Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

1999-10-08

2002-09-03

Raymond, Richard L. (Department: 1611)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S335000, C544S336000, C544S409000, C546S332000

Reexamination Certificate

active

06444817

ABSTRACT:

The present invention relates to novel carbo- and heterocyclic amidines, the preparation thereof and the use thereof as thrombin inhibitors.
Thrombin belongs to the group of serine proteases and plays a central part in the blood coagulation cascade as terminal enzyme. Both the intrinsic and the extrinsic coagulation cascades lead via several amplification stages to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates the coagulation of blood and the aggregation of the platelets which in turn enhance, owing to the binding of platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators, the formation of thrombin.
The formation and action of thrombin are central events in the production both of white, arterial and of red, venous thrombi and therefore potentially effective points of attack for drugs. Thrombin inhibitors are, in contrast to heparin, able to inhibit completely, independently of cofactors, simultaneously the actions of free thrombin and that bound to platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous trasluminal coronary angioplasty (PTCA) and lysis and to act as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be generally used for the prophylaxis of thrombosis, for example after surgical operations.
It is known that synthetic arginine derivatives influence the enzymatic activity of thrombin by interacting with the active serine residue of the protease thrombin. Peptides based on Phe-Pro-Art in which the N-terminal amino acid is in the D form have proved to be particularly beneficial. D-Phe-Pro-Arg isopropyl ester has been described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol, 109 (1983) 43-51).
Derivatization of the C-terminal arginine to the aldehyde leads to an enhancement of the inhibitory effect. Thus, a large number of arginals able to bind the hydroxyl group of the “active” serine in the form of a hemiacetal have been described (EP 185 390, 479 489, 526 877, 542 525; WO 93/15756, 93/18060).
The thrombin-inhibitory activity of peptide ketones, fluorinated alkyl keteones and of keto esters, boric acid derivatives, phosphoric esters and &agr;-keto carboxamides can likewise be explained by this interaction with serine (EP 118 280, 195 212, 362 002, 364 344, 410 411, 471 651, 589 741, 293 881, 503 203, 504 064, 530 167; WO 92/07869, 94/08941).
DE 31 08 810 and WO 93/11152 describe &ohgr;-aminoalkylguanidine dipeptides.
The diphenyl 4-amidinophenylglycinephosphonate peptides described by J. Oleksyszym et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity with respect to other serine proteases.
WO 94/29336 and WO 95/23609 describe benzylamidines as thrombin inhibitors.
The invention relates to compounds of the formula I
and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings:
R
1
: H, C
1-4
-alkyl;
R
2
: H, C
1-4
-alkyl, phenyl, phenyl-C
1-4
-alkyl; R
18
O—CH
2
—, R
18
—CO—, R
18
—O—CH
2
—CO—, R
18
O—CO—CO—, R
18
—H—CO—CO—, where R
18
is H, C
1-4
-alkyl, phenyl-C
1-4
—alkyl or phenyl, or CF
3
—CO—, C
2
F
5
—CO— or C
1-4
alkyl—O—CO—,
in which the substituents have the following meanings:
m: 0 or 1,
n: 1, 2, 3 or 4,
R
3
: H, C
1-12
-alkyl, aryl-C
1-4
-alkyl, R
19
OOC—C
1-6
-alkyl (R
19
═H, C
1-4
-alkyl, benzyl), HO
3
S—C
1-3
-alkyl, C
1-12
-alkyl-CO—, aryl-CO—, aryl-C
1-4
-alkyl-CO—, R
19
OOC—C
1-6
-alkyl-CO—, HO
3
S—C
1-3
-alkyl-CO—, C
1-7
-alkyl-OOC—, benzyl-OOC—, or
 R
20
R
21
N—CO—(R
20
and R
21
are identical or different and are H, C
1-6
-alkyl, aryl, aryl-C
1-4
-alkyl, R
19
OOC—C
1-4
-alkyl and R
19
—NH—CO—C
1-4
-alkyl, where R
20
and R
21
may also together be a —(CH
2
)
3-6
— group), or R
