Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-19
2001-12-25
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S575000
Reexamination Certificate
active
06333320
ABSTRACT:
TECHNICAL FIELD
The present invention relates to hexahydro-1,4-diazepine derivatives or their salts which are useful as drugs, especially as an activated blood coagulation factor X inhibitor.
BACKGROUND OF THE INVENTION
Recently, thromboembolic disorders, such as myocardial infarction, cerebral thrombosis and peripheral arteriothrombosis, are increasing year by year with the popularization of Western life-styles and the increase in aged population, and there is much increasing social demand for the treatment of such disorders.
Anticoagulant therapy as well as adenolytic therapy and antiplatelet therapy is a part of medical therapy for treatment and prevention of thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, anticoagulants for prevention of thrombosis indispensably require high safety for long-term administration and the ability of surely and appropriately expressing the anticoagulation activity.
However, the anticoagulating ability of warfarin potassium, which is only one oral anticoagulant now being popularly used in the world, is difficult to control because of the characteristic of itself based on the action and the mechanism thereof (
J. Clinical Pharmacology
, 32, 196-209, 1992; and
N. Eng. J. Med
., 324 (26), 1865-1875, 1991), and the drug is extremely difficult to use in clinics.
It is known that thrombin acts to convert fibrinogen into fibrin in the final stage of coagulation, while deeply participating in the activation and the coagulation of platelets. At present, however, no oral thrombin inhibitor is commercially available because of its low bioavailability in oral administration and of its low safety (Biomed. Biochim. Acta, 44, 1201-1210, 1985).
On the other hand, the activated blood coagulation factor X is a key enzyme existing in the junction of intrinsic and extrinsic coagulation cascade reactions, and inhibiting this factor is more efficient than thrombin inhibition, and could bring about specific inhibition of coagulation systems (
THROMBOSIS RESEARCH
(19), 339-349, 1980).
As compounds having the ability of inhibiting the activated blood coagulation factor X, known are amidinonaphthylbenzene derivatives or their salts (JP-A-5-208946
; Thrombosis Haemostasis
, 71 (3), 314-319, 1994
; Thrombosis Haemostasis
, 72 (3), 393-396, 1994); and WO96/16940 discloses amidinonaphthyl derivatives of the following general formula or their salts.
[In the formula, B represents a lower alkylene group, etc.; R
1
represents a hydrogen atom or a group of a formula, —A—W—R
4
[where A represents —CO—, —SO
2
—, etc.; W represents a single bond or an —NR
5
— group (where R
5
represents a hydrogen atom, a —CONH
3
group, etc.); R
4
represents an optionally-substituted lower alkyl group, etc.]; R
2
represents a lower alkyl group; R
3
represents a hydrogen atom, a halogen atom, etc.; and n=0 or 1.]
As so mentioned above, inhibitors for the activated blood coagulation factor X are more effective than thrombin inhibitors in anticoagulant therapy, and are expected to bring about specific inhibition of coagulation systems.
Accordingly, it is desired to create selective activated blood coagulation factor X inhibitors, which are different from the known compounds noted above in the chemical structure, can be orally administered and are more effective.
DISCLOSURE OF THE INVENTION
We, the present inventors have found that hexahydro-1,4-diazepine derivatives of the following general formula (I) or their salts, of which the chemical structure is characterized in that an amidinonaphthylmethyl group or the like is bonded to a phenyl group or a pyridyl group via a nitrogen atom and that the phenyl group or the pyridyl group is directly bonded to the nitrogen atom of the hexahydro-1,4-diazepine ring, have an excellent activity of inhibiting the activated blood coagulation factor X, and have completed the present invention.
