PHARMACEUTICALLY ACTIVE AMINES BACKGROUND OF THE INVENTION 1. Field of the Invention Disclosed are aromatic, alkyl, bicyclic and cycloalkyl amines These compounds are useful pharmaceutical agents in treating hea injury, spinal cord trauma, stroke and a number of other relate injuries and conditions.

2. Description of the Related Art The non-amine portion of some of the aromatic amines (I) ar known.

The non-amine portions of the alkyl amines (II) are known t those skilled in the art or can readily be prepared from know compounds by methods known to those skilled in the art.

The non-amine portions of the bicyclic amines (III) are known t those skilled in the art. See, in particular, US Patents 3,947,473

4,003,919, 4,018,799, 4,026,907 and 4,681,890. See also Britis

- Patent 947,885 and Chem. Abst. , 60, 11991 (1964). EP 202,580- discloses 3,4-dihydrobenzopyran derivatives, similar to the non-amin portion of the bicyclic amines (III) , which are attached to a 4 phenylmethyl-1-piperazinyl or a 4- (4-pyridinylmethyl)-1-piperaziny group. While these compounds are similar to the bicyclic amine

(III) of the present invention, the bicyclic amines (III) do not hav a methylene group between the phenyl or 4-pyridinyl substituent an the piperazinyl group. The non-amine portions of the cycloalkyl amines (IV) are know to those skilled in the art or can readily be prepared from know compounds by methods known to those skilled in the art.

The non-amine portions of the aromatic bicyclic amines (V) ar known to those skilled in the art. See, in particular, US Patents 4,181,665 (isochromans - 6 member heterocyclic ring) and 4,153,612 (2-benzoxepins - 7 member heterocyclic ring). These patents also disclose the non-amine portion of the aromatic bicyclic amines (V) , attached to various amines, but different amines than included within the present invention. Those amines were disclosed as possessing antihypertensive and tranquilization activity including antidepres- sant and antianxiety effects. The activity of the aromatic bicyclic amines (V) is quite different.

Published PCT patent application serial No US 86/01797, Interna-

tional Disclosure Number WO87/01706 (PCT 86/01797) discloses amino steroids where the amlne portion includes acyclic, aromatic and heterocyclic amine functionality very similar to the amino sub¬ stituents, where M is -NR _A R _B , of the present invention. In PCT 86/01797, the amino substituent was attached to the terminal carbon atom of the C side chain of a steroid. The present invention differs from PCT 86/01797 in that the non-amine portion Is not a steroid. PCT 86/01797 also disclosed numerous references involving various amines and amino substituents which are incorporated here by reference. PCT 86/01797 is the reference which discloses amino substituents most similar to those of the present Invention.

The non-amine portion of the hydroquinones (VI) and quinones (VII) are well known to those skilled in the art. Great Britin patent 2,127,814A disloses amino-quinones containing a fused ring containing a nitrogen atom, the hydroquinones (VI) and quinones (VII) of the present patent do not contain a ring fused to the hydroquinone or quinone. J6 1,254,546A discolses acyclic amine quinone deriva¬ tives which contain only a simple nitrogen atom in a long side chain of carbon atoms. US Patent discloses amino-quinones but of an indole type.

The non-amine portion of the amino ethers (VIII) are known to those skilled in the art. JA-7,124,369 discloses heptatrienes which are not similar to the bicyclic aromatic/7-member nitrogen-oxygen containing ring system of the amino ethers (VIII) The non-amine portion of the bicyclic amino ethers (IX) are known to those skilled in the art. EP 244018-A discloses oxazole- amine derivatives but where the oxazole ring is not fused to a phenyl ring as in the present situation. EP 199400-A discloses a fused oxazole-phenyl ring system having a side chain containing nitrogen. EP 202,580-A discloses 3,4-dihydrobenzopyran derivatives almost identical with the compounds encompassed by formula (XI) . The utility of the compounds disclosed in EP 202,580-A is as a prophylac¬ tic for gastritis caused by inflammation of the gastric mucosa. The utility claimed for these agents in the present patent applica- tion has nothing to do with gastritis caused by inflammation of the gastric mucosa.

SUMMARY OF INVENTION Disclosed are aromatic amines of formula (I) where:

(I) R^ or and R3 taken together are -O-CH2-O- and the other

R ₂₂ is -H, -Cl or C-L-Cβ alkyl; R ₂₃ is -H, -Cl or C -C ₃ alkyl; (II) R and R ₂ are the same or different and are -H, C—C4 alkyl, -F, -Cl and -Br, and R3 is -H, -OH, C -C ₃ alkoxy, -0-S0 ₂ -CH ₃ , -0-C0-(C -C alkyl) and -0-prodrug where prodrug is -P0 ₂ -0-, -C0-CH2-C0-NH-CH ₂ -S0 ₂ -0- , - ^C0 "( ^CH 2 _' ^, n21'' ^R 51 where ⁿ 21 ^{is 1} "^ ^{and R} 51 ^is - ^c00 ~> - ^•• " ^• -51- l ^R 51-2 where ^R 51-l ^an< -' ^R 51-2 ^{are le same or} different and are -H or Cχ-C ₃ alkyl, -N ⁺ 5i_ιR5χ_2 5i_. ₃ halide ^" where 5l-l 5l-2 ^R 51-3 ^{are the} same or different and are -H or C -C alkyl, and where halide. is -Cl or -Br, -CO-CH-CH-CO-O ^" ,

-CO-N*-CH=CH-N=CH* where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring,

-C0-C*-C[ CH _{2 n} 22-NH2]- ^GH - ^CH - ^CH " ^CH * where n ₂ 2 is 1 or 2 and where the atoms marked with an asterisk ( ) are bonded to each other resulting in the formation of a ring,

-C0-C*-CH-CH-C(-NR ₅ 2)-CH-CH* where R ₅₂ is -H or Cχ-C ₃ alkyl and where the atoms marked with an asterisk ( *_.) are bonded to each other resulting in the formation of a ring,

-C0-(CH ₂ ) _n 2l-C0-O-[C ₆ H ₁₂ 0 ₆ sugars] , -CO-0-CH(CH2-0-CO-R ₅₃ )2 where the 5 ₃ 's are the same or different and are C -C g,

-CO-(CH2)6- ^c °- ^N ( ^CH 3)- ^CH 2- ^CH 2- ^so 3 ^~ cation ^" * ^* where cation ^*1* is sodium, potassium or trialkylammonium where alkyl is C -C ₃ ,

-CH2-0-C0-(CH2) _n 21-NR51_lR51-2 where n2χ, 51.1 and R51.2 are as defined above,

-CO- H-C6H4-R55 where R55 is -H or Cχ-C ₃ alkyl, -N0 ₂ , -NR5I-IR5I-2 where 51.1 and 5 .2 are as defined above and R ₂ 2 is -H, -OH, -Cl, Cχ-C ₃ alkyl, -0CH ₃ or -OC ₂ H ₅ ; R ₂₃ is -H, -OH, -Cl, C -C ₃ alkyl, -0CH ₃ or -OC ₂ H ₅ ; with the proviso that only two of R ₃ , R ₂ 2 and R ₂₃ can have a variable sub¬ stituent containing an oxygen atom attached to the benzene ring; where X^ is -0- , -CH ₂ -,

-C(CH ₃ )(CH ₃ )-,

-C(H R2 )- where R24 is C ₁ -C alkyl or phenyl optionally substituted with 1 or 2 -OH, -CH ₃ or -0CH ₃ ,

-C(OH)(R ₃ ) where R*L ₃ is -H or C ₁ -C ₃ alkyl, or phenyl optionally substituted with 1 or 2 -OH, -CH3 or -0CH ₃ ,

-S-, -S1-, -CO-, -NH-CO- and -NR4- where R ₄ is -H or C -C4 alkyl; -L is 0-10;

R3 and Rg are the same or different and are -H or C -C3 alkyl; n*L3 is 0 or 1; ₁ is 2-5; M is (I) -NR _A R _B where: (A) R _A is (1) -(CH2) ^' _m -NR _M . -heteroaryl, where m is 2, 3 or 4, where

^R M-1 *- ^s ""**** ^or *-'l"^3 alkyl, where heteroaryl is:

(a) pyridIn-2- (F-l) , 3- (F-2) or 4-yl (F-3) or the N- oxide thereof optionally substituted by 1 or 2 R _j __2 _ι being the same or different, where JI_2 i (i) -F,

(ϋ) -Cl, (ϋi) -Br, (iv) C-L-C-5 alkyl, (v) -CH ₂ -CH-CH ₂ , ^' (vi) -aryl, where aryl is phenyl optionally substituted with 1 through 2 -F, -Cl, -Br, C*L-C ₃ alkoxy, -C00H, - H2, C1-C3 alkylamino, di(C-> _L -C ₃ )alk lamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexa- meth lenimino- , l-heptamethylenlmino-, C2-C acylamino and -NH-CHO or with 1 -F or -CF ₃ ;

(vii) - R _j _ ₃ Rtø_ ₃ where the Rft_ ₃ s are the same or different and are -H, C ₁ -C ₃ alkyl or -CH ₂ -CH-CH _2>

(viiiα) *CH ₂ -(CH ₂ ) _q -CH2-N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5,

(viii3) *CH ₂ -(CH ₂ ) _c -G-(CH ₂ ) _d -CH ₂ -N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring (F-4) , where G is -0- , -S-, -S0-, -S0 ₂ - or

-N .4-, where R«_4 is -H, C ₁ -C ₃ alkyl, or aryl as defined above where c and d are the same or different and are 0 through 2 with th proviso that the total number of ring carbon atons is 4, 5 or 6,

(ix) 3-pyrrolin-l-yl, (F-5 (x) pyrrol-1-yl optionally substituted with C -C alkyl, (F-6

(xi) piperidin-1-yl optionally substituted with or 2 Cχ-C ₃ alkyl, (F-7

(xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-8 (xiii) l-hexameth leneimino containing a 3- or 4 double bond or 3- and 5- double bonds, (F-9

(xiv) 1,4-dihydro-l-pyridinyl substituted in th 4 position by two Cχ-C ₃ alkyl being the same or different, (F-10

(xv) -OH, (xvi) C -C ₃ alkoxy,

(xvii) -NR _M _7-(CH ₂ ) _e -Q where Q is 2-pyridiny where ft_7 is -H or C*^-C ₃ alkyl and e is 0 through 3,

(xviii) pyridin-2-, 3- or 4-yl, (xix) -CF ₃ , (xx) -CC1 _3>

(xxi) -SCH ₃ , (b) 1,3 ,5-triazin-2-yl or the N-oxide thereof option ally substituted at the 4- and/or 6- position with R _j( -2 - ^{s a} defined above, (F-ll (c) pyrimidin-4-yl or the N-oxide thereof optionall substituted at the 2- and/or 6-, and 5- and/or 6- position with R^_ is as defined above, (F-12)

(d) pyrimidin-2-yl optionally substituted at 4- and/o 6- position with 1 or 2 tø-2 as is defined above, (F-13) (e) pyrazin-2-yl optionally substituted with 1 or 2

R _M _2 as is defined above, (F-14)

^■ (f) imidazol-2-yl optionally substituted in the 1 position with C -C alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 R _j( _2 ^as defined above, (F-15)

(g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C- _^ -C^ alkyl or -aryl, where aryl is as defined above, and further optionally substituted with tø_2 as defined above, (F-16)

(h) imidazol-4- or 5-yl optionally substituted in the

1 position with C*L-C ₃ alkyl or -aryl, where aryl is as defined above, and further optionallysubstitutedwith 1 or 2 j_£-2 as definedabove, (F-17)

(i) benzo[b]thien-2-yl, (F-18) (j) indol-2-yl, (F-19)

(k) benzo[b]thiazol-2-yl, (F-20)

(1) benzimidazol-2-yl, (F-21)

(m) 4- [2- [4- [2,6-bis(l-pyrrolidinyl)-4- pyrimidinyl] -1-piperazinyl]ethyl] , (F-22) (n) l,2,4-triazin-3-yl optionally substituted at the

5- and/or 6- position with fl-2 ^as i defined above, (F-23)

(2) -(CH2)2- "C-l"P P ^er azin l) optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(3) -heteroaryl, as defined above, (4) - CH2 _m - 4 where m is as defined above and where X is

(a) -0-CH ₂ CH2- , where Y is C;j_-C ₃ alkylamino, di(C-*_- C ₃ )alk lamino where the alkyl groups are the same or different, C ₃ - Cg alkyleneimino _r optionally substituted with 1 or 2 C*L~C ₃ alkyl,

(b) -NR _M . ₅ CH ₂ CH ₂ -Y, where R _κ . ₅ is -H or C^C-J alkyl and Y is as defined above,

(c) -(CH ₂ ) _g -N(R _M .5)-heteroaryl, where g is 2, 3 or 4, and where tø_5 and heteroaryl are as defined above,

(5) -(CH ₂ ) _m -NR ₁₁ . ₆ R _M . ₈ , where R _jj .g is -H or C -C ₃ alkyl and ^R M-8 *** ^s -aryl or -heteroaryl as defined above, or ft-6 and R _j _£_g are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C ₃ -Cg heterocyclic ring and where is as defined above,

(6) -(CHCH ₃ ) _D -(CH ₂ )f-aryl where b is 0 and f is 1 through 4 or b is 1 and f is 0 through 3, where aryl is as defined above, (7) -(CH2)ι-heteroaryl, where i is 1 through 4 and hetero¬ aryl is as defined above,

(8) (1-piperazinyl)acetyl substituted in the 4- position by heteroaryl where heteroaryl is as defined above, (F-25)

(9) (1-piperazinyl)carbonylmethyl substituted in the 4- positionby -heteroarylwhereheteroaryl is as definedabove, and(F-26) (B) R _B is

(1) -H,

(2) Cχ-C ₃ alkyl,

(3) C ₅ -C ₇ cycloalkyl,

(4) - (CH2) _m -NR*f-i-heteroaryl, where m, R^.i and heteroaryl are as defined above,

(5) (1-ρiperazinyl)-(C2-C4 lkyl optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(6) -(CH2) _m - 4_ where m and X4 are as defined above,

(7) -(CH ₂ ) _m -NR _M . ₆ R _M . ₈ , where m, E . and R _j ^.g are as defined above,

(8) -(CHCH ₃ )j--(CH2)f-R-M_.9. where b, f and R^.g are as defined above,

(9) 2-pyridinylmethyl,

(C) _A and R _β are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of

(1) 2-(carboxy)-1-pyrrolidinyl optionally as the C -C~ alkyl ester or as a pharmaceutically acceptable salt, (F-27)

(2) 2-(carboxy)-1-piperidinyl optionally as the C -C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-28)

(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C-^- C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-29) (4) 2-(carboxy)-1-heptamethyleneimino optionally as the C-^-

C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-30)

(5) 1-ρiperazinyl optionally substituted in the 4- position with R _M . 2-C°-( ^CH 2- ⁾ j" ^where -12 ^is - ^a ~y- > -heteroaryl, -N MI ₃ - heteroaryl and 2-furanyl, where Rtø-13 is -H or C -C ₃ alkyl, where j is 0 through 3, and aryl and heteroaryl are as defined above, (F-31)

(6) 1-piperazinyl substituted in the 4- position with heteroaryl-(CH )4 - , where heteroaryl and j are as defined above, (F-32)

(7) 1-piperazinyl substituted in the 4- position with aryl-(CH ₂ )-i - , where aryl and j are as defined above, (F-33) (8) 4-hydroxy-l-piperidinyl substituted in the 4- position with aryl as defined above, (F-34)

(9) 1-piperazinyl substituted in the 4- position with heteroaryl-NRtø_*L ₃ -C0-(CH ) - , where heteroaryl, RH_-J_ ₃ and i are as defined above; (F-35) (10) 1-piperazinyl substituted in the 4- position with

-(CH ₂ )j-C*-C(2-pyridinyl)-N=N-C(2-pyridinyl)-C*H, where * and j are as defined above, (F-36)

(11) 1-piperazinyl substituted in the 4- position with

- (CH ₂ ) i- [4- [2 , 6-bis(l-pyrrolidinyl) -4-pyrimidinyl] - 1-piperazine] (F-37) or

(II) -C*-C(2-pyridinyl)-N-N-C(2-pyridInyl)-C*H where * is as defined above and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof. Preferred are compounds where X- _j _ is -0- , -CH2- or X^ is -CO-; where τiι * ³ ***"*' ^inore preferrably n-]_ is 1-6; where R-^ and R ₂ are the same and are -H, C-^ alkyl or C alkyl; where R is -OH or C*^-C ₃ alkoxy; where Rg and Ro are both -H; where n-^ ₃ is 0 and the compounds of EXAMPLES 24-52, 56-59, 65, 69, 70, 72-74, 77 and 182.

Also disclosed are alkyl amines of the formula X ₂ - CH2) _n 2-tt (II) where: n2 Is 4-14; X ₂ is -H, -OH, -0-C0-(C ₁ -C alkyl), -O-CO-H, -0-CO-O-(C- ₁ -C4 alkyl), (C1-C ) alkoxycarbonyl, -O-CO-aryl where aryl is φ optionally substitued with -OH,

-0CH ₃ , -F, -Cl,

-Br, -CF ₃ ,

-C ^* L-C alkyl, and -CO-R5 where R5 is -OH, -NH ₂ ,

-NHRg where Rg is φ or C -C ₃ alkyl, and

-N(R-L ) Rχ ₅ ) where R-^4 and R ₁₅ are the same or different and are C--_-C ₃ alkyl; M is

(I) -NR _A R _B where: (A) R _A is

(1) -(CH2 _m - _M .- _] _-heteroaryl, where m is 2, 3 or 4, where R{__*L is -H or C -C ₃ alkyl, where heteroaryl is: (a) pyridin-2- (F-l) , 3- (F-2) or 4-yl (F-3) or the N- oxide thereof optionally substituted by 1 or 2 R^_ _> being the same or different, where Rtø_2 is

(I) -F,

(ϋ) -Cl, (iii) -Br, (iv) C-L-C ₅ alkyl, (v) -CH -CH-CH ₂ , (vi) -aryl, where aryl is phenyl optionally substituted with 1 through 2 -F, -Cl, -Br, C -C ₃ alkoxy, -COOH, -NH ₂ , C-L-C ₃ alkylamino, di(C ₁ -C )alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl- , 1-piperidinyl, 1-hexa- methylenimino- , 1-heptamethylenimino- , C ₂ -C4 acylamino and -NH-CHO or with 1 -F or -CF ₃ ;

(vii) - Rj ⁴ i_ Rtø_ ₃ where the M. S are the same or different and are -H, C ₁ -C ₃ alkyl or -CH ₂ -CH-CH ₂ ,

(viii ) *CH ₂ -(CH ) _q -CH ₂ -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5,

(viii/3) *CH ₂ -(CH ₂ ) _c -G-(CH ₂ ) _d -CH ₂ -N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring (F-4) , where G is -0- , -S-, -SO-, -S0 ₂ - or -N -tf. -, where R^- is -H, C- _] _-C ₃ alkyl, or aryl as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6,

(ix) 3-pyrrolin-l-yl, (F-5)

(x) pyrrol-1-yl optionally substituted with C -C ₃ alkyl, (F-6) (xi) piperidin-1-yl optionally substituted with 1 or 2 C -C ₃ alkyl , (F- 7)

(xii) 1 , 2 , 3 , 6- tetrahydropyridin- l-yl , (F- 8)

(xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-9) (xiv) 1,4-dihydro-l-pyridinyl substituted in the

4 position by two C -C ₃ alkyl being the same or different, (F-10)

(xv) -OH,

(xvi) C -C ₃ alkoxy,

(xvii) -NR _M _ ₇ -(CH ₂ ) _e -Q where Q is 2-pyridinyl where Rrø_7 is -H or C- _j _-C ₃ alkyl and e is 0 through 3,

(xviii) pyrIdin-3- or 4-yl, (xix) -CF ₃ , (xx) -CC1 ₃ ,

(xxi) -SCH ₃ , (b) l,3,5-triazin-2-yl or the N-oxide thereof option¬ ally substituted at the 4- and/or 6- position with Rtø_2 i as defined above, (F-ll) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6-, and 5- and/or 6- position with j^.2 is as defined above, (F-12)

(d) pyrimidin-2-yl optionally substituted at 4- and/or 6- position with 1 or 2 _ ₂ ^{as is} de ined above, (F-13) (e) pyrazin-2-yl optionally substituted with 1 or 2

^R M-2 ^as *** ^s defined above, (F-14)

(f) imidazol-2-yl optionally substituted in the 1 position with C -C ₃ alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 R _j{ _. ₂ as defined above, (F-15)

(g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C*L-C ₃ alkyl or -aryl, where aryl is as defined above, and further optionally substituted with ^β ^-2 ^as defined above, (F-16)

(h) imidazol-4- or 5-yl optionally substituted in the 1 position with C -C ₃ alkyl or -aryl, where aryl is as defined above, andfurther optionally substitutedwith1 or 2 _jj .2 as definedabove, (F-17)

(i) benzo[b]thien-2-yl, (F-18)

(j) indol-2-yl, (F-19)

(k) benzo[b]thiazol-2-yl, (F-20) (1) benzimidazol-2-yl, (F-21)

(m) 4-[2-[4-[2 _r 6-bis(l-pyrrolidinyl)-4- pyrimidinyl] -1-piperazinyl]ethyl] , (F-22)

(n) l,2,4-triazin-3-yl optionally substituted at the

5- and/or 6- position with tø_ as is defined above, (F-23) (2) -(CH ) ₂ ..4-(1-piperazinyl) optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(3) -heteroaryl, as defined above,

(4) -(CH ₂ ) _m -X4 where m is as defined above and where X4 is

(a) -0-CH ₂ CH ₂ -Y, where Y is C- _j ^^ alkylamino, di(C ₁ - C )alkylamino where the alkyl groups are the same or different, C3-

Cg alkyleneimino, optionally substituted with 1 or 2 C-^-C alkyl,

(b) -N _ ₅ CH ₂ CH ₂ -Y, where R^_ ₅ is -H or 0-^0-3 alkyl and Y is as defined above,

(c) -(CH2) _g -N(R _M .5) -heteroaryl, where g is 2, 3 or 4, and where Rtø-5 and heteroaryl are as defined above,

(5) -(CH ₂ ) _m -NR _M .gR _M _g, where R _M .g is -H or C -C ₃ alkyl an R^. is -aryl or -heteroaryl as defined above, or Rft-6 ^an JI-8 ^ar taken together with the attached nitrogen atom to form a saturate mono-nitrogen C ₃ -Cg heterocyclic ring and where m is as define above,

(6) -(CHCH ₃ ) _b -(CH ₂ )f-aryl where b is 0 and f is 1 through or b is 1 and f is 0 through 3, where aryl is as defined above, (7) -(CH ₂ )i-heteroaryl, where i is 1 through 4 and hetero¬ aryl is as defined above,

(8) (1-piperazinyl)acetyl substituted in the 4- position b heteroaryl where heteroaryl is as defined above, (F-25)

(9) (l-piperazinyl)carbonylmethyl substituted in the 4- positionby -heteroaryl where heteroaryl is as definedabove, and(F-26) (B) R _B is

(1) -H,

(2) C-L-C-3 alkyl,

(3) C5-C7 cycloalkyl, (4) -(CH ) _m -NR _M . -heteroaryl, where m, R^-i " heteroaryl are as defined above,

(5) (1-piperazinyl)-(C ₂ -C4)alkyl optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(6) -(CH2 _m -X , where m and X4 are as defined above, (7) -(CH ₂ ) _m -NR _M .gR _M -.g, where m, _jj .g and I .g are as defined above,

(8) -(CHCH ₃ ) _b -(CH ₂ )f-R _M _9 _> where b, f and R _M _ ₉ are as defined above,

(9) 2-pyridinylmethy1, (C) R and Rg are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of

(1) 2-(carboxy)-1-pyrrolidinyl optionally as the C- C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-27)

(2) 2-(carboxy)-1-piperidinyl optionally as the C -C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-28)

(3) 2-(carboxy)-1-hexamethyleneimino optionally as the 0 - C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-29)

(4) 2-(carboxy)-1-he tamethyleneimino optionally as the C _] _-

C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-30)

(5) 1-piperazinyl optionally substituted in the 4- position with R _M _i2-C0-(CH ₂ )j- where RM-12 ^is -- ^" "-T ¹ - -heteroaryl, -NR _H13 - heteroaryl and 2-furanyl, where -i ₃ is -H or C -C ₃ alkyl, where j is 0 through 3, and aryl and heteroaryl are as defined above, (F-31)

(6) 1-piρerazinyl substituted in the 4- position with heteroaryl-(CH2)-i- , where heteroaryl and j are as defined above, (F-32)

(7) 1-piperazinyl substituted in the 4- position with aryl-(CH ₂ )-i- . where aryl and j are as defined above, (F-33) (8) 4-hydroxy-l-piperidinyl substituted in the 4- position with aryl as defined above, (F-34)

(9) 1-piperazinyl substituted in the 4- position with heteroaryl-NR _M . ₃ -CO-(CH2)ι-, where heteroaryl, R _j _t_ι ₃ and i are as defined above; (F-35) (10) 1-piperazinyl substituted in the 4- position with

-(CH ₂ )j-C*-C(2-pyridinyl)-N-N-C(2-pyridinyl)-C*H, where * and j are as defined above, (F-36)

(11) 1-piperazinyl substituted in the 4- position with -(CH ₂ ) _i -[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazi ne](F-37) or

(II) -C*-C(2-pyridinyl)-N-N-C(2-pyridinyl)-C*H where * is as defined above, and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof. Preferred are compounds where n ₂ is 4-8, more preferrably where n ₂ is 6 and where X ₂ is -H, -OH, -0-C0-(C ₁ -C alkyl) or -0-CO-aryl and the compounds of EXAMPLES 1-17.

Further disclosed are bicyclic amines of formula (III) where: W ₂ is -0-, -S-, -NR54- where R54 is -H or C -C ₃ alkyl, ng is 0, 1 or 2,

R ₇ is -H or -C1-C alkyl, -C0-(C -C4 alkyl), -CO-φ or -prodrug where prodrug is

-PO ₂ -O-, -C0-CH2-C0-NH-CH ₂ -S0 ₂ -0 ^"" , -C0-(CH ₂ ) _n21 -R ₅₁ where n ₂₁ Is 1-7 and R ₅₁ is -COO", -NR ₅₁ . l ^R 51-2 l ^* - ^ere R51-1 and R5χ_ are the same or different and are -H or ^-05 alkyl, -N ⁺ R5 ₁ . ₁ R ₅₁ . ₂ R ₅₁ . ₃ halide ^" where R5i_ιR5i_ ₂ R5i_ ₃ are the same or different and are -H or C -C ₃ alkyl, and where halide is -Cl

or -Br,

-C0-CH-CH-C0-0-,

-CO-N*-CH-CH-N-CH* where the atoms marked with an asteris (*) are bonded to each other resulting in the formation of a ring, -CO-C*-C[(CH ₂ ) _n22 -NH ₂ ]-CH-CH-CH-CH* where n ₂₂ is 1 or 2 an where the atoms marked with an asterisk ( ) are bonded to each othe resulting in the formation of a ring,

-CO-C*=CH-CH-C(-_ra ₅₂ )-CH--CH* where R ₅₂ is -H or C ₁ -C ₃ alky

*_-? and where the atoms marked with an asterisk ( ) are bonded to eac other resulting in the formation of a ring,

-CO-(CH ₂ ) _n 2i-CO-0-tCgH ₁₂ Og sugars],

-CO-O-CH(CH2-0-CO-R5 ₃ ) ₂ where the 5 ₃ 's are the same o different and are C^-C^g,

-CO-(CH ₂ )g-CO-N(CH ₃ )-CH2-CH ₂ -S0 ₃ - cation ^*1" where cation ^"1" i sodium, potassium or trialkylammonium where alkyl is C^-C- _j ,

-CH ₂ -0-C0-(CH ) _n - R5 _.χR5 _.2 where n ₂ ι, R51-I and R51. are as defined above,

-C0-NH-C ₆ H4-R ₅ 5 where R55 is -H or C -C ₃ alkyl, -N0 ₂ , -NR5 .-LR5 .2 where R5 .1 and R51.2 ^are as defined above and

R i is -H or -CH ₃ , ^* L2 i- ^{3 *H or} -CH ,

(18-1) R-^ is α-Rl -l ^* 3- ι .2 where one of ι _ι and Rχ _2 is -H, -CH ₃ , -CH ₂ CH ₃ or -φ and the other is -X ₃ -M where X3 is -CO-, -(CH ₂ ) _n ιg-C0- where n-^ is 1 or 2, -(CH ₂ ) _n3 - where n ₃ is 1-6, or -CO-O-(CH _n "L5- where n 5 is 2-6, R ₂ 5 and R ₂ g are -H and where M is (I) -NR _A R _B where: (A) R _A is (1) -(CH ₂ ) _m -N _M _ -heteroaryl, where m is 2, 3 or 4, where

^R M-1 - ^s " ^{H or C} 1 ^_G 3 alkyl, where heteroaryl is:

(a) pyridin-2- (F-l), 3- (F-2) or 4-yl (F-3) or the N- oxide thereof optionally substituted by 1 or 2 R _j _ι_2. being the same or different, where Rtø_2 is (i) -F,

(ϋ) -Cl,

(ϋi) -Br,

(iv) C ₁ -C ₅ alkyl,

(v) -CH ₂ -CH-CH ₂ ,

(vi) -aryl, where aryl is phenyl optionally substituted with 1 through 2 -F, -Cl, -Br, C -C ₃ alkoxy, -COOH, - H2, C -C ₃ alkylamino, di(C--_-C )alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexa- methylenimino- , 1-heptamethylenimino-, C2-C acylamino, -NH-CHO, with 1 -F or -CF ₃ or with 3,4-methylenedioxy and 3,4-ethylenedioxy;

(vii) -NRM-3 ^R M-3 where the Rjf_ ₃ s ^are the same or different and are -H, C-L-C ₃ alkyl or -CH ₂ -CH-CH ₂ , (viiiα) *CH ₂ -(CH ₂ ) _q -CH ₂ -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5,

(viii3) *CH ₂ -(CH ₂ ) _c -G-(CH ₂ ) _c i-CH ₂ -N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring (F-4) , where G is -0- , -S-, -SO-, -SO2- or - R _M _4-, where tø-4 is -H, C -C ₃ alkyl, or aryl as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6,

(ix) 3-pyrrolin-l-yl, (F-5) (x) pyrrol-1-yl optionally substituted with C -C ₃ alkyl, (F-6)

(xi) plperidin-l-yl optionally substituted with 1 or 2 C -C ₃ alkyl, (F-7)

(xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-8) (xiii) 1-hexamethyleneimlno containing a 3- or 4- double bond or 3- and 5- double bonds, (F-9)

(xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C-L-C alkyl being the same or different, (F-10)

(xv) -OH, (xvi) C*L-C ₃ alkoxy,

(xvii) -NR _M _ ₇ -(CH ₂ ) _e -Q where Q is 2-pyridInyl where ^-7 is -H or C-^- C^ alkyl and e is 0 through 3,

(xviii) pyridin-2-, 3- or 4-yl, (xix) -CF ₃ , (xx) -CCI3.

