Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-10
2004-09-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S277000, C514S299000, C514S311000, C514S345000, C514S351000, C546S001000, C546S152000, C546S159000, C546S290000, C546S293000, C546S294000
Reexamination Certificate
active
06787534
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a sulfonamide-containing heterocyclic compound which is useful as a medicament and to an antiangiogenic effect thereof. Further, 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 is resulted. 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. Effective therapeutic drugs have been demanded.
In GB 662798, hydroxy- and acyloxy-phenylsulfonylamino-substituted quinoline and quinoxaline are disclosed, but relates to antiviral agents and are different from the present invention. In J. Sci. Ind. Res., sect. B, 21(1962), 3-p-toluenesulfonylamino-8-hydroxyquinoline is disclosed. Though, there is no description relating to an antiangiogenic effect. In JP-A 1-254682, 1,8-naphthylidine and pyrido[2,3-d]pyrimidine derivatives having a substituted sulfonamide are disclosed, but relates to herbicides and are different from the present invention. In JP-A 62-426 and 7-267936, sulfonamidequinoxaline derivatives having antitumor activity are disclosed. Though, there is no description relating to an antiangiogenic effect.
Accordingly, an object of the present invention is to provide a novel sulfonamide-containing heterocyclic compound that has an excellent an antiangiogenic effect and has a different structure from those of conventional antiangiogenic agent. Another object of the present invention is to provide an intermediate of the compound and a pharmaceutical composition containing the compound as an active ingredient.
DISCLOSURE OF THE INVENTION
The present inventors have made intensive investigations for an antiangiogenic agent. As a result, they have found that a novel sulfonamide-containing heterocyclic compound has an excellent antiangiogenic effect and has an excellent effect as a pharmaceutical drug. Thus, they have accomplished the present invention.
Specifically, the present invention provides a sulfonamide-containing heterocyclic compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate of them.
In the formula:
A is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group, —(CO)kNR
2
R
3
(wherein, R
2
and R
3
are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and k means 0 or 1), a C2-C4 alkenyl group or alkynyl group which may have a substituent, or a phenyl group or phenoxy group which may have a substituent selected from the following group A;
B is an aryl group or monocyclic heteroaryl group which may have a substituent selected from the following group A, or
(wherein, the ring Q is an aromatic ring which may have one or two nitrogen atoms; the ring M is an unsaturated C5-C12 monocyclic or polycyclic ring which shares a double bond with the ring Q, and the ring may have 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; the ring Q and the ring M may share nitrogen atom with each other; and the ring Q and the ring M may each have a substituent selected from the following group A);
K is a single bond or —(CR
4
R
5
)m— (wherein, R
4
and R
5
are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m is an integer of 1 or 2);
T, W, X and Y are the same as or different from each other and each means ═C(D)— (wherein D is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted by a halogen atom, cyano group, —(CO)nNR
6
R
7
(wherein R
6
and R
7
are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and n means 0 or 1), or a C2-C4 alkenyl group or alkynyl group which may have a substituent), or nitrogen atom;
U and V are the same as or different from each other and each means ═C(D)— (wherein, D has the same meaning as defined above), nitrogen atom, —CH
2
—, oxygen atom or —CO—;
Z is a single bond or —CO—NH—;
R1 is hydrogen atom or a C1-C4 alkyl group; and
means a single or double bond,
Group A
a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted by a halogen atom, cyano group, —R
8
R
9
N(NH)p— (wherein R
8
and R
9
are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and p means 0 or 1, and R
8
and R
9
may be combined with the nitrogen atom to which they bound to form a 5- or 6-membered ring which may include nitrogen atom, oxygen atom or sulfur atom and may have a substituent), an aminosulfonyl group which may be substituted with one or two C1-C4 alkyl groups, an optionally substituted C1-C8 acyl group, a C1-C4 alkyl-S(O)s-C1-C4 alkylene group (wherein s means an integer of 0, 1 or 2), a phenylsulfonylamino group which may have a C1-C4 alkyl or a substituent, —(CO)qNR
10
R
11
(wherein R
10
and R
11
are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with an amino grou
Funahashi Yasuhiro
Hamaoka Shinichi
Haneda Toru
Hata Naoko
Kamata Jun-ichi
Eisai Co. Ltd.
Patel Sudhaker B.
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