19
—O—
R
4
: H, C
1-12
-alkyl, aryl-C
1-4
-alkyl or R
19
OOC—C
1-4
-alkyl (R
19
═H, C
1-4
-alkyl, benzyl),
R
5
: H, C
1-4
-alkyl or benzyl,
R
6
: C
3-8
-cycloalkyl, where the aliphatic rings can be provided with up to 4 C
1-4
-alkyl and/or CH
3
O groups, and one or more methylene group(s) can be replaced by —O—, —S— or N—C
1-4
-alkyl,
 phenyl which can be substituted by up to 3 identical or different radicals from the group of C
1-4
-alkyl, CF
3
—, C
1-4
-alkoxy, F— or Cl—,
 R
25
R
26
CH—, where R
25
is C
1-6
-alkyl and R
26
is H or C
1-6
-alkyl,
 adamantyl, norbornyl-, 1-decalinyl-, 1-tetralinyl-, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmentyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH
3
)
2
—, phenyl-CH(CH
2
—CH
2
—OR
19
)—, C
1-4
-alkyl-C≡C—, aryl-C≡C—, (CH
3
)
3
Si—, R
19
—S—CH
2
—,
 R
22
O—C(R
23
R
24
)—, where R
22
is H, C
1-4
-alkyl, phenyl, benzyl or C
1-4
-alkyl-CO—, R
23
is H, C
1-4
-alkyl, HO—C
1-3
-alkyl, phenyl or benzyl and R
24
is H, C
1-4
-alkyl, HO—C
1-3
-alkyl, phenyl or benzyl,
R
7
: H, C
1-12
-alkyl, C
1-20
-alkyl-CO—, R
19
OOC—C
1-4
-alkyl, R
19
OOC—C
1-4
-alkyl-CO—, R
19
NH—CO—C
1-4
-alkyl, R
20
R
21
N—CO—, HO
3
S—C
1-4
-alkyl, HO
3
S—C
1-4
-alkyl—CO—, 5-(1H)-tetrazolyl-CH
2
— or (R
19
O)
2
OP—CH
2
— or the acyl radical of a natural or unnatural bile acid,
R
8
: phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, C
1-3
-alkyl, C
1-3
-alkyl-O—, HO— or CF
3
—,
 C
3-8
-cycloalkyl, where the aliphatic rings can be provided with up to 4 C
1-4
-alkyl and/or CH
3
O groups, and one or more methylene group(s) can be replaced by —O—, —S— or N—C
1-4
-alkyl,
 R
25
R
26
CH— in which R
25
is C
1-6
-alkyl, C
5-8
-cycloalkyl or phenyl, which can be substituted by 1 to 3 F, Cl, C
1-3
-alkyl, C
1-3
-alkyl-O—, HO— or CF
3
, and R
26
is H or has one of the meanings stated for R
25
,
 or R
22
O—CH
2
—, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, C
1-4
-alkyl-C═C, aryl-C═C, (CH
3
)
3
Si or dibenzosuberyl which can be monosubstituted on one or both aromatic rings,
R
9
: H, C
1-4
-alkyl, aryl or C
5-6
-cycloalkyl (R
9
can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2)
in which the substitutents R
10
, R
11
and R
12
, and p, q, r and Y have the following meanings:
p: 0 or 1
q: 1 or 2
r: 1, 2, 3, 4 or 5
Y a methylene group an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl, oxo or C
1-4
-alkoxy group,
 —CH
2
—S—, —CH
2
SO—, —CH
2
—O, —CH═CH— or a propylene group, in which the ring resulting therefrom can carry on the carbon in position 3 and/or 4 a C
1-4
-alkyl group or in which a CH
2
group can be replaced by —O—, —S— or —SO—,
R
10
: H, C
1-4
-alkyl or phenyl,
R
11
: H, C
1-4
-alkyl, C
3-8
-cycloalkyl, phenyl or benzyl,
R
12
: H, C
1-6
-alkyl, C
3-8
-cycloalkyl, phenyl or benzyl,
in which the substituents have the following meanings:
R
13
, R
14
and R
15
, which can be identical or different, are H, NO
2
, F, Cl, Br, I, C
3-6
-cycloalkyl, R
30
—O—, R
30
OOC—, R
30
—NH—, R
30
—CO—NH—, where R
30
is H, C
1-6
-alkyl, C
3-6
-cycloalkyl, benzyl or phenyl, or
 R
13
and R
14
together are chains —CH
2
—CH
2
—CH
2
CH
2
—, —CH
2
—CH
2
—CH
2
—, —O—CH
2
O— or —CH═CH—CH═CH—,
R
16
: H, F, Cl, C
1-4
-alkyl, phenyl-C
1-2
-alkyl, phenyl, R
31
OOC—(R
31
═H, C
1-4
-alkyl, phenyl or benzyl), R
31
—NH—, R
31
—O— or R
31
OOC—CH
2
—O—,
R
17
: H, F, Cl, C
1-4
alkyl, phenyl-C
1-2
-alkyl, phenyl, R
31
OOC—, R
31
—NH—, R
31
—O— or R
31
OOC—CH
2
O—,
R
29
: H or C
1-4
-alkyl, C
1-4
-alkoxy, C
1-4
-alkoxy-CO,
X: ═CH— or ═N—.
Preferred compounds are from the following groups Ia to Ii:
In this, the substituents R and A and B have the following meanings:
R
2
: H, C
1-4
-alkyl, phenyl and phenyl-C
1-4
-alkyl, R
18
O—CH
2
—, R
18
—CO—, R
18
—O—CH
2
—CO—, R
18
O—CO—CO—, R
18
—NH—CO—CO—, where R
18
is H or C
1-4
-alkyl, CF
3
—CO— or C
2
F

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