BACKGROUND OF THE INVENTION

The invention herein is directed to compounds and a method of treating gastrointestinal motility disorders of a mammal by administering to the mammal in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. The method can be practiced to treat gastrointestinal motility disorders such as gastroesophageal reflux, diseases characterized by delayed gastric emptying, ileus, irritable bowel syndrome, and the like. The compounds of the invention are serotonergic 5-HT ₃ antagonists and as such are useful for the treatment of conditions, for example, such as anxiety, psychoses and depression.

There are classes of compounds known for the treatment of such disorders. For example, azatetracycle compounds are disclosed in co-pending U.S. patent application serial no. 07/515,391 filed April 27, 1990, and N-Azabicyclo [3.3.0] octane amides of aromatic acids are disclosed in co-pending application serial no. 07/406,205 filed September 11, 1989.

Aza-adamantyl compounds are disclosed in U.S. Patent 4,816,453 and are mentioned generically in U.K. Patent 2,152,049A and European application 0189002A2.

Azabiσyclic nonanes are disclosed in European Patent application 0094742A2. Additional azabicyclic compounds are disclosed in U.S. Patents 4,797,387 and 4,797,406.

Benzamides have been known as 5-HT ₃ antagonists and as compounds possessing gastrointestinal motility-enhancing properties. Benzamides of the following formula:

compounds wherein X can be an azabicycloalkane moiety and which exhibit gastrointestinal motility enhancing and/or 5-HT ₃ antagonist properties are disclosed in EP 0094742A2 and in U.S. patent 4,797,406. In addition, UK Patent 2,152,049 discloses that certain benzamide derivatives exhibit serotonin M antagonistic activity.

Indoleamides of the following formula have also been described as possessing gastrointestinal motility-enhancing and/or 5-HT ₃ antagonist properties:

Compounds wherein X contains an aminergic side chain or an azabicycloalkane moiety are described in U.S. Patent 4,797,406.

European patent publication number 0,230,718 discloses certain substituted benzamide derivatives, substituted with piperidinyl analogues as having gastrointestinal motility- enhancing and/or antiemetic activity and/or 5-HT ₃ receptor antagonist activity.

SUMMARY OF THE INVENTION The compounds of the present invention are serotonergic 5-HT ₃ antagonists. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT ₃ receptors is beneficial. Therapy is indicated for, but not limited to, the treatment of anxiety, psychoses, depression (especially depression accompanied by anxiety) , cognitive disorders, substance abuse dependence and withdrawal, gastrointestinal motility disturbancies (including esophageal reflux,

dyspepsia, gastric stasis, irritable bowel syndrome) , emesis caused by chemotherapeutic agents, and visceral pain. Additionally, the compounds of the present invention may find utility as enhancers of nasal absorption of bioactive compounds. The invention herein is directed to compounds of the formula

the stereoisomers and pharmaceutically acceptable salts thereof, wherein Ar represents a radical of the formula

H

Wherein in group A R _x is H, or C _ ₆ alkyl, and R ₂ is H, or halogen;

In group B, K is N or CR ₄ , L is N or CR ₅ , R ₂ & R ₃ are independently H or halogen, R ₄ is H, or _ ₆ alkoxy and R ₅ is H, halogen, CF ₃ , C _ ₆ alkyl, C _α _ ₆ alkoxy, C-^g alkythio, C ₁ _ ₅ alkylsulfonyl, C _ _& alkylsulfinyl, C _x _ _n acyl, cyano, C ₂ _ ₆ alkoxycarbonyl, C _1-7 acylamino, hydroxy, nitro, amino, aminocarbonyl, or aminosulfonyl optionally N-substituted by one or two groups selected from C ₁ _ ₆ alkyl, C ₃ _ ₈ cycloalkyl, and C ₃ _ ₈ cycloalkylC ₁ _ alkyl or disubstituted by C ₄ or C ₅ polymethylene; phenyl or phenyl C _1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C^ _g alkoxy or C-^ _g alkyl groups;

In group C, M is N or CR ₄ , R ₂ & R ₃ are independently H or halogen, R is H or C^g alkoxy and R ₅ is H, halogen, CF ₃ , C ₁ „ ₆ alkyl, C^ alkoxy, C ₁ _ ₆ alkylthio, C ₁ _ ₆ alkylsulfonyl, C ₂ _ ₆ alkylsulfinyl, C _1# . ₇ acyl, cyano, C ₁ _ ₆ alkoxycarbonyl, C-^ acylamino, hydroxy, nitro, amino, aminocarbonyl, or aminosulfonyl optionally N-substituted by one or two groups selected from C-^ alkyl, C ₃ _ ₈ cycloalkyl, and C ₃ _ ₈ cycloalkylC ₁ _ ₄ alkyl or disubstituted by C ₄ or C ₅ polymethylene, phenyl or phenyl C _1-4 alkyl group optionally the phenyl ring by one or two of halogen, alkoxy or C _j .g alkyl groups;

In group D one of R ₆ and R ₇ is C^g alkyl and the other is C _{l 6} alkyl, phenyl or phenyl C ₁ _ ₄ alkyl optionally substituted in either phenyl ring by one or two of C _x _ ₆ alkyl, C^ alkoxy, or halogen, or R ₆ & R ₇ together are C ₂ _ ₆ polymethylene or C ₂ _ ₅ polymethylene interrupted by an -O- linkage, and R ₂ & R ₃ are independently H or halogen;

In group E, R is H or C^ alkoxy, R ₅ is H or C _x _ _g alkoxy, and R ₂ is H, halogen, CF ₃ , C _1-6 alkyl, C-^g alkoxy, C-_ ₆ alkylthio, C ₁ _ ₆ alkylsulfonyl, C^ _g alkylsulfinyl, C _ ₇ acyl, cyano, C _1-6 alkoxycarbonyl, C^- _j acylamino, hydroxy, nitro, amino, aminocarbonyl, or aminosulfonyl, optionally N- substituted by one or two groups selected from C _1-6 alkyl, ^c ₃ - ₈ cycloalkyl, and C ₃ _ ₈ cycloalkylC ₁ _ ₄ alkyl or disubstituted by C or C ₅ polymethylene, phenyl or phenyl C _1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C _x _ ₆ alkoxy or C^ alkyl groups, and R ₂ & R ₃ are independently H or halogen;

In group F, ₂ is H or C ₁ _ ₆ alkyl, and R ₂ is H or halogen; and

In group H R ₁₅ & R ₁₆ are independently H or -CH=CH-CH=CH-;

Y represents NH or 0; and

Z represents a radical of the formula

'10

Wherein in group Z _x m is 1 or 2;

In group Z ₂ n and p are independently l or 2 and o is 0, 1, or

2 such that n + p + o > 3, and R^ and R' ₂ are independently H, C^ alkyl, phenyl or phenyl-C ₁ _ ₆ alkyl, which phenyl moieties may be substituted by C _1-6 alkyl, C^g alkoxy, or halogen;

In group Z ₃ k is 0 to 2, 1 is 0 to 3, j is 0 to 4, and one of R ^/ ₃ and R' ₄ is H, C^ _g alkyl, phenyl, or phenyl-C ₁ _ ₃ alkyl, which phenyl moieties may be optionally substituted by C _1-6 alkyl, C _1-6 alkoxy, CF ₃ or halogen, and the other of R' ₃ and R' ₄ is H or C ₁ _ ₆ alkyl;

In group Z ₄ a is 0 or 1;

In group Z ₇ d is 0 or l, and R' ₅ is C ₁ _ ₇ alkyl, C ₃ _ ₈ cycloalkyl, C ₃ _ ₈ cycloalkyl-C ₁ _ ₂ alkyl, C ₂ _ ₇ alkenyl, C ₂ _ ₇ alkylenyl-C ₁ _ ₄ alkyl, or phenyl-C- _j^g alkyl.

