The imidazopyridines compounds of the present invention are serotonergic 5-HT.sub.3 antagonists. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT.sub.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.

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.sub.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 Ser. No. 07/515,391 filed Apr. 27, 1990, and 
N-Azabicyclo [3.3.0] octane amides of aromatic acids are disclosed in 
co-pending application Ser. No. 07/406,205 filed Sep. 11, 1989. 
Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and are 
mentioned generically n U.K. Patent 2,152,049A and European application 
0189002A2. 
Azabicyclic nonanes are disclosed in European Patent application 0094742A2. 
Additional azabicyclic compounds are disclosed in U.S. Pat. Nos. 4,797,387 
and 4,797,406. 
Benzamides have been known as 5-HT.sub.3 antagonists and as compounds 
possessing gastrointestinal motility-enhancing properties. Benzamides of 
the following formula: 
##STR1## 
compounds wherein X can be an azabicycloalkane moiety and which exhibit 
gastrointestinal motility enhancing and/or 5-HT.sub.3 antagonist 
properties are disclosed in EP 0094742A2 and in U.S. Pat. No. 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.sub.3 
antagonist properties: 
##STR2## 
Compounds wherein X contains an aminergic side chain or an 
azabicycloalkane moiety are described in U.S. Pat. No. 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.sub.3 receptor antagonist activity. 
SUMMARY OF THE INVENTION 
The compounds of the present invention are serotonergic 5-HT.sub.3 
antagonists. As such they are useful for the treatment of humans and 
animals wherein antagonism of 5-HT.sub.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 
##STR3## 
the stereoisomers and pharmaceutically acceptable salts thereof, wherein 
Ar represents a radical of the formula 
##STR4## 
Wherein in group A R.sub.1 is H, or C.sub.1-6 alkyl, and R.sub.2 is H, or 
halogen; 
In group B, K is N or CR.sub.4, L is N or CR.sub.5, R.sub.2 & R.sub.3 are 
independently H or halogen, R.sub.4 is H, or C.sub.1-6 alkoxy and R.sub.5 
is H, halogen, CF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 
alkythio, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-7 
acyl, cyano, C.sub.1-6 alkoxycarbonyl, C.sub.1-7 acylamino, hydroxy, 
nitro, amino, aminocarbonyl, or aminosulfonyl optionally N-substituted by 
one or two groups selected from C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and 
C.sub.3-8 cycloalkylC.sub.1-4 alkyl or disubstituted by C.sub.4 or C.sub.5 
polymethylene; phenyl or phenyl C.sub.1-4 alkyl group optionally 
substituted in the phenyl ring by one or two of halogen, C.sub.1-6 alkoxy 
or C.sub.1-6 alkyl groups; 
In group C, M is N or CR.sub.4, R.sub.2 & R.sub.3 are independently H or 
halogen, R.sub.4 is H or C.sub.1-6 alkoxy and R.sub.5 is H, halogen, 
CF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, 
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-7 acyl, cyano, 
C.sub.1-6 alkoxycarbonyl, C.sub.1-7 acylamino, hydroxy, nitro, amino, 
aminocarbonyl, or aminosulfonyl optionally N-substituted by one or two 
groups selected from C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 
cycloalkylC.sub.1-4 alkyl or disubstituted by C.sub.4 or C.sub.5 
polymethylene, phenyl or phenyl C.sub.1-4 alkyl group optionally 
substituted in the phenyl ring by one or two of halogen, C.sub.1-6 alkoxy 
or C.sub.1-6 alkyl groups; 
In group D one of R.sub.6 and R.sub.7 is C.sub.1-6 alkyl and the other is 
C.sub.1-6 alkyl, phenyl or phenyl C.sub.1-4 alkyl optionally substituted 
in either phenyl ring by one or two of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 
or halogen, or R.sub.6 & R.sub.7 together are C.sub.2-6 polymethylene or 
C.sub.2-5 polymethylene interrupted by an --O-- linkage, and R.sub.2 & 
R.sub.3 are independently H or halogen; 
In group E, R.sub.4 is H or C.sub.1-6 alkoxy, R.sub.5 is H or C.sub.1-6 
