Compounds and compositions as protease inhibitors

Details Compounds and compositions as protease inhibitors Compounds and compositions as protease inhibitors

2001-12-14

2003-07-15

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254020, C514S326000, C514S342000, C544S121000, C544S133000, C544S360000, C544S369000, C544S372000, C544S390000, C546S209000, C546S270400, C546S270700, C548S194000

Reexamination Certificate

active

06593327

ABSTRACT:

THE INVENTION
This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or 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, peeiodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
SUMMARY OF THE INVENTION
This Application relates to compounds of Formula I:
in which:
R
1
is a group of Formula (a) or (b):
 wherein:
X
1
and X
2
independently are —C(O)— or —CH
2
S(O)
2
—;
R
5
and R
6
independently are hydrogen, (C
1-6
)alkyl or as defined below;
R
7
and R
8
independently are hydrogen or (C
1-6
)alkyl or as defined below;
R
9
and R
10
independently are (i) (C
1-6
)alkyl optionally substituted with cyano, halo, halo-substituted (C
1-3
)alkyl, nitro, —NR
12
R
12
, —NR
12
C(O)OR
12
, —NR
12
C(O)NR
12
R
12
, —NR
12
C(NR
12
)NR
12
R
12
, —OR
12
, —SR
12
, —C(O)OR
12
, —OC(O)R
12
, —C(O)NR
12
R
12
, —S(O)
2
NR
12
R
12
, —P(O)(OR
12
)OR
12
, —OP(O)(OR
12
)OR
12
, —NR
12
C(O)R
13
, —S(O)R
13
, —S(O)
2
R
13
, —C(O)R
13
, —OR
14
, —SR
14
, —S(O)R
14
, —S(O)
2
R
14
, —C(O)R
14
, —C(O)OR
14
, —OC(O)R
14
, —NR
14
R
15
, —NR
15
C(O)R
14
, —NR
15
C(O)OR
14
, —C(O)NR
14
R
15
, —S(O)
2
NR
14
R
15
, —NR
15
C(O)NR
14
R
15
or —NR
15
C(NR
15
)NR
14
R
15
, wherein R
12
at each occurrence independently is hydrogen, (C
1-6
)alkyl or halo-substituted (C
1-3
)alkyl, R
13
is (C
1-6
)alkyl or halosubstituted (C
1-3
)alkyl, R
14
is (C
3-12
)cycloalkyl(C
0-6
)alkyl, hetero(C
3-12
)cycloalkyl(C
0-6
)alkyl, (C
6-12
)aryl(C
0-6
)alkyl, hetero(C
5-12
)aryl(C
0-6
)alkyl, (C
9-12
)polycycloaryl(C
0-6
)alkyl or hetero(C
8-12
)polycycloaryl(C
0-6
)alkyl and R
15
is hydrogen or (C
1-6
)alkyl, and wherein within R
14
said cycloalkyl, heterocycloalkyl, aryl, heteroary, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R
16
, —X
3
OR
16
, —X
3
SR
16
, —X
3
S(O)R
16
, —X
3
S(O)
2
R
16
, —X
3
C(O)R
16
, —X
3
C(O)OR
16
, —X
3
OC(O)R
16
, —X
3
NR
16
R
17
, —X
3
NR
17
C(O)R
16
, —X
3
NR
17
C(O)OR
16
, —X
3
C(O)NR
16
R
17
, —X
3
S(O)
2
NR
16
R
17
, —X
3
NR
17
C(O)NR
16
R
17
or —X
3
NR
17
C(NR
17
)NR
16
R
17
, wherein X
3
is a bond or (C
1-6
)alkylene, R
16
is hydrogen or (C
1-6
)alkyl and R
17
is (C
3-12
)cycloalkyl(C
0-6
)alkyl, hetero(C
3-12
)cycloalkyl(C
0-6
)alkyl, (C
6-12
)aryl(C
0-6
)alkyl, hetero(C
5-12
)aryl(C
0-6
)alkyl, (C
9-12
)polycycloaryl(C
0-6
)alkyl or hetero(C
8-12
)polycycloaryl(C
0-6
)alkyl, or (ii) a group selected from (C
3-12
)Cycloalkyl(C
0-6
)alky), hetero(C
3-12
)cycloalkyl(C
0-6
)alkyl, (C
6-12
)aryl(C
0-6
)alkyl, hetero(C
5-12