In group Z ₈ d and R' ₅ are as previously defined;

In group Z _g e is l or 2, and R' ₅ is as previously defined;

In group Z ₁₀ R's is as previously defined; and

In group Z ₁₂ r is 1 to 4, R' ₆ and R' ₇ are independently C-^g alkyl, C^g alkenyl, or C^ _g alkynyl or together form -(CH2)s-, wherein s is 3-7 and one of the CH ₂ units may optionally be replaced by -0-, or NR ^, ₈ , wherein R' ₈ is H or C-^ alkyl;

with the proviso that when Ar is group B, C, D or E, then Z cannot be Z ₅ , Z ₇ or Z ₉ .

The term "cycloalkyl ¹ * embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl and cyclobutyl. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two bromo atoms, such as a dibromomethyl group, or two chloro atoms, such as a dichloromethyl group, or one bromo atom and one chloro atom, such as a bromochloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3-tetrafluoropropyl groups. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group.

Specific examples of alkyl groups are methyl; ethyl,, n- propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, methyl-butyl, di ethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one

unsaturated bond, such as an allyl group, or may have a plurality or unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.

Included within the family of compounds of the described are the tautomeric forms of the described compounds, isomeric forms including diastereoisomers and individual enantiomers, and the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Since the compounds contain basic nitrogen atoms, such salts are typically acid addition salts. The phrase "pharmaceutically-acceptable salts" is intended to embrace alkyl quaternary ammonium salts and n-oxides. The nature of the salt is not critical, provided that it is pharmaceutically acceptable, and acids which may be employed to form such salts are, of course, well known to those skilled in this art. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid, and such organic acids as maleic acid, succinic acid and citric acid. Other pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium, or with organic bases, such as dicyclohexylamine.

All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid or base with the corresponding compound of the invention.

The compounds that are the subject of the invention herein can be prepared according to the following reaction schemes,

SCHEME 1

The preparation of compounds of formula I wherein the Ar group is A is shown in Scheme I. Compounds of formula I A are prepared starting from commercially available 2- aminonicotinic acid l_s_ Chloroacetaldehyde is reacted with 1 at elevated temperature in an alcoholic solvent (preferably EtOH at reflux) to afford compound 2A, which is converted to the acid chloride by conventional methods (preferably thionyl chloride/chloroform/dimethylformamide at reflux) . This acid chloride _2B is then reacted with the appropriate amine 3. in the presence of a tertiary amine (preferably triethylamine) in a polar organic solvent (preferably dimethylformamide) to afford the desired compounds of formula IA. Alternatively, the imidazopyridine carboxylic acid 2A is reacted with the amine _3 using other acid-activating reagents (dicyclohexylcarbodiimide, iso-butylchloroformate, carbonyldiimidazole (CDI) , etc.; preferably CDI in dimethylformamide at room temperature) to afford compounds of formula IA.

Ring halogenated analogs of formula IA' are prepared according to scheme I. 2-Aminonicotinic acid JL is converted to its methyl ester by conventional means. Treatment of this ester with halogenating reagents (NBS, NCS, C12, t- butylhypochlorite; preferably t-butylhypochorite/methanol/ room temperature) gives rise to the ring halogenated intermediate 4., which is converted to the imidazopyridine carboxylic acid ester 5A using conditions described above for the preparation of 2A. The corresponding imidazopyridine carboxylic acid 5 B is converted to compounds of formula IA ^/ using reagents and conditions described above for the preparation of I A from 2A.

SCHEME 2

The preparation of compounds of formulae IB, IC, ID, and IE are shown in scheme 2. In each case, the known acids 10. [EP 0254584A2, J. Medicinal Chemistry (1990), 33, 1924], 11 [EP 0289170A2, J. Medicinal Chemistry (1990), 3 , 1924], 12 & 13 [EP 0289170A2, J. Medicinal Chemistry (1990), 33___ 1929] are reacted with the appropriate amine or alcohol under conditions analogous to those described for scheme l or as described in EP 0254584A2 and EP 0289170A2.

SCHEME 3

The preparation of compounds of formula IF are shown in scheme 3. 2-Aminopyridine 14. is reacted with ethyl bromopyruvate 15 in an alcoholic solvent (preferably ethanol) to afford the imidazopyridine carboxylic acid ester 16A. Hydrolysis of the ester to the acid 16B occurs under conventional acid-catalyzed conditions. Conversion of 16B to amides and ester of formula £F is affected by employing one of a number of acid-activating reagents as sited above [preferably carbonyldiimidazole (CDI) in dimethylformamide at room temperature] .

SCHEME 4

The preparation of compounds of formulae I-G and I-H are shown in Scheme 4. The known triazole aldehyde 12 [G. Jones et al., J. Chemical Society Perkin I (1981), 78] is oxidized by use of chromium trioxide/sulfuric acid or other conventional oxidizing agents to afford the triazole carboxylic acid 18. Coupling of 11 with the appropriate amine or alcohol using conditions sited above [preferably CDI in dimethylformamide at room temperature] affords the desired triazoles of formula l-G.

For preparation of compounds of formula I-H, the known lithiated compound 1 [B. Abarca et al, J. Chemical Society Perkin I (1985) , 1897] is quenched with carbon dioxide or alkylhaloformate to afford 20B and 20A. respectively. 20A is converted to the acid 20B by conventional acid-catalyzed hydrolysis. Coupling of 20B with the appropriate amine or alcohol 1 is affected by using the conditions sited above [preferably CDI in dimethylformamide at room temperature] to afford the desired I-H. Alternatively, the appropriate amine is converted to its carbamoyl halide 21 (Q = CI, Br) or isocyanate 22. The lithiated species _L9 is directly quenched with 21 or 22 to directly afford I-H (Y = NH) .

These examples, as well as all examples herein, are given by way of illustration only and are not to be construed as limiting the invention, either in spirit or scope, as many modifications, both in materials and methods, will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees Celsius ( ^Q C) and quantities of materials in grams and milliliters unless otherwise noted.

Scheme I: Preparation of Imidazopyridines (Ar group = A)

5A,X=OMe IA' 5B,X=OH 5C, x=α

Scheme 2: Preparation of Compounds of Formulae IB, IC, ID and IE

10 IB

II IC

12 ID

I) Carboxyl Activation 2) Amine or Alcohol 2

13 IE

SCHEME 3: Preparation of Compounds of Formula I-F.

lcohol 2

1_E

SCHEME 4: PREPARATION OF COMPOUNDS OF FORMULAE I-G AND I-H

17 18

2

I-G

20A:R = Alkyl

19 20B:R = H

Q-CO-Y-Z(2ϋor CDI. DMF, 0=C=N-Z(22) Amine or Alcohol __

Example A (Methyl 2-aminonicotinate)

Procedure

The 2-aminonicotinic acid (5.0 g, 0.0362 mol) and K ₂ C0 ₃ (5.0 g, 0.0362 mol) were suspended in 50 ml of DMF and heated to reflux. Almost complete solution occurred. The mixture was cooled to 25° C and the CH ₃ I (5.1 g/2.2 ml, 0.0362 mol) was added and the mixture was stirred 18 hours. The mixture was filtered and concentrated. The residue was placed on a bed of silica and eluted with 5%/ EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH. The fractions containing the product were combined and concentrated. The residue was suspended in Et ₂ 0, filtered and washed with Et ₂ 0 to yield 3.2 g (58%) the title compound.

ound

Example B (Methyl 2-amino-5-chloronicotinate)

Procedure

The compound of example A (800 mg, 0.00525 mol) was dissolved in MeOH (15 ml) and HC1 gas was passed over the solution until the solution was acidic (pH 2) . The solution was concentrated and the residue redissolved in MeOH (15 ml) . The t-butylhypochlorite (570 mg, 0.00525 mol) was added and the reaction mixture stirred until the yellow color dissipated. Additional t-butylhypochlorite was added until tic (5% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH) indicated that the starting material was consumed.