(xxi) -SCH ₃ , (b) l,3,5-triazin-2-yl or the N-oxide thereof option¬ ally substituted at the 4- and/or 6- position with R _j f_2 - _* - ^{Ξ as}

defined above, (F-ll)

(c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6-, and 5- and/or 6- position with R^-2 is as defined above, (F-12) (d) pyrimidin-2-yl optionally substituted at 4- and/or

6- position with 1 or 2 Rj^-2 ^{as is} defined above, (F-13)

(e) pyrazin-2-yl optionally substituted with 1 or 2 ^R M-2 ^as _~ ^s defined above, (F-14)

(f) imidazol-2-yl optionally substituted in the 1 position with C -C ₃ alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 RM-2 as defined above, (F-15)

(g) 1,3,4- riazol-2-yl optionally substituted in the 1 position with C -C ₃ alkyl or -aryl, where aryl is as defined above, and further optionally substituted with _2 as defined above, (F-16)

(h) imidazol-4- or 5-yl optionally substituted in the

1 position with C -C ₃ alkyl or -aryl, where aryl is as defined above, and further optionally substitutedwith 1 or 2 Rtø_2 ^as de ined above, (F-17)

(i) benzo[b]thien-2-yl, (F-18) (j) indol-2-yl, (F-19)

(k) benzo[b]thiazol-2-yl, (F-20)

(1) benzimidazol-2-yl, (F-21)

(m) 4-[2-[4-[2,6-bis(l-pyrrolidinyl)-4- pyrimidinyl] -1-piperazinyl]ethyl] , (F-22) (n) l,2,4-triazin-3-yl optionally substituted at the

5- and/or 6- position with RM_2 ^as i- ³ defined above, (F-23)

(2) -(CH2)2-4- (1-piperazinyl) optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(3) -heteroaryl, as defined above, (4) -(CH2) _m - where m is as defined above and where X4 is

(a) -0-CH ₂ CH ₂ -Y, where Y is C;L-C ₃ alkylamino, di(C--_- C ₃ )alkylamino where the alkyl groups are the same or different, C3- Cg alkyleneimino, optionally substituted with 1 or 2 C -C ₃ alkyl,

(b) -NR _M . ₅ CH ₂ CH ₂ -Y, where 1^.5 is -H or C -C-3 alkyl and Y is as defined above,

(c) -(CH ₂ )g-N(R _M .5) -heteroaryl, where g is 2, 3 or 4, and where R _j ^_5 and heteroaryl are as defined above,

(5) -(CH ₂ ) _m -NR _M . ₆ R _M .g, where R^. is -H or C _j ^ alkyl and

Ru.g is -aryl or -heteroaryl as defined above , or ft- g ^and ft-8 ^are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C ₃ -Cg heterocyclic ring and where m is as defined above , ' (6) - (CHCH3) - (CH ₂ )f-aryl where b is 0 and f is 1 through 4 or b is 1 and f is 0 through 3 , where aryl is as defined above,

(7) - (CH2) i-het roar l , where i is 1 through 4 and hetero¬ aryl is as defined above ,

(8) (l-piperazinyl)acetyl substituted in the 4- position by heteroaryl where heteroaryl is as defined above, (F-25)

(9) (1-piperazinyl) carbonylmethyl substituted in the

4- position by -heteroaryl where heteroaryl is as defined above , and(F-26) and

(B) R _B is (1) -H,

(2) C-L-C3 alkyl,

(3) C ₅ -C ₇ cycloalkyl,

(4) -(CH ₂ ) _m -NR _M . -heteroaryl, where m, R^-i and heteroaryl are as defined above, (5) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24)

(6) -(CH ) _m -X4, where m and X are as defined above,

(7) -(CH ₂ ) _m -NR _M .gR _M .g, where m, Ry.g and R _jj . are as defined above, (8) -(CHCH ₃ ) _b -(CH2)f- _ ₉ , where b, f and R^.g are as defined above,

(9) 2-pyridinylmeth l _^

(10) 2-phenylethyl,

(C) R and R _B are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of

(1) 2-(carboxy)-1-pyrrolidinyl optionally as the C*L-C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-27)

(2) 2-(carboxy)-1-piperidinyl optionally as the C-^-C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-28) (3) 2-(carboxy)-1-hexamethyleneimino optionally as the C-^-

C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-29)

(4) 2-(carboxy)-1-heptamethyleneimino optionally as the C-ι -

C ₃ alkyl ester or as a pharmaceutically acceptable salt, (F-30)

(5) 1-piperazinyl optionally substituted in the 4- positio with R _M _i2- ^C0 "'( ^CH 2 _' ⁾ j'' ^{where R} M-12 ^is - ^ar y ¹ * -heteroaryl, -NR _M13 - heteroaryl and 2-furanyl, where Rn_χ ₃ is -H or C* _| _-C ₃ alkyl, where j is 0 through 3, and aryl and heteroaryl are as defined above, (F-31) (6) 1-piperazinyl substituted in the 4-position with heteroaryl(CH2)- _j - where heteroaryl and j are as defined above with the proviso that j is not 1 when heteroaryl is pyridin-4-yl or pyridin-4-yl substituted with C-^-C ₃ alkoxy, optionally substituted at the 2-position with -NR44R45 where R45 and R45 are the same or different and are -H, C--_-C ₃ alkyl and where R44 and R45 can be taken together with the attached nitrogen atom to form 1-pyrrolidinyl, 1- morpholinyl and 1-piperidinyl, (F-32)

(7) 1-piperazinyl substituted in the 4-position with aryl- (CH2)-*-, where aryl and j are as defined above with the proviso that j is not 1, (F-33)

(8) 4-hydroxy-1-piperidinyl substituted in the 4- position with aryl as defined above, (F-34)

(9) 1-piperazinyl substituted in the 4- position with heteroaryl-NR _M . ₃ -CO-(CH2)ι- , where heteroaryl, Rtø-13 and i are as defined above; (F-35)

(10) 1-piρerazinyl substituted in the 4- position with -(CH )j-C*-C(2-pyridinyl)-N--N-C(2-pyridinyl)-C*H, where * and j are as defined above, (F-36)

(11) 1-piperazinyl substituted in the 4- position with -(CH ₂ ) _i - [4- [2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl] -1-piperazine] (F-37)

(12) 1-piperazinyl substituted in the 4-position with C^- C3 alkyl optionally substituted with 1 or 2 aryl, or

(II) -C*«C(2-pyridinyl)-N ^« N-C(2-pyridinyl)«C*H where * is as defined above

(18-2) ng is 0, R-^g is Ri6-3 ^:R 16-4 where one of ι .3 and Rχ . is taken together with R ₂ 5 to form a second bond between the carbon atoms to which R-^ and R 5 are attached and the other of R g_ ₃ and R g_4 is -X ₃ -M where X ₃ and M are as defined above, (18-3) ng is 1, R ₂ 5 and R g are taken together to form a second bond between the carbon atoms to which R 5 and R ₂ g are attached and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof.

Preferred compounds are where R is -H; where R-io- Rn and R ₂ are all -CH ₃ ; where ng is 1; where one of Rιg.χ or Rι _ ₂ is -CH ₃ ; where X ₃ is -CO- or -CH ₂ - ; where W ₂ is -0- and the compounds of EXAMPLES 18-23, 66-68, 75, 78-82, 84-94, 96, 99-124, 129-143, 145- 164 and 178-181.

Disclosed are the cycloalkene amines of formula (IV) where: n is 1-14, n5 is 1-3 and where

M is as defined above for the aromatic amines (I) and phar- maceutically acceptable salts thereof, and hydrates and solvates thereof. Preferred compounds are where n5 is 2; and where n4 is 3-6 and the compounds of EXAMPLES 60-64.

Also disclosed are the aromatic bicyclic aaines of formula (V) where ng is 1 or 2, 18« 19* 20 ^an< *** 21 ^are ^ same or different and are -H, -OH, -Cl, -Br, -C;χ-C alkyl, C*L-C ₃ alkoxy, and where any two adjacent groups are be taken together to form o-methylenedioxy, where one of 18* 19' 20 ^anc 21 *** ^s "OH, alkoxy or o-methylenedioxy, R-^ ₇ is c.- i7-.i'/9- i7-2 where one of 7.1 and 7.2 is -H or -CH ₃ and the other is

(I-R ₇ ) -(CH2) _n 9-W where ng is 1, 2 or 3 and w ^" ^ is selected from the group consisting of

2,6-bis(l-pyrrolldinyl)-4-(1-piperazinyl)-pyrimidine, 3-(ethylamino)-2-(l-piperazinyl)pyridine,

2,6-bis(2-pyridinyl)-4-(l-piperazinyl)pyridine,

3,6-bis(2-pyridinyl)-4-(methyl- [1-piperazinyl] )-pyridazine,

6-methoxy-2-morpholino-4-(1-piperazinyl)-pyrimidine

(II-R ₁₇ ) -(CH ₂ ) _nl o-0-(CH ₂ ) _n ιι-0-(CH ₂ ) _Iχl2 - ₁ where n ₁₀ is 1 or 2, n*L*L is 1, 2 or 3 and n-|_ ₂ is 1 or 2 and where ϊ--_ i as defined above and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof. Preferred are compounds where Rχ ₇ _ι or ι ₇ _2 I ^s * -(CH ₂ ) _n g-W-L and the compounds of EXAMPLES 53-55.

Disclosed are the hydroquinone (VI) and corresponding quinone (VII) amines where

R ₂₇ and R g are the same or different and are -H, C-^-C ₃ alkyl, C1-C4 acyl, -CO-^ where φ is optionally substituted with -F, -Cl,

-Br, -OH, C-L-C ₃ alkoxy, -N0 ₂ , -N(CH ₃ ) ₂ , -CE ₂ -φ and -Si(CH ₃ ) ₂ -C(CH ₃ ) ₃

and -prodrug where prodrug is as defined for the aromatic amines (I) and 29 _> 30 ^and 31 ^{re t} ^" ^{e same or} different and are -H, -C -C alkyl and C -C ₃ alkoxy, n ₁₈ is 1-20,

M is as defined for the aromatic amines (I) and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof.

Preferred are the compounds where n-^g is 1-4, R27 and R2g are -H or

C _j _-C4 acyl, and R29, ₃ 0 ^and R ₃ χ are -CH ₃ and the compounds of EXAMPLES 165-174.

Also disclosed are the amino-ethers (VIII) where

R ₃₂ is -0 or -H: -H,

R ₃₃ and R ₃ are the same or different and are -H or C-^-C ₃ alkyl,

^R 35* ^R 36 ^an< ^ ^R 38 ^{are t} ^ ^{ie same or} different and are -H, -C -C alkyl and C -C ₃ alkoxy,

R ₃₇ is -H, C-^-C ₃ alkyl, C -C4 acyl, -CO-φ where φ is optionally substituted with -Cl, -Br, -OH, C -C ₃ alkoxy, -N0 ₂ , -N(CH ₃ ) ₂ , -CE ₂ -φ , -Si(CH ₃ )2-C(CH ₃ ) ₃ and -prodrug where prodrug and R _A are as defined for the aromatic amines (I) and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof. Preferred amino-ethers are wherr R ₃ and R ₃ 4 are the same and are -H:-H or -CH ₃ :-CH ₃ , R 5, R ₃ g and R ₃ g are -CH ₃ or t-butyl, R ₃₇ is -H or C1-C4 acyl and the compounds of EXAMPLES 175-177.

Further disclosed are the bicyclic amino ether amines (IX which includes IXA and IXB) where where A-^ and A2 taken together are

-0-(CH ₂ ) _n 2θ-C(=R ₅ θ)- ^N ( ^R A)- ^and -N(R _A )-C(-R ₅₀ )-(CH ₂ ) _n20 -O- where n2 _Q is 0-3, R50 is -0 or -H:-H and R4 ₇ is -H or -prodrug where prodrug and R _A are as defined for the aromatic amines (I) and pharmaceutically acceptable salts thereof, and hydrates and solvants thereof. Preferred are the compounds where R4-7 is -H and where

^R 46 > 48 ^and 49 ^are "••*• - ^c - ^" *3 ^or t-butyl and the compounds of EXAMPLES 185-188. Disclosed is a method of treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subse¬ quent cerebral vasospasm, ischemic (thromboembolic) stroke, excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced

cardiac toxicity, Parkinsonism, Alzheimer ' s disease , other degenera¬ tive neurological disorders , multiple sclerosis , organ damage during reperfuslon after transplant, skin graft rej ection, hemorrhagic , traumatic and septic shock, and conditions such as severe burns , ARDS , inflammatory diseases such as osteo- or rheumatoid arthritis , nephrotic syndrome (immunologlcal) , systemic lupus erythematosis , allergic reactions , atherosclerosis , inflammation (for example derm- atological , Inflammatory and psoriasis conditions) , emphysema, stress induced ulcers , cluster headaches , complications from brain tumors (e. g. peritumoral edema) , radiation damage (for example during reaiation treatment or from accidental exposure to radiation) , damage after MI , pre -birth infant strangulation and infant hypoxia syndrome , such opthalmic disorders as uveitis and optic neuritis , and malignant hperthermia as well as preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and from cardiac infarction which comprises administering an effective amount of a 3 ,4-dihydrobenzopyran of formula (XI) where R ₃₉ is -H or -CH ₃ ,

R40 is -H, C -C4 alkyl, C1-C4 alkenyloxy, R ₄₁ is -H or -CH ₃ ,

R ₄₂ is -H or -CH ₃ ,

R4 ₃ is α-R4 ₃ .-χ:^-R4 ₃ . ₂ where one of 4 ₃ .χ and R4 ₃ . ₂ is

-H, -CH ₃ , -CH ₂ CH ₃ or -φ and the other is - (CH ₂ ) _nl7 - (1-piperazinyl substituted in the 4 position with -CH ₂ -< or 4-pyridinylmethyl where each can be optionally substituted with 1-4 C-^-C ₃ alkoxy) where n-1 ₇ is 1-3 or - (CH ₂ ) _n -CO- (1-piperazinyl substituted in the 4 position with with -CH ₂ -<*5 or 4-pyridiny_Lmethyl where each can be optionally substituted with 1-4 C -C ₃ alkoxy) where n^g is 0- 2 pharmaceutically acceptable salts thereof, and hydrates and solvates thereof to a human who is in need of such treatment. It is preferred that the treatment be treating spinal trauma, mild and/or moderate to severe head injury, asthma and damage after MI . It is preferred that the effective amount Is from about 0.05 to about 10 mg/kg/day IV or about

0. 5 to about 50 mg/kg/day, one to four times daily by mouth. It Is preferred that the compounds of EXAMPLES 83 , 95 , 125 , 183 and 184 be used in the treatment.

DETAILED DESCRIPTION OF THE INVENTION The aromatic amines (I) are produced by condensing the amine

corresponding to the desired aromatic amine (I) with the non-amine portion corresponding to the desired aromatic amine (I) . With regard to the non-amine portion, when _] _ and R ₂ are not -H, and R ₃ is -OH, Cι-C ₃ alkoxy or -0-C0-(C -C4 alkyl) the non-amine portion is produced by starting with the desired aromatic ring as the phenol and alkyl- ating it with the appropriate unsaturated halide, such as allyl bromide (for n* _j _ »» 2) to form the unsaturated phenolic ether. This compound is then rearranged to give the unsaturated group para to the R ₃ group by the procedure of Tarbell & Kincaid see, J. Am. Chem. Soc, 62, 728 (1940). The terminal unsaturated group is then transformed to the alcohol by known methods, which is then converted to a good leaving group such as chloride, bromide, iodide, mesylate, tosylate, etc and this compound is then condensed with the appropri¬ ate amine by the procedures disclosed in PCT 86/01797. Suitable solvents include acetonitrile, THF and DMF; acetonitrile is preferr¬ ed. Suitable bases include carbonate, bicarbonate and TEA; preferred is carbonate. While not necessary, it is preferred, to add a cataly¬ tic amount of iodide ion when reacting the non-amine and amine portion to produce the desired, aromatic amine (I). When R ₃ is -H, it is preferred to start with the appropriate substituted benzoic acid or benzaldehyde derivative. Here again the side chain is built-up to the desired length, a good leaving group added and then condensed with the appropriate amine. The compounds where X^ is -CH ₂ - and n-, is 0 are prepared by reducing Ar-CHO or Ar-COOH (Ar refers to φ with the appropriate variable substituents as defined in the claims for the aromatic amines (I)) with lithium aluminum hydride to Ar-CH ₂ -0H. The mesylate or tosylate of the alcohol is prepared in the usual way (using mesyl or tosyl chloride and triethylamine in methylene chloride) and it is then reacted with the appropriate amine (except A-55 which is generated in situ, this exception will be understood to apply in all cases) to yield the desired product. Alternatively, one can react Ar-H and chlotomethylate with paraformaldehyde and con¬ centrated hydrochloric acid. This reaction works best if the aromatic ring is activated by one or more alkoxy groups. The product, Ar-CH2C1, is then reacted with the appropriate amine. When X*L is -CH ₂ - and n- _j^ is 1, the above procedure can be followed starting with the corresponding Ar-CH -CH0 or Ar-CH ₂ -C00H. Alternatively, one can begin with a phenol which is unsubstituted at either the ortho or

para positions . The allyl ether Is prepared in the usual way from allyl chloride and the phenol . Next the allyl ether is thermally rearranged in a Claissen Rearrangement. If the phenol is substituted at C-2 and C-6 positions , the rearrangement will give a 4-CH ₂ CH-CH2 substituent. This can be cleaved by ozone and reduced to the 4- CH ₂ CH ₂ 0H group . The chloride/bromide/iodide/mesylate/tosylate is prepared from this alcohol in the usual way and reacted with the appropriate amine . Where X-^ is -CH ₂ - and n--_ is 2 , the above method produces a phenol having a -CH ₂ CH-«CH group . This olefin is reacted with diborane in the usual way to form the organoborane which is then oxidized with hydrogen peroxide and base to the terminal alcohol - CH CH ₂ CH ₂ 0H. The leaving group and reaction with the appropriate amine are performed in the usual manner. Alternatively, one can begin with a Ar-CHO , which is reacted with malonic acid and a weak base to form Ar-CH=CHC00H which can be hydrogenated and reduced with lithium aluminum hydride to Ar-CH ₂ CH ₂ CH ₂ 0H [J . Med. Che . , 751 , (1980) ] which can be converted in the usual way to the aromatic amine (I) . When -^ is -CH ₂ - and n-χ is 3 , it is preferred to begin with a substituted anisole which is unsubstituted at C-2 or C-4. This is reacted with succinic anhydride and aluminum chloride in benzene or toluene. The product, Ar-C0CH ₂ CH ₂ C00H, is reduced with diborane in THF, followed sometimes by hydrogenation over Palladium on carbon in acetic acid, to the desired Ar-CH ₂ CH ₂ CH ₂ CH ₂ 0H which is converted to the aromatic amine (I) . When X-^ is -CH ₂ - and n-_ is 4 , 5 or 6 , it is preferred to first prepare a Grignard reagent from Ar-Br. The Grignard reagent is reacted with the appropriate 5 - 7 membered cyclic ketone. The alcohol product is oxidized and cleaved to the keto-acid which is reduced with boron hydride to the alcohol Ar- (CH2)4_gCH 0H which is converted to the aromatic amine in the usual way. The aromatic amines (I) where X-^ is -CR(CH ₃ ) - and n^ is 1 are prepared by reacting the amine M with a haloketone such as chloro- acetone. The adduct , CH ₃ COCH ₂ -M, is reacted with a Grignard such as Ar-MgBr. The product has the above structure when R is -OH. The alcohol can be acetylated and reduced to give R — -H . The aromatic amines (I) where X-_ is -0- are prepared by begining with the cor¬ responding phenol. This Is reacted with the dibromide Br(CH ₂ ) _n χ-Br (or the corresponding dichloride) where n-^ is 4 , 5 , 6 in the presence of hydroxide and in an alcoholic solvent such as ethanol . The

product, Ar-0-(CH2) _n ι-Br, is reacted with the amine M in a solvent such as acetonitrile in the presence of a base such as carbonate to yield the desired product. Alternatively, starting with the same phenol, it is reacted with chloroethanol in an alcoholic solvent in the presence of hydroxide to give Ar-0-CH ₂ CH2θH, which is converted to the aromatic amine (I) is the usual manner. For aromatic amines (I) where Xi is -CO- it is preferred to start with the known com¬ pounds where Ar-CO- CH2) _n ι-halogen. The halide is then reacted with the appropriate amine in the ususal manner to produce the aromatic amine (I). Where X--_ is -CH(OH)-, one starts with product above (X^ is -CO- ) and reduces it with a reducing agent such as sodium borohydride in ethanol. For the aromatic amines (I) where X-^ is -C(OH)(Rχ ₃ )- where R-^ ₃ is C -C ₃ alkyl or phenyl (optionally sub¬ stituted) these compounds are prepared by reaction of the compounds where X^ is -CO- with the appropriate Grignard reagent (R ₃ -Mg-X) . For the aromatic amines (I), where X-^ is - (R )-, known anilines are the starting materials. The corresponding amides are formed by reaction of the aniline with an acid chloride (R4-COCI) or anhydride R4-C0 C-R4 in the presence of a base such as triethylamine in a solvent such as methylene chloride. The resulting amides are reduced with lithium aluminum hydride to Ar-NH(R4) . These compounds are reacted with the dibromide Br(CH2) _n Br or analogous dichloride or diiodide where n — 4, 5, 6 in the presence of hydroxide and in an alcoholic solvent such as ethanol. The product, Ar-N(R4) (CH2 _n Br, is reacted with the amine, M, in acetonitrile in the presence of carbonate to give the aromatic amine (I).

For the aromatic amines (I) where n ₃ is 1, Ar-X-^-.-^(Rg) (Rg)- 0-(CH2) _n 4, where x-^ is not -NH-CO- or -NR4- and n^ is 2 or more it is preferred to begin with the compound Ar-X^-C _n (Rg) (Rg)-OH and convert it to the halide, mesylate or tosylate in the usual way. This is reacted with HO-(CH ₂ ) _n ;L4-0-Protecting group where the protecting group is tetrahydropyranyl or trimethylsilyl in the presence of a base such as sodium hydride or potassium t-butoxide. Next the protecting group is removed to give Ar-Xχ-C _n (Rg)(Rg)-0- (CH ₂ ) _n χ4-0H. The terminal alcohol is converted to the mesylate, tosylate, halide and reacted with the appropriate amine in the usual way to obtain the desired product.

With regard to isolation, the compounds are generally isolated

by extraction between sodium bicarbonate and methylene chloride. The organic phase is washed and dried in the usual manner and con¬ centrated. When necessary, the products are purified by silica gel chromatography eluting with either methanol and methylene chloride or ethyl acetate and hexane.

The alkyl amines (II) are produced by condensing the amine corresponding to the desired alkyl amine (II) with the non-amine portion corresponding to the desired alkyl amine (II) by the proceed- ures disclosed in PCT 86/01797. The non-amine portion should have a good leaving group such as mesylate, tosylate, -Br, etc. While not necessary it is preferred to add a catalytic amount of iodide ion, see EXAMPLE 1. In the case of certain 3,6-bis(2-pyridinyl)pyrida- zines (A-55) the amine is not preformed and then attached to the non- amine portion; the amine is formed in situ, see EXAMPLE 17. The bicyclic amines (III) are prepared from the corresponding amine and bicyclic portions by means well known to those skilled In the art. The bicyclic portions where the terminal group is -COOH are known or can readily be produced from known compounds, see US Patents 3,947,473, 4,003,919, 4,018,799, 4,026,907 and 4,681,890. The acid can be activated with an agent such as 1,1' -carbonyldiimidazole or 1,3-dicyclohexylcarbodiimide in a solvent such as THF, ether or methylene chloride following which it is contacted with the desired amine to form the desired bicyclic amine where X ₃ is -CO-. Alterna¬ tively, the related acid chlorides can be used to react with the desired amine, see EXAMPLE 68. In the cases where X ₃ is -(CH ₂ ) _n3 -, the methylene compounds are formed by first forming the amide as above then reducing it with a reducing agent such as lithium aluminum hydride or borane dimethylsulfide. Alternatively, though less preferrably, the -COOH group can be reduced to the corresponding- CH ₂ -0H which can then be transformed to a good leaving group such as mesylate, tosylate or bromide and then reacted with the desired amine to form the desired corresponding bicyclic amine (III) . In the case where X ₃ is -C0-0-, the phenol acetate (or other ester) of 6-hydroxy- 2,5,7,8-tetramethychroman-2-carboxylic acid is activated with oxalyl chloride in a solvent such as acetonitrile, see Helv. Chim. Acta 61, 1675 (1978) . A solution of the requisite aminoalcohol in pyridine or pyridine/acetonitrile is added. The reaction mixture is allowed to stand several hours at 20-25°, followed by workup. The reaction

ixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated, the organic phase is dried, concentrated, chromatographed, if needed, over silica gel to give the bicyclic amine (III) where X ₃ is -C0-0-. See EXAMPLES 161 and 162. A general procedure for synthesis of the amide type (X ₃ is -CO-) bicyclic amines (III) is as follows. 1,1' -Carbonyldiimidazole (1.1 equivalents) is added to a stirred solution of non-amine portion of the starting material (6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid) about 4-8 mmol in THF (10-12 ml). The mixture is stirred at 20-25° for 30-60 min. and the appropriate amine (1.0-1.1 equivalents) in THF or methylene chloride (10-20 ml) is added dropwise and the mixture stirred at 20-25° for 4-18 hr (monitored by TLC) . When the reaction is complete the mixture is concentrated under reduced pressure and partitioned between ether (100-150 ml) and water (100-150 ml). The ether phase is washed with water, saline, dried over sodium sulfate and the solvent removed under reduced pressure. If purification is necessary, column chromatography is performed as needed on silica gel. In some cases the products containing basic nitrogen atoms are converted to acid addition salts. A general procedure for reduction of the amide type (X ₃ is -C0- ) to the reduced type (X ₃ is -CH ₂ -) of bicyclic amine (III) is as follows. To a stirred suspension of lithium aluminum hydride (LAH, 4 molar equivalents) in dry THF (20-25 ml), maintained at 0-50° depending on the nature of the particular compound, is added dropwise over 10-15 min a solution of the appropriate amide (4-8 mmol) in dry THF (25-50 ml) . The mixture is stirred at the appropriate temperature for 30 -120 min and then cooled in an ice-water bath. To the reaction mixture is carefully added dropwise water (1 ml/g of IAH) , followed by aqueous sodium hydroxide (15%, 1 ml/g of LAH) and finally water (3 ml/g of LAH) . The mixture is stirred for 30 min and filtered through celite. The filtered solids are washed with ether (50-100 ml, 2 times) . The combined washes and filtrate were extracted with aqueous hydrogen chloride (10%, 50-75 ml, 2 times). The pH of the combined acidic extracts is raised to approximately 12 with aqueous sodium hydroxide (50%) with ice bath cooling and the basic mixture is extracted with chloroform (50-100 ml, 2 times). The combined chlorof¬ orm extracts are dried over sodium sulfate, the solvent removed at reduced pressure and the crude product flash chromatographed on

silica gel. In some cases the products were converted to acid addition salts.

The cycloalkyl amines (IV) are prepared by methods well known to those skilled In the art. It is preferred to start with a 3-alkoxy- cyclopent-2-en-l-one, 3-alkoxycylcohex-2-en-l-one or 3-alkoxycyclo- hept-2-en-l-one depending on whether n5 is 1, 2 or 3. It is prefer¬ red that the alkoxy group be ethoxy. Grignard reaction with X-Mg- (CH2) _n 4-0-magnesium to the a,β-unsaturated ketone followed by acid hydrolysis gives the desired 3-substituted cycloalkyl-2-en-l-one. The terminal hydroxyl group is then oxidized with an oxidizing agent such as pyridinium dichromate to the corresponding aldehyde which Is then contacted with the amine corresponding to the amino portion of the desired cycloalkyl amine (IV) . It is preferred to contact the amine with the non-amine portion in the presence of sodium cyanoboro- hydride. When n ₄ is 3 it is preferred to use X-Mg-(CH ₂ )2-C*(H)-0- (CH ₂ ) ₂ -0 [where the atoms marked with an asterisk ( ) are bonded to each other resulting in the formation of a ring] as the Grignard reagent.

The non-amine portions of the aromatic bicyclic amines (V) are known to those skilled in the art. See, in particular, US Patents 4,181,665 and 4,153,612. The aromatic bicyclic amines (V) of the present invention are made by the same method as the amines of US Patents 4,181,665 and 4,153,612.

The hydroquinones (VI) and quinones (VII) are readily inter- changable as is well known to those skilled in the art. It is realized that with the hydroquinones (VI) when R ₂ and R ₂ g are other than -H, that these groups are lost in the conversion to the cor¬ responding quinone (VII) . A hydroquinone (VI) and its corresponding quinone (VII) are both useful in the same manner and same way and therefore when the term hydroquinone (VI) is used it means and includes the corresponding quinone (VII) for purposes of this patent.

The hydroquinones (VI) are prepared by reaction of the aldehyde group of the non-amine portion of the hydroquinone starting material with the desired amine. The reaction is performed in the presence of an agent such as sodium cyanoborohydride in a polar solvent such as methanol or acetonitrile at about 20-25°, preferred is methanol. Several of the non-amine starting materials are known, see for example, Hel. Che . Acta 46, 650 (1963) and Chem. Phar . Bull. 30,

2797 (1982). Starting materials with the desired chain length ar synthesized by known chemical reactions. The free hydroquinone o hydroxyprotected non-amine portion of the hydroquinone (VI) can b used. In the later case, the hydroxy-protecting groups, usuall esters such as acetate or ethers such as t-butyldimethylsilyl, ar removed by means well known to those skilled in the art, for example, hydroxide/water/acetone followed by acidification or tetra-N-buty ammonium chloride. The hydroquinones (VI) can readily be transforme into the corresponding quinones (VII) by means known to those skille in the art, for example ferric chloride/ethyl acetate. Alternative¬ ly, using means known to those skilled in the art, one can start wit the non-amine portion of a quinone, see Chem. Pharm. Bull. 30, 2797 (1982), transform it to the corresponding hydroquinone, and react i with the appropriate amine to produce the desired hydroquinone (VI). The amino ethers (VIII) are prepared by contacting the hydroxyl protected (or unprotected) aldehyde group of the non-amine portion o the amino ether (VIII) with the desired amine in the presence of reducing agent such as sodium cyanoborohydride in a polar solvent such as methanol. Alternatively the appropriate aldehyde and amine can be contacted in a non-polar solvent such as toluene at about 50- 116° and removing the solvent. The resultant imine can then be contacted with a reducing agent such as sodium borohydride in a polar solvent such as methanol. The non-amine portion of the amino ether (VIII) starting materials are known to those skilled in the art, see for example, Hel. Chem. Acta 46, 650 (1963) and Chem. Pharm. Bull. 30, 2797 (1982). If present the hydroxy protecting groups can be removed at this time. The hydroquinone-amine intermediate is then reacted with an agent such as chloroacetylchloride in the presence of a base, such as pyridine or triethylamine at about 0-30° in a solvent such as ether to provide the appropriate chloroacetamide. Final cyclization can be effected by treatment of the acetamide with base, such as potassium carbonate, in a polar solvent, such as acetone at about 0-50° . If desired the cyclic amide can be reduced with a reducing agent such as lithium aluminum hydride in an aprotic solvent such as ether to the corresponding amine. The protected hydroq¬ uinones can be prepared by standard methods, see for example J. Am. Chem. Soc. 94, 6190 (1972) from known hydroquinone carboxaldehydes.

The amino ethers (IX) are of two types, ones with the nitroger.

atom "up" (IXA) and with the nitrogen atom "down ^"* (IXB) . The amino ethers (IXB) are prepared by reacting the appropriate 4-aminores- orcinol with chloracetyl chloride (or an equivalent reagent) in the presence of a base, such as pyridine or triethy1amine at 0-30° in an aprotic solvent such as ether. The resorcinol starting materials are known to those skilled in the art or can readily be prepared from known compounds by known methods. Cyclizatlon is effected by treatment with a base such as potassium or sodium carbonate in a polar solvent such as acetone. Alkylation of the sodium or postas- slum salt of the cyclic amide (hydroxy protected) with the ap¬ propriate reagent, R _A -leaving group where leaving group is -Br, Cl or -0-tosyl at about -78° to about 25" in a solvent such as ether, provides the amide product. The amide can be reduced, if desired, by reaction with a reducing agent such as lithium aluminum hydride or borane at about 0-50° to provide the cyclic amine. Alternatively, the cyclic amide can be reduced with lithium aluminum hydride or borane and the cyclic amine reacted with R -leaving group or with R _A - CHO in the presence of a base such as potassium carbonate or sodium cyanoborohydride respectively. The amino ethers (IXA) are prepared in a similar manner. The starting materials are known, see Synthesis 69 (1982) and Can. J. Chem. 44, 1874 (1966).

Prodrugs of the aromatic amines (I) , bicyclic amines (III) , hydroquinones (VI) , amino ether amines (VIII) and bicyclic amino ether amines (IX) are prepared in general by reacting the phenol or salt of the phenol with the appropriate prodrug substituent such as carboxylic acid, isocyanate, anhydride, etc. More specifically, for the prodrug -P0 ₂ -0 ^" the phenol is reacted with phosphorous oxy- chloride and this intermediate compound is then reacted with water. For -CO-(CH ₂ )n ₂₁ -R ₅₁ where R ₅₁ is -N(alkyl) ₂ , and -C0-C*-CH-CH=C(- 5 ₂ )-CH-CH* (where R ₅₂ is -H or C -C ₃ alkyl and where the atoms marked with an asterisk ( ) are bonded to each other resulting in the formation of a ring) , the prodrugs are prepared from the phenol and the carboxylic acid in the presence of 1,3-dicyclohexylcarbodiimIde in a polar aprotic solvent such as methylene choride. When R* _j ^ is -NH ₂ , the t-butyl carbamate of the prodrug is prepared as above, followed by cleavage of the carbamate by reaction with an acid such as hydrochloric acid in methanol or trifluoroc acetic acid about 0- 25° . The compounds with the prodrug of the formula -0-CH ₂ -0-C0-

^are P ^re P ^are d by reaction of the salt of the phenol with the appropriate chloromethyl ether in a solvent such as tetrahydrofuran. The chloromethyl ethers can be prepared by the procedure of J. Org. Chem. 48, 5280 (1983). Prodrugs of -CO-CH-CH- C0-0 ^" or -C0-(CH2) _n 21* ^C0 ° ^{" are} Prepared by reaction of the (sodium) salt of the phenol with the anhydride at about 0-60°. Alternatively, the phenol may be coupled with the diacid utilizing 1,3-dicyclohexyl- carbodiimide and the resulting acid exposed to a base such as sodium carbonate to form the desired salt. Other prodrugs are prepared by known procedures.

The aromatic amines (I), alkyl amines (II), bicyclic amines (III), cycloalkyl amines (IV), aromatic bicyclic amines (V), hydro¬ quinone amines (VI), quinone amines (VII), amino ether amines (VIII) and bicyclic amino ether amines (IX) collectively are referred to as amines (X) , of the present invention are reacted with acids to form amine salts by methods known to those skilled in the art and the resulting salts are more water soluble and therefore preferable to use when an aqueous formulation is desired such as a solution for IV use. Generally the amines (X) possess one or more basic nitrogen atoms. Because of this they can be converted to an acid addition pharmaceutically acceptable salt. The pharmaceutically acceptable salt forms of the amines (X) are generally preferred over the free base form since the salts have greater water solubility and form crystals more suitable for pharmaceutical purposes. An acid addition salt of the amines (X) can be converted to the free base, which can be converted to any desired pharmaceutically acceptable acid addition salt by methods known to those skilled in the art. It is preferred that the acid addition salt be prepared by reacting the free base of the amines (X) with an approximately stoichiometric amount of an acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, acetic, lactic, citric, succinic, benzoic, salicyclic, pamoic, cyclohexanesulfamic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, oxalic acid and the like. It is preferred that the acid be selected from the group consisting of hydrochloric, maleic, methanesulfonic and fumaric acids.

