Methods for anti-tumor therapy

Details Methods for anti-tumor therapy Methods for anti-tumor therapy

2001-08-29

2004-04-06

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S603000, C514S604000

Reexamination Certificate

active

06716879

ABSTRACT:

BACKGROUND OF THE INVENTION
Approximately twenty percent of deaths from all causes in the United States are cancer-related. Although chemotherapy is a principal means of cancer treatment, the rate at which effective new drugs have become available for use in cancer chemotherapy has not increased (Horowitz et al., Journal of Clinical Oncology, Vol. 6, No. 2, pp. 308-314 (1988)). Despite many years of promising new therapies, cancer remains a major cause of morbidity and mortality (Bailar et al., N. Engl. J. Med. 336:1569-1574, 1997). Accordingly, there is a substantial need for new drugs that are effective in inhibiting the growth of tumors.
The compounds of the general class sulfonylamino carboxylic acid N-arylamides are known in the art as useful agents for soluble guanylate cyclase activation (Schindler, et al., WO 00/02850). Several other pharmacological uses have been described including, for example, anti-parasitic, antimicrobial, and fungicidal effects (EP-A-420 805 and Chemical Abstracts 122, 136 749; 120, 560; 119, 116 978; 116, 228 237; 116, 207 806; 115, 158 666, and 106, 152 850), an anthelminitic effect (DE-A-35 23 705), psychotropic effects (Chemical Abstracts 104, 33 896), and use in the treatment of atherosclerosis or arthritis (EP-A-347 168). The use of these compounds for anti-tumor treatment has not been disclosed or suggested.
SUMMARY OF THE INVENTION
The present invention is based on the entirely unexpected finding that sulfonylamino-substituted N-aryl- or heteroarylcarboxamide derivatives are an effective class of anti-tumor agent. In one aspect, the present invention provides novel methods for treating tumors that involve administering an effective amount of sulfonylamino-substituted N-aryl- or heteroarylcarboxamide derivatives, or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, to a patient in need of treatment. In a preferred embodiment, the compounds administered in the method of the present invention are N-phenyl{2-[(phenylsulfonyl)amino]phenyl}carboxamide derivatives. In an even more preferred embodiment, the compounds are {5-substituted-2-[(phenylsulfonyl)amino]phenyl}-N-benzamide derivatives.
In further aspects, the present invention provides a pharmaceutical composition comprising an effective amount for treating tumors of a compound according to the general formula or specific compound hereinafter disclosed, or a pharmaceutical salt thereof, in a suitable carrier. In yet a further aspect, the present invention discloses articles of manufacture comprising packaging material and the above pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention discloses the use of sulfonylamino-substituted N-aryl- or heteroarylcarboxamides, and their pharmaceutically acceptable salts, esters, amides, and prodrugs thereof as anti-tumor agents.
The present compounds, or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, are useful in treating tumors from any tissue type. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to, sarcomas, carcinomas, and mesotheliomas.
As used herein the term “mesothelioma” is used to refer to a neoplasm derived from the cells lining the pleura, pericardium, or peritoneum, including but not limited to lung mesotheliomas.
As used herein the term “sarcoma” refers to tumors of mesenchymal origin, including but not limited to stromal cell sarcomas, leiomyosarcomas, malignant fibrous histiocytoma, Ewing sarcoma, fibrosarcomas, chondrosarcomas, osteosarcomas, liposarcomas, rhabdomyo-sarcomas, hemangiocytomas, and myxosarcomas.
As used herein the term “carcinoma” is used to refer to a neoplasm derived from epithelial cells.
As used herein the term “ovarian carcinoma” refers to neoplasms derived from ovarian cells of epithelial origin, including but not limited to ovarian papillary serous cystadenoma, ovarian endometroid carcinoma, mucinous, clear cell and Brenner epithelial tumors.