The reaction mixture was concentrated and the residue dissolved in CH ₂ C1 ₂ . The organics were washed with 5% NaHC0 ₃ then 5% sodium thiosulfate. The organic layer was dried over MgS0 and concentrated to afford a solid. The solid was suspended in 1:1 CH ₂ C1 ₂ /hexane, filtered, washed with hexane and suction dried to yield 250 mg (26%) of the title compound m.p. 139-40° C.

C

Example C (6-Chloroimidazo[l,2-a]pyridine-8-carboxylic acid, monohydrochloride)

Procedure

The compound of example B (1.2 g, 0.0063 mol) and chloroacetaldehyde [45% aqueous solution (930 mg, 0.007 mol)] was heated to reflux in EtOH until tic (5% EtOH/ CH ₂ C1 ₂ /1/10% NH ₄ OH) indicated that the reaction was complete. The solution was concentrated and the residue was suspended in acetone, filtered, washed with acetone, and air dried to yield 1.3 g (77%) of the methyl ester of the title compound m.p. 148-150° C (resolidify) 235-238° C (decomp) .

Elements Calc Found

Carbon 40.50 40.58 C ₉ H ₇ C1N ₂ 0 ₂ *1.05 HCl*1.0H ₂ 0

Hydrogen 3.80 3.82

Nitrogen 10.50 10.53 MW 266.92

Chlorine 27.23 27.43

The methyl ester was heated to reflux in 15 ml of con HCl until tic (5% EtOH/CH ₂ Cl ₂ /l/l0% NH ₄ OH) indicated that the starting material was consumed. Concentration gave a residue which was suspended in acetone, filtered and dried to afford 1.15 g (99%) of the title compound: softens 275° C; m.p. 279- 281° C (decomp) .

eme ts Ca c

Example D

(Imidazo[l,2-a]pyridine-8-carboxylic acid, monohydrochloride)

Procedure

Using 2-aminonicotinic acid (14.1 g, 0.102 mol) and chloroacetaldehyde [45% aqueous solution (8.6 g, 0.11 mol)], the same procedure as described above in example C was used. After workup 17.5 g (88%) of the title compound, m.p. 299- 300° C (decomp) , was isolated.

s C lc Fou

Example E (Imidazo[l,2-a]pyridine-2-carboxylic acid monohydrochloride)

Procedure

2-aminopyridine (25.0 g, 0.128 mol) and ethyl bromopyruvate (12.0 g, 0.128 mol) were heated to reflux in EtOH (225 ml) . The reaction mixture was concentrated and the residue partitioned between dilute K ₂ C0 ₃ and CH ₂ C1 . The organic layer was passed through a small bed of silica, eluting with .5% EtOH/CH ₂ Cl ₂ . The product eluted at the solvent front and this fraction was concentrated. The solid residue was suspended in Et ₂ 0 then filtered to yield 10.9 g (44%) of the ethyl ester of the title compound.

Elements Calc Found

H ₂ 0

The ethyl ester (5.0 g, 0.0256 moles) was refluxed in 50 ml of con HCl until tic (5% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH) indicated that the starting material was consumed. Concentration gave a residue which was suspended in acetone, filtered and dried to afford 5.2 g (95%) of the title compound.

Elements Calc Found

Carbon 44.36 44.23 C ₈ HgN ₂ 0 ₂ *HC1

Hydrogen 4.19 4.17

Nitrogen 12.93 12.77 MW 216.62

Chlorine 16.37 16.45

Example 1 (endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)-6- chloroimidazo[1,2-a]pyridine-8-carboxamide, dihydrochloride)

Procedure

The compound of example C (l.l g, 0.0047 mol) was suspended in CHC1 ₃ /DMF (25 ml/3 drops). S0C1 ₂ (560 mg/0.338 ml, 0.0047 mol) was added and the mixture was heated to reflux with additional S0C1 ₂ added until tic (5% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ 0H) indicated that the starting material was consumed. The mixture was concentrated in vacuo, azeotroping once with toluene.

To the residue, dissolved in DMF (15 ml) and cooled in an ice bath, was added Et ₃ N (1.19 g/1.64 ml, 0.0118 mol) followed by endo-4-amino-l-azabicyclo[3.3.1]nonane (649 mg, 0.0047 mol) dissolved in 5 ml of DMF. The mixture was warmed to room temperature and stirred for 4 hours. Tic (10% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH) on basic alumnia indicated that the acid chloride was consumed. Concentration afforded a residue which was chromatographed on basic alumnia eluting with 1% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ 0H. The fractions containing the product were combined and concentrated in vacuo.

The residue was converted to the hydrochloride salt by dissolving in iPrOH and passing HCl gas over the solution. The solid was filtered, washed with iPrOH and dried in a vacuum desicator to yield 445 mg (20%) of the title compound, softens 230° C; m.p. 264-266° C (decomp) .

Elements Calc Found

Carbon 43.72 43 .57 C ₁₆ H ₁₉ C1N ₄ 0 ^* 2 . 6 HCl*2.0H ₂ O ^* 0.45 iPrOH

Hydrogen 6.17 5.80 Nitrogen 11.58 11.40 MW476. 68 Chlorine 26.77 26.52

Example 2

(endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)imidazo[1,2- a]pyridine-8-carboxamide, dihydrochloride)

Procedure

Employing the compound of example D (1.4 g, 0.0071 mol), S0C1 ₂ (2.3 g/1.4ml, 0.02 mol), endo-4-amino-l- azabicyclo[3.3.1]nonane (1.0 g, 0.00713 mol), and Et ₃ N (2.5 g/3.84 ml, 0.0249 mo) dissolved in CHC1 ₃ /DMF (25 ml/3 drops), the same procedure as described in example 1 was used. After workup 121 mg (5%) of the title compound was isolated.

s Found

51.43 C ₁₅ H ₂₀ N ₄ O ^* 2 HCl ^* l/3H ₂ O ^* 0.25 iPrOH

6.38 15.12 MW 366.24 19.26

Example 3

(endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl) ^■

6-chloroimidazo[l,2-a]pyridine-8-carboxamide, dihydrochloride)

Procedure

The compound of example C (233 mg, 0.001 mol) and 1,1'- carbonyldiimidazole (241 mg, 0.0015 moles) were suspended in DMF (5 ml) and the mixture was stirred until solution occured (three hours) . Endo-N-8-methyl-8-azabicyclo[3.2.1]-octane-3- amine [produced in accordance with the procedure in J. Am. Chem. Soc. 79. 4194(1957)] was added and the mixture was stirred for 18 hours. Tic (30% EtOH/CH ₂ Cl ₂ /i/lθ% NH ₄ OH) indicated that the reaction was complete. Concentration afforded' a residue which was purified by radial chromatography [(2 mm plate) , gradient elution with 25% to 75% i-PrOH/CH ₂ Cl ₂ /l/10% NH ₄ OH] . Three components were collected. The desired was found in the third-eluted component. Concentration afforded a residue which was converted to the hydrochloride salt by dissolving in iPrOH and passing HCl gas over the solution. The solid was filtered, washed with iPrOH and dried in a vacuum desicator to yield 113 mg (25%) of the title compound.

