Substituted dipeptides as inhibitors of enkephalinases
First Claim
1. A method for inhibiting the action of enkephalinases in a mammal to thereby elicit an analgesic effect in said mammal, which method comprises administering an enkephalinase inhibitory effective amount of a compound having structural formula I
or a racemate, enantiomer and diasterioisomer thereof or a pharmaceutically acceptable salts thereof to said mammal wherein;
R1 is alkyl having from 1to 6 carbon atoms, adamantylmethyl, cycloakylmethyl having from 4 to 8 carbon atoms or A--Xm --Cn H2 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;
R2 and R6 may be the same or different and are hydroxy, alkoxy having from 1 to 8 carbon atoms, B--Xm--Cn H2 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, --OCH2 OCO-alkyl having from 3 to 8 carbon atoms, --OCH2 CO-phenyl {the phenyl ring of which may be substituted with the group, Y, as defined herein}, 1-glyceryl, ##STR8## wherein Rb 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 R8 is hydrogen or alkyl having from 1 to 6 carbon atoms;
R2 may also --NR7 R8 wherein R7 and R8 are as defined herein;
R3 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;
R4 is D--Cn H2n --Om --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;
R4 may also be --NR5 COR7 {wherein R5 and R7 are defined herein}, and --NR5 CO2 R9 {wherein R5 is defined herein and R9 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;
R5 is hydrogen or alkyl having from 1 to 6 carbon atoms; and
p is 0, 1 or 2.
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Accused Products
Abstract
A method for inhibiting the action of enkephalinases in a mammal to thereby elicit an analgesic effect in said mammal is described.
Novel compound and compositions useful for accomplishing the method of the invention are also described.
23 Citations
16 Claims
- 1. A method for inhibiting the action of enkephalinases in a mammal to thereby elicit an analgesic effect in said mammal, which method comprises administering an enkephalinase inhibitory effective amount of a compound having structural formula I
- space="preserve" listing-type="equation">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
or a racemate, enantiomer and diasterioisomer thereof or a pharmaceutically acceptable salts thereof to said mammal wherein; R1 is alkyl having from 1to 6 carbon atoms, adamantylmethyl, cycloakylmethyl having from 4 to 8 carbon atoms or A--Xm --Cn H2 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;R2 and R6 may be the same or different and are hydroxy, alkoxy having from 1 to 8 carbon atoms, B--Xm--Cn H2 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, --OCH2 OCO-alkyl having from 3 to 8 carbon atoms, --OCH2 CO-phenyl {the phenyl ring of which may be substituted with the group, Y, as defined herein}, 1-glyceryl, ##STR8## wherein Rb 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 R8 is hydrogen or alkyl having from 1 to 6 carbon atoms; R2 may also --NR7 R8 wherein R7 and R8 are as defined herein; R3 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; R4 is D--Cn H2n --Om --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;R4 may also be --NR5 COR7 {wherein R5 and R7 are defined herein}, and --NR5 CO2 R9 {wherein R5 is defined herein and R9 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; R5 is hydrogen or alkyl having from 1 to 6 carbon atoms; and p is 0, 1 or 2. - View Dependent Claims (2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 14, 15, 16)
-
8. 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]-62 -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. - View Dependent Claims (10)
- -methoxy-β
Specification
-
- Resources
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Current AssigneeSchering Corporation (Merck & Co., Inc.)
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Original AssigneeSchering Corporation (Merck & Co., Inc.)
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InventorsBerger, Joel G.
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Primary Examiner(s)Phillips, Delbert R.
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Application NumberUS06/890,667Time in Patent Office550 DaysField of Search514/464, 514/467, 514/533, 514/547, 514/566US Class Current514/464CPC Class CodesA61K 38/00 Medicinal preparations cont...C07C 51/373 by introduction of function...C07C 59/84 containing six membered aro...C07D 307/89 with two oxygen atoms direc...C07D 317/24 esterifiedC07F 9/301 Acyclic saturated acids whi...C07F 9/3808 Acyclic saturated acids whi...C07F 9/4006 Esters of acyclic acids whi...C07K 5/022 containing the structure -X...C07K 5/06008 with the first amino acid b...C07K 5/06034 the side chain containing 2...C07K 5/06078 and aromatic or cycloaliphaticC07K 5/06139 with the first amino acid b...C07K 5/06191 containing heteroatoms diff...
