Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-28
2003-02-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S252130, C514S255020, C540S460000, C540S463000, C540S526000, C544S359000, C544S360000, C544S385000, C548S543000
Reexamination Certificate
active
06525042
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel, orally-administrable sulfonyl derivative or salt thereof which inhibits an activated coagulation factor (which will hereinafter be abbreviated as “FXa”), thereby exhibiting strong anticoagulant action; and a coagulation suppressor or preventive and/or remedy for thrombosis or embolism which comprises the derivative or salt as an effective ingredient.
BACKGROUND ART
Exasperation of coagulation capacity is an important factor for unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization or formation of thrombus upon extracorporeal circulation. There is accordingly a demand for an excellent anticoagulant which is excellent in dose-responsiveness, has long-lasting effects, has a low risk of hemorrhage, has less side effects and exhibits rapid and sufficient effects even by oral administration (Thrombosis Research, 68, 507-512, 1992).
Studies on anticoagulants based on various acting mechanisms suggest that a FXa inhibitor has a possibility of becoming an excellent anticoagulant. The coagulation system is a series of reactions wherein a large amount of a thrombus is produced through an amplification step due to a multi-stage enzymatic reaction and induces the formation of insoluble fibrin. In the intrinsic system, after the multi-stage reaction following the activation of a contact factor, activated Factor IX activates factor X on a phospholipid membrane in the presence of activated Factor VIII and a calcium ion, while in the extrinsic system, activated Factor VII activates Factor X in the presence of a tissue factor. In other words, the activation of Factor X into FXa in the coagulation system is an essential reaction in the formation of thrombin. Activated Factor X (FXa) in each system carries out limited proteolysis of prothrombin, thereby forming thrombin. The resulting thrombin activates the coagulation factors on the upstream side, whereby the formation of thrombin is amplified further. As described above, the coagulation system upstream of FXa is separated into intrinsic and extrinsic systems so that the inhibition of the enzyme of the coagulation system upstream of FXa does not suppress the production of FXa sufficiently, inevitably resulting in the production of thrombin. Furthermore, the coagulation occurs as a self-amplifying reaction so that the suppression of the coagulation system can be accomplished more efficiently by the inhibition of FXa which exists upstream of the thrombin than by the inhibition of the thrombin formed (Thrombosis Research, 15, 617-629(1979)).
Another merit of the FXa inhibitor is that an effective dose in a thrombus model is largely different from the dose for extending the bleeding time in an experimental hemorrhage model. From the experimental result, the FXa inhibitor is presumed to be an anticoagulant with a low risk of hemorrhage.
As a FXa inhibitor, various compounds are reported. In general, antithrombin III or antithrombin III-dependent penta-saccharide is known to have no inhibitory action against a prothrombinase complex which plays a practical role in the thrombus formation in vivo (Thrombosis Research, 68, 507-512(1992); Journal of Clinical Investigation, 71, 1383-1389(1983); Mebio, August issue, 1992-1997) and moreover, it does not exhibit effectiveness in oral administration. Although tick anticoagulant peptide (TAP) (Science, 248, 593-596(1990)) or antistacin (AST) (Journal of Biological Chemistry, 263, 10162-10167(1988)) isolated from a tick or leech which is a bloodsucker inhibits FXa and exhibits anti-thrombus effects on the models of from venous thrombus to arterial thrombus, it is not effective when orally administered because it is a high-molecular peptide. From such a viewpoint, a low-molecular FXa inhibitor which directly inhibits a coagulation factor without depending on antithrombin III has been developed.
An object of the present invention is to provide, as an excellent anticoagulant, a novel compound which has strong FXa inhibitory action, exhibits prompt, sufficient and long-lasting anti-thrombus effects even by the oral administration and has less side effects.
DISCLOSURE OF THE INVENTION
With the forgoing in view, the present inventors have carried out an extensive investigation on the synthesis of a novel FXa inhibitor and its pharmacological action. As a result, it has been found that a novel sulfonyl derivative, salt thereof or solvate thereof exhibits strong FXa inhibitory action and strong anticoagulant action, inhibits FXa strongly, promptly and continuously by the oral administration, exhibits anti-coagulant action and anti-thrombus action, is highly safe and is useful as a preventive or remedy for various diseases caused by a thrombus or embolus, thus leading to completion of the present invention. The present invention provides a sulfonyl derivative represented by the following formula (I):
[wherein:
R
1
represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A
1
-B
1
— (in which A
1
represents an amino group which may have one or two substituents, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B
1
represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group),
R
2
and R
3
each independently represents a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group or R
2
or R
3
may be coupled together with R
1
to form a C
1-3
alkylene or alkenylene group,
R
4
and R
5
each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (with the proviso that R
4
and R
5
do not represent a hydrogen atom at the same time),
Q
1
represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a saturated or unsaturated bicyclic or tricyclic fused ring group which may have a substituent,
Q
2
represents a single bond, an oxygen atom, a sulfur atom, a linear or branched C
1-6
alkylene group, a linear or branched C
2-6
alkenylene group, a linear or branched C
2-6
alkynylene group, a group —N(R
6
)—CO— (in which R
6
represents a hydrogen atom or an alkyl group), a group —N(R
7
)—(CH
2
)
m
— (in which R
7
represents a hydrogen atom or an alkyl group and m stands for an integer of 0 to 6) or a group of the following formula:
(which represents a divalent, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a divalent, saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a divalent, saturated or unsaturated dicyclic fused ring group which may have a substituent and ←C means the bonding of the carbon atom of this group to Q
1
),
Q
3
represents any one of the following groups:
(in which when the carbon atom to which each of R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
15
and R
16
has been bonded is not adjacent to a nitrogen atom, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
15
and R
16
each independently represents:
a hydrogen atom,
a hydroxyl group,
an alkyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkyloxy group,
a hyroxyalkyl group,
a hydroxyalkyloxy group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
Haginoya Noriyasu
Horino Haruhiko
Ito Masayuki
Kobayashi Syozo
Komoriya Satoshi
Balasubramanian Venkataraman
Daiichi Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
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