In one embodiment, the sulfonylamino-substituted N-aryl- or heteroarylcarboxamides compounds comprise the general formula I, in all their stereoisomenc forms and mixtures thereof, in all proportions (see Schindler, et al., WO 00/02850).
wherein
A
1
is aryl or heteroaryl, each of which may be optionally substituted with one, two or three groups independently selected from halogen, aryl, —CF
3
, —NO
2
, —OH, —O—(C
1
-C
7
)-alkyl, —O—(C
2
-C
4
)-alkyl-O—(C
1
-C
7
)-alkyl, —O-aryl, (C
1
-C
2
)-alkylenedioxy, —NR
5
R
6
, —CN, —CO—NR
5
R
6
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, heterocyclyl, —CHO, —CO—(C
1
-C
10
)-alkyl, —CO-aryl, —CO-heteroaryl, or
(C
1
-C
10
)-alkyl, (C
3
-C
10
)-cycloalkyl, (C
1
-C
10
)-alkenyl or (C
1
-C
10
)-alkynyl, each of which is optionally substituted with up to five groups independently selected from halogen, —OH, aryl, heteroaryl, —O—(C
1
-C
10
)-alkyl, —O—(C
1
-C
7
)-alkyl-R
7
, —O-aryl, —O-heteroaryl, —SH, —S—(C
1
-C
10
)-alkyl, —S—(C
1
-C
7
)-alkyl-R
7
, —S-aryl, —S-heteroaryl, —P(O)(O—(C
1
-C
5
)-alkyl)
2
, —P(O)(OH)
2
, —CN, —NR
8
R
9
, —CO—NH
2
, —CO—NH—(C
1
-C
3
)-alkyl, —CO—N((C
1
-C
3
)-alkyl)
2
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, heterocyclyl, and oxo;
A
2
represents a ringed structure consisting of aryl, heteroaryl, heterocyclyl or (C
3
-C
10
)-cycloalkyl;
R
2
is —NR
5
R
6
, or
aryl, heteroaryl, heterocyclyl, (C
1
-C
10
)-alkyl, (C
3
-C
10
)-cycloalkyl, (C
1
-C
10
)-alkenyl or (C
1
-C
10
)-alkynyl, each of which may be optionally substituted with one, two or three groups selected from halogen, —OH, aryl, heteroaryl, —O—(C
1
-C
10
)-alkyl, —O—(C
1
-C
7
)-alkyl-R
7
, —O-aryl, —O-heteroaryl, —SH, —S—(C
1
-C
10
)-alkyl, —S—(C
1
-C
7
)-alkyl-R
7
, —S-aryl, —S-heteroaryl, —P(O)(O—(C
1
-C
5
)-alkyl)
2
, —P(O)(OH)
2
, —CN, —NR
8
R
9
, —CO—NH
2
, —CO—NH—(C
1
-C
3
)-alkyl, —CO—N((C
1
-C
3
)-alkyl)
2
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, heterocyclyl, and oxo;
R
3
is one, two or three substituents independently selected from hydrogen, halogen, —CF
3
, —OH, —O—(C
1
-C
10
)-alkyl, —O—(C
1
-C
7
)-alkyl-R
7
, —O-aryl, —O-heteroaryl, —SH, —S—(C
1
-C
10
)-alkyl, —S—(C
1
-C
7
)-alkyl-R
7
, —S-aryl, —S-heteroaryl, (C
1
-C
3
)-alkylene dioxy, —CN, —NO
2
, —NR
8
R
9
, —CONR
5
R
6
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, heterocyclyl, —S(O)
n
—(C
1
-C
7
)-alkyl, —S(O)
n
—aryl, —S(O)
n
—heteroaryl, —S(O)
n
—NR
5
R
6
or
(C
1
-C
7
)-alkyl, (C
3
-C
7
)-cycloalkyl, (C
1
-C
7
)-alkenyl or (C
1
-C
7
)-alkynyl, each of which is optionally substituted with up to five groups independently selected from halogen, —OH, aryl, heteroaryl, —O—(C
1
-C
10
)-alkyl, —O—(C
1
-C
7
)-alkyl-R
7
, —O-aryl, —O-heteroaryl, —SH, —S—(C
1
-C
10
)-alkyl, —S—(C
1
-C
7
)-alkyl-R
7
, —S-aryl, —S-heteroaryl, —P(O)(O—(C
1
-C
5
)-alkyl)
2
, —P(O)(OH)
2
, —CN, —NR
8
R
9
, —CO—NH
2
, —CO—NH—(C
1
-C
3
)-alkyl, —CO—N((C
1
-C
3
)-alkyl)
2
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, heterocyclyl, and oxo;
R
5
and R
6
independently are hydrogen, or
(C
1
-C
10
)-alkyl, (C
3
-C
10
)-cycloalkyl, (C
1
-C
10
)-alkenyl or (C
1
-C
10
)-alkynyl, each of which is optionally substituted with one, two or three groups selected from aryl, heteroaryl, heterocyclyl, —CO—(C
1
-C
10
)-alkyl, —CO-aryl, —CO-heteroaryl, —CO-heterocyclyl, —SO
2
—(C
1
-C
10
)-alkyl, —SO
2
-aryl -SO
2
-heteroaryl, or -SO
2
-heterocyclyl; or
R
5
and R
6
together with the nitrogen atom to which they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up to two of which members are optionally hetero atoms selected from N, O, and S, the carbocyclic ring being optionally substituted with up to five groups selected from halogen, (C
1
-C
5
)-alkyl, (C
3
-C
6
)-cycloalkyl, (C
1
-C
5
)-alkenyl, (C
1
-C
5
)-alkynyl, (C
1
-C
3
)-hydroxyalkyl, (C
1
-C
3
)-alkyl-O—(C
1
-C
4
)-alkyl, aryl, heteroaryl, —CF
3
, —OH, —O—(C
1
-C
7
)-alkyl, —O-aryl, —O-heteroaryl, —O—(C
2
-C
4
)-alkyl-O—(C
1
-C
7
)-alkyl, (C
2
-C
3
)-alkylenedioxy, —NR
8
R
9
, —CN, —CO—NH
2
, —CO—NH—(C
1
-C
3
)-alkyl, —CO—N((C
1
-C
3
)-alkyl)
2
, —COOH, —CO—O—(C
1
-C
5
)-alkyl, —CHO, CO—(C
1
-C
5
)-alkyl, —S(O)
n
—(C
1
-C
4
)-alkyl,

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