N-substituted peptidyl nitriles as cysteine cathepsin...

Details N-substituted peptidyl nitriles as cysteine cathepsin... N-substituted peptidyl nitriles as cysteine cathepsin...

2002-11-07

2004-11-02

Richter, Johann (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S343000, C514S381000, C514S391000, C514S466000, C548S338100, C548S252000, C548S222000, C548S253000, C548S472000, C548S477000, C546S113000, C546S326000, C549S484000, C549S466000, C549S072000, C549S304000, C558S392000

Reexamination Certificate

active

06812237

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to novel cysteine cathepsin inhibitors and their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsins are implicated.
The cysteine cathepsins, e.g. cathepsins B, L and S, are a class of lysosomal enzymes which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases (including asthma and chronic obstructive pulmonary disease), infectious diseases and immunologically mediated diseases (including transplant rejection).
The compounds of the invention are particularly useful as cathepsin inhibitors, primarily as cathepsin B inhibitors, and can be used for the treatment of the above-cited cathepsin dependent conditions.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the novel cathepsin inhibitors of the formula
wherein
R
1
is aryl or biaryl;
R
2
is aryl-lower alkyl, biaryl-lower alkyl, benzo-fused cycloalkyl, cycloalkyl-lower alkyl, bicycloalkyl-lower alkyl, aryloxy-lower alkyl, or aryl-C
2
-C
7
-alkyl in which C
2
-C
7
-alkyl is interrupted by Y;
Y is O, S, SO, SO
2
, CO or NR
6
;
R
3
is hydrogen or lower alkyl; or
R
2
and R
3
combined are C
2
-C
7
-alkylene or C
2
-C
7
-alkylene interrupted by Y;
R
4
is hydrogen or lower alkyl;
R
5
is hydrogen, optionally substituted lower alkyl, aryl-lower alkyl, biaryl-lower alkyl, cycloalkyl-lower alkyl, bicycloalkyl-lower alkyl, aryloxy-lower alkyl, or aryl-C
2
-C
7
-alkyl in which C
2
-C
7
-alkyl is interrupted by Y;
R
6
is hydrogen, lower alkyl or aryl-lower alkyl;
and pharmaceutically acceptable salts thereof.
A particular embodiment of the invention relates to the compounds of formula I wherein R
5
represents the grouping
—X—Ar—Q—Z
in which X is lower alkylene, lower alkyleneoxy or C
2
-C
7
-alkylene interrupted by Y; Ar is monocyclic carbocyclic or monocyclic heterocyclic arylene; Q is a direct bond, lower alkylene, or thio- or oxy-lower alkylene: Z is hydroxy, acyloxy, carboxyl, or carboxyl derivatized as a pharmaceutically acceptable ester or amide; or Z is 5-tetrazolyl; Y is O, S, SO, SO
2
or NR
6
; and R
6
is hydrogen, lower alkyl or aryl-lower alkyl; and pharmaceutically acceptable salts thereof.
A specific embodiment of the invention relates to the compounds of formula II
wherein
R
1
is aryl or biaryl;
R′
2
aryl-lower alkyl, biaryl-lower alkyl, benzo-fused cycloalkyl, cycloalkyl-lower alkyl or bicycloalkyl-lower alkyl;
Ar is monocyclic carbocyclic or monocyclic heterocyclic arylene;
X′ is lower alkylene or C
2
-C
7
-alkylene interrupted by Y′;
Y′ is O or S;
Q is a direct bond, lower alkylene, or thio- or oxy-lower alkylene; and
Z′ is carboxyl, carboxyl derivatized as a pharmaceutically acceptable ester or amide, 5-tetrazolyl, or hydroxymethyl;
and pharmaceutically acceptable salts thereof.
A specific embodiment of the invention is directed to compounds of formula II wherein R
1
is aryl; R′
2
is aryl-lower alkyl, X′ is C
1
-C
5
-alkylene, or X′ is C
2
-C
4
-alkylene interrupted by O or S; Ar is monocyclic carbocyclic arylene; Q is a direct bond, oxy-C
1
-C
4
-alkylene or C
1
-C
4
-alkylene; and Z′ is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
A more specific embodiment of the invention is directed to compounds of formula If wherein R
1
is monocyclic carbocyclic aryl; R′
2
is carbocyclic aryl-methyl; X′ is C
1
-C
3
-alkylene; or X′ is C
2
