Dipeptide benzamidine as a kininogenase inhibitor

Details Dipeptide benzamidine as a kininogenase inhibitor Dipeptide benzamidine as a kininogenase inhibitor

1999-02-10

2002-08-27

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S020800, C530S331000, C548S535000

Reexamination Certificate

active

06440937

ABSTRACT:

TECHNICAL FIELD
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 a plurality of amplifying stages to the production of thrombin from prothrombin. Thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and aggregation of platelets which, in turn, due to the binding of platelet factor 3 and coagulation factor XIII, and a large number of highly active mediators, enhance thrombin formation.
The formation and action of thrombin are central events in the development both of white, arterial and of red, venous thrombi and are therefore potentially effective points of attack for drugs. Thrombin inhibitors are, by contrast with heparin, able independently of cofactors completely to inhibit simultaneously the effects of free thrombin and of that bound to platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis, and to act as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be used generally for the prophylaxis of thrombosis, for example after surgical operations.
BACKGROUND ART
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-Arg in which the N-terminal amino acid is in the D form have proven particularly beneficial. D-Phe-Pro-Arg isopropyl ester is described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol, 109 (1983) 43-51).
Derivatization of the arginine at the C terminus 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 a hemiacetal have been described (EP 185390, 479489, 526877, 542525; WO 93/15756, 93/18060).
The thrombin-inhibitory activity of peptide ketones, fluorinated alkyl ketones and of keto esters, boric acid derivatives, phosphoric esters and a-keto carboxamides can likewise be explained by this serine interaction (EP 118280, 195212, 362002, 364344, 410411, 471651, 589741, 293881, 503203, 504064, 530167; WO 92/07869, 94/08941).
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 in respect of other serine proteases.
DE 3 108 810, WO 93/11152 and EP 601 459 describe agmatine and hence arginine derivatives which are unable to interact with the active serine in serine proteases.
WO 94/29336, EP 0 601 459 and WO 95/23609 represent a further development in which the agmatine is replaced by an arylamidine residue.
Kininogenases are serine proteases which liberate vasoactive peptides, called kinins (bradykinin, kallidin and Met-Lys-bradykinin), from kininogens. Kininogens are multifunctional proteins which occur in coagulation and inflammation cascade reactions. As inhibitors, they protect cells from damage by cysteine proteases (Müller Esterl, FEBS Lett. 182 (1985) 310-314).
Important kininogenases are plasma kallikrein, tissue kallikrein and mast cell tryptase.
Kinins like bradykinin and kallidin are vasoactive peptides which influence a large number of biological processes. They play an essential part in inflammatory processes. By increasing vascular permeability, they lead to hypotension and edema. Furthermore, they are very potent pain-producing autacoids and have great importance as cellular mediators in the pathophysiology of asthma, of allergic rhinitis and of arthritis (K. D. Bhoola, C. D. Figueroa, K. Worthy, Pharmacological Reviews 44 (1992)1-80).
Irrespective of the mechanisms underlying inflammatory processes, fluid containing all the protein systems in the circulating blood escapes from blood vessels. This means that escape of plasma fluid from vessels is involved in diseases such as asthma, rhinitis and inflammatory internal diseases. Moreover, mast cell tryptase is released particularly in allergic processes (Salomonsson et al., Am. Rev. Respir. Dis., 1992, 146, 1535-1542).
