Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-31
2004-11-23
Raymon, Richard L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S465000, C548S494000, C548S495000, C548S496000, C546S166000, C514S419000
Reexamination Certificate
active
06821986
ABSTRACT:
The present invention relates to new derivatives of amino acids and their use as medicaments. These derivatives have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or (according to preference):
either an activity which traps the reactive oxygen species (ROS);
or an antioxidant regenerating activity such as glutathione or reactive oxygen species (ROS) traps and more generally an influence on the redox status of the thiol groups.
Therefore the invention relates in particular to the derivatives corresponding to general formula (I) defined hereafter, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic ends, in particular their use as inhibitors of NO-synthases and/or (according to preference):
either as ROS traps;
or as agents allowing the regeneration of antioxidants such as glutathione or ROS traps entities and intervening in a more general fashion in the redox status of the thiol groups.
Given the potential role of NO, the ROS's and the metabolism of glutathione in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where nitrogen monoxide, the ROS's and the metabolism of glutathione as well as the redox status of the thiol groups are involved, and in particular:
cardiovascular and cerebrovascular disorders comprising, for example, atherosclerosis, migraine, arterial hypertension, septic shock, cardiac or cerebral