Benzothiazepine and benzoxazepine derivatives as cholecystokinin receptor antagonists

The present invention relates to novel substituted benzothiazepines and benzoxazepines of the formula ##STR1## wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9 and X are as defined below, and to novel intermediates used in the synthesis of such compounds. Such compounds are useful in the treatment and prevention of gastrointestinal disorders, pain and anxiety disorders.

BACKGROUND OF THE INVENTION 
This is a 371 of PCT/US93/03389filed Apr. 14, 1993. 
The present invention relates to novel substituted benzothiazepines and 
benzoxazepines, pharmaceutical compositions comprising such compounds and 
the use of such compounds in the treatment and prevention of central 
nervous system and gastrointestinal disorders. The pharmaceutically active 
compounds of this invention are cholecystokinin (CCK) receptor 
antagonists. 
Cholecystokinin (CCK) is a 33-amino acid peptide originally discovered and 
characterized in 1971. (See Mutt et al., Biochem. J., 125, 57 (1971 )). It 
carries out its biological responses by binding to its two receptor types: 
CCK-A and CCK-B. The CCK-A receptor is located primarily in the 
gallbladder and pancreas, and mediates CCK-induced enzyme secretion and 
gallbladder contraction during a meal. The CCK-B receptor is located in 
the stomach, where it is involved in acid secretion, and in the brain, 
where it mediates pain and anxiety responses. 
A number of potent and selective non-peptide antagonists for these two 
receptors are known (See M. G. Bock, Drugs of the Future, 16(7), 631-640 
(1991) and R. M. Freidinger, Med. Res. Rev., 9, 271-290 (1989)). Merck's 
L-364,718 (devazepide) is a selective CCK-A antagonist. (See O'Neill et 
al., Brain Res., 534, 287-290 (1990)). Merck's benzodiazepine L-365,260 is 
a selective CCK-B antagonist that was found to have an analgesic effect on 
squirrel monkeys. (See O'Neill et al., Brain Res., 534, 287-290 (1990)). 
Parke-Davis' CI-988 is a selective CCK-B antagonist that was found to 
reverse the pentagastrin-induced anxiogenic response in rats. (See Singh 
et al., Proc. Nat'l. Acad. Sci., U.S., 88, 1130-33 (1991 )). U.S. patent 
application 825,677, filed Jan. 27, 1992, refers to substituted 
hexahydroazepinones and tetrahydrobenzazepinones that are selective CCK-B 
receptor antagonists. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds of the formula 
##STR2## 
wherein X is oxygen, sulfur, sulfoxide or sulfone; 
##STR3## 
R.sup.2 is phenyl optionally substituted with one or more substituents, 
preferably one or two substituents, independently selected from (C.sub.1 
-C.sub.6)alkyl, nitro, amino, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 
-C.sub.6)alkylamino, halo, hydroxy, CO.sub.2 H, CO.sub.2 (C.sub.1 
-C.sub.6)alkyl, tetrazolyl, SO.sub.3 H, SO.sub.2 NH.sub.2, SO.sub.2 
NH(C.sub.1 -C.sub.6)alkylamino, SO.sub.2 N-di-(C.sub.1 -C.sub.6)alkylamino 
and a group of the formula 
##STR4## 
R.sup.3 and R.sup.5 are independently selected from (C.sub.1 
-C.sub.6)alkyl, 1-adamantyl and 2-adamantyl; 
R.sup.4 is hydrogen or (C.sub.1 -C.sub.6)alkyl; 
R.sup.6 is a six membered saturated heterocyclic ring containing 5 carbon 
atoms and one nitrogen atom, wherein the nitrogen atom is the point of 
attachment, one of the carbon atoms may optionally be replaced by an 
oxygen or nitrogen atom, and one or more of said carbon atoms may 
optionally be substituted with one or two substituents independently 
selected from cyano and (C.sub.1 -C.sub.6)alkyl; 
R.sup.7 is hydrogen or methyl; 
R.sup.8 is hydrogen or methyl; and 
R.sup.9 is hydrogen, halo, phenyl or (C.sub.1 -C.sub.6)alkyl. 
