Amidino derivatives and their use as thormbin inhibitors

Details Amidino derivatives and their use as thormbin inhibitors Amidino derivatives and their use as thormbin inhibitors

2001-07-10

2002-08-13

Solola, Taofiq (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S571000, C548S950000, C514S428000

Reexamination Certificate

active

06433186

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel pharmaceutically useful compounds, in particular compounds that are, and/or compounds that are metabolised to compounds which are, 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.
PRIOR ART
The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411.
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 A&agr; 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 &agr;,&ohgr;-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 &agr;-keto esters and amides, European Patent Application 0 362 002 fluoroalkylamide ketones, European Patent Application 0 364 344 &agr;,&bgr;,&dgr;-triketocompounds, and European Patent Application 0 530 167 &agr;-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, WO 98/57932, WO 99/29664 and WO 00/35869. In particular WO 97/02284 and WO 00/42059 disclose thrombin inhibitors with substituted mandelic acids in 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 which have a favourable pharmacokinetic profile (e.g. low clearance) 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
R
1
represents C(O)CH
3
or C
1-3
alkyl; and
Y represents —CH
2
— or —(CH
2
)
2
—,
and pharmaceutically-acceptable derivatives thereof.
The term “pharmaceutically-acceptable derivatives” includes inter alia pharmaceutically-acceptable salts (e.g. acid addition salts).
Preferred compounds of formula I include those in which:
R
1
represents C(O)CH
3
, methyl or ethyl;
Y represents —CH
2
—.
Particularly preferred compounds of formula I include
Ph(3-Cl)(5-NHMe)—CH(OH)C(O)-Aze-Pab;
Ph(3-Cl)(5-NHAc)—CH(OH)C(O)-Aze-Pab.
Abbreviations are listed at the end of this specification.
Compounds of formula I may be made in accordance with techniques well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which comprises:
(i) the coupling of a compound of formula II
wherein R
1
is as hereinbefore defined, with a compound of formula III,
wherein Y is as hereinbefore defined, for example in the presence of a coupling agent (e.g. oxalyl chloride in DMF, EDC, DCC, HBTU, HATU, PyBOP or TBTU), an appropriate base (e.g. pyridine, DMAP, TEA, 2,4,6-collidine or DIPEA) and a suitable organic solvent (e.g. dichloromethane, acetonitrile, EtOAc or DMF);
(ii) the coupling of a compound of formula IV,
wherein R
1
and Y are as hereinbefore defined, with para-amidinobenzylamine, for example under conditions as described in step (i) above; or
(iii) deprotection of a protected derivative of a compound of formula I under standard conditions.
Compounds of formula I may be prepared by way of deprotection of a corresponding compound of formula XV, as defined hereinafter, which deprotection comprises removal of the group C(O)OR
X
, in which R
X
is as defined hereinafter, from the compound of formula XV, for example under conditions known to those skilled in the art (e.g. by reacting with QF or TFA (e.g. as described hereinafter)).
Further, compounds of formula I may be prepared by way of deprotection of a corresponding compound of formula Ia, as defined hereinafter, in which R
2
represents OR
3
, wherein R
2
and R
3
are as defined hereinafter, for example by hydrogenation in the presence of a suitable catalyst (e.g. a supported metal catalyst such as Pd/C (e.g. 10% (w/w) Pd/C)) and an appropriate solvent (e.g. a lower (e.g. C
1-6
) alkyl alcohol such as ethanol), and optionally in the presence of a suitable acid (e.g. acetic acid).
Compounds of formula II are available using known and/or standard techniques.
For example, compounds of formula II may be prepared by reaction of an aldehyde of formula V,
wherein R
1
is as hereinbefore defined with:
(a) a compound of formula VI,
R″CN   VI
wherein R″ repres

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