47.77 C ₁₆ H ₁₉ C1N ₄ 0 *2 HCl *H ₂ 0 *0.75 iPrOH

6.36 11.98 MW 454.82 23.18

Example 4

(endo-N-(8-methyl-8-azabicyclo [ 3 .2. 1] octan-3- yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride)

Procedure

The compound of example D (200 mg, 0.00101 mol) and 1,1'-carbonyldiimidazole (164 mg, 0.00101 mol) were suspended in the DMF (2 ml) and the mixture was stirred until solution occured (2.5 hours). Endo-N-8-methyl-8-azabicyclo[3.2.1]- octane-3-amine was added and the mixture was stirred for 48 hours. The mixture was concentrated to one half the original volume and EtOAc (2 ml) was added. The solid was filtered to afford (126 mg, 39%) the title compound.

Elements Calc Found

Carbon 58.26 58.00 C ₁₆ H ₂₀ N ₄ O »*1-.1 HCl 0.3H ₂ 0

Hydrogen 6.63 6.65

Nitrogen 16.99 17.02 MW 329.67

Chlorine 11.82 11.90

S calcd for C ₁₆ H ₂₀ N ₄ O 284.1637; found 284.1640.

Example 5

(exo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3- yl)imidazo[l,2-a]pyridine-8-carboxamide, hydrochloride)

^EESSS!aaEe

The compound of example D (200 mg, 0.00101 mol) and 1,1'-carbonyldiimidazole (164 mg, 0.00101 mol) were suspended in DMF (2 ml) and the mixture was stirred until solution occured (2.5 hours). Exo-N-8-methyl-8- azabicyclo[3.2.1]octane-3-amine [prepared in accordance with the procedure in Berichte 31. 1202(1898)] was added to the mixture and the resulting suspension was stirred for 4 days. EtOAc was added to the mixture and the solid filtered to afford (282 mg, 76%) the title compound.

MS calcd for C ₁₆ H ₂₀ N ₄ O 284.1637; found 284.1643

Example 6

(endo-N- (9-Methyl-9-azabicyclo [3 .3 . l] nonan-3-yl) -6- chloroimidazo[1,2-a]pyridine-8-carboxamide hydrochloride)

Procedure

The compound of example C (233 mg, 0.001 mol) and 1,1'- carbonyldiimidazole (178 mg, 0.001 mol) were suspended in DMF (5 ml) , and the mixture was stirred for one hour before adding endo-N-9-methyl-9-azabicyclo[3.3.1]-nonane-3-amine (154 mg, 0.0011 moles). The mixture was stirred for 18 hours. Tic (30% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH) indicated that the reaction was complete. Concentration afforded a residue which was suspended in water and the pH adjusted to ll with K ₂ C0 ₃ . The solid was filtered and purified by radial chromatography [ (2 mm plate) , gradient elution 25% to 75% i-PrOH/CH ₂ Cl ₂ /l/10% NH ₄ OH]. Two components were collected. The desired product was found in the second-eluted component. Concentration afforded a residue which was converted to the hydrochloride salt by dissolving the residue in iPrOH then acetone and passing HCl gas over the solution. The solid was filtered, washed with i-PrOH then acetone and dried in a vacuum desicator to yield 168 mg (32%) of the title compound.

Elements Calc Found

Carbon 45.57 45.36 C ₁₇ H ₂₁ CIN ₄ 0 * 2.5 HCl * 2.5 H ₂ 0 * acet

Hydrogen 6.60 6.68

Nitrogen 10.63 10.61 MW 527.106

Chlorine 23.54 23.67

Example 6A

(endo-N-(9-Methyl-9-azabicyclo[3.3.l]nonan-3-yl)- imdazo[1,2a]pyridine-8-carboxamide)

Procedure

The compound of Example D (198 mg, 0.001 moles) and l _f l'-carbonyldi-imidazole (178 mg, 0.001 moles) were suspended in the DMF (5 ml) and the mixture was stirred until solution occured (three hours) . Endo-N-8-methyl-8- azabicyclo[3.2.1]-octane-4-amine and triethylamine (560 μl; 0.004 mole) were added and the mixture was stirred for 18 hours. Tic 30% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH indicated that the reaction was complete. Concentration afforded a residue which was purified by radial chromatography (2 mm plate) , gradient elution with 200 ml portions of 10% i- PrOH/CH ₂ Cl ₂ /l/10% NH ₄ OH, 15, 20% i-PrOH (isό-propylalcohol) . Three components were collected. The desired was found in the third component. Concentration afforded a residue which was converted to the hydrochloride salt by dissolving the residue in i-PrOH and passing HCl gas over the solution. The

solid was filtered, washed with i-PrOH and dried in a vacuum desicator to yield 133 mg (44.6%) of the title compound.

Elements Ca_Lc Found

Carbon 53.45 53.75 C ₁₇ H ₂₂ N ₄ 0 * 2.05 HCl *0.2 iPrOH

Hydrogen 6.93 6.59

Nitrogen 15.01 14.79 MW 373.14

Chlorine 19.48 19.63

Example 7

(N-(1-Azabicyclo[2.2.2]octan-3-yl)-6-chloroimidazo[1,2- a]pyridine-8-carboxamide dihydrochloride)

procedure

Using the compound of example C (233 mg, 0.001 moles), 1,1'-carbonyldiimidazole (241 mg, 0.0015 moles), and 3- aminoquinuclidine dihydrochloride (280 mg, 0.002 moles) in DMF (5 ml) the coupling was performed as discribed in example 3.

The residue was partitioned between dilute K ₂ C0 ₃ and CH ₂ C1 ₂ . The organic layer was separated, dried over MgS0 ₄ and concentrated to afford to an oil. The oil was purifed by silica gel chromatography [gradient elution with 20% to 100% iPrOH/CH ₂ Cl ₂ /l/10% NH ₄ OH] . The fractions containing the desired product were combined and concentrated to an oil which crystallized. The solid residue was converted to the hydrochloride salt by dissolving the residue in iPrOH and passing HCl gas over the solution. The solid was filtered, washed with iPrOH and dried in a vacuum desicator to yield 221 mg (56 %) of the title compound.

Elements Calc Found

Carbon 45.55 45.95 C ₁₅ H ₁₇ C1N ₄ 0 2 HCl H ₂ 0 Hydrogen 5.35 5.13 Nitrogen 14.16 14.45 MW 395.72 Chlorine 26.88 27.11

Example 8

(N-(l-Azabicyclo[2.2.2]octan-3-y1)i idazo[1,2-a]pyridine-

8-carboxamide, dihydrochloride)

Procedure

Employing the compound of example D (1.98 g, 0.01 mol), S0C1 ₂ (2.3 g/1.4ml, 0.02 mol) , 3-aminoquinuclidine dihydrochloride (200 mg, 0.01 mol), and Et ₃ N (4.0 g/5.6 ml, 0.04 mol) dissolved in CHC1 ₃ /DMF (25 ml/3 drops) the same procedure as described in example 1 was used. After workup 2.2 mg (59%) of the title compound was isolated, m.p. 222° C (softens) ; 241-245° C (decomposes) .