The amines (X) and acid addition salts thereof can be isolated as hydrates or solvates, and such forms are regarded as equivalent to the corresponding amines (X) not containing water or solvent.

It is preferred that the amine (X) be an aromatic amine (I) , alkyl amine (II) or bicyclic amine (III). It is more preferred that the amine (X) be an aromatic amine (I) or bicyclic amine (III) . It is preferred that the amine portion be a 1-piperazine substituted in the 4- position with -(CH )j-heteroaryl where j is preferrably 0 and heteroaryl is preferrably (a) pyrimidin-4-yl substituted in the 2- and/or 6- position with 4-morpholinyl, 1-pyro11idinyl or (b) pyridi- nyl substituted in the 3- position with - _m . ₃ R _j{ . ₃ . It is more preferred that the amine be A-22 (PREPARATION A-22) or A-47 (PREPARA- TION A-47).

With the aromatic amines (I), it is preferred that X^ be -0-, -CH ₂ - or -CO-. It is preferred that n^ be 0-6, it is more preferred that ni be 1-6. It is preferred that R ₃ be -OH or C -C ₃ alkoxy. It is preferred that Rg and Rg be -H. It is preferred that R ₂₂ and R ₂₃ are -H. It is preferred that R-χ and R are the same and are -H, -CH ₃ or t-butyl.

With the alkyl amines (II) it is preferred that n ₂ is 4-8 more preferrably 6. It is preferred that X ₂ be -H, -OH, -0-C0-(C*L-C4 or -0-CO-aryl. For the bicyclic amines (III) it is preferred that ι _ι or R g_ 2 is -CH ₃ . It is preferred that R ₇ is -H. It is also preferred that ^R 10> ^R ll ^{and R} 12 ^are a -CH ₃ . It is preferred that ng is 1. It is preferred that X ₃ is -CO- or -CH - and that W ₂ is -0-.

For the cycloalkyl amines (IV) it is preferred that n4 is 3-6 and n5 is 2.

With the aromatic bicyclic amines (V) it is preferred that R-^ ₇ is -(CH ₂ ) _n9 -W ₁ .

The amines (X) of the present invention are useful pharmaceuti¬ cal agents In treating a number of different medical conditions in humans and useful warm blooded animals. The 3,4-dihydrobenzopyran compounds (XI) are known, see EP 202,580-A. These compounds are use in the same way for the same purposes as the amines (X) of the present Invention.

In humans, the amines (X) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic

(thromboembolic) stroke, excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced cardiac toxicity, Parkinsonism,

Alzhei er's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological) , systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcers, cluster headaches, complications from brain tumors (e.g. peritumoral edema), radiation damage (for example during reaiation treatment or from accidental exposure to radiation), damage after MI, pre-birth infant strangula¬ tion and infant hypoxia syndrome, such opthalmic disorders as uveitis and optic neuritis, and malignant hyperthermia.

In humans, the amines (X) are useful in preventing damage following cardiopulmonary resuscitation, neurological or cardiov¬ ascular surgery and from cardiac infarction.

Generally, the amines (X) are used like the glucocorticoid phar¬ maceuticals for the treatment of the above human conditions as well as the animal conditions listed below. ■ While the amines (X) are useful in both humans and animals in treating many of the same conditions and preventing damage from the same problems as the gluco¬ corticoids, the amines (X) are useful in treating a number of conditions and preventing damage from conditions where the glucocor¬ ticoids are not useful. The amines (X) have no glucocorticoid activity and therefore, unlike the glucocorticoids, they can be given daily for long periods of time (used chronically) without the side effects associated with the glucocorticoids. This is a distinct advantage.

It is to be understood that each of the amines (X) is useful to a different degree for treating each of the conditions above. However, as is known to those skilled in the art, some of the amines (X) are better for treating some conditions and others are better,for treating other conditions. In order to determine which compounds are better than others for a particular condition one can utilize known tests that do not require expermentation but only routine analysis.

For example, the fertile egg or chick embryo assay of Folkman, Nature 288, 551 (1980) or Science 221, 719 (1983), discloses an assay

to determine antlangiogenic activity which is indicative of inhibi¬ tion of tumor growth and anti-cancer utility. Because of the ability of the compounds which are active in the Folkman embryo test to inhibit tumor growth, they are useful in the treatment of various diseases and conditions, especially various forms of cancer. Accordingly, they are administered to animals and humans to prolong survival or reduce pain and/or discomfort secondary to tumor growth and the alike. Further, the arachidonic acid LD50 test of Kohler, Thrombosis Res., 9, 67 (1976), identifies compounds which are antioxidants, which inhibit lipid peroxidation, and/or which inhibit the prostaglandin cascade and are useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc. Another method useful for determining which par¬ ticular compounds inhibit lipid peroxidation and which are therefore useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc is described by Pryor in Methods of Enzymology 105, 293 (1984). Further, the mouse head injury assay of Hall, J. Neurosurg. , 62, 882 (1980) discloses an assay from which one skilled in the art can readily determine which particular amines (VI) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury. Additionally, the cat 48 hr motor nerve degeneration model of Hall et al, Ex- p. Neurol. , 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular amines (VI) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, Alzheimer's disease etc. H. Johnson in Int. Arch. Allergy Appl. Immunol., 70 _r 169 (1983) has described the ascarias sensitized rhesus monkey assay for anti-asthma drugs.

The standard conditions for treatment are to give the amines (VI) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a standard dose of about 0.05 to about 10 mg/kg/day IV or about 0.5 to about 50 mg/kg/day, one to four times daily by mouth.

For treating spinal trauma, mild and moderate to severe head injury, damage following cardiopulmonary resuscitation, cardiac infarction, organ damage during reperfusion after transplant, hemor- rhagic, traumatic and septic shock, severe burns, ARDS, and nephrotic syndrome and preventing skin graft rejection, the standard conditions

are used. Typical treatment will involve an initial loading dose, e.g. an IV dose of 0.01 mg to 2 mg/kg followed by maintenance dosing e.g. IV infusion for a day to a week depending on the particular condition of the patient and the particular compound used. This may be supplemented with IM or oral dosing for days, weeks or months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury).

In treating subarachnoid hemorrhage and subsequent cerebral vasospasm or ischemic (thromboembolic) stroke the standard conditions are used and patients at risk are pre-treated orally.

In treating excess mucous secretion and asthma, the amines (X) are administered orally, IV and by inhalation in the standard dose. In treating excess mucous secretions the oral dose of the amines (X) used is from about 0.5 to about 50 mg/kg/day. The frequency of ad- ministration is one through 4 times daily. The oral administration of the amines (X) to treat excess mucous secretions may go on for months or even years. The susceptible individuals can be pre-treated a few hours before an expected problem. The IV dose is about 0.05 to about 20 mg/kg/day. The aerosol formulation contains about 0.05 to about 1.0% of the amines (X) and is administered or used about four times daily as needed.

In treating muscular dystrophy, Parkinsonism, Alzheimer's disease and other degenerative neurological disorders (amyotrophic lateral sclerosis; multiple sclerosis) amines (X) are administered orally using a dose of about 0.5 to about 50 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.

In addition, utility in disorders or physiological phenomena dependent on angiogenesis or neovascularization such as embryo implantation (antifertility) , arthritis, and atherosclerosis is exhibited with the amines (X) with or without co-administered oral heparin or systemic heparin fragments, see Science 221, 719 (1983).

In treating adriamycin-induced cardiac toxicity, the amines (X) are administered orally or IV using a dose of about 0.05 to about 50 mg/kg/day, preferrably about 0.5 to about 10 mg/kg/day. The amines (X) are preferably given concomitantly with IV adriamycin or the individual is pre-treated with the amines (X).

For prophylaxis prior to and preventing damage after neurologi¬ cal or cardiovascular surgery the amines (X) are used according to

the standard conditions. The patient can be pretreated with a single IV or IM dose just prior to surgery or orally before and after surgery.

In treating osteo- or rheumatoid arthritis and other inflam- matory diseases, the amines (X) are given orally or IM in doses of about 0.5 to about 50 mg/kg/day, one to four times daily. Orally the drug will be given over a period of months or years alone or with other steroidal or nonsteroidal antiinflammatory agents. The Initial dose with some severe rheumatoid patients may be given IV and followed with an IV drip for up to 24 hr or more. In addition, intra-arterial administration may be employed.

In treating drug allergic reactions, the amines (X) are given in a dose of about 0.5 to 50 mg/kg/day, administered one to four times daily orally and IV. Typical treatment would be an initial IV loading dose followed by oral dosing for a few days or more.

In treating atherosclerosis and emphysema, the amines (X) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily for months or years.

In treating dermatological inflammatory conditions including psoriasis, the amines (X) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentra¬ tion of about 0.05 to about 5% as long as needed. In treating these conditions the amines (X) can be used with steroidal agents. The amines (X) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as non¬ steroidal anti-inflammatory compounds (NOSAC) . Stress ulcers are ulcers that develop after exposure to severe conditions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. Patients in Intensive care units are particularly prone to develop stress ulcers . Stress ulcers also include lesions that can lead to upper gastrointestinal bleeding; such bleeding is likely to be prevented by these compounds . NOSAC includes drugs such as ibuprofen, aspirin, indomethacin, naproxen, piroxicam and the like that are usually taken for analgesia, and that are often associated with gastrointestinal intolerance characterized by pain and lesions that may lead to bleeding. The amines (X) will be administered preferentially by the oral route either as tablets , capsules or

liquids, in doses ranging from about 5 to about 500 mg, two to four times a day. The treatment would be either preventive, i.e., start¬ ing before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ulcers have formed. In patients whose clinical condition precludes swallowing the oral dosage forms, the amines (X) would be given either through a nasog- astric tube, or parenterally, i.e., IV or IM. The parenteral doses would range from about 1 to about 100 mg and be administered one to four times a day or by IV. In dogs, the amines (X) trauma, intervertebral diseases (slipped disk), traumatic shock, flea bite and other allergies.

In horses, the amines (X) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis) . In cattle, the amines (X) are useful in treating acute coliform mastitis, bovine mastitis, acute allergic reaction to feed lot vaccination and shipping fever.

In pigs, the amines (X) are useful in treating porcine stress syndrome and. thermal stress syndrome. The term treatment or treating as used in this patent is used broadly and includes both treatment of an existing condition as well as preventing the same condition from occurring where such is possible as is well known to those skilled in the art. For example, the amines (X) can be used to treat existing asthma conditions and to prevent future ones from occurring. For example, the amines (X) treat spinal trauma and prevent rejection of skin grafts.

The amines (X) can be used with other pharmaceutical agents in treatment of the conditions listed above as is known to those skilled in the art. The exact dosage and frequency of administration depends on the particular amines (X) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the amines (X) in the patient's blood and/or the patients response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

The chemical formulas representing various compounds or molecu¬ lar fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Zi" or "R^" where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Zi would repres¬ ent a bivalent variable if attached to the formula CH ₃ -C(=*-Z )H. Groups R^ and R_: would represent monovalent variable substituents if attached to the formula CH ₃ -CH -C(R _i ) j)H2- When chemical formulas are drawn in a linear fashion, such as those above, variable sub¬ stituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R. _j _ and R,- are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C _j _, where "i" is the integer cor¬ responding to the carbon atom number. For example, Cg represents the 6 position or carbon atom number in the steroid nucleus as tradition¬ ally designated by those skilled in the art of steroid chemistry. Likewise the term "Rg" represents a variable substituent (either monovalent or bivalent) at the Cg position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol ⁿ -" in general represents a bond between two atoms in the chain. Thus CH ₃ -0-CH ₂ - CH(R _i )-CH ₃ represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol " ^• «" represents a double bond, e.g., CH ₂ -=C(R _i )-0-CH ₃ , and the symbol " ^* --" represents a triple bond, e.g., HC≡C-CH(R )-CH2-CH ₃ . Carbonyl groups are represented in either one

of two ways: -CO- or -C(-O)-, with the former --being preferred fo simplicity.

Chemical formulas of cyclic (ring) compounds or molecula fragments can be represented in a linear fashion. Thus, the compoun 4-chloro-2-methylpyridine can be represented in linear fashion by

N*=C(CH ₃ )-CH-CC1-CH-=C*H with the convention that the atoms marke with an asterisk (*) are bonded to each other resulting in th formation of a ring. Likewise, the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N -(CH ₂ -N(C H5 -CH ₂ - C*H ₂ .

A cyclic (ring) structure for any compound herein defines a orientation with respect to the plane of the ring for substituents attached to each carbon atom of the cyclic compound. In formulas depicting such compounds, a substituent attached to a carbon ato below the plane of the ring is identified as being in the alpha (α) configuration and is indicated by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol ^π - - -" -or "....". The corresponding substituent attached above the plane of the ring is identified as being in the beta (β) configuration. When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R^ attached to a carbon atom as -C(-=R^)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R _j j and ^-R^.^. When a bivalent variable, R^, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R _j i and J- i-k are attached to the carbon atom to yield -C(α-R^. (^-Ri-k)- • For example, when the bivalent variable Rg , -C(=*=Rg) -is defined to consist of two monovalent variable substituents, two monovalent variable substituents are α-Rg.^ :3-Rg_ , .... α-Rg_g :,_3-Rg_

₁₀ , etc, yielding -C( -Rg_ ₁ ) ( -Rg_ ₂ ) - -C(α-Rg.g) ( -Rg_ ₁₀ ) - , etc. Likewise, for the bivalent variable R-_-_, -C(-R- _] _^) - , two monovalent variable substituents are ^Q! -Rιι_ι"3- ιι_ • For a ring substituent for which separate α and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring) , and for a substituent bonded to a carbon atom which is not

par _t of a ring the above convention is still used, but the α and 3 designations are omitted.

Just as a bivalent variable may be defined as two separate monovalent variable substituents , two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example , in the formula -C (R _i )H-C ₂ (Rj )H- (0χ and C ₂ define arbitrarily a first and second carbon atom, respectively) 3. _j _ and R _* may be defined to be taken together to form (1) a second bond between C-^ and C ₂ or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When R^ and R _* are taken together to form a more complex entity, such as the group -X-Y- , then the orientation of the entity is such that C*^ in the above formula is bonded to X and C ₂ is bonded to Y. Thus , by convention the designa¬ tion " . . . R^ and Ri are taken together to form -CH ₂ -CH -0-CO- . . . ^π means a lactone in which the carbonyl is bonded to C ₂ . However , when designated ^π . . . R and R^ are taken together to form -CH -CH ₂ -0-C-0- the convention means a lactone in which the carbonyl is bonded to C _. .

The carbon atom content of variable substituents is indicated in one of two ways . The first method uses a prefix to the entire name of the variable such as ^π C -C4" , where both "1" and ^π 4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "Ci-C^ alkyl" represents alkyl of 1 through 4 carbon ato∑r≤ , (including isomeric forms thereof unless an express indication to the contrary is given) . Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH ₃ - (CH ) _n -0- C0- where n is zero, one or 2. By the second method the carbon atom content of only each portion of the definition is indicated separate- ly by enclosing the "Ci-Cj " designation In parentheses and placing it immediately (no intervening space) before the portion of the defini¬ tion being defined. By this optional convention (C -C ₃ )alkoxv- carbonyl has the same meaning as C ₂ -C4 alkoxycarbonyl because the "C -C ₃ " refers only to the carbon atom content of the alkoxy gro n . Similarly while both C ₂ -Cg alkoxyalkyl and (C -C ₃ )alkoxy(C -C ₃ )alkvl define alkoxyalkyl groups containing from 2 to 6 carbon atoms , the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while

the latter definition limits either of these groups to 3 carbo atoms.

When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular sub- stituent will be a notation in (parentheses) which will correspond t the same name/designation in one of the CHARTS which will also se forth the chemical structural formula of that particular substituent.

II. DEFINITIONS All temperatures are in degrees Centigrade. TLC refers to thin-layer chromatography. THF refers to tetrahydrofuran. TEA refers to triethylamine. DMF refers to dimethylformamide.

Saline refers to an aqueous saturated sodium chloride solution. IR refers to infrared spectroscopy.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ ) downfield from tetramethyl- silane. φ refers to phenyl (C H5) . Ar refers to φ with the appropriate variable substituents as defined in the claims for the aromatic amines (I) .

MS refers to mass spectrometry expressed as m/e or mass/charge unit. MT ^*" refers to the positive ion of a parent. [M + H] ⁺ refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. Cl refers to chemical ionization. FAB refers to fast atom bombardment. HR refers to high resolution.

Ether refers to diethyl ether.

When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) . PCT 86/01797 refers to published PCT patent application No US 86/01797, International Publication No W087/01706.

Suleptanate ester refers to the (sulfonylethyl-N-methylamido) - suberic acid (ester) R-O-CO-(CH ₂ )g-C0-N(CH ₃ )-CH CH ₂ -S0 ₂ -0 ^H .

The term "amines (X)" refers to all the amines of the nine different types, the aromatic amines (I), the alkyl amines (II), the bicyclic amines (III) , the cycloalkyl amines (IV) , the aromatic bicyclic amines (V) , the hydroquinone amines (VI) , the quinone amines

(VII) , the amino ether amines (VIII) and the bicyclic amino ether

amines (IX) , see CHART A.

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacolog- ical/toxicological point of view including bioavailability and patient acceptance or to the manufacturing chemist from a physical- chemical point of view regarding composition, formulation, stability and isolatability.

NNNNNN-NN-N refers to Chemical Abstracts Service (CAS, Columbus, Ohio) registry numbers where each ^π N" is an integer from 0 thru 9, but deleting leading zeros in the 6-digit portion of the number. Registry numbers are assigned to a particular chemical compound by CAS criteria, that the compound has been found to exist and it has been characterized in some way. Compounds published from approx¬ imately 1967 to the present are registered publicly and the registry number is the key to finding references in the CAS data base for such a registered compound. The CAS data base is publicly available from several database vendors such as STN International, System Develop¬ ment Corporation (SDC) Orbit Search Service, Lockheed Dialog, Bibliographic Retrieval Systems, Questrel, etc. CAS registry numbers are included in the EXAMPLES for some of the compounds which have been, registered.

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention, to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION A-l Methyl[2-(methyl-2-pyrIdinylamino)ethyl]amine

A mixture of N,N' -dimethylethylene-diamine (25 g) and 2-chloro- pyridine (1.3 g) is warmed at 85° with stirring for 18 h. The excess dimethylethylenediamine is removed by distillation at reduced pressure. The distillation residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic phase is separated, dried over sodium sulfate and the organic solvent removed under

reduced pressure to give the title compound. PREPARATION A-2 2-Carboxy-1-piperidine [535-75-1], see Aldrich item P4,585-0. PREPARATION A-3 4-(2-Furonylcarbonyl)piperazine See Example 6B.

PREPARATION A-6 4-(2-Pyridinyl)piperazine

[34803-66-2], see French Patent 7253 M. PREPARATION A-7 4-(2-Pyridinylmethyl)piperazine

[55579-01-6], see European Patent application 49,683. PREPARATION A-8 4-(6-Methoxy-2-pyridinyl)piperazine [51047-54-2], see Canadian Patent 979,894. PREPARATION A-9 4-[(3-Hydroxy-2-pyridinyl)methyl]piperazine

A mixture of t-butyloxycarbonylpiperazine (2.3 g) , 3-hydroxy- pyridine (0.98 g) , formaldehyde (37%, 2.0 ml) and absolute ethano (25 ml) are heated at 78° for 44 hr. The ethanol is removed unde reduced pressure and the residue distributed between chloroform (15 ml) and sodium carbonate (0.1 N, 100 ml). The aqueous phase i extracted with chloroform (100 ml). The organic phases are combine and washed with saline, dried over sodium sulfate and concentrated t a solid. The solid is dissolved in chloroform and chromatographed o a flash column using silica gel (150 g) eluting with ethyl acetate/- methanol/ammonium hydroxide (9.9/0.8/0.2). The appropriate fraction are pooled and concentrated to give 4- [ (3-hydroxy-2-pyridinyl)- methyl] -1-piperazinecarboxylic acid t-butyloxy ester. This material is dissolved in methylene chloride (10 ml), cooled to 0 ^β in a ice/water bath. Trifluoroacetic acid (10 ml) is added over 3 min. The mixture is stirred at 0° for 30 min and then allowed to warm to 20-25° for 1 hr. The solvents are removed under reduced pressure and the residue is distributed between chloroform (100 ml) and saturated sodium bicarbonate (100 ml) . The aqueous phase is extracted (2x) with chloroform (75 ml) . The organic phases are combined, dried over sodium sulfate and concentrated to an oil. The aqueous bicarbonate phase is extracted with ethyl acetate for 48 hr. The ethyl acetate is removed under reduced pressure to leave an oil. These oils are combined to give the title compound, m.p. 254°; MS 193 (electron impact) m/e. PREPARATION A-10 4- [6-(1-Pyrrolidinyl)-2-pyridinyl]piperazine

A solution of 2,6-dichloropyridine (10 g) and piperazine (25 g)

in pyridine (30 ml) is stirred at 65° for 3 h and at 20-25° over¬ night. The reaction mixture is concentrated, the residue is parti¬ tioned between ether and aqueous potassium carbonate. The organic phase is separated, washed with saline, dried over sodium sulfate and concentrated. The residue is added to pyrrolidine (15 g) , pyridine (100 ml) and heated at 100° for 6 days. The reaction mixture is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated, dried and concentrated. The residue is chromatographed on silica gel, eluting with methanol/ammonium hydroxide/methylene chloride (15/1/84) . The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCL ₃ ) 1.9, 2.9, 3.4, 5.75, 6.5, 7.3 S . PREPARATION A-11 4-[3-Amino-6-(diethylamino)-2-pyridinyl]- piperazine Diethylamine (3.29 ml) is added dropwise over 1 hr to a mixture of 2,6-dichloro-3-nitropyridine (6.13 g) , acetonitrile (100 ml) and potassium carbonate (5.2 g) precooled to 0°. The resulting mixture is allowed to slowly warm to 20-25° and is stirred for 16 hr. The mixture is filtered, the filtrate combined with piperazine (12.2 g) and potassium carbonate (6.0 g) . The resulting mixture is heated at reflux for 24 hr and allowed to cool to 20-25° . Aqueous workup (methylene chloride, water wash of organic layers and potassium carbonate) and purification by flash chromatography over silica gel eluting with methylene chloride/methanol (20/1 to 5/1) , pooling and concentration of the appropriate fractions gives 6-N,N-diethylamino- 3-nitro-2-(l-piperazinyl)piρeridine.

A mixture of 6-N,N-diethylamino-3-nitro-2-(l-piperazinyl)plpe- ridine (21.8 g) , ethanol (275 ml), hydrochloric acid (1.2 N, 27 ml) and palladium on charcoal (10%, 5.25 g) is exposed to hydrogen at 50 psi in a Parr flask. After 16 h the residue is filtered through celite, concentrated and partitioned between chloroform and 5% sodium hydroxide. The organic phase is separated, dried over potassium carbonate, concentrated and the residue passed through a plug of silica gel eluting with chloroform/methanol/ammonium hydroxide (4/1/0.25). The appropriate fractions are pooled and concentrated to give the title compound, IR (nujol) 3309, 2967, 2828, 1581, 1474, 1451, 1258 and 803 cm ^"1 ; NMR (CDC1 ₃ ) 1.05, 2.9-3.1, 3.2, 3.2-3'.4, 6.25 and 6.94 δ ; MS (electron impact) 2.49, 2.20, 207, 193, 177 and

163 .

PREPARATION A- 13 4 - [ 6 - ( D i e t hy l am i n o ) - 3 - ( d i a e th y l am i no ) -

2-pyridinyl]piperazine Sodium cyanoborohydride (0.5 g) is added to a mixture of 3- amino-6-N,N-diethylamino-2-((4-t-butylcarbamate)piperazin-l- yl)- piperidine (1.1 g) , formalyn (37%, 11 ml) and acetonitrile (33 ml). The mixture is stirred for 24 h at 20-25°, basic workup (chloroform, sodium carbonate, sodium sulfate) and flash chromatography over silica gel eluting with hexane ethyl acetate (4/1) provides the protected form of the title compound. The protected amine (967 ml), ethyl acetate (20 ml) and hydrochloric acid (3.0 N, 50 ml) is stirred for 3 h at 20-25°. Basic workup (chloroform, 10% sodium hydroxide, sodium carbonate) gives the title compound, IR (nujol) 3289, 2935, 2820, 1589, 1566, 1479, 1445, 1429, 1373, 1263, 1236 and 940 cm" ¹ ; NMR (CDC1 ₃ ) 2.9-3.1, 3.3-3.5, 3.51, 6.06 and 7.10 S .

PREPARATION A-14 4- [4,6-Bis(2-propenylamino)-1,3,5-triazin-2-yl]- piperazine A solution of 2-chloro-4,6-bis(2-propenylamino)-1,3,5-triazine (10.44 g) and 15.95 g of piperazine in 150 ml of DMF is heated under reflux for about 18 hours. The reaction mixture is cooled and stored at 5° and crystals are deposited. The soluble fraction is con¬ centrated and the residue is extracted with ethyl acetate. The extracts are washed with aqueous potassium carbonate, 50% saline and dried over magnesium sulfate and concentrated to give a gum. Chromatography on silica gel (400 g) and elution (200 ml fractions) with 20% acetone-methylene chloride gives the formamide. The formamide (9.2 g) in 200 ml of methanol is heated to reflux, then cooled under nitrogen and mixed with 4 ml of 45% potassium hydroxide solution. The mixture is heated under reflux for about 20 hours, then cooled and concentrated. The residue is partitioned between ethyl acetate and water. The organic extracts are washed with water and saline, dried over magnesium sulfate and concentrated to give a gum. Crystallization from 50 ml of carbon tetrachloride gives the title compound, mp 93-94.5°. PREPARATION A-15 4- [2,6-Bis(diethylamino)-4-pyrimidinyl]piperazine See Example 0. PREPARATION A-16 4- [ 6-Amino-4 - (diethylamino) - 2 -pyrimidinyl- piperazine

Dry piperazine (3.59 g) and 2-amino-4-diethylamino-6-chloro- pyrimidine (1.55 g) are heated at 100 ^* in ethylene glycol (20 ml) for 4 h. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated, the organic phase is dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate to 1% methanol/ethyl acetate to 20% methanol/1% ammonia/ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound, TLC (ethyl acetate/0.5% ammonium hydroxide) Rf - 0.7. PREPARATION A-17 4- [2,6-Bis(dimethylamino)-4-pyrimidinyl]- piperazine

A mixture of dimethylamine (16.6 g, 25% in water), triethylamine

(20 g) and 1,3,5-trichloropyrimidine (8.3 g) in ethanol (100 ml) is stirred at 20-25° for 2 h. The mixture is stored at 0° overnight. Additional dimethylamine solution (2 g) is added and the reaction is stirred at 20-25° for 2 h. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel eluting with 10% ethyl acetate/hexane to give pure 2,4-bis[dimethylamino] -6-chloropyrimidine. This bis- adduct is heated with piperazine (2.6 g) in ethanol (100 ml) for 1 h. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated, the organic phase is dried over sodium sulfate and concentrated. The residue is crystall- ized from ether and hexane to give the title compound, NMR (CDC1 ₃ )

2.05, 3.0, 3.75 and 5.7 5.

PREPARATION A-18 4-[2-(Diethylamino)-6-(1-pyrrolidinyl)- pyrimidinyl]piperazine A solution of 2-diethylamino-4-piperazino-6-chloropyrimidine (4.10 g) in pyrrolidine (4.10 g) is heated at 100° for 12 h. The mixture is concentrated and the residue is partitioned between aqueous sodium bicarbonate and methylene chloride. The phases are separated and the organic phase is dried and concentrated to give the title compound, NMR (CDC1 ₃ ) 1.15, 1.90, 2.90, 3.45, 3.70 and 4.75 δ . PREPARATION A-19 4- [2,6-Bis(4-methyl-1-piperazinyl)-4-pyrimidin¬ yl]piperazine Trichloropyrimldine is added in portions to an ice cool solution of N-methylpiperazine (40 g) In ethanol (200 ml) . The mixture is

then heated at 60° for 2 h. The mixture is concentrated and chromat ographed on silica gel with 2-5% methanol and methylene chloride t give 2,4-bis[4-methylpiperazino]-6-chloropyrimidine. This materia is heated at 130° in water (30 ml) with piperazine (32 g) in a Par bomb for 20 h. The product is partitioned between methylene chlorid and aqueous sodium carbonate. The phases are separated and th organic phase is dried over sodium sulfate and concentrated to giv the title compound, TLC (methylene chloride/methanol/ammoniu hydroxide - 91.5/8/0.5) R _f - 0.3. PREPARATION A-20 4- [2-(Diethylamino)-6- (4-methyl-l-piperazinyl)-4 pyrimidinyl]piperazine 2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted wit piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. Th mixture is concentrated and the product isolated by silica ge chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimi dine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) an N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then wate (2.5 ml) is added and the mixture is heated at 100° for 50 hr. Th mixture is chromatographed on silica gel, the appropriate fraction are pooled and concentrated to give the title compound, NMR (CDC1 ₃ 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ. PREPARATION A-21 4- [2-(Diethylamino)-6-(1-piperidinyl)-4- pyrimidiny1]piperazine A solution of 2-diethylamino-4,6-dichloropyrimidine (4 g) i piperidine (6 g) is heated at 80° for 20 min. The mixture is stirre at 20-25° for 15 h and then partitioned between methylene chlorid and aqueous sodium carbonate. The phases are separated, the organi phase is dried over sodium sulfate and concentrated. The residue an piperazine (8 g) are refluxed in pyridine (100 ml) for 6 h. Th reaction is partitioned between methylene chloride and aqueous potas sium carbonate. The organic phase is dried over sodium sulfate, concentrated to a residue which is chromatographed on silica ge eluting with methylene chloride to 6% methanol/1% ammonium hydroxi de/methylene chloride. The appropriate fractions are pooled an concentrated to give the title compound, NMR (CDC1 ) 1.15, 1.53, 2.90, 3.45 and 4.95 δ .

PREPARATION A-22 4- ^' [ 2 , 6 -Bis (1-pyrrolidinyl) -4-pyrimidinyl] - piperazine

A solution of pyrrolidine (80 g) in THF (500 ml) is chilled in an Ice water bath and stirred mechanically under nitrogen. With a syringe pump of 2,4,6-trichloropyrimidine (50 g) is added over 35 minutes. The reaction is stirred in the ice bath for 1 hour and is then warmed to 20-25° over 4 h. Pyridine (100 ml) is added to the reaction and the mixture stirred at 20-25° overnight. The reaction is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is concentrated and the residue chromatographed on silica gel (10% ethyl acetate/hexane) to yield 51 g of crystalline 2,4-bis[pyrrolidino] - -6-chloropyrimidine. Immediately after the initial addition of reagents, two spots are seen with 25% ethyl acetate on a silica gel plate. These are the 2- and the 4- adducts. The bis product forms over time. It moves between these first two spots. The 51 g of product is reacted with piperazine (40 g) in 100 ml of dry pyridine at 100° for 50 h. The reaction is concentrated. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and concentrated. The residue is chromatographed on silica gel eluting with methylene chloride to 10% methanol/1% ammonia/methylene chloride to give the title com¬ pound, NMR (CDC1 ₃ ) 1.90, 2.9, 3.35 and 4.80 δ . PREPARATION A-23 4- [2,6-Bis(morpholino)-4-pyrimidinyl]piperazine

A solution of 160 g of morpholine in 1000 ml of methylene chloride is treated dropwise with 100 g of 2,4,6-trichloropyrimidine. The reaction is immersed in an ice water bath. After 1 h, 300 ml of pyridine is added. The reaction is stirred for two days and concen¬ trated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The residue is chromatographed on silica gel (10% ethyl acetate/hexane to 25% to methylene chloride) to give 2,4-[bis(morpholino) ] -6-chloropyrimidine. A solution of 40 g of 2,4- [bis-morpholino]-6-chloropyrimidine and 34 g of piperazine in 60 g of pyridine is heated at 100° for 24 h. The mixture is partitioned between methylene chloride and aqueous potassium carbonate. The organic phase is filtered through sodium sulfate and concentrated. The residue is chromatographed (methylene chloride to 4% methanol/1 _% ammonium hydroxide/methylene chloride) to give the title compound, NMR (CDC1 ₃ ) 2.90, 3.50, 3.75, 3.80 and 5.10 δ . PREPARATION A-24 4-[2,6-Bis(allylamino)-4-pyrimidinyl] iperazine

Following the general procedure for PREPARATION A-22, and making non-critical variation but substituting allylamine for pyrrolidine the title compound is obtained.

PREPARATION A-25 4-(2-Pyrimidinyl)piperazine [20980-22-7] See US Patent 4,409,223.

