US 5,206,238 AGranted

Cholecystokinin antagonists

AssigneeMerck & Co., Inc.

InventorsMark G. Bock, Roger M. Freidinger

Life of this patent

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Abstract

Compounds of the formula: ##STR1## are disclosed which are antagonists of gastrin and cholecycstokinin (CCK) and have properties useful for treating panic disorder and for directly inducing anlagesia.

Claims6

Dependent claims

A method of treating panic disorder or anxiety disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I:

##STR43## wherein:
X is one or two of the substituents:
F, Cl or Br;
C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl;
C.sub.1 -C.sub.4 -alkoxy;
C.sub.1 -C.sub.4 -alkylthio;
hydroxy;
nitro;
cyano;
amino;
or trifluoromethyl, and may be attached at either or both the 7- and/or 8-positions;
Y is independently, the same as X, and may be attached at any of positions 2-6 on the aromatic ring;
R is H, C.sub.1 -C.sub.4 -alkyl, cyclo-C.sub.3 -C.sub.5 -alkyl, C.sub.1 -C.sub.4 -alkenyl, or acetyl;
R.sup.1 is H, C.sub.1 -C.sub.4 -alkyl, or cyclo-C.sub.3 -C.sub.5 -alkyl;
R.sup.2 is unsubstituted or mono- or disubstituted phenyl, where the substituents are as defined under X, above;
##STR44## where R.sup.3 is (CH.sub.2).sub.n -C.sub.1 -C.sub.4 -alkyl, --(CH.sub.2).sub.n -2-indole, --(CH.sub.2).sub.n -3-indole, or --(CH.sub.2).sub.n -phenyl (unsubstituted or mono- or disubstituted, where the substituents are as defined for X, above), where n is 0-4, and R.sup.4 is H or C.sub.1 -C.sub.4 -alkyl;
##STR45## where R.sup.5 is ##STR46## wherein R.sup.6 is (CH.sub.2).sub.n -2-indole, or (CH.sub.2).sub.n -3-indole, where n is 0-4, where R.sup.7 is H, COOR.sup.8, or ##STR47## and where R.sup.8 is C.sub.1 -C.sub.4 -alkyl;
where R.sup.5 is (CH.sub.2).sub.m SCH.sub.2 NHCOCH.sub.3, where m is 1-4;
where R.sup.5 is C.sub.1 -C.sub.4 -alkyl;
where R.sup.5 is pyrazine (unsubtituted or mono-substituted where the substituents may be Cl, COOR.sup.8, CN or NO.sub.2), wherein R.sup.8 is as defined above;
where R.sup.5 is ##STR48## wherein Z is O, S or NR, (CH.sub.2).sub.n is attached at the 2- or 3-position, and R, n and x are as defined above;
where R.sup.5 is ##STR49## wherein (CH.sub.2).sub.n is attached at the 4- or 5-position, and n and Z are as defined above;
where R.sup.5 is (CH.sub.2).sub.m CO.sub.2 CH.sub.2 phenyl, wherein m is as defined above;
where R.sup.5 is --O--C.sub.1 -C.sub.4 -alkyl, --CHOHC.sub.6 H.sub.5, or ##STR50## or of the formula II:
##STR51## wherein:
X, Y, R and R.sup.1 are as defined above;
and R.sup.21 is R.sup.2 as defined above, including wherein R.sup.5, as defined above, also is pyridine, ##STR52## where (CH.sub.2).sub.n is attached at the 2-, 3- or 4-position and n and X are as defined above;
##STR53## where the point of attachment is at any position on the ring and n and X are as defined above;
or ##STR54## where the point of attachment is at the 2- or 3-position and W is H, straight or branched chain C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkoxy, nitro, F, Cl or Br, and Z is as defined above;
or
the optical isomers of formula I, or pharmaceutically acceptable salts of the compounds of formulas I or II.

28 more elements

A method of directly inducing analgesia, anesthesia or loss of sensation of pain in a mammal which comprises administering to an animal requiring such treatment therapeutically effective amount of a compound of formula I:

##STR55## wherein:
X is one or two of the substituents:
F, Cl or Br;
C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl;
C.sub.1 -C.sub.4 -alkoxy;
C.sub.1 -C.sub.4 -alkylthio;
hydroxy;
nitro;
cyano;
amino;
or trifluoromethyl, and may be attached at either or both the 7- and/or 8-positions;
Y is independently, the same as X, and may be attached at any of positions 2-6 on the aromatic ring;
R is H, C.sub.1 -C.sub.4 -alkyl, cyclo-C.sub.3 -C.sub.5 -alkyl, C.sub.1 -C.sub.4 -alkenyl, or acetyl;
R.sup.1 is H, C.sub.1 -C.sub.4 -alkyl, or cyclo-C.sub.3 -C.sub.5 -alkyl;
R.sup.2 is unsubstituted or mono- or disubstituted phenyl, where the substituents are as defined under X, above;
##STR56## where R.sup.3 is (CH.sub.2).sub.n -C.sub.1 -C.sub.4 -alkyl, --(CH.sub.2).sub.n -2-indole, --(CH.sub.2).sub.n -3-indole, or --(CH.sub.2).sub.n -phenyl (unsubstituted or mono- or disubstituted, where the substituents are as defined for X, above), where n is 0-4, and R.sup.4 is H or C.sub.1 -C.sub.4 -alkyl;
##STR57## where R.sup.5 is ##STR58## wherein R.sup.6 is (CH.sub.2).sub.n -2-indole, or (CH.sub.2).sub.n -3-indole, where n is 0-4, where R.sup.7 is H, COOR.sup.8, or ##STR59## and where R.sup.8 is C.sub.1 -C.sub.4 -alkyl;
where R.sup.5 is (CH.sub.2).sub.m SCH.sub.2 NHCOCH.sub.3, where m is 1-4;
where R.sup.5 is C.sub.1 -C.sub.4 -alkyl;
where R.sup.5 is pyrazine (unsubstituted or mono-substituted where the substituents may be Cl, COOR.sup.8, CN or NO.sub.2), wherein R.sup.8 is as defined above;
where R.sup.5 is ##STR60## wherein Z is O, S or NR, (CH.sub.2).sub.n is attached at the 2- or 3-position, and R, n and X are as defined above;
where R.sup.5 is ##STR61## wherein (CH.sub.2).sub.n is attached at the 4- or 5-position, and n and Z are as defined above;
where R.sup.5 is (CH.sub.2).sub.m CO.sub.2 CH.sub.2 phenyl, wherein m is as defined above;
where R.sup.5 is --O--C.sub.1 -C.sub.4 -alkyl, --CHOHC.sub.6 H.sub.5, or
R.sup.5 is ##STR62## or of the formula II:
##STR63## wherein:
X, Y, R and R.sup.1 are as defined above;
and R.sup.21 is R.sup.2 as defined above, including wherein R.sup.5, as defined above, also is pyridine, ##STR64## where (CH.sub.2).sub.n is attached at the 2-, 3-or 4-position and n and X are as defined above;
##STR65## where the point of attachment is at any position on the ring and n and X are as defined above;
or ##STR66## where the point of attachment is at the 2- or 3-position and W is H, straight or branched chain C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkoxy, nitro, F, Cl or Br, and Z is as defined above;
or
the optical isomers of formula I, or pharmaceutically acceptable salts of the compounds of formulas I or II.

29 more elements

Dependencies are inferred from the claim text.

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