US4906615A — Substituted dipeptides as inhibitors of enkephali…

Claim 1

Independent Claim 529 words

A method for treating depression or schizophrenia in a mammal which method comprises administering an antidepressant or antipsychotic effective amount of a compound having the structural formula I R.sub.1 C*H(COR.sub.2)--NH--C*HR.sub.3 --CONH(CH.sub.2).sub.p --C*(R.sub.4 R.sub.5)--COR.sub.6 I or a racemate, enantiomer and diasterioisomer thereof or a pharmaceutically acceptable salt thereof to said mammal wherein: R 1 is alkyl having from 1 to 6 carbon atoms, adamantylmethyl, cycloakylmethyl having from 4 to 8 carbon atoms or A-X m -C n H 2 n- wherein X is oxygen or sulfur, A is phenyl which may be substituted with the group, Y, wherein Y is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms, 2- and 3-furanyl, 2- and 3-thienyl, or phenyl {which may be substituted with halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbon atoms} benzyl {the phenyl ring of which may be substituted with the group, Y, as defined herein}, 1- and 2-naphthyl, 2- and 3-furanyl or 2- and 3-thienyl; m is 0 or 1 and n is 0, 1, 2, 3, or 4; R 2 and R 6 may be the same or different and are hydroxy, alkoxy having from 1 to 8 carbon atoms, B-X m -C n H 2 n-O- wherein B is phenyl {which may be substituted with the group, Y, as defined herein} or 1- and 2-naphthyl, X, m, and n are as defined herein provided that when n=0, m=0, -OCH 2 OCO-alkyl having from 3 to 8 carbon atoms, -OCH 2 CO-phenyl {phenyl ring of which may be substituted with the group, Y, as defined herein}, 1-glyceryl, ##STR8## wherein R 7 is hydrogen, alkyl having from 1 to 6 carbon atoms, or phenyl which may be substituted with the group, Y, as defined herein, and R 8 is hydrogen or alkyl having from 1 to 6 carbon atoms; R 2 may also be --NR 7 R 8 wherein R 7 and R 8 are as defined herein; R 3 is alkyl having from 1 to 6 carbon atoms, cyclo-alkylmethyl having from 4 to 8 carbon atoms, 2- and 3-thienylmethyl, 2- and 3-furanylmethyl, 1- and 2-naphthylmethyl, or benzyl the phenyl ring of which may be substituted with the group, Y, as defined herein; R 4 is D--C n H 2n --O m -- wherein D is hydrogen, alkyl having from 1 to 4 carbon atoms or phenyl which may be substituted with the group, Z, wherein Z is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms; m and n are as defined herein; R 4 may also be --NR 5 COR 7 {wherein R 5 and R 7 are defined herein}, and --NR 5 CO 2 R 9 {wherein R 5 is defined herein and R 9 is alkyl having from 1 to 6 carbon atoms or phenyl which may be substituted with the group Y, as defined herein} provided that p is 1 or 2; R 5 is hydrogen or alkyl having from 1 to 6 carbon atoms; and p is 1 or 2.