Examples of possible R.sup.6 groups are the groups having the formula 
##STR5## 
wherein Z is NH or CH.sub.2 and R.sup.10, R.sup.11, R.sup.12 and R.sup.13 
are independently selected from hydrogen and (C.sub.1 -C.sub.3)alkyl. 
The present invention also relates to the pharmaceutically acceptable acid 
addition salts of compounds of the formula I. The acids which are used to 
prepare the pharmaceutically acceptable acid addition salts of the 
aforementioned base compounds of this invention are those which form 
non-toxic acid addition salts, i.e., salts containing pharmacologically 
acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, 
nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, 
citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, 
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, 
benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts. 
The term "alkyl", as used herein, unless otherwise indicated, includes 
saturated monovalent hydrocarbon radicals having straight, branched or 
cyclic moieties or combinations thereof. 
The term "halo", as used herein, unless otherwise indicated, includes 
chloro, fluoro, bromo and iodo. 
Preferred compounds of the formula I include those wherein X is oxygen. 
Preferred compounds of the formula I also include those wherein R.sup.1 is 
##STR6## 
and R.sup.6 is a group of the formula 
##STR7## 
Preferred compounds of the formula I also include those having the absolute 
stereochemistry depicted below 
##STR8## 
and wherein R.sup.2 is as defined above. 
Using the Cahn-lngold-Prelog convention, preferred compounds of the formula 
I wherein X is sulfur include those having the "S" configuration at the 
carbon adjacent to the oxo substituent, and preferred compounds of the 
formula I wherein X is oxygen include those having the "R" configuration 
at the carbon adjacent to the oxo substituent. 
Specific preferred compounds of the formula I include the following: 
3(S)-1-[3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-benz 
othiazepin-5(2H)-acetyl]-3,3-dimethyl piperidine; 
3(S)-1-[3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-benz 
othiazepin-5(2H)-acetyl]-4,4-tetramethylene piperidine; 
3(S)-1-[3,4-dihydro-4-oxo-3-[[(3-methoxyphenylamino)carbonyl]amino]-1,5-ben 
zothiazepin-5(2H)-acetyl]-3,3-dimethyl piperidine; 
7(R)-1-{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9 
-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-chlorophenyl-urea; 
7(R)-1-{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9 
-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
7(R)-(3-dimethylamino-phenyl)-3-{8-oxo-9-[2-oxo-2(3,3,5,5-tetramethylpiperi 
din-1-yl)-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl-urea; 
7(R)-1-{9-[2-(3,3-dimethylpiperidin-1-yl)-2-oxo-ethyl]-3-fluoro-8-oxo-6,7,8 
,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
7(R)-1-{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-3-fluoro-8oxo 
-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
6(S),7(R)-1{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-6-methyl- 
8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
6(S),7(R)-1-(3-dimethylamino-phenyl)-3-{6-methyl-8-oxo-9-[2-oxo-2-(3,3,-dim 
ethylpiperidin-1-yl)-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten- 
7-yl-urea; 
6(S),7(R)-1-(3-dimethylamino-phenyl)-3-{6-methyl-8-oxo-9-[2-oxo-2-(3,3,5,5- 
tetramethylpiperidin-1-yl)-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloh 
epten-7-yl-urea; 
6(S),7(R)-1{9-[2-(3,3-dimethylpiperidin-1-yl)-2-oxo-ethyl]-6-methyl-8-oxo-6 
,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-chlorophenyl-urea; 
6(S),7(R)-1{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-6-methyl- 
8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-chloropheny 
l-urea; 
6(S),7(R)-1{9-[2-(3,3,5,5-tetramethylpiperidin-1-yl)-2-oxo-ethyl]-3-fluoro- 
6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-to 
lyl-urea; and 
3(S)-1-[3,4-dihydro-4-oxo-3-[[(3-chlorophenylamino)carbonyl]amino]-1,5-benz 
othiazephin-5(2H)-acetyl]-3,3-dimethyl piperidine-1,1-dioxide. 
