Thrombin inhibitors, the preparation and use thereof

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.

Reexamination Certificate

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C514S018700, C514S019300

Reexamination Certificate

active

06455671

ABSTRACT:

BACKGROUND OF THE INVENTION
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 cascade lead, via several amplifying stages, to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in their turn enhance thrombin formation by the binding of platelet factor 3 and coagulation factor XIII as well as a whole series of highly active mediators.
The formation and effect 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 contrast with heparin in being able completely to inhibit, independently of cofactors, simultaneously the effects of thrombin both in the coagulation cascade and on platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis and to serve as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be used generally for thrombosis prophylaxis, for example after surgical interventions.
It is known that synthetic arginine derivatives influence the enzymic activity of thrombin by interacting with the active serine residue of the protease. Peptides based on Phe-Pro-Arg 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 (1982) 43-51).
Derivatization of the C-terminal arginine to the aldehyde leads to an enhancement of the inhibitory action. Thus, a large number of arginals able to bind the hydroxyl group of the “active” serine as hemiacetal have been described (EP 185,390, 479,489, 526,877, 542,525; WO 93 15 756, 93 18 060).
The thrombin inhibitory activity of peptide ketones, fluorinated alkyl ketones and of keto esters, boric acid derivatives, phosphoric esters and &agr;-keto carboxamides can likewise be explained by this serine interaction (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 07 869; 94 08 941).
DE 31 08 810 and WO 93 11 152 describe &ohgr;-aminoalkylguanidine di-peptides.
The peptide 4-amidinophenylglycinephosphonate diphenyl esters described by J. Oleksyszyn et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity for other serine proteases.
EP 601,459 and WO 94/29336, which are not prior publications, describe thrombin inhibitory peptides.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to novel thrombin inhibitors, to the preparation thereof and to the use thereof for controlling diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the formula
and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings:
where in all the abovementioned A radicals the &agr;-NH or &agr;-NH
2
group can be mono- or disubstituted by C
1-12
-alkyl, phenyl-C
1-4
-alkylene, X
12
OC—C
1-6
-alkylene, X
12
OC—C
1-6
-alkylcarbonyl, -&agr;- or &bgr;-naphthyl-C
1-4
-alkylene, C
1-12
-alkylcarbonyl, phenyl-C
1-4
-alkylcarbonyl, C
1-7
-alkoxycarbonyl, phenyl-C
1-5
-alkoxycarbonyl, -&agr;- or &bgr;-naphthyl-C
1-4
-alkylcarbonyl-, C
1-6
-alkylaminocarbonyl or phenyl-C
1-4
-alkylaminocarbonyl
also A: X
1
—NH—CH
2
—CH
2
—CO—, X
1
—NH—CH
2
—CH
2
—CH
2
—CO—
X
15
—(CH
2
)
f
—SO
2
—(f=0,1,2,3,4, X
15
=a phenyl or &agr;- or &bgr;-naphthyl radical which is unsubstituted or substituted by 1-3 CH
3
and/or CH
3
O groups, or one of the radicals
X
18
—O—CO—C
1
-
4
-alkylene-CO— (X
18
=H, C
1
-
4
-alkyl),
C
1
-
12
-alkyl-CO—, C
1
-
10
-alkyl-NH—CO-phenyl-C
1-4
-alkylene-NH—CO—, &agr;- or &bgr;-naphthyl-CO— or
 (X
18
=H or C
1-4
-alkyl,
 X
19
=H, C
1-6
-alkyl, phenyl, benzyl, cyclohexyl or cyclohexylmethyl)
R
1
: H or C
1-4
-alkyl
R
2
: H or C
1-4
-alkyl
R
3
: H, C
1-8
-alkyl, phenyl, phenyl-C
1-4
-alkylene, CH
2
OH, —CO—X
20
