Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-31
2004-06-29
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S175000
Reexamination Certificate
active
06756385
ABSTRACT:
FIELD OF THE INVENTION
The subject invention relates to imidazole derivatives, pharmaceutical compositions comprising such derivatives and methods of using such derivatives to treat abnormal cell growth and certain diseases and conditions of the central nervous system. The compounds of the present invention act as inhibitors of cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The compounds of the present invention also are inhibitors of the enzyme GSK-3 (glygocen synthase kinase-3) enzyme.
BACKGROUND OF THE INVENTION
The serine/threonine kinase cdk5 along with its cofactor p25 (or the longer cofactor, p35) has been linked to neurodegenerative disorders, and inhibitors of cdk5/ p25 (or cdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. Treatment of such neurodegenerative disorders using cdk5 inhibitors is supported by the finding that cdk5 is involved in the phosphorylation of tau protein (
J. Biochem
, 117, 741-749 (1995)). cdk5 also phosphorylates Dopamine and Cyclic AMP-Regulated Phosphorprotein (DARPP-32) at threonine 75 and is thus indicated in having a role in dopaminergic neurotransmission (
Nature
, 402, 669-671 (1999)).
The serine/threonine kinase cdk2 is essential for normal cell cycling and plays a critical role in disorders arising from abnormal cell cycling, a common characteristic of many oncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various types of cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al.,
Properties and Potential
-
applications of Chemical Inhibitors of Cyclin
-
dependent Kinsases, Pharmacology
&
therapeutics
, 82 (2-3), 279-284 (1999); Sausville, et al.,
Cyclin
-
dependent Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology
&
therapeutics
82 (2-3) 285-292 (1999)).
GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases which phosphorylate glycogen synthase (Embi, et al.,
Eur. J. Biochem
. 107:519-527 (1980); Hemmings, et al.,
Eur. J. Biochem
. 119:443-451 (1982)). GSK-3 exists in two isoforms, &agr; and &bgr;, in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively. Both isoforms phosphorylate muscle glycogen synthase (Cross, et al.,
Biochemical Journal
303: 21-26 (1994)). The amino acid identity among GSK-3 species homologs has been indicated to be in excess of 98% within the catalytic domain (Plyte, et al.,
Biochim. Biophys. Acta
1114:147-162) (1992)). Due to a remarkably high degree of conservation across the phylogenetic spectrum, a fundamental role of GSK-3 in cellular processes is suggested.
GSK-3 has been implicated in numerous different disease states and conditions. For example, Chen, et al,
Diabetes
43: 1234-1241 (1994) have suggested that an increase in GSK-3 activity can be important in Type 2 diabetes. Increased GSK-3 expression in diabetic muscle is also though to contribute to the impaired glycogen synthase activity and skeletal muscle insulin resistance present in Type 2 diabetes (Nikoulina, et al.,
Diabetes
49: 263-271 (2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile sperm was attributed to higher GSK-3 activity and was indicated as responsible for holding the sperm motility in check (Vijayaraghavan, et al.
Biology of Reproduction
54: 709-718 (1996)). Vijayaraghavan et al. indicate that such results suggest a biochemical basis for the development and regulation of sperm motility and a possible physiological role for a protein phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity has also been associated with Alzheimer's disease and mood disorders such as bipolar disorder (WO 97/41854). Among other conditions, GSK-3 has furthermore been implicated in hair loss, schizophrenia, and neurodegeneration, including both chronic neurodegenerative diseases (such as Alzheimer's, supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.