Other examples of compounds of the formula I include the following: 
7(S)-1-{9-[2-(3,3-dimethyl-4-oxo-piperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8, 
9,-tetrahydro-5-oxo-9-azabicyclohepten-7-yl}-3-m-tolyl-urea; 
7(S)-1-{9-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9-tetra 
hydro-5-oxo-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
(R,S)-1-[3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-ben 
zothiazepin-5(2H)-acetyl]-3,3-pentamethylene piperidine; 
(R,S)-1-[3,4-dihydro-4-oxo-3-[[(3-methoxyphenylamino)carbonyl]amino]-1,5-be 
nzothiazepin-5(2H)-acetyl]-2-methyl piperidine; 
(R,S)-1-[3,4-dihydro-4-oxo-3-[[(3-methoxyphenylamino)carbonyl]amino]-1,5-be 
nzothiazepin-5(2H)-acetyl]-4,4-tetramethylene piperidine; 
3(S)-2-[4-oxo-3-(3-m-tolyl-ureido)-3,4-dihydro-2H-benzo[b]-[1,4]-thiazepin- 
5-yl]-N-thiochroman-4-yl-acetamide; 
7(S)-1-{9-[2-(3,5-dimethylpiperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9-tetrah 
ydro-5-oxo-9-aza-benzocyclohepten-7-yl}-3-m-tolyl-urea; 
7(R)-1-{9-[2-(3,3-dimethylpiperidin-1-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9-tetrah 
ydro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-methoxyphenyl-urea; 
7(R)-1-{9-[2-(7-aza-spiro[4.5]dec-7-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9-tetrahyd 
ro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-methoxyphenyl-urea; 
7(R)-1-{9-[2-(3,3-dimethylpiperidin-yl)-2-oxo-ethyl]-8-oxo-6,7,8,9-tetrahyd 
ro-5-oxa-9-aza-benzocyclohepten-7-yl}-3-m-ethylphenyl-urea; 
7(R)-1-(3-chloro-phenyl)-3-{8-oxo-9-[2-oxo-2-(3,3,5,5-tetramethyl-4-oxo-pip 
eridin-1-yl)-ethyl]-6,7,8,9-tetrahydro-5-oxa-8-aza-benzocyclohepten-7-yl-ur 
ea; 
(S)-1-[3,4-dihydro-4-oxo-3-[[(3-chlorophenylamino)carbonyl]amino]-1,5-benzo 
thiazepin-5(2H)-acetyl]-3,3-dimethyl piperidine; 
(R,S)-3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-benzot 
hiazepine-5(2H)-acetic acid-1,1-dimethylethylester; 
(R,S)-3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-benzot 
hiazepine-5(2H)-acetic acid-1,1-dimethylethyl ester, 1,1-dioxide; 
(R,S)-1-[3,4-dihydro-4-oxo-3-[[(3-methylphenylamino)carbonyl]amino]-1,5-ben 
zothiazepin-5(2H)-acetyl]-3,3-dimethylpiperidine-1,1-dioxide; and 
(S)-1-[3,4-dihydro-4-oxo-3-[[(3-methoxyphenylamino 
)carbonyl]amino]-1,5-benzothiazepin-5(2H)-acetyl]-3,3-dimethyl 
piperidine-1,1-dioxide. 
This invention also relates to compounds of the formulae 
##STR9## 
wherein X, R.sup.1, R.sup.2, R.sup.7, R.sup.8 and R.sup.9 are defined as 
above. These compounds are useful as intermediates in the synthesis of 
compounds of the formula I. 
Preferred compounds of the formulae XIX and XX include those wherein the 
substituents R.sup.1, R.sup.2, R.sup.7, R.sup.8 and R.sup.9 are as defined 
above for the preferred compounds of formula I, and those having the 
preferred stereochemistry as defined above for compounds of the formula I. 
