Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-13
2001-03-13
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S145000, C546S201000, C548S455000, C548S468000, C548S518000, C548S525000, C548S538000
Reexamination Certificate
active
06201006
ABSTRACT:
TECHNICAL FIELD
The present invention relates a novel thrombin inhibitor which is effective even when orally administered. More specifically, the present invention relates to an aromatic amidine derivative represented by formula (I) and the salts thereof, which show potent selective inhibitory activity for thrombin:
in which
R represents a group of formula
wherein
R
1
represents hydrogen, hydroxy, alkyl, alkoxy, alkylcarbonyl, alkylcarbonyloxy, aralkoxycarbonyl, or a radical of formula (a).
wherein
B represents oxygen or sulfur;
R
11
and R
12
independently of one another represent hydrogen, haloalkyl, alkylcarbonyloxy, dialkylamino, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring; and
g denotes an integer of 0 to 3;
R
2
represents hydrogen, hydroxy, halogen, carboxy, aminocarbonyl, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, or substituted or unsubstituted arylsulfonyl;
R
3
represents hydrogen, halogen, alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, carboxy, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, or a radical of formula (b),
wherein
R
13
and R
14
independently of one another represent hydrogen, alkyl, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring; and
h denotes an integer of 0 to 3;
the group of formula
represents a radical selected from the group consisting of indolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, indanyl, dihydrobenzofuranyl and dihydrobenzothienyl;
A represents a saturated or unsaturated alkylene group having 2 to 4 carbon atoms, which may have 1 or 2 substituents selected from the group consisting of carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl and alkoxycarbonylalkyl;
W represents a group of formula (c), (d) or (e),
wherein
o, p and q independently of one another denote an integer of 0 to 3,
R
4
, R
5
and R
6
independently of one another represent hydrogen, hydroxy, carboxy, alkoxycarbonyl, substituted or unsubstituted arylsulfonyl, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, or represents a group of formula (f), (g) or (h),
wherein
R
15
, R
16
, R
17
and R
18
independently of one another represent hydrogen, alkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring;
R
19
and R
20
independently of one another represent hydrogen, carboxy, aminocarbonyl or alkoxycarbonyl, or represents 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings; and
r denotes an integer of 0 to 3;
Y represents hydrogen or a 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings and which may be substituted on any atom of the ring with a substituent selected from the group consisting of oxygen, halogen, nitro, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, and a group of formula (i), (j) and (k),
wherein
R
21
and R
22
independently of one another represent hydrogen, alkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonylalkyl, or substituted or unsubstituted arylsulfonyl;
R
23
and R
24
independently of one another represent hydrogen, carboxy, aminocarbonyl, alkoxycarbonyl, or 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings;
R
25
, R
26
and R
27
independently of one another represent hydrogen, hydroxy, thio, amino, carboxy, aminocarbonyl, alkoxy, alkoxycarbonyl, alkylamino, alkylsulfonylamino, alkenyl, alkoxycarbonylamino, cycloalkylamino, alkoxycarbonylalkylamino, substituted or unsubstituted arylsulfonylamino, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring;
s denotes an integer of 0 to 3;
t denotes an integer of 0 to 6; and
u denotes an integer of 0 to 8; and
n denotes an integer of 0 to 2,
provided that when each of g, h, o, p, q, r, s, t and u denotes number of 3 or more, the corresponding alkylene chain may be straight or branched.
The present invention also relates to a process for preparation of the compound of formula (I), and a thrombin inhibitor composition containing the compound of formula (I) as an active component.
BACKGROUND ART
Thrombosis is a pathological process in which platelets aggregation or a fibrin clot occludes a blood vessel. Anticoagulants interfere with fibrin formation and are used for prophylaxis of thrombosis.
The blood coagulation system involves a number of zymogens (inactive enzymes) that are activated through a cascade of enzymatic reactions. The final step in coagulation is the formation of the fibrin clot from fibrinogen by a trypsin-like serine protease thrombin, which in turn is generated from prothrombin by the action of factor Xa. Accordingly, the blood coagulation enzyme thrombin plays a central role in hemostasis and thrombosis. Thrombin inhibitors are therefore expected to be effective anticoagulants by inhibition of platelets, fibrin formation and fibrin stabilization. It also activates factor V and factor VIII in a positive feed back reaction.
In recent years, numerous thrombin inhibitors have been developed as potential antithrombotic and anticoagulant agents, for example, tripeptide derivatives such as PPACK [D-Phe-Pro-Arg-CH
2
Cl, Thromb. Res., 14, 969 (1979)], D-Phe-Pro-Arg, Boc-D-Phe-Pro-Arg, and D-MePhe-Pro-Arg [J. Med. Chem., 33, 1729 (1990)], DuP-714 [Ac-(D)-Phe-Pro-boroArg-OH, J. Biol. Chem., 265, 18289 (1990)], Efegatran [D-MePhe-Pro-Arg.H
2
SO
4
, Thromb. Haemost., 67, 325 (1992)], Inogatran [HOOC—CH
2
—(R)Cha-Pic-Nag, where Cha: cyclohexylamine, Pic: pipecolic acid and Nag: noragmatine, WO 93/11152, Blood Coag. Fibrinol., 7, 69 (1996)] and CVS-1123 [(CH
3
CH
2
CH
2
)
2
—CHCO—Asp(OCH
3
)-Pro-Arg, WO 93/15756] and piperidine amide derivatives such as Argatroban [U.S. Pat. No. 4,258,192, Thromb. Haemost., 18, 13 (1992)] and NAPAP [J. Biol. Chem., 266, 20085 (1991)]. But, they are not necessarily sufficient for practical use in view of oral bioavailability, inhibition selectivity for thrombin over other serine proteases, stability, duration of action and toxicity at the therapeutic dosages.
In view of the above, the present inventors have conducted intensive studies to develop potent thrombin inhibitors which are orally bioavailable, selective in inhibition of thrombin over other serine proteases and sufficient for practical use. As a result of such efforts, we have found that the compound of formula (I) exhibits excellent thrombin inhibitory activity even when orally administered and has a high selectivity for thrombin in comparison to trypsin, and have thereby completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to an aromatic amidine derivative of formula (I), as defined above, and pharmaceutically acceptable salts thereof.
In addition, the present invention relates to a process for preparation of the compound of formula (I).
The present invention further relates to a thrombin inhibitor composition containing the compound of formula (I) or its pharmaceutically acceptable salts as an active component.
BEST MODE FOR CARRYING OUT T
Hong Woo Sang
Kim Jong Min
Koo Bon Am
Min Jae Ki
Nam Woong Hyun
C & C Research Laboratories
Gerstl Robert
McDermott & Will & Emery
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