alkoxy, and R.sub.2 is H, halogen, CF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 
alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6 
alkylsulfinyl, C.sub.1-7 acyl, cyano, C.sub.1-6 alkoxycarbonyl, C.sub.1-7 
acylamino, hydroxy, nitro, amino, aminocarbonyl, or aminosulfonyl, 
optionally N-substituted by one or two groups selected from C.sub.1-6 
alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 cycloalkylC.sub.1-4 alkyl or 
disubstituted by C.sub.4 or C.sub.5 polymethylene, phenyl or phenyl 
C.sub.1-4 alkyl group optionally substituted in the phenyl ring by one or 
two of halogen, C.sub.1-6 alkoxy or C.sub.1-6 alkyl groups, and R.sub.2 & 
R.sub.3 are independently H or halogen; 
In group F, R.sub.1 is H or C.sub.1-6 alkyl, and R.sub.2 is H or halogen; 
and In group H R.sub.15 & R.sub.16 are independently H or 
--CH.dbd.CH--CH.dbd.CH--; 
Y represents NH or O; and 
Z represents a radical of the formula 
##STR5## 
Wherein in group Z.sub.1 m is 1 or 2; 
In group Z.sub.2 n and p are independently 1 or 2 and o is 0, 1, or 
2 such that n+p+o.gtoreq.3, and R'.sub.1 and R'.sub.2 are independently H, 
C.sub.1-6 alkyl, phenyl or phenyl-C.sub.1-6 alkyl, which phenyl moieties 
may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or halogen; 
In group Z.sub.3 k is 0 to 2, 1 is 0 to 3, j is 0 to 4, and one of R'.sub.3 
and R'.sub.4 is H, C.sub.1-6 alkyl, phenyl, or phenyl-C.sub.1-3 alkyl, 
which phenyl moieties may be optionally substituted by C.sub.1-6 alkyl, 
C.sub.1-6 alkoxy, CF.sub.3 or halogen, and the other of R'.sub.3 and 
R'.sub.4 is H or C.sub.1-6 alkyl; 
In group Z.sub.4 a is 0 or 1; 
In group Z.sub.7 d is 0 or 1, and R'.sub.5 is C.sub.1-7 alkyl, C.sub.3-8 
cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-2 alkyl, C.sub.2-7 alkenyl, 
C.sub.2-7 alkylenyl-C.sub.1-4 alkyl, or phenyl-C.sub.1-6 alkyl. 
In group Z.sub.8 d and R'.sub.5 are as previously defined; 
In group Z.sub.9 e is 1 or 2, and R'.sub.5 is as previously defined; 
In group Z.sub.10 R'.sub.5 is as previously defined; and 
In group Z.sub.12 r is 1 to 4, R'.sub.6 and R'.sub.7 are independently 
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, or C.sub.1-6 alkynyl or together form 
--(CH2)s--, wherein s is 3-7 and one of the CH.sub.2 units may optionally 
be replaced by --O--, or NR'.sub.8, wherein R'.sub.8 is H or C.sub.1-6 
alkyl; 
with the proviso that when Ar is group B, C, D or E, then Z cannot be 
Z.sub.5, Z.sub.7 or Z.sub.9. 
The term "cycloalkyl" 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, dimethylbutyl 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 1. 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 1A. 
Ring halogenated analogs of formula IA' are prepared according to scheme I. 
2-Aminonicotinic acid 1 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), 33, 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 1 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 IF 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 17 [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 18 with the appropriate amine or alcohol 3 using 
conditions sited above [preferably CDI in dimethylformamide at room 
temperature] affords the desired triazoles of formula 1-G. 
For preparation of compounds of formula I-H, the known lithiated compound 
19 [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 3 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 3 is converted to its carbamoyl 
halide 21 (Q=Cl, Br) or isocyanate 22. The lithiated species 19 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 
(.degree.C.) and quantities of materials in grams and milliliters unless 
otherwise noted. 
Scheme I: Preparation of Imidazopyridines (Ar group=A) 
##STR6## 
Scheme 2: Preparation of Compounds of Formulae IB, IC, ID and IE 
##STR7## 
SCHEME 3: Preparation of Compounds of Formula I-F. 
##STR8## 
SCHEME 4: PREATION OF COMPOUNDS OF FORMULAE I-G AND I-H 
##STR9##