Acylhydrazine derivatives, their production and use

Details Acylhydrazine derivatives, their production and use Acylhydrazine derivatives, their production and use

2001-12-18

2004-04-20

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253110, C544S364000

Reexamination Certificate

active

06723722

ABSTRACT:

This application is the National Phase filing of International Patent Application No. PCT/JP00/04034, filed Jun. 21, 2000.
TECHNICAL FIELD
The present invention relates to novel acyl hydrazine derivatives which inhibit activated coagulation factor X (FXa) to exhibit anti-coagulative effect and which are useful as pharmaceuticals, as well as their production and use.
BACKGROUND ART
It is important to inhibit the formation of a thrombus in preventing and treating cardiac infarction, cerebral thrombosis and the like, and various anti-thombotic agents such as anti-thrombin agents and platelet aggregation inhibitors have been developed. Nevertheless, platelet aggregation inhibitors as well as anti-thrombin agents have bleeding side effects and problems in their safety, since these agents posses a platelet aggregation-inhibiting activity in combination with anticoagulative effect. On the other hand, FXa inhibitors specifically inhibit on a coagulation factor, and thus are useful as anticoagulant.
So far, compounds having FXa-inhibiting effects are disclosed for example in JP-A-7-112970, JP-A-5-208946, WO-96/16940, WO96/40679 and WO 96/10022, as well as Journal of Medicinal Chemistry, Vol.41, page 3357 (1998), etc.
Since such compounds having FXa-inhibiting effects described above do not have sufficient FXa-inhibiting effects and, in particular, do not exhibit sufficient activities when given orally, therefore, they have not been successful in giving any practically satisfactory pharmaceutical effects.
DISCLOSURE OF THE INVENTION
The invention provides novel acylhydrazine derivatives which specifically inhibit FXa, which are capable of being given orally and which are useful as a pharmaceutical capable of being used safely in preventing and treating a disease associated with thrombus or infarction.
The present inventors made an effort and finally was successful for the first time to synthesis a compound characterized chemically by the presence of a two nitrogen atoms [nitrogen atom in —n(R
2
)—; and nitrogen atom in —n(R
3
)— or —N═] adjacent to a carbonyl group and the presence of an optionally substituted amino group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group at its terminal, i.e., a compound represented by Formula:
wherein R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, each of R
1
and R
2
is a hydrogen atom or an optionally substituted hydrocarbon group, or R
1
and R
2
or a substituent on X
1
and R
2
are bound to each other to form an optionally substituted ring, each of X
1
and X
2
is a bond, an optionally substituted alkylene group or an optionally substituted imino group, D is an oxygen atom or a sulfur atom, A is —N(R
3
)—Y— or —N═Y—, R
3
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, Y is an optionally substituted linear hydrocarbon group or an optionally substituted cyclic group, 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 (hereinafter sometimes referred to as Compound (I)), and discovered that this compound exhibits an unexpectedly excellent FXa inhibiting effect due to its particular chemical structure, and thus can safely be given orally as a prophylactic and therapeutic agent for a disease associated with a thrombus or an infarction, thus establishing the invention.
Accordingly, the invention relates to:
(1) a Compound (I);
(2) a prodrug of a compound according to Section (1) described above or a salt thereof;
(3) a compound according to Section (1) described above wherein R is an optionally substituted hydrocarbon group;
(4) a compound according to Section (1) described above wherein R is an optionally substituted heterocyclic group;
(5) a compound according to Section (1) described above wherein R is a halogen atom or an aryl group optionally substituted by a C
2-4
alkenyl;
(6) a compound according to Section (1) described above wherein R is a naphthyl group optionally substituted by a halogen atom;
(7) a compound according to Section (1) described above wherein R is a benzopyranyl group optionally substituted by a halogen atom;
(8) a compound according to Section (1) described above wherein R
1
and R
2
are bound to each other and taken together with —N—X
1
—CD—N— to form a group represented by Formula:
wherein X
3
is an optionally substituted C
1-2
alkylene, X
4
is an optionally substituted C
1-3
alkylene and D is an oxygen atom or a sulfur atom;
(9) a compound according to Section (1) described above wherein R
1
and R
2
are bound to each other and taken together with —N—X
1
—CD—N— to form a group represented by Formula:
wherein n is 1 or 2, m″ is 1 or 2, R
8
is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group), and D is an oxygen atom or a sulfur atom;
(10) a compound according to Section (1) described above wherein R
1
and R
2
are bound to each other and taken together with —N—X
1
—CD—N— to form a group represented by Formula:
wherein n is 1 or 2 and m is 2 or 3.
(11) a compound according to Section (10) described above wherein n=1 and m=2;
(12) a compound according to Section (1) described above wherein a substituent on X
1
and R
2
are bound to each other and a divalent group represented by —X
1
—CD—N(R
2
)— is a group represented by Formula:
wherein X
5
is a bond or an optionally substituted methylene, X
6
is an optionally substituted C
2-3
alkylene and D is an oxygen atom or a sulfur atom;
(13) a compound according to Section (1) described above wherein a substituent on X
1
and R
2
are bound to each other and a divalent group represented by —X
1
—CD—N(R
2
)— is a group represented by Formula:
wherein n′ is 0 or 1 and m′ is 2 or 3;
(14) a compound according to Section (13) described above wherein n′=0 and m′=2;
(15) a compound according to Section (1) described above wherein each of R
1
and R
2
is a hydrogen atom or an optionally substituted lower alkyl;
(16) a compound according to Section (1) described above wherein an optionally substituted imino group is a group represented by Formula —N(R
4
)— wherein R
4
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group;
(17) a compound according to Section (1) described above wherein X
1
is methylene;
(18) a compound according to Section (1) described above wherein X
2
is a bond;
(19) a compound according to Section (1) described above wherein R
3
is a hydrogen atom, an optionally substituted lower alkyl group, formyl or an optionally substituted lower alkanoyl group;
(20) a compound according to Section (1) described above wherein R
3
is a hydrogen atom or an optionally substituted lower alkyl group;
(21) a compound according to Section (1) described above wherein Y is an optionally substituted cyclic hydrocarbon group;
(22) a compound according to Section (1) described above wherein A is —N(R
3
)—Y— and Y is an optionally substituted phenylene;
(23) a compound according to Section (1) described above wherein Y is an optionally substituted heterocyclic group;
(24) a compound according to Section (1) described above wherein Y is an optionally substituted piperidine residue;
(25) a compound according to Section (1) described above wherein Z is an optionally substituted nitrogen-containing hetero

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