Examples of compounds of the formula XIX are the following: 
(S)-N-(3-methylphenyl)-N'-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl 
)-urea; 
(S)-N-(3-methoxyphenyl)-N'-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-y 
l)-urea; 
3(S)-N-(3-chlorophenyl)-N'-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-y 
l)-urea; 
7(R)-1-(8-oxo -6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl) 
-3-m-tolyl-urea; 
7(R)-1-(3-methoxy-phenyl)-3-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycl 
ohepten-7-yl)-urea; 
7(R)-1-(3-chloro-phenyl)-3-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclo 
hepten-7-yl)-urea; 
7(R)-1-(3-dimethylamino-phenyl)-3-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-ben 
zocyclohepten-7-yl)-urea; 
7(R)-1-(3-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl 
)-3-m-tolyl-urea; 
7(R)-1-(3-chloro-phenyl)-3-(3-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-b 
enzocyclohepten-7-yl)-urea; 
7(R)-1-(3-dimethylamino-phenyl)-3-(3-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa- 
9-aza-benzocyclohepten-7-yl )-urea; 
6(S),7(R)-1-(6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten 
-7-yl)-3-m-tolyl-urea; 
6(S),7(R)-1-(3-chloro-phenyl)-3-(6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9- 
aza-benzocyclohepten-7-yl)-urea; 
6(S),7(R)-1-(3-dimethylamino-phenyl)-3-(6-methyl-8-oxo-6,7,8,9-tetrahydro-5 
-oxa-9-aza-benzocyclohepten-7-yl)-urea; 
6(S),7(R)-1-(3-fluoro-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycl 
ohepten-7-yl)-3-m-tolyl-urea; 
6(S),7(R)-1-(3-chloro-phenyl)-3-(3-fluoro-methyl-8-oxo-6,7,8,9-tetrahydro-5 
-oxa-9-aza-benzocyclohepten-7-yl)-urea; and 
6(S),7(R)-1-(3-dimethylamino-phenyl)-3-(3-fluoro-6-methyl-8-oxo-6,7,8,9-tet 
rahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-urea. 
Examples of compounds of the formula XX are: 
7(R)-amino-8-[2-oxo-2-(3,3-dimethyl-piperidin-1-yl)-ethyl]-6,7-dihydro-9H-5 
-oxa-9-aza-benzocyclohepten-8-one; 
3(S)-amino-5-[2-oxo-2-(3,3-dimethyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1,5- 
benzothiazepin-4-one; 
7(R)-amino-8-[2-oxo-2-(3,3,5,5-tetramethyl-piperidin-1-yl)-ethyl]-6,7-dihyd 
ro-9H-5-oxa-9-aza-benzocyclohepten-8-one; 
6(S),7(R)-6-methyl-7-amino-8-[2-oxo-2-(3,3,5,5-tetramethyl-piperidin-1-yl)- 
ethyl]-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one; 
7(R)-3-fluoro-7-amino-8-[2-oxo-2-(3,3,5,5-tetramethyl-piperidin-1-yl)-ethyl 
]-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one; and 
6(S),7(R)-3-fluoro-6-methyl-7-amino-8-[2-oxo-2-(3,3,5,5-tetramethyl-piperid 
in-1-yl)-ethyl]-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one. 
The present invention also relates to a pharmaceutical composition for 
treating or preventing a condition selected from the group consisting of 
pain, gastrointestinal disorders such as ulcer and colitis, and central 
nervous system disorders such as anxiety and panic disorder in a mammal, 
including a human, comprising an amount of a compound of the formula I, or 
a pharmaceutically acceptable salt thereof, effective in treating or 
preventing such condition, and a pharmaceutically acceptable carrier. 
The present invention also relates to a method of treating or preventing a 
condition selected from the group consisting of pain, gastrointestinal 
disorders such as ulcer and colitis, and central nervous system disorders 
such as anxiety and panic disorder in a mammal, including a human, 
comprising administering to said mammal an amount of a compound of the 
formula I, or a pharmaceutically acceptable salt thereof, effective in 
treating or preventing such condition, 
The present invention also relates to a pharmaceutical composition for 
antagonizing the effects of cholecystokinin in a mammal, including a 
human, comprising a cholecystokinin antagonizing amount of a compound of 
the formula I, or a pharmaceutically acceptable salt thereof, and a 
pharmaceutically acceptable carrier. 
The present invention also relates to a method of antagonizing the effects 
of cholecystokinin in a mammal, including a human, comprising 
administering to said mammal a cholecystokinin antagonizing amount of a 
compound of the formula I, or a pharmaceutically acceptable salt thereof. 
