Aminostatin derivatives for the treatment of arthrosis

Patent metadata

Field	Value
Publication number	US-9345742-B2
Application number	US-201213983848-A
Country	US
Kind code	B2
Filing date	Jan 9, 2012
Priority date	Feb 8, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The present invention relates to compounds of the formula (I) and in particular medicaments comprising at least one compound of the formula (I) for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states in the triggering of which cathepsin D is involved, in particular for use in the treatment and/or prophylaxis of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia or hyperalgesia.

First claim

The invention claimed is:

1. A compound selected from the following compounds:
a.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-2-((S)-2-tert-butoxy-carbonylamino-4-methylpentanoylamino)butyrylamino]-5-phenyl-pentanoyl amino}-3-methylpentanoylamino)-3-methylbutyrate
b.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-2-((S)-2-amino-4-methylpentanoylamino)butyrylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
c.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-4-methyl-2-(3-methyl-butyrylamino)pentanoylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
d.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]-1-oxobutylamino}-5-phenylpentanoyl-amino)-3-methylpentanoylamino]-3-methylbutyrate
c.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[2-(3-trifluoromethoxyphenyl)acetylamino]butyrylamino}-5-phenylpentanoyl-amino)-3-methylpentanoylamino]-3-methylbutyrate
f.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[2-(naphthalen-1-yloxy)acetylamino]butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
g.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-2-[2-(3-methane-sulfonylaminophenyl)acetylamino]-3-methylbutyrylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
h.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]-1-oxobutylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
i.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]-3-phenylpropionylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
j.) ethyl 1-[(2S,3S)-2-((S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoyl-amino)-3-methylpentanoylamino]cyclopropanecarboxylate
k.) methyl (2S,3S)-2-[(S)-2-((S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoylamino)-3-methyl-1-(S)-oxopentylamino]-3-methylpentanoate
l.) methyl (S)-2-[(2S,3S)-2-((S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-4-methylpentanoate
m.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-2-((S)-2-tert-butoxy-carbonylamino-4-methylpentanoylamino)-3-methylbutyrylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
n.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-3-methyl-2-(3-phenyl-propionylamino)butyrylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
o.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-4-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]pentanoylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
p.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[(S)-2-(3-methylbutyrylamino)-3-phenylpropionylamino]butyrylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
q.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-2-((S)-2-tert-butoxy-carbonylamino-3-phenylpropionylamino)-3-methylbutyrylamino]-5-phenyl-pentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
r.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(S)-2-((S)-2-amino-3-phenylpropionylamino)-3-methylbutyrylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
s.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-2-[2-(2,4-dichloro-phenoxy)acetylamino]-3-methylbutyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
t.) (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoyl-amino)-3-methylpentanoylamino]-3-methylbutyric acid
u.) N-((1S,2S)-2-methyl-1-phenethylcarbamoylbutyl)-(S)-3-amino-4-{(S)—(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoyl-amino]butyrylamino}-5-phenylpentanamide
