Phosphinic peptide derivatives for use as MMP-12 inhibitors

Patent metadata

Field	Value
Publication number	US-10179797-B2
Application number	US-201615774649-A
Country	US
Kind code	B2
Filing date	Nov 23, 2016
Priority date	Nov 30, 2015
Publication date	Jan 15, 2019
Grant date	Jan 15, 2019

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

The invention claimed is:

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 aryl C 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 chain of an amino acid.

3. The 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, asparagine and cysteine.

4. The 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.

5. The compound according to claim 1 ,
wherein
n is 0, 1 or 2,
R 1 is H or an amino acid side chain selected from the group consisting 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 or methyl, 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. The compound according to claim 1 ,
wherein
n is 0 or 2,
R 1 is H or an amino acid side chain selected from the group consisting 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. The compound according to claim 1 , which is a compound selected from the group consisting of:

(I)-a

(I)-b

(I)-c

(I)-d

(I)-e

(I)-f

(I)-g

(I)-h

(I)-i

(I)-j

(I)-k

(I)-l

(I)-m

(I)-n

(I)-o

(I)-p

(I)-q

(I)-r

8. The compound according to claim 1 , which is a compound selected from the group consisting of:

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

3-yl)-1-methoxy-1-oxopropan-2-yl)amino)-3-

oxopropyl)(phenethyl)phosphinic acid

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

phosphoryl)methyl)propanoyl)-L-alloisoleucine

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

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-
(I)-D

butoxycarbonyl)amino)-1-methoxy-1-oxobutan-2-

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

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

butoxy)-4-methyl-1-oxopentan-2-yl)amino)-3-

oxopropyl)(phenethyl)phosphinic acid

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

(benzyloxy)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)-

3-oxopropyl)(phenethyl)phosphinic acid

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

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

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

phosphoryl)methyl)propanoyl)-L-asparagine

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

phosphoryl)methyl)propanoyl)-L-alanine

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

phosphoryl)methyl)propanoyl)-L-tryptophan

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

4-(3-([1,1′-biphenyl]-4-yl)-2-((hydroxy(phenethyl)-
(I)-L

phosphoryl)methyl)propanamido)butyric acid

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

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

• C07C53/18

  containing fluorine · CPC title

• A61Q19/08

  Anti-ageing preparations · CPC title

• C07F9/5728

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• A61K31/16

  Amides, e.g. hydroxamic acids · CPC title