Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-28
2002-10-22
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S428000, C548S469000, C548S467000, C548S490000, C548S509000
Reexamination Certificate
active
06469043
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a sulfonamide-containing indole compound and to an antiangiogenic effect thereof. More particularly, it relates to an antitumor agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis and a therapeutic agent for hematoma on the basis of an antiangiogenic effect.
PRIOR ART
It has become clear that there is a close relation between proliferation of cancer and angiogenesis. Thus, when angiogenesis is not generated at the site of cancer, the cancer remains in a state of dormant tumor. However, it has become clarified that, when angiogenesis is generated, oxygen and nutrients in blood are supplied to the tumor whereby proliferation and metastasis of cancer are promoted resulting in a clinically malignant state. Accordingly, it is expected that, when angiogenesis of cancer is suppressed, proliferation and metastasis of cancer can be suppressed. Since angiogenetic vessels are composed of endothelial cells and interstitial cells of the host, target of the antiangiogenic agent is not cancer cells but such normal cells of the host. Because of the fact that the cancer cells are not a direct target, efficacy to the cancer which does not respond to known anticancer agents can be expected as well and, in addition, it is presumed that the possibility of occurrence of tolerant cancer which is a big problem in cancer therapy is little. In addition, angiogenesis is a tumor-specific phenomenon and, in mature individuals, it is limited to the formation of endometrium, etc. accompanied by a menstrual cycle. Accordingly, its adverse effect is thought to be little as compared with known anticancer drugs. Recently, it has been experimentally proved in preclinical tests that antiangiogenic agents are able to suppress and further to reduce the proliferation of cancer in the cancer-transplanted models and that tolerant cancer is not generated and, in clinical tests, the correlation between angiogenesis and malignization of many solid cancers such as breast cancer, prostatic cancer, lung cancer and cancer of the colon has been shown.
In cancer tissues, apoptosis and proliferation of cancer cells continuously occur and it has been known that, depending upon the balance between them, progressive cancer or dormant tumor results. An antiangiogenic agent does not directly kill the cancer cells but cuts off the nutrient sources so that the said balance is inclined to apoptosis inducing dormant tumor or reduction in cancer whereby it is a drug which can be expected to exhibit an excellent effect (prolongation of life, inhibition of recurrence and suppression of metastasis) by a long-term therapy.
In a preclinical stage, there are antiangiogenic agents by various action mechanisms but, since their antitumor effect in a preclinical stage is insufficient, their usefulness in clinical stage is still doubtful and, therefore, there has been a brisk demand for antiangiogenic agents where the effect is reliable.
It has been also known that angiogenesis participates in retinopathy or retinitis. When blood vessel is proliferated in retina, eyesight gets worse and, when progressed, blindness is resulted. There has been no effective therapeutic drug therefor at present and effective therapeutic drugs have been demanded.
WO 9301182 discloses antitumor agents due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are indolylmethylene-2-indolinone compounds and are different from the present invention. Similarly, WO 964016 discloses an antitumor agent due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are 2-indolinone-3-methylene compounds and are different from the present invention. Sulfonamide compounds having an indole structure are disclosed in JP-A 7-165708 and JP-A 8-231505. However, the compounds which are specifically disclosed in JP-A 7-165708 and have two substituents other than aryl (or heteroaryl) sulfonylamino group on an indole ring are limited and combinations of those substituents are only six, i.e. (1) 3-Cl and 4-Cl; (2) 3-Cl and 4-OCH
3
; (3) 3-Cl and 4-OH; (4) 3-Cl and 4-CH
3
; (5) 3-Cl and 4-CN; and (6) 3-CN and 5-Br. There is no combination of (a) 3-CN and 4-CH
3
; (b) 3-Cl and 5-Br; (c) 3-Cl and 4-Br; and (d) 3-Br and 4-CH
3
. With regard to 4-halogen monosubstituted compounds, there is a description for 4-Br compounds but its sulfonyl moiety is a p-nitrophenol compound only. Further, indole compounds disclosed in JP-A 8-231505 are 3-halogen or 3-cyano monosubstituted compounds only. In those laid-open publications, there is no description for an antiangiogenic effect at all and there is no description suggesting that as well.
DISCLOSURE OF THE INVENTION
An object of the present invention is to create a novel antiangiogenic agent and to provide an antitumor agent which shows a high safety and a sure effect as compared with conventional antitumor agents and is able to be administered for a long period.
The present inventors have carried out an intensive study, found that the sulfonamide-containing indole compound represented by the following formula achieves the aimed object and accomplished the present invention. That is, the present invention relates to a sulfonamide-containing indole compound represented by the following formula (I), its pharmacologically acceptable salt or hydrates thereof.
In the formula, R
1
represents hydrogen atom, a halogen atom or cyano group; R
2
and R
1
are the same as or different from and each represents hydrogen atom, a C
1
~C
4
lower alkyl group or a halogen atom; R
4
represents hydrogen atom or a C
1
~C
4
lower alkyl group; and the ring A represents cyanophenyl group, aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, halopyridyl group or cyanothiophenyl group, provided that the case where all of R
1
, R
2
and R
3
are hydrogen atoms, where both R
2
and R
3
are hydrogen atoms, or where the ring A is aminosulfonyl group and both R
1
and R
2
are halogen atoms is excluded. Further, when the ring A is cyanophenyl group, 2-amino-5-pyridyl group or a 2-halo-5-pyridyl group and R
1
is cyano group or a halogen atom, at least one of R
2
and R
3
should not be a hydrogen atom.
The present invention relates to a method for the prevention or therapy of the disease against which inhibitory of angiogenesis at the site of tumor, rheumatic arthritis or diabetic retinopathy is effective for the prevention or therapy, by administering a pharmacologically effective dose of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof to a patient.
The present invention further relates to a use of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof for the manufacture of a preventive or therapeutic agent for the disease against which an antiangiogenic agent is effective for the prevention or therapy.
The present invention furthermore relates to an antiangiogenic agent, an antitumor agent, a therapeutic agent for pancreatic cancer, a therapeutic agent for cancer of the colon, a therapeutic agent for gastric cancer, a therapeutic agent for breast cancer, a therapeutic agent for prostatic cancer, a therapeutic agent for lung cancer, a therapeutic agent for ovarian cancer, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis or a therapeutic agent for hematoma, which comprises the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof as an effective ingredient. It relates to a method for prevention, therapy and improvement by use of any of those pharmaceutical agents. Further, it relates to a use of the above compound for the manufacture of any of those pharmaceutical agents.
In the above formula (I), a halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom. A C
1
~C
4
lower alkyl group means a linear or branched alkyl group such
Funahashi Yasuhiro
Hamaoka Shinichi
Haneda Toru
Hata Naoko
Kamata Jun-ichi
Birch Stewart Kolasch & Birch, LLP.
Eisai Co. Ltd.
Patel Sudhaker B
Shah Mukund J.
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