v.) N-[(1S,2S)-2-methyl-1-(pyridin-3-ylcarbamoyl)butyl]-(S)-3-amino-4-{(S)—(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoyl-amino]butyrylamino}-5-phenylpentanamide
w.) methyl (S)-2-((2S,3S)-2-{(3S,4S)-3-amino-4-[(R)-2-((S)-2-amino-3-phenylpropionylamino)-3-methylbutyrylamino]-5-phenylpentanoylamino}-3-methylpentanoylamino)-3-methylbutyrate
x.) N-[(1S,2S)-2-methyl-1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)butyll]-(S)-3-amino-4-{(S)—(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)-pentanoylamino]butyrylamino}-5-phenylpentanamide
y.) N-((1S,2S)-1-benzylcarbamoyl-2-methylbutyl)-(S)-3-amino-4-{(S)—(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyryl amino)pentanoylamino]butyryl-amino}-5-phenylpentanamide
z.) N-[(1S,2S)-1-(cyclopropylmethylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoyl-amino]butyrylamino}-5-phenylpentanamide
aa.) methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3,3-dimethyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate
bb.) (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[2-(3-trifluoromethoxy-phenyl)acctylamino]butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyric acid
cc.) (S)-2-[(2S,3S)-2-((3S)-3-amino-4-{(S)-3-methyl-2-[(S)-2-(3-methyl-butyrylamino)-3-phenylpropionylamino]-1-oxobutylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-3-methylbutyric acid
dd.) N-[(1S,2S)-1-((S)-1-hydroxymethyl-2-methylpropylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methyl-butyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanamide
ee.) N-[(1S,2S)-2-methyl-1-(3-methylbutylcarbamoyl)butyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[2-(3-trifluoromethoxyphenyl)acetylamino]butyrylamino}-5-phenylpentanamide
ff.) (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(1S,4S)-3-methyl-2-[2-(3-trifluoromethoxyphenyl)acetylamino[pentanoylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylamino]-3-methylbutyric acid
gg.) N-[(1S,2S)-1-(1-ethylpropylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoyl-amino]butyrylamino}-5-phenylpentanamide
hh.) N-{(2S,3S)-1-[1-((S)-hydroxymethyl)-2-methylpropylcarbamoyl]-2-methylbutyl}-3-(S)-amino-4-{(S)-(2S,3S)-3-methyl-2-[2-(3-trifluoromethoxy-phenyl)acetylamino]pentanoylamino}-5-phenylpentanamide
ii.) N-[(1S,2S)-1-((S)-1-hydroxymethyl-2-methylpropylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-2-(3-methylbutyryl-amino)-3-phenylpropionylamino]butyrylamino}-5-phenylpentanamide
jj.) N-[(1S,2S)-1-(1-ethylpropylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-phenylpropionylamino)pentanoylamino]-1-oxobutylamino}-5-phenylpentanamide
kk.) N-[(1S,2S)-1-(1-ethylpropylcarbamoyl)-2-methylbutyl]-(S)-3-(S)-amino-4-{(S)-2-[(S)-2-(3,3-dimethylbutyrylamino)-4-methylpentanoylamino]-3-methyl-1-oxobutylamino}-5-phenylpentanamide
ll.) (S)-2-[(2S,3S)-2-((S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-phenylpropionylamino)pentanoylamino]-1-oxobutylamino}-5-phenyl-pentanoylamino)-3-methylpentanoylaminol]-3-methylbutyric acid
mm.) (S)-2-[(2S,3S)-2-((S)-3-(S)-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(4-trifluoromethoxybenzoylamino)pentanoylamino]-1-oxobutylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyric acid
nn.) (S)-2-((2S,3S)-2-{(S)-3-(S)-amino-4-[(S)-3-methyl-2-((S)-4-methyl-2-phenylacetylaminopentanoylamino)-1-oxobutylamino]-5-phenylpentanoyl-amino}-3-methylpentanoylamino)-3-methylbutyric acid
oo.) N—[(S)-1-(1-{(S)—(S)-2-(S)-amino-1-benzyl-3-[(1S,2S)-1-(1-ethyl-propylcarbamoyl)-2-methylbutylcarbamoyl]propylcarbamoyl}-2-methylpropylcarbamoyl)-3-methylbutyl]-4-trifluoromethoxybenzamide
pp.) (S)-2-[(2S,3S)-2-((S)-3-(S)-amino-4-{(S)-2-[(S)-2-(3,3-dimethylbutyryl-amino)-4-methylpentanoyl

Assignees

• Klein Markus
• Tsaklakidis Christos
• Guehring Hans
• Leuthner Brigitta
• Merck Patent Gmbh

Inventors

• Klein Markus
• Tsaklakidis Christos
• Guehring Hans
• Leuthner Brigitta

Classifications

• A61K38/08 Primary

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title