Compounds and compositions as cathepsin S inhibitors

Details Compounds and compositions as cathepsin S inhibitors Compounds and compositions as cathepsin S inhibitors

2000-09-15

2002-12-10

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S415000, C514S438000, C514S448000, C514S238500, C544S169000, C544S130000, C544S160000, C544S163000, C548S504000, C558S397000, C549S071000

Reexamination Certificate

active

06492362

ABSTRACT:

THE INVENTION
This Application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsin S.
DESCRIPTION OF THE FIELD
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. An increase in cathepsin S activity contributes to the pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases.
SUMMARY OF THE INVENTION
This Application relates to compounds of Formula I:
in which:
X
1
and X
2
are both methylene or X
1
is ethylene and X
2
is a bond;
R
1
is hydrogen and R
2
is cyano, hetero(C
5
)aryl or (C
1-4
)alkyl-substituted hetero(C
5
)aryl or both R
1
and R
2
are hydrogen, halo, (C
1-4
)alkyl or —X
3
OR
9
, wherein X
3
and R
9
are as defined below, or R
1
and R
2
together with the carbon atom to which both R
1
and R
2
are attached form (C
3-8
)cycloalkylene or (C
3-8
)heterocycloalkylene;
R
3
is —CR
5
═CHR
6
or —CR
7
═NR
8
, wherein R
5
and R
6
together with the atoms to which R
5
and R
6
are attached form (C
2-6
)alkenyl, (C
5-12
)cycloalkenyl, hetero(C
5-12
)cycloalkenyl, (C
6-12
)aryl, hetero(C
6-12
)aryl, (C
9-12
)bicycloaryl or hetero(C
8-12
)bicycloaryl and R
7
and R
8
together with the atoms to which R
7
and R
8
are attached form hetero(C
5-12
)cycloalkenyl, hetero(C
6-12
)aryl or hetero(C
8-12
)bicycloaryl, wherein R
3
optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C
1-4
)alkyl, cyano, halo, halo-substituted (C
1-4
)alkyl, nitro, —X
3
NR
9
R
9
, —X
3
OR
9
, —X
3
SR
9
, —X
3
C(O)NR
9
R
9
, —X
3
C(O)OR
9
, —X
3
S(O)R
10
, —X
3
S(O)
2
R
10
and —X
3
C(O)R
10
, wherein X
3
is a bond or (C
1-2
)alkylene, R
9
at each occurrence independently is hydrogen, (C
1-3
)alkyl or halo-substituted (C
1-3
)alkyl and R
10
is (C
1-3
)alkyl or halo-substituted (C
1-3
)alkyl; and
R
4
is —C(O)X
4
R
11
or —S(O)
2
X
4
R
11
, wherein X
4
is a bond, —O— or —NR
12
—, wherein R
12
is hydrogen or (C
1-6
)alkyl, and R
11
is (i) (C
1-6
)alkyl optionally substituted by —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
13
, —C(O)R
13
, —C(O)OR
3
, —C(O)NR
13
R
14
, —NR
13
R
14
, —NR
14
C(O)R
13
, —NR
14
C(O)OR
13
, —NR
14
C(O)NR
13
R
14
or —NR
14
C(NR
14
)NR
13
R
14
, wherein R
13
is (C
3-12
)cycloalkyl(C
0-3
)alkyl, hetero(C
5-12
)cycloalkyl(C
0-3
)alkyl, (C
6-12
)aryl(C
0-3
)alkyl, hetero(C
5-12
)aryl(C
0-3
)alkyl, (C
9-12
)bicycloaryl(C
0-3
)alkyl or hetero(C
8-12
)bicycloaryl(C
0-3
)alkyl and R
14
at each occurrence independently is hydrogen or (C
1-6
)alkyl, or (ii) (C
3-12
)cycloalkyl(C
0-3
)alkyl, hetero(C
5-12
)cycloalkyl(C
0-3
)alkyl, (C
6-12
)aryl(C
0-3
)alkyl, hetero(C
5-12
)aryl(C
0-3
)alkly, (C
9-12
)bicycloaryl(C
0-3
)alkyl or hetero(C
8-12
)bicycloaryl(C
0-3
)alkyl or (iii) (C
3-6
)cycloalkyl(C
0-3
)alkyl, hetero(C
5-6
)cycloalkyl(C
0-3
)alkyl, phenyl(C
0-3
)alkyl or hetero(C
5-6
)aryl(C
0-3
)alkyl substituted by —X
5
OR
15
, —X
5
SR
15
, —X
5
S(O)R
15
, —X
5
S(O)
2
R
15
, —X
5
C(O)R
15
, —X
5
C(O)OR
15
, —X
5
C(O)NR
15
R
16
, —X
5
NR
15
R
16
, —X
5
NR
16
C(O)R
15
, —X
5
NR
16
C(O)OR
15
, —X
5
NR
16
C(O)NR
15
R
16
or —X
5
NR
16
C(NR
16
)NR
15
R
16
, wherein X
5
is a bond or methylene, R
15
is (C
3-6
)cycloalkyl(C
0-3
)alkyl, hetero(C
5-6
)cycloalkyl(C
0-3
)alkyl, phenyl(C
0-3
)alkyl or hetero(C
5-6
)aryl(C
0-3
)alkyl and R
16
is hydrogen or (C
1-6
)alkyl; wherein R
4
optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C
1-6
)alkyl, (C
1-6
)alkylidene, cyano, halo, nitro, halo-substituted (C
1-3
)alkyl, —X
5
NR
17
R
17
, —X
5
NR
17
C(O)OR
17
, —X
5
NR
17
C(O)NR
17
R
17
, —X
5
NR
17
C(NR
17
)NR
17
R
17
, —X
5
OR
17
—X
5
SR
17
, —X
5
C(O)OR
17
, —X
5
C(O)NR
17
R
17
, —X
5
S(O)
2
NR
17
R
17
, —X
5
P(O)(OR
8
)OR
17
, —X
5
OP(O)(OR
8
)OR
17
, —X
5
NR
17
C(O)R
18
, —X
5
S(O)R
18
, —X
5
S(O)
2
R
18
and —X
5
C(O)R
18
and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR
17
R
17
, —NR C(O)OR
17
, —NR
17
C(O)NR
17
R
17
, —NR
17
C(NR
17
)NR
17
R
17
, —OR
17
, —SR
17
, —C(O)OR
17
, —C(O)NR
17
R
17
, —S(O)
2
NR
17
R
17
, —P(O)(OR
17
)OR
17
, —OP(O)(OR
17
) OR
17
, —NR
17
C(O)R
18
, —S(O)R
18
, —S(O)
2
R
18
and —C(O)R
18
, wherein X
5
is a bond or (C
1-6
)alkylene, R
17
at each occurrence independently is hydrogen, (C
1-6
)alkyl or halo-substituted (C
1-3
)alkyl and R
18
is (C
1-6
)alkyl or halo-substituted (C
1-3
)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
A second aspect of the invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
A third aspect of the invention is a method for treating a disease in an animal in which inhibition of cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof.
A fourth aspect of the invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.
“Alicyclic” means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
“Aliphatic” means a moiety characterized by a straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
“Alkyl” represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C
1-6
)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C
6-12
)aryl(C
0-3
)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
“Alkylene”, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radi

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