3-methvlphenvl1-5- fluoro-2-methylbenzamide

Example 565 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] ^■ benzazepin-6-vl)carbonvl1-3-methvlphenvl1-2- chloro-5-fluorobenzamide SXamPle 566 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]• benzazepin-6-yl)carbonyl1-3-methylphenyl1-2.3- dimethvlbenzamide Example 567 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] benzazepin-6-vl)carbonvl1-3-methvlPhenvl1-2.5- dimethvlbenzamide

Example 568 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [l]- benzazepin-6-vl)carbonvl1-3-methvlphenvl1-2.4- dichlorobβnzamide Example 56.9 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] ^■ benzazepin-6-vl)carbonvl1-3-methvlphenvl1-2- methoxv-4-chlorobenzamide

Example 570 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-vl)carbonvl1-3-methvlphenvl1-2- ftriflMorQmethgXY)benzamjde

Examole 571 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [l]• benzazepin-6-yl)carbonyl1-3-methylphenyl1-2-

(methylthio)benzamide Example 572 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1] ^■ benzazepin-6-yl)carbonyl]-3-methoxyphenyl1-2- methylbenzamide

Example 573 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-methoxyphenyl1-2.4- dichlorobenzamide Example 574 N-[4-[ (4,5-Dihydro-2-methy1-6H-thiazolo[5,4-d] [l]- benzazepin-6-yl)carbonyl1-3-methoxyphenyl1-2- chloro-4-fluorobenzamide Example 575 N-[4-[ (4,5-Dihydro-2-methyl-6H-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl1-3-methoxyphenyl1-3- fluoro-2-methylbenzamide Example 576 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [l]• benzazepin-6-yl)carbonyl1-3-methoxyphenyl1-5- fluoro-2-methylbenzamide Example 577 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [!]• benzazepin-6-yl)carbonyl]-3-methoxyphenyl1-2.3- dimethylbenzamide Example 578 N-[4-[ (4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]• benzazepin-6-yl)carbonyl1-3-methoxyphenyl1-2- methylbenzeneacetamide

Example 579 N-[4-[(4,5-Dihydro-2-methyl-6g-thiazolo[5,4-d] [1]- benzazepin-6-yl)carbonyl]-3-methoxyphenyl]-2- chlorobenzeneacetamide Example 580 6.ll-Dihvdro-5-r4-r (3-methylbutanoyl)amino]benzoyl]-

5g-dibenz[b,e]azepine To a stirred solution of 0.16 g of 6,ll-di- hydro-5-(4-aminobenzoyl)-5g-dibenz[b,e]azepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.09 g of iso-valeryl chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue. The re¬ sidue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na ₂ S0 ) , filtered through hydrous magnesium silicate and evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.21 g of light yellow solid. MS(CI): 399(M+H).

Examnl e 581

Ethyl 6- r 4- r (5-fluoro-2-methvlbenzovl) aminol benzoyll -

4 , 5-dihvdro-6H-thienor3.2-dl \1 )benzazeoine-2-carboxylate

(a) To 20 ml of M-M-dimethylformamide (cooled to 0°C) is added dropwise (with rapid stirring) 1.80 ml (19.4 mmol) of phosphoryl chloride. After stirring for 10 minutes, 2.0 g (6.45 mmol) of 1, 2 , 3 , 4-tetrahydro-l-

( 4-nitrobenzoyl) -5H-l-benzazepin-5-one is added. The mixture is stirred at 0°C for 1 hour and at 80°C for 3.5 hours and poured into 70 ml of cold aqueous 20% sodium acetate. Additional water is added and the solid is filtered off, washed with water and dried under vacuum. The 2 , 3-dihydro-5-chloro-l- (4-nitrobenzoyl) -1H-1- benzazepine-4-carboxaldehyde (2.15 g) is stored at 0°C and used in the next step without further purification.

