Diazepan derivatives or salts thereof

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S217120, C540S597000, C540S610000

Reexamination Certificate

active

06642224

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel diazepan derivative or a salt thereof, which is useful as a pharmaceutical particularly as an activated blood coagulation factor X inhibitor and also to such a pharmaceutical agent.
BACKGROUND ART
With the changes into European and American life styles and the increase in aged population in recent years, the number of patients with thromboembolic diseases including myocardial infarction, cerebral thrombosis and peripheral arterial thrombosis have been increasing year by year and social importance of their treatment has been increasing more and more. As well as the fibrinolysis therapy and antiplatelet therapy, the anticoagulation therapy takes a part of the medical therapy in treating and preventing thrombosis (
Sogo Rinsho,
41: 2141-2145, 1989). In particular, the safety which withstands long-term administration and accurate and proper expression of the anticoagulation activity are essential in the prevention of thrombosis. Warfarin potassium is frequently used in the world as the sole oral anticoagulant but this drug is extremely difficult to use clinically because it is difficult to control the anticoagulation capacity due to the characteristics based on its action mechanism (
J. Clinical Pharmacology,
32, 196-209, 1992 and
N. Eng. J. Med.,
324(26), 1865-1875, 1991) whereby a great concern has been directed toward the development of more useful and easily usable anticoagulants.
Thrombin controls conversion of fibrinogen into fibrin which is the final step of coagulation and is also concerned deeply in the activation and aggregation of platelets (“T-PA and Pro-UK” edited by S. Matsuo, published by Gakusai Kikaku, pp. 5-40 “Blood Coagulation”, 1986) and its inhibitor has been the center of anticoagulant studies as a target of development of pharmaceuticals. However, thrombin inhibitors which can be administered orally have not been put into the market until now because of their low bioavailability by oral administration and problems from the viewpoint of safety (
Biomed. Biochim. Acta,
44, 1201-1210, 1985).
Activated blood coagulation factor X is a key enzyme which is located at the joining point of the extrinsic and intrinsic coagulation cascade reactions and located upstream to thrombin whereby there is a possibility that inhibition of this factor is more efficient than the thrombin inhibition and such an inhibitor can inhibit this coagulation system in a specific manner (
THROMBOSIS RESEARCH
(19), 339-349, 1980).
As the compounds having an activated blood coagulation factor X inhibiting action, amidinonaphthyl alkylbenzene derivatives or salts thereof have been known (Japanese Patent Laid-Open No. 208946/1993
; Thrombosis Haemostasis,
71(3), 314-319, 1994; and
Thrombosis Haemostasis,
72(3), 393-396, 1994).
In WO 96/16940, it is mentioned that an amidinonaphthyl derivative or a salt thereof represented by the following general formula is the compound having an activated blood coagulation factor X inhibiting action (Prior Art 1).
(For the symbols in the formula, refer to the gazette.)
In WO99/00121, WO99/00126, WO99/00127, WO99/00128, WO00/39111, WO00/39117 and WO00/39118, phenylenediamide compounds, etc. represented by the following general formula are mentioned as an factor Xa inhibitor (Prior Art 2).
(For the symbols in the formula, refer to the gazette.)
Further, in WO99/32477, a broad range of compounds represented by the following general formula is mentioned as an anticoagulant (Prior Art 3).
(For the symbols in the formula, refer to the gazette.)
DISCLOSURE OF THE INVENTION
The present inventors have produced a diazepan derivative represented by the following general formula (I) or a salt thereof and found that it has an excellent activated blood coagulation factor X inhibiting action and particularly has an excellent activity by oral administration.
Specifically, this invention relates to a diazepan derivative represented by the following general formula (I) or a salt thereof and also to a pharmaceutical composition, particularly an activated blood coagulation factor X inhibitor, containing the same as an effective ingredient.
(Symbols in the above formula have the following meanings:
Rings A and B: They are the same or different and are each aryl or heteroaryl which may have 1 to 3 substituents;
X
1
: —C(═O)—NR
4
—, —NR
4
—C(═O)—, —NR
4
—CH
2
—, —O—CH
2
—, —CH
2
—CH
2
— or —CH═CH—;
X
2
: —C(═O)—NR
5
— or —NR
5
—C(═O)—;
R
1
: hydrogen atom, lower alkyl, -lower alkylene-O-lower alkyl, C
3-8
cycloalkyl, aryl, heteroaryl, -lower alkylene-C
3-8
cycloalkyl, -lower alkylene-aryl, -lower alkylene-heteroaryl or —C(═NR
6
)-lower alkyl;
R
2
: —OH, —O-lower alkyl, —O-lower alkylene-OH, —O—SO
2
—OH, —O-lower alkylene-COOH, —O-lower alkylene-COO-lower alkyl, —COOH, —COO-lower alkyl or halogen atom;
R
3
: hydrogen atom, halogen atom or lower alkyl; and
R
4
, R
5
and R
6
: They are the same or different and are each hydrogen atom or lower alkyl.)
The compound of this invention (I) has a different structure from the compounds mentioned in the Prior Art 1 in such a respect that it has a diazepan-1-yl group and at least four cyclic moieties and that the nitrogen atom of diazepan is directly linked to a ring B. Further, the compound of this invention has a different structure from the Prior Art 2 in such a respect that it has a diazepan-1-yl group. Moreover, in the Prior Art 3, no compound having a diazepan-1-yl group is specifically mentioned. Thus, the characteristic feature of the compound (I) of this invention in terms of chemical structure is that diazepanylaryl or diazepanylheteroaryl is linked to a benzene ring via an amide linkage, that the benzene ring is further linked to aryl or heteroaryl via an amide linkage and further that the benzene ring has —OH, —O-lower alkyl or halogen atom, etc.
As hereunder, the compound (I) of this invention will be illustrated in detail.
The term “lower” in the definition for the general formula in the specification means a straight or branched carbon chain having 1 to 6 carbons unless otherwise mentioned. Therefore, examples of the “lower alkyl” for R
1
to R
6
and of that exemplified for the substituents which will be mentioned later are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-timethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Among them, those having 1 to 3 carbons are preferred and methyl and ethyl are particularly preferred.
“Lower alkylene” means C
1-6
alkylene that is one in which arbitrary one hydrogen atom has been removed from the above-described “lower alkyl” and is preferably methylene, ethylene, propylene or isopropylene.
“Aryl” means an aromatic hydrocarbon ring including a fused ring and is preferably aryl having 6 to 14 carbons, and more preferably phenyl, naphthyl, etc.
“Heteroaryl” means a heterocyclic aryl having 1 to 4 same or different heteroatoms selected from a group consisting of N, S and O including a fused ring and its specific examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, indolidinyl, quinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, dihydrobenzofuranyl, naphthylidinyl, 1,2-benzoisoxazolyl, benzoxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl and benzothienyl although this invention is not limited thereto.
“C
3-8
cycloalkyl” means a cycloalkyl having 3 to 8 carbons and is particularly preferably cyclopropyl or cyclobutyl.
Examples of the “substituent” for “aryl or heteroaryl which may have 1 to 3 substituents” are optionally substitute

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