PREPARATION A-26 4- [4,6-Bis(diethylamino)-2-pyri idinyl]piperazine Diethylamine (80 g) is reacted with trichloropyrimidine (50 g) in THF. The reaction after chromatography yields a mixture of the mono- and di-adduct. This material is dissolved in pyridine (58 g) and reacted*with diethylamine (35 g) at 50° for 3 h. The reaction is concentrated to a residue. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated and concentrated. The residue is chromatographed on silica gel, eluting with ethyl acetate/hexane (10/90). The ap- propriate fractions are pooled and concentrated to give 2,4-bis[diet¬ hylamino] -6-chloropyrimidine. This material is dissolved in pyridine (100 g) and reacted with piperazine (40 g) at 100° for 50 h. Following the above workup procedure the title compound is obtained, NMR (CDC1 ₃ ) 1.15, 2.90, 3.45 and 4.9 δ . ^' PREPARATION A-27 4-(3,6-Dimethylpyrazinyl)piperazine [59215-42-8] See Canadian Patent 979,894. PREPARATION A-28 4- [(5-Methyl)-4-phenyl-4H-l,2,4-triazol-3-yl] - piperazine A mixture of 3-bromo-5-methyl-4-phenyl-4H-l,2,4-triazole (4.16 g) , 15.07 g of piperazine and 20 ml of pyridine is stirred at 100° under nitrogen for 22 h. The reaction is monitored by TLC (8% methanol/methylene chloride) and after this period of time no change occurs. The mixture is subsequently placed in a Parr bomb and heated in an oil bath at 180° for 24 h. Bomb pressure increases by 40 psi. The mixture is worked up by partitioning between chloroform and water. The organic phase is washed with saturated aqueous sodium bicarbonate (2 x) and with saline (2 x) , dried over sodium sulfate and concentrated to a solid, the product is recrystallized in ethyl acetate, MS [M + H] ⁺ 243.1484 PREPARATION A-29 4-(Benzo[b]thien-2-yl)piperazine

2-Chlorobenzothiazole (5 g) is heated in ethanol (75 ml) with piperazine (3.05 g) for 20 h. The mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate. The organic

phase is separated, dried with sodium sulfate and concentrated to give the title compound.

PREPARATION A-30 4-(2-Methoxyphenyl)piperazine [35386-24-4], see Aldrich item M2,260-1. PREPARATION A-31 ^' 4-( -Methoxyphenyl) iperazine [70849-64-8], see Aldrich item M2,300-4. PREPARATION A-32 4- [(3,4-Dimethoxyphenyl)methyl]piperazine

See French Patent 7031 M. PREPARATION A-33 4-(4-Fluorophenyl)piperazine [2252-63-3], see Aldrich item 19,133-7.

PREPARATION A-34 4-[2-Amino-5-(l-pyrrolidinyl)phenyl]piperazine

Pyrrolidine (2.0 ml) is added to a mixture of 2,4-dichloronitro- benzene (4.50 g) , acetonitrile (25 ml) and potassium carbonate 4.90 g) . After stirring for 48 hr at 20-25° basic workup gives l-nitro-2- piperazinyl-4-pyrrolidinylbenzene.

A mixture of l-nitro-2-piperazinyl-4-pyrrolidinylbenzene (4.57 g) , ethanol (110 ml), hydrochloric acid (1.2 N, 6 ml) and palladium on carbon (10%, 1 g) is exposed to hydrogen 51 psi at 20-25° in a Parr flask. After 16 h (49 psi total uptake) the mixture is fil- tered. Basic workup (chloroform, potassium carbonate) and column chromatography silica gel (50 g) eluting with chloroform/methanol (4/1) gives the title compound as an oil, IR (nujol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm ^"1 ; NMR (CDCl ₃ ) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 δ; MS (electron impact) 246, 204 and 189. PREPARATION A-35 4- [[4-(D__methyl__mino)phenyl]methyl]piperazine See US Patent 4,421,753. PREPARATION A-36 4-Hydroxy-4- [4-(trifluoromethyl)phenyl]piperidine

[39757-71-6], see US Patent 3,936,464. PREPARATION A-37 (2-Diethylaminoethyl)amine [111-74-0], see Aldrich item 12,694-2.

PREPARATION A-38 [2-(3,4-Dimethoxyphenyl)ethyl]amine

[120-20-7], see Aldrich item D13,620-4. PREPARATION A-39 [2-(2,4-Dimethoxyphenyl)-1-methylethyl]amine See J. Pharm. Sci. 60, 1232 (1971). PREPARATION A-40 [2- (3,4-Dimethoxyphenyl)ethyl] [3,4,5-trimethoxy- phenyl)-methyl]amine A mixture of 3,4-dimethoxyphenylamine (2.87 g) , 3,4,5-trimeth- oxybenzaldehyde (3.15 g) , benzene (100 ml) and p-TSA (276 ml) is

heated at reflux in a Dean Stark apparatus. After 16 hours, th mixture is allowed to cool to 20-25°. Basic workup (methylen chloride, sodium bicarbonate, magnesium sulfate) gives an imine Sodium borohydride (1.2 g) is added in several portions over 2 hour to the imine in methanol (65 ml) and hydrochloric acid (1.2 N, 7. ml). After 3 hours, acidic workup (ether, chloroform, sodiu carbonate) gives the title compound as an oil, IR (Nujol) 2939, 1591 1516, 1463, 1420, 1236 and 1128 cm ^"1 ; NMR (CDC1 ₃ ) 2.7-3.0, 3.7-4. and 6.5-6.9 δ; MS (chemical ionization) [M + H] ⁺ 360, 199, 182, 181. PREPARATION A-41 [2-(3, -Dimethoxyphenyl)ethyl] [ [4-(dimethylamino phenyl]methyl]amine [13159-97-2], see Chem. Abst. 65:7001f. PREPARATION A-42 [ (3 ,4-Dihydroxyphenyl)methyl] [2- (3,4-dimethoxy pheny1)-ethy1]amine A mixture of 3,4-dihydroxybenzaldehyde (1.25 g) t-butyldimethyl silyl chloride (3.5 g) , dimethylformamide (10 ml) and imidazole (1.5 g) is stirred for 18 h at 20-25°. The mixture is diluted with ethe and washed successively with dilute hydrochloric acid and dilut sodium bicarbonate. The organic phase is separated and dried ove magnesium sulfate and concentrated to give an oil homogeneous b TLC. The oil (3.3 g) , 3,4-dimethoxyethylamine (1.77 g) toluene (5 ml) and p-TSA (150 ml) is heated at reflux in a Dean Stark apparatu for 24 h. Afterwards the solution is permitted to cool to 20-25° methanol (35 ml), hydrochloric acid (1.2 N, 4.2 ml) and sodiu borohydride (1 g) are added. After 2 h the mixture is concentrated basic workup (chloroform, sodium carbonate, sodium sulfate) gives compound which is purified by flash chromatography over silica ge diluting with chloroform/ ethanol (30/1) . The appropriate fraction are pooled and concentrated to give the title compound as an oil, I (nujol) 2931, 2858, 1511, 1297, 1259, 909, 840 and 782 cm" ¹ ; NM (CDC1 ₃ ) 0.19, 0.99, 2.7-2.9, 3.68, 3.87, and 6.6-6.9 δ ; MS (chemica ionization) [M + H] ⁺ 532, 386, 351. PREPARATION A-43 (2-Pyridinyl)methylamine [3731-51-9], see Aldrich item A6,520-4. PREPARATION A-44 4- [2- [4- [2 ,δ-Bis(l-pyrrolidinyl)-4-pyrimidinyl] -

1-piperazinyl]ethyl]piperazine Several batches of di- -butyl dicarbonate (17.7 g) is added t a stirred mixture of 2-hydroxyethylpiperazine (10.6 g) in ether (300

ml) . The mixture is stirred at 20-25° for 1.5 hr and then washed with sodium hydroxide (5%, 200 ml), saline (200 ml), dried over sodium sulfate, and filtered. The organic solvent is removed under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (100 g) , eluting with ethyl acetate/methanol/aamonium hydroxide (9.5/0.4/0.1). The appropriate fractions are pooled and concentrated to give the N-protected 2-hydroxyethylpiperazine.

The N-protected 2-hydroxyethylpiperazine (3.0 g) , triethyla ine (1.42 g) and methylene chloride (30 ml) is cooled to 0° in an ice bath under nitrogen. A mixture of methanesulfonyl chloride (1.64 g) in methylene chloride (30 ml) is added dropwise over 10 min. The cooling bath is removed and the mixture allowed to warm to 20-25° for 30 min. The mixture is then washed with water (60 ml) , dried over sodium sulfate and the solvent removed to give crude mesylate. 4-[2,6-Bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine (4.23 g) , potassium carbonate (1.93 g) and acetonitrile (150 ml) are added to the crude mesylate. The mixture is heated at reflux for 18 hr. The acetonitrile is removed under reduced pressure and the residue distributed between chloroform (200 ml) and water (200 ml) . The phases are separated, the organic phase is washed with saline, dried over sodium sulfate and the solvent removed under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (200 g) with ethyl acetate/methanol/ammonium hydroxide (9.5/0.4/0.1). The appropriate fractions are pooled and concentrated to give the N-protected form of the title compound as a solid, p 148-149°.

This solid (0.75 g) in methylene chloride (10 ml) is stirred and cooled to 0° in an ice/water bath. Trifluoroacetic acid (10 ml) is added dropwise over 5 min. The cooling bath is removed and the mixture is stirred at 20-25° for 1 hr. The organic solvent is removed under reduced pressure and the residue is distributed between methylene chloride (50 ml) and sodium hydroxide (iθ%, 50 ml). The organic phase is separated, and dried over sodium sulfate. The solvent is removed to give the title compound. PREPARATION A-45 4-[4,6-Bis(l-pyrrolidinyl)-l,3,5-triazin-2-yl] -1- piperazine

Pyrrolidine (28.5 g) is cooled with an ice bath. 1,3,5-Tri- chlorotriazine (18.4 g) is added with vigorous stirring. After 1-1.5 h the mixture is permitted to warm to 20-25°. The solid is filtered

and rinsed several times with water and dried under reduced pressur to give the monochloro-bis(l-pyrrolidinyl)triazine.

This material (23.18 g) in piperazine (31.55 g) and DMF (295 ml) is refluxed under nitrogen. When the reaction is complete (TLC) the solvent is removed under reduced pressure. The mixture is trans¬ ferred to a separatory funnel containing ethyl acetate (100 ml) an potassium carbonate (100 ml) . The layers are separated, the organic layer is washed with saline (100 ml) and back-washed with ethyl acetate (2 x 100 ml) . The organic layers are combined, dried over magnesium sulfate at room temperature, filtered and concentrated under reduced pressure. This material is chromatographed on a silica gel column (500 g) eluting with acetone/methylene chloride (5/95) . The appropriate fractions (500 ml) are pooled and concentrated to give a solid. The splid (10.13 g) is refluxed in methanol (200 ml) and cooled under nitrogen. Potassium hydroxide (45% aqueous, 4 ml) is added, the mixture degassed with nitrogen and heated to reflux. After 8 h the mixture is cooled to room temperature and concentrated under reduced pressure. The solid is transferred to a separatory funnel containing ethyl acetate (200 ml) and water (100 ml) . The phases are separated, the organic layer is washed with water (2 x 100 ml) and 50% brine (100 ml) followed by brine (2 x 100 ml). The aqueous washes are back-washed with 200 ml of ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered, con- centrated under reduced pressure to give the title compound, m.p. 162.5-166" ^* . PREPARATION A-46 4- [3,6-Bis(diethylamino)-2-pyridinyl]piperazine

Diethylamine (3.29 ml) is added dropwise over 1 h to a mixture of 2,6-dichloro-3-nitropyridine (6.13 g) , acetonitrile (100 ml) and potassium carbonate (5.2 g) precooled to 0°. The mixture is allowed slowly to warm to 20-25° and is stirred for 16 h. The mixture is filtered, the filtrate combined with piperazine (12.2 g) and potas¬ sium carbonate (6 g) . The resulting mixture is heated at reflux for 24 h and then permitted to cool to 20-25° . Aqueous workup (methylene chloride, water washed over organic layers, potassium carbonate) and purification by flash chromatography (silica gel) eluting with chlorofoπn/methanol (20:1 — ^► 5:1) gives 6-N,N-diethylamino-3-nitro- 2-(l-piperazinyl)pyridine.

This material (21.8 g) , ethanol (275 ml) , hydrochloric acid (1. 2 N, 27 ml) and 10% palladium on charcoal (5.25 g) is exposed to hydrogen at 50 pounds per square inch in a Parr flask. After 16 h the residue is filtered through celite , concentrated and partitioned between chloroform and sodium hydroxide (5%) . The organic layers are separated, dried using potassium carbonate and concentrated. The concentrate is passed through a plug of silica gel , eluting with chloroform/methanol/anmonium hydroxide (4/1/0.25) to give 3 -amino -6 - N,N-diethylamino-2- (l-piperazinyl)pyridine . A solution of di- t-butyl dicarbonate (11.8 g) and methylene chloride (25 ml) is added dropwise over 30 min to a mixture of 3 - amino-6 -N,N-diethylamino-2- (l-piperazinyl)pyridine (13.5 g) , triethy- la ine (8 . 33 ml) and methylene chloride (400 ml) precooled to 0° . The resulting mixture is allowed to slowly warm to 20-25° . After 16 h using basic workup (methylene chloride , sodium bicarbonate , potassium carbonate) the t-butyl carbamate as a solid is obtained.

The protected piperazinyl pyridine (4 g) , acetaldehyde (12.8 ml) , acetonitrile (80 ml) is mixed. Sodium cyanoborohydride (1.73 g) is added to the pyridine mixture . The resultant solution is stirred for 48 h at 20-25° . After 24 h additional sodium cyanoboroh¬ ydride (0.5 g) and acetaldehyde (5 ml) are added. Basic workup (chloroform/potassium carbonate , potassium carbonate) and purifica¬ tion by flash chromatography using silica gel and eluting with hexane ethyl acetate (5/1) gives an oil . The oil (2.36 g) , ethyl acetate (50 ml) , and hydrochloric acid (3 .0 N, 37.5 ml) are stirred for 16 h at 20-25° . Basic workup (chloroform, 10% sodium hydroxide, potassium carbonate) gives the title compound, MS (electron impact) 305. PREPARATION A-47 4- T3- (Ethyla ino) - 2 -pyridinyl] piperazine

2- (1-piperazinyl) -3-nitropyridine (24.50 g) , ethanol (445 ml) and hydrochloric acid (1.2 N , 44 ml) are combined and hydrogenated overnight at 40 psi in a Parr bomb , refilling when necessary. The mixture is filtered through celite , washed with ethanol , chloroform, ethanol and water. The organic solvents are removed with reduced pressure . The remaining material is partitioned between methylene chloride (3 x 250 ml) and sodium bicarbonate . The organic layers are combined, dried over potassium carbonate , filtered and concentrated under reduced pressure to give an oil which slowly solidified upon standing to give 3 -amino-2- (l-piperazinyl)pyridine .

3-Amino-2-(l-piρerazinyl)pyridine (19.58 g) , methylene chlorid 600 ml), triethylamine (17.2 ml) are combined and cooled to 0°. Di- t-butyl-dicarbonate (24.34 g) in methylene chloride (50 ml) is adde to the pyridine mixture over 30 min and permitted to stand at 0° fo 1 hr, then allowed to warm to 20 - 25°. After 30 min, TLC indicates no starting material remains. The reaction mixture is partitione between sodium bicarbonate (500 ml) and methylene chloride (3 x 250 ml). The organic phases are combined, dried over potassium car¬ bonate, filtered and concentrated under reduced pressure and heat to give a solid which is recrystallized from ethyl acetate to give 3- amino-2- [(4-t-butyl carbamate)-l-piperazinyl]pyridine.

3-Amino-2- [ (4-t-butyl carbamate)-1-piperazinyl]pyridine (2.361 g) , methanoi (23.6 ml) and acetaldehyde (2.1 ml) are combined at 20 - 25° to form a solution. Sodium cyanoborohydride (586 mg) is added and the mixture stirred overnight. The organic solvent is removed with reduced pressure and heat, the remaining mixture is partitioned between sodium bicarbonate (50 ml) and chloroform (3 x 50 ml). The chloroform extracts are combined and dried over potassium carbonate and filtered. The filtrate is concentrated with heat and reduced pressure. The concentrate is column chromatographed on silica gel 60 (40 63 μ) eluting with hexane/ethyl acetate (2/1) containing tri¬ ethylamine (1%) . The appropriate fractions are pooled and con¬ centrated to give 3-ethylamino-2- [ (4-t-butyl carbamate)-1-piperazin¬ yl]piperidine. 3-Ethylamino- ^' 2- [ (4-t-butyl carbamate)-1-piperazinyl]piperidine (2.47 g) , ethyl acetate (67 ml) and hydrochloric acid (3 N, 49 ml) are combined and stirred for 2 hr at 20 - 25° . TLC indicates no starting material. Potassium hydroxide (14 g) and water (80 ml) is added. The organic layer is removed and extracted with chloroform (3 x 60 ml). The organic layers are combined, dried over potassium carbonate, filtered and the filtrate concentrated to give the title compound, NMR (CDC1 ₃ ) 1.25, 1.50, 3.1, 3.5, 6.90.and 7.75 δ . PREPARATION A-48 4- [3- (Diethylamino) -2-pyridinyl]piperazine

Following the general procedure of PREPARATION A-47 and making non-critical variations but reacting the protected ethyla ine compound with additional acetaldehyde and again reducing the title compound is obtained, NMR (CDC1 ₃ ) 0.95, 3.25,6.80, 7.20 and 7.90 δ . PREPARATION A-49 4- [4,6-Bis(2-pyridinyl)-1,3,5-triazin-2-yl] -

piperazine A mixture of 4-formyl-piperazinecarboxImidamide hydrolodide (prepared according to US Patent 4 , 351 , 832) in ethanol (4 ml) and ethanolic sodium ethoxide (1.4 N, 6.8 ml) Is stirred for 15 min, then 2-cyanopyridine (2.08 g) is added. The mixture is concentrated at atmospheric pressure and heated at about 200° for 5 hr, then cooled and chromatographed on silica gel eluting with methanol/methylene chloride (30/70) . The appropriate fractions are pooled and con¬ centrated to give the 1-formyl 4- [4, 6-bis (2-pyridinyl) - 1 , 3 , 5 -triazin- 2 -yl] piperazine. Hydrolysis of the formamide in the usual way

(PREPARATION A-14) gives the title compound.

PREPARATION A-50 4- [ 5 , 6 -Bis (2-pyridinyl) - 1 , 2 , 4-triazin-3-yl] - piperazine A mixture of 4-formyl-piperazinecarboximidamide hydroiodide (prepared according to US Patent 4.351 , 832) in ethanol (4 ml) and ethanolic sodium ethoxide (1.4 N, 6.8 ml) is stirred for 15 min and then anhydrous hydrazine (0.32 g) in ethanol (3 ml) is added. The mixture is stirred an additional 15 min, then 2 , 2' -pyridll (2.12 g) is added. The mixture is stirred for 12 hours at 25° and con- centrated. The residue is chromatographed on silica gel eluting with a methylene chloride/methanol mixture . The appropriate fractions are pooled and concentrated to give 1-formyl 4- [ 5 , 6-bis (2-pyridinyl) - 1, 2 , 4-triazin-3 -yl] -piperazine . Hydrolysis of the formamide in the usual way (PREPARATION A-14) gives the title compound. PREPARATION A-51 4- [2 , 6-Bis (2-pyridinyl) -4-pyrimidinyl]piperazine

4-Chloro-2, 6-bis(2-pyridinyl)pyrimidine [prepared by the method of J .A. C . S . 32 , 1591 (1967) , 4.2 g] piperazine (13 .44 g) and ethanol (70 ml) are heated at reflux for 2 hr . The mixture is allowed to cool and the solvent is removed under reduced pressure. The residue is dissolved in chloroform (250 ml) , washed with water (twice) , dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is crystallized from ether to give the title compound, m.p . 159 -161° ; MS (m/e) 318 (M ^*1" ) PREPARATION A-55 3 , 6 -Bis (2-pyridinyl) -4-pyridazine PREPARATION A- 56 6 -Methoxy- 2 -morpholino -4- ( 1 -piper azinyl) - pyrimidine A solution of 2 , 4 , 6 - trichloropyrimidine (55 g) , methanol (50 ml) and collidine (50 g) is heated in dry tetrahydrofuran (400 ml) for 4S

hr. Ether is added and the precipitate is collected. The precipit ate is column chromatographed on silica gel to give 6-methoxy-2,4 dichloropyrimidine. This product is mixed with morpholine in THF an stirred at 20-25° to give 6-methoxy-2-morpholino-4-chloropyrimidine. The 6-methoxy-2-morpholino-4-chloropyrimidine is heated with piperaz ine in pyridine at 60° for 24 hr to give the title compound. PREPARATION A-57 4-(3-Chlorophenyl)piperazine

[65369-76-8], see Aldrich catalog, 1986-7, 12,518-0. PREPARATION A-58 4- [3-(Diethylamino)-2-pyridinyl] iperazine Sodium cyanoborohydride (3.06 g) is added to a solution of l-[2- (3-ethylamino)pyridinyl] -4-(t-butyl carbamate)piperazine (5.38 g) , acetaldehyde (5.0 ml) and methanol (54 ml). The mixture is stirre for 10 days at 20-25°. Acetaldehyde (5.0 ml) is added at 2, 3, 4 an 7 days. Sodium cyanoborohydride (3.06 g) is added at 3 and 7 days. After 10 days no further change in the reaction occurred as measure by TLC. Basic workup (chloroform/sodium bicarbonate/magnesiu sulfate) gives an oil. The crude residue is resubmitted to the above reaction conditions. After 5 days the reaction is worked up as described above. Purification by flash chromatography (hexane/ethyl acetate; 5/1) provides the carbamate of the title compound, NMR (CDC1 ₃ ) 0.98, 1.49, 3.21, 3.35-3.65, 6.82, 7.16 and 7.92 δ; IR (neat) 2974, 1699, 1577, 1438, 1234 and 1172 cm ^"1 ; MS (El) m/e (relative percent) 334 (79), 205 (64), 178 (45), 162 (56), 57 (100).

The carbamate (1.17 g) , ethyl acetate (29.0 ml) and hydrochloric acid (3 N, 21.2 ml) are stirred at 20-25° for 1.5 hr. Potassium hydroxide (8 g) and water (30 ml) are added. Aqueous workup (chloro¬ form/potassium carbonate) gives the title compound, IR (nujol) 2957, 2925, 1574, 1450, 1249 and 776 cm ^"1 ; NMR (CDCI3) 0.96, 3.16, 3.15- 3.3, 3.7-3.85, 6.84, 7.17 and 7.91 δ; MS (El, relative percent) 234 (60), 178 (66), 162 (100) and 148 (67).

PREPARATION A-59 4-(5-Diethylamino-2-pyridinyl)piperazine

2-Chloro-5-nitropyridine (25 g) is dissolved in acetonitrile (150 ml) and the mixture is added dropwise over 30 min to a stirred suspension of piperizine (61.3 g) and potassium carbonate (26.2g) in acetonitrile (550 ml). The reaction mixture is stirred at 20-25° for 16 hr. The solvent is removed on a rotary evaporator and the residue is diluted with methylene chloride/water. The organic layer is separated and washed with water (twice) and saline, dried over

po _t assium carbonate and concentrated to give l-(5-nitro-2-pyridinyl>- piperazine, IR 3338, 3102, 3068, 1603, 1570, 1482, 1347, 1340, 1320, 1306 and 1253 cm ^"1 .

The nitro compound (30.7 g) is dissolved in ethanol (500ml), and palladium/carbon (10%, 10 g) and hydrochloric acid (1.2 N, 55 ml) are added and the mixture hydrogenated on a Parr apparatus (50 psi) for 4 hr. The mixture is then filtered thru celite and the filtrate evaporated to dryness to give an oil. The residue is partitioned between saturated sodium bicarbonate and chloroform, the layers are separated, the aqueous layer is reextracted with chloroform (2 x 250 ml) and the organic phases are combined, dried over potassium car¬ bonate and concentrated under reduced pressure. The pH of the aqueous phase is raised to 11 by the addition of solid potassium hydroxide, the mixture reextracted with chloroform, dried and con- centrated to give the crude 5-amino compound. The aqueous layer is concentrated to half the volume, excess sodium chloride is added and the mixture is reextracted with chloroform. The extract is dried and concentrated to obtain additional 5-amino compound.

The amine (21 g), triethylamine (17.9 g) ^" and methylene chloride (600 ml) are cooled to 0°. Di-t-butyl dicarbonate (25.8 g) in methylene chloride (200 ml) Is added over 30 min at 0° . The reaction mixture is stirred at 0° for 1 hr and allowed to warm to 20-25° . The reaction mixture is washed with saturated sodium bicarbonate (3 x 200 ml) , dried over potassium carbonate and the solvent removed under reduced pressure to give a solid. The solid is dissolved in ether, petroleum ether is added until the mixture is cloudy, the mixture is filtered thru celite and the filtrate is concentrated to give piperazine protected compound.

The protected piperazine compound (2.6 g) and acetaldehyde (1.7 g) in methanol (25 ml) is cooled to 0° . Sodium cyanoborohydride (0.62 g) is added In one portion. The cooling bath is removed and the mixture is permitted to warm to 30° . The mixture is stirred at 20-25° for 2 hr. The methanol is removed under reduced pressure and the residue is partitioned between methylene chloride and a saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with saturated sodium bicarbonate solution, saline, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil is purified by HPLC on silica gel,

MS (M ⁺ ) 334 .

The oil (2.1 g) , aqueous hydrochloric acid (3 N, 42 ml) and ethyl acetate (57 ml) are stirred for 1 hr at 20-25°. The mixture is cooled in ice, basified (pH - 11) with potassium hydroxide (20%), the phases separated and the aqueous phase extracted again with ethyl acetate. The combined extracts are washed with saline, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound. NMR (CDCl ₃ ) 1.13, 6.68, 7.12 and 7.87 δ. PREPARATION A-60 4- [4- (5-Ethylamino-6-diethylamino)pyrimidinyl] - piperazine

A solution of di-t-butyldicarbonate (4.78 g) and methylene chloride (20 ml) is added to a mixture of 1- [4-(5-amino-6-diethyl- amino)pyrimidinyl]piperazine (4.97 g) , methylene chloride (70 ml), triethylamine (3.33 ml) and dimethylaminopyridine (10 mg) . The mixture is stirred overnight. Basic workup (sodium bicarbonate/- methylene chloride/magnesium sulfate) and purification by flash chromatography (hexane/ethyl acetate; 2/1) gives the carbamate of 4- [4-(5-amino-6-diethylamino)pyrimidinyl]piperazine, MS (El) 350.

Sodium cyanoborohydride (0.300 g) is added to a solution of the carbamate (0.652 g) , methanol (13 ml) and acetaldehyde (2.1 ml). The mixture is stirred for 1 week at 20-25° . At two day intervals similar amounts of sodium cyanoborohydride and acetaldehyde are added. Concentration and basic workup (chloroform/sodium bicar¬ bonate/magnesium sulfate) and purification by flash chromatography (hexane/ethyl acetate; 2/1) give the t-butyl carbamate of the title compound, MS (El) 378.

The carbamate of the title compound (465 mg) , ethyl acetate (9.5 ml) and hydrochloric acid (3 N, 7 ml) are stirred at 20-25° for 2 hr. Basic workup (chloroform/solid potassium hydroxide/magnesium sulfate) provide the title compound, NMR (CDC1 ₃ ) 1.06, 1.07, 2.98, 2.95-3.1, 3.25, 3.35-3.45 and 8.16 δ; MS (El) 278. PREPARATION A-61 4-(5-amino-6-diethylamino)ρyrimidinylpiperazine

A solution of diethylamine (4.0 ml) and acetonitrile (25 ml) is added dropwise over 40 min to a mixture of 4,6-dichloro-5-nitro- pyrimidine (7.5 g) , acetonitrile (150 ml) and potassium carbonate (6.41 g) at 0°. The mixture is stirred for an additional 50 min at 0° and is then allowed to warm to 20-25°. After 16 hr, the mixture is filtered, and the residue washed with acetonitrile (2 x 25 ml).

The crude filtrate, piperazine (25.8 g) and potassium carbonate (6.41 g) are combined and heated at reflux for 6 hr. After cooling to 20-25°, basic workup (sodium bicarbonate/chloroform/magnesium sulfate) and purification by flash chromatography (chloroform/- methanol/ammonlum hydroxide; 200/10/1) an oil is obtained which solidifies upon standing to give 5-nitro-6-diethylamino-4-piperazin- ylpyrimidine, MS (Cl, relative percent) 281 (100), 265 (13), 249 (18) and 234 (71).

5-Nitro-6-diethylamino-4-piperazinylpyrimidine (0.980- g) , ethanol (25 ml) and palladium/carbon (10%, 0.25 g) are exposed to hydrogen (50 psi) for 24 hr. The mixture is filtered and the residual solids are washed with chloroform/ethanol. The combined filtrates are concentrated under reduced pressure. Basic workup (aqueous potassium hydroxide, chloroform, magnesium sulfate) provided a solid, p 58-59°; NMR (CDC1 ₃ ) 1.11, 2.95-3.05, 3.15-3.4 and 3.29 δ. PREPARATION NA-1 8-Mesyloxy-l-octanol

Octanediol (3.656 g) in pyridine (50 ml) is stirred at 0° and

^• methanesulfonyl chloride (2.32 ml) is added slowly. The mixture is stirred with continued cooling for about 2 hr and then is poured into a mixture of ice (200 g) and hydrochloric acid (49 ml) . The mixture is allowed to warm then is extracted with ethyl acetate (2 x 100 ml) .

The extracts are combined, washed with water, aqueous potassium bicarbonate and saline, then dried over magnesium sulfate and concentrated. The concentrate is chromatographed on silica gel (400 g) eluting with acetone/methylene chloride (5/95 and 10/90) . The appropriate fractions are pooled and concentrated ^* to give the title compound, NMR (CDC1 ₃ ) 1.2-2.0, 3.02, 3.65 and 4.25 δ.

PREPARATION NA-2 5-Mesyloxy-l-pentanol

Following the procedure of PREPARATION NA-1 and making non- critical variation but stating with the appropriate diol, the title compound is obtained. PREPARATION NA-3 6-Mesyloxy-l-hexanol

Following the procedure of PREPARATION NA-1 and making non- critical variation but stating with the appropriate diol, the title compound is obtained.

PREPARATION NA-4 10-Mesyloxy-l-decanol

Following the procedure of PREPARATION NA-1 and making non- critical variation but stating with the appropriate diol, the title

co pound is obtained.

PREPARATION NA-5 12-Mesyloxy-l-dodecanol

Following the procedure of PREPARATION NA-1 and making non critical variation but stating with the appropriate diol, the titl compound is obtained.

PREPARATION NA-6 8-[(Tetrahydropyran-2-yl)oxy] -1-octyne

6- [(Tetrahydropyran-2-yl)oxy] -1-bromohexane (2.0 g) is added with a mild exotherm, to a stirred mixture of lithium acetylid ethylenediamine (4.9 g) at 20-25°. The mixture is stirred overnight then is poured into ice and aqueous ammonium chloride and extracte with ether/pentane. The extracts are dried over magnesium sulfat and concentrated to give the title compound, NMR (CDC1 ₃ ) 1.3-2.5, 3.3-4.1 and 4.7 δ.

PREPARATION NA-7 4-(6-bromohexyloxy)phenol A mixture of hydroquinone (16.5 g) , 1,6-dibromohexane (7.32 g and ethanol (60 ml) is added dropwise over 3-5 min to a solution o potassium hydroxide (85%, 2.0 g) and ethanol (20 ml). The mixture i heated at reflux for 4 hr and then allowed to cool. Silica gel (30 g is added to the solution and the ethanol is removed at reduce pressure. The residue is chromatographed on silica gel (200 g) an eluted with ethyl acetate/hexane (33/67) to give the title compound, m.p. 43-45°; MS (m/e) = 272, 274 (M+) . PREPARATION NA-8 4-(5-Iodopentyloxy)phenol

Following the general procedure of PREPARATION NA-7 and makin non-critical variations but starting with 1,5-diiodopentane, th title compound is obtained, MS (m/e) - 306 (M ⁺ ) . PREPARATION NA-9 4-(4-Iodobutyloxy)phenol

Following the general procedure of PREPARATION NA-7 and makin non-critical variations but starting with 1,4-diiodobutane, the title compound is obtained, m.p. 51-53°; MS (m/e) - 292 (M+) . PREPARATION NA-10 4-(6-Bromohexyloxy)anisole

A mixture of 4-methoxyphenol (5.0 g) , 1,6-dibromohexane (31 ml), potassium carbonate (6.13 g) and acetonitrile (50 ml) are heated at reflux for 24 hr. The mixture is allowed to cool to 20-25° and the small amount of solids that formed are collected, dissolved in chloroform, washed with water, dried over sodium sulfate and the solvent removed at reduced pressure to give the diarylhexane side product. The reaction mother liquor is concentrated at reduced

pressure and the 1,6-dibromohexane distilled off (bp - 75° at 0.25 mm) . The distillation residue is dissolved in ether (50 ml) and the product allowed to crystallize to give the title compound, m.p. 51.5- 53°; MS (m/e) - 286, 288 (M+) . PREPARATION NA-11 4-(6-Hydroxyhexyloxy)anisole

A mixture of 4-methoxyphenol (8.7 g) , potassium carbonate (9.7 g), 6-chlorohexanol (9.55 g) and DMSO (80 ml) is heated at 120° for 18 hr. Most all of the DMSO is removed at reduced pressure and the residue distributed between ether (400 ml) and water (400 ml) . The ether phase is washed with water, saline, dried over sodium sulfate and the solvent removed at reduced pressure to give a residue which is crystallized from ether to give the title compound, m.p. 63-64°; MS (m/e) 224 (M+) . PREPARATION NA-12 l,2-Methylenedioxy-4-[3-mesyloxypropyl]benzene A solution of l,2-methylenedioxy-4-[3-hydroxypropyl]benzene, (10.0 g) , methanesulfonyl chloride (6.33 g, 4.28 ml) and triethyl- amine (5.6 g) in methylene chloride (100 ml) is stirred at 0° for 2 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in acetonitrile (100 ml) . PREPARATION NA-13 2-Bromo-4-methoxyacetophenone

Can be purchased from Aldrich Chemical Co. PEPARATION NA-14 4- [3,5-Dimethyl-4-methoxyphenyl)butanol A mixture of 2,6-dimethylanisole (4.45 g) , succinic "anhydride (4.80 g) and aluminum chloride (4.70 g) in toluene (60 ml) is stirred for 2.7 hr at 20-25°. A 100 ml aliquot of methylene chloride is added for solubility. The reaction is run for 6 hr. The reaction is poured onto ice and extracted with methylene chloride-isopropanol. The organic phase is washed with saline, dried over sodium sulfate, concentrated and dried under reduced pressure overnight to give a solid. This material is stirred with borane-methyl sulfide complex (1.0 M, 38 ml) in THF at 20-25° for 24 hr. Aqueous sodium bicar¬ bonate, methylene chloride and water are added. The ketoalcohol product is combined with other partly reduced materials and treated with borane-methyl sulfide complex in excess in methylene chloride for 72 hr. It is important that the ketoacid Friedel Crafts adduct should be reduced exhaustively with excess borane-methyl sulfid.

complex.