Claim 2

Independent Claim 529 words

A method for treating depression or schizophrenia in a mammal which method comprises administering an antidepressant or antipsychotic effective amount of a compound having the structural formula I R.sub.1 C*H(COR.sub.2)--NH--C*HR.sub.3 --CONH(CH.sub.2).sub.p --C*(R.sub.4 R.sub.5)--COR.sub.6 I or a racemate, enantiomer and diasterioisomer thereof or a pharmaceutically acceptable salt thereof to said mammal wherein: R 1 is alkyl having from 1 to 6 carbon atoms, adamantylmethyl, cycloakylmethyl having from 4 to 8 carbon atoms or A-X m -C n H 2 n- wherein X is oxygen or sulfur, A is phenyl which may be substituted with the group, Y, wherein Y is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms, 2- and 3-furanyl, 2- and 3-thienyl, or phenyl {which may be substituted with halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbon atoms} benzyl {the phenyl ring of which may be substituted with the group, Y, as defined herein}, 1- and 2-naphthyl, 2- and 3-furanyl or 2- and 3-thienyl; m is 0 or 1 and n is 0, 1, 2, 3, or 4; R 2 and R 6 may be the same or different and are hydroxy, alkoxy having from 1 to 8 carbon atoms, B-X m -C n H 2 n-O- wherein B is phenyl {which may be substituted with the group, Y, as defined herein} or 1- and 2-naphthyl, X, m, and n are as defined herein provided that when n=0, m=0, -OCH 2 OCO-alkyl having from 3 to 8 carbon atoms, -OCH 2 CO-phenyl {phenyl ring of which may be substituted with the group, Y, as defined herein}, 1-glyceryl, ##STR8## wherein R 7 is hydrogen, alkyl having from 1 to 6 carbon atoms, or phenyl which may be substituted with the group, Y, as defined herein, and R 8 is hydrogen or alkyl having from 1 to 6 carbon atoms; R 2 may also be --NR 7 R 8 wherein R 7 and R 8 are as defined herein; R 3 is alkyl having from 1 to 6 carbon atoms, cyclo-alkylmethyl having from 4 to 8 carbon atoms, 2- and 3-thienylmethyl, 2- and 3-furanylmethyl, 1- and 2-naphthylmethyl, or benzyl the phenyl ring of which may be substituted with the group, Y, as defined herein; R 4 is D--C n H 2n --O m -- wherein D is hydrogen, alkyl having from 1 to 4 carbon atoms or phenyl which may be substituted with the group, Z, wherein Z is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms; m and n are as defined herein; R 4 may also be --NR 5 COR 7 {wherein R 5 and R 7 are defined herein}, and --NR 5 CO 2 R 9 {wherein R 5 is defined herein and R 9 is alkyl having from 1 to 6 carbon atoms or phenyl which may be substituted with the group Y, as defined herein} provided that p is 1 or 2; R 5 is hydrogen or alkyl having from 1 to 6 carbon atoms; and p is 1 or 2.

Claim 3

Dependent Claim 100 words

A method as defined in claim 1 wherein the compound administered has the name: N-[N-[(L-1-carboxy-2-phenylethyl)]-L-phenylalanyl]-β-alanine; N-[N-[L-1-(2,2-dimethyl-1-oxopropoxy)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine, (2,2-dimethyl-1-oxopropoxy)methyl ester; N-[N-[L-1-[phenylmethoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine, (2,2-dimethyl-1-oxopropoxy)methylester; N-[N-[L-1-carboxy-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)-methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine, (2,2-dimethyl-1-oxopropoxy)methyl ester; N-[N-[L-1-carboxy-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)-methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl-β-alanine, (2,2-dimethyl-1-oxopropoxy)methyl ester; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)-methoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine, (2,2-dimethyl-1-methyl ester; N-[N-[L-1-carboxy-2-phenylethyl]-L-phenylalanyl]-L-(1-methyl)-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-L-(1-methyl)-β-alanine, (2,2-dimethyl-1-oxopropoxy)methyl ester; N-[N-[(L-1-carboxy-2-phenylethyl)]-L-phenylalanyl]-β-alanine, 2-phenoxyethyl ester; N-[N-[(L-1-carboxy-3-phenylpropyl)]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-.beta.-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-phenylethyl]-L-phenylalanyl-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]-carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)methoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-phenylethyl]L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxopropoxy)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[2,3-dihydroxy)-1-propoxy]-carbonyl]-2-(4-phenyl)-phenylethyl]-L-(4-phenyl)-phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]-carbonyl]-2-phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)-methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-D,L-α-methyl -β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]-carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]-carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2-phenoxy)ethoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(1-oxo-3-isobenzofuranyloxy)]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,3-dihydroxy)-1-propoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-(4-phenyl)phenylethyl]-L-(4-phenyl)phenylalanyl]-D,L-α-methyl-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-2-thienylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)-methoxy]carbonyl]-2-phenylethyl]-L-3-thienylalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-2-furoalanyl]-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-L-α-hydroxy-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-D-α-hydroxy-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-L-α-methoxy-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1-oxypropoxy)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-D-α-methoxy-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-R-α-hydroxy-β-alanine; N-[N-[L-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-(L)-phenylalanyl]-β-alanine, hemimaleate; N-[N-[(L)1-carboxy-2-phenylethyl)]-L-phenyl-alanyl]-S-2-[N-[(1,1-dimethylethoxy)carbonyl]amino-β-alanine; or a pharmaceutically acceptable salt of such a compound.

