Amino acid derivatives with anticholecystokinin activity

A compound of the formula ##STR20## wherein Ar is selected from the group consisting of naphthyl, naphthylmethyl, 1,2,3,4-tetrahydronaphthyl, phenethyl, styryl, and indanyl and is optionally substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;

• R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkenyl, cycloalkyl, --(CH.sub.2).sub.q aryl, or --(CH.sub.2).sub.q aryl substituted by 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, wherein q is 0 to 4;
• R.sub.2 is H, methyl or ethyl;
• R.sub.3 is C.sub.1 to C.sub.3 alkylene or is absent;
• T is carboxyl, --CONR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently H or C.sub.1 to C.sub.4 alkyl, tetrazolyl or --COOR.sub.13 wherein R.sub.13 is C.sub.1 to C.sub.4 alkyl, benzyl or benzyl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;
• X is --C(O)-- or --CH.sub.2 --;
• and
• Y is --NR.sub.6 R.sub.7 or --O--R.sub.6 wherein R.sub.6 and R.sub.7 are independently H, C.sub.1 to C.sub.15 hydrocarbyl or halo-substituted C.sub.1 to C.sub.15 hydrocarbyl in which up to 6 carbon atoms may be replaced by --O--, --S--, or --NR.sub.8 -- (R.sub.8 being absent or selected from H, C.sub.1 to C.sub.12 hydrocarbyl, C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl and C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl, provided that neither R.sub.6 and R.sub.7 contains a --O--O-- group, and wherein R.sub.6 and R7 may be linked by a single or double bond,
• or a pharmaceutically acceptable salt thereof,
• provided that Ar is not 1-naphthyl, 1-naphthylmethyl or 1-(1,2,3,4-tetrahydronaphthyl), and that
• when (a) R.sub.3 is --(CH.sub.2).sub.n -- wherein n is from 0 to 3;
• (b) X is --C(O)--;
• (c) R.sub.1 is not --(CH.sub.2).sub.q (substituted heterocyclic);
• (d) T is COOR.sub.13 and ›(d)! (e) Y is ##STR21## wherein R is H, C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.r -aryl or --(CH.sub.2).sub.r -aryl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, r being from 0 to 4;
• V is C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylthio, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR.sub.9 R.sub.10, R.sub.9 and R.sub.10 being independently H or C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkylaryl in which aryl is substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, C.sub.1 to C.sub.4 alkylaryl, or halo;
• m is 1 to 3;
• and
• p is 0 to 3,
• then R.sub.13 is selected from C.sub.1 to C.sub.4 alkyl and substituted benzyl,
• and further provided that T is not carboxyl when X is --C(O)-- and Y is --OH.

A method of treating the physiological effects of cholecystokinin or gastrin in a patient, comprising the step of administering to a patient, suffering from a condition which can be alleviated by counteracting the effects of cholecystokinin or gastrin, an effective cholecystokinin inhibiting amount of a compound of the formula ##STR22## wherein Ar is selected from the group consisting of naphthyl, naphthylmethyl, 1,2,3,4-tetrahydronaphthyl, phenethyl, styryl, and indanyl and is optionally substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;

• R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkenyl, cycloalkyl, --(CH.sub.2).sub.q aryl, or --(CH.sub.2).sub.q aryl substituted by 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, wherein q is 0 to 4;
• R.sub.2 is H, methyl or ethyl;
• R.sub.3 is C.sub.1 to C.sub.3 alkylene or is absent;
• T is carboxyl, --CONR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently H or C.sub.1 to C.sub.4 alkyl, tetrazolyl or --COOR.sub.13 wherein R.sub.13 is C.sub.1 to C.sub.4 alkyl, benzyl or benzyl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;
• X is --C(O)-- or --CH.sub.2 --;
• and
• Y is --NR.sub.6 R.sub.7 or --O--R.sub.6 wherein R.sub.6 and R.sub.7 are independently H, C.sub.1 to C.sub.15 hydrocarbyl or halo-substituted C.sub.1 to C.sub.15 hydrocarbyl in which up to 6 carbon atoms may be replaced by --O--, --S--, or --NR.sub.8 -- (R.sub.8 being absent or selected from H, C.sub.1 to C.sub.12 hydrocarbyl, C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl and C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl, provided that neither R.sub.6 and R.sub.7 contains a --O--O-- group, and wherein R.sub.6 and R.sub.7 may be linked by a single or double bond,
• or a pharmaceutically acceptable salt thereof,
• provided that Ar is not 1-naphthyl, 1-naphthylmethyl or 1-(1,2,3,4-tetrahydronaphthyl), and that
• when (a) R.sub.3 is --(CH.sub.2).sub.n -- wherein n is from 0 to 3;
• (b) X is --C(O)--;
• (c) R.sub.1 is not --(CH.sub.2).sub.q (substituted heterocyclic);
• (d) T is --COOR.sub.13 ;
• and (e) Y is ##STR23## wherein R is H, C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.r -aryl or --(CH.sub.2).sub.r -aryl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, r being from 0 to 4;
• V is C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylthio, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR.sub.9 R.sub.10, R.sub.9 and R.sub.10 being independently H or C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkylaryl in which aryl is substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, C.sub.1 to C.sub.4 alkylaryl, or halo;
• m is 1 to 3;
• and
• p is 0 to 3,
• then R.sub.13 is selected from C.sub.1 to C.sub.4 alkyl and substituted benzyl, and that
• T is not carboxyl when X is --C(O)-- and Y is --OH.

