Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-11
2002-03-19
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S330000, C514S352000, C514S354000, C514S408000, C514S436000, C514S461000, C544S242000, C546S309000, C546S184000, C546S336000, C548S400000, C549S029000, C549S429000
Reexamination Certificate
active
06358960
ABSTRACT:
TECHNICAL FIELD
This invention is related to amidino derivatives of the formula (I), non-toxic salts thereof, hydrates thereof, processes for the preparation thereof, and the blood coagulation factor VIIa inhibitors containing the derivatives as active ingredient.
More particularly, this invention is related to amidino derivatives of the formula (I)
wherein all the symbols are as hereinafter defined, non-toxic salts thereof, hydrates thereof, processes for the preparation thereof, and the blood coagulation factor VIIa inhibitors containing the derivatives as active ingredient.
BACKGROUND ART
The blood coagulation is a protective reaction which is caused by vascular injury or irritate stimulus with endotoxin or the other foreign bodies. This reaction proceeds on the membrane of platelets which aggregate at the injured site or on the membrane of injured endothelial cells and it requires Ca ion. The blood coagulation system contains eight kinds of serine proenzymes (e.g. plasma prekallikrein factor XII, factor XI, factor VII, factor IX, factor X, prothrombin, protein C), five protein co-factor (e.g. macromolecule kininogen, tissue factor, factor VIII, factor V, protein S), and a fibrillar protein, fibrinogen. &agr;-Thrombin produced by the coagulation cascade give information to endothelial cells and form insoluble fibrin gel. The scheme of the blood coagulation cascade is shown below.
The blood coagulation cascade consists of the intrinsic pathway and the extrinsic pathway. The intrinsic pathway acts on foreign surface charged negatively. However, foreign surface in the body is uncertain, so the significance of the intrinsic pathway in hemostasis is not established. On the other hand, the extrinsic pathway is triggered by the complex formation of the blood coagulation factor VIIa (FVIIa) and tissue factor which is expressed by a vascular damage or the presence of endotoxin. This pathway confluents with the intrinsic pathway at a point of factor X and factor IX activation.
The extrinsic pathway seems to be more important than the intrinsic pathway in the physiologic condition (hemostasis) or pathological condition (thrombosis). The reasons are as follows.
1) The presence of tissue factor (TF) is recognized in physiological condition.
2) The expression of TF is induced by endotoxin on the membrane of vascular endothelial cells or/and monocytes.
3) Since TF is observed on foam cells in the plaque of arteriosclerosis, the extrinsic pathway is considered to contribute the topical coagulation activity.
Warfarin, an anticoagulant agent, inhibits the production of various factors, including protein C and S. Thrombin inhibitors such as heparin, which act at the downstream of a coagulation cascade, may inhibit blood coagulation excessively and do not inhibit the consumption of coagulation factors. Because of these reasons, bleeding tendency is the main problem in clinic.
On the other hand, FVIIa is located at the top site of the cascade in the extrinsic pathway. Therefore, FVIIa inhibitors inhibit the extrinsic pathway, leaving intact the activity of the intrinsic pathway.
Consequently, FVIIa inhibitors are different from thrombin inhibitors leaving a function of the intrinsic pathway. It is considered that FVIIa inhibitors have a resistance to bleeding, then it is expected to be able to reduce a bleeding tendency as a side effect.
FVIIa inhibitors suppress a coagulation activity of the extrinsic pathway, and then they are useful for treatment and/or prevention for several thormbotic diseases triggered by the extrinsic pathway. For example, several angiopathy caused by enhancing a coagulation activity, such as disseminated intravascular coagulation, coronary thrombosis (e.g. acute myocardial infarction, unstable angina), cerebral infarction, cerebral embolism, transient ischemic attack, cerebrovascular disorders, pulmonary vascular diseases (e.g. pulmonary infarction, pulmonary embolism), deep venous thrombosis, peripheral arterial obstruction, thrombosis after artificial vascular transplantation and artificial valve transplantation, post-operative thrombosis, reobstruction and restenosis after coronary artery bypass operation, reobstruction and restenosis after PTCA (percutaneous transluminal coronary angioplasty) or PTCR (percutaneous transluminal coronary recanalization), thrombosis by extracorporeal circulation and procoagulative diseases such as glomerlonephriitis.