)aryl(C
0-6
)alkyl, (C
9-12
)polycycloaryl(C
0-6
)alkyl and hetero(C
8-12
)polycycloaryl(C
0-6
)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R
16
, —X
3
OR
16
, —X
3
SR
16
, —X
3
S(O)R
16
, —X
3
S(O)
2
R
16
, —X
3
C(O)R
16
, —X
3
C(O)OR
16
, —X
3
OC(O)R
16
, —X
3
NR
16
R
17
, X
3
NR
17
C(O)R
16
, —X
3
NR
17
C(O)OR
16
, —X
3
C(O)NR
16
R
17
, —X
3
S(O)
2
NR
16
R
17
, —X
3
NR
17
C(O)NR
16
R
17
or —X
3
NR
17
C(NR
17
)NR
16
R
17
, wherein X
3
, R
16
and R
17
are as defined above; wherein within R
9
and/or R
10
any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C
1-6
)alkyl, (C
1-6
)alkylidene, cyano, halo, halo-substituted (C
1-4
)alkyl, nitro, —X
3
NR
12
R
12
, —X
3
NR
12
C(O)OR
12
, —X
3
NR
12
C(O)NR
12
R
12
, —X
3
NR
12
C(NR
12
)NR
12
R
12
, —X
3
OR
12
, —X
3
SR
12
, —X
3
C(O)OR
12
, —X
3
C(O)NR
12
R
12
, —X
3
S(O)
2
NR
12
R
12
, —X
3
P(O)(OR
3
)OR
12
, —X
3
OP(O)(OR
3
)OR
12
, —X
3
NR
12
C(O)R
13
, —X
3
S(O)R
13
, —X
3
S(O)
2
R
13
and —X
3
C(O)R
13
, wherein X
3
, R
12
and R
13
are as defined above; or
R
9
together with R
7
and/or R
10
together with R
8
form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C
1-4
)alkyl or methylene; or
R
9
and R
5
together with the carbon atom to which both R
9
and R
5
are attached and/or R
10
and R
6
together with the carbon atom to which both R
10
and R
6
are attached form (C
3-8
)cycloalkylene or (C
3-8
)heterocycloalkylene; and
R
11
is —X
4
X
5
R
18
, wherein X
4
is —C(O)—, —C(O)C(O)— or —S(O)
2
—, X
5
is a bond, —O— or —NR
19
—, wherein R
19
is hydrogen or (C
1-6
)alkyl, and R
18
is (i) (C
1-6
)alkyl optionally substituted by cyano, halo, halo-substituted (C
1-3
)alkyl, nitro, —NR
14
R
14
, —NR
14
C(O)OR
14
, —NR
14
C(O)NR
14
R
14
, —NR
14
C(NR
14
)NR
14
R
14
, —OR
14
, —SR
14
, —C(O)OR
14
, —C(O)NR
14
R
14
, —S(O)
2
NR
14
R
14
, —P(O)(OR
14
)OR
14
, —OP(O)(OR
14
)OR
14
, —NR
14
C(O)R
15
, —S(O)R
15
, —S(O)
2
R
15
, —C(O)R
15
, —OR
20
, —SR
20
, —S(O)R
20
, —S(O)
2
R
20
, —C(O)R
20
, —C(O)OR
20
, —C(O)NR
20
R
21
, —NR
20
R
21
, —NR
21
C(O)R
20
, —NR
21
C(O)OR
20
, —NR
21
C(O)NR
20
R
21
or —NR
21
C(NR
21
)NR
20
R
21
, wherein R
14
and R
15
are as defined above, R
20
is (C
3-12
)cycloalkyl(C
0-6
)alkyl, hetero(C
3-12
)cycloalkyl(C
0-6
)alkyl, (C
6-12
)aryl(C
0-6
)alkyl, hetero(C
5-12
)aryl(C
0-6
)alkyl, (C
9-12
)polycycloaryl(C
0-6
)alkyl or hetero(C
8-12
polycycloaryl(C
0-6
)alkyl and R
21
at each occurrence independently is hydrogen or (C
1-6
)alkyl, or (ii) (C
3-12
)cycloalky(C
0-6
)alkyl, hetero(C
3-12
)Cycloalkyl(C
0-6
)alkyl, (C
6-12
)aryl(C
0-6
)alkyl, diphenyl(C
0-6
)alkyl, hetero(C
5-12
)aryl(C
0-6
)alkyl, dihetero(C
5-6
)aryl(C
0-6
)alkyl, (C
9-12
)polycycloaryl(C
0-6
)alkyl or hetero(C
8-12
)polycycloaryl(C
0-6
)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, diphenyl, heteroaryl, diheteroaryl, polycycloaryl or heterpolycycloaryl ring may

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