Heteropolycyclic inhibitors of protein kinases

Details Heteropolycyclic inhibitors of protein kinases Heteropolycyclic inhibitors of protein kinases

2001-07-06

2003-02-04

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S183000, C544S184000, C544S342000, C544S343000, C514S250000

Reexamination Certificate

active

06514972

ABSTRACT:

BACKGROUND OF THE INVENTION
Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and, hence, the activity of specific target proteins. One of the predominant roles of protein phosphorylation is in signal transduction, where extracellular signals are amplified and propagated by a cascade of protein phosphorylation and dephosphorylation events.
Signal transduction also plays a key regulatory role in the growth and metastatic potential of tumor cells. These signaling pathways form an interconnecting grid that serves to regulate the homeostatic, survival and invasive functions of the cell. Among the key regulatory molecules in these pathways are the serinelthreonine-protein kinases cyclic AMP-dependent protein kinase (PKA), Akt (PKB) and protein kinase C (PKC). These protein kinases modulate pathways associated with tumor proliferation, cell survival and multidrug resistance, and at a molecule level are likely to serve as effective targets for drug design.
SUMMARY OF THE INVENTION
Pharmaceutical compositions and compounds are provided. The compounds of the invention are heteropolycyclic compounds. In one embodiment of the invention, formulations of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical formulations are useful in the treatment of disorders associated with hyperproliferation, and responses to insulin signaling.
For example, in one aspect, the present invention provides compounds having the formula
wherein, independently at each occurrence, v, w, and x are selected from C, N, O, and S, with H substitution as needed to fulfill open valence sites; y and z are selected from N and C, with H substitution as needed to fulfill open valence sites, with the proviso that each of w, v, x, y and z is not simultaneously C; the ring formed from v, w, x, y and z may be saturated or unsaturated; and R
1
, R
2
, R
3
and R
4
are selected from hydrogen, alkyl, aryl, alkaryl, aralkyl, heteroalkyl, and heteroaryl; wherein any adjacent two of R
1
, R
2
, R
3
and R
4
may join together to form a 5, 6 or 7-membered carbocyclic or heterocyclic ring, with the proviso that each of R
1
, R
2
, R
3
and R
4
is not simultaneously hydrogen.
In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent, and a compound of the formula
wherein, independently at each occurrence, v, w, and x are selected from C, N, O, and S, with H substitution as needed to fulfill open valence sites; y and z are selected from N and C, with H substitution as needed to fulfill open valence sites, with the proviso that each of w, v, x, y and z is not simultaneously C; the ring formed from v, w, x, y and z may be saturated or unsaturated; and R
1
, R
2
, R
3
and R
4
are selected from hydrogen, alkyl, aryl, alkaryl, aralkyl, heteroalkyl, and heteroaryl; wherein any adjacent two of R
1
, R
2
, R
3
and R
4
may join together to form a 5, 6 or 7-membered carbocyclic or heterocyclic ring. In an optional embodiment, each of R
1
, R
2
, R
3
and R
4
is not simultaneously hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel heteropolycyclic fused ring compounds, compositions and methods as set forth within this specification. In general, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs, unless clearly indicated otherwise. For clarification, listed below are definitions for certain terms used herein to describe the present invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise clearly indicated.
DEFINITION OF TERMS
As used herein the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. For example, “a compound” refers to one or more of such compounds, “a group” refers to one or more of such groups, etc., while “the enzyme” includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art.
“Acyl” is a heteroalkyl wherein a terminal carbon of the heteroalkyl group is in the form of a carbonyl group, i.e., (alkyl or heteroalkyl)-C═O, where examples include acetyl (CH
3
—(C═O)—).
“Alkaryl” is another name for alkylarylene, wherein an alkyl group is bonded to an arylene group, and the arylene group is bonded to the remainder of the molecule. Tolyl (CH
3
-phenyl-) and xylyl ((CH
3
)
2
-phenyl-) are representative alkaryl groups. Thus, in compounds of the present invention, any of R
1
, R
2
, R
3
and R
4
may be alkaryl.
“Alkenyl” is an alkyl group, where an alkenyl group has at least one carbon—carbon double bond.
“Alkyl” is a monovalent, saturated or unsaturated, straight, branched or cyclic, aliphatic (i.e., not aromatic) hydrocarbon group. In various embodiments of the present invention, the alkyl group has 1-20 carbon atoms, i.e., is a C1-C20 group (i.e., is a C
1
-C
20
group), or is a C1-C18 group, a C1-C12 group, a C1-C6 group, or a C1-C4 group. Independently, in various embodiments of the present invention, the alkyl group: has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches; is saturated; is unsaturated (where an unsaturated alkyl group may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than two triple bonds); is, or includes, a cyclic structure; is acyclic. Exemplary alkyl groups include C
1
alkyl (i.e., —CH
3
(methyl)), C
2
alkyl (i.e., —CH
2
CH
3
(ethyl), —CH═CH
2
(ethenyl) and —C≡CH (ethynyl)) and C
3
alkyl (i.e., —CH
2
CH
2
CH
3
(n-propyl), —CH(CH
3
)
2
(i-propyl), —CH═CH—CH
3
(1-propenyl), —C≡C—CH
3
(1-propynyl), —CH
2
—CH═CH
2
(2-propenyl), —CH
2
—C═CH (2-propynyl), —C(CH
3
)═CH
2
(1-methylethenyl), and —CH(CH
2
)
2
(cyclopropyl)), which identify specific lower alkyl groups. Thus, in compounds of the present invention, any of R
1
, R
2
, R
3
and R
4
may be alkyl.
“Alkylene” is a polyvalent, saturated or unsaturated, straight, branched or cyclic, aliphatic (i.e., not aromatic) hydrocarbon group. In various embodiments, the alkylene group has 1-20 carbon atoms, i.e., is a C1-C20 group, or is a C1-C18 group, a C1-C12 group, a C1-C6 group, or a C1-C4 group. Independently, in various embodiments, the alkylene group: has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches; is saturated; is unsaturated (where an unsaturated alkylene group may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than three triple bonds); is or contains a cyclic group; is acyclic; is divalent, i.e., has two open sites that each bond to a non-alkylene group; is trivalent, i.e., has three open sites that each bond to a non-alkylene group; has more than three open sites. Exemplary alkylene groups include C
1
alkylene (i.e., —CH
2
—) and C
2
alkylene (i.e., —CH
2
CH
2
—, —CH═CH—, —C≡C—, —C(═CH
2
)—, and —CH(CH
3
)—).
“Aralkyl” is another name for arylalkylene, wherein at least one of the open bonding sites of an alkylene group is bonded to an aryl group, where benzyl is an example. Thus, in compounds of the present invention, any of R
1
, R
2
, R
3
and R
4
may be aralkyl.
“Aryl” is a monovalent, aromatic, hydrocarbon, ring system. The ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.). In various embodiments of the present invention, the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the aryl ring system. A C6 ring system, i.e., a phenyl ring, is a preferred aryl group. In various embodiments, the polycyclic ring is a bicyclic aryl group, where preferred

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