The present invention also relates to a pharmaceutical composition for 
treating or preventing a cholecystokinin mediated disorder in a mammal, 
including a human, comprising a cholecystokinin antagonizing amount of a 
compound of the formula I, or a pharmaceutically acceptable salt thereof, 
and a pharmaceutically acceptable carrier. 
The present invention also relates to a method of treating or preventing a 
cholecystokinin mediated disorder in a mammal, including a human, 
comprising administering to said mammal a cholecystokinin antagonizing 
amount of a compound of the formula I, or a pharmaceutically acceptable 
salt thereof. 
The present invention also relates to a pharmaceutical composition for 
treating or preventing a condition selected from the group consisting of 
pain, gastrointestinal disorders such as ulcer and colitis, and central 
nervous system disorders such as anxiety and panic disorder in a mammal, 
including a human, comprising an amount of a compound of the formula I, or 
a pharmaceutically acceptable salt thereof, effective in antagonizing the 
effect of cholecystokinin at its receptor site, and a pharmaceutically 
acceptable carrier. 
The present invention also relates to a method of treating or preventing a 
condition selected from the group consisting of pain, gastrointestinal 
disorders such as ulcer and colitis, and central nervous system disorders 
such as anxiety and panic disorder in a mammal, including a human, 
comprising administering to said mammal an amount of a compound of the 
formula I, or a pharmaceutically acceptable salt thereof, effective in 
antagonizing the effect of cholecystokinin at its receptor site. 
The compounds of the formulae I and VII have chiral centers and therefore 
exist in different enantiomeric and diastereomic forms. This invention 
relates to all optical isomers and all stereoisomers of compounds of the 
formulae I and VII, and mixtures thereof. 
Formula I and formula VII above include compounds identical to those 
depicted but for the fact that one or more hydrogen or carbon atoms are 
replaced by isotopes thereof. Such compounds are useful as research and 
diagnostic tools in metabolism pharmacokinetic studies and in binding 
assays. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the formulae I and II may be prepared as described in the 
following reaction schemes and discussion. Unless otherwise indicated, 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and X in the 
reaction schemes and discussion that follow are defined as above. 
##STR10## 
Scheme 1 illustrates the preparation of the pharmaceutically active 
compounds of the formula I and the intermediate compounds of the formulae 
XIX and XX from starting materials of the formula VII. The method 
illustrated in scheme 1 preserves the stereochemical configuration of the 
carbon adjacent to the oxo substituent in compounds of the formula VII, 
and therefore can be used to prepare any racemic compound or stereoisomer 
of the formula I from the appropriate starting material having the same 
configuration. 
Referring to scheme 1, compounds of the formula I may be prepared by adding 
the R.sup.2 containing sidechain to the starting material and then adding 
the R.sup.1 substituent, or, alternatively, performing the two foregoing 
steps in the opposite order. If the R.sup.2 containing sidechain is added 
first, the compounds are prepared in the following manner. 
A compound of the formula VII is reacted with an isocyanate of the formula 
R.sup.2 NCO. This reaction is generally carried out at a temperature from 
about -78.degree. C. to about 50.degree. C., preferably at about 0.degree. 
C., in an aprotic solvent such as methylene chloride, ethyl acetate, 
chloroform or ether, preferably in methylene chloride. It yields a 
compound of the formula XIX. The compound of formula XIX is then reacted 
with a compound having the formula R.sup.1 I in the presence of a strong 
base to produce the desired compound of formula I wherein X is either 
oxygen or sulfur. This reaction is typically conducted at a temperature 
from about -78.degree. C. to about 0.degree. C., preferably at about 
-78.degree. C., in an anhydrous, aprotic solvent such as dimethylformamide 
(DMF), tetrahydrofuran (THF), ether or dimethylsulfoxide (DMSO), 
preferably in THF. Preferably, the reactant of formula R.sup.1 I is added 
to the reaction mixture at about -78 .degree. C., after which the mixture 
is warmed to room temperature and stirred for about two hours. Suitable 
strong bases include sodium hydride, potassium hydride, lithium 
bis(trimethylsilyl)amide and lithium diisopropylamide. Lithium 
bis(trimethylsilyl)amide is preferred. 