PREPARATION NA-15 4- [3,5-Dimethyl-4-hydroxyphenyl]butanol

A solution of 4- [3, 5-dimethyl-4-methoxyphenyl]butanol (PREPARA¬ TION NA-14, 4.96 g) , boron tribromide (1.0 M in methylene chloride, 47 ml) in methylene chloride (200 ml) is stirred at -70° and then allowed to warm to 20-25° over 4 hr. The reaction did not begin until the reaction reached room temperature. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicar¬ bonate. The organic phase is dried over sodium sulfate and con- centrated to give the phenol which had a consistent NMR. A sample of the phenol (5.00 g) is dissolved in methylene chloride (100 al) and is treated at 0° with triethylamine (6.28 g) and methanesulfonyl chloride (7.09 g) . After 3 hr, the reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated to give the title compound which had an NMR consistent for the bis-mesylate. PREPARATION NA-16 l-Bromo-3-phenylpropane [637-59-2] PREPARATION NA-17 6-(4.-Methoxyphenoxy)-1-iodohexane Methanesulfonyl chloride (3.2 ml) is added slowly to a stirred solution of 6-(4-methoxyphenoxy)-1-hexanol (7.84 g) in pyridine (88 ml) at 0° . The mixture is stirred for 1 hr then poured into a mixture of ice (300 g) and concentrated hydrochloric acid (87 ml) . The mixture is stirred for about 1 hr, then filtered. The filter cake is washed with water. The damp product is dissolved in ethyl acetate, the solution is washed with saline, dried over magnesium sulfate and concentrated to give the mesylate of the desired com¬ pound. The mesylate and sodium iodide (28 g) in acetone (400 ml) are stirred under reflux for 1 hr, and then filtered. The filter cake is washed with acetone. The filtrate is concentrated and the residue is dissolved in ethyl acetate. The solution is washed with sodium thiosulfite (2% aqueous), saline, dried over sodium sulfate and concentrated to give a solid. The solid is chromatographed on silica gel (550 g) and eluted with methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound, m.p. 64-66° . PREPARATION NA-18 8- (4-Methoxyphenoxy)-1-octyne

Following the general procedure of PREPARATION NA-6 and making

non-critical variations but starting with 6-(4-methoxyphenoxy)-1- iodohexane (PREPARATION NA-17) , the title compound is obtained, NMR (CDC1 ₃ ) 1.3-2.3, 3.78, 3.92 and 6.92 δ .

PREPARATION NA-19 3-(3,5-Dimethyl-4-hydroxyphenyl)propanol bis- mesylate

Part I - 3-(3,5-Dimethyl-4-hydroxyphenyl)propanol 2,6-Dimethylphenol (1.22 g) is added to a mixture of powdered potassium hydroxide (2.24 g) In dimethylsul oxide (20 ml). Then 3- bromopropane (2.42 g) Is added at 20-25° and stirred for 0.5 hr. The mixture is diluted with water (100 ml) and extracted with methylene chloride (3x) . The organic extracts are washed with water (2x) and then with saline, dried over sodium sulfate and concentrated under reduced pressure to give l-allyloxy-2,6-dimethylbenzene.

A mixture of l-allyloxy-2,6-dimethylbenzene (1.4 g) and 1- methyl-2-pyrrolidinone (3 ml) is refluxed under nitrogen for 6 hr. The reaction mixture is cooled, diluted with ether, washed with aqueous hydrochloric acid (10%, 2x) , dried over sodium sulfate and concentrated to give 3-(3,5-dimethyl-4-hydroxy)propene.

A solution of borane-dimethylsulfide (10 M) is added to an ice- cold solution of 3-(3,5-dimethyl-4-hydroxy)propene (1.6 g) and stirred at 0° for 0.5 hr, then at 20-25° for 0.5 hr. The reaction is then quenched with water (3 ml) . After the effervescence ceases, a solution of aqueous sodium hydroxide (20%) is added until a faint pink color develops, and then aqueous hydrogen peroxide (30%, 1.3 ml) is added to the mixture at 0° . The reaction is stirred overnight at 20-25°. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried over magnesium sulfate, and concentrated. The concentrate is flashed chromatographed on silica gel (230-400 mesh) eluting with ethyl acetate/hexane (30/70) . The appropriate fractions are pooled and concentrated to give 3-(3,5-dimethyl-4-hydroxyphenyl)propanol.

Part II - 3-(3,5-Dimethyl-4-hydroxyphenyl)propanol bismesylate Methanesulfonyl chloride (1.2 g) in dichloromethane (2 ml) is added dropwise to an ice-cold solution of 3-(3,5-dimethyl-4-hydroxv- phenyl)propanol (0.85 g) and triethylamine (1.6 ml) in methylene chloride (10 ml). The mixture is stirred for 0.5 hr and then diluted with an ice-cold aqueous solution of sodium bicarbonate. The phases are separated, the organic phase is dried over sodium sulfate and

concentrated to give 3- (3,5-dimethyl-4-hydroxyphenyl)propanol bismesylate.

PREPARATION NA-20 3- (3,5-Dimethyl-4-methoxyphenyl) -1-propanol

3-(3,5-Dimethyl-4-hydroxyphenyl)-l-propene (5.0 g) is added to a mixture of powdered potassium hydroxide (7.98 g) in dimethylsulfoxide (50 ml) at 15°. Iodomethane (8.8 g) is then added and stirred below 20° for 0.5 hr. The reaction mixture is poured into ice/water and the product is extracted with ether (2x). The ether extracts are washed with water (3x) , saline, dried over sodium sulfate and con- centrated under reduced pressure to give 3-(3,5-dimethyl-4-methoxy- phenyl-1-propene. The "propene" is transformed to the corresponding "propanol" with borane-dimethylsulfide by the general procedure of PREPARATION NA-19 to give the title compound. PREPARATION NA-21 2-(3,5-Dimethyl-4-hydroxyphenyl)-1-ethanol Ozone is bubbled into a solution of 3-(3,5-dimethyl-4-hydroxy)- propene (see PREPARATION NA-19, Part I, 3.77 g) in methanol (60 ml) at -78° until the starting material is no longer detected by TLC. Nitrogen is then passed through the solution for 15 min at -78°. Sodium borohydride (1.0 g) is added carefully in portions and the mixture is then permitted to warm to 20-25° . The reaction is quenched with saturated aqueous solution of ammonium chloride. The mixture is acidified with aqueous hydrochloric acid, following which the product is extracted with methylene chloride (5x) . The extracts are combined, washed with saline, dried over sodium sulfate and concentrated. The concentrate is flash chromatographed on silica gel (230-400 mesh), eluting with ethyl acetate/hexane (50/50). The appropriate fractions are pooled to give the title compound. PREPARATION NA-22 2-(3,5-Dimethyl-4-methoxyphenyl)-1-ethanol

Following the general procedure of PREPARATION NA-21 and making non-critical variations but starting with 3-(3,5-dimethyl-4-methoxy)- propene (see PREPARATION NA-20), the title compound is obtained. PREPARATION NA-23 6 -(3 , 5-Dimethyl-4-methoxyphenyl) -1-hexanol mesylate Bromine is added dropwise to a solution of 2,6-dimethylanisole (12.0 g) in chloroform (100 ml) at about 5°. The solution is stirred at 5° for 2 hr and then allowed to warm to 20-25°. The reaction mixture is poured into ice-water, and the phases are separated. The chloroform phase is washed with water, aqueous sodium bisulfite

solutlon, then with water, dried over sodium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-4-methoxybromobenzene.

3,5-Dimethyl-4-methoxybromobenzene (8.0 g) in THF is added dropwise to a mixture of magnesium turnings (1.1 g) , a crystal of iodine and THF (25 mL) at 20-25°. The mixture is refluxed for 18 hr. The Grignard reagent is cooled to 20-25° and a solution of cyclohexanone (4.0 g) in THF (60 ml) is added over a period of 5 min. The mixture is stirred at 20-25° , then refluxed for 6 hr. The solution is quenched with a saturated aqueous solution of ammonium chloride, and the product is extracted with ether (2x) . The ether extracts are washed with water then with saline, dried over magnesium sulfate and concentrated under reduced pressure at 45° to give the desired alcohol, the structure of which is supported by NMR. Chromium trioxide (18.4 g) is added in portions to the alcohol 7.85 g) in glacial acetic acid (250 ml) at 20-25° . An induction period of about 15 min takes place with a termperature rise to 35° . The mixture Is maintained between 28-32° with occassional cooling with a water bath. The reaction is stirred for an additional hour after the exotherm ceases and then poured into ice (1 1) . The product is extracted with chloroform (3x) , the extracts washed with water (100 ml), then with saline, dried over sodium sulfate and concentrated. The concentrate is dissolved in aqueous sodium hydroxide and washed with ether (2x) . The aqueous basic phase is chilled, traated with activated charcoal, filtered, and acidified with hydrochloric acid (12 N) . The product is extracted with chloroform (2x) , dried over sodium sulfate and concentrated to give the keto-acid.

Borane-tetrahydrofuran (IN, 40 ml) is syringed into an ice-cold solution of the keto-acid (5.1 g) in THF (50 ml). The solution is stirred at 5° for 0.5 hr, then at 20-25° for 20 hr. The solution is quenched with aqueous hydrochloric acid. The phases are separated and the aqueous phase is extracted with ether. The extracts are washed with water and then with saline, dried over magnesium sulfate and concentrated. The concentrate is dissolved in acetic acid (90 ml) , absolute ethanol (20 ml) and concentrated hydrochloric acid (6 ml) in a Parr bottle. Palladium on charcoal (10%, 2.65 g) is added and the mixture charged with 50 psi of hydrogen. Hydrogen uptake ceases after 4.5 hr. The catalyst is removed by filtration and washed with ethanol. The filtrate is concentrated under reduced

pressure, diluted with water and the product extracted with ether. The ether extracts are washed wilth saturated sodium bicarbonate, water, saline, dried over magnesium sulfate and concentrated. The concentrate (3.2 g) is refluxed in a mixture of sodium hydroxide (20%, 25 ml) and methanol (10 ml) for 1 hr. The mixture is cooled and then extracted with ether (2x) . The ether extracts are washed with water, dried over magnesium sulfate and concentrated.

A solution of methanesulfonyl chloride (1.18 g) in methylene chloride (10 ml) is added dropwise to an ice-cold solution of the concentrate (2.1 g) , triethylamine (1.7 ml) in methylene chloride (50 ml). The mixture is stirred and then washed with water, sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give the title compound. PREPARATION NA-24 3-0xo-l-cyclohexene butanal Butylmagnesium chloride (2.0 M, 20.0 ml) is added dropwise over 20 min to a solution of 4-chloro-l-butanol (4.05 g) and THF (40.0 ml) . The resultant solution is stirred for 20 min and then is added dropwise over 20 min to a mixture of magnesium (1.46 g) and THF (5.0 ml). The resulting warm mixture is heated at reflux for 3 hr, and then cooled in an ice bath. A solution of 3-ethoxy-2-cyclohexene-l- one (5.39 ml) and THF (20.0 ml) is then added dropwise over 20 min. The resultant solution is allowed to warm to 20-25° and stir for 2 hr. Acidic workup using ether and hydrochoric acid (1%) and purific¬ ation by flash chromatography eluting with ethyl acetate/ hexane (4/1) provides 3- (4-hydroxybutyl)-cyclohex-2-en-l-one as an oil, IR (neat) 3413, 2942, 1664, 1600, 1257, 1185 cm" ¹ ; MS (El) m/e

(relative %) 168 (25), 123 (25), 97 (40), 82 (36), 55 (44), 42 (100).

Following the procedure of Corey, Tetrahedron Lett 2647 (1975), a mixture of 3-(4-hydroxybutyl)-cyclohex-2-en-l-one (539 mg) pyridinium dichromate (2.05 g) and methylene chloride (8.0 ml) is stirred for 25 hr at 20-25°. The reaction is diluted with ether, filtered, dried over magnesium sulfate and concentrated to give the title compound, IR (neat) 2950, 1724, 1666, 1255, 1193, 888 cm" ¹ . PREPARATION NA-25 3-Oxo-l-cyclohexanal Following the general procedure of PREPARATION NA-24 and making non-critical variations but using 6-chloro-l-hexanol, the title compound is obtained, IR (neat) 2938, 1730, 1667, 1254, 1193 cm" ¹ . PREPARATION NA-26 3-0xo-l-cyclohexene propanal

A solution of 2-(2-bromoethyl)l,3-dioxalane (14.8 g) and THF (76 ml) is added dropwise over 35 min to a mixture of magnesium (3.98 g) and THF (27.1 ml). The resultant mixture is stirred for 1.5 hr at 20-25° before being cooled to 0° in an ice bath. A solution of 3- ethoxy-2-cyclohexene-l-one (8.45 g) and THF (27.0 ml) is added dropwise over 20 min. The resultant solution is stirred for 1 hr at 0° and 30 min at 20-25° . Acidic workup using ether and hydrochloric acid (1%) and purification by flash chromatography ethyl acetate/- hexane (4/1 - 1/0) provides 3-(2-(l,3-dioxolan-2-yl)ethyl)cyclohex-2- en-l-one as an oil, IR (neat) 2950, 2886, 1667, 1138 cm ^-1 .

A solution of 3-(2-(l,3-dioxolan-2-yl)ethyl)cyclohex-2-en-l-one (3.00 g) , acetone (60.0 ml) and perchloric acid (3 N, 10.0 ml) is stirred for 4 hr at 20-25° . Aqueous saturated sodium bicarbonate (150 ml) is added and the mixture concentrated. Aqueous workup provides the title compound, IR (neat) 2950, 1720, 1666, 1257, 1194, 969, 732 cm- ¹ . PREPARATION NA-27 4-Phenoxy-l-bromobutane

[1200-03-9] EXAMPLE 1 4- [4, 6-Bis(1-pyrrolidinyl) -1,3 ,5-trlazin-2-yl] -1- piperazinehexanol (II/A-45)

A mixture of 6-bromohexanol (0.905 g) , 2,6-bis(l-pyrrolidinyl)- 4-(1-piperazinyl)-1,3,5-triazine (PCT 86/01797, PREPARATION A-45, 1.517 g) , potassium carbonate (0.346 g) and sodium iodide (0.075 g) in acetonitrile (165 ml) are stirred under reflux for 4.5 hr. The mixture is concentrated and the residue is partitioned between methylene chloride and potassium bicarbonate (1 N) . The phases are separated, the organic phase is washed with water and saline, then filtered through sodium sulfate and concentrated. The residue is chromatographed on silica gel (230 g) packed in methanol/ ethylene chloride (5/95) . Elution is performed with 5% methanol/methylene chloride (3 1) followed by 10% methanol/methylene chloride (2 1) . 50 ml fractions are collected, fractions 61-78 are pooled and con¬ centrated to give the title compound. EXAMPLE 1A 4-[4,6-Bis(1-pyrrolidinyl)-1,3,5-triazin-2-yl] -1- piperazinehexanol methane sulfonate (II/A-45)

A mixture of 4-[4,6-bis(l-pyrrolidinyl)-l,3,5-triazin-2-yl]-1- piperazinehexanol (EXAMPLE 1, 1.22 g) in methylene chloride/ether (1/1, 30 ml) Is mixed with a solution of methanesulfonic acid (0.28

g) in ether (15 ml) . The mixture is concentrated and the residue crystallized twice from methanol /ether to give the title compound. EXAMPLES 2 - 16

See CHART D for Column A and Column B. Following the general procedure of EXAMPLE 1 and making non- critical variations but starting with (a) the non-amine halide or mesylate (Column A) corresponding to the non-amine portion of the desired alkyl amine (II) and (b) the amine (Column B) corresponding to the .imine portion of the desired alkyl amine (II) , the alkyl amines (II, Column C) are obtained:

EXAMPLE Column C. Alkyl amine (II)

2 4- (2-pyridinyl) -1-piperazinehexanol (II/A-6)

3 4- [3- (ethylamino) -2-pyridinyl] -1-piperazinehexanol (II/A-47) 4 4.- [ (3 , 6-bis (2-pyridinyl) -4-pyridazinyl)methyl] -1- piperazinehexanol (II/A-52)

5 6- [bis(2-pyridinylmethyl)amino] -1-hexanol (II/A-54)

6 2 ,4-bis (1-pyrrolidinyl) -6- (4- tetradecyl- 1-piperazinyl) - pyrimidine (II/A-22) 7 methyl 5- [4- (2 ,6-bis(l-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]pentanoate (II/A-22) 8 2, 4 -bis (1-pyrrolidinyl) -6 - ( -hexyl- 1-piperazinyl) pyrimidine

(II/A-22) 9 4- [2 , 6-bis (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazine hexanol (II/A-22)

10 4- [2, 6-bis (1-pyrrolidinyl) -4-pyrimidinyl] -1 -piperazine - dodecanol (II/A-22)

11 4- [2 ,6 -bis (1-pyrrolidinyl) -4-pyrimidinyl] - 1-piperazine - octanol (II/A-22) 12 4- [2 , 6-bis(l-pyrrolidinyl) -4-pyrimidinyl] -1-piperazine- pentanol (II/A-22)

13 4- [ 2 , 6 -bis (1-pyrrolidinyl) -4-pyrimidinyl ] - 1-piperazine - decanol (II/A-22)

14 4- [3- (ethylamino) -2-pyridinyl] -1-piperazinedecanol (II/A-47)

15 4- [3- (ethylamino) -2-pyridinyl] -1-piperazineoctanol (II/A-47)

16 4- [ 2 , 6-bis (2-pyridinyl) -1,3,5- triazin-4-yl] -1-piperazine

hexanol (II/A-49) EXAMPLES 2A - 16A

Following the general procedure of EXAMPLE 1A and making non- critical variations but using the alkyl amines (II) of EXAMPLES 2- 5 16 and the appropriate acid, the salts of the corresponding alkyl amines (II) of EXAMPLES 2A - 16A are obtained.

EXAMPLE Alkyl amine salt (II)

2A 4-(2-pyridinyl)-1-piperazinehexanol monomethane sulfonate 3A 4- [3-(ethylamino)-2-pyridinyl]-1-piperazinehexanol dihydro- 0 chloride

4A 4-[(3,6-bis(2-pyridinyl)-4-pyridazinvl)methyl]-1- piperazinehexanol dihydrochloride 5A 6-[bis(2-pyridinylmethyl)amino] -1-hexanol dihydrochloride 6A 2,4-bis(1-pyrrolidinyl)-6-(4-tetradecyl-l-piperazinyl) - 15 pyrimidine dihydrochloride

7A methyl 5-[4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1- piperazinyl]pentanoate methane sulfonate 8A 2,4-bis(1-pyrrolidinyl)-6-(4-hexyl-l-piperazinyl)pyrimidine monomethane sulfonate 20 9A 4- [2,6-bis(1-pyrrolidinyl) -4-pyrimidinyl]-1-piperazine¬ hexanol monomethane sulfonate 9B 4- [2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl] -1-piperazine hexanol dihydrochloride 10A 4- [2, 6-bis(1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazine- 25 dodecanol dihydrochloride

11A 4- [2,6-bis(1-pyrrolidinyl) -4-pyrimidinyl]-1-piperazine- octanol dihydrochloride 12A 4- [2,6-bis(1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazine- pentanol dihydrochloride 30 13A 4- [2 , 6-bis(1-pyrrolidinyl) -4-pyriaidinyl] -1-piperazine- decanol dihydrochloride 14A 4-[3-(ethylamino)-2-pyridinyl]-1-piperazinedecanol dihydro- chloride 15A 4- [3-(ethylamino)-2-pyridinyl] -1-piperazineoctanol dihydro-

-.-. choride 16A 4- [2,6-bis(2-pyridinyl) -1, 3 ,5-triazin-4-yl] -1-piperazine hexanol monomethane sulfonate EXAMPLE 17 3,6-Bls(2-pyridinyl)-4-pyridazine hexanol (II/A-55)

A mixture of 8- [ (tetrahydropyran-2-yl)oxy] -1-octyne (PREPARATION NA-6, 1.5 g) and 3,6-bis(2-pyridinyl) -1,2,4,5-tetrazine (1.68 g) in toluene (50 ml) is heated under reflux for about 48 hr. The mixture is concentrated and the residue chromatographed on silica gel (200 g) packed in acetone/methylene chloride (20/80). Elution is preformed with acetone/methylene chloride (1 1 of 1/99 and 3 1 of 20/80) . The appropriate fractions are pooled to give the tetrahydropyranyl ether of the title compound. A mixture of this compound (1.23 g) in acetone (45 ml, methanol is preferred) and hydrochloric acid (1 N, 5 ml) is allowed to stand overnight at 20-25°. The mixture is con¬ centrated and extracted with ether. The extracts are dried over magnesium sulfate and concentrated to an oil. The oil is chromatogr¬ aphed on silica gel (100 g) eluting with methanol/methylene chloride (5/95) . The appropriate fractions are pooled to give the title compound.

EXAMPLE 17A 3,6-Bis(2-pyridinyl)-4-pyridazine hexanol dihydro¬ chloride 3,6-Bis(2-pyridinyl)-4-pyridazine hexanol (EXAMPLE 17, 0.167 g) is dissolved in water (6 ml) containing hydrochoric acid (2 equiv- alents) , filtered and freeze dried to give the title compound.

EXAMPLE 18 [4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl)-1-piper¬ azine] -6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide (III/A-22) 6-Hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid (1.0 g) in THF (10 ml) is added in several batches 1,1' -carbonyldiimidazole (0.64 g) . The mixture was stirred at 20°-25° for 30 min at which time a slurry of 2,6-bis(1-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine (PREPARATION A-22, 1.2 g) in THF (10 ml) is allowed to slowly run into the mixture. The last traces of the amine are washed into the reaction mixture with THF (5-10 ml). The mixture was stirred for 18 hr, the solvent was removed at reduced pressure. The residue is dissolved in chloroform (75 ml), washed with water (75 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue. This material is flash chromatographed on silica gel (100 g) eluting with 50 % ethyl acetate in hexane to give a solid which is crystallized from ethyl acetate to give the title compound. EXAMPLE 19 [4- (3- (N-Ethylamino)pyrid-2-yl) -piperazin-1-yl) - methyl] -6-hydroxy-2,5,7,8-tetramethylchroman-2-

carboxamide (III/A-47) Following the general procedure of EXAMPLE 18 and making non- critical variations but using 4- [3-(ethylamino)-2-pyridinyl]piperazi¬ ne (PREPARATION A-47) the title compound is obtained. EXAMPLE 20 [4-(2, 6-Bis(pyridi__-2-yl)pyrimidin-4-yl)ρiperazln-l- yl] -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (III/A-51) Following the general procedure of EXAMPLE 18 and making non- critical variations but using 4-[2,6-bis(2-pyridinyl)-4-pyrimidinyl]- piperazine (PREPARATION A-51) the title compound is obtained.

EXAMPLE 21 2-[ [4-(2,6-Bis- (1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl-

2H-l-benzopyran-6-ol (III/A-22)

To a suspension of lithium aluminum hydride (0.55 g) and THF (50 ml) Is added dropwise over 20-30 min at 25° a solution of [4-(2,6- bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazine] -6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (EXAMPLE 18, 3.5 g) in THF (50 ml).

The mixture is stirred for 18 hr at 20-25°, cooled to 0° and treated dropwise with water (0.6 ml) , ^' aqueous sodium hydroxide (10%, 0.6 ml) and water (1.5 ml) with stirring for 30 min. The mixture is filtered through celite, the solids are washed with ethyl acetate (50 ml, 2x) and the combined wash and filtrates are concentrated under reduced pressure. The residue is dissolved in methylene chloride (150 ml), washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residue Is flashed chromatographed on silica gel (100 g) eluting with hexane in ethyl acetate (33/67) to give a residue, which after crystallization from ether and hexane gives the title compound.

EXAMPLE 22 2- [ [4- [3- (Ethylamino) -2-pyridinyl] -1-piperazinyl]- methyl] -3,4-dihydro-2,5,7,8-tetramethylbenzopyran-6-ol

(III/A-47) Following the generaL procedure of EXAMPLE 21 and making non- critical variations but starting with [4-(3-(N-ethylamino)pyrid-2- yl)-piperazin-l-yl)methyl] -6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide (EXAMPLE 19), the title compound is obtained.

EXAMPLE 22A 2- [4-3(-N-Ethylamino)pyrld-2-yl) -piperazin-1-yl) - methyl] -6-hydroxy-2,5,7,8-tetramethylchroman hydrochloride (III-47)

The hydrogen chloride addition salt was prepared by the addition of a saturated solution of hydrogen chloride in ether to a ether solution of 2- [4-3(-N-ethylamino)pyrid-2-yl)-piperazin-l-yl)methyl] -

6-hydroxy-2,5,7,8-tetramethylchroman (EXAMPLE 22). The solvent is removed at reduced pressure and the material crystallized from methanol and ether to give the title compound partially hydrated.

EXAMPLE 23 2- [4- ( (2 , 6-Bispyrid-2-yl)pyrimidin-4-yl)piperazin-l- yl)methyl] -6 -hydroxy- 2,5,7, 8-tetramethylchroman

(III/A-51) A mixture of 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid (5.0 g) , methanol (100 ml) and p-toluenesulfonic acid (5 mg) is heated at reflux for 18 hr. The mixture is allowed to cool to 20-25° and the solid collected and washed with ether and dried to give methyl-6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylate. Methyl-6- hydroxy-2,5,7,8-tetramethychroman-2-carboxylate in THF (50 ml), is added to a suspension of lithium aluminum hydride (1.58 g) in THF (50 ml) at 0° dropwise over 15-20 min. The mixture is stirred at 0° for 30 min then at 20-25° for 18 hr. The mixture is cooled to 0° and quenched by dropwise addition of ethyl acetate (10 ml), water (1.6 ml), aqueous sodium hydroxide (15%, 1.6 ml) and then water (4.8 ml). The mixture is stirred at 0° for 30 min then filtered. The solids are washed with THF (25 ml, 2x) . The combined washes and filtrate are concentrated at reduced pressure and the residue is dissolved in ethyl acetate (150 ml) , washed with water (100 ml) , dried over sodium sulfate and the solvent removed at reduced pressure to a solid. A mixture of the solid (3.0 g) , pyridine (3 ml) and chloroform (15 ml) is cooled to 0°. To this mixtue is added p-toluenesulfonyl chloride (3.6 g) in several small portions. The mixture is allowed to stand at 15° for 3 days then chloroform (50 ml) is added. The mixture is washed with water (100 ml), aqueous hydrochloric acid (5%, 100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to give a crude tosylate (5.0 g) . The crude tosylate is heated at 120° with piperazine (21.5 g) for 5 hr. The mixture was allowed to cool and distributed between dichloromethane (150 ml) and water (100 ml) . The phases are separated and the organic phase is washed with water (100 ml) , dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil. This material is flash chromato¬ graphed on silica gel (200 g) eluting with ammonia, methanol, ethyl

acetate (0.5/4.5/95). The appropriate fractions are pooled and concentrated to give a residue. A mixture of the residue (0.3 g) , chlorodipyridinylpyrimidine (J.A.C.S., 32, 1591 (1967), 0.27 g) , potassium carbonate (0.14 g) and acetonitrile (15 ml) is heated at reflux for 2 days. The solvent is removed at reduced pressure, the residue was distributed between methylene chloride (30 ml) and water (30 ml) . The phases are separated and the organic phase is dried is dried over sodium sulfate and the solvent removed at reduced pressure to leave a solid. This material was flash chromatographed on silica gel (30 g) eluting with ammonia, methanol, ethyl acetate (1/9/90) to give a solid which upon crystallization from ethyl acetate give the title compound.

EXAMPLE 24 2 , 6-Bis(l, 1-dimethylethyl) -4[ [4- [2- [4- (2 ,6-bis (1- pyrrolidinyl) -4-pyrimidinyl)-1-piperazinyl]ethyl]-1- piperazinyl]methyl]phenol (I/A-53)

A solution of methanesulfonylchloride (0.29g) in methylene chloride (5 ml) is added dropwise to a stirred solution of 4- [[3,5- bis(l,1-dimethylethyl)-4-hydroxyphenyl]methyl] -1-piperazineethanol (0.8 g) , triethylamine (0.25g) and methylene chloride (10 ml) is added at 0 _o . The mixture is stirred at Oo for 30 min and then at 20- 25° for 1 hr. The mixture is washed with water, dried over sodium sulfate and the solvent removed at reduced pressure to give an oil The oil is flash chromatographed on silica gel (60 g) eluting with methanol/ethyl acetate (5/95) . The appropriate fractions are pooled and concentrated to give the desired mesylate. Acetonitrile (5 ml),

2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)-pyrimidine (0.3 g) and potassium carbonate (0.13 g) are added to the mesylate. The mixture is heated at reflux for 4hr, cooled and the solvent removed at reduced pressure. The residue is dissolved in methylene chloride (25 ml), washed with water, dried over sodium carbonate and the solvent removed at reduced pressure to give a residue which is flash chromat¬ ographed on silica gel (60g) eluting with ethyl acetate/hexane (33/67) to give the title compound. EXAMPLE 24A 2 , 6-Bis(1, 1-dimethylethyl) -4[ [4- [2- [4- (2 , 6-bis(1- pyrrolidinyl) -4-pyrimidinyl)-1-piperazinyl]ethyl]-1- piperazinyl]methyl]phenol fumerate (1:1) The fumarate salt is prepared by addition of fumaric acid (84 mg) to 2,6-bis(l,l-dimethylethyl)-4[[4-[2-[4-(2,6-bis(l-pyrrolidin-

yl) -4-pyrimidinyl) -1-piperazinyl]ethyl] -1-piperazinyl]methyl]phenol (EXAMPLE 24) in methanol to obtain the title compound. EXAMPLE 25 4- [4- [ 6- (4-Methoxyphenoxy)hexyl] -1-piperazinyl] -2,6 bis(1-pyrrolidinyl]pyrimidine (I/A-22) p-Toluenesulfonylchloride (2.34 g) is added to a mixture of

4-(6-hydroxyhexyloxy)anisole (PREPARATION NA-11, 2.5 g) in pyridin (25 ml) previously cooled to about 15° . The mixture is allowed t stand at about -15° for 24 hr and then allowed to warm to 20-25° fo 4 hr. The mixture is dissolved in ether (200 ml) and washed with col aqueous hydrochoric acid (10%, 200 ml). The phases are separated an the ethereal phase is washed with water, saturated sodium bicarbon¬ ate, saline, dried over sodium sulfate and the solvent removed a reduced pressure to give the crude tosylate. To this tosylate (0.6 g) is added 2,6-bis(l-pyrrolidinyl) -4-(l-piperazinyl)pyrimidine (PREPARATION A-22, 0.56 g) , potassium carbonate 260 mg) and acetoni¬ trile (20 ml). The mixture is heated at reflux for 2.5 hr and the solvent removed at reduced pressure. The residue is distribute between chloroform (75 ml) and water (75 ml) . The organic phase is dried over sodium sulfate and the solvent removed at reduced pressure to give a solid which is crystallized from ethyl acetate to give the title compound.

EXAMPLE 26 N-Ethyl-2- [4- [6-(4-methoxyphenoxy)hexyl] -1-piperazin¬ yl] -3-pyridinamine (I/A-47) A mixture of the tosylate (EXAMPLE 25, 0.66 g) , 4- [3-(ethyla i- no)-2-pyridinyl]piperazine (PREPARATION A-47, 1.2 g) , potassui carbonate (0.44 g) and acetonitrile (10 ml) is heated at reflux for 2.5 hr. The solvent is removed at reduced pressure and the residue is distributed between chloroform (30 ml) and water (30 ml) . The organic phase is dried over sodium sulfate and the solvent removed at reduced pressure to give an oil. The oil is flashed chromatographed on silica gel eluting with ethyl acetate. The appropriate fractions are pooled to give the title compound.

EXAMPLE 26A N-Ethyl-2- [4- [ 6- (4-methoxyphenoxy)hexyl] -1-piperazin yl] -3-pyridinamine fumerate N- Ethyl-2- [4- [6- (4-methoxyρhenoxy)hexyl] -1-piperazinyl] -3- pyridinamine (EXAMPLE 26) is dissolved in methanol (10 ml) , fumeric acid (0.24 g) is added and the mixture allowed to. sta'nd for 30 min at 20-25°. The mixture is clouded with ether and allowed to crystallize

at about 15° to give the title compound. EXAMPLES 27 - 39

See CHART E for Column A and Column B.