(b) To a slurry of 0.240 g (6.01 mmol) of sodium hydride (60% in oil) in 20 ml of M , U-dimethy1- formamide, chilled in an ice bath, is added 0.656 ml (6.01 mmol) of ethyl 2-mercaptoacetate. The mixture is stirred for 10 minutes and a slurry of 2.14 g (6.01 mmol) of 2 , 3-dihydro-5-chloro-l- (4-nitrobenzoyl) -1H-1- benzazepine-4-carboxaldehyde in 6 ml of U,£J-dimethyl- formamide is added dropwise. The mixture is stirred at room temperature overnight and then concentrated under high vacuum. The residue is partitioned between chloroform and water and the organic layer separated. The aqueous layer is extracted (twice) with chloroform and the organic layer and extracts combined and dried (Na2Sθ4) . The solvent is removed and the residue chromatographed on silica gel with dichloromethane as eluent (2 liter) and then with 4% ethyl acetate in dichloromethane as eluent . Fractions containing product are combined and the solvent removed under vacuum to give 2.1 g of ethyl 4 , 5-dihydro-6- (4-nitrobenzoyl) -6H-

thieno [3 , 2-dJ [l]benzazepine-2-carboxylate as a yellow foam.

(c) A mixture of ethyl (4 , 5-dihydro-6- (4- nitrobenzoyl) -6H-thieno[3 ,2-dJ [l]benzazepine-2- carboxylate (0.800 g) and 2.14 g of stannous chloride dihydrate in 36 ml of ethanol is refluxed for 1 hour, cooled to room temperature and diluted with ice water. The mixture is made basic with 10% sodium bicarbonate and stirred 3.8 hours. The mixture is extracted with chloroform and the extracts combined, treated with activated carbon and filtered through anhydrous magnesium sulfate. The filtrate is concentrated under vacuum to give 0.690 g of ethyl 4 , 5-dihydro-6- (4- aminobenzoyl) -6H-thieno [3 , 2-dJ [l]benzazepine-2- carboxylate as a tan foam: mass spectrum (CD 393 (MH ⁺ ) .

(d) To a solution of the preceding product (0.660 g) in 15 ml of dichloromethane is added 0.187 g of triethylamine and then a solution of 0.318 g of 5- fluoro-2-methylbenzoyl chloride in 2 ml of dichloro¬ methane is added. The mixture is stirred overnight and then washed with H2θ, 10% HCl, 10% NaHC03 and dried (MgS04) . The solvent is removed and the residue chromatographed on silica gel with ethyl acetate- dichloromethane (1:9) as eluent to give 0.70 g of ethyl 6- [ 4- [ (5-fluoro-2-methylbenzoyl) amino] benzoyl3 -4 , 5- dihydro-6H-thieno [3 , 2-d.] [1]benzazepine-2-carboxylate as a tan foam; mass spectrum (high resolution FAB) 529.1592 (MH+) .

Example 582 6- f4- r (5-Fluoro-2-methvlbenzovl)amino1benzov11 fi 1 -4.5- dihvdro-6H-thienof3.2-dl f 11benzazepine-2-carboxylic acid A slurry of 0.43 g of ethyl 6- [4- [ (5-fluoro-2- methylbenzoyl) amino]benzoyl] -4 , 5-dihydro-6H-thieno- [3, 2-d.] [1]benzazepine-2-carboxylate in 5 ml of methanol, 2 ml of tetrahydrofuran and 1.30 ml of 1 M

NaOH is stirred overnight. To the solution is added 2 M hydrochloric acid until the mixture is acidic. The volatiles are removed under vacuum and the residue diluted with water. The mixture is extracted with chloroform and the extracts combined and then concentrated under vacuum. Methanol is added (several times) and the solvent removed to give a solid. The solid is triturated with diethyl ether to give 0.38 g of white crystals, m.p. 290-292°C; mass spectrum (high resolution-FAB) 501.1255 (MH ⁺ ) .

Example 583

N- f4- f (4.5-Dihvdro-6H-thienor3.2-dl f1lbenzazepin-6- vl) carbonvllohenvll -2-methvl-3-fluorobenzamide

(a) A mixture of 0.80 g of ethyl 4,5-dihydro- 6- (4-nitrobenzoyl) -6H-thieno[3 , 2-dJ [1] -benzazepine-2- carboxylate in 25 ml of ethanol, 6 ml of tetrahydrofuran and 3.13 ml of 1 M sodium hydroxide is stirred at room temperature for 22 hours. The mixture is acidified with 2 ml of 2 M HCl and the solvents removed. The residue is dried under vacuum and extracted several times with CHCI3-CH3OH (1:1) . The extracts are combined and the solvent removed to give 0.72 g of 4 , 5-dihydro-6- (4- nitro-benzoyl) -6H-thieno [3 , 2-dJ [1]benzazepine-2- carboxylic acid as a yellow solid; mass spectrum (CD 395 (MH ⁺ ) .