Specifically, the invention relates to hexahydro-1,4-diazepine derivatives of the following general formula (I) or their salts, as well as pharmaceutical compositions, especially, activated blood coagulation factor X inhibitors comprising them as active ingredients:
(In the formula, the symbols have the following meanings:
A: a phenylene or pyridylene group (which may be substituted),
B: forming a 5- or 6-membered aryl or heteroaryl,
X: a group of formula, —CO—, —CONH—, —CSNH—, —SO
2
—, —SO
2
NH—, or —SO
2
N(-lower alkyl)-,
Y: a bond or a lower alkylene group,
R
1
: a hydrogen atom, or a lower alkyl, —L-aryl, —L-heteroaryl, —L—COO—R
6
, —L—CON(—R
6
)—R
7
, —C(═NH)—NH
2
, or —C(═NH)-lower alkyl group,
R
2
: a hydrogen atom, an —O-lower alkyl, —COOH, —COO-lower alkyl, —CONH
21
—CONH-lower alkyl, or —CON—di-lower alkyl group, or an aryl or heteroaryl group (which may be substituted),
R
3
: an amidino group or a group capable of being converted into an amidino group in a living body,
R
4
, R
5
: a hydrogen atom or a lower alkyl group, which may be the same or different,
R
6
, R
7
: a hydrogen atom or a lower alkyl group, which may be the same or different, and
L: a bond, or a lower alkylene group.)
The structure of the compounds of the invention is obviously different from that of the known compounds noted above in the basic skeleton, in which hexahydro-1,4-diazepinylphenyl (or hexahydro-1,4-diazepinyl-pyridyl) is bonded to the amidinonaphthylmethyl group via a nitrogen atom in the former, while the pyrrolidinyl- (or piperidinyl)oxyphenyl group is bonded to the amidinonaphthylmethyl group via a nitrogen atom in the latter.
Of the compounds of the invention, preferred are hexahydro-1,4-diazepine derivatives of the general formula (I), wherein the ring
is naphthalene or benzofuran, or their salts, or hexahydro-1,4-diazepine derivatives where R
4
and R
5
are each a hydrogen atom, or their salts.
More preferred are hexahydro-1,4-diazepine derivatives of the general formula (I), wherein the ring
is naphthalene; A is a phenylene group (the phenylene group may be substituted with a substituent selected from a halogen atom, or an amino, cyano, nitro, —OH, —COOH, lower alkyl, —O-lower alkyl, or —COO-lower alkyl group) or a pyridyl group; R
3
is an amidino group; and R
4
and R
5
are each a hydrogen atom, or their salts.
Of the compounds of the invention, particularly preferred are hexahydro-1,4-diazepine derivatives of the general formula (I), wherein the ring
is naphthalene; A is a phenylene or pyridylene group; x is a group of formula, —CO—, —CSNH—, —SO
2
—, or —SO
2
NH—; R
1
is a hydrogen atom, or a lower alkyl, pyridyl, or —C(═NH)—CH
3
group; R
2
is a hydrogen atom, or a —COOH, —COO-lower alkyl, or tetrazolyl group; R
3
is an amidino group; and R
4
and R
5
are each a hydrogen atom, or their salts.
Of the compounds of the invention, most preferred are tho se enumerated below:
N-[4-(4-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl) -phenyl]-N-[((7-amidino-2-naphthyl)methyl]-acetamide,
Ethyl [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl]-N-[(7-amidino-2-naphthyl)methyl]-sulfamoyl]acetate,
Ethyl N-[N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]-sulfamoyl]glycinate,
Ethyl N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]malonamate,
[N-[6-(4-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-pyridyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetic acid,
[N-[4-(4-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl] sulfamoyl]-acetic acid,
N-[4-(4-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl] succinamic acid,
Ethyl N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-pyridyl]-N-[(7-amidino-2-naphthyl)methyl]-malonamate,
Ethyl N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-pyridyl]-N-[(7-amidino-2-naphthyl)methyl]-succinamate,
N-[4-(4-Acet
Funatsu Masashi
Hirayama Fukushi
Ishihara Tsukasa
Kawasaki Tomihisa
Koshio Hiroyuki
Coleman Brenda
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Yamanouchi Pharmaceutical Co.
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