Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-24
2002-09-10
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S119000
Reexamination Certificate
active
06448264
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inhibitors of cyclin dependent kinase and their use in the treatment of proliferative diseases.
BACKGROUND OF THE INVENTION
Normal cellular proliferation is stringently regulated by a series of proteins that constitute the cell cycle machinery. Proteins that play a key role in controlling cell cycle progression are the cyclin dependent kinases (CDKs). CDKs are serine/threonine protein kinases that are the driving force behind the cell cycle and cell proliferation. The active CDK enzyme is a multi-subunit complex composed of at least one catalytic (CDK) subunit and one regulatory (cyclin) subunit. See, Brooks and La Thangue, DDT, 4, 455-464 (1999). It has been found that inhibitors of CDK activity are effective for the treatment of proliferative diseases (e.g. cancer). See, Webster and Kimball, Emerging Drugs, 5, 45-59 (2000).
SUMMARY OF THE INVENTION
The present invention is directed to the use of compounds of formula
and pharmaceutically acceptable salts thereof as inhibitors of cyclin dependent kinases. As used in formula I, and throughout the specification, the symbols have the following meanings:
R
1
is hydrogen, aryl or lower alkyl;
R
2
and R
4
are each independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R
3
is hydrogen or lower alkyl; and
n is an integer of 0, 1 or 2.
The compounds of formula I are protein kinase inhibitors and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for a method of using compounds of formula I as inhibitors of cyclin dependent kinases, which are active in the treatment of proliferative diseases, such as for example, but not limited to, cancer, Alzheimer's disease, arthritis, inflammation, and cardiovascular disease. The present invention also contemplates pharmaceutical compositions employing such compounds.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
It should be noted that any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
Carboxylate anion refers to a negatively charged group —COO
—
.
The term “alkyl” or “alk” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. The term “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, as defined below, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituent groups (or substituents) may include, but are not limited to, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl
3
or CF
3
), alkoxy, aryloxy, alkyl S(O)
m
(m=0, 1, 2), aryl S(O)
m
(m=0, 1, 2), hydroxy, carboxy (—COOH), alkyloxycarbonyl (—COOR′), alkylcarbonyloxy (—OCOR′), amino (—NH
2
), quaternary nitrogen, carbamoyl (—NHCOOR′— or —OCONHR′—), urea (—NHCONHR′—), thiol (—SH), cyano or nitro. Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds.
The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond.
The term “alkynyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.
Cycloalkyl is a type of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl, hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
The terms “alkoxy” or “alkylthio”, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl radical is represented by the formula —C(O)OR, where the R group is a straight or branched C
1-6
alkyl group.
The term “alkylcarbonyl” refers to an alkyl group bonded through a carbonyl group.
The term “alkylcarbonyloxy”, as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage.
The term “arylalkyl”, as used herein, denotes an aromatic ring bonded through an alkyl group as described above.
The term “aryl” refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkylS(O)
m
(m=0, 1, 2), or thiol.
The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur. Exemplary heteroaryl groups include the following: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl and tetrahydropyranyl. Exemplary substituents include one or more of the following: halo, alkyl, alkoxy, hydroxy, cycloalkyl, nitro, cyano, amino, alkylS(O)
m
(m=0, 1, 2), or thiol. The term “heteroarylalkyl”, as used herein denotes a heteroaryl ring bonded through an alkyl group as described hereinabove.
The term “heteroarylium” refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge.
The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. In addition, the sulfur may be oxidated to the sulfone (—SO
2
—) or sulfoxide (—SO—) a
Bristol--Myers Squibb Company
Dentz Bernard
Patel Rena
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