Following the general procedures of EXAMPLES 25 and 26 and making non-critical variations but starting with the non-amine (NA-#) of Column A and the amine (A-#) of Column B, the corresponding aromatic amine (I) of Column C is obtained: EXAMPLE Column C. Aromatic Amine (I.

27 4- [4- [4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-pipera zinyl]butoxy]phenol (I/A-22)

28 4- [5- [4- (2,6-bis(1-pyrrolidinyl) -4-pyrimidinyl)-1-piper¬ azinyl]pentoxy]phenol (I/A-22)

29 4- [4- [4- (2, 6-bis(2-pyridInyl)-4-pyrimidinyl)-1-piperazin¬ yl]butoxy]phenol (I/A-51) 30 4- [6- [4-(2 ,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-piper¬ azinyl]hexyloxy]phenol (I/A-22)

31 4- [6- [4- [3- (ethylamino)-2-pyridinyl] -l-piperazinyl]hexyl- oxy]phenol (I/A-47)

32 4- [6- [4- (3,6-bis(2-pyridinyl) -4-pyridazinyl)methyl-l- piperazinyl]hexyloxy]phenol (I/A-52)

33 4-[6-[4-(2,6-bis(2-pyridinyl)-4-pyrimidinyl)-1-piperazin¬ l]hexyloxy]pheno1 (I/A-51)

34 4-[6-[4-(2, 6-bis(2-pyridinyl)-4-pyrimidinyl)-1-piperazin¬ yl]hexyloxy]anisole (I/A-51) 35 5- [3-(4-(2,6-bis(l-pyrrolidinyl)pyrimldin-4-yl)piperazin-l- yl)propylbenzodioxole (I/A-22)

36 5- [3-N-ethylaminopyridin-2-yl)piperazin-l-yl)propyl- benzodioxole (I/A-47)

37 l,2-methylenedioxy-4-[(3-[1-piperazinyl-(4-(2-morpholino-6- methoxypyrimidinyl))]propyl]benzene (I/A-56)

38 2- [4-2, 6-bis(l-pyrrolidinyl)-4-pyrimidinyl-l-piperazinyl] - 4-methoxyphenylethane

39 1-Phenyl-3-[4- (2,6-bis (1-pyrrolidinyl)-4-pyrimidinyl)-1- piperazinyl] -propane (I/A-22) EXAMPLE 40 4- [2- [4- (2,6-Bis(1-pyrrolidinyl) -4-pyrimidinyl)-1- piperazinyl]ethoxy]phenol ((I/A-22) To a stirred solution of oxalyl chloride (2.0 ml) and dichloro- methane (20ml), previously cooled to -78° in a dry ice/ acetone bath,

is added dropwise over 5 min a solution of DMSO (3.4 ml) and methyl¬ ene chloride (5 ml). The mixture is stirred at -78° for 5 min an then allowed to warm to 0° in an ice bath. To the mixture is adde dropwise a solution of 4- (2-hydroxyethoxy)-phenol (1.54 g) i methylene chloride (15 ml) over 10-15 min. The mixture is stirred a 0° for 30 min, triethyl amine (7 ml) is added dropwise and the mixture allowed to warm to 20-25°. The mixture is diluted wit methylene chloride (25 ml) and washed with hydrochloric acid (5%, 50 ml)-, twice with water (50 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil that is flash chromatographed on silica gel (25 g) eluting with ethyl acetate/- hexane (33/67) to give 4-hydoxyphenylacetaldehyde which is carried on immediately by the addition of 2,6-bis(l-pyrrolidinyl)-4-(l-plper- azinyl)pyrimidine (PREPARATION A-22, 0.79 g) and methanol (10 ml). To the mixture is added sodium cyanoborohydride (0.16 g) and the mixture is stirred at 20-25° for 18 hr. The mixture is treated with aqueous hydrochloric acid (10%, 10 ml) HC1 at 0° and the methanol removed at reduced pressure. The residue is distributed between ethyl acetate (50 ml) and water (40 ml) . The aqueous phase is brought to pH 8 with aqueous potassium hydroxide (45%) at 0° and then extracted methylene chloride (2 x 50 ml) . The combined extracts are dried over sodium sulfate and the solvent removed at reduced pressure to give a foam that is flash chromatographed on silica gel (35 g) eluting with hexane/ethyl acetate (33/67) to give the title compound. EXAMPLE 41 1-[4-(4-Hydroxy-3,5-dimethylphenyl)2-hydroxypropyl] -4-

[2,6-(bis(l-pyrrolidinyl))pyrimidin-4-yl)piperazine] (I/A-22) A mixture of chloroacetone (1.00 g) , 2,4-bis(l-pyrrolidino)-4- (1-piperazinyl)pyrimidine (PREPARATION A-22, 3.02 g) and potassium carbonate (1.32 g) is stirred in acetonitrile (50 ml) for 24 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel eluting with 2-3% methanol/methylene chloride to give the methyl ketone derivative of 2,4-bis(l-pyrrolidino)-4-(l-piperazinyl)pyrimid- ine which had a consistent NMR.

A mixture of 2,6-dimethyl-4-bromoanisole (1.62 g) and powdered magnesium (181 mg) is refluxed for 6 hr in dry THF (20 ml) . This

mixture is added to a solution of the methyl ketone derivative in dry THF (20 ml). The mixture is stirred at 35° for 18 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel, eluting with 2-3% methanol/methylene chloride to give the title compound.

EXAMPLE 42 1- [4- (4-Methoxy-3 ,5-diaethylphenyl)butyl) ] -4-(2,6- bis(1-pyrrolidinyl))pyrimidin-4-yl)piperazine - (I/A-22)

A solution of 4- [3 , 5-dimethyl-4-methoxyphenyl) ]butanol (600 mg) , methanesulfonyl chloride (490 mg) and triethylamine (460 mg) in methylene chloride Is stirred at 0° for 1 hr . The reaction mixture is partitioned between methylene chloride and aqueous sodium bicar- bonate . The organic phase is dried over sodium sulfate and con¬ centrated. The residue is dissolved in acetonitrile (60 ml) and treated with 2 ,4-bis (l-pyrrolidino) -4- (1- piperazinyl )pyrimidine

(PREPARATION A-22 , 1.73 g) and potassium carbonate (0.57 g) . The reaction is run overnight at 20-25° and then at 50° for 3 hr . The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate . The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel , eluting with methanol/methylene chloride (4/96) to give an oil . EXAMPLE 42A 1- [4 - (4-Methoxy- 3 , 5 - dime thylphenyl) butyl) ] -4- (bls (l- pyrrolidinyl) )pyrimidIn-4-yl)piperazine methane sulfonate 1- [4- (4-Methoxy- 3 , 5 - dimethylphenyl)butyl) ] -4- (bis(lpyrrolidin- yl) )pyrimidin-4-yl)piperazine (EXAMPLE 42) is treated with methane¬ sulfonic acid (180 mg) in THF to give the title compound. EXAMPLE 42' 1- [4 - (4-Methoxy- 3 , 5 -dime thylphenyl) butyl) ] -4- (bis (l- pyrro lidiny 1 ) ) pyrimidin- 4-yl ) p iperaz ine 4- [ 3 , 5 -Dimethyl-4-methoxyphenyl) Jbutanol (1.26 g) Is treated with methanesulfonyl chloride (0.57 ml) and triethylamine (0.73 g) in methylene chloride (15 ml) at 0° . The mixture is partitioned between cold water and methylene chloride. The organic phase is dried over sodium sulfate and concentrated. The residue is stirred with 2 , 4- bis (l-pyrrolidino) -4- (l-piperazinyl)pyrimidine (PREPARATION A-22 , 2.00 g) , potassium carbonate (0.960 mg) and potassium iodide (400 mg)

in acetonitrile (20ml) for 20 hr. The reaction mixture is parti¬ tioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel, eluting with methanol/- methylene chloride (2/98) to give the title compound which crystall¬ ized on standing.

EXAMPLE 42B 1- [4- (4-Methoxy-3, 5-dimethylphenyl)butyl)] -4- (bis(l- pyrrolidinyl))pyrimidin-4-yl)piperazine dihydro¬ chloride 1- [4- (4-Methoxy-3 , 5-dimethylphenyl)butyl)] -4-(bis(lpyrrolidin- yl))pyrimidin-4-yl)piperazine (EXAMPLE 42') is dissolved in acetone and treated in excess with ether which was saturated with hydrogen chloride gas. The salt is filtered, triturated with ether and dried under reduce pressure to give the title compound. EXAMPLE 43 2- [4-(4-(3,5-Dimethyl-4-methoxyphenyl)butyl)ρiperazin-

1-yl] -N-ethyl-3-ρyridineamine ((I/A-47) Following the general procedure of EXAMPLE 42' and making non- critical variations but starting with 4- [3-(ethylamino))-2-pyridin¬ yl]piperazine (PREPARATION A-47, 1.00 g) the title compound is obtained.

EXAMPLE 43A 2- [4-(4-(3,5-Dimethyl-4-methoxyphenyl)butyl)piperazin-

1-yl] -N-ethyl-3-pyridineamine dihydrochloride

2-[4-(4-(3, 5-Dimethyl-4-methoxyphenyl)butyl)piperazin-l-yl] -N- ethyl-3-pyridineamine (EXAMPLE 43) is dissolved in ether/acetone and treated in excess with ether which was saturated with hydrogen chloride gas. The salt is filtered, dried under reduced pressure to give the title compound.

EXAMPLE 44 2- [4-(4-(3,5-Dimethyl-4-hydroxyphenyl)butyl)piperazin-

1-yl] -N-ethyl-3-pyridineamine (I/A-47) 4-[2,6-Dimethyl-l-hydroxy-4-phenyl]butanol (PREPARATION NA-15,

4.22g) in acetonitrile (50 ml) is treated with 4- [3- (ethylamino))-2- pyridinyl]-piperazine (PREPARATION A-47, 2.68g), potassium carbonate

(1.72 g) and potassium iodide (0.8 g) . The reaction is heated at 50° for 20 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel, eluting with methanol/methylene chloride (3/97) to give the phenol O-mesylate alkylation product. The O-mesylate is

hydrolyzed with sodium hydroxide (50%, 11 ml) in methanol (60 ml) heated at 50° for 10 hr. (Potassium carbonate, methanol and water does not hydrolyze the O-mesylate) . The mixture is made acidic with hydrochloric acid and then neutralized with aqueous sodium blear- bonate. The mixture is extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated to give the title compound which had a consistent NMR.

EXAMPLE 44A 2-[4-(4-(3,5-Dimethyl-4-hydroxyphenyl)butyl)piperazin-

1-yl] -N-ethyl-3-pyridineamine dihydrochloride 2- [4- (4- (3 ,5-Dimethyl-4-hydroxyphenyl)butyl)piperazin-l-yl] -N- ethyl-3-pyrldineamine (EXAMPLE 44) Is dissolved in ethyl acetate and treated in excess with ether which was saturated with hydrogen chloride gas. The salt Is filtered and dried tinder reduced pressure to give the title compound. EXAMPLE 45 1- [4- (4-Hydroxy-3, 5-dimethylphenyl)butyl) ] -4-(di(l- pyrrolidinyl))pyrimidin-4-yl)piperazine (I/A-22) Following the general procedure of EXAMPLE 44 and making non- crltical variations but starting with 2,4-bis(l-pyrrolidino)-4-(l- piperazinyl)pyrimidine (PREPARATION A-22, 3.93 g) , the title compound is obtained.

EXAMPLE 45A 1- 4- (4-Hydroxy-3, 5-dimeth lphenyl)butyl) ] -4-(di(l- pyrrolidinyl))pyrimidin-4-yl)piperazine dihydro chloride

1- [4- (4-Hydroxy-3 , 5-dimethylphenyl)butyl)]-4-(di(l-pyrrolidin- yl))pyrimidin-4-yl)piperazine (EXAMPLE 45) is dissolved in ethyl acetate and treated in excess with ether which is saturated with hydrogen chloride gas. The salt is filtered and dried under reduced pressure to give the title compound.

EXAMPLE 46 1- (4-Methoxyphenoxy) -6- [3, 6-bis(2-pyridinyl) -4- pyridazinyl] -hexane (I/A-55)

Following the general procedure of EXAMPLE 17 and making non- critical variations but starting with 8-(4-methoxyphenoxy)-1-octyne (PREPARATION NA-18) , the title compound is obtained.

EXAMPLE 47 2,6-Dimethyl-4- [3-(2,4-bis(l-pyrrolidinyl)-6-pyrimidi- nyl)piperazinyl)propyl phenol (I/A-22)

Part - I 2,6-Dimethyl-4-[3-(2,4-bis(l-pyrrolidinyl}-6-pyrimidi-

. nyl) piperazinyl) propylphenol O-mesylate A mixture of 3- (3 , 5 -Dimethyl- 4 -hydroxyphenyl)propanol bis-

mesylate (PREPARATION NA-19, 1.1 g) , potassium iodide, powdered potassium carbonate (1.38 g) and 2,4-bis(l-pyrrolidino) -4-(1-piper¬ azinyl)pyrimidine (PREPARATION A-22, 1.61 g) in acetonitrile (50 ml) is refluxed for 72 hr. The mixture is cooled and diluted with water and methylene chloride. The phases are separated and the organic phase is washed with water, dried over sodium sulfate and con¬ centrated. The concentrate is flash chromatographed on silica gel (230-400 mesh) eluting with methanol/chlorofoπt (2.5/97.5). The appropriate fractions are pooled to give the mesylate. Part - II 2,6-Dimethyl-4- [3- (2,4-bis(l-pyrrolidinyl) -6-pyrimidi- nyl)piperazinyl)propylphenol 2,6-Dimethyl-4-[3-(2,4-bis(1-pyrrolidinyl)-6-pyrimidinyl)- piperazinyl)propyl phenol O-mesylate (Part I, 1.0 g) in aqueous sodium hydroxide (25%, 10 ml) and methanol (20 ml) are stirred at 50° under nitrogen for 20 hr. The mixture is cooled and the methanol removed under reduced pressure. The aqueous layer is acidified with aqueous hydrochloric acid (10%) and then the pH adjusted to 8 with aqueous saturated sodium bicarbonate. The product is extracted with methylene chloride (2x). The extracts are washed with water, dried over sodium sulfate and concentrated. The concentrate is crystall¬ ized from ether/hexane to give the title compound.

EXAMPLE 47A 2,6-Dimethyl-4- [3- (2,4-bis(1-pyrrolidinyl)-6-pyrimidi¬ nyl)piperazinyl)propylphenol 0.25 hydrate EXAMPLE 48 4- [3- (4- (3- (N-Ethylamino)pyridin-2-yl)piperazin-l- yl)propyl]-2,6-dimethylphenol (I/A-47)

Following the general procedure of EXAMPLE 47 (parts I and II) and making non-critical variations but using 4- [3- (ethylamino))-2- pyridinyl] -piperazine (PREPARATION A-47), the title compound is obtained. EXAMPLE 49 2 , 6 -Bis (1-pyrrolidinyl) -4- [4- (3- (3 , 5-dimethyl-4- methoxyphenyl)propyl)piperazinyl]pyrimidine (I/A-22)

Following the general procedures of PREPARATION NA-19 Part - II

(but using only 1 equivalent of mesylate) and EXAMPLE 47 Part - I and making non-critical variations but starting with 3-(3,5-dimethyl-4- methoxyphenyl) -1-propanol (PREPARATION NA-20) and 2,4-bis(l-pyrro- lidino)-4-(l-piperazinyl)pyrimidine (PREPARATION A-22), the title compound is obtained. EXAMPLE 50 N-Ethyl-2- [4- [3- (4-methoxy-3,5-dim thylphenyl)propyl] -

1-piperazinyl] -3-pyridinamine (I/A-47) Following the general procedures of EXAMPLE 49 and making non- critical variations but starting with 4- [3-(ethylamino))-2-pyridin¬ yl] -piperazine (PREPARATION A-47), the title compound is obtained. EXAMPLE 51 4- [2- [4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl-l- piperazinyl]ethyl] -2,6-dimeth lphenol (I/A-22) Following the general procedure of PREPARATION NA-19 Part - II and EXAMPLE 47 but starting with 2-(3,5-dimethyl-4-hydroxyphenyl)-l- ethanol (PREPARATION NA-21) and 2,4-bis(l-pyrrolidino)-4-(l-piper- azlnyl)pyrimidine (PREPARATION A-22) , the title compound is obtained. EXAMPLE 52 4- [-2- [4- [3- (Ethylamino)-2-pyridinyl] -1-piperazinyl] - ethyl] -2,6-dimethyIphenol (I/A-47) Following the general procedure of PREPARATION NA-19 Part - II and EXAMPLE 47 but starting with 2-(3,5-dimethyl-4-hydroxyphenyl)-1- ethanol (PREPARATION NA-21) and 4-[3-(ethylamino))-2-pyridinyl] - piperazine (PREPARATION A-47) , the title compound is obtained. EXAMPLE 53 4- [Bis- (1-pyrrolidinyl) -4-pyrimidinyl]_-l- [2-(6 ,7- dimethoxy-isochromyl)eth-l-yl]piperazine (V/A-22) A solution of 6,7-dimethoxy-l-[2-chloroethyl]isochroman (2.58 g) , 2,4-bis(l-pyrrolidino)-4-(l-piperazinyl)pyrimidine (PREPARATION A-22, 3.02 g) , potassium carbonate (1.32 g) and potassium iodide (0.88 g) in dry acetonitrile (40 ml) is stirred at 50° for 20 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel eluting with methanol/methylene chloride (3/97) to give the title compound.

EXAMPLE 54 2,4-Bis-(1-pyrrolidinyl)-6-[4-[2-[2-[(1,3,4,5-tetra- hydro-7,8-dimethoxy-2-benzoxepin-l-yl)methoxy]ethoxy]- ethyl] -l-piperazinyl]pyrimidine (V/A-22)

Following the gereral procedure of EXAMPLE 53 and making non- critical variations but using 7,8-dimethoxy-l-[CH ₂ -0-CH ₂ CH2-0- CH2CH2Cl]benzo epi e (250 mg) , the title compound is obtained. EXAMPLE 55 4- [3-Ethylamino-2-pyridinyl] -1- [2- [6 ,7-dlmethoxy- isochromyl]eth-l-yl]piperazine (V/A-47)

Following the general procedure of EXAMPLE 53 and making non- critical variations but starting with 4- [3-(ethylamino))-2-pyridin¬ yl] -piperazine (PREPARATION A-47), the title compound is obtained.

EXAMPLE 56 4 - [ 4 - [ 2 - (4 -Methoxy- 3 , 5 -dimethylphenyl)ethyl] -1- piperazinyl] -2,6-bis(l-pyrrolidinyl)pyrimidine (I/A-22) Following the general procedures of EXAMPLE 49 and making non- critical variations but starting with 2-(3,5-dimethyl-4-methoxy¬ phenyl)-1-ethanol (PREPARATION NA-22) and 2,4-bis(l-pyrrolidino)-4- (l-piperazinyl)pyrimidine (PREPARATION A-22), the title compound is obtained.

EXAMPLE 57 N-Ethyl-2- [4- [2-(4-methoxy-3,5-dimethylphenyl)ethyl] - 1-piperazinyl] -3-pyridinamine (I/A-47)

Following the general procedures of EXAMPLE 49 and making non- critical variations but starting with 2-(3,5-dimethy1- -methoxy¬ phenyl)-1-ethanol (PREPARATION NA-22) and 4- [3-(ethylamino))-2- pyridinyl] -piperazine (PREPARATION A-47), the title compound is obtained.

EXAMPLE 58 2 , 6 -Bis (1 -pyrrolidinyl) -4- [4- (6- (3 , 5-dimethyl-4- methoxy)phenyl)hexyl]pyrimidine (I/A-22)

Following the general procedure of EXAMPLE 47 - Part I and making non-critical variations but starting with 6-(3,5-dimethyl-4- methoxyphenyl)-1-hexanol mesylate (PREPARATION NA-23) and 2,4-bis(l- pyrrolidino)-4-(l-piperazinyl)pyrimidine (PREPARATION A-22), the title compound is obtained.

EXAMPLE 59 2- [4- (6- (3 ,5-dimethyl-4-methoxyphenyl)hexyl)piperazi- nyl-N-ethyl-3-pyridinamine ((I/A-47) Following the general procedure of EXAMPLE 47 - Part I and making non-critical variations but starting with 6-(3,5-dimethyl-4- methoxyphenyl)-1-hexanol mesylate (PREPARATION NA-23) and 4- [3-

(ethylamino))-2-pyridinyl] -piperazine (PREPARATION A-47), the title compound is obtained. EXAMPLE 60 3- [ 6 - (4- ( 3 - (Ethylamino)pyridin-2-yl)piperazin-1- y1)hexy1]cyclohex-2-en-1-one (IV/A-47) Following the procedure of Borch, J. Am. Chem. Soc. , 93, 2897 (1971). sodium cyanoborohydride (144 mg) is added to a solution of 3- oxo-1-cyclohexanal (PREPARATION NA-25, 405 mg) , , 4- [3-(ethylamino)) - 2-pyridinyl] -piperazine (PREPARATION A-47, 495 mg) and methanol (4.20 ml). After stirring for 16 hr at 20-25°, acetic acid (2 drops) and sodium cyanoborohydride (40 mg) are added. After 3 hr, concentra¬ tion, basic workup with chloroform and aqueous sodium bicarbonate and

purification by flash chromatography eluting with ethyl acetate/tri- ethyla ie (99/1) provides the title compound. EXAMPLES 61 - 64

See. CHART E for Column A and Column B. Following the general procedure of EXAMPLE 60 and making non- critical variations but using the non-amine (NA-#) of Column A and the amine (A-#) of Column B, the corresponding cycloalkyl amine (IV) of Column C is obtained:

EXAMPLE Column C. Cycloalkyl amine (IV) 61 3- [6-( (2 ,6-bispyrrolidin-l-yl)pyrimidin-4-yl)piperazin-l- yl)hexyl]cyclohex-2-en-1-one (IV/A-22)

62 3- [4-(4- (3-(ethylamlno)pyrid-2-yl)piperazin-l-yl)butyl]- cyclohex-2-en-l-one (IV/A-47)

63 3- [3- (4- (3-(ethylamino)pyrid-2-yl)piperazin-l-yl)propyl] - cyclohex-2-en-1-one (IV/A-47)

64 3-[3-(4-(2,6-bis(l-pyrrolldinyl)pyrimidin-4-yl)piperazin-l- yl)propyl] -cyclohex-2-en-l-one (IV/A-22)

EXAMPLE 65 l-Phenoxy-4-[4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl- 1-piperazinyl] -butane (I/A-22) Following the general procedure of EXAMPLE 1 and making non- critical variations but using 4-phenoxy-l-bromobutane (PREPARATION NA-27) and 2,4-bis(l-pyrrolidino)-4-(l-piperazinyl)pyrimidine (PREPARATION A-22) , the title compound is obtained.

EXAMPLE 66 1- [3,4-Dihydro-6-hydroxy-2,5 ,7 ,8-tetramethyl-2H-l- benzopyran-2-yl)acetyl]-4-(2,6-bis(l-pyrrolidinyl)-4- pyrimidinyl)-piperazine (III/A-22) Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with (6-hydroxy-2,5,7,8-tetramethyl¬ chroman-2-yl)acetic acid, the title compound is obtained. EXAMPLE 67 1- [3 ,4-Dihydro-6-hydroxy-2,5 ,7,8-tetramethyl-2H-l- benzopyran-2-yl)ethyl]-4-(2,6-bis(l-pyrrolidinyl)-4- pyrimidinyl)-piperazine (III/A-22) Following the general procedure of EXAMPLE 21 and making non- critical variations but starting with 1-[3,4-dihydro-6-hydroxy- 2,5,7, 8- etrame hyl-2H-l-benzopyran-2-yl)acetyl] -4- (2,6-bis(1- pyrrolidinyl)-4-pyrimidinyl)-piperazine (EXAMPLE 66), the title compound Is obtained. EXAMPLE 68 1-[ [6-(Acetyloxy)-3,4-dihydro-2,5,7,8-tetramethy-2H-l-

benzopyran - 2 - yl ] ac e tyl ] -4- [ 3 - (ethylamino) - 2 -pyridin¬ yl ] -piperazine ( III/A-47) An etheral solution of ( 6 -acetoxy- 2 , 5 , 7 , 8- tetramethylchroman- 2 - yl) acetyl chloride (10 ml , 1. 3 g) is added slowly to a stirred solution of 4- [ 3- (ethylamino) ) - 2-pyridinyl] -piperazine (PREPARATION A-47 , 0. 81 g) in chloroform ( 70 ml) . The mixture is stirred 2 hr and then is washed with aqueous potassium bicarbonate and saline . The organic extracts are dried over magnesium sulfate and concentrated to give the title compound. EXAMPLE 69 2 , 6-Bis (l , 1-dimethylethyl) -4- [ [4- (2 , 6 -bis (l - pyrrolidinyl - 4 - pyrimidinyl ) - l - piperazinyl ]methyl ] - phenol (I/A- 22)

2,6-bis(l-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine

(PREPARATION A-22) is stirred in methanol (10 ml). To the above solution is added saturated ethereal hydrochloric acid until the solution clarifies. To this mixture is added 3,5-di-t-butyl-4- hydroxybenzaldehyde and the mixture stirred for 30 min at which time sodium cyanoborohydride is added in two batches. The mixture is stirred at 20-25° for 18 hr and quenched with hydrochoric acid (10%, 25 ml) added dropwise at 0°. The methanol is removed under a stream of nitrogen and the acidic mixture is extracted with ethyl acetate

(25 ml) . The aqueous phase is then made basic with hydroxide (45%) at 0°. The aqueous basic phase is then extracted with methylene chloride (2x) . The organic phases are combined and dried over sodium sulfate, following which the mixture is concentrated under at reduced pressure. The concentrate is flashed chromatographed on silica gel eluting with hexane/ethyl acetate (1/1) or ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound. EXAMPLES 70-72

Following the general procedure of EXAMPLE 69 and making non- critical variations but starting with 4- (2-pyridinyl)piperazine (PREPARATION A-6, for EXAMPLE 70), 4- (ethanol)piperazine (for EXAMPLE 71) and 4- [3-(ethylamino)-2-pyridinyl]piperazine (PREPARATION A-47, for EXAMPLE 72) , compounds listed below are obtained:

EXAMPLE Compound

70 2,6-bis(1,1-dimethylethyl) -4- [ [4-(2-pyridinyl)-1-piperazin¬ yl]methyl]phenol (I/A-6)

71 4- [ [3 , 5-Bis(l,1-dimethylethyl)-4-hydroxyphenyl]methyl]-1- piperazineethanol (I)

72 2,6-bis(l, 1-dimethylethyl)-4- [ [4-3-(ethylamino)-2-pyridin¬ yl] -l-piperazinyl]methyl]phenol (I/A-47) EXAMPLE 73 4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl)-N- (4- hydroxy-3,5-dimeth lphenyl)-1-piperazineacetamide (I/A-22) To 2,6-dimethyl-4-aminoρhenol hydrogen chloride (5.0 g) in methlylene chloride (20 ml) is added triethylamine (6.5 g) in methylene chloride (20 ml) dropwise at 0°. To the cold solution is added chloroacetylchloride (3.6 g) in methylene chloride (20 ml) dropwise over 5-10 m. The mixture is stirred at 0° for 30 min and then at 20-25° for 1 hr. The mixture is washed with water (60 ml), dried over sodium sulfate and the solvent removed at reduced pressure to give a solid. MS (El, m/e) - 213,215 (M ^* * ^" ) . Acetonitrile (40 ml), 2,δ-bis(l-pyrrolidlnyl)-4-(l-piperazinyl)pyrimidine (PREPARATION A- 22, 1.42 g) , potassium carbonate (0.65g) are added to the solid and the mixture is heated at reflux for 10 hr. The solvent is removed at reduced pressure and residue is distributed between chloroform (100 ml) and water (100 ml) . The phases are separated and the organic phase is dried over sodium sulfate and the solvent is removed at reduced pressureto give an oil. The oil is flash chromatographed on silica gel (175 g) eluting with ethyl acetate/hexane (2/1) . The appropriate fractions were pooled and concentrated to give the title compound.

EXAMPLE 74 4- [4-(6-(4-Methoxyl-l-thiohexylphenyl)-1-piperazinyl)- 2,6-bis(l-pyrrolidinyl)pyrimidine (I/A-22) A mixture of thioanisole (0.88 ml), 6-chlorohexanol (1.07 g) , potassium carbonate (1.08 g) and acetone (10 ml) is heated at reflux for 18 hr. The solvent is removed at reduced pressure and the residue distribute between methylene chloride (50 ml) and water (50 ml) . The phases are separated, the organic phase is dried over sodium sulfate, the solvent removed at reduced pressure to leave an oil that crys¬ tallizes from hexane. The crystalline material is dissolved in a mixture of chloroform (10 ml) and pyridine (0.66 g) and cooled to 0°. To the mixture is added dropwise over 3-5 min a solution of p- toluenesulfonylchloride (1.2 g) in chloroform (5 ml). The mixture is stirred at 0° for 1 hr then at 20-25° for 18 hr. The reaction mixture

is washed with hydrochloric acid (0.1N), saline, dried over sodiu sulfate and the solvent removed at reduced pressure to give the crud tosylate. To the crude tosylate is added 2,6-bis(l-pyrrolidinyl) -4 (l-piperazinyl)pyrimidine (PREPARATION A-22, 1.4 g) , potassiu carbonate (1.28 g) and acetonitrile (25 ml). The mixture is heated a reflux for 18 hr. The solvent is removed at reduced pressure and th residue distributed between chloroform (50 ml) and water (50 ml) . Th phases are separated, the organic phase is dried over sodium sulfat and the solvent removed to leave an oil that is flash chromatographe on silica gel (100 g) eluting with ethyl acetate. The appropriat fractions are pooled and concentrated. The concentrate is crystall ized from ethyl acetate to give the title compound.