(b) A mixture of 0.500 g of the preceding compound and 50 mg of copper powder in 7.5 ml of quinoline under argon is heated at 100-105°C for 1.5 hours. To the cooled mixture is added methanol and the mixture is filtered through diatomaceous earth. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution washed (twice) with 6 M HCl and dried (MgS04) . The solvent is removed to give a tan solid. This procedure was repeated three times to give 0.87 g of 4 , 5-dihydro-6- (4-nitrobenzoyl ) -6g-

thieno [3 , 2-cl] [l]benzazepine as tan crystals; mass spectrum (CD 351 (MH ⁺ ) .

(c) A mixture of 0.570 g of the preceding compound and 1.84 g of SnCl2*2H2θ in 26 ml of ethanol under argon is refluxed for 1 hour and cooled to room temperature. Ice water is added and 10% NaHC03 added to bring the pH to 8. After stirring for 4 hours, the mixture is extracted with chloroform (4 times) . The combined extracts are dried (MgS04) and the solvent removed to give a brown oil. The product oil from two batches is combined and chromatographed on silica gel with dichloromethane as eluent and then dichloromethane- ethyl acetate (9:1) as eluent. Fraction containing product are combined and the solvent removed to give 0.69 g of 4 , 5-dihydro-6- (4-aminobenzoyl) -6H-thieno

[3 , 2-d.] [1]benzazepine as a tan foam; mass spectrum (CD 321 (MH ⁺ ) .

(d) To a mixture of 0.310 g of the preceding compound and 147 mg of triethylamine in 7 ml of di¬ chloromethane is added 0.249 g of 2-methyl-3 -fluoro- benzoyl chloride in 1 ml of dichloromethane. The solution is stirred overnight and water added. The water is removed (solid at interface) and the organic layer washed with 10% HCl and then 10% NaHCθ3. The organic layer (containing solid) is filtered and the solid washed with dichloromethane. The filtrate is dried (MgS04 ) and the solvent removed to give a solid. The two crops of solid are triturated with cold dichloromethane to give crystals. The filtrate is filtered through a short silica gel column with CH2CI2 as eluent (discard) and then the silica gel is washed with ethyl acetate-dichloromethane (1:9) to give (on evaporation of solvent) 0.38 g of a white solid; mass spectrum (FAB-high resolution) 457.1388 (M+H) .

Example 584

N-T4-f (2-Chloro-4.5-dihvdro-6H-thienor3.2-dl r11benzazepin-6-yl)carbonyllohenvll -2-methyl-3- fl _U QrQbβηzamjde To a solution of 0.457 g (1.0 mmol) of N-[4- [ (4, 5-dihydro-6H-thieno[3, 2-dJ [1]benzazepin-6-yl)car- bonyl]phenyl] -2-methyl-3-fluorobenzamide in 25 ml of ethyl acetate is added 1.0 mmol of N-chlorosuccinimide. The mixture is stirred overnight and filtered. The filtrate is washed with water, 1 N HCl, 1 M NaHCθ3 , H2O and dried (Na2Sθ4) . The solvent is removed to give the product as a solid.

Example 585

N-f4-r (4.5-Dihvdro-6H-thienor3 ,2-dl f11benzazepin-6- vl) carbonvllphenvl1 -2-methvl-5-fluorobenzamide

To a mixture of 0.310 g of 4, 5-dihydro-6- (4- aminobenzoyl) -6H-thieno[3 ,2-dJ [l]benzazepine and 150 mg of triethylamine in 7 ml of dichloromethane is added 0.249 g of 2-methyl-5-fluorobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred overnight and the solvent removed. To the residue is added ethyl acetate and the mixture washed with H2O, 10% HCl, 10% NaHC03 and dried (Na2Sθ4) . The solvent is removed to give the product as a solid. The solid is chromato¬ graphed on silica gel with dichloromethane-ethyl acetate (95:5), then dichloromethane-ethyl acetate (9:1) as eluent. The fraction containing product is collected and the solvent removed to give 0.40 g of a tan foam; mass spectrum (high resolution FAB) 457:1388 (M+H) .