As indicated above, the two foregoing reaction steps may be performed in 
the opposite order. This reverse reaction sequence is depicted in scheme 1 
as sequence VII.fwdarw.XX.fwdarw.I. 
Compounds of the formula I wherein X is sulfur may be converted into the 
corresponding compounds of the formula I wherein X is sulfoxide by 
reacting them with sodium periodate or metachloroperbenzoic acid. When 
sodium periodate is used, the reaction is generally carried out in a 
water/alcohol solvent, and when metachloroperbenzoic acid is used, the 
reaction is generally carried out in methylene chloride or peracetic acid. 
The reaction temperature may range from about room temperature to about 
100.degree. C. Preferably, the reactant is added and the reaction mixture 
is heated to about 60.degree. C. for about five hours. 
Compounds of the formula I wherein X is sulfur may be converted into the 
corresponding compounds of the formula I wherein X is sulfone by reacting 
them with hydrogen peroxide. This reaction is usually carried out in an 
appropriate solvent at a temperature from about -50.degree. C. to about 
100.degree. C. Preferably, 30 percent aqueous hydrogen peroxide is added 
to acetic acid so that the reaction mixture contains 1 equivalent of 
hydrogen peroxide per equivalent of the formula I compound, and the 
mixture is stirred at room temperature for about 3 days. Other appropriate 
solvents include methanesulfonic acid and formic acid. 
Scheme 2 illustrates a method of preparing racemic mixtures of the starting 
materials of the formula VII. This method is exemplified in Example 1 of 
this application for compounds of the formula VII wherein X is sulfur. 
Compounds of the formula VII wherein X is oxygen may be prepared in an 
analogous fashion, by replacing the reactant of the formula 
##STR11## 
wherein X is sulfur, which is depicted in scheme 2 and referred to in 
Example 1B, sulfur with the corresponding reactant wherein X is oxygen. 
Scheme 3 illustrates a method of synthesizing the "R" and "S" enantiomers 
of the starting materials of the formula VII wherein X is sulfur. These 
compounds are designated in scheme 3 as having the formula VII-A. (The 
chiral center of such compounds is designated with an asterisk in 
structure VII-A. Asterisks are also used to designate the same chiral 
carbon in the synthetic intermediates from which compounds of the formula 
VII-A are made.) Example 2 of this application describes the preparation 
of the "S" enantiomer by the method shown in scheme 3. The "R" enantiomer 
may be prepared in an analogous fashion by replacing the "S" enantiomer of 
the compound of formula IX depicted in scheme 3 and referred to in Example 
3A (i.e., D-cysteine) with the corresponding "R" enantiomer (i.e., 
L-cysteine). 
Scheme 4 illustrates a method of preparing the "R" and "S" enantiomers of 
compounds of the formula VII wherein X is oxygen. These compounds are 
referred to in scheme 4 as having the formula VII-B. (The chiral center of 
such compounds is designated with an asterisk in structure VII-B. 
Asterisks are also used to designate the same chiral carbon in the 
synthetic intermediates from which compounds of the formula VII-B are 
made.) Example 105 of this application describes the preparation of the 
"R" enantiomer by the method shown in scheme 4. The "S" enantiomer may be 
prepared in an analogous fashion, by replacing the "R" enantiomer of the 
compound of formula XV depicted in scheme 4 and referred to in Example 
105A (i.e., N-t-butoxycarbonyl-D-serine) with the corresponding "S" 
enantiomer (i,e., N-t-butoxycarbonyl-L-serine). Racemic mixtures of 
compounds of the formula VII may be prepared in an analogous fashion 
according to the procedure of scheme 4, using the racemate of the starting 
material of formula XV. 