SUMMARY OF THE INVENTION
This invention provides compounds of the formula
wherein R
1
is a straight chain or branched (C
1
-C
8
)alkyl, a straight chain or branched (C
2
-C
2
)alkenyl, a straight chain or branched (C
2
-C
8
)alkynyl, (C
3
-C
6
)cycloalkyl, (C
4
-C
8
)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C
5
-C
11
)bicycloalkyl, (C
7
-C
11
)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C
6
-C
14
) aryl, or (5-14 membered) heteroaryl; and wherein R
1
is optionally substituted with from one to six substituents R
5
independently selected from F, Cl, Br, I, nitro, cyano, —CF
3
, —NR
7
R
8
, —NR
7
C(═O)R
8
, —NR
7
C(═O)OR
8
, —NR
7
C(═O)NR
8
R
9
, —NR
7
S(═O)
2
R
8
, —NR
7
S(═O)
2
NR
8
R
9
, —OR
7
, —OC(═O)R
7
, —OC(═O)OR
7
, —C(═O)OR
7
, —C(═O)R
7
, —C(═O)NR
7
R
8
, —OC(═O)NR
7
R
8
, —OC(═O)SR
7
, —SR
7
, —S(═O)R
7
, —S(═O)
2
R
7
, —S(═O)
2
NR
7
R
8
, —O—S(═O)
2
R
7
, —N
3
and R
7
;
R
2
is H, F, CH
3
, CN, or C(═O)OR
7
;
R
3
is —C(═O)NR
9
—, —C(═O)O—, —C(═O)(CR
10
R
11
)
n
—, or —(CR
10
R
11
)
n
—;
R
4
is a straight chain or a branched (C
1
-C
8
)alkyl, a straight chain or a branched (C
2
-C
8
)alkenyl, a straight chain or branched (C
2
-C
8
alkynyl), (C
3
-C
8
)cycloalkyl, (C
4
-C
8
)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C
5
-C
11
)bicycloalkyl, (C
7
-C
11
)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C
6
-C
14
)aryl, or (5-14 membered) heteroaryl; and wherein R
4
is optionally substituted with from one to three substitutents R
6
independently selected from F, Cl, Br, I, nitro, cyano, —CF
3
, —NR
7
R
8
, —NR
7
C(═O)R
8
, —NR
7
C(═O)OR
8
, —NR
7
C(═O)NR
8
R
9
, —NR
7
S(═O)
2
R
8
, —NR
7
S(═O)
2
NR
8
R
9
, —OR
7
, —OC(═O)R
7
, —OC(═O)OR
7
, —C(═O)OR
7
, —C(═O)R
7
, —C(═O)NR
7
R
8
, —OC(═O)NR
7
R
8
, —OC(═O)SR
7
, —SR
7
, —S(═O)R
7
, —S(═O)
2
R
7
, —S(═O)
2
NR
7
R
8
, or R
7
;
each R
7
, R
8
, and R
9
is independently selected from H, straight chain or branched (C
1
-C
8
)alkyl, straight chain or branched (C
2
-C
8
)alkenyl, straight chain or branched (C
2
-C
8
alkynyl), (C
3
-C
8
)cycloalkyl, (C
4
-C
8
)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C
5
-C
11
)bicycloalkyl, (C
7
-C
11
)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C
6
-C
14
)aryl, and (5-14 membered) heteroaryl, wherein R
7
, R
8
, and R
9
are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO
2
, —CN, —CF
3
, —NR
10
R
11
, —NR
10
C(═O)R
11
, —NR
10
C(═O)OR
11
,
13
NR
10
C(═O)NR
11
R
12
, —NR
10
S(═O)
2
R
11
, —NR
10
S(═O)
2
NR
11
R
12
, —OR
10
, OC(═O)R
10
, —OC(═O)OR
10
, —OC(═O)NR
10
R
11
, —OC(═O)SR
10
, —SR
10
, —S(═O)R
10
, —S(═O)
2
R
10
, —S(═O)
2
NR
10
R
11
, —C(═O)R
10
, —C(═O)OR
10
, —C(═O)NR
10
R
11
, and R
10
;
or, when R
7
and R
8
are as in NR
7
R
8
, they may instead optionally be connected to form with the nitrogen of NR
7
R
8
to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S;
each R
10
, R
11
, and R
12
is independently selected from H, straight chain or branched (C
1
-C
8
)alkyl, straight chain or branched (C
2
-C
8
)alkenyl, straight chain or branched (C
2
-C
8
alkynyl), (C
3
-C
8
)cycloalkyl, (C
4
-C
8
)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C
5
-C
11
)bicycloalkyl, (C
7
-C
11
)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C
6
-C
14
)aryl, and (5-14 membered) heteroaryl, wherein R
10
, R
11
, and R
12
are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO
Ahlijanian Michael K.
Cooper Christoper B.
Helal Chris J.
Lau Lit-Fui
Menniti Frank S.
Anderson Rebecca
Konstas K. L.
Ling L. B.
Pfizer Inc.
Ramsuer Robert W.
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