, —CO—CO—X
20
, (X
20
=H, C
1-4
-alkoxy, C
1-4
-alkyl, phenyl, phenyl-C
1-4
-alkylene, phenyl-C
1-4
-alkoxy, CF
3
, C
2
F
5
, an N-terminally linked natural amino acid, CH
2
OH, —CH
2
—O—C
1-4
-alkyl, NH—(C
1-4
-alkylene)-phenyl or NH—C
1-6
-alkyl),
m: 0,1,2 or 3
D: phenylene on which (CH
2
)
m
and (NH)
n
are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH
2
)
m
by F, Cl, Br, HO—CH
2
—, OH, NH
2
, NO
2
, C
1-4
-alkoxy, C
1-6
-alkyl or COX
21
(X
21
=H, C
1-4
-alkyl, C
1-4
-alkoxy, OH, NH
2
, NH—C
1-4
-alkyl) —O—(CH
2
)
1-3
—CO—X
21
or —(CH
2
)
1-3
—CO—X
21
,
pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, on which (CH
2
)
m
and (NH)
n
are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH
2
)
m
by F, Cl, Br, OH, NH
2
, C
1-4
-alkoxy or C
1-4
-alkyl,
1,4- or 1,3-cyclohexylene, in which one CH
2
group in the ortho position to (CH
2
)
m
can be replaced by NH, O, S or SO, or piperidinylene which is connected in the 3 or 4 position to the nitrogen to (CH
2
)
m
, and in which the nitrogen atom itself carries the C(═NH)NHR
4
group,
n: 0 or 1
R
4
: H, —CO—C
1-20
-alkyl, —CO—O—C
1-20
-alkyl, OH or NH
2
.
The alkyl radicals present in the formula I may be straight-chain or branched.
Preferred compounds of the formula I are those where the substituents have the following meanings:
(X
4
=H, F, Cl, Br, CF
3
, C
1-4
-alkyl, OH, OCH
3
, NO
2
, phenyl, preferably H, F, Cl, Br, CH
3
, t-butyl, OH, OCH
3
, NO
2
, X
5
=H, F, Cl, Br, CH
3
, OH, OCH
3
, phenyl, preferably H, F, OH, OCH
3
, phenyl, X
6
=H, F, Cl, Br, CH
3
, OH, OCH
3
, preferably H, F, OH, OCH
3
, X
7
=H, F, X
8
=H, F),
R
1
: H, CH
3
R
2
: H
R
3
: H, CH
3
, CHO, COCF
3
, COC
2
F
5
, CO—CH
2
OH, CO—CH
3
, CO—CH
2
-phenyl, CH
2
OH,
R
4
: H, OH, NH
2
m: 0, 1
a preferred group of D building blocks is
preferred building blocks of the combination —(CH
2
)
m
-D-(NH)
n
— in the general formula I are:
Particularly preferred compounds of the formula I are those in which the substituents have the following meanings:
Among the particularly preferred compounds, the following combinations should be emphasized, where A and B have the meanings described as particularly preferred:
The following substances are mentioned by way of example:
1. Boc-(D)-Phe-Pro-NH-(4-Am)-2-phenethyl
2. H-(D)-Phe-Pro-NH-(4-Am)-2-phenethyl
3. Boc-Phe-Pro-NH-pAmb
4. H-Phe-Pro-NH-pAmb
5. Boc-(D)-Phe-Pro-NH-pAmb
6. Ac-(D)-Phe-Pro-NH-pAmb
7. H-(D)-Phe-Pro-NH-pAmb
8. H-(D)-Phe-Pro-N(Me)-pAmb
9. Me-(D)-Phe-Pro-NH-pAmb
10. Z-Me-(D)-Phe-Pro-NH-pAmb
11. HOOC—CH
2
-(D)-Phe-Pro-NH-pAmb
12. MeOOC—CH
2
-(D)-Phe-Pro-NH-pAmb
13. t-BuOOC—CH
2
-(Boc)-(D)-Phe-Pro-NH-pAmb
14. EtOOC-(D)-Phe-Pro-NH-pAmb
15. Boc-(D)-Phe-Pro-NH-mAmb
16. H-(D)-Phe-Pro-NH-mAmb
17. Z-(D)-Phe-Pro-(D,L)(4-Am)-PhgOH
18. Z-(D)-Phe-Pro-(D,L)(4-Am)-PhgOMe
19. H-(D)-Phe-Pro-(D,L)(4-Am)-Phg—OH
20. Boc-(D)-Phe-Pro-(4-Am)-PhgCH
2
Ph
21. H-(D)-Phe-Pro-(4-Am)-PhgCH
2
Ph
22. H-(D)-Phe-Pro-NH-pAm-[(D,L)-&agr;-Me]-benzyl
23. Me-(D)-Phe-Pro-(D or L)(4-Am)-Phg&psgr;[CH
2
—OH]/a
24. Me-(D)-Phe-Pro-(D or L)(4-Am)-Phg&psgr;[CH
2
—OH]/b
25. Boc-(D)-Phe(4-F)-Pro-NH-pAmb
26. H-(D)-Phe(4-F)-Pro-NH-pAmb
27. Boc-(D)-Phe(4-Cl)-Pro-NH-pAmb
28. H-(D)-Phe(4-Cl)-Pro-NH-pAmb
29. Boc-(D,L)-Phe(4-Br)-Pro-NH-pAmb
30. H-(D,L)-Phe(4-Br)-Pro-NH-pAmb
31. H-(D)-Phe(4-OH)-Pro-NH-pAmb
32. Boc-(D)-Phe(4-MeO)-Pro-NH-pAmb
33. H-(D)-Phe(4-MeO)-Pro-NH-pAmb
34. Boc-(D,L)-Phe(4-EtO)-Pro-NH-pAmb
35. H-(D,L)-Phe(4-EtO)-Pro-NH-pAmb
36. Boc-(D)-Phe(4-BzlO)-Pro-NH-pAmb
37. H-(D)-Phe(4-BzlO)-Pro-NH-pAmb
38. Boc-(D,L)-Phe(4-Et)-Pro-NH-pAmb
39. H-(D,L)-Phe(4-Et)-Pro-NH-pAmb
40. Boc-(D,L)-Phe(4-iPr)-Pro

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