Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-01-05
2003-02-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S521000, C514S238500, C514S352000, C514S357000, C544S168000, C544S336000, C544S344000, C544S366000, C544S389000, C544S393000, C544S400000, C546S017000, C546S133000, C546S175000, C546S231000, C546S330000, C548S214000, C548S253000, C548S336100, C548S455000, C548S484000, C558S384000, C558S386000, C558S392000
Reexamination Certificate
active
06525036
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 increased 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. 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 osteoclast-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. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to asthma; and allogenic 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:
X
1
is selected from a group consisting of —CR
4
R
5
—, —CR
6
R
7
— and —NR
7
—, wherein:
R
4
and R
5
along with the carbon atom to which they are attached represents
where
R
31
and R
32
independently represent hydrogen or hydroxy, alternatively R
31
and R
32
can be taken together to represent an oxo (═O) group;
R
6
is hydrogen or (C
1-6
)alkyl; and
R
7
is (C
1-8
)alkyl or (CH
2
)
1-3
cyclopropyl;
R
1
is hydrogen or (C
1-6
)alkyl;
R
2
is selected from a group consisting of hydrogen and R
2a
; alternatively R
1
and R
2
together represent C
2-5
alkylene or —CH
2
NR
8
CH
2
—, or both R
1
and R
2
simultaneously represent fluoro;
R
2a
represents (C
1-8
) alkyl optionally substituted with a group selected from —NR
8
R
35
, —NR
8
C(O)R
35
, —NR
8
C(O)OR
35
, —NR
8
C(O)NR
8
R
35
, —NR
8
C(NR
8
)NR
8
R
35
, —OR
35
, —SR
35
, —S(O)R
35
, —S(O)
2
R
35
, —C(O)R
35
, —C(O)OR
35
, —OC(O)R
35
, —C(O)NR
8
R
35
, —OC(O)NR
8
R
35
, —S(O)
2
NR
8
R
35
, —P(O)(OR
8
)OR
35
, —OR
52
, —CONR
8
R
52
, —SO
2
NR
8
R
52
and —OP(O)(OR
8
)OR
35
;
R
35
is selected from a group consisting of (C
1-4
)alkyl, —(CH
2
)
0-3
(C
3-12
)cycloalkyl, —CH
2
)
0-3
hetero(C
5-10
)cycloalkyl, —(CH
2
)
0-3
(C
6-10
)aryl, —CH
2
)
0-3
hetero(C
5-10
)aryl, —(CH
2
)
0-3
(C
9-10
)bicycloaryl and -(CH
2
)
0-3
hetero(C
8-10
)bicycloaryl;
R
3
is selected from a group consisting of (C
6-10
)aryl, (C
3-10
)cycloalkyl, (C
3-10
)heterocycloalkyl, hetero(C
5-10
)aryl, (C
9-10
)bicycloaryl and hetero(C
8-10
)bicycloaryl, wherein:
R
3
may be substituted further by a radical selected from a group consisting of —X
3
NR
8
R
21
, —X
3
NR
8
C(O)R
21
, —X
3
NR
8
C(O)OR
21
, —X
3
NR
8
C(O)NR
8
R
21
, —X
3
NR
8
C(NR
8
)NR
8
R
21
, —X
3
OR
21
, —X
3
SR
21
, —X
3
S(O)R
21
, —X
3
S(O)
2
R
21
, —X
3
C(O)R
21
, —X
3
C(O)OR
21
, —X
3
OC(O)R
21
, —X
3
C(O)NR
8
R
21
, —X
3
OC(O)NR
8
R
21
, —X
3
S(O)
2
NR
8
R
21
, —X
3
P(O)(OR
8
)OR
21
, —X
3
OR
52
, —X
3
CONR
8
R
52
, —X
3
SO
2
NR
8
R
52
, —X
3
OP(O)(OR
8
)OR
21
and —R
21
, wherein:
X
3
is a bond or (C
1-6
)alkylene, R
8
at each occurrence independently is hydrogen or (C
1-6
)alkyl, R
52
represents —CH
2
CH
2
—N(CH
2
CH
2
OH)
2
, —CH(CH
3
)CH
2
N(CH
3
)
2
, —CH
2
CH
2
OH, —CH
2
CH
2
N(CH
3
)
2
or —CH
2
CN, and R
21
is —(C
1-8
)alkyl or —X
3
R
22
, wherein X
3
is as defined above and R
22