Elements Calc Found

Carbon 50.88 50.73 C ₁₅ H ₂₁₈ N ₄ 0 2 HCl 0.25H ₂ 0 0.75 iPrOH

Hydrogen 6.37 6. 06 Nitrogen 15. 07 15.40 MW 371.79 Chlorine 19.07 18.83

Example 9

((±)-endo-N-(Hexahydro-lH-2,53-methano-3aα,6aα- cyclopenta[c]pyrrol-4α-yl)-6-chloroimidazo[l,2-a]pyridine-

8-carboxamide, monohydrochloride)

Procedure

The compound of example C (115 mg, 0.0005 mol) and 1,1'' carbonyldiimidazole (86 mg, 0.000525 mol) were suspended in DMF (2.5 ml ), and the mixture was stirred for one hour before adding (+)-endo-N-hexahydro-lH-2,5/5"-methano-3ac.,6aα- cyclopenta[c]pyrrol-4c--amine [U.S. Patent Appl. serial no. 07/515,391] (69 mg, 0.0005 mol). A solid precipitated from solution. The mixture was stirred for an additional hour. The solid was filtered, washed with acetone, and dried to yield 97 mg (52%) of the title compound.

l lc Found

Example 10 ( (±) -endo-N- (Hexahydro-lH-2 , 5j8-methano-3aα , 6aα- cyclopenta[c]pyrrol-4α-yl) imidazo[l, 2-a]pyridine-8- carboxamide, hydrochloride)

^PrθCedUrβ

The compound of example D (53 mg, 0.00027 mol) and 1,1'' carbonyldiimidazole (43 mg, 0.00027 mol) were suspended in DMF (2 ml), and the suspension was stirred for 4.5 h. (±)- Endo-N-hexahydro-lH-2,5/3-methano-3aα,6aα-cyclopenta[c]pyr rol- 4α-amine was added and the mixture was stirred for 16 h. The mixture was diluted with EtOAc and the solid filtered to afford (46 mg, 58%) the title compound.

Elements Calc Found

Carbon 58.28 58.17 C ₁₆ H ₁₈ N ₄ 0 ^* 1.3HC1

Hydrogen 5.90 5.97

Nitrogen 16.99 17.04 MW 329.54

MS calcd for C ₁₆ H ₂₁₈ N ₄ 0282.1480; found 282.1472.

Example ll

(exo-N-(1-azatricyclo[3.3.1.1 ³ ' ⁷ ]decan-4-yl)-6- chloroimidazo[1,2-a]pyridine-8-carboxamide, monohydrochloride)

Procedure HCl

The compound of example c (150 mg, 0.00064 mol) and 1,1'-carbonyldiimidazole (104 mg, 0.00064 mol) were suspended in DMF (1 ml) , and the suspension was stirred for 2 h. A solution of exo-N-(l-azatricyclo[3.3.l.l ^3,7 ]decane-4-amine in DMF (1 ml) was added and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (4 ml) . The solid was filtered to afford 226 mg of a solid which was recrystallized from MeOH to yield (139 mg, 59%) the title compound.

c Fo

Example 11A (lα,3β,5c-,7β-l-azatricyclo[3.3.1.1 ³ ' ⁷ ]decan-4β-7yl) 6-chloroimidazo[1,2-a] yridine-8-carboxamide dihydrochloride

Procedure

The compound of Example C (153 mg, 0.00065 moles) and l,l'-carbonyldi-imidazole (106 mg, 0.00065 moles) were suspended in the DMF (2.5 ml) and the mixture was stirred until solution occured (three hours) . At this time, lα,3β,5α,7β-l-azatricyclo[3.3.1.l ³ ' ⁷ ]decan-4β-amine and triethylamine (280 μl; 0.002 mole) were added and the mixture was stirred for 18 hours. Tic 30% EtOH/CH ₂ C1 ₂ /1/10% NH ₄ OH indicated that the reaction was complete. Concentration afforded a residue which was partitioned between dilute K ₂ C0 ₃ and CHC1 ₃ . The organic layer was dried over MgS0 ₄ and concentrated. The residue was recrystalized from i-PrOH/HCl. The solid was filtered, washed with i-PrOH and dried in a vacuum desicator to yield 113 mg (39%) of the title compound.

Elements Calc Found

Carbon 49.68 49.97 C ₁₇ H ₁₉ C1N ₄ 0*2HC1 *0.75 H ₂ 0 *0.5 i-PrOH Hydrogen 5.97 5.84 Nitrogen 12.53 12.39 MW 447.30 Chlorine 23.78 23.78

Example 12

(N-[2-(Diethylamino)ethyl]imidazo[l,2-a]pyridine-8- carboxamide)

Procedure

Employing the compound of example D (1.98 g, 0.01 mol), S0C1 ₂ (2.3 g/1.4ml, 0.02 mol), N,N-diethylenediamine (1.27 g, 0.011 mol), and Et ₃ N (2.0 g/2.8 ml, 0.02 mol) dissolved in CHC1 ₃ /DMF (25 ml/3 drops) , the same procedure as described in example 1 was used. After workup 610 mg (23%) of the title compound was isolated as an oil.

l ments Calc Found

,25H ₂ 0

Example 13

(Cis-N-[[3-(4-Fluorophenoxy)propyl]-3-methoxy-4- piperidinylamine]imidazo[1,2-a] yridine-8-carboxamide)

Procedure

Employing the compound of example D (1.98 g, 0.01 mol),

S0C1 ₂ (2.3 g/1.4ml, 0.02 mol), cis-l-[3-(4- fluorophenoxy)propyl]-3-methoxy-4-pipendinylamne (3.1 g ,

0.011 mol), and Et ₃ N (3.5 g/3.84 ml, 0.035 mol) dissolved in

CHC1 ₃ /DMF (25 ml/3 drops) , the same procedure as described in example 1 was used. After workup 2.29 mg (42%) of the title compound was isolated.

Elements Calc Found

Carbon 50. 64 50.74 C ₂₃ H ₂₉ FN ₄ 0 ₃ ^* 2 . 4 HCl *1.75H ₂ 0

Hydrogen 6.08 5.69

Nitrogen 10.27 10.44 MW 545.53

Chlorine 15.60 15.44

Example 14

(N-[l-(Phenylmethyl)-4-piperidinyl]imidazo[l,2-a]pyridine -

8-carboxamide, dihydrochloride)

Procedure

Employing the compound of example D (1.98 g, 0.01 moles), S0C1 ₂ (2.3 g/1.4 ml, 0.02 mol), 4-amino-l- benzylpiperidine (2.0 g, 0.011 mol), and Et ₃ N (3.5 g/4.89 ml, 0.035 mol) dissolved in CHC1 ₃ /DMF (25 ml/3 drops), the same procedure as described in example 1 was used. After workup 3.1 g (72%) of the title compound was isolated, m.p. 290-291* C (decomposes) .

