Amidine derivatives, preparation and use thereof as medicines

Details Amidine derivatives, preparation and use thereof as medicines Amidine derivatives, preparation and use thereof as medicines

2002-04-23

2004-08-03

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06770669

ABSTRACT:

The present invention relates to new derivatives of amidines, their preparation and their use as medicaments. It relates in particular to the use of said derivatives for preparing a medicament intended to inhibit NO synthases (NOS) and/or monoamine oxydases (MAO).
Taking into account the potential role of NOS and MAO in physiopathology, the new described derivatives corresponding to general formula (I) can produce beneficial or favourable effects in the treatment of pathologies where these two enzymes are involved. In particular the following pathologies are involved.
disorders of the central or peripheral nervous system such as for example neurological diseases where Parkinson's disease, cerebral or spinal cord traumatisms, cerebral infarction, sub arachnoid hemorrhage, epilepsy, ageing, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, peripheral neuropathies, pain;
schizophrenia, depressions, psychoses;
disorders of the memory and the humour;
pathologies such as for example migraine;
behavioural disorders, boulimia and anorexia;
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications (in particular impotence linked to diabetes), multiple sclerosis;
addiction to toxic substances;
proliferative and inflammatory pathologies;
and more generally all the pathologies characterized by an excessive production of NOS and/or participation by MAO.
In all of these pathologies, experimental evidence exists which demonstrates the involvement of NOS (
J. Med. Chem
. (1995) 38, 4343-4362) as well as the involvement of MAO (Goodman & Gilman's:
The pharmacological hosts of therapeutics
, 9th ed., 1995, 431-519).
The inventors have already described inhibitors of NO Synthases and their use in previous patents (U.S. Pat. Nos. 5,081,148; 5,360,925). The PCT Patent Application WO 95/05363 describes certain derivatives of amidines and their use as inhibitors of NO synthases. The Applicant has itself described more recently other derivatives of amidines, which inhibit NO synthases and/or trap the reactive oxygen species (ROS for
Reactive Oxygen Species
) (cf. in particular PCT Patent Applications WO 98/42696 and WO 98/58934).
The Applicant has just now discovered that, surprisingly, the derivatives of amidines corresponding to general formula (I) defined hereafter are inhibitors of NOS and/or MAO.
The compounds of the invention correspond to the general formula (I)
in which:
R
1
and R
2
represent, independently, a hydrogen atom or an alkyl, cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, —(CH
2
)
g
—Z
1
R
4
or —(CH
2
)
k
—COR
5
radical,
Z
1
representing —O—, —NR
6
—, —S— or a bond,
R
4
and R
6
representing, independently, a hydrogen atom or an alkyl, alkenyl, allenylalkyl, alkynyl, alkoxy or cyanoalkyl radical,
R
5
representing an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR
7
R
8
radical,
R
7
and R
8
representing, independently, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl or alkoxy radical,
or R
1
and R
2
together with the nitrogen atom form a non-aromatic heterocycle with 4 to 8 members, the elements of the chain being chosen from a group comprising —CH(R
9
)—, —NR
10
—, —O—, —S—, —CO—, said heterocycle being able to be substituted by one or more substituents —(CH
2
)
k
—Z
2
R
11
or —(CH
2
)
k
—COR
12
, said heterocycle being able to be for example an azetidine, a piperazine, a homopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, a morpholine or a thiomorpholine,
Z
2
representing —O—, —NR
13
— or —S— or a bond,
R
11
, each time that it occurs, representing independently a hydrogen atom, an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R
13
, each time that it occurs, representing, independently, a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R
12
, each time that it occurs, representing an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, or alkoxy or NR
14
R
15
radical,
R
14
and R
15
, each time that they occur, representing, independently, a hydrogen atom or an alkyl, alkoxy, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
R
9
and R
10
, each time that they occur, representing independently a hydrogen atom, —(CH
2
)
k
—Z
3
R
16
or —(CH
2
)
k
COR
17
,
Z
3
representing —O—, —NR
18
—, —S— or a bond,
R
18
representing, independently, a hydrogen atom or an alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, alkoxy or cyanoalkyl radical,
R
16
, each time that it occurs, representing independently a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R
17
, each time that it occurs, representing independently an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR
19
R
20
radical,
R
19
and R
20
representing, independently, each time that they occur, a hydrogen atom or an alkyl alkoxy, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical;
X represents a —CO— or —(CH
2
)
m
— radical;
R
3
represents a hydrogen atom or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
A represents a linear or branched alkyl radical having 1 to 6 carbon atoms or a carbocyclic or heterocyclic aryl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furane, pyrrole or thiazole radicals, said aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
g, each time that it occurs, representing, independently, an integer from 1 to 6,
m, k and n, each time that they occur, representing, independently, integers from 0 to 6;
it being understood however that, when R
3
represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, then R
1
and R
2
do not represent, independently, a hydrogen atom or an alkyl radical, and moreover NR
1
R
2
do not represent one of the non substituted piperidinyl, morpholinyl, pyrrolidinyl groups or the piperazinyl group optionally substituted in position 4 by an alkyl radical containing 1 to 6 carbon atoms.
By alkyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, when it is not specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By allenyl, is meant the —CH═C═CH
2
radical. By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By heterocycle, is meant a mono- or polycyclic system said system comprising at least one heteroatom chosen from O, N and S and being saturated, partially or totally unsaturated or aromatic. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) are replaced by a halogen atom.
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, cyanoalkyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, cyanoalkyl and aralkyl radicals of which the alkyl radical has the meaning indicated previously.
By heterocycle, is meant in particular the thiophene, pyrrole, pyrrolidine, furane, tetrahydrofuran, piperidine, piperazine, quinoline, indoline and indole radicals. By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethy

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