Thiochromane derivatives and their use as thrombin inhibitors

Details Thiochromane derivatives and their use as thrombin inhibitors Thiochromane derivatives and their use as thrombin inhibitors

2002-11-12

2004-04-06

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S362000

Reexamination Certificate

active

06716834

ABSTRACT:

This application is a national stage filing under 35 U.S.C. 371 of PCT application PCT/SE01/01052, filed May 14, 2001, which claims priority from Sweden Application No. 0001803-6, filed May 16, 2000, the specifications of each of which are incorporated by reference herein. PCT Application PCT/SE01/01052 was published under PCT Article 21(2) in English.
FIELD OF THE INVENTION
This invention relates to novel pharmaceutically useful compounds, in particular compounds that are, or are prodrugs of, competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.
BACKGROUND
Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.
Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a “positive feedback” generation of thrombin from prothrombin.
By inhibiting the aggregation of platelets and the formation and crosslinking of fibrin, effective inhibitors of thrombin would be expected to exhibit antithrombotic activity. In addition, antithrombotic activity would be expected to be enhanced by effective inhibition of the positive feedback mechanism.
Further, it is known that administration of prodrugs of thrombin inhibitors may give rise to improvements in:
(a) certain pharmacokinetic properties after administration of; and
(b) the prevalence of certain side effects associated with, those inhibitors.
PRIOR ART
The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 41 1.
Blombäck et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reported thrombin inhibitors based on the amino acid sequence situated around the cleavage site for the fibrinogen
chain. Of the amino acid sequences discussed, these authors suggested the tripeptide sequence Phe-Val-Arg (P9-P2-P1, hereinafter referred to as the P3-P2-P1 sequence) would be the most effective inhibitor.
Thrombin inhibitors based on dipeptidyl derivatives with an
-aminoalkyl guanidine in the P1-position are known from U.S. Pat. No. 4,346,078 and International Patent Application WO 93/11152. Similar, structurally related, dipeptidyl derivatives have also been reported. For example International Patent Application WO 94/29336 discloses compounds with, for example, aminomethyl benzamidines, cyclic aminoalkyl amidines and cyclic aminoalkyl guanidines in the P1-position (International Patent Application WO 97/23499 discloses prodrugs of certain of these compounds); European Patent Application 0 648 780, discloses compounds with, for example, cyclic aminoalkyl guanidines in the P1-position.
Thrombin inhibitors based on peptidyl derivatives, also having cyclic aminoalkyl guanidines (e.g. either 3- or 4- aminomethyl-1-amidino-piperidine) in the P1-position are known from European Patent Applications 0 468 231, 0 559 046 and 0 641 779.
Thrombin inhibitors based on tripeptidyl derivatives with arginine aldehyde in the P1-position were first disclosed in European Patent Application 0 185 390.
More recently, arginine aldehyde-based peptidyl derivatives, modified in the P3-position, have been reported. For example, International Patent Application WO 93/18060 discloses hydroxy acids, European Patent Application 0 526 877 des-amino acids, and European Patent Application 0 542 525 O-methyl mandelic acids in the P3-position.
Inhibitors of serine proteases (e.g. thrombin) based on electrophilic ketones in the P1-position are also known. For example, European Patent Application 0 195 212 discloses peptidyl
-keto esters and amides, European Patent Application 0 362 002 fluoroalkylamide ketones, European Patent Application 0 364 344
,
,
-triketocompounds, and European Patent Application 0 530 1675
-alkoxy ketone derivatives of arginine in the P1-position.
Other, structurally different, inhibitors of trypsin-like serine proteases based on C-terminal boronic acid derivatives of arginine and isothiouronium analogues thereof are known from European Patent Application 0 293 881.
More recently, thrombin inhibitors based on peptidyl derivatives have been disclosed in European Patent Application 0 669 317 and International Patent Applications WO 95/35309, WO 95/23609, WO 96/25426, WO 97/02284, WO 97/46577, WO 96/32110, WO 96/31504, WO 96/03374, WO 98/06740, WO 97/49404 and WO 99/29664. Certain prodrugs of thrombin inhibitors have been disclosed in WO 97/33576.
WO 98/57932 and WO 00/35869 disclose thrombin inhibitors, and prodrugs of thrombin inhibitors, based on peptidyl derivatives with fused, bi- or tri-cyclic acids at the P3-position.
However, there remains a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is, also a need for compounds that have a favourable pharmacokinetic profile (e.g. low clearance), are orally bioavailable, and are selective in inhibiting thrombin over other serine proteases, in particular those involved in haemostatis. Compounds which exhibit competitive inhibitory activity towards thrombin would be expected to be especially useful as anticoagulants and therefore in the therapeutic treatment of thrombosis and related disorders.
DISCLOSURE OF THE INVENTION
According to the invention there is provided compounds of formula I,
wherein
Y represents S(O) or S(O)
2
;
R
1
represents halo; and
R
2
represents H, halo or C
1-4
alkoxy (which latter group is optionally substituted by one or more halo groups);
or a pharmaceutically acceptable derivative thereof, which compounds are referred to hereinafter as “the compounds of the invention”.
The term “pharmaceutically acceptable derivatives” of compounds of formula I includes pharmaceutically acceptable salts. Suitable salts include inorganic acid (e.g. hydrogen halide), and organic acid (e.g. acetic, methanesulfonic or trifluoroacetic acid), addition salts.
The alkyl part of alkoxy groups which R
2
may represent, may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be optionally interrupted by an O atom.
Halo groups which R
1
and R
2
may represent, and with which R
2
may be substituted, include fluoro, chloro, bromo and iodo.
Abbreviations are listed at the end of this specification.
Compounds of the invention that may be mentioned include those in which Y represents S(O)
2
.
Preferred compounds of the invention include those in which:
R
1
represents chloro;
R
2
represents H, halo or C
1-2
alkoxy (which latter group is optionally substituted by one or more halo (e.g. fluoro) groups).
More preferred compounds of the invention include those in which:
R
1
represents chloro; and
R
2
represents H, chloro, OCHF
2
, OCF
3
or, especially, OCH
3
.
Preferred compounds of formula I include the compounds of the Examples described hereinafter, particularly the compound of Example 1.
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(i) the coupling of a compound of formula III,
 wherein Y, R
1
and R
2
are as hereinbefore defined, with 4-amidinobenzyl-2-azetidinecarboxamide (see, for example, international patent application WO 97/02284), for example in the presence of a coupling agent (e.g. EDC, DCC, HBTU, HATU, TBTU, PyBOP or oxalyl chloride in DMF), an appropriate base (e.g. pyridine, 2,4,

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