Use of cysteine derivatives for preparing a medicine for...

Details Use of cysteine derivatives for preparing a medicine for... Use of cysteine derivatives for preparing a medicine for...

2001-01-04

2003-04-08

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S350000

Reexamination Certificate

active

06544995

ABSTRACT:

The present invention relates in particular to the use of derivatives of cysteine for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein. These diseases include in particular diseases linked to the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign and malign proliferative diseases.
The G proteins are in fact the structural association of three distinct sub-units called &agr;, &bgr; and &ggr;, but operate as dissociable entities constituted by &agr; sub-units on the one hand and &bgr;/&ggr; dimers on the other hand.
The G proteins participate in the transmission of signals outside the cell thanks to its interaction with receptors with seven transmembrane domains inside using different effectors including adenylate cyclase, phospholipase C or also the ionic channels. The adenylate cyclase enzyme generates cyclic AMP (cAMP) (cf. Gilman, A. G.
Biosci. Rep.
15, 65-97 (1995)). Thus, it is known that, in order to activate the adenylate cyclase, it is necessary for the G proteins to be transitionally in a heterotrimeric form, in which form the monomer constituted by an &agr; sub-unit is associated with the dimer constituted by the &bgr; and &ggr; sub-units. It is only in this situation that the signal outside the cell can activate the a sub-unit of &agr; G protein, which can, after disassociation, modulate the adenylate cyclase and modulate the production of cAMP.
It is also known that the &bgr;/&ggr; dimers can directly activate the effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases. A direct link between the &bgr;/&ggr; sub-units and the src or src like kinases has been demonstrated (cf. Gutkind, J. S.
J.Biol.Chem.
273, 1839-1842 (1998)).
Moreover, bacterial toxins such as
Vibrio cholera
and
Bortella pertussis
, peptides such as mastoparan and suramin have been presented as directly modulating the activity of the G proteins (cf. Freissmuth, M., Boehm, S., Beindl, W., et al.
Mol.Pharmacol.
49, 602-611 (1996); Boehm, S., Huck, S., Motejlek, A., et al.
Journal of Neurochemistry
66, 1019-1026 (1996); Cachero, T. G., Rigual, R., Rocher, A. & Gonzalez, C.
Eur.J.Neurosci.
8, 2320-2327 (1996); Danilenko, M., Worland, P., Carlson, B., Sausville, E. A. & Sharoni, Y.
Biochem. Biophys. Res. Commun.
196, 1296-1302 (1993); Beindl, W., Mitterauer, T., Hohenegger, M., Ijzerman, A. P., Nanoff, C. & Freissmuth,
M. Mol. Pharmacol.
50, 415-423 (1996)).
For example, the choleric toxin modifies the &agr;
S
sub-unit of the G protein by adding an ADP-ribose originating from the NAD to an arginine-specific acceptor site. This completely blocks the activity of the GTPase, provoking persistent stimulation of its next effector, adenylate cyclase and leading to overproduction of cAMP.
The harmful effects of an abnormal cAMP level are also known and occur in particular at the level of the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes and obesity.
The Applicant has just discovered that certain derivatives of cysteine, namely the compounds of general formula (A)
corresponding to sub-formulae (A1) or (A2):
in which:
X represents R
12
and Y represents R
8
, or X and Y complete a ring with 6 members, the X-Y set representing the —CH(R
8
)—CH(R
9
)— radical;
R
1
represents H, a lower alkyl or alkylthio radical;
R
2
and R
3
represent independently H or a lower alkyl radical;
R
4
represents H
2
or O;
R
5
represents H, or one of the lower alkyl, lower alkenyl, lower alkynyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising a lower alkyl radical, —O—R
10
, —S(O)
m
R
10
(m representing 0, 1, or 2), —N(R
10
)(R
11
), —N—C(O)—R
10
, —NH—(SO
2
)—R
10
, —CO
2
—R
10
, C(O)—N(R
10
)(R
11
), and —(SO
2
)—N(R
10
)(R
11
);
R
6
and R
7
represent independently H, a —C(O)—NH—CHR
13
—CO
2
R
14
radical, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R
10
)(R
11
), COOH, CON(R
10
)(R
11
), and halo radicals, or R
6
and R
7
form together an aryl radical or a heterocycle;
R
8
and R
9
represent independently, H, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R
10
)(R
11
), COOH, CON(R
10
)(R
11
) and halo radicals, or R
8
and R
9
together form an aryl radical or a heterocycle;
R
10
and R
11
represent independently H, an aryl radical or a heterocycle, or an alkyl, arylalkyl or lower alkyl heterocycle radical;
R
12
represents NR
9
, S, or O;
R
13
represents a lower alkyl radical optionally substituted by a radical chosen from the lower alkyl, —OR
10
, —S(O)
m
R
10
(m representing 0, 1, or 2) and —N(R
10
)(R
11
) radicals;
R
14
represents H or a lower alkyl radical;
or the compounds of general formula (B):
W
1
—Ar—W
2
  (B)
in which:
W
1
represents a remainder originating from a cysteine in reduced or non reduced form;
Ar represents a radical derived from an aminobenzoic acid, the aromatic ring of which is optionally substituted;
W
2
represents an amino acid, preferably an aliphatic amino acid;
or also the compounds of general formula (C):
in which:
Z
1
represents a lower alkyl radical;
Z
2
and Z
3
both represent H or Z
2
and Z
3
together form a chain having 2 to 4 elements chosen from the —C(O)—, —CH
2
—, —CH(NH
2
)— and —S— radicals, it being understood that two successive elements are not both —C(O)—;
it being understood that the compounds of general formula (C) can also be presented in the form of dimers, when the Z
2
radical represents a hydrogen atom which can be eliminated by oxidization;
or also a pharmaceutically acceptable salt of a compound of general formula (A), (B) or (C);
can be used to prepare medicaments intended to treat pathologies which result from the formation of the heterotrimeric G protein.
By lower alkyl radical, is understood a linear or branched alkyl radical containing 1 to 6 carbon atoms, and in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By heterocycle radical is understood a radical constituted by one or more rings and including at least one heteroatom. By arylalkyl, alkyl heterocycle, alkylthio or lower alkoxy radical, is understood the radicals of which the alkyl radical has the meaning indicated previously.
Preferably, the Ar radical included in formula (B) is optionally substituted by an alkyl radical comprising 1 to 6 carbon atoms or an aryl radical, these alkyl or aryl radicals themselves being optionally substituted preferentially by an alkoxy radical having 1 to 4 carbon atoms, fluoro, chloro, bromo. The aryl radical preferably a phenyl can itself be substituted by an alkyl radical.
Preferably also, the compounds of general formula (B) are such that Ar represents a radical derived from an aminobenzoic acid the aromatic ring of which is substituted by a phenyl radical and W
2
represents an aliphatic amino acid.
In particular, the following compounds can be used to prepare medicaments intended to treat pathologies which result from the formation of the heterotrimeric G protein:
7-(2-amino-1-oxo-3-thiopropyl)-8-(c

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