is selected from a group consisting of (C
3-10
)cycloalkyl, hetero(C
5-10
)cycloalkyl, (C
6-10
)aryl, hetero(C
5-10
)aryl, (C
9-10
)bicycloaryl and hetero(C
8-10
)bicycloaryl, wherein:
R
22
may be substituted further by a radical selected from a group consisting of —X
3
NR
8
R
23
, —X
3
NR
8
C(O)R
23
, —X
3
NR
8
C(O)OR
23
, —X
3
NR
8
C(O)NR
8
R
23
, —X
3
OR
23
, —X
3
NR
8
C(NR
8
)NR
8
R
23
, —X
3
SR
23
, —X
3
S(O)R
23
, —X
3
S(O)
2
R
23
, —X
3
C(O)R
23
, —X
3
OC(O)R
23
, —X
3
C(O)OR
23
, —X
3
C(O)NR
8
R
23
, —X
3
OC(O)NR
8
R
23
, —X
3
S(O)
2
NR
8
R
23
, —X
3
OR
52
, —X
3
CONR
8
R
52
, —X
3
SO
2
NR
8
R
52
, —X
3
P(O)(OR
8
)OR
23
, —X
3
OP(O)(OR
8
)OR
23
and —R
23
, wherein:
X
3
is a bond or (C
1-6
)alkylene and R
8
at each occurrence independently is hydrogen or (C
1-6
)alkyl, R
52
represents CH
2
CH
2
—N(CH
2
CH
2
OH)
2
, CH(CH
3
)CH
2
N(CH
3
)
2
, CH
2
CH
2
OH, CH
2
CH
2
N(CH
3
)
2
or CH
2
CN, and R
23
is (C
1-8
)alkyl or —X
3
R
24
, wherein X
3
is as defined above and R
24
is selected from a group consisting of (C
3-10
)cycloalkyl, hetero(C
5-10
)cycloalkyl, (C
6-10
)aryl, hetero(C
5-10
)aryl, (C
9-10
)bicycloaryl and hetero(C
8-10
)bicycloaryl, wherein
R
24
may be substituted further by a radical selected from a group consisting of —X
3
NR
8
R
25
, —X
3
NR
8
C(O)R
25
, —X
3
NR
8
C(O)OR
25
, —X
3
OR
25
, —X
3
NR
8
C(O)NR
8
R
25
, —X
3
NR
8
C(NR
8
)NR
8
R
25
, —X
3
SR
25
, —X
3
S(O)R
25
, —X
3
S(O)
2
R
25
, —X
3
C(O)R
25
, —X
3
OC(O)R
25
, —X
3
C(O)OR
25
, —X
3
C(O)NR
8
R
25
, —X
3
OC(O)NR
8
R
25
, —X
3
S(O)
2
NR
8
R
25
, —X
3
P(O)(OR
8
)OR
25
, —X
3
OR
52
, —X
3
CONR
8
R
52
, —X
3
SO
2
NR
8
R
52
, —X
3
OP(O)(OR
8
)OR
25
and —R
25
, wherein:
X
3
is a bond or (C
1-6
)alkylene and R
8
at each occurrence independently is hydrogen or (C
1-6
)alkyl, R
52
represents —CH
2
CH
2
—N(CH
2
CH
2
OH)
2
, —CH(CH
3
)CH
2
N(CH
3
)
2
, —CH
2
CH
2
OH, —CH
2
CH
2
N(CH
3
)
2
or —CH
2
CN, and R
25
is —(C
1-8
)alkyl or —X
3
R
26
, wherein X
3
is as defined above and R
26
is selected from a group consisting of (C
3-10
)cycloalkyl, hetero(C
5-10
)cycloalkyl, (C
6-10
)aryl, hetero(C
5-10
)aryl, (C
9-10
)bicycloaryl and hetero(C
8-10
)bicycloaryl; wherein any of the (C
3-10
)cycloalkyl, hetero(C
5-10
)cycloalkyl, (C
6-10
)aryl, hetero(C
5-10
)aryl, (C
9-10
)bicycloaryl and hetero(C
8-10
)bicycloaryl contained within R
3
, R
22
, R
24
and R
26
may be substituted further with up to five substituents selected from a group consisting of (C
1-6
)alkyl, (C
1-6
)alkylidene, cyano, halo, nitro, halo-substituted (C
1-3
)alkyl, —X
3
NR
16
R
16
, —X
3
NR
16
C(O)OR
16
, —X
3
NR
16
C(O)NR
16
R
16
, —X
3
NR
16
C(NR
16
)NR
16
R
16
, —X
3
OR
16
, —X
3
SR
16
, —X
3
C(O)OR
16
, —X
3
C(O)NR
16
R
16
, —X
3
S(O)
2
NR
16
R
16
, —X
3
P(O)(OR
8
)OR
16
, —X
3
OR
52
, —X
3
CONR
8
R
52
, —X
3
C(O)R
16
, —X
3
SO
2
NR
8
R
52
, —X
3
S(O)R
17
, —X
3
OP(O)(OR
8
)OR
16
, —X
3
NR
16
C(O)R
17
, —X
3
S(O)
2
R
17
and —X
3
C(O)R
16
, wherein:
X
3
is a bond or (
Isabel Elise
Mendonca Rohan V.
Oballa Renata Marcella
Prasit Petpiboon
Robichaud Joel Stephane
Daniel Mark R.
Merck & Co. , Inc.
Raymond Richard L.
Wallinger Nicole M.
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