The arginine chloromethyl ketones H-(D)-Pro-Phe-Arg-CH
2
Cl and H-(D)-Phe-Phe-Arg-CH
2
-Cl have been described by Kettner and Shaw as plasma kallikrein inhibitors (Biochem. 17 (1978) 4778-4784 and Meth. Enzym. 80 (1981) 826-842).
Various synthetic derivatives of benzamidines and benzylamines have proven to be inhibitors of plasma kallikrein, with the benzamidines having a considerably stronger inhibitory effect (F. Markward, S. Drawert, P. Walsmann, Biochemical Pharmacology 23 (1974) 2247-2256).
PKSI-527, the hydrochloride of N-(trans-4-aminomethylcyclo-hexylcarbonyl)-L-phenylalanin-4-carboxymethylanilide, is also an effective inhibitor of this kininogenase (Wanaka, Ohamoto et al., Thromb. Res., 57 (1990) 889-895).
DISCLOSURE OF INVENTION
The present invention relates to novel benzamidines, to their preparation and to their use as competitive inhibitors of trypsin-like serin proteases, especially thrombin and kininogenases such as kallikrein. The invention also relates to pharmaceutical compositions which contain the compounds as active ingredients, and to the use of the compounds as thrombin inhibitors, anticoagulants and antiinflammatory agents.
The invention relates to compounds of the formula I
where R, R
1
, R
2
, R
3
, R
4
, R
5
and R
6
, and l, m and n have the following meanings:
l 0 or 1,
m 0, 1 or 2,
n 0, 1 or 2,
R H or C
1-4
-alkyl-,
R
1
HOOC—, C
1-6
-alkyl-OOC—, benzyl-OOC— or —OH,
R
2
H—, C
1-4
-alkyl- or R
1
—(CH
2
)
m
—,
R
3
H— or C
1-4
-alkyl- which can be substituted by —OH or —COOH,
R
4
H—, C
1-4
-alkyl-, HOOC—C
1-4
-alkylene-,
R
5
C
1-8
-alkyl-, cycloalkyl-(CR
8
R
9
)
r
—, (r=O or 1, R
8
, R
9
=H—, cycloalkyl- or C
1-4
-alkyl-), in which up to four CH
2
groups in the cycloalkyl radical can be replaced, independently of one another, by CR
10
R
11
(R
10
=H— or C
1-4
-alkyl-, R
11
=C
1-4
-alkyl-) and/or the CH group in the cycloalkyl radical which is bonded CR
8
R
9
can be replaced by CR
12
(R
12
=C
1-4
-alkyl-), and/or one or two C—C single bond(s) in the ring can be replaced by a C═C double bond,
R
6
H—, C
1-4
-alkyl- or
R
4
and R
5
together —CH
2
—CH
2
—CH(R
7
)—, (R
7
=H—, phenyl- or cyclohexyl-)
R
2
and R
5
together —CH
2
—CH
2
— or —CH
2
—CH
2
—CH
2
—, in which one hydrogen atom can be replaced by C
1-4
-alkyl-, phenyl- or cycloalkyl-,
and salts thereof with physiologically tolerated acids.
The amino acid residues represented by —NR
4
—C(R
5
R
6
)—CO— preferably have the (D) configuration, and 3,4-dehydroproline and 4,5-dehydropipecolic acid preferably have the (L) configuration.
Preferred compounds of the formula I are those where
is HOOC—(CH
2
)
t
— (t=1, 2 or 3), (HOOC—CH
2
)
2
—CH—, (HO—CH
2
)
2
CH—, HOOC—CH
2
—CH(COOH)—, HOOC—CH(CH
2
—CH
2
—OH)—, HOOC—CH(C
1-4
-alkyl-), C
1-4
-alkyl-OOC—CH
2
—, benzyl-OOC—CH
2
—,
and where
is
(R
a
, R
b
=H, cyclohexyl- or C
1-4
-alkyl-) (R
c
, R
d
, R
e
, R
f
, R
g
, R
h
=H— or C
1-4
-alkyl-, where the CH
2
-group of the ring can be mono- or disubstituted),
(R
i
=phenyl- or cyclohexyl-)
(R
j
=cyclopentyl-, cycloheptyl-, 1-adamantyl-, 1-norbornyl-, 1-bicyclo[2.2.2]octyl-, neopentyl-, tert-butyl-, diisopropylmethyl- or 1-(1,4-cyclohexadienyl-))
where this building block preferably has the D configuration,
l is 0 and
R is H— or CH
3
—.
Further preferred compounds of the formula I are those where
is HOOC—(CH
2
)
t
— (t=1, 2 or 3), (HOOC—CH
2
)
2
—CH—, (HO—CH
2
)
2
CH—, HOOC—CH
2
—CH(COOH)—, HOOC—CH(CH
2
—CH
2
—OH)—, HOOC—CH(C
1-4
-alkyl)-, C
1-4
-alkyl-OOC—CH
2
—, benzyl-OOC—CH
2
,
and where
is
(R
a
, R
b
=H, cyclohexyl- or C
1-4
-alkyl-) (R
c
, R
d
, R
e
, R
f
, R
g
, R
h
=H— or C
1-4
-alkyl-, where the CH
2
groups of the ring can be mono- or disubstituted),
(R
i
=phenyl- or cyclo

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