Sulfonamide derivatives, their production and use

Details Sulfonamide derivatives, their production and use Sulfonamide derivatives, their production and use

1999-11-30

2002-03-19

Raymond, Richard L. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S238000, C544S242000, C514S252100, C514S252130, C514S256000, C514S269000

Reexamination Certificate

active

06359134

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel sulfonamide derivatives which are useful as 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 researches 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 problems in their safety, since thrombin is a final mediator causing blood coagulation and platelet aggregation. On the other hand, FXa inhibitors specifically inhibit coagulation factor and are useful as an anti-coagulant.
So far, compounds having FXa inhibitory activity are disclosed in e.g. 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, ischemia 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) a divalent nitrogen-containing heterocyclic group between a sulfonyl group and a carbonyl group and (2) an amino group substituted with a hydrocarbon group, an imidoyl group or a nitrogen-containing heterocyclic group at terminals of a substituent of the carbonyl group, 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, in addition to being substituted by the group of the formula:
and the group of the formula:
Y is an optionally substituted divalent hydrocarbon group or an optionally substituted divalent heterocyclic group;
X is a direct bond or an optionally substituted alkylene chain; Z is (1) an amino group substituted with an optionally substituted hydrocarbon group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group; provided that when X is a direct bond and Z is an optionally substituted 6-membered nitrogen-containing aromatic heterocyclic group, Y is an optionally substituted divalent hydrocarbon group or an optionally substituted divalent unsaturated 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 the finding, the present invention was accomplished.
More specifically, the present invention relates to (1) the compound (I); (2) a compound of the above (1), wherein
R
1
is (1) a C
1-10
alkyl group, (2) a C
2-6
alkenyl group, (3) a C
2-6
alkynyl group, (4) a C
3-9
cycloalkyl group, (5) a C
3-6
cycloalkenyl group, (6) a C
4-6
cycloalkanedienyl group, (7) a C
6-14
aryl group or (8) a heterocyclic group selected from the class consisting of (i) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) a 8- to 12-membered aromatic fused heterocyclic group and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group and containing 1 to 4 hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom besides carbon atoms; each of said groups (1)-(8) being unsubstituted or substituted by 1 to 5 substituents selected from the class consisting of
(a) a C
1-6
alkyl group optionally substituted with C
1-6
alkoxy, halogen, C
1-6
alkyl, amino, hydroxy, cyano group or amidino,
(b) a C
2-6
alkenyl group optionally substituted with C
1-6
alkoxy, halogen, C
1-6
alkyl, amino, hydroxy, cyano group or amidino,
(c) a C
2-6
alkynyl group optionally substituted with C
1-6
alkoxy, halogen, C
1-6
alkyl, amino, hydroxy, cyano group or amidino,
(d) a C
6-14
aryl group optionally substituted with C
1-6
alkoxy, halogen, C
1-6
alkyl, amino, hydroxy, cyano group or amidino,
(e) a C
3-7
cycloalkyl or C
3-6
cycloalkenyl group optionally substituted with C
1-6
alkoxy, halogen, C
1-6
alkyl, amino, hydroxy, cyano group or amidino,
(f) a heterocyclic group selected from the class consisting of (i) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) a 8- to 12-membered aromatic fused heterocyclic group and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group and containing 1 to 4 hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom besides carbon atoms, which may be substituted by C
1-6
alkyl, C
1-6
alkanoyl or benzoyl,
(g) an amino group optionally substituted with C
1-6
alkyl group, C
1-6
alkanoyl, benzoyl, optionally halogenated C
1-6
alkoxy-carbonyl, C
1-6
alkylimidoyl, formimidoyl or amidino,
(g′) a 3- to 8-membered cyclic amino group optionally having C
1-6
alkyl, C
7-10
aralkyl or C
6-10
aryl,
(h) an imidoyl group optionally substituted with C
1-6
alkyl group, C
1-6
alkanoyl, benzoyl or optionally halogenated C
1-6
alkoxy-carbonyl,
(i) an amidino group optionally substituted with C
1-6
alkyl group, C
1-6
alkanoyl, benzoyl or optionally halogenated C
1-6
alkoxy-carbonyl,
(j) a hydroxy group optionally substituted with C
1-6
alkyl group, C
1-6
alkanoyl, benzoyl or optionally halogenated C
1-6
alkoxy-carbonyl,
(k) a thiol group optionally substituted with C
1-6
alkyl group, C
1-6
alkanoyl, benzoyl or optionally halogenated C
1-6
alkoxy-carbonyl,
(l) a carboxyl group,
(l′) a C
1-6
alkoxy-carbonyl group,
(l″) a C
7-2
aryloxycarbonyl group being unsubstituted or substituted by hydroxy, amino optionally having 1 to 2 substituents selected from C
1-6
alkyl, C
1-6
alkanoyl and benzoyl, halogen, nitro, cyano, C
1-6
alkyl optionally substituted with 1 to 5 halogen atoms or C
1-6
alkoxy optionally substituted with 1 to 5 halogen atoms,
(l′″) a C
6-10
aryl-C
1-4
alkoxy-carbonyl group being unsubstituted or substituted by hydroxy, amino optionally having 1 to 2 substituents selected from C
1-6
alkyl, C
1-6
alkanoyl and benzoyl, halogen, nitro, cyano, C
1-6
alkyl optionally substituted with 1 to 5 halogen atoms or C
1-6
alkoxy optionally substituted with 1 to 5 halogen atoms,
(m) a carbamoyl group,
(m′) a carbamoyl group having one substituent selected from C
1-6
alkyl, C
3-6
cycloalkyl, C
6-10
aryl, C
7-10
aralkyl and heterocyclic group selected from the class consisting of (i) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) a 8- to 12-membered aromatic fused heterocyclic group and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group and containing 1 to 4 hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom besides carbon atoms; each of said alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups being unsubstituted or substituted by hydroxy, amino optionally having 1 to 2 substituents selected from C
1-6
alkyl, C
1-6
alkanoyl and benzoyl, halogen, nitro, cyano, C
1-6
alkyl optionally substituted with 1 to 5 halogen atoms or C
1-6
alkoxy optionally substituted with 1 to 5 halogen atoms,
(m″) a carbamoyl group having one substituent selected from C
1-6
alkyl, C
3-6
cycloalkyl, C
6-10
aryl,

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