When R.sup.7 and R.sup.8 are both hydrogen, the compound of formula XV 
employed is the N-t-butoxycarbonyl derivative ("the BOC derivative") of 
D-serine, L-serine or a racemic mixture of these amino acids. Other 
variations of R.sup.7 and R.sup.s may be obtained using the BOC 
derivatives of D- and L-threonine, D- and L-allothreonine, and D- and 
L-2-amino-3-methyl-3-hydroxybutyric acid and the respective racemates of 
these compounds. D- and L-threonine and D- and L-serine are commercially 
available. D-allothreonine and L-allothreonine may be prepared as 
described by Pons et al., Tetrahedron Letters, 31, 5023 (1990). D- and 
L-2-amino-3-methyl-3-hydroxybutyric acid may be prepared as described by 
Belakon et al., J.A.C.S., 107, 4252 (1985). The BOC derivatives of all of 
the above amino acids may be prepared as described by Keller et al., 
Organic Synthesis, 63, 160 (1984). All of the foregoing references are 
incorporated herein in their entirety. 
The preparation of other compounds of the formulae I, XIX and XX not 
specifically described in the foregoing experimental section can be 
accomplished using combinations of the reactions described above that will 
be apparent to those skilled in the art. 
In each of the reactions discussed or illustrated in schemes 1 to 3 above, 
pressure is not critical unless otherwise indicated. Pressures from about 
0.5 atmospheres to about 5 atmospheres are generally acceptable, and 
ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of 
convenience. 
The compounds of the formula I (the active compounds of this invention) 
which are basic in nature are capable of forming a wide variety of 
different salts with various inorganic and organic acids. Although such 
salts must be pharmaceutically acceptable for administration to animals, 
it is often desirable in practice to initially isolate a compound of the 
formula I from the reaction mixture as a pharmaceutically unacceptable 
salt and then simply convert the latter back to the free base compound by 
treatment with an alkaline reagent and subsequently convert the latter 
free base to a pharmaceutically acceptable acid addition salt. The acid 
addition salts of the active base compounds of this invention are readily 
prepared by treating the base compound with a substantially equivalent 
amount of the chosen mineral or organic acid in an aqueous solvent medium 
or in a suitable organic solvent, such as methanol or ethanol. Upon 
careful evaporation of the solvent, the desired solid salt is readily 
obtained. 
The active compounds of this invention and their pharmaceutically 
acceptable salts are useful as CCK receptor antagonists, i.e., they 
possess the ability to antagonize the effects of CCK at its receptor site 
in mammals, and therefore they are able to function as therapeutic agents 
in the treatment of the aforementioned disorders and diseases in an 
afflicted mammal. 
The active compounds of this invention and their pharmaceutically 
acceptable salts can be administered via either the oral, parenteral or 
topical routes. In general, these compounds are most desirably 
administered in dosages ranging from about 5.0 mg up to about 1500 mg per 
day, although variations will necessarily occur depending upon the weight 
and condition of the subject being treated and the particular route of 
administration chosen. However, a dosage level that is in the range of 
about 0.07 mg to about 21 mg per kg of body weight per day is most 
desirably employed. Variations may nevertheless occur depending upon the 
species of animal being treated and its individual response to said 
medicament, as well as on the type of pharmaceutical formulation chosen 
and the time period and interval at which such administration is carried 
out. In some instances, dosage levels below the lower limit of the 
aforesaid range may be more than adequate, while in other cases still 
larger doses may be employed without causing any harmful side effect, 
provided that such larger doses are first divided into several small doses 
for administration throughout the day. 
The active compounds of the invention may be administered alone or in 
combination with pharmaceutically acceptable carriers or diluents by 
either of the three routes previously indicated, and such administration 
may be carried out in single or multiple doses. More particularly, the 
novel therapeutic agents of this invention can be administered in a wide 
variety of different dosage forms, i.e., they may be combined with various 
pharmaceutically acceptable inert carriers in the form of tablets, 
capsules, lozenges, troches, hard candies, powders, sprays, creams, 
salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous 
suspensions, injectable solutions, elixirs, syrups, and the like. Such 
carriers include solid diluents or fillers, sterile aqueous media and 
various non-toxic organic solvents, etc. Moreover, oral pharmaceutical 
compositions can be suitably sweetened and/or flavored. In general, the 
therapeutically-effective compounds of this invention are present in such 
dosage forms at concentration levels ranging from about 5.0% to about 70% 
by weight. 