-alkylene interrupted by O; Ar is monocarbocyclic arylene; Q is a direct bond or oxymethylene; Z′ is carboxyl, carboxyl derivatized as a pharmaceutically acceptable ester, or 5-tetrazolyl; and pharmaceutically acceptable salts thereof.
A particular embodiment of the invention relates to the compounds of the formula IIa
wherein R′
2
, X′, Ar, Q and Z′ have meaning as defined above, W represents O, CH
2
or NR
6
in which R
6
is lower alkyl; and R
7
and R
8
independently represent hydrogen or lower alkyl; or R
7
and R
8
together represent oxo; and pharmaceutically acceptable salts thereof.
Another embodiment of the invention relates to compounds of formula III
wherein
R
1
is aryl or biaryl;
R″
2
is aryl-lower alkyl, biaryl-lower alkyl, cycloalkyl-lower alkyl or bicycloalkyl-lower alkyl;
Ar is monocyclic carbocyclic or monocyclic heterocyclic arylene;
X″ is lower alkylene;
Q′ is a direct bond or lower alkylene;
Z″ is carboxyl, carboxyl derivatized as a pharmaceutically acceptable ester, or 5-tetrazolyl;
and pharmaceutically acceptable salts thereof.
A specific embodiment of the invention relates to compounds of formula III wherein R
1
is monocyclic carbocyclic or heterocyclic aryl; R″
2
is aryl-lower alkyl; Q′ is a direct bond or lower alkylene; and Z″ is carboxyl; and pharmaceutically acceptable salts thereof.
A more specific embodiment relates to the compounds of formula III wherein R
1
is monocyclic carbocyclic aryl; R″
2
is carbocyclic aryl-methyl; X″ is C
3
-alkylene; Ar is monocyclic carbocyclic arylene; Q′ is a direct bond; Z″ is carboxyl; and pharmaceutically acceptable salts thereof.
The compounds of the invention depending on the nature of substituents, possess one or more asymmetric carbons. The resulting diastereomers and enantiomers are encompassed by the instant invention.
Preferred are the compounds of the invention wherein the asymmetric carbon to which are attached R
2
and/or R
3
corresponds to that of an L-amino acid precursor and the asymmetric carbon to which is attached the cyano group also corresponds to that of an L-amino acid; both asymmetric centers are typically assigned the (S)-configuration. As an illustration, the preferred compounds of the formula I wherein R
3
and R
4
represent hydrogen can be represented by formula IV
wherein R
1
, R
2
and R
5
have meaning as previously defined.
Particularly preferred are the compounds of the formula V
wherein R′
1
and Ra are aryl; W is O or CH
2
; Ar′ is arylene selected from pyridylene, furanylene, thienylene, thiazolylene, phenylene or phenylene substituted by 1 to 3 of alkyl or halo; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable esters thereof.
Further preferred are the compounds of formula V wherein R′
1
and Ra are independently phthalidyl, phenyl, or phenyl mono-, di- or tri-substituted by lower alkyl, halo, trifluoromethyl, cyano, nitro, hydroxy, acyloxy, acyl, carboxyl, lower alkylsulfonyl, or esterified or amidated carboxyl; W is O; Ar′ is 1,3-phenylene or 1,3-phenylene mono- or di-substituted by chloro or fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable esters thereof.
Especially preferred are the compounds of formula V wherein R′
1
is phthalidyl, phenyl, or phenyl mono- or disubstituted by halo, lower alkyl or esterified or amidated carboxyl; Ra is 3-tolyl; W is O; Ar′ is 1,3-phenylene or 1,3-phenylene mono- or disubstituted by chloro or fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable esters thereof.
Further preferred are the compounds of formula V wherein R′
1
is phenyl; Ra is 3-tolyl; W is O; Ar′ is 1,3-phenylene or 1,3-phenylene mono- or disubstituted by chloro or fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable esters thereof.
The general definitions used herein have the following meaning within the scope of the invention, unless otherwise specified.
The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines such as branched or unbranched with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
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