A method of treating the physiological effects of cholecystokinin or gastrin in a patient, comprising the step of administering to a patient, suffering from a condition which can be alleviated by counteracting the effects of cholecystokinin or gastrin, an effective cholecystokinin inhibiting amount of a compound of the formula ##STR24## wherein Ar is selected from the group consisting of naphthyl, naphthylmethyl, 1,2,3,4-tetrahydronaphthyl, phenethyl, styryl, and indanyl and is optionally substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;

• R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkenyl, cycloalkyl, --(CH.sub.2).sub.q aryl, or --(CH.sub.2).sub.q aryl substituted by 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, wherein q is 0 to 4;
• R.sub.2 is H, methyl or ethyl;
• R.sub.3 is C.sub.1 to C.sub.3 alkylene or is absent;
• T is carboxyl, --CONR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently H or C.sub.1 to C.sub.4 alkyl or tetrazolyl;
• X is --C(O)-- or --CH.sub.2 --;
• and
• Y is --NR.sub.6 R.sub.7 or --O--R.sub.6 wherein R.sub.6 and R.sub.7 are independently H, C.sub.1 to C.sub.15 hydrocarbyl or halo-substituted C.sub.1 to C.sub.15 hydrocarbyl in which up to 6 carbon atoms may be replaced by --O--, --S--, or --NR.sub.8 -- (R.sub.8 being absent or selected from H, C.sub.1 to C.sub.12 hydrocarbyl, C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl and C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl, provided that neither R.sub.6 and R.sub.7 contains a --O--O-- group, and wherein R.sub.6 and R.sub.7 may be linked by a single or double bond,
• or a pharmaceutically acceptable salt thereof,
• provided that when X is --C(O)-- and R.sub.3 is --(CH.sub.2).sub.n - wherein n is from 0 to 3, Y is not ##STR25## wherein R is H, C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.r -aryl or --(CH.sub.2).sub.r -aryl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, r being from 0 to 4;
• V is C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylthio, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR.sub.9 R.sub.10, R.sub.9 and R.sub.10 being independently H or C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkylaryl in which aryl is substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, C.sub.1 to C.sub.4 alkylaryl, or halo;
• m is 1 to 3;
• and
• p is 0 to 3.

A method of treating the physiological effects of cholecystokinin or gastrin in a patient, comprising the step of administering to a patient, suffering from a condition which can be alleviated by counteracting the effects of cholecystokinin or gastrin, an effective cholecystokinin inhibiting amount of a compound of the formula ##STR26## wherein Ar is selected from the group consisting of naphthyl, naphthylmethyl, 1,2,3,4 -tetrahydronaphthyl, phenethyl, styryl, and indanyl and is optionally substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;

• R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkenyl, cycloalkyl, --(CH.sub.2).sub.q aryl, or --(CH.sub.2).sub.q aryl substituted by 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, wherein q is 0 to 4;
• R.sub.2 is H, methyl or ethyl;
• R.sub.3 is C.sub.1 to C.sub.3 alkylene or is absent;
• T is carboxyl, --CONR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently H or C.sub.1 to C.sub.4 alkyl, tetrazolyl, or --COOR.sub.13 wherein R.sub.13 is C.sub.1 to C.sub.4 alkyl, benzyl or benzyl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano;
• X is --C(O)-- or --CH.sub.2 --;
• and
• Y is --NR.sub.6 R.sub.7 or --O--R.sub.6 wherein R.sub.6 and R.sub.7 are independently H, C.sub.1 to C.sub.15 hydrocarbyl or halo-substituted C.sub.1 to C.sub.15 hydrocarbyl in which up to 6 carbon atoms may be replaced by --O--, --S--, or --NR.sub.8 -- (R.sub.8 being absent or selected from H, C.sub.1 to C.sub.12 hydrocarbyl, C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl and C.sub.1 to C.sub.12 hydrocarbyloxycarbonyl, provided that neither R.sub.6 and R.sub.7 contains a --O--O-- group, and wherein R.sub.6 and R.sub.7 may be linked by a single or double bond,
• or a pharmaceutically acceptable salt thereof,
• provided that when X is --C(O)-- and R.sub.3 is --(CH.sub.2).sub.n - wherein n is from 0 to 3, Y is not ##STR27## wherein R is H, C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.r -aryl or --(CH.sub.2).sub.r -aryl substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, r being from 0 to 4;
• V is C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylthio, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR.sub.9 R.sub.10, R.sub.9 and R.sub.10 being independently H or C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkylaryl in which aryl is substituted by from 1 to 3 substituents selected from the group consisting of C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulfamoyl and cyano, C.sub.1 to C.sub.4 alkylaryl, or halo;
• m is 1 to 3;
• and
• p is 0 to 3.