EXAMPLE 75 1- [ [6- (Hydroxy) -3,4-dihydro-2,5,7,8-tetramethy-2H-l benzopyran-2-yl]acetyl] -4- [3-(ethylamino)-2-pyridin yl] -piperazine (III/A-47)

A solution of 1- [ [6-(acetyloxy)-3,4-dihydro-2,5,7,8-tetramethy 2H-1-benzopyran-2-yl]ac tyl] -4-[3-(ethylamino)-2-pyridinyl] -piperaz ine (EXAMPLE 68, 0.80 g) in methanol (20 ml) is mixed with potassiu carbonate (10% aqueous, 1.5 ml) and stirred for 3.5 hr at 20-25° under a nitrogen atmosphere. Then acetic acid (0.2 ml) is added an the solution is concentrated. The residue is partitioned betwee methylene chloride and potassium bicarbonate (1 N) . The organi extracts are combined and washed with water, dried over magnesiu sulfate and concentrated to give the title compound. EXAMPLE 77 2 , 6-Bis(1-pyrrolidinyl) -4- [4- ( (2- (3 , 5-dimethyl-4- methoxyphenyl) -2- (4-methoxyphenyl)-2-hydroxyethyl)- piperazinylpyrimidine (I/A-22) 1- [ [ (4-Methoxyphenyl) -2-ketoeth-1-yl]butyl] -4- (bis (1-pyr¬ rolidinyl))pyrimidin-4-yl)piperazine (EXAMPLE 38) is dissolved in dry THF and is reacted with a Grignard reagent which is prepared from 2,6-dimethyl-4-bromoanisole and magnesium. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicar¬ bonate. The organic phase is dried over sodium sulfate and con¬ centrated. The residue is chromatographed over silica gel eluting with methanol/methylene chloride (3/97) to give the title compound. EXAMPLES 78-99

Following the general procedure of EXAMPLE 18 and the descrip¬ tion of the general procedure in the specification to prepare the

amide type bicyclic amines (III) where X ₃ Is -CO- , the following compounds are obtained:

Example Bicyclic amine (III)

78 1- [3 ,6 -Bis (diethylamino) -2-pyridinyl] -4- [ (3, 4-dihydro-6- hydroxy-2, 5,7, 8-tetramethyl] -2H-l-benzopyran-2-yl)carbon- yl ] p iperaz ine

79 l-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l- benzopyran- 2 -yl) carbonyl] -4- (2-methoxyphenyl)piperazine

80 l-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l- benzopyran- 2 -yl) carbonyl] -4-(2-pyridinyl)piperazine

81 1- [ (3 ,4-Dihydro-6-hydroxy-2, 5 , 7 , 8- tetramethyl- 2H-1- benzopyran- 2 -yl) carbonyl] -4- (2-pyrimidinyl)piperazine

82 1- (3 -Chi orophenyl) -4- [(3, 4-dihydro -6 -hydroxy -2, 5,7,8 - tetramethyl - 2H- 1 -benzopyran- 2 -yl) carbonyl ] piperazine 83 l-(l,3-Benzodioxol-5-ylmethyl)-4-[(3,4-dihydro-6-hydroxy-

2,5,7, 8- tetramethyl-2H-l-benzopyran-2-yl)carbonyl]piper- azlne

84 1- [ (4-Chlorophenyl)phenylmethyl] -4- [ (3 , 4-dihydro- 6 -hydrox - 2,5,7, 8- tetramethyl -2H-1- benzopyran- 2-yl) carbonyl ] piper - azine

85 1 - (4- Chlorophenyl) -4- [ (3 , 4-dihydro -6 -hydroxy- 2 , 5,7,8- tetramethy 1 - 2H- 1 - benzopyran- 2 -yl ) carbonyl ] p iperaz Ine

86 l-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l- benzopyran-2-yl)carbonyl] -4- (4-methoxyphenyl) piperazine 87 N- [2-(3,4-Dimethoxyphenyl)ethyl] -3 ,4-dihydro-6-hydrox -

2 , 5 , 7 , 8 - tetramethyl ] - 2H- 1 -benzopyran- 2 -carboxamlde

88 3 , 4-dihydro- 2 , 5 , 7 , 8- tetramethyl- 2- (1-piperazinylcarbonyl) - 2H- 1-benzopyran- 6 -ol

89 N- (2 -Pyridinylmethyl) -3 ,4-dihydro-6-hydroxy-2, 5 , 7,8-tetra- methyl] -2H-1 -benzopyran- 2 -carboxamide

90 N- [ 2- (4-Aminophenyl) ethyl] -3 ,4-dihydro-6-hydroxy-2 , 5,7,8- tetramethyl ] - 2H- 1 -benzopyran- 2 -carboxamide

91 N- [3 ,4-Methylenedioxophenylmethyl] - 3, 4-dihydro -6 -hydroxv- 2,5,7,8- tetramethyl ] - 2H - 1 -benzopyran- 2 - carboxamide 92 N-[2-(2-Pyridinyl)ethyl]-3,4-dihydro-6-hydroxy-2,5,7,8- tetrameth l] -2H-l-benzopyran-2-carboxamide 93 N-Methyl-N-[2-(2-pyridinyl)ethyl]-3,4-dihydro-6-hydroxy-

2,5,7,8- tetramethyl] -2H- 1-benzopyran- 2 -carboxamide

94 N- (3-Pyridinylmethyl) -3 ,4-dihydro-6-hydroxy-2,5,7,8-tetra- methyl] -2H-1-benzopyran-2-carboxamide

95 1- [ 3 ,4-Dihydro-6-hydroxy-2 ,5,7,8-tetramethyl-2H-1-benzo¬ pyran-2-yl)carbonyl] -4- (phenyl ethyl)piperazine 96 1- [3 ,4-Dihydro-6-hydroxy-2 ,5 , 7 ,8-tetramethyl-2H-l-benzo- pyran-2-yl)carbonyl] -4-ρhenylpiperazine

97 N- [2- (Dimethylamino)ethyl] -3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H-1-benzopyran-2-carboxamide, m.p. 127-128°

98 3,4-Dihydro-2,5,7,8-tetramethyl-2-(l-pyrrolidinylcarbonyl)- 2H-1-benzopyran-6-ol

99 N-[2-(Phenylethyl)]-N-[2-(2-pyridinylethyl)]-3,4-dihydro-6- hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide

100 1- [3-Diethylamino-2-pyridinyl] -4-[(3,4-dihydro-6-hydroxy- 2,5,7,8-tetramethyl] -2H-1-benzopyran-2-yl)carbonyl]piperaz- .ine

101 1- [5 -Diethylamino- 2-pyridinyl] -4- [ (3 , 4-dihydro- 6 -hydroxy - 2,5,7,8- tetramethyl ] - 2H - 1 -benzopyran- 2 -yl) carbonyl ] piperaz - ine

102 N- [2-Pyridinyl]-3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl - 2H-l-benzopyran-2-carboxamide

103 N- [Phenyl] -3 ,4-dihydro-6-hydroxy-2,5,7 , 8- tetramethyl -2H-1- benzopyran- 2 - carboxamide

104 N- [ 4 -Pyr idinyl] -3, 4 -dihydro -6 -hydroxy- 2 , 5,7,8- tetra ethyl- 2H- 1-benzopyran- 2 - carboxamide 105 N- [4-Methoxy-3-pyridinyl] -3 ,4-dihydro-6-hydroxy-2,5 ,7 , 8- tetramethyl - 2H- 1 -benzopyran- 2 - carboxamide 106 1- [5-Amino-6-diethylamino-4-pyrimidinyl] -4- [ (3,4-dihydro-6- hydroxy-2 ,5,7,8- tetramethyl] -2H-l-benzopyran-2-yl)carbon- yl] piperazine 107 1- [ 5-Ethylamino- 6-diethylamino-4-pyrimidinyl] -4- [ (3 ,4- dihydro- 6-hydroxy- 2 ,5,7 , 8-tetramethyl] - 2H- 1-benzopyran- 2- yl ) carbonyl ] piperaz ine 108 N- [4-Phenylbutyl] - 3 , 4-dihydro- 6-hydroxy- 2 , 5 , 7 , 8-tetra¬ methyl - 2H - 1-benzopyran- 2 - carboxamide 109 N- [ 3 , 4-Dime thoxyphenylmethyl ] -3 ,4-dihydro-6-hydroxy-

2,5,7,8- tetramethyl - 2H- 1 -benzopyran- 2 -carboxamide 110 N- [3-Phenylpropyl] -3 , 4-dihydro-6-hydroxy-2, 5, 7 , 8-tetra¬ methyl - 2H- 1 -benzopyran- 2 - carboxamide

111 N- [2- (4 -Methoxyphenyl) ethyl ] - 3 , -dihydro-6 -hydroxy- 2,5,7,8- tetramethyl-2H-l-benzopyran-2- carboxamide

112 N - [ 2 - Pheny le thyl ] - 3 , 4 - dihydro - 6 -hydroxy- 2,5,7,8- tetr - methyl- 2H-1 -benzopyran- 2 - carboxamide EXAMPLES 113-143

Following the general procedure of EXAMPLES 21 and 23 and the description of the general procedure in the specification to prepare the reduced type bicyclic amines (III) where X ₃ is -CH2-, the following compounds are obtained: Example Bicyclic amine (III)

113 2- [ [4- [3, 6 -Bis (diethylamino) -2-pyridinyl] -1 -piperazinyl] - me hyl] - 3 , 4-dihydro- 2 , 5 , 7 , 8- tetramethyl- 2H- 1-benzopyran- 6- ol

114 2- [ [ [2-(3,4-Dimethoxypyhenyl)ethyl] ] amino] me thyl] -3,4- dihydro-2 ,5,7.8- tetramethyl- 2H- 1-benzopyran- 6 -ol

115 3 , 4-Dihydro-2- [ [4- (2 -methoxyphenyl) -1-piperazinyl] me thyl] - 2 , 5 , 7, 8- tetramethyl- 2H- 1-benzopyran- 6- ol

116 3,4-Dihydro-2,5,7,8-tetramethyl-2-[[4-(2-pyridinyl)-l- piperazinyljmethyl] -2H-l-benzopyran-6-ol 117 3,4-Dihydro-2,5,7,8-tetramethyl-2-[[4-(2-pyrimidinyl)-l- piperazinyl]methyl] -2H-l-benzopyran-6-ol

119 2- [ [4-(3-Chlorophenyl) -piperazinyl]methyl] -3,4-dihydro- 2,5,7.8- tetramethyl- 2H- 1 -benzopyran- 6 - ol

120 2- [ [4- (l,3-Benzodioxol-5-ylmethyl) -1-piperazinyl] -3,4- dihydro-2 , 5,7, 8- tetramethyl- 2H- 1-benzopyran- 6 -ol

121 2- [ [4- [ (4-Chlorophenyl)phenylmethyl] -1-piperazinyl] methyl] - 3,4-dihydro-2,5,7.8-tetramethyl-2H-l-benzopyran-6-ol

122 2- [ [4- (4-Chlorophenyl)-l-piperazinyl]methyl] -2,5,7,8- tetramethyl- 2H-l-benzopyran- 6 - ol 123 3 , 4-Dihydro-2-[ [4- (4-methoxyphenyl) -1-piperazinyl] methyl] -

1- piperazinyl ]me thyl] -2,5,7, 8- tetramethyl- 2H-l-benzopyr an - 124 2- [ [ [(3 , 4-MethylenedIoxyphenyl)methyl]amino]methyl]-3,4- dihydro - 2 , 5 , 7 , 8 - tetramethyl - 2H- 1 -benzopyran -6 - ol 125 3,4-Dihydro-2,5,7,8-tetramethyl-2-[ [4- (phenylmethyl) -l- piper zinyl]methyl] -2H- 1-benzopyran- 6 -ol 126 3 , 4-Dihydro- 2 ,5,7,8- tetramethyl-2- (1-piperazinylmethyl) -

2H- 1-benzopyran- 6 -ol

127 3 ,4-Dihydro-2 ,5,7, 8 - tetramethyl- 2- (1-pyrrolidinylme thyl) - 2H- 1-benzopyran- 6 -ol

128 2- [ [ [2- (Dime thyl amino) eth l] amino] methyl ] -3 , 4 -dihydro - 2, 5, 7, 8 -te trame thyl -2H- 1-benzopyran- 6 -ol 129 2- [ [ [2- (4-Aminophenyl)ethyl]amino]methyi] -3 ,4-dihydro-

2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol

130 2- [ [ (4-Pyridinyl)amino]methyl] -3, 4-dihydro-2, 5, 7, 8-tetra¬ methyl - 2H- 1-benzopyran- 6 - ol

131 2-[ [4- [(3 -Diethylamino) -2-pyridinyl] -1-piperazinyl] me thyl] - 3,4- dihydro -2,5,7,8- te trame thyl - 2H - 1-benzopyran - 6 - ol

132 2- [ [Phenylamino] methyl] -3,4-dihydro-2,5 , 7 ,8- tetramethyl-2H- 1 -benzopyran- 6 - ol

133 2- [ [4- [5-Diethylamino-2-pyridinyl] -1-piperazinyl] methyl] - 3,4- dihydro -2,5,7,8- tetramethyl - 2H- 1 -benzopyran- 6 - ol 134 2- [ [2-Pyridinyl] amino ]me thyl] -3, 4-dihydro-2, 5, 7, 8-tetra¬ methyl - 2H- 1 -benzopyran- 6 -ol

135 2 - [ [ [ 2 -me thoxy- 5 -pyridinyl] amino ] me thyl] -3 , 4 -dihydro - 2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol

136 2- [ [ [2- (phenyl)ethyl] amino] methyl] -3 ,4-dihydro-2,5, 7 ,8- tetramethyl -2H- 1-benzopyran- 6 -ol

137 2- [ [ [4-(phenyl)butyl]amino]methyl] -3 , 4 -dihydro-2 , 5 , 7 ,8- te trame thyl - 2H- 1 -benzopyran- 6 - ol

138 2- [ [ [3-(phenyl)propyl]amino]methyl]-3,4-dihydro-2,5,7,8- te rame thyl - 2H - 1 -benzopyran- 6 - ol 139 2- [ [ [1- (3, 4-Dimethoxyphenyl) me thyl] amino] m thyl] -3,4- dihydro -2,5,7,8- tetramethyl - 2H - 1-benzopyran- 6 - ol

140 2- [ [ [1- (2 -Pyr idinyl) me thyl] amino] methyl] -3 ,4-dihydro - 2 , 5 , 7 , 8 - te trame thy 1 - 2H- 1 -benzopyran- 6 - ol

141 2- [ [ [1- (3-Pyridinyl)methyl]amino]methyl] -3 ,4-dihydro- 2,5 , 7, 8 -te trame thyl -2H- 1-benzopyran- 6 -ol

142 2-[ [ [2-(2-Pyridinylethyl)-2-(phenyl)ethyl]amino]methyl]- 3,4- dihydro -2,5,7,8- tetramethyl - 2H- 1 -benzopyran- 6 - ol

143 2- [ [ [2- (2-Pyr idinyl) ethyl] amino] methyl] -3 ,4-dihydro- 2,5,7, 8- tetramethyl -2H- 1-benzopyran- 6 -ol 145 3,4-Dihydro-2,5,7,8-tetramethyl-2[(4-phenyl-l-piperazinyl)- methyl] -2H- 1-benzopyran- 6 -ol 146 2- [ [4- [2 , 6 -bis (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazin¬ yl] me thyl] -3 ,4- dihydro -2 ,5,7 , 8- tetramethyl -2H- 1-benzopyran-

6-ol

147 2- [ [ [2- (2- Pyridinyl) ethyl] me thylaminoj e thyl] -3 ,4-dihydro- 2,5,7 , 8- tetramethyl- 2H- 1-benzopyran- 6 -ol

148 2- [2-[4- [4,6-bis(l-pyrrolidinyl)-l,3,5-triazin-2-yl]-l- piperazinyl] ethyl] -3, -dihydro-2, 5,7,8- tetramethyl- 2H-1- benzopyran- 6 - ol EXAMPLE 149 3 , 4-Dlhydro - 2 , 5 , 7 , 8 -tetramethyl- 2- [ [4- [ 6- (1-pyr¬ rolidinyl) -4-pyrimidinyl] -1-piperazinyl] methyl] -2H- benzopyran-6-ol (III) To a stirred suspension of 3 ,4-dihydro-2,5,7 , 8 -t tramethyl- 2- (1- piperazinylmethyl)-2H- 1-benzopyran- 6 -ol (EXAMPLE 126, 0.7g), tri¬ ethylamine (0.23g,2.3mmol) and THF (10 ml), cooled to 0° in an ice- water bath, is added in a steady stream 4,6-dichloropyrimidine In THF (5ml). The cooling bath is removed and the mixture stirred at 20-25° for 18 hr. Ethyl acetate (50 ml) is added and the mixture is washed with water (50 ml) , saline, dried over sodium sulfate and he solvent removed at reduced pressure to leave a residue that is dissolved in pyrrolidine (5 ml) . The mixture is heated at reflux for 2 hr and concentrated at reduced pressure. The residue is flashed chromatogr- aphed on silica gel (50 g) eluting with ammonia, methanol and ethyl acetate (0.5/4.5/95) to give the product which is crystallized from hexane -ethyl acetate to give the title compound.

EXAMPLE 150 l-Benzoyl-4- [ (3 ,4-dihydro-6-hydroxy-2 , 5 , 7,8-tetra- methyl-2H- 1-benzopyran- 2 -yl)me thyl] piperazine (III) To stirred solution of 3 ,4- dihydro -2, 5, 7 , 8- tetramethyl -2- (1- piperazinylmethyl)-2H- 1-benzopyran- 6 -ol (EXAMPLE 126, 0.3g, 1.0 mmol), triethylamine (O.llg, 1.1 mmol) and methylene chloride (3 ml) is added dropwise over 1-2 min a solution of benzoyl chloride (0.16g, 1.1 mmol) in methylene chloride (2ml). The mixture is stirred at 20- 25° for 1 hr and diluted with methylene chloride (20 ml) , washed with water (20 ml) , dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue. The residue is flashed chromat¬ ographed on silica gel (25 g) eluting with ethyl acetate/hexane (1/1) to give the product as an oil that is crystallized from ether to give the title compound.

EXAMPLE 151 2 -[ [4- (2 , 6 -Bis (1-pyrrolidinyl) -4-pyrimidinyl) -1- piperaziny 1 ] me thyl ] - 3 , -dlhydro-2 , 5,7, 8-tetramethyl - 2H-l-benzopyran-6-(l-imidazole carbamate) (III-

prodrug) A solution of 2- [ [4- (2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl)-1- piperazinyl] -3,4-dihydro-2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol (84 mg) , 1,1-carbonyldiimidazole (30 mg) and THF (1.0 ml) is heated at reflux for 16 hr. After cooling to 20-25°, the residue is con¬ centrated. Purification by flash chromatography hexane/ethyl acetate (1/1) provides the title compound.

EXAMPLE 152 2 -[[4-(2 , 6 -Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8- etrameth l- 2H-l-benzopyran-6-(diethylaminoacetoxy) (III-prodrug)

A solution of 2-[ [4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1- piperazinyl]me hyl] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran- 6-ol (0.20 g) and THF (1.5 ml) are added to a suspension of sodium hydride (25 mg of 50% mineral oil disp, washed with hexanes) and THF (0.50 ml).. The resultant solution is stirred for 1 hr at 20-25° and is then cooled to 0°C. Chloroacetylchloride (33 μl) is added and the resultant solution is stirred for 1 hr at 0°, and 2 hr at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) provides an oil. The crude oil is combined with acetonitrile (2.0 ml) and diethylamine (0.10 ml) and the resultant solution stirred for 40 hr at 20-25°. After removing solvent in vacuo, basic workup (ethyl acetate, sodium bicarbonate and magnesium sulfate) and flash chromat¬ ography, eluting with hexane/ethyl acetate (1/1) and concentrating the appropriate fractions provides the title compound.

EXAMPLE 153 2 -[ [4-(2 , 6 -Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl- 2H-1-benzopyran-6-dimethylaminoacetoxy (III-prodrug) Methylene chloride (4.0 ml) and pyridine (1.0 ml) are added to a solid mixture of 2- [ [4-(2,6-Bis(1-pyrrolidinyl)-4-pyrimidinyl)-1- piperaziny1]methyl] -3, -dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran- 6-ol (0.200 g) , dimethylglycine (48 mg) , dicyclohexylcarbodiimide (95 mg) and dimethylaminopyridine (1 mg) . After 7 days at 20-25°, aqueous workup (chloroform, magnesium sulfate) and flash chromatog- raphy eluting with ethyl acetate/hexane (3/1) provides the title com¬ pound.

EXAMPLE 154 2 - [ [ 4-( 2 , 6 -Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl-

2H-1-benzopyran-6-(4-dimethylaminobutoxy) (III- prodrug) Following the general procedure of EXAMPLE 153 and making non- critical variations but using dimethylamino butyric acid, the title compound is prepared.

EXAMPLE 155 2- [ [4- [3- (Ethylamino) -2-pyridinyl] -1-piperazinyl] - methyl] -3,4-dih dro-2,5,7,8-tetramethyl-2H-1-ben- zopyran-6-(dim thylaminoacetoxy) (III-prodrug) Following the general procedure of EXAMPLE 153 and making non- critical variations but using 2- [ [4-[3-(ethylamino)-2-pyridinyl] -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl-2H-l-benzopyran- 6-(dimethylaminoacetoxy) , the title compound is prepared. EXAMPLE 156 2- [ [4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl- 2H-l-benzopyran-6-(5-aminopentanoate) (III-prodrug)

Following the general procedure of EXAMPLE 159 and making non- critical variations but using 5-t-butyloxycarbonylamino pentanoic acid, the protected amino ester is prepared. The t-butyl carbonate is deprotected by treatment with methanolic hydrochloric acid over 18 hr Concentration and trituration with ether provides the title compound.

EXAMPLE 157 2-[ [4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl- 2H-l-benzopyran-6-0-succinate sodium (III-prodrug) Following the general procedure of EXAMPLE 158 and making non- critical variations but utilizing succinic anhydride the title compound is obtained.

EXAMPLE 158 2- [ [4- [3-(Ethylamino) -2-pyridinyl] -1-piperazinyl] - methyl] -3 ,4-dihydro-2,5,7,8-tetramethyl-2H-1-ben- zopyran-6-0-malate sodium (III-prodrug)

A solution of tetrahydrofuran (2.0 ml), sodium hydride (0.60 mmol) , and 2- [ [4-[3-(ethylamino)-2-pyridinyl]-l-piperazinyl]methyl] - 3,4-dihydro-2,5,7,8-tetrameth l-2H-l-benzopyran-6-ol is stirred for 1 hr at 20-25°. Maleic anhydride (0.59 mmol) is added. After 2 days, the solution was concentrated and tritrated with ether to give the title compound.

EXAMPLE 159 2- [ [4- (2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl-

2H-1-benzopyran-6-(6-aminohexanoate) (III-prodrug) Methylene chloride (3.0 ml) is added to a solid mixture of 2- [[4-(2,6-Bis(l-pyrrolidinyl) -4-pyrimidinyl)-1-piperazinyl]methyl } - 3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (0.30 g) , dicyclohexylarlodiimide (143 mg) and dime hylaminopyridine (1 mg) . After 72 hr the reaction is filtered. The filtrate is partitioned between aqueous sodium bicarbonate and methylene chloride. The combined organic layers are dried (magnesium sulfate) and con¬ centrated. Purification by flash chromatography hexane/ethyl acetate (1.5/1) provides the protected amino ester.

A solution of the amino ester (387 mg) methylene chloride (5.0 ml) and trifluoroacetic acid (5.0 ml) are stirred for 30 min at 0°C. After concentration, basic workup (chloroform, postassium carbonate, magnesium sulfate) provides an oil which is immediately taken up into methanol and added to a solution of oxalic acid (2.2 equivalents) in methanol. Concentration and tritration with ether provides the title compound.

EXAMPLE 160 2-[[4-(2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl- 2H-1-benzopyran-6-(4-aminobutyrate) (III-prodrug)

Following the general procedure of EXAMPLE 156 and making non- critical variation but using 4-t-butyloxycarbonylamino butyric acid, the title compound is obtained.

EXAMPLE 161 6 -Acetyloxy-3,4-dihydro-2 , 5 , 7 , 8-tetramethyl-2H-1- benzopyran-2-carboxylic acid 2- [(2,6-bis(l-pyrrolidin- yl)-4-pyrimidinylmethylamino]ethyl ester (III) A solution of oxalyl chloride (0.4 ml) in acetonitrile (0.4 ml) is added dropwise to a solution of 1 ml of DMF and 2.4 ml of acetoni¬ trile. The mixture is stirred (mechanically) for 15 minutes at -20° and a precipitate separates. Powdered 6-acetoxy-2,5,7,8-tetramet¬ hylchroman-2-carboxylic acid (1.169 g, 4 mmol) is added, the mixture is stirred 20 minutes at -20° , 20 minutes at 0° and then is recooled to -20°. A solution of 1.165 g (4 mmol) of N-(2-hydroxyethyl)-N- methyl- [2,δ-bis(l-pyrrolidinyl)] -4-pyrimidinamine in 1 ml of pyridine and a total of 4 ml of acetonitrile is added. The mixture is allowed to warm and stand overnight at 20-25° and then is diluted with methylene chloride. The solution is washed with water, aqueous potassium bicarbonate and water, then dried and concentrated to give

a foam. Chromatography on silica gel and elution with acetone/- methylene chloride (10/90) gives the title compound. NMR 4.70, 4.27, 3.9-3.2, 2.85, 2.58, 2.32, 2.17, 2.16, 2.02, 1.9 and 1.58 δ; m.p. 69.5-76°. EXAMPLE 162 6- cetyloxy-3 ,4-dihydro-2, 5, 7, 8-tetramethyl-2H-1- benzopyran-2-carboxylic acid 2- [(2,6-bis(l-pyrrolidin- yl)-4-pyrimidinylmethylamino]propyl ester (III) Following the general procedure of EXAMPLE 161 -and making non- critical variations the title compound is obtained. MS (El) m/e 634; methanesulfonate salt m.p. 97-104

EXAMPLE 163 Sodium Suleptanate Ester of 2-[[4-(2,6-bis(1-pyr¬ rolidinyl) -4-pyrimIdinyl)-l-piperazinyl]methyl] -3,4- dihydro-2 ,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (III-prodrug) Triethylamine (0.022 ml) and diethylcyanophosphonate (0.0255 ml) are added to a mixture of 2- [ [4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidin¬ yl) -1-piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethyl-2H-l- benzopyran-6-ol (EXAMPLE 21, 0.064 g) and suleptanic acid' mono- triethyla ine salt, H0-C0-(CH ₂ )g-C0-N(CH ₃ )-CH ₂ CH ₂ -S0 ₂ -0 ^" (ethyl) ₃ -N ⁺ -H (0.23 ml) as a 0.65 M solution in acetonitrile. The mixture is stirred for 7 days after which the solvents are removed under reduced pressure. Methylene chloride and several drops of aqueous sodium bicarbonate are added. The material is concentrated and chromatogra¬ phed on silica gel using methanol/methylene chloride (15/85). The appropriate fractions are pooled and concentrated to give the triethylamine salt of the suleptanate ester. The triethylamine salt is taken up in n-butanol and partitioned with aqueous sodium sulfate (lg/10 ml of water) . The n-butanol layer Is separated and the n- butanol Is removed under reduced pressure. Water is added to the residue and the material is lyophilized to give the title compound, mp - 160-180° (phase change); MS (FAB) [M + H] ⁺ at m/e = 798 (for free sulfonic acid), at m/e - 820.

EXAMPLE 164 Sodium Suleptanate Ester of 2- [ [4-[3-(ethylamino)-2- pyridinyl] -1-piperazinyl]methyl] -3,4-dihydro-2,5,7,8- tetramethylbenzopyran-6-ol (III-prodrug)

Following the general procedure of EXAMPLE 163 and making non- critical variations but using 2-[[4-[3-(ethylamino)-2-pyridinyl]-1- piperazinyl]methyl] -3,4-dihydro-2,5,7,8-tetramethylbenzopyran-6-ol

(EXAMPLE 22) the title compound is obtained.

EXAMPLE 165 1- [ (2-Hydroxy-5-methoxy-1-phenyl)methyl] -4- [3-ethyl- amino-2-pyridinyl]piperazine (VI-47) Sodium cyanoborohydride (290 mg) is added to a solution of 2- hydroxy-5-methoxybenzaldehyde (0.452 ml), 1- [ (3-(ethylamino) -2- pyridinyl]piperazine (1.12 grams), methanol (14 ml), and hydrochloric acid (10%, 0.10 ml). The mixture is stirred for 16 hours at 20-25°. The mixture is then concentrated, worked up by aqueous extraction with chloroform. The organic phase is separated, dried over mag- nesium sulfate and purified by flash chromatography eluting with hexane/ethyl acetate (1/1) . The appropriate fractions are pooled and concentrated to give the title compound, MS (El) m/e 342 (M ⁺ ) . EXAMPLES 166-172

Following the general procedure of EXAMPLE 165 and making non- critical variations but starting with the appropriate known phenols and amines the following compounds are obtained: EXAMPLE Hydroquinone (VI)

166 1- [ (2 , 5-Dihydroxy-l-phenyl)methyl] -4- [2 , 6-bis(1-pyr¬ rolidinyl)-4-pyrimidinyl]piperazine (VI-22), MS (El) m/e 424 (M+)

167 1- [ ( 2 -Hydroxy- 5 -me hoxy -1 -phenyl ) ethyl J -4-[2,6-bis(l- pyrrolidinyl)-4-pyrimidinyl]piperazine (VI-22), MS (El) m/e 438 (M+)

168 1- [ (2 , 5-Dihydroxy-l-phenyl)methyl] -4- [ 3 -ethylamino -2 - pyridinyl]piperazine (VI-47), MS (El) m/e 328 (M+)

169 1- [ (2 , 5-Dihydroxy-l-phenyl)methyl] -4- [ 3 , 6-bis (diethyl¬ amino) -2 -pyridinyl] piperazine (VI-46), MS (El) m/e 427 (M ^*1* )

170 1- [ (2-Hydroxy-5-methoxy-l-phenyl)methyl] -4- [3 , 6-bis(di- ethylamino)- 2 -pyridinyl ] piperazine (VI-46), MS (El) m/e 441 (M+)

171 1- [(2-Hydroxy-5-methoxy-l-phenyl)methyl] -4- [5-diethylamino- 2 -pyridinyl] piperazine (VI-59), MS (El) m/e 370 (M+)

172 1- [ (2,5-Dihydroxy-l-phenyl)methyl] -4- [ 5 , diethylamino- 2- pyridinyl] piperazine (VI-59), MS (El) m/e 356 (M+) EXAMPLE 173 2 , 5 -Dihydroxyphenylmethyl - 3 , 4- dime thoxyphenyl ethyl - amine (VI -38) Imidazole (3.08 grams) is added to a mixture of 2 ,4-dihydroxy- benzaldehyde (2.50 grams), t-butyldimethylsilylchloride (6.46 grams)

and DMF (20 ml). After stirring overnight at 20-25° the crude reaction mixture is partitioned between ether and hydrochloric acid (0.5 N) . The layers are separated and the organic phase is washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to provide the disilylated aldehyde inter¬ mediate.

A solution of the disilylated aldehyde intermediate (8.26 grams), 3,4-dime hoxyphenylethylamine (3.54 grams), toluene (30 ml) and toluene sulfonic acid (150 milligrams) is heated at reflux for 24 hours ^* removing 10 ml of the solvent in a Dean-Starke trap. After cooling to 20-25° sodium borohydride (1.2 grams), and ethanol (40 ml) are added. After stirring for an additional 2 hours additional sodium borohydride (0.60 grams) and hydrochloric acid (10%, 4.0 ml) are added. The resulting mixture is stirred for 20 hours. After a concentration the mixture is worked up under basic conditions using chloroform, sodium bicarbonate and drying the resultant extract over magnesium sulfate. The mixture is then concentrated, the concentrate is flash chromatographed eluting with hexane/ethyl acetate (1.5/1) to provide a 3,4-dimethoxyphenylethylamine disilylated intermediate. Tetrabutylammoniumfluoride (5.8 ml) is added to the silylated intermediate (2.1 grams) in THF (25 ml). The mixture is stirred for 1 hour at 20-25°. The mixture is worked up under acidic conditions using ether and chloroform and drying over magnesium sulfate. Upon concentration the title compound is obtained as an oil. EXAMPLE 174 2-Hydroxy-5-methoxyphenylmethyl-3-4-dimethoxyphenyl- ethylamine (VI-38) Following the general procedure of EXAMPLE 173 and making non- critical variations but starting with 2-hydroxy-5-methoxybenz- aldehyde, the title compound is obtained, m.p. 66-67. EXAMPLE 175 3 ,4-Dihydro-3- [2- (3,4-dimethoxyphenyl)ethyl]-1,3,2- benzoxazin-6-ol (VIII-66) A mixture of 2,5-dihydroxyphenylmethyl-3,4-dimethoxyphenylethy1- amine (EXAMPLE 175, 0.476 gm) , paraformaldehyde (56 mg) , THF (10 ml) and magnesium sulfate (0.240 gm) are stirred at 20-25° for 5 days. The mixture is worked up under aqueous conditions using chloroform and drying over magnesium sulfate to provide the title compound, MS (El) m/e 315 (M+) EXAMPLE 176 2, 3,4, 5-Tetrahydro-7-methoxy-4- [2- (3 ,4-dimethoxy)-

phenylethyl-l,4-benzoxazepin-3-one (VIII-38) Chloroacetylchloride (0.26 ml) is added dropwise over 10 minutes to a mixture of 2-hydroxy-5-methoxyphenylmethyl-3-4-dihydroxyphenyl- amine (EXAMPLE 174, 1.0 grams), THF (5 ml), ether (15 ml) and triethylamine (0.49 ml) at 20-25°. After 20 hours, the residue is partitioned between hydrochloric acid (0.05 N) and ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude amide. A mixture of the crude amide (1.18 grams), acetone (50 ml), and potassium carbonate (0.69 grams) are stirred at 20-25° for 60 hours. The mixture is filtered, concentrated and worked up under aqueous conditions using methylene chloride and magnesium sulfate. The concentrate is purified by flash chromatography eluting with ethyl acetate/hexane (3/1) . The appropriate fractions are pooled and concentrated to give the title compound, m.p. 102-103° EXAMPLE 177 2,3,4,5-Tetrahydro-4-(2-(3,4-dimethoxyρhenyl)ethyl)-7- methoxy-1,4-benzoxazepine (VIII-38) A solution of 2,3,4,5-tetrahydro-7-methoxy-4- [2-(3,4-dimethoxy) - phenylethyl-1,4-benzoxazepin-3-one (EXAMPLE 176, 0.382 gm) and THF (3 ml) are added dropwise over 15 minutes to a mixture of lithium aluminum hydride (101 mg) and ether (3 ml). The resulting mixture is stirred for 20 hours at 20-25°. Water (0.12 ml), sodium hydroxide (15%, 0.12 ml) and water (0.36 ml) are added successively. The mixture is then diluted with ether and stirred for 30 minutes. The mixture is filtered, the residual salts are washed with ethyl acetate chloroform and ethyl acetate again. The organic mixtures are combined, dried over magnesium sulfate and concentrated to give the title compound. EXAMPLE 178 1- [ [6- (Acetyloxy) -3,4-dihydro-2,5,7,8-tetramethyl-2H- l-benzopyann-2-yl]acetyl] -4-(4,6-bis(l-pyrrolidinyl) - 1,3,5-triazin-2-yl)piperazine (III-45) Following the general procedure of EXAMPLE 68 and making non- critcial variation but starting with 4,6-bis(1-pyrrolidinyl)- l,3,5-triazin-2-yl)piperazine (PREPARATION A-45), the title compound is obtained.

EXAMPLE 179 1- [ (3,4-Dihydro-6-hydroxy-2, 5, 7,8-tetramethyl-2H-1- benzopyran-2-yl)acetyl] -4- [4 , 6-bis(l-pyrrolininyl) -

l,3,5-triazin-2-yl]piperazine (111-45)

Following the general procedure of EXAMPLE 75 and making non- critcial variation but starting with 1- [[6-(acetyloxy)-3,4-dihydro-

2,5,7,8-tetramethyl-2H-l-benzopyann-2-yl]acetyl]-4-(4,6-b is(l-pyr- rolidinyl)-l,3,5-triazin-2-yl)ρiperazine (EXAMPLE 178), the title compound is obtained.

