Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-03
2002-06-11
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...
C514S255050, C544S360000, C544S386000, C544S398000, C544S402000
Reexamination Certificate
active
06403595
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP99/00470, filed Feb. 4, 1999.
TECHNICAL FIELD
The present invention relates to novel sulfonamide derivatives which are useful as a medicine and which inhibit activated coagulation factor X (FXa) to show anti-coagulant activity, their production and use.
BACKGROUND ART
For the purpose of the prevention and treatment of cardiac infarction, cerebral thrombosis, etc., it is important to inhibit formation of thrombus and various investigations and developments of thrombus inhibitors such as anti-thrombin agents, platelet aggregation inhibitors, etc. have been carried out. However, anti-thrombin agents as well as platelet aggregation inhibitors have side effects such as bleeding and safety problems. On the other hand, FXa inhibitors specifically inhibit the coagulation factor and are useful as anti-coagulants.
So far, compounds having FXa inhibitory activity are disclosed in e.g. Japanese Unexamined Patent Publication No. 1995 (H7)-112970, Japanese Unexamined Patent Publication No. 1993 (H5)-208946, WO 96/16940, WO 96/40679 and WO 96/10022, etc.
However, the above compounds having FXa inhibitory activity do not have sufficient FXa inhibitory activity and, in particular, do not show sufficient action when orally administered, therefore, they are not practically useful as a medicine.
DISCLOSURE OF INVENTION
The present invention is to provide novel sulfonamide derivatives which specifically inhibit FXa, which are effective when orally administered and which are useful as a safe medicine for the prevention (prophylaxis) or treatment (therapy) of diseases caused by thrombus or infarction.
The present inventors diligently made extensive studies and, as a result, they succeeded in synthesizing a compound or a salt thereof [hereinafter, referred to as Compound (I)], whose characteristic feature in the chemical structure lies in having (1) an oxo group on the ring A and (2) an optionally substituted amino group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group at the end of a substituent on the ring A, represented by the formula (I):
wherein R
1
is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; the ring A is an optionally substituted divalent nitrogen-containing heterocyclic group; X′ is a chemical bond or an optionally substituted alkylene chain; Y is an optionally substituted divalent cyclic group; X is a chemical bond or an optionally substituted alkylene chain; and Z is (1) an optionally substituted amino group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group; or a salt thereof, and further found that the compound (I) unexpectedly possesses potent FXa inhibitory activity based on its specific chemical structure and that the compound (I) can be safely and orally administered as a medicine for the prevention or treatment of diseases such as thrombus and infarction. Based on these findings the present invention was accomplished.
More specifically, the present invention relates to
(1) the Compound (I) or a salt thereof;
(2) a pro-drug of the Compound (I) or a salt thereof;
(3) a compound of the above (1) wherein R
1
is an optionally substituted hydrocarbon group;
(4) a compound of the above (1) wherein R
1
is an optionally substituted heterocyclic group;
(5) a compound of the above (1) wherein R
1
is an aryl group optionally substituted with a halogen atom or C
2-4
alkenyl group;
(6) a compound of the above (1) wherein R
1
is a benzopyranyl group optionally substituted with a halogen atom;
(7) a compound of the above (1) wherein the ring A is
wherein n is 1 or 2, and m is 2 or 3;
(8) a compound of the above (1) wherein X′ is an optionally substituted alkylene chain which may be substituted with 1-3 substituents selected from an optionally substituted lower alkyl group, an optionally substituted carbamoyl group, cyano group, hydroxy group and an optionally esterified carboxyl group;
(9) a compound of the above (1) wherein Y is an optionally substituted divalent cyclic hydrocarbon group, and Z is an optionally substituted amino group or an optionally substituted imidoyl group;
(10) a compound of the above (1) wherein Y is an optionally substituted divalent heterocyclic group;
(11) a compound of the above (1) wherein Y is an optionally substituted divalent heterocyclic group, and Z is an optionally substituted nitrogen-containing heterocyclic group;
(12) a compound of the above (1) wherein Y is an optionally substituted phenylene;
(13) a compound of the above (1) wherein Y is an optionally substituted piperidine;
(14) a compound of the above (1) wherein Z is an optionally substituted amidino group;
(15) a compound of the above (1) wherein Z is an optionally substituted nitrogen-containing heterocyclic group;
(16) A compound selected from the class consisting of 1-(4-amidinobenzyl)-4-(6-chloronaphthanlene-2-sulfonyl)-2-piperazinone, 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 1-[1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone and 1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone or a salt thereof,
(17) a pro-drug of the compound as described in the above (16) or a salt thereof;
(18) a pharmaceutical composition comprising the compound (I) of the above (1) or a salt thereof;
(19) a composition of the above (18) which is an anti-coagulant;
(20) a composition of the above (18) which is an inhibitor of activated coagulation factor X;
(21) a composition of the above (18) which is for the prevention or treatment of cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(22) use of the compound (I) of the above (1) or a salt thereof for manufacturing an anti-coagulant;
(23) use of the compound (I) of the above (1) or a salt thereof for manufacturing a pharmaceutical composition for inhibiting activated coagulation factor X;
(24) use of the compound (I) of the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(25) a method for inhibiting coagulation in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(26) a method for inhibiting activated coagulation factor X in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(27) a method for preventing or treating cardiac infarction, cerebral thrombosis or deep vein thrombosis in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(28) A method for producing Compound (I) as described in the above (1) or a salt thereof by reacting Compound (II) or a salt thereof represented by the formula:
R
1
SO
2
Q (II)
wherein Q is a halogen atom, and the other symbol is as defined in the above (1)
with Compound (III) or a salt thereof represented by the formula:
wherein each symbol is as defined in the above (1); or producing Compound (I) as described in the above (1) or a salt thereof by reacting Compound (IV) or a salt thereof represented by the formula:
wherein each symbol is as defined in the above (1) with Compound (V) or a salt thereof represented by the formula:
Q
1
—X′—Y—X—Z (V)
wherein Q
1
is a halogen atom or a group of the formula:
R
2
—SO
2
—O—
(wherein R
2
is a lower alkyl group optionally s
Banno Hiroshi
Itoh Fumio
Tawada Hiroyuki
Terashita Zen-ichi
Chao Mark
Patel Sudhaker B.
Ramesh Elaine M.
Shah Mukund J.
Takeda Chemical Industries Ltd.
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