Amidino derivatives and their use as thrombin inhibitors

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

2000-03-21

2004-06-15

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S525000, C548S953000

Reexamination Certificate

active

06750243

ABSTRACT:

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, 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-amidinopiperidine) 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 land 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 96/03374, WO 96/25426, WO 96/31504, WO 97/02284, WO 97/46577, WO 96/32110, WO 98/06740, WO 97/49404 and WO 98/57932.
However, there remains a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is a particular need for compounds which are both orally bioavailable and selective in inhibiting thrombin over other serine proteases. 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 a compound of formula I,
wherein
R
1
represents H, C
1-4
alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C(O)OR
1a
or C(O)N(R
1b
)R
1c
) or OR
1d
;
R
1d
represents H, C(O)R
11
, SiR
12
R
13
R
14
or C
1-6
alkyl, which latter group is optionally substituted or terminated by one or more substituent selected from OR
15
or (CH
2
)
q
R
16
;
R
12
, R
13
and R
14
independently represent H, phenyl or C
1-6
alkyl;
R
16
represents C
1-4
alkyl, phenyl, OH, C(O)OR
17
or C(O)N(H)R
18
;
R
18
represents H, C
1-4
alkyl or CH
2
C(O)OR
19
;
R
15
and R
17
independently represent H, C
1-4
alkyl or C
1-3
alkylphenyl;
R
1a
, R
1b
, R
1c
, R
11
and R
19
independently represent H or C
1-4
alkyl; and
q represents 0, 1 or 2;
R
x
represents a structural fragment of formula IIa, IIb or IIc,
 wherein
the dotted lines independently represent optional bonds;
A and E independently represent O or S, CH or CH
2
(as appropriate), or N or N(R
21
) (as appropriate);
D represents —CH
2
—, O, S, N(R
22
), —(CH
2
)
2
—, —CH═CH—, —CH
2
N(R
22
)—, —N(R
22
)CH
2
—, —CH═N—, —N═CH—, —CH
2
O—, —OCH
2
—, —CH
2
S— or —SCH
2
—;
X
1
represents C
2-4
alkylene; C
2-3
alkylene interrupted by Z; —C(O)—Z—A
1
—; —Z—C(O)—A
1
—; —CH
2
—C(O)—A
1
—; —Z—C(O)—Z—A
2
—; —CH
2
—Z—C(O)—A
2
—;
—Z—CH
2
—C(O)—A
2
—; —Z—CH
2
—S(O)
m
—A
2
—; —C(O)—A
3
; —Z—A
3
—; or —A
3
—Z—;
X
2
represents C
2-3
alkylene, —C(O)—A
4
— or —A
4
—C(O)—;
X
3
represents CH or N;
X
4
represents a single bond, O, S, C(O), N(R
23
), —CH(R
23
)—, —CH(R
23
)—CH(R
24
)— or —C(R
23
)═C(R
24
)—;
A
1
represents a single bond or C
1-2
alkylene;
A
2
represents a single bond or —CH
2
—;
A
3
represents C
1-3
alkylene;
A
4
represents C(O) or C
1-2
alkylene;
Z represents, at each occurrence, O, S(O)
m
or N(R
25
);
R
2
and R
4
independently represent one or more optional substituents selected from C
1-4
alkyl, C
1-4
alkoxy (which latter two groups are optionally substituted by one or more halo substituent), methlylenedioxy, halo, hydroxy, cyano, nitro, S(O)
2
NH
2
, C(O)OR
26
, SR
26
, S(O)R
26a
, S(O)
2
R
26a
or N(R
27
)R
28
;
R
3
represents one or more optional substituents selected from OH, C
1-4
alkoxy, C
1-6
alkyl (optionally substituted by one or more halo group), or N(R
29a
)R
29b
;
R
25
, R
29a
and R
29b
independently represent H, C
1-4
alkyl or C(O)R
30
;
R
26
represents H or C
1-4
alkyl;
R
26a
represents C
1-4
alkyl;
R
27
and R
28
independently represent H, C
1-4
alkyl or C(O)R
30
, or together represent C
3-6
alkylene, thus forming a 4- to 7-membered ring, which ring is optionally substituted, on a carbon atom that is &agr; to the nitrogen atom, with an ═O group;
R
21
, R
22
, R
23
, R
24
and R
30
independently represent, at each occurrence, H or C
1-4

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