Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-16
2002-08-06
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S417000, C546S183000, C546S141000, C548S473000, C548S480000, C548S422000
Reexamination Certificate
active
06429212
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition which comprises a cyclic imide derivative or its salt. The cyclic imide derivative or its salt includes the isoindole derivative or its salt, a certain N-phenylimide compound or its salt, a certain phthalimide derivative or its salt, and an N-phenylphthalimide derivative or its salt. Particularly, the present invention relates to an aminopeptidase N inhibitor or an angiogenesis inhibitor, which comprises, as an active ingredient, the cyclic imide derivative or its salt.
The present invention further relates to a novel isoindole derivative or its salt, a method for producing it, and a pharmaceutical composition comprising it. It also relates to a pharmaceutical which modulates production of tumor necrosis factor (TNF-&agr;) and which comprises, as an active ingredient, a novel isoindole derivative or its salt.
BACKGROUND ART
JP-A-50-121432 discloses phthalimide derivatives as active ingredients for agricultural and horticultural fungicides, and JP-A-62-22760 discloses isoindoline derivatives as active ingredients for agricultural and horticultural fungicides. However, they are respectively different in their chemical structures from the cyclic imide derivatives of the present invention.
Further, in the field of pharmaceuticals, the cyclic imide derivatives of the present invention differ in the chemical structures from N-alkylphthalimides disclosed in CHEMICAL & PHARMACEUTICAL BULLETIN vol. 43, 1, 177-179, 1995, and from benzylphthalimides and phenethylphthalimides disclosed in BIOLOGICAL PHARMACEUTICAL BULLETIN vol. 18, 9, 1228-1233, 1995.
A pharmaceutical which modulates (enhances or suppresses) production of tumor necrosis factor (TNF-&agr;) which is considered to be one of factors which cause various diseases, is useful also as a biological response modulator. It is expected to be used widely, as an immunostimulant or an immunosuppressant, and development of it as a pharmaceutical is desired.
Further, aminopeptidase N (APN) is distributed mainly in epithelial cells of kidney and small intestine, monocytes and granulocytes, cancer cells and on cell surface membrane of placenta, liver and pancreas, and its various physiological functions such as digestion and absorption of amino acids, biosyntheses and degradation of bioactive substances such as peptide hormones, growth factors and autacoid and degradation of extracellular matrix, have been studied. And a pharmaceutical which inhibits the activity of APN is expected as a preventive drug or a therapeutic drug for cancer, cancer metastasis, inflammatory diseases, autoimmune diseases and allergic diseases, and development of a pharmaceutical drug which is an aminopeptidase N inhibitor is desired.
Excessive activation of angiogenesis is known to relate to onset or progression steps of various diseases, and development of a pharmaceutical which is an angiogenesis inhibitor which is useful as a preventive drug or a therapeutic drug of such diseases is desired.
Further, it is meaningful to find out an excellent pharmaceutical composition with respect to a certain novel and characteristic isoindole derivative or its salt.
DISCLOSURE OF THE INVENTION
In order to find out an excellent pharmaceutical a composition with respect to a certain isoindole derivative or its salt, the present inventors have paid attention to modulate production of tumor necrosis factor (TNF-&agr;) which is considered to be one of factors which cause various diseases. Further, they have found that by using an optically active substance of the isoindole derivative or its salt, the control of TNF-&agr; production can be divided into enhancing effect and suppressive effect, whereby a compound which has only one of these effects can be obtained, and as a result, they have accomplished the present invention.
Further, they have found that a cyclic imide derivative having a certain chemical structure or its salt has amino peptidase N inhibitory effect or anti-angiogenetic effect, and have accomplished the present invention.
Namely, the present invention relates to:
(1) An aminopeptidase N inhibitor which comprises a cyclic imide derivative represented by the general formula (I):
wherein Q
1
is a single bond, —CH
2
—, —O—, —S— or —NH—, each of Q
2
and Q
3
which are independent of each other, is —C(O)—, —C(S)— or —CH
2
—, provided that at least one of Q
2
and Q
3
is —C(O)— or —C(S)—, Z is a single bond or a lower alkanediyl group, R is an aryl group which may be substituted or a cycloalkyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt, and a pharmaceutically acceptable carrier;
(2) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q
1
is a single bond or —CH
2
—, and Z is a single bond;
(3) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q
1
is a single bond or —CH
2
—, Z is a single bond, and R is a phenyl group which may be substituted;
(4) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q
1
is —CH
2
—, Z is a single bond, and R is a phenyl group which may be substituted;
(5) An angiogenesis inhibitor which comprises a cyclic imide derivative represented by the general formula (I):
wherein Q
1
is a single bond, —CH
2
—, —O—, —S— or —NH—, each of Q
2
and Q
3
which are independent of each other, is —C(O)—, —C(S)—, or —CH
2
—, provided that at least one of Q
2
and Q
3
is —C(O)— or —C(S)—, Z is a single bond or a lower alkanediyl group, R is an aryl group which may be substituted or a cycloalkyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, and provided that when Z is a single bond, R is an aryl group which may be substituted, or its salt, and a pharmaceutically acceptable carrier;
(6) The angiogenesis inhibitor according to (5), wherein Q
1
in the cyclic imide derivative is a single bond or —CH
2
—;
(7) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q
1
is a single bond or —CH
2
—, and R is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted;
(8) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q
1
is a single bond or —CH
2
—, Z is a single bond or a 1,1-ethanediyl group, R is a phenyl group which may be substituted, a inaphthyl group which may be substituted or a cyclohexyl group which may be substituted;
(9) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q
1
is a single bond or —CH
2
—, Z is a single bond or a 1,1-ethanediyl group, R is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a fluorine atom and m is 4;
(10) A cyclic imide derivative represented by the general formula (I′):
wherein Z′ is an alkyl group, R′ is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, Y is an oxygen atom or a sulfur atom, and Q
3
is —C(O)—, —C(S)— or —CH
2
—, or its salt;
(11) The cyclic imide derivative according to (10), wherein the compound of the formula (I′) is an optically active s
Ishihara Sangyo Kaisha Ltd.
Murray Joseph
Solola T. A.
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