Elements Calc Found

Carbon 56.01 56.32 C ₂₀ H ₂₂ N ₄ 0 ₃ 2 HCl .5H ₂ 0

Hydrogen 5.99 5.94

Nitrogen 13.06 12.67 MW 383.92

Chlorine 16.53 16.54

Example 14A

N-exo((4-s,7α-s)-tetrahydro-lH-pyrrolizin- (5H)-yl)-6- chloroimidazo[l,2-a]pyridine-8-carboxamide dihydrochloride

Procedure

The acid of the compound of Example B (118 mg, 0.00051 moles) and l,l'-carbonyldi-imidazole (70 mg, 0.00051 moles) were suspended in the DMF (1 ml) and the mixture was stirred until solution occured (three hours) . At this time, exo(4-s,7α-s)-tetrahydro-lH-pyrrolizin-4-amine (70 mg; 0.000499 moles) and triethylamine (280 μl; 0.002 mole) were added and the mixture was stirred for 18 hours. Tic 30% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ 0H indicated that the reaction was complete. Concentration afforded a residue which was purified by prep tic chromatography, elution w'ith 30% MeOH/CH ₂ Cl ₂ /l/10% NH ₄ 0H to yield 182 mg (90%) of the pyridine derivative.

This compound (120mg; 0.00045 moles) was combined with chloroacetaldehyde (45% in H ₂ 0) (142mg; 0.0009 moles) in EtOH (10 ml) and refluxed until tic 30% EtOH/CH ₂ C1 ₂ /1/10% NH ₄ OH indicated that the reaction was complete. Concentration

afforded a residue which was purified by prep tic chromatography, elution with 30% MeOH/CH ₂ Cl ₂ /l/lO% NH ₄ OH to yield 105 mg (73%) of the product. The residue was converted to the HCl salt with MeOH/HCl.

Elements Calc Found

Carbon 42.24 42.43 C ₁₅ H ₁₈ C1N ₄ 0*2.35 HC1*2.75 H ₂ 0 0.25

MeOH Hydrogen 6.08 6.01 Nitrogen 12.13 12.13 MW 462.04 Chlorine 25.70 25.72

Example 14 B

N-exo(tetrahydro-lH-pyrrolizin-4(5H)-yl)-6- chloroimidazofl,2-a]pyridine-8-carboxamide dihydrochloride

Procedure

The compound of Example D (198 mg, 0.001 moles) and 1,1•-carbonyldi-imidazole (178 mg, 0.0011 moles) were suspended in the DMF (5 ml) and the mixture was stirred until solution occured (three hours) . At this time, exo- tetrahydro-lH-pyrrolizin-4(5H)-amine and triethylamine (560 μl; 0.004 mole) were added and the mixture was stirred for 18 hours. Tic 30% EtOH /CH ₂ C1 ₂ /1/10% NH ₄ OH indicated that the reaction was complete. Concentration afforded a residue which was partitioned between dilute K ₂ C0 ₃ and CHC1 ₃ . The organic layer was dried over MgS0 ₄ and concentrated. The residue was recrystalized from i-PrOH/HCl. The solid was filtered, washed with i-PrOH and dried in a vacuum desicator to yield 244 mg (60%) of the title compound.

Elements Calc Found

Carbon 47.24 47.58 C ₁₅ H ₁₇ C1N ₄ 0 * 2 HCl *0.50 H ₂ 0 *0.33 i-PrOH Hydrogen 5.61 5.47 Nitrogen 13.78 13.60 MW 406.54 Chlorine 26.16 26.03

Example 14 C

N-exo(tetrahydro-lH-pyrrolizin-4(5H)-yl)i idazo[1,2-a] pyridine-8-carboxamide dihydrochloride

Procedure

The compound of Example D (233 mg, 0.001 moles) and l,l'-carbonyldi-imidazole (178 mg, 0.0011 moles) were suspended in the DMF (5 ml) and the mixture was stirred until solution occured (three hours) . Exo-tetrahydro-lH- pyrrolizin-4(5H)-amine and triethylamine (560 μl; 0.004 mole) were added and the mixture was stirred for 18 hours. Tic 30% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ OH indicated that the reaction was complete. Concentration afforded a residue which was purified by radial chromatography (2 mm plate) , gradient elution with 200 ml portions of 10% i-PrOH/CH2Cl ₂ /l/10% NH ₄ 0H, 15, 20% i-PrOH. The residue was crystalized from i- PrOH/HCl. The solid was filtered, washed with i-PrOH and dried in a vacuum desicator to yield 176 mg (48%) of the title compound.

Example 15 ( (±)-endo-N-(Hexahydro-lH-2,5β-methano-3aα, 6aα- cyclopenta[c]pyrrol-4aα-yl)-3-ethylindolizine-l- carboxamide monohydrochloride)

procedure

3-Ethylindolizine-l-carboxylic acid (76.7 mg, 0.000405 mol) [prepration described by Bermudez et al. in Journal of Medicinal Chemistry (1990)33: 1928] and 1,1'- carbonyldiimidazole (65.7 mg, 0.000405 mol) were suspended in DMF (5 ml) and the mixture was stirred for 4 h. (±)-Endo-N- (Hexahydro-lH-2,50-methano-3ac_, 6aα-cyclopenta[c]pyrrol-4α- amine (56 mg, 0.000405 mol) in DMF (1 ml) was added and the mixture stirred an additional 22h. An additional premixed portion of 3-ethylindolizine-l-carboxylic acid (38 mg, 0.20 mmol) and 1,1'-carbonyldiimidazole (33 mg, 0.20 mmol) in DMF (1 ml) was added. This mixture was stirred for an additional 16 h. The reaction mixture was concentrated in vacuo to give a residue which was treated with 20% K ₂ C0 ₃ (1 ml) and extracted with CHC1 ₃ (3X) . The combined extracts were washed with water and brine and dried over Na ₂ S0 ₄ . Concentration in vacuo gave 74 mg of an oil which was chromatographed on silica gel eluting with 3/97 MeOH(NH ₃ ) /CHC1 ₃ to give the desired amide (21.4 mg, 17%) as the free base. The free base

was converted to the hydrochloride salt by dissolving in HCl/MeOH [prepared from acetyl chloride (4.9 μl, 0.069 mmol) and MeOH (1 ml) ] . Concentration in vacuo gave the desired hydrochloride salt (24.2 mg) as a solid.

Elements Calc Found

Carbon 60. 61 60.55 C ₁₉ H ₂₃ N ₃ 0 1. 1 HCl 1. 5H ₂ 0

Hydrogen 7.25 6. 80

Nitrogen 11.16 11.06 MW 376.31

S calcd for C ₁₉ H ₂₃ N ₃ 0: 309.1841; found 309.1845.

Example 15A

(lα , 3 β , 5α, 7 β-l-azatr icyclo [3.3.1. l ³ ' ⁷ ]decan-4β-yl ) -

3-ethylindolizine-l-carboxamide monohydrochloride

Procedure

3-ethylindolizine-l-carboxylic acid (190 mg, 1.0 mmole) was dissolved in CHC1 ₃ (dry), oxalyl chloride (184 μl, 2.1 mmole) was added and the mixture stirred for 2 hours. Concentration in vacuo gave a solid, which was redissolved in CHC1 ₃ (5 ml)/DMF (.3 is). A solution of endo-N-(l- azatriσyclo[3.3.1.1.] decane-4 amine (140 mg, .92 mmole), trie-thyl amine [280 μl, 2.0 mmole) in CHC1 ₃ (2 ml) was added. The mixture was stirred for 18 hours. The organic layer was washed with IN NaOH, brine and dried over K ₂ C0 ₃ . Filtration and concentration in vacuo afforded .420 mg of a solid which was chromatographed on silica gel eluting with 8% CH ₃ OH (NH ₃ t)/CHCl ₃ to give the title compound (197 mg, 66%) as the free base.