(1) In the specification of WO 9620689, boric acid derivatives of the formula (A):
R
1A
—Z
A
—CHR
2A
—A
A
(A)
wherein A
A
is —BY
1A
Y
2A
, in which Y
A1
and y
2A
each independently, is —OH, C1-8 alkoxy; —COOR
3A
, in which R
3A
is hydrogen, C1-8 alkyl; R
2A
is
in which pA is 0-2, qA is 0-4, X
A
is C(NH)NHR
14A
, in which R
14A
is hydrogen, C1-4 alkyl; Z
A
is (CH
2
)
mA
CONR
8A
, (CH
2
)
mA
CSNR
8A
, (CH
2
)
mA
SO
2
NR
8A
, (CH
2
)
mA
CO
2
, (CH
2
)
mA
CSO, (CH
2
)
mA
SO
2
O, R
8A
is hydrogen, C1-8 alkyl, mA is 0-6, R
1A
is (CH
2
)
PA
aryl, in which pA is 0-2, aryl is phenyl, naphthyl, biphenyl, and they may be substituted by 1-3 of (CH
2
)
WA
CO
2
R
8A
, (CH
2
)
WA
CNR
8A
R
9A
; WA is 0-5, R
8A
and R
9A
is hydrogen, C1-8 alkyl; with the proviso that explanations of each inhibitory activity of thrombin, Fxa, FVIIa.
(2) In the specification of WO 9429273, the compound of the formula (B):
wherein A
1B
to A
4B
form a substituted 6 membered ring optionally unsaturated, and optionally containing up to two hetero atoms selected from O, S and N;
D
1B
to D
4B
form a substituted 6 membered aromatic ring optionally containing up to two nitrogens, D
1B
-D
4B
is CR
11B
or N; R
B
is at least one substituent selected from R
7
, Q
B
—C1-4 alkyl, Q
B
—C2-4 alkenyl and Q
B
—C2-4 alkynyl;
R
*B
is hydrogen, Q
B
—C1-6 alkyl, Ar
B
or Het
B
;
Q
B
is hydrogen, C3-6 cycloalkylHet
B
or Ar
B
;
R
6B
is W
B
—(CR′
B2
)q
B
—Z
B
—(CR′
B
R
10B
)r
B
—U
B
—(CR′
B2
)s
B
—V
B
—;
R
7B
is —COR
8B
, —PO(OR′
B
)
2
and Tet
B
;
R
8B
is —OR′
B
, —NR′
B
R″
B
, —NR′
B
OR′
B
;
R
10B
is hydrogen, C1-4 alkyl or —NR′
B
R″
B
;
R
11B
is Q
B
—C0-6 alkyl;
R′
B
, R″
B
are hydrogen, C1-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl, or Ar
B
—C0-4 alkyl;
UB and VB is absent or CONR′
B
, NR′
B
CO, S(O)
nB
NR′
B
, NR′
B
S(O)
nB
, NR′
B
CR′
B
2
,
CR′
B
2
NR′
B
, CR′
B
2
O, OCR′
B
2
, C≡C, CR′
B
═CR′
B
;
W
B
is
Y
B
is absent, S or O;
Z
B
is (CH
2
)
tB
, Het
B
, Ar
B
or C3-7 cycloalkyl;
nB is 0-3; qB is 0-3; rB is 0-2; sB is 0-2; tB is 0-2; with the proviso that explanations of each groups were disclosed only necessary parts; or salts thereof are described to possible an inhibitory activity of fibrinogen receptor GPIIb/IIIa.
In the specification of WO 9300095 and WO 9412478, similarity compounds are described to possible an inhibitory activity of fibrinogen receptor GPIIb/IIIa.
(3) In the specification of WO 9730971, the compound of the formula (C):
wherein D
C
is CN, C(=NR7
C
)NR
8C
R
9C
, NHC(=NR
7C
)N
R8
CR
9C
, NR
8C
CH(=NR
7C
) etc.; E
C
is phenyl, 2-pyridyl, 4-pyridyl, etc.; R
aC
is a single bond or CH═CH; R
bC
is C(O)R
C
or G
C
; G
C
is hydrogen, OG
1C
, SG
1C
, NG
1C
G
2C
, etc.; G
1C
is hydrogen, C1-6 alkyl; G
2C
is hydrogen, C1-6 alkyl; R
C
is hydrogen, OH, C1-6 alkoxy, etc.; R
7C
is hydrogen, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, etc.; R
8C
and R
9C
are hydrogen, C1-6 alkyl, (CH
2
)
n
-phenyl; X
C
is CHCH(R
1C
), N, etc.; Z
C
is (CH
2
)
n
, C(═O), etc.; p
C
is 1-4; A
C
is benzyl, C3-10 carbocyclic ring, 5-10 membered heterocyclic ring; B
C
is hydrogen, C1-6 alkyl, benzyl, C3-10 carbocyclic ring, 5-10 membered heterocyclic ring; are described to possible an inhibitory activity of FXa.
DISCLOSURE OF INVENTION
Energetic investigations have been carried out in order to make the blood coagulation factor VIIa inhibitors. The present inventors have found that the present compound of the formula (I) acc
Ogawa Koji
Senokuchi Kazuhiko
Davis Zinna Northington
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
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