Pyrazolobenzodiazepines

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C540S557000

Reexamination Certificate

active

06440959

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel pyrazolobenzodiazepines which inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are anti-proliferative agents useful in the treatment or control of cell proliferative disorders, in particular cancer. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or prevention of cancer, particularly in the treatment or control of solid tumors. The compounds of the invention are especially useful in the treatment or control of breast, colon, lung and prostate tumors. The invention is also directed to intermediates useful in the preparation of the above anti-proliferative agents.
BACKGROUND OF THE INVENTION
Uncontrolled cell proliferation is the hallmark of cancer. Cancerous tumor cells typically have some form of damage to the genes that directly or indirectly regulate the cell-division cycle.
Cyclin-dependent kinases (CDKs) are enzymes which are critical to cell cycle control. See, e.g., Coleman et al., “Chemical Inhibitors of Cyclin-dependent Kinases,”
Annual Reports in Medicinal Chemistry
, vol. 32, 1997, pp. 171-179. These enzymes regulate the transitions between the different phases of the cell cycle, such as the progression from the G
1
phase to the S phase (the period of active DNA synthesis), or the progression from the G
2
phase to the M phase, in which active mitosis and cell-division occurs. See, e.g., the articles on this subject appearing in
Science
, vol. 274, Dec. 6, 1996, pp 1643-1677.
CDKs are composed of a catalytic CDK subunit and a regulatory cyclin subunit. The cyclin subunit is the key regulator of CDK activity, with each CDK interacting with a specific subset of cyclins: e.g. cyclin A (CDK1, CDK 2). The different kinase/cyclin pairs regulate progression through specific stages of the cell cycle. See, e.g., Coleman, supra.
Aberrations in the cell cycle control system have been implicated in the uncontrolled growth of cancerous cells. See, e.g., Kamb, “Cell-Cycle Regulators and Cancer,”
Trends in Genetics
, vol.11, 1995, pp.136-140; and Coleman, supra. In addition, changes in the expression of or in the genes encoding CDK's or their regulators have been observed in a number of tumors. See, e.g., Webster, “The Therapeutic Potential of Targeting the Cell Cycle,”
Exp. Opin. Invest Drugs
, Vol. 7, pp. 865-887 (1998), and references cited therein. Thus, there is an extensive body of literature validating the use of compounds inhibiting CDKs as anti-proliferative therapeutic agents. See, e.g. U.S. Pat. No. 5,621,082 to Xiong et al; EP 0 666 270 A2; WO 97/16447; and the references cited in Coleman, supra, in particular reference no. 10. Thus, it is desirable to identify chemical inhibitors of CDK kinase activity.
It is particularly desirable to identify small molecule compounds that may be readily synthesized and are effective in inhibiting one or more CDKs or CDK/cyclin complexes, for treating one or more types of tumors.
Several classes of compounds that inhibit cyclin-dependent kinases have been and are being investigated as therapeutic agents. These are, for example, as follows:
Analogs of Flavopiridol:
U.S. Pat. No. 5,733,920 (Mitotix)
WO 98/1344 (Bristol-Myers Squibb)
WO 97/42949 (Bristol-Meyers Squibb)
Purine Derivatives:
WO 98/05335 (CV Therapeutics)
WO 97/20842 (CNRS)
Acridones and Benzothiadiazines:
WO 98/49146 A2 (US Dept. of Health and Human Services)
Antisense
U.S. Pat. No. 5,821,234 (Stanford University).
Furthermore, certain N,N-substituted dihydropyrazolobenzodiazepines have been disclosed in an article discussing CNS-acting compounds. See, M. A. Berghot,
Arch. Pharm
. 325:285-289 (1992).
There continues to be a need for easily synthesized, small molecule compounds for the treatment of one or more types of tumors, in particular through regulation of CDKs. It is thus an object of this invention to provide such compounds and compositions containing such compounds.
SUMMARY OF THE INVENTION
The present invention relates to pyrazolobenzodiazepines capable of inhibiting the activity of one or more CDKs, in particular CDK2. Such compounds are useful for the treatment of cancer, in particular solid tumors. In particular the compounds of the present invention are especially useful in the treatment or control of breast, colon, lung and prostate tumors. The invention is also directed to intermediate compounds useful in the preparation of the above-mentioned pyrazolobenzodiazepines.
The compounds of the present invention are compounds of formula I below
and prodrugs and metabolites of the foregoing compounds, as well as pharmaceutically acceptable salts of each of the foregoing compounds, wherein
R
1
is selected from the group consisting of
—H,
—NO
2
,
—CN,
-halogen,
-lower alkyl which is straight-chained and which optionally may be substituted by the group consisting of —OH and halogen,
—OR
5
,
—R
6
OR
7
,
—COOR
7
,
—CONR
8
R
9
(a.k.a. carboxamide),
—NR
10
R
11
,
—NHCOR
12
, and
—NHSO
2
R
13
;
R
2
and R
4
are each independently selected from the group consisting of
—H,
-halogen,
—NO
2
,
—CF
3
, and
-straight chained lower alkyl;
R
3
is selected from the group consisting of
—H,
-lower alkyl which optionally may be substituted by —OH, —OR
9
, F, and aryl,
-cycloalkyl,
-aryl,
-heterocycle,
-heteroaryl,
—COOR
7
—CN,
-alkenyl,
—CONR
8
R
9
, and
-alkynyl;
R
5
is selected from lower alkyl which optionally may be substituted by halogen;
R
6
is selected from lower alkylene;
R
7
is selected from the group consisting of —H and lower alkyl;
R
8
and R
9
are each independently selected from the group consisting of —H and -lower alkyl which itself optionally may be substituted by —OH and —NH
2
; alternatively, R
8
and R
9
may form a 5- or 6-membered heterocycle which optionally may be substituted by the group consisting of —OH, —NH
2
, and lower alkyl;
R
10
, R
11
and R
12
are each independently selected from the group consisting of —H and lower alkyl;
R
13
is selected from the group consisting of lower alkyl which optionally may be substituted by the group consisting of halogen and —NR
14
R
15
; and
R
14
and R
15
are each independently selected from the group consisting of —H and lower alkyl which optionally may be substituted Halogen, or alternatively, —NR
14
R
15
is a heterocycle.
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more of the above-described compounds, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
The present invention is also directed to a method for treating solid tumors, in particular breast, colon, lung and prostate tumors, more specifically breast and colon tumors, by administering to a human patient in need of such therapy an effective amount of a compound of formula I, its salts or prodrugs.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms shall have the following definitions.
“Aryl” means an aromatic group having 5 to 10 atoms and consisting of 1 or 2 rings. Examples of aryl groups include phenyl and 1- or 2-naphthyl.
“Alkenyl” means a straight-chain or branched, substituted or unsubstituted, aliphatic unsaturated hydrocarbon having 2 to 6, preferably 2 to 4, carbon atoms and containing double bonds. Typical alkenyl groups include ethylene, propylene, isopropylene, butylene and the like. Preferred alkenyl groups are straight-chained.
“Alkynyl” means a straight-chain or branched, substituted or unsubstituted, aliphatic unsaturated hydrocarbon having 2 to 6, preferably 2 to 4, carbon atoms and containing triple bonds. Typical alkynyl groups include acetylene and the like. Preferred alkynyl groups are straight-chained.
“Cycloalkyl” means a non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopen

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