Phosphinic peptide derivatives for use as mmp-12 inhibitors

Patent metadata

Field	Value
Publication number	US-2018319829-A1
Application number	US-201615774649-A
Country	US
Kind code	A1
Filing date	Nov 23, 2016
Priority date	Nov 30, 2015
Publication date	Nov 8, 2018
Grant date	—

Abstract

This invention relates to compounds that are selective inhibitors of Matrix Metalloprotease-12 (MMP-12), to cosmetic and pharmaceutical compositions containing them, and to their use in the prevention and/or treatment of ailments associated with MMP-12. Formula (I).

First claim

1 . A compound of formula (I)

wherein n is 0, 1 or 2,
R 1 is H, or an amino acid side chain which, if a functional group is present, may optionally be substituted by a C 1 -C 6 alkyl group, a C 1 -C 6 alkylcarbonyl group or a C 1 -C 6 alkoxycarbonyl group,
R 2 is H or Methyl, and
R 3 is selected from the group consisting of H, a C 1 -C 6 alkyl group and an arylC 1 -C 6 alkanyl group

or a cosmetically acceptable salt thereof.

2 . The compound according to claim 1 , wherein the amino acid side chain is a nonpolar or an uncharged polar side chains of an amino acid.

3 . A compound according to claim 1 , wherein the amino acid side chain is selected from the side chains of glutamine, phenylalanine, methionine, valine, glycine, 2,4-diaminobutyric acid, 2-aminobutyric acid, alanine, leucine, isoleucine, norleucine, tryptophan, thiotryptophan, cyclohexylglycine, α-amino-2-naphthalenepropionic acid, serine, threonine, tyrosine, proline and cysteine, preferably of phenylalanine, methionine, valine, thiotryptophan, isoleucine, tryptophan, 2,4-diaminobutyric acid, leucine, α-amino-2-naphthalenepropionic acid, norleucine, asparagine, alanine, 2-amino butyric acid, and cyclohexylglycine, most preferably of thiotryptophan, isoleucine, tryptophan, 2,4-diaminobutyric acid, leucine, α-amino-2-naphthalenepropionic acid, norleucine, asparagine, alanine, 2-amino butyric acid, and cyclohexylglycine

4 . A compound according to claim 1 , wherein the amino acid side chain has a functional group which is substituted with a C 1 -C 6 alkoxycarbonyl group, preferably with a tert-Butyloxycarbonyl (Boc) group.

5 . A compound according to claim 1 ,
wherein n is 0, 1 or 2,
R 1 is H or an amino acid side chain of thiotryptophan, isoleucine, tryptophan, 2,4-diaminobutyric acid, leucine, a-amino-2-naphthalenepropionic acid, norleucine, asparagine, alanine, 2-amino butyric acid, cyclohexylglycine, 2-amino-4-(tert-butoxycarbonylamino)butyric acid and 1-[(1,1-dimethylethoxy)carbonyl]-tryptophan
R 2 is H or methyl, preferably H, and
R 3 is selected from the group consisting of H, a methyl group, a tert.-butyl group and a benzyl group,
or a cosmetically acceptable salt thereof.

6 . A compound according to claim 1 ,
wherein n is 0 or 2,
R 1 is H or an amino acid side chain of thiotryptophan, isoleucine, tryptophan, 2,4-diaminobutyric acid, leucine, α-amino-2-naphthalenepropionic acid, norleucine, asparagine, alanine, 2-amino butyric acid, cyclohexylglycine, 2-amino-4-(tert-butoxycarbonylamino)butyric acid and 1-[(1,1-dimethylethoxy)carbonyl]-tryptophan
R 2 is H and
R 3 is selected from the group consisting of H, a methyl group, a tert.-butyl group and a benzyl group,
or a cosmetically acceptable salt thereof.

7 . A compound according to claim 1 , which is

8 . A compound according to claim 1 , which is

Name

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-3-(benzo[b]thiophen-3-yl)-1-methoxy-
(I)-A

1-oxopropan-2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((2S)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-B

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-alloisoleucine

((2S)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-C

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-tryptophan salt with 2,2,2-

trifluoroacetic acid (1:1)

((R)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-4-((tert-butoxycarbonyl)amino)-1-
(I)-D

methoxy-1-oxobutan-2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-(tert-butoxy)-4-methyl-1-oxopentan-
(I)-F

2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((R)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-(benzyloxy)-3-(naphthalen-2-yl)-1-
(I)-G

oxopropan-2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-methoxy-1-oxohexan-2-yl)amino)-3-
(I)-H

oxopropyl)(phenethyl)phosphinic acid

((2R)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-I

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-asparagine

((2S)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-J

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-alanine

((2R)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-K

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-tryptophan compound with

2,2,2-trifluoroacetic acid (1:1)

4-(3-([1,1′-biphenyl]-4-yl)-2-
(I)-L

((hydroxy(phenethyl)phosphoryl)methyl)propanamido)butyric acid

(2S)-2-((2R)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-M

((hydroxy(phenethyl)phosphoryl)methyl)propanamido)-3-(benzo[b]thiophen-3-

yl)propanoic acid

(2S)-2-((2R)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-N

((hydroxy(phenethyl)phosphoryl)methyl)propanamido)hexanoic acid

((2S)-3-([1,1′-biphenyl]-4-yl)-2-
(I)-O

((hydroxy(phenethyl)phosphoryl)methyl)propanoyl)-L-asparagine

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-(tert-butoxy)-1-oxobutan-2-
(I)-P

yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-(benzyloxy)-3-(naphthalen-2-yl)-1-
(I)-Q

oxopropan-2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

(2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-(tert-butoxy)-3-(1-(tert-butoxycarbonyl)-
(I)-R

1H-indol-3-yl)-1-oxopropan-2-yl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((S)-2-([1,1′-biphenyl]-4-ylmethyl)-3-(((S)-1-cyclohexyl-2-methoxy-2-
(I)-S

oxoethyl)amino)-3-oxopropyl)(phenethyl)phosphinic acid

((R)-

Assignees

• Dsm Ip Assets Bv

Inventors

• Boudon Stéphanie
• Jackson Eileen
• Schuetz Rolf
• Vollhardt Jürgen Herbert
• Wikstroem Peter
• Wandeler Eliane Ursula

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K8/64

  Proteins; Peptides; Derivatives or degradation products thereof · CPC title

• C07F9/655354 Primary

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• A61K31/662

  Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon · CPC title

• A61Q19/08

  Anti-ageing preparations · CPC title