EXAMPLE 180 1- [2 , 6-Bis(1-pyrrolidinyl) -4-pyrimidinyl] -4- [(3,4- dihydro-6-acetyloxy-2,5,7, 8-tetramethyl-2H-l-benzo- pyan-2-yl)carbonyl]piprazine (III-22) Acetic anhydride (0.056 g) , [4-(2,6-bis(1-pyrrolidinyl)-4- pyrimidinyl)-1-piperazine]-6-hydroxy-2,5,7,8-tetramethylchro man-2- carboxamide (EXAMPLE 18, 0.26 g) and pyridine (1 ml) are stirred for 2 hr at 20-25°, Hydrochloric acid (0.01N, 5 ml) and ethyl acetate (5 ml) are added, the layers separated, the organic phase washed with saline and dried over magnesium sulfate. The solvent is removed under reduced pressure to give a residue which is crystallized to give the title compound, m.p. 191-192°; MS (El) m/e 576 (M+) EXAMPLE 181 N- [2- [1- (2-Pyridinyl)ethyl] ] -N-[2-(1-phenyl)ethyl] - 3 , 4-dihydro-6-hydroxy-2, 5,7, 8-tetramethyl-2H-1- benzopyran-2-carboxamide (111-82)

Following the general procedure of EXAMPLE 18 and the descrip¬ tion of the general procedure in the specification to prepare the amide type bicyclic amines (III) where X ₃ is -CO-, the title compound is obtained. EXAMPLE 182 4- [4- [2- (Ethylamino) -4-(2-pyridinyl)-1-piperazinyl]- butyl]-2,6-dimethylphenol methanesulfonate (1-63) Following the general procedure of EXAMPLE 44 and making non critical variations 4-[2,6-dimethyl-l-hydroxy-4-phenyl]butanol (PREPARATION NA-15) is reacted with 2-(ethylamino)-4-(2-pyridin- yl)piperazine (Amine-63) to provide the hydroxy intermediate of the title compound. This hydroxy intermediate is esterified with methanesulfonic acid to give the title compound.

EXAMPLE 183 1- [ [6-(Acetyloxy)3,4-dihydro-2,5,7,8-tetramethyl-2H-l- benzopyran-2-yl]acetyl] -4- (phenylmethyl)piperazine (III)

Following the general procedure of EXAMPLE 68 and making non- critical variations and starting with benzylpiperazine, the title compound is obtained.

EXAMPLE 184 3 , 4 - Dihydro - 2 , 5 , 7 , 8 - tetramethyl-2 - [ 2 - [4 - (phenyl methyl) -1-piperazinyl] ethyl] -2H- 1-benzopyran- 6 -o

(III) Following the general procedure of EXAMPLE 21 and making non critical variations but starting with 1- [ [6- (acetyloxy) 3 , 4-dihydro 2,5,7,8- tetramethyl- 2H- 1 - benzopyran- 2 -yl] acetyl] -4- (phenylmethyl) piperazine (EXAMPLE 183), the title compound is obtained. EXAMPLE 185 3 , 4-Dihydro- 7-hydroxy-4- [ 2 - (3 , 4-dimethocyphenyl) - ethyl] -l,4,2-benzooxazine-3-one (IX) . To a solution of 4-aminoresorsinal hydrochloride (1.00 mmol) i dichloromethane (2.0 ml) at 0° is added successively a solution o chloroacetylchloride (1.1 eq) and triethylamine (2.5 eq) . Stirred a 0° for 2 hr and at 20-25° 4 h. Concentrated, the residue is taken up into acetone (10.0 ml) and potassium carbonate (1.2 eq) is added. Stirred for 24 h at 20-25°. After concentration the residue was partitioned between water and chloroform. The chloroform layers were dried over magnesium sulfate and concentrated. Purification by flash chromatography eluting with ethyl acetate provided the unsubstituted amide. A solution of the amide (0.50 mmol) was added to a mixture of sodium hydride (2.3 mmol) and dimethyl formamide (2.0 ml). After stirring for 30 min a solution of l-bromo-2- (3,4-dimethyocyphenyl) - ethane (0.50 mmol) in dimethyl formamide (1.0 ml) was added at 0°C. After 2 h an aqueous workup with ethyl acetate was performed. The organic layers were dried with magnesium sulfate and concentrated. Purification by flash chromatography provided the title compound. EXAMPLE 186 3,4-dihydro-7-hydroxy-4- [2-phenylethyl)-l,4,2 ben- zooxazine-3-one (IX) Following the general procedure of EXAMPLE 185 and making non- critical variations but using 2-phenethyl-l-bromide, the title compound is obtained.

EXAMPLE 187 3 , 4 - Dihydro - 2 -hydroxy - 4 - [ 1 -phenylmethyl ] -1 , 4 , 2 - benzoxazine-3-one (IX) Following the general procedure of EXAMPLE 185 and making non- critical variations but using benzyl bromide, the title compound is obtained.

EXAMPLE 188 3 , 4-dihydro- 7 -hydroxy-4- [ 1 - (4-dime thyl-aminophen- yl] ethyl] l,4,2-benzoxazine-3-one (IX)

Following the general procedure of EXAMPLE 185 and making non- critical variations but using 4-dimethylaminobenzylbromide, the title compound is obtained. EXAMPLE SALTS Following the general procedure of EXAMPLES 1A, 17A, 22A, 24A,

26A, 42A, 42B, 43A, 44A and 45A and making non-critical variations and starting with the free amine bases of EXAMPLES 29-32, 35-39, 48- 57, 60-67, 71 and 72 the corresponding salts are formed

EXAMPLE Salt 29A 4- [4- [ 4- (2 ,6 -bis (2 -pyridinyl) -4-pyrimidinyl) -1-piperazin¬ yl Jbutoxy] phenol 3.4 hydrochloride 30A 4-[6-[4-(2 ,6 -bis (1-pyrrolidinyl) -4-pyrimidinyl) -1-piper¬ azinyl] hexyloxy] phenol fumerate 31A 4-[6-[4-[3- (ethylamino) -2 -pyridinyl J -1-piperazinyl ]hexyl- oxy] phenol monomethane sulfonate

32A 4- [6- [4- (3, 6-bis (2-pyridinyl) -4-pyridazinyl)methyl-l - p ip eraz iny 1 ] hexyloxy ] pheno 1 tr ihydr o chloride 35A 5- [3-(4- (2,6-bis(l-pyrrolidinyl)pyrimidin-4-yl)piperazin-l- yl) ropylbenzodioxole dihydrochloride 36A 5- [3-N-ethylaminopyridin-2-yl)piperazin-l-yl)propylben- zodioxole dihydrochloride 38A 1- [ [ (4 -methoxyphenyl) -2-ketoeth-l-yl]butyl] -4- (bis (1-pyrr¬ olidinyl) )pyrimidin-4-yl)piperazine monomethane sulfonate 39A 1 -phenyl -3 -[4- (2, 6 -bis (1-pyrrolidinyl) -4-pyrimidinyl) -1- piperazinyl] -propane monomethane sulfonate

48A 4- [3-(4-(3-(N-ethylamino)pyridin-2-yl)piperazin-l-yl)- propyl ] - 2 , 6 - dime thy lphenol hydrochloride 49A 2,6-bls(l-pyrrolidinyl)-4-[4-(3-(3,5-dimethyl-4-methoxy- phenyl)propyl)piperazinyl] pyrimidine dihydrochloride 0.66 H ₂ 0

50A N-ethyl-2- [4- [3- (4-methoxy-3 , 5-dime thylphenyl )propyl] -1- piperazinyl] -3 -pyridinamine hydrochoride 51A 4- [2- [4- (2, 6 -bis (1-pyrrolidinyl) -4-pyrimidinyl-l-piperazin- yl ] ethyl ] -2 , 6 -dime thy lphenol dihydrochloride hydrate 52A 4- [2- [4- [3 -(ethylamino) -2-pyridinyl] -1-piperazinyl] -ethyl] -

2,6- dime thy lphenol dihydrochloride 53A 4- [bis- (1-pyrrolidinyl) -4-pyrimidinyl] -l-[2-(6, 7-dimethoxy- isochromyl)eth-l-yl] piperazine hydrochloride

54A 2, -bis- ( 1-pyrrolidinyl) -6- [4- [2- [2- [ (1 , 3 ,4 , 5- tetrahydro

7 , 8-dimethoxy-2-benzoxepin-l-yl)methoxy]ethoxy]ethyl] -1 piperazinyl] pyrimidine monomethane sulfonate 55A 4- [ 3 -ethylamino- 2 -pyr idinyl] -1- [2- [6 , 7 -dime thoxy - iso chromyl]eth-l-yl] piperazine dihydrochloride

56A 4- [4- [2- (4-methoxy-3 , 5 -dime thylphenyl) ethyl] -1-piperazin yl] -2, 6 -bis (1-pyrrolidinyl )pyrimidine dihydrochloride 1.3 hydrate 57A N-ethyl-2- [4- [ 2- (4-methoxy-3 , 5 -dimethylphenyl) ethyl] -1 piperazinyl] -3 -pyridinamine dihydrochloride hydrate

59A 2- [4- (6- (3 ,5-dimethyl-4-methoxyphenyl)hexyl)piperazinyl-N ethyl - 3 -pyridinamine hydrochloride 60A 3- [6- (4- (3- (ethylamino)pyridin-2-yl)piperazin-l-yl) - hexyl ] cyclohex- 2 - en- 1 - one hydrochloride 61A 3- [6- ( (2 , 6-bispyrrolidin-l-yl)pyrimidin-4-yl)piperaz-l yl)hexyl ] cyclohex- 2 - en- 1 -one hydrochloride 62A 3- [4- (4- (3- (ethylamino)pyrid-2-yl)piperazin-l-yl)butyl] cyclohex- 2 - en- 1 - one hydrochloride 63A 3-[3-(4-(3- (ethylamino)pyrid-2-yl)piperazin-l-yl)propyl] - cyclohex- 2- en- 1-one hydrochloride

64A 3-[3-(4-(2,6-bis (1-pyrrolidinyl) pyrimidin- 4 -yl) piperaz in - l-yl)propyl] -cyclohex- 2 -en- 1-one hydrochloride 65A l-phenoxy-4- [4- (2 , 6 -bis (1-pyrrolidinyl) - 4-pyrimidinyl - piperazinyl] -butane monomethane sulfonate 66A 1- [3, 4 -dihydro -6 -hydrox -2, 5 ,7 ,8-tetramethyl-2H-l-benzo- pyran- 2 -yl) acetyl] -4- (2 , 6-bis (1-pyrrolidinyl) -4 -pyrimidi yl) -piperazine methane sulfonate 67A 1- [3, 4 -dihydro -6 -hydroxy -2, 5, 7 , 8- tetramethyl -2H- 1-benzo¬ pyran- 2- yl) ethyl] -4- (2 , 6-bis (1-pyrrolidinyl) -4-pyrimid- inyl) -piperazine methane sulfonate

71A 4- [ [3,5-Bis(l,l-dimethylethyl)-4-hydroxyphenyl]methyl]-l- piperazineethanol fumerate 72A 2, 6-bis (1, 1-dimethylethyl) -4- [[4-3- (ethylamino) -2-ρyridin- yl] -1-piperazinyl] methyl] phenol fumerate 73A 4- (2, 6 -bis (1-pyrrolidinyl) -4-pyrimidinyl) -N- (4-hydroxy- 3,5 - dimethylphenyl) -1-piperazineacetamide monomethane sulfonate Following the general procedure of EXAMPLES 1A, 17A, 22A, 24A, 26A, 42A, 42B, 43A, 44A and 45A and making non-critical variations

and starting with the free amine bases of the corresponding EXAMPLES (No) the following salts (NoA) are formed by use of the appropriate acid

EXAMPLE Salt

113A poly-hydrochloride hydrate crystallized from methanol-ether

114A hydrochloride

115A dihydrochloride hydrate

116A poly-phdrochloride hydrate

117A hydrochloride

119A dihydrochloride hydrate

120A dihydrochloride hydrate

121A dihydrochloride hydrate

125A dihydrochloride hydrate

126A dihydrochloride

135A oxalate

136A oxalate

137A hydrochloride

138A oxalate

141A oxalate

142A oxalate

143A oxalate

145A dihydrochloride hydrate

147A oxalate

151A oxalate

152A oxalate

153A dioxalate

154A dioxalate

155A dioxalate

160A m.p. 162-164°

166A hydrochloride

167A oxalate

168A oxalate

169A oxalate

170A oxalate

17LA oxalate

172A oxalate

173A oxalate _r m.p. 167-169°.

175A oxalate, m.p. 49°.

CHART A

10

X ₂ -(CH ₂ ) _rι2 -M (ID

^l 12

20

(V)

CHART A - Continued

OR,28

10

30

49

CHART A - Continued

9

10

20 9

2

-ιϋo- CHART B

Formula

Name Chemical Structure No .

pyrIdin-2- , (F-l)

(0) 0-1

or 4-yl optionally substituted optionally as the N-oxide

-*CH ₂ - (CH ₂ ) _c -G- (CH ₂ ) _d -CH ₂ -N

3 -pyrrolin-l-yl

pyrrol-1-yl optionally substituted (C _r C ₃ alkyl )

-N 0-1 (F-6)

CHART B - Continued

Formula

Name Chemical Structure No .

piperidin-1-yl optionally (F-7 substituted

1 , 2 , 3 , 6- tetrahydropyridin-l-yl (F-8

1-hexamethyleneimino containing a 3- or 4- (F-9 double bond or 3- and 5- double bonds

1,4-dihydro-1-pyridinyl substituted in the 4-position different groups

I-,3,5-triazin-2-yl or the (R M M_-2.)'0-1 Ni-oxide thereof optionally

(F-ll) substituted at the 4- and/or 6- position

pyrimidin-4-yl or thereof optionally at the 2- and/or 6 (F-12) 6- position

CHART B - Continued

Formula

Name Chemical Structure No.

pyrimidin-2-yl optionally M-2--0-2 (F-13) substituted

pyrazin-2-yl optionally (F-14) substituted

imidazol-2-yl optionally // -j- -— ( ^R -2*0-2- (F-15) substituted in

I

(C- _j -C ₃ al kyl or aryl ) _Q _- N— N l,3,4-triazol-2-yl optionally substituted - -H— ^(R M _-2 ⁾ θ-l ^(F* 16)

N — '

al kyl or aryl ) _Q _,

imidazol-4- or 5-yl optionally substituted

benzo[b]thien-2-yl

indol-2-yl

(F-19)

- i.0 - CHART B - Continued

Formula

Name Chemical Structure No.

benzo[b]thiazol-2-yl (F-20

benzimidazol - 2 -yl (F-21

(F-22)

1,2,4-triazin-3-yl

(1-piperazinyl) - (C ₂ -C4) optionally substituted (C ₂ -C alkyl) -N N-(aryl or heteroaryl) in the 4-position (F-24)

(l-piperazinyl)acetyl substituted in the -C0-CH ₂ -N N-heteroaryl (F-25) 4-position

CHART B - Continued

Formula

Name Chemical Structure No .

(1- piperazinyl) carbonyl -

-CH ₂ -CO-N S-heteroaryl (F-26) methyl substituted in the 4-position

-N

(F-27)

2- (carboxy) -1-pyrrolidinyl

COOH

2 - (carboxy) - 1-piperidinyl

2 - (carboxy) - 1 -hexame hyleneimino (F-29)

2 - (carboxy) -1-heptamethyleneimino (F-30)

1-piperazinyl substituted in -N N- (CH ₂ )j -C0-R _M . ₁₂ (F-31) the 4-position

1-piperazinyl substituted in -N N- (CH ₂ )j -heteroaryl (F-32) the 4-position

CHART B - Continued

Formul

Name Chemical Structure No

1-piperazinyl substituted in ^■ N N-(CH ₂ )j-aryl (F-33 the 4-position

4-hydrox -1-piperidinyl (F-34 substituted in the 4-position

l.,_p_r_.l r_ .<_.._«__._ in the 4-position 35

1-piperazinyl substituted in -N N-(CH ₂ ) . (F-36) the 4-position

1-piperazinyl (F-37) substituted in the 4-position

CHART C - Physical Data

Example Physical Data

1 NMR (CDCI3) 1.40, 1.88, 2.46, 3.52, and 3.82 δ.

1A m.p. 164-164.5°

2 NMR (CDC1 ₃ ) 1.4, 2.3-2.7, 3.4-3.8, 6.55-6.8, 7.3-7.7 and

8.25 δ.

2A m.p. 106-108°

3 NMR (CDC1 ₃ ) 1.2-1.8, 2.4-2.9, 3.25, 3.7, 4.2, 6.95 and 7.8 δ.

3A m.p. 128-129°

4 NMR (CDC1 ₃ ) 1.36, 2.45,3.62, 4.02, 7.3-7.6, 7.85-8.35 and

8.7-9.0 δ

4A m.p. 121-135 dec

5 NMR (CDCI3) 1.1-1.8, 2.56, 3.62, 3.87, 7.1-7.4, 7.5-7.9 and

8.45-8.6 δ

5A m.p. 62-71°

6 NMR (CDC1 ₃ ) 0.88, 1.30, 1.8-2.1, 2.25-2.65, 3.35-3.7 and

4.88 δ

6A m.p. 132-133°

7 NMR (CDC1 ₃ ) 1.4-2.1, 2.2-2.7, 3.3-3.8, 3.68 and 4.88 δ

7A mp 178° dec

8 NMR (CDC1 ₃ ) 0.88, 1.30, 1.92, 2.2-2.65, 3.3-3.8 and 4.88 δ.

8A mp 216-217°

9 NMR (CDC1 ₃ ) 1.42, 1.8-2.1, 2.3-2.7, 3.3-3.8 and 4.88 δ

9A m.p. 174-175°

9B m.p. 74-100°

10 NMR (CDC1 ₃ ) 1.3, 1.8-2.0, 2.25-2.65, 3.35-3.8 and 4.9 δ

10A m.p. 152.5-158°

11 NMR (CDC1 ₃ ) 1.35, 1.75-2.1, 2.25-2.75, 3.3-3.8 and 4.88 δ

11A m.p. 110-118°

12 NMR (CDC1 ₃ ) 1.35-1.65, 1.65-1.95, 2.2-2.65, 3.25-3.75 and 4.8 δ

12A m.p. 63-80°

13 NMR (CDCI3) 1.3, 1.8-2.1, 2.25-2.7, 3.0-3.8 and 4.9 δ 13A m.p. 109-112°

14 NMR CDC1 ₃ ) 1.25, 2.3-2.8, 3.0-3.3, 3.6, 4.1, 6.7-7.1 and 7.8 δ

14A m.p. 153.5-156°

CHART C - Continued Example Physical Data

15 NMR (CDC1 ₃ ) 1.1-1.85, 2.3-2.75, 2.9-3.3, 3.62, 4.1, 6.7-7. and 7.8 δ 15A m.p. 151.5-153.5°

16 NMR (CDC1 ₃ ) 1.42, 2.55, 3.62, 4.15, 7.48, 7.9, 8.65 and 8. δ

17 NMR (CDC1 ₃ ) 1.0-1.8, 2.35, 3.05, 3.55, 7.25-7.5, 7.7-8.2, 8.55 and 8.65-8.9 δ. 18 m.p. 123-127°; MS - 534 (M+)

19 m.p. 200-201°; MS - 438 (M+)

20 m.p. 178-181°; MS = 550 (M+)

21 m.p. 153-155°; MS = 520 (M+)

22 NMR (CDC1 ₃ ) 1.28, 1.29, 1.75, 1.96, 2.09, 2.12, 2.16, 2.55, 2.62, 2.71, 2.81, 3.07, 4.20, 4.31, 6.79, 6.88 and 7.70 δ

22A m.p. 208-211° dec; MS - 424 (M+)

23 m.p. 132-136°; MS (FAB) - 537 (M + H) ⁺

24 NMR (CDCL ₃ ) 7.1, 5.1, 4.85, 3.6-3.3, 2.5-1.3, 1.43 δ 24A m.p. 223° 25 m.p. 92-93°; MS (m/e) = 508 (M+)

26 NMR (90 MHz, CDCl ₃ ) 1.3, 1.3-1.8, 2.45, 2.5-2.65, 3.25- 3.95, 3.72, 3.9, 4.2, 6.9, 6.7-6.95 and 7.7-7.8 δ

26A m.p. 127-128°; MS (m/e) - 412 (M+)

27 m.p. 130-133° 28 m.p. 146-148°

29 NMR (300 MHz, CDC1 ₃ ) 1.66-1.79, 2.42, 2.44-2.5, 3.85-3.94, 6.71-6.79, 7.35-7.41, 7.65, 7.87-7.81, 8.57, 8.60, 8.66- 8.67 and 8.80 δ

29A m.p. 255-260° dec; MS (m/e) - 482 (M+) 30 NMR (90 MHz, CDCl ₃ ) 1.3-1.5, 1.6-2.0, 2.2-2.62, 3.3-3.65, 3.83, 4.88 and 6.70 δ.

30A m.p. 210-212° dec; MS (m/e) 494 (M+)

31 NMR (90 MHz, CDCl ₃ ) 1.22, 1.3-1.55, 1.55-1.9, 2.9-3.2, 3.25-3.67, 3.85, 6.8, 6.8-7.05 and 7.6-7.7 δ 31A m.p. 98-102°; MS (m/e) - 388 (M+)

32 NMR (300 MHz, CDC1 ₃ ) 1.25-1.40, 1.40-1.51, 1.63-1.73, 2.28,

2.45, 3.84, 3.97, 6.75, 7.377.45, 7.88-7.95, 8.11, 8.14 and 8.69-8.81 δ

CHART C - Continued

Example Physical Data

32A m.p. 145° dec; MS (m/e) - 524 (M ^"1" )

33 m.p. 171-172°; MS (m/e) - 510 (M+)

34 m.p. 160.-166°; MS (m/e) - 525 (M+)

35 m.p. 148° softens, 155-160° melts with dec

36A m.p. 95° softens, 115° dec

38A m.p. 146-155° dec; MS (m/e) - 450 M ⁺

39 NMR (CDC1 ₃ ) 1.7-2.2, 2.3-2.8, 3.3-3.8, 4.88, 5.32 and 7.3 δ

39A m.p. 187-190°

40 m.p. 166-168°; MS (m/e) - 438 (M+)

41 MS m/e 494

42A m.p. 115-120° dec

42B MS (m/e) = 493 (M+)

43A m.p. 180-188°

44A m.p. 160°

45 m.p. 138° softens, 160° dec; MS (m/e) = 478 (M ^"1" )

46 NMR (CDC1 ₃ ) 1.2-1.9, 3.12, 3.77, 3.87, 6.88, 7.3-7.6, 7.8-

8.3, 8.57 and 8.7-9.0 δ; m.p. 76-76.5°

47A m.p. 170-171° 48A mp.p 224-226° dec 49 TLC (10% methanol/chloroform) R _f = 0.6 49A ^C 28 ^H 42 ^N46 ° ^" MH 563.68

Calc C - 59.66, H - 8.11, N - 14.91, Cl - 12.58

Found C - 59.68, H - 7.73, N - 14.59, Cl - 12.94

50 MS (m/e) -= 382 (M+)

51A m.p. 205-210° 52A ^G 21 ^H 30 ^N 4°->

Calc C - 59.01, H - 7.55, N - 3.11, Cl - 13.59

Found C - 59.39, H -7.68, N - 13.28, Cl - 11.92

53A m.p. 177° softens, 195-200° dec

54A m.p. 85-90° dec

55 m.p. 135° softens, 137-141° dec; MS (m/e) = 426 (M ^* *")

56A m.p. 60° shrinks, 150° liquid, 222° dec; MS m/e 464

57A m.p. 130° shrinks, 210 dec

58 m.p. 98°, MS (m/e) - 520 (M ^*4" )

59 MS (m/e) = 424 (M+)

59A m.p. 140°

CHART C - Continued

Example Physical Data 60 IR (neat) 3358, 2933, 1669, 1580, 1481, 1417, 1234 cm" ¹ ,

NMR (CDC1 ₃ ) 7.60, 6.79, 6.69, 5.77, 4.01, 2.9-3.1, 0.90-2. δ; MS (El) m/e (relative %) 384 (25), 237 (24), 162 (69),

150 (69), 137 (100)

60A m.p. 128-130° dec 61 IR (neat) 2932, 2856, 1670, 1564, 1435, 1345, 787 cm" ¹ ,

NMR (CDC1 ₃ ) 5.80, 4.78, 3.0-3.6, 1.0-2.6 δ; MS (El) m/e

(relative %) 480 (4), 330 (7), 246 (100), 233 (15)

61A m.p. 146-150° dec 62 IR (neat) 3361, 2938, 1669, 1580, 1481, 1417, 1371, 1234,

1150, 788, 772 cm" ¹ ,

NMR (CDCI3) 7.71, 6.90, 6.80, 5.89, 4.13, 3.0-3.2, 2.1-2.8,

1.4-1.6, 1.30 δ; MS (El) m/e (relative %) 356 (27), 162

(21), 150 (83), 137 (100)

62A m.p. 97-99° dec 63 IR (neat) 3363, 2944, 2844, 1667, 1580, 1482, 1456, 1418, 1234, 1150, 790, 773 cm ^"1 ; MS (El) m/e (relative %) 342 (38), 162 (28), 150 (100), 137 (90)

63A m.p. 112-114° dec 64 IR (neat) 2947, 2868, 1667, 1562, 1450, 1346, 1242, 1224,

788, 731 cm ^"1 ; MS (El) m/e (relative %) 438 (5), 329 (12),

246 (100), 121 (8)

64A m.p. 103-106° dec 65 NMR (CDCI3) 1.7-2.2, 2.4-2.7, 3.3-3.8, 4.0, 4.88, 6.9-

7.15, 7.25-7.5 δ

65A m.p. 169-170° 66 NMR (CDCI3) 1.39, 1.63, 1.98, 2.09, 2.12, 2.16, 2.65, 2.73,

3.3-4.0 and 4.78 δ

66A m.p. 60-71° 67 NMR (CDCI3) 1.26, 1.95, 2.11, 2.13, 2.18, 2.65, 3.42, 3.52.

3.67 and 4.84 δ

67A m.p. 148-152°

68 m.p. 67-71

69 m.p. 163-164°

70 m.p. 121-123°

71 NMR (80 MHz, CDCI3) 1.4, 2.55, 3.56, 4.7, 5.3 and 7.25 δ

CHART C - Continued

Example Physical Data

71A m.p. 213-214°

72 NMR (80 MHz, CDC1 ₃ ) 1.25, 1.44, 2.45-2.65, 2.95-3.2, 3.48,

5.06, 6.75-6.85, 7.11, 7.6-7.75 δ

72A m.p. 190-192°

73 TLC (ethyl acetate/hexane, 2/1) R _f «- 0.47

73A m.p. 181-184°

74 m.p. 80-81°

75 NMR (CDC1 ₃ ) 1.31, 1.40, 1.99, 2.10, 2.12, 2.15, 2.65, 2.75,

3.0-3.2, 3.6-3.9, 4.16, 4.51, 6.88, 6.96 and 7.71 S

78A m.p. 130-140° dec; MS (El) m/e 537 (M+)

79 m.p 150-151° MS (El) m/e 424 (M+)

80 m.p 153-155° MS (El) m/e 395 (M ^" )

81 m.p 166-169° MS (El) m/e 396 (M ^*1" )

82 m.p 130-131° MS (El) m/e 428, 430 (M+)

83 m.p 196-198° MS (El) m/e 452 (M+)

84 m.p 115-125° MS (El) m/e 519 (M+)

85 m.p 164-165° MS (El) m/e 428 (M+)

86 m.p 157-159°

87 m.p 127-127.5°; MS (El) m/e 413 (M+)

88 m.p 153-155°; MS (El) m/e 318 (M ^*1" )

89 m.p 131-132°; MS (El) m/e 340 (M+)

90 m.p 58-60°; MS (El) m/e 368 (M )

91 m.p 177-178°; MS (El) m/e 383 (M+)

92 m.p. 105-107°; MS (El) m/e 354 (M+)

93 MS (El) m/e 368 (M ^"1" )

94 m.p. 136.5-138.5°; MS (El) m/e 340 (M+)

96 m.p. 178-179°; MS (El) m/e 395 (M+)

99 m.p. 65-67°; MS (El) m/e 458 (M )

100 m.p. 147-148°; MS (HR) 466.2938

101 m.p. 85-88°; MS (HR) 466.2913

102 m.p. 173-174°; MS (El) m/e 326 (M+)

103 m.p. 105-106°; MS (El) m/e 325 (M+)

104 m.p. 218-220 ^* -; MS (El) m/e 326 (M+)

105 m.p. 108-109°; MS (El) m/e 356 (M+)

106 m.p. 154-155°; MS (El) m/e 482 (M ⁺ )

107 m.p. 75-78°; MS (HR) 510.3318

CHART C - Continued

Example Physical Data

108 m.p 73-74°; MS (El) m/e 381 (M ^*1" )

109 m.p 156-157°; MS (El) m/e 399 (M+)

110 m.p 91-92°; MS (El) m/e 367 (M+)

111 m.p 91-92°; MS (HR) 383.2107

112 m.p 90-91°; MS (El) m/e 353 (M+)

113A m.p, 215-220°; MS (El) m/e 523 (M+)

114A m.p. 187-189" MS (El) m/e 399 (M ^"1" )

115A m.p. 213-216' MS (El) m/e 410 (M+)

116A m.p. 277-278' MS (El) m/e 381 (M ^* )

117A m.p. 253-256' MS (El) m/e 382 (M ⁺ )

119A m.p. 189-193 ^" MS (El) m/e 414 (M+)

120A m.p. 210° (dec); MS (El) m/e 438 (M+)

121A m.p. 210° (dec); MS (El) m/e 504 (M+)

122 m.p. 141-142°; MS (El) m/e 414, 416 (M+)

123 m.p. 109-110°; MS (El) m/e 410 (M ^* )

124A m.p. 186-188° MS (El) m/e 369 (M ^*1* )

125A m.p. 248-250° MS (El) m/e 394 (M+)

126A m.p. 210-212° MS (El) m/e 304 (M+)

127 m.p. 99-100°; MS (El) m/e 289 (M+)

128 m.p. 104-106°; MS (El) m/e 306 (M+)

129A m.p. 154-157°; MS (El) m/e 354 (M ^*1" )

130A m.p. 304-305° MS (El) m/e 312 (M+)

131 m.p. effer 63 ; MS (HR) 452.3164

132A m.p. 125-127° MS (HR) 311.1895

133A m.p. effer 92 ; MS (HR) 452.3170

134 m.p. 140-143° MS (El) m/e 312 (M+)

135A m.p. effer 92 ; MS (HR) 342.1946

136A m.p. 219-220° MS (El) m/e 339 (M+)

137A m.p. 179-180° MS (El) m/e 367 (M+)

138A m.p. 201-202° MS (El) m/e 353 (M+)

139A m.p. 224-225°; MS (El) m/e 385 (M+)

140A m.p. 146-148°; MS (El) m/e 326 (M+)

141A m.p. 229-231°: MS (El) m/e 326 (M+)

142A m.p. 170-173°; MS (El) m/e 444 (M+)

143A m.p. 151-154°; MS (El) m/e 340 (M+)

145A m.p. 204-207°; MS (El) m/e 380 (M ⁺ )

CHART C - Continued

Example Physical Data

146 m.p. 171-172.5°; MS (El) m/e 562 (M ^"1" )

147A m.p. 229-230°; MS (El) m/e 354 (M+)

148A m.p. 150-155°

149 m.p. 174-175°; MS (El) m/e 451 (M+)

150 m.p. 133-134°; MS (El) m/e 408 (M ^"1" )

151A m.p. 185-187°

152A m.p. 167-168°

153 MS (El) m/e 605 (M ^* * ^* )

154A m.p. 137°

155A m.p. 217-219°

156A m.p. 117-180°

157 MS (El) m/e 657

158A m.p. 247-249°

159A m.p. 78-80°

173A m.p. 167-169°

177 MS m/e 343

178 IR (mineral oil) 3459, 1753, 1626, 1570, 1508, 1417, 1321,

1249, 1209 and 1171 cm" ¹

179 IR (mineral oil) 3266, 1626, 1570, 1508, 1478, 1417, 1321,

1254, 1230 and 1169 cm" ¹

181 MS m/e 458 182 m.p. 82° softens, 107° decomp, 126°

CHART D

EXAMPLE Column A. non-amine

2 6-bromohexanol

3 6-bromohexanol 4 6-bromohexanol

5 6-bromohexanol

6 1-bromotetradecane

7 methyl 5-bromovalerate

8 1-bromohexane 9 6-mesyloxyhexanol (PREPARATION NA-3)

10 12-mesyloxydodecanol (PREPARATION NA-5)

11 8-mesyloxyoctanol (PREPARATION NA-1)

12 5-mesyloxypentanol (PREPARATION NA-2)

13 10-mesyloxydecanol (PREPARATION NA-4) 14 ip-mesyloxydecanol

15 8-mesyloctanol

16 6-bromohexano1 Column B. amine ^■ .

2 2-pyridinyl-1-piperazine (PREPARATION A-6) 3 3-ethylamino-2-(l-piperazinyl)pyridine (PREPARATION A-47)

4 3 , 6 -bis ( 2 - pyridinyl ) -4 - (methyl [ 1 -p iperaz inyl ]pyridazine (PREPARATION A- 52)

5 bispicolylamine (PREPARATION A-54)

6 2,6-bis(1-pyrrolidinyl)-4- (1-piperazinyl)pyrimidine (PREPARATION A-22)

7 2,6-bis(l-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine

8 2,6-bis(l-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine

9 2,6-bis(1-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine

10 2,6-bis(l-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine 11 2,6-bis(l-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine

12 2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine

13 2,6-bis(1-pyrrolidinyl)-4-(l-piperazinyl)pyrimidine

14 3-ethylamino-2-(l-piperazinyl)pyridine

15 3-ethylamino-2-(l-piperazinyl)pyridine 16 2,6-bis(2-pyridinyl)-4-(l-piperazinyl)-l,3,5-triazine (PREPARATION A-49)

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