Calculated MS for C ₂₀ H ₂₅ N ₃ O : 323.20 Found: 323.199

DSC = 188.12 - 191.72°C § 82.5 5/g. And: Calculated for C ₂₀ H ₂₅ N ₃ O .2H ₂ 0 : C, 73.45; H, 7.83;

N, 12.85 Found: C, 73.32; H, 7.80; N, 12.70 The HCl salt was made by adding acetyl chloride (87μl, 1.22 mmole) to CH ₃ 0H (1 ml) stirring for 25 minutes, and addition of the free base (197 mg, .609 mole). The solution was stirred 1 hour. Concentration in vacuo to about .4 ml and addition of Et ₂ O(200 ml) gave a solid was filtered and dried under vacuum to yield 182 mg (83%) of the title compound.

Calculated for C ₂₀ H ₂₅ N ₃ O ^« HCL.4H ₂ 0 : Found

C, 65.44 65.66

H, 7.36 7.20

N, 11.45 11.21

CI, 9.66 9.91

Calculated HRMS for C ₂₀ H ₂₅ N ₃ 0 « 323.42 Found = 323.1986

Example 15B

(lα,3β,5α,7β-l-azatricyσlo[3.3.1.l ³ ' ⁷ ]decan-4α-yl)-

3-ethylindolizine-l-carboxamide monohydrochloride

Procedure

To 3-ethylindolizine-l-carboxylic acid (190 mg, 1.0 mmole) in dry CHC1 ₃ was added oxalyl chloride (184 μl, 2.1 mmole) and the resulting solution was stirred for 2 hours. Concentrated in vacuo gave a solid which was dissolved in CHC1 ₃ (5 is)/DMF (.3 is) and to the resulting solution was then added a solution of exo-N-(1-azatricyclo[3.3.1.1.] decane-4- amine (140 mgs, .92 mmole) and triethyl amine [280 μl, 2.0 mmole) in CHC1 ₃ (2 mis) . The solution was then stirred for 18 hours. The CHC1 ₃ layer was then washed with IN NaOH, brine and dried over K ₂ C0 ₃ , filtered, and concentrated in vacuo to give a solid. The solid was chromatographed on silica gel eluting with 8% CH ₃ OH (NH ₃ t)/CHCl ₃ to give 280 mg (70.5%) as the free base. The hydrochloride salt was made by the same procedure as in Example 15A to give 192 mg (85%) solid.

Calculated for C ₂₀ H ₂₅ N ₃ O . HCl . .35H ₂ 0 Found

C, 65.50 65.96

H, 7.35 7.57

N, 11.47 11.08

CI, 9.68 9.70

Calculated MS for C ₂₀ H ₂₅ N ₃ 0 = 323.420

Found 323.196

Example 16

( (+) -endo-N- (Hexahydro-IH, 2 , 5 _/ 9-methano-3aα, 6aα- cyclopenta[c]pyrrol-4α-yl)-3-ethylimidazo[1,5-a]pyridine-

1-carboxamide, monohydrochloride)

Procedure

3-Ethylimidazo[l,5-a]pyridine-l-carboxylic acid (72.9 mg, 0.00038 mol) [prepration described by Bermudez et al. in Journal of Medicinal Chemistry, (1990)33, 1928] and 1,1'- carbonyldi-imidazole (62 mg, 0.00038 mol) were suspended in DMF (0.5 ml) and the mixture was stirred for 4 h. (±)-Endo-N- (Hexahydro-lH-2,5^-methano-3aα,6aα-cyclopenta[c]pyrrol-4α - amine (53 mg, 0.00038 mol) in DMF (1 ml) was added and the mixture stirred an additional 40h. The reaction mixture was concentrated in vacuo to give a residue which was treated with 20% K ₂ C0 ₃ (1 ml) and extracted with CHC1 ₃ (3X) . The combined extracts were washed with water and brine and dried over Na ₂ S0 . Concentration in vacuo gave 127 mg of a solid which was chromatographed on silica gel eluting with 2/98 MeOH (NH ₃ )/CHC1 ₃ to give the desired amide (43 mg, 36%) as the free base. The free base was converted to the hydrochloride salt by dissolving in NCI/MeOH [prepared from acetyl chloride (8.8 μl, 0.00014 mol) and MeOH (1 ml)]. Addition of this methanolic solution to diethyl ether (75 ml)

and filtration gave the title compound as the hydrochloride salt (39 mg) .

S calcd for C ₁₈ H ₂₂ N ₄ 0: 310.1793; found 310.1791.

Example 16A

N-exo(tetrahydro-lH-pyrrolizin-4(5H)-ylmethyl)-3-ethyl- imidazo[l,2-a]pyridine-l-carboxamide monohydrochloride

Procedure

3-ethylimidazo[l,5-a]pyridine-l-carboxylic acid (190 mg, 1.0 mmole) was suspended in CHC1 ₃ (2 ml) . Oxalyl chloride (184 μl, 2.1 mmole) and DMF (1 drop) were added and mixture stirred for 2 hours. Reaction mixture was concentrated in vacuo, azeotroping once with toluene.

The residue dissolved in CHC1 ₃ was added a solution of exo-tetrahydro-lH-pyrrolizin-4(5H)-methylamine (140 mg, 1.0 mmole), triethyl amine (279 μl, 2.0 mmole) in CHC1 ₃ (2 ml) and the mixture stirred for 18 hours. Organic solution was washed with IN NaOH, brine, dried over K ₂ C0 ₃ , filtered and concentrated to give a crude oil. Oil was chromatographed on silica gel eluting with 5% CH ₃ OH(NH ₃ t) CHC1 ₃ to give 110 mg

(35%) of desired compound as the free base. HCl salt was made by same method as in Example 15A.

Calculated for C ₁₈ H ₂₄ N ₄ O.HC1.3/4 H ₂ 0

C, 57.91 58.15 Calculated MS H, 7.24 6.95 for C ₁₈ H ₂₄ N ₄ 0 N, 15.01 14.95 312.42

CI, 12.35 12.25 Found 312.195

Example 17

(R-N-(l-Azabicyclo[2.2.2]octan-3-y1)imidazo[1,2- a]pyridine-2-carboxamide dihydrochloride)

Procedure

The compound of example E (216 mg, 0.001 mol) and 1,1'- carbonyldiimidazole (178 mg, 0.001 mol) were suspended in DMF (5 ml) , and the mixture was stirred for l h before adding R- 3-aminoquinuclidine dihydrochloride (200 mg, 0.001 mol), synthesized using the procedure in European Patent #0280 603. The mixture was stirred for 18 hours. Tic (30% EtOH/CH ₂ Cl ₂ /l/10% NH ₄ 0H) indicated that the reaction was complete. Concentration afforded a residue which was suspended in water and the pH adjusted to 11 with K ₂ C0 ₃ . The solid which formed was filtered and purified by radial chromatography [(2 mm plate) , gradient elution 25% to 75% i- PrOH/CH ₂ Cl ₂ /l/10% NH ₄ OH] to afford a residue which was converted to the hydrochloride salt by dissolving the residue in i-PrOH and passing HCl gas over the solution. The solid was filtered, washed with i-PrOH and dried in a vacuum desicator to yield 169 mg (47%) of the title compound.

