US 5,331,006 A · Amino acid analogs as CCK antagonists

Amino acid analogs as CCK antagonists

AssigneeWarner-Lambert Company

InventorsDavid C. Horwell, Julian Aranda, Corinne Augelli-Szafran, Hans-Jurgen Betche, Ann Holmes, Michael D. Mullican, Martyn C. Pritchard, Reginald S. Richardson, Edward Roberts, Bruce D. Roth, Bradley D. Tait, Bharat K. Trivedi, Uwe Trostmann, Paul C. Unangst

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Abstract

Novel unnatural dipeptoids useful as agents in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics are disclosed. Further, the compounds are antianxiety agents and antiulcer agents. The compounds are agents useful for preventing the response to withdrawal from chronic treatment or use of nicotine, diazepam, alcohol, cocaine, caffeine, and opioids. The compounds are also useful in treating and/or preventing panic attacks. Also disclosed are pharmaceutical compositions and methods of treatment using the dipeptoids as well as processes for preparing them and novel intermediates useful in their preparation. An additional feature of the invention is the use of the subject compounds to prepare diagnostic compositions.

A compound of formula ##STR119## or a pharmaceutically acceptable salt thereof wherein:

R.sup.1 is a cycloalkyl or polycycloalkyl hydocarbon of from three to twelve carbon atoms with from zero to four substituents each independently selected from the group consisting of alkyl, halogen, CN, OR*, SR*, CO.sub.2 R*, CF.sub.3, NR.sup.5 R.sup.6, and --(CH.sub.2).sub.n OR.sup.5 wherein R* is hydrogen or alkyl, R.sup.5 and R.sup.6 are each independently hydrogen or alkyl and n is an integer from zero to six with the proviso that n is an integer from one to six where R.sup.1 is --(CH.sub.2).sub.n OR.sup.5 ;
A is --(CH.sub.2).sub.n CO--, --SO.sub.2 --, --S(.dbd.O)--, --NHCO--, ##STR120## --O--(CH.sub.2)CO--, --O--(CH.sub.2).sub.2 CO--, --O--(CH.sub.2).sub.3 CO--, --O--(CH.sub.2).sub.4 CO--, --O--(CH.sub.2).sub.5 CO--, --O--(CH.sub.2).sub.6 CO--, or --HC.dbd.CHCO-- wherein n is an integer from zero to six;
R.sup.2 is alkyl, --(CH.sub.2).sub.n --CH.dbd.CH.sub.2, --(CH.sub.2).sub.n C.tbd.CH, --(CH.sub.2).sub.n Ar, --(CH.sub.2).sub.n OR*, --(CH.sub.2).sub.n OAr, --(CH.sub.2).sub.n CO.sub.2 R*, or --(CH.sub.2).sub.n NR.sup.5 R.sup.6 wherein n, R*, R.sup.5, and R.sup.6 are as defined above and Ar is as defined below;
R.sup.3 and R.sup.4 are each independently selected from hydrogen, R.sup.2 and --(CH.sub.2).sub.n' -.beta.-D wherein:
n' is an integer of from zero to three;
.beta. is a bond,
--OCO(CH.sub.2).sub.n --,
--O(CH.sub.2).sub.n --,
--NHCO--,
--NHCOCH.sub.2 --,
--NHCO(CH.sub.2).sub.3 --,
--NHCO(CH.sub.2).sub.4 --,
--NHCO(CH.sub.2).sub.5 --,
--NHCO(CH.sub.2).sub.6 --,
--CONH--,
--CONHCH.sub.3 --,
--CONH(CH.sub.2).sub.3 --,
--CONH(CH.sub.2).sub.4 --,
--CONH(CH.sub.2).sub.5 --,
--CONH(CH.sub.2).sub.6 --,
--COO(CH.sub.2).sub.n --,
--CO(CH.sub.2).sub.n --,
--S--(CH.sub.2).sub.n --,
--S(.dbd.O)--(CH.sub.2).sub.n --,
--SO.sub.2 --(CH.sub.2).sub.n --,
--NHSO.sub.2 --(CH.sub.2).sub.n --,
--SO.sub.2 NH(CH.sub.2).sub.n --, ##STR121## wherein R.sup.7 or R.sup.8 are independently selected from hydrogen and R.sup.2 or together form a ring (CH.sub.2).sub.m wherein m is an integer of from 1 to 5 and n is as defined above;
D is
--COOR*,
--CH.sub.2 OR*,
--CHR.sup.2 OR*,
--CH.sub.2 SR*,
--CHR.sup.2 SR*,
--CONR.sup.5 R.sup.6,
--CN,
--NR.sup.5 R.sup.6,
--OH,
--H and the acid replacements ##STR122## wherein R.sup.10 is OH, NH.sub.2 CH.sub.3 or Cl, wherein m is an integer of from 0 to 2, wherein R*, R.sup.2, R.sup.5, and R.sup.6 are as defined above;
R.sup.9 is hydrogen or alkyl, --(CH.sub.2).sub.n CO.sub.2 R*, --(CH.sub.2).sub.n OAr', --(CH.sub.2).sub.n NR.sup.5 R.sup.6, wherein n, R*, R.sup.5, and R.sup.6 are as defined above or taken from R.sup.3 and Ar' is taken from Ar as defined below;
R.sup.12 and R.sup.13 are each independently hydrogen;
Ar is an unsubstituted or substituted hydrocarbon ring system selected from a monocyclic 5- or 6-member ring or a bicyclic ring system wherein each ring is independently a 5- or 6-member ring and a tricyclic ring system wherein each ring is independently a 5- or 6-member ring wherein the substituent is independently selected from nitro, NR.sup.5 R.sup.6, halogen, alkyl, hydroxy or alkoxy;
and
Ar.sup.2 is selected from Ar as defined above or, naphthyl or the CH.sub.2 Ar.sup.2 moiety of formula I is the sidechain of phenylalanine or tyrosine,
the above alkyl or alkoxy groups have a straight or branched chain of from one to six carbon atoms.

41 more elements

Abstract

Claims24