Claim 4

Dependent Claim 68 words

The method defined in claim 1 wherein R 1 is benzyl, p-chlorobenzyl, p-methoxybenzyl, p-methylbenzyl, p-phenylbenzyl, 2-phenylethyl or 1- and 2-naphthylmethyl; R 2 and R 6 may be the same or different and are hydroxy, methoxy, ethoxy, benzyloxy, 2-phenoxyethoxy, 1-glyceryl, ##STR9## or pivaloyloxymethoxy; R 3 is benzyl, p-methylbenzyl, p-phenylbenzyl, 1-naphthylmethyl or 3-thienylmethyl; R 4 is hydrogen, methyl or benzyl; R 5 is hydrogen; and p is 1 or 2.

Claim 5

Dependent Claim 48 words

The method defined in claim 1 wherein R 1 is benzyl or p-phenylbenzyl; R 2 is hydroxy, 2-phenoxyethoxy, 1-glyceryl, ##STR10## pivaloyloxymethoxy or benzyloxy; R 3 is benzyl or p-phenylbenzyl; R 4 is hydrogen, methyl or benzyl; R 5 is hydrogen; R 6 is hydroxy; and p is 1.

Claim 6

Dependent Claim 19 words

The method defined in claim 3 wherein R 2 is 2-phenoxy-ethoxy, 1-glyceryl, pivaloyloxymethoxy, ##STR11## and R 6 is hydroxy.

Claim 7

Dependent Claim 19 words

The method defined in claim 3 wherein R 2 is hydroxy and R 6 is 2-phenoxyethoxy, 1-glyceryl, pivaloyloxymethoxy, ##STR12##

Claim 8

Dependent Claim 10 words

The method defined in claim 1 wherein p is 1.

Claim 9

Dependent Claim 23 words

The method as defined in claim 1 wherein the compound administered has the name N-[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy]-carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine, or a diasterioisomer and/or pharmaceutically acceptable salt thereof.

Claim 10

Dependent Claim 23 words

The method as defined in claim 8 wherein the compound is in the form of a 1 to 1 salt with maleic acid.

Claim 11

Dependent Claim 21 words

The method as defined in claim 1 wherein the compound administered has the name N-[N-[L-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy]-carbonyl]-2-phenylethyl]-L-phenylalanyl]-R-α-hydroxy-β-alanine, or a pharmaceutically acceptable salt thereof.

Claim 12

Dependent Claim 24 words

The method as defined in claim 1 wherein the compound administered has the name N-[N-[(L-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-β-alanine, or a a diasterioisomer and/or pharmaceutically acceptable salt thereof.

Claim 13

Dependent Claim 22 words

The method according to claim 1 wherein the compound administered has the name N-[N-[(L)-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]phenylethyl]-L-phenylalanyl]-β-alanine or a diasterioisomer and/or pharmaceutically acceptable salt thereof.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1993-03-05	1993-09-04	1994-03-06	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1997-03-05	1997-09-04	1998-03-06	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2001-03-05	2001-09-04	2002-03-06	$7700.00	Window Closed / Lapsed

Substituted dipeptides as inhibitors of enkephalinases

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