Elements Calc Found

Carbon 51.61 51.83 C ₁₅ H ₁₈ N ₄ 0 ^* 2.15 HCl *0.1 H ₂ O*0.15iPr0H

Hydrogen 6.04 6.06 Nitrogen 15.58 15.44 MW 359.54 Chlorine 21.20 21.11

Example 18

(S-N-(1-Azabicyclo[2.2.2]octan-3-y1)imidazo[1,2- a]pyridine-2-carboxamide dihydrochloride)

Procedure ^■ ,NH*S

Employing the compound of example E (216 mg, 0.001 mol), 1,1'-carbonyldiimidazole (178 mg, 0.001 mol) DMF (5 ml), S-3- aminoquinuclidine dihydrochloride (200 g, 0.001 mol) [synthesized using the procedure in European Patent #0 280 603], the same procedure described in example 17 was used to afford the title compound (182 mg, 50%) .

Elements Calc Found

Carbon 51.18 51.53 C ₁₅ H ₁₈ N ₄ 0 *2.1 HCl 0.4 H ₂ 0 0.2 i-PrOH

Hydrogen 6.19 6.02 Nitrogen 15.30 15.19 MW 366.13 Chlorine 20.33 20.09

Example 19

Endo-N-(8-Methyl-8-azabicyclo[3.2.1]octane-3-yl) triazolylpyridine-3-carboxamide)monohydrochloride

Triazolylpyridine-3-carboxylic acid (110 mg, .606 mmole) [prepared in accordance with the procedure in Chem. Ber., 1968, 99, 2918], was suspended in CH ₂ C1 ₂ (5 ml). Thionyl chloride (442 μl, 6.60 mmole) and DMF (1 drop) were added and the mixture heated to reflux for 2.5 hr. Solvent was removed via rotary evaporator to give a solid. The solid was dissolved in CH ₂ C1 ₂ (5 ml) , and a solution of endo-N-8- methyl-8-azabicyclo[3.2.1] octane-3-amine (85.0 mg, .606 mmole), triethyl amine (338 μl, 2.43 mmole) in CH ₂ C1 ₂ (1 ml) was added and the mixture stirred for 50 hours. Filtration afforded an organic solution which was chromatographed on silica gel eluting with 10% CH ₃ 0H/1% NH ₄ 0H/CH ₂ C1 ₂ to give 145 mg (80%) of the title compound as the free base. The free base was converted to the hydrochloride salt by the method

described in Example 15A to yield 51 mg (33%) as the HCl salt.

Anal: Calculated for C ₁₅ H ₁₉ N ₃ 0-HCl. .2H ₂ 0

C, 55.37

H, 6.01

N, 21.52

CI, 10.90

mp - 237-245 ^β C Found 55.08 6.26 21.97 11.08

Example 20

Endo-N-(9-Methyl-9-azabicyclo[3.3.l]nonan-3-yl) triazolylpyr-3-carboxamide)monohydrochloride

CH ₃

N

Triazolylpyridine-3-carboxlic acid (120.0 mg, .661 mmole) was suspended in CH ₂ C1 (.5 ml). Thionyl chloride (481 μl, 6.61 mmole) and DMF (1 drop) were added and the mixture stirred for 2 1/2 hours. Concentration afforded a solid. The solid was dissolved in CH ₂ C1 ₂ , and a suspension of endo-N-9-methyl- 9-azabicyclo[3.3.1]-nonane-3-amine (150 mg .661 mmole) and triethyl amine (369μl, 2.64 mmole) in CH ₂ C1 ₂ (2 ml) was added. The mixture was stirred 18 hours. The contents were washed with 5% K C0 ₃ , water, and dried over MgS0 ₄ . Filtration and concentration gave a foam. The residue was chromatographed on silica 60 eluting with 5% CH ₃ 0H(NH ₃ t)/CHCl ₃ to give 97 mg (49%) of a white foam as the free base. The free base was converted to the HCl salt by the method described in Example 15A to give 44 mg of the title compound (71%) as a solid.

Anal: Calculated C ₁₆ H ₂₁ N ₅ 0 .9HC1 1.3H ₂ 0 C, 54.04; H, 6.94;

N, 19.69; CI, 8.97; Found: C, 54.50; H, 6.36; N, 19.05; CI, 9.31 m.p. ^***■ 225-233 ^β C

The compounds herein exhibit 5-HT3 antagonism. 5-HT3 antagonism can be determined by the radioligand receptor binding assay as described herein and in the in vivo Bezold- Jarisch reflex procedure.

Serotonin (5-HT ₃ )

Procedure:

GR65630 binds to the 5-HT ₃ receptor. Brain cortices are obtained from male rats and a membrane fraction prepared by standard techniques. 0.04 mg of membrane prep is incubated with 0.2 nM [ ³ H]-GR656630 for 60 minutes at 22°C. Non¬ specific binding is estimated in the presence of 1 uM ICS 205-930. Membranes are filtered and washed 3 times and the filters are counted to determine [3H]-GR65630 specifically bound.*

Results:

Kd = 2.46 nM

Bmax ^■ = 154 fmol/mg protein

% Specific Binding: 70

*Literature Reference:

Kilpatrick GJ, Jones BJ and Tyers MB. Identification and distribution of 5-HT ₃ receptors in rat brain using radioligand binding. Nature, 330 : 746-748, 1987.

Bezold-Jarisch Reflex

The test sample is administered i.p. (mg/kg) to a group of 3 mice. Thirty minutes later, a 5-HT (0.25 mg/kg i.v.)-induced bradycardia is recorded in pentobarbital anesthetized animals. A greater than 50 percent (>50) reduction in the bradycardic response relative to vehicle-treated control mice is considered significant.

This method has been described by Saxena, P. R. and Lawang, A., Arch. Int. Phar acodyn. , 277:235-252. 1985.

TEST PROCEDURE

Example No. 5-HT3 BINDING: BEZOLD JARISCH N6108-15 Cells REFLEX (Mice); IC50 % Inhibition @ Dose (IP)

6.3 nM 87% @ 10 274 nM 73% @ 3 Ki = 137 nM 68% @ 1 N @ 0.3

53% @ 10 1% @ 5

19.34 nM 99 nM

Ki = 50 nM

500 nM 82% @ 10 831 nM 2% @ 3 Ki - 416 nM

475 nM 80% @ 10 628 nM N @ 3 Ki = 314 nM

2.36 nM

9.8 nM

Ki = 4.9 nM

17.5 nM

23 nM

Ki = 12 nM

70 nM 100% @ 10 95% @ 5 88% @ 2.5 82% @ 0.5 N @ 0.25

16 nM 127 nM

Ki = 64 nM

10 200 nM 81% @ 10 243 nM N @ 3 Ki = 122 nM

11 > 100 nM 12 17 nM N 6 10 13 23% @ 100 nM 23% @ 10 14 N @ 10

TEST PROCEDURE

Example No. 5-HT3 BINDING: BEZOLD JARISCH NG108-15 Cells REFLEX (Mice); IC50 % Inhibition @ Dose (IP)

15 26.33 nM 16 30 nM

Also embraced within this invention is a class of pharmaceutical compositions comprising one or more of the described compounds in association with one or more non- toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of

the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os. the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and

modes of administration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.