Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-18
2003-05-27
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S376000, C514S394000
Reexamination Certificate
active
06569877
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to therapeutic and prophylactic agents for neoplasms which comprise a fused heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient; to the use of such a compound in the preparation of a medicament for the treatment and prevention of neoplasms; and to a method for treatment and prevention of neoplasms which comprises administering a pharmaceutically effective amount of such a compound to a warm-blooded animal (preferably a human).
The term ‘neoplasms’ in this specification includes sarcoma, various cancers, and leukemia, which include fibrosarcoma, liposarcoma, osteosarcoma, angiosarcoma, cancers of the lung, the stomach, the large intestine, the breast, the prostate gland, the kidney, the liver, the pancreas, the esophagus, the tongue, the pharynx, the bladder and ovary, brain tumors, acute leukemia, chronic leukemia, and lymphoma.
The compounds which are useful for the present invention and general methods of preparing these compounds are described in Japanese Patent Application Publication Hei 9-295970, EP 0745600 and U.S. Pat. No. 5,886,014 (all incorporated by reference). However, these descriptions about these compounds do not disclose their suppressive effects against proliferation of cancer cells. Further, these compounds have been disclosed as therapeutic or prophylactic agents for diabetes mellitus or hyperlipidemia; thus, the prior art documents differ from the present invention.
Compounds having the benzimidazole ring group are disclosed in WO 99/18081. However, the fused hetero ring has phenoxy, phenylthio, pyridyloxy or pyridylthio groups as substituents. The present invention compounds do not have such substituents.
Numerous compounds are commercially available as chemotherapeutic agents for cancer. However, it has become clear that the efficacy of currently available chemotherapeutic agents against various cancers is sometimes insufficient, i.e., in some cases cancer cells have developed natural tolerance against the therapeutic agents. Further, some therapeutic or prophylactic agents exert side effects, or make cancer cells gain tolerance during clinical use. Therefore, clinical use of chemotherapeutic agents for cancers has been complicated. Under these circumstances, novel anticancer agents have always been desired in cancer chemotherapy.
The problem to be solved by the present invention is to provide novel anticancer agents to satisfy the desire described above.
The inventors have earnestly carried out research on the synthesis of fused heterocyclic compounds, pharmaceutically acceptable salts thereof, and their pharmacological activity in order to solve this problem. The inventors have found that some fused heterocyclic compounds exhibit excellent suppressive effects against proliferation of cancer cells and that they are excellent therapeutic and prophylactic agents for cancer.
BRIEF SUMMARY OF THE INVENTION
This invention comprises a therapeutic and prophylactic agent for neoplasms which comprises as active ingredient a fused heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
X is a benzimidazolyl group which is optionally substituted with 1 to 5 substituents selected from Group A;
Y is an oxygen or sulfur atom;
Z is a group selected from the following formulae:
(hereinafter, these groups are referred to as i) 2,4-dioxothiazolidin-5-ylidenylmethyl, ii) 2,4-dioxothiazolidin-5-ylmethyl, iii) 2,4-dioxooxazolidin-5-ylmethyl, iv) 3,5-dioxooxadiazolidin-2-ylmethyl and v) N-hydroxyureidomethyl groups, respectively);
R is hydrogen, straight or branched chain C
1
-C
6
alkyl, straight or branched chain C
1
-C
6
alkoxy, halogen, hydroxyl, nitro, amino which is optionally substituted with one or more substituents selected from Group B and straight or branched chain C
7
-C
11
aralkyl which is optionally substituted with one or more substituents selected from Group C;
m is an integer from 1 to 5 inclusive;
Group A comprises straight or branched chain C
1
-C
6
alkyl, straight or branched chain C
1
-C
6
alkoxy, straight or branched chain C
7
-C
11
aralkyloxy, halogen, hydroxyl, straight or branched chain C
1
-C
11
aliphatic acyloxy, straight or branched chain C
1
-C
6
alkylthio, straight or branched chain C
1
-C
6
halogenoalkyl, nitro, amino which is optionally substituted with one or more substituents selected from Group B, C
6
-C
10
aryl which is optionally substituted with one or more substituents selected from Group C, and straight or branched chain C
7
-C
11
aralkyl which is optionally substituted with one or more substituents selected from Group C;
Group B comprises straight or branched chain C
1
-C
6
alkyl, straight or branched chain C
7
-C
11
aralkyl, C
6
-C
10
aryl, straight or branched chain C
1
-C
11
aliphatic acyl, C
8
-C
12
aromatic aliphatic acyl and C
7
-C
11
aromatic acyl; and
Group C comprises straight or branched chain C
1
-C
6
alkyl, straight or branched chain C
1
-C
6
alkoxy, halogen, hydroxyl, nitro, C
6
-C
10
aryl, straight or branched chain C
1
-C
6
halogenoalkyl, and amino which is optionally substituted with one or more substituents selected from Group B.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of formula (I) are:
(1) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein X is benzimidazolyl which is optionally substituted with 1 to 3 substituents selected from Group A;
(2) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein X is benzimidazolyl which is optionally substituted with two substituents selected from Group A;
(3) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Y is an oxygen atom;
(4) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Y is a sulfur atom;
(5) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Z is 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl;
(6) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Z is 2,4-dioxothiazolidin-5-ylmethyl;
(7) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein R is hydrogen, straight or branched chain C
1
-C
4
alkyl, straight or branched chain C
1
C
4
alkoxy, halogen, hydroxyl, nitro, amino, or straight or branched chain C
7
-C
11
aralkyl;
(8) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein R is hydrogen;
(9) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein m is an integer from 1 to 3 inclusive;
(10) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein m is 1;
(11) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises straight or branched chain C
1
C
6
alkyl, straight or branched chain C
1
C
6
alkoxy, straight or branched chain C
7
-C
11
aralkyloxy, halogen, hydroxyl, straight or branched chain C
1
-C
7
aliphatic acyloxy, straight or branched chain C
1
C
6
alkylthio and straight or branched chain C
7
-C
11
aralkyl;
(12) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises straight or branched chain C
1
-C
4
alkyl, straight or branched chain C
1
C
4
alkoxy and straight or branched chain C
7
-C
11
aralkyloxy;
(13) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises methyl, methoxy and benzyloxy;
(14) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group B comprises straight or branched chain C
1
C
4
alkyl, straight or branched chain C
7
-C
11
aralkyl and straight or branched chain C
1
-C
7
aliphatic acyloxy; and
(15) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group C comprises straight or branched chain C
1
-C
4
alkyl, straight or branched chain C
1
C
4
alkoxy, halogen, hydroxyl, straight or branched chain C
1
-C
4
halogenoalkyl and amino.
In a
Fujita Takashi
Fujiwara Kosaku
Kurakata Shinichi
Frishauf Holtz Goodman & Chick P.C.
Goldberg Jerome D.
Sankyo Company Limited
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