For oral administration, tablets containing various excipients such as 
microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium 
phosphate and glycine may be employed along with various disintegrants 
such as starch (and preferably corn, potato or tapioca starch), alginic 
acid and certain complex silicates, together with granulation binders like 
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, 
lubricating agents such as magnesium stearate, sodium lauryl sulfate and 
talc are often very useful for tabletting purposes. Solid compositions of 
a similar type may also be employed as fillers in gelatin capsules; 
preferred materials in this connection also include lactose or milk sugar 
as well as high molecular weight polyethylene glycols. When aqueous 
suspensions and/or elixirs are desired for oral administration, the active 
ingredient may be combined with various sweetening or flavoring agents, 
coloring matter or dyes, and, if so desired, emulsifying and/or suspending 
agents as well, together with such diluents as water, ethanol, propylene 
glycol, glycerin and various like combinations thereof. 
For parenteral administration, solutions of an active compound of the 
present invention in either sesame or peanut oil or in aqueous propylene 
glycol may be employed. The aqueous solutions should be suitably buffered 
(preferably pH greater than 8) if necessary and the liquid diluent first 
rendered isotonic. These aqueous solutions are suitable for intravenous 
injection purposes. The oily solutions are suitable for intraarticular, 
intramuscular and subcutaneous injection purposes. The preparation of all 
these solutions under sterile conditions is readily accomplished by 
standard pharmaceutical techniques well known to those skilled in the art. 
Additionally, it is also possible to administer the active compounds of the 
present invention topically when treating inflammatory conditions of the 
skin and this may preferably be done by way of creams, jellies, gels, 
pastes, ointments and the like, in accordance with standard pharmaceutical 
practice. 
The activity of the compounds of the present invention as CCK antagonists 
may be determined by an assay that measures their ability to inhibit the 
binding of 125-I-BH-CCK-8 to the CCK-B receptor in a guinea pig cortical 
membrane preparation. This procedure is carried out as follows. The cortex 
is dissected from one male Hartley Guinea pig and homogenized (15 strokes) 
with a teflon homogenizer in 20 volumes (w./v.) of the assay buffer, which 
consists of 50 mM Tris (i.e., trimethamine, which is 
2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloric acid having pH 7.4 
and 5 mM of manganese chloride at 4.degree. C. The homogenate is 
centrifuged at 4.degree. C. for 30 minutes at 100,000.times.G. The pellet 
is resuspended in the same buffer and spun as described above. The final 
pellet is diluted to a concentration of 20 mg/ml with the assay buffer for 
use in the binding assay. The tissue is kept on ice at all times. 
An incubation mixture is prepared, which consists of 50 uL of the tissue 
preparation, prepared as described above, 100 uL 125-I-BH-CCK-8 (to give a 
concentration of 50 pM in the final assay), 20 uL of a blank or the 
compound being tested, and 30 uL of Tris with 4% DMSO. All drugs and 
dilutions are made using 4% DMSO in the assay buffer yielding a final 
assay DMSO concentration of 1%. 
The reaction is initiated with the addition of tissue to a 96-well plate 
containing 125-I-BH-CCK-8 and the appropriate blank or compound being 
tested. Non-specific binding is estimated using 1 uM sulphated CCK-8. The 
reaction is terminated by spinning the plates in a H1000B rotor fitted on 
a Sorvall RT6000 refrigerated centrifuge at 4.degree. C. The supernatant 
is discarded, and the pellets washed with 200 uL of assay buffer, and the 
plate is spun as above. The supernatant is decanted again, and the pellet 
is harvested onto Betaplate filters (which have been soaked in 0.2% 
polyethyleneimine for a minimum of 2 hours) using a Skatron cell harvester 
at setting 222 using Tris HCI pH 7.4 as the wash buffer. The filtermats 
are counted on a Betaplate counter for 45 seconds per sample. 
Data are expressed as IC.sub.50 values (the concentration which inhibits 
50% of the specific binding of 125-I-BH-CCK-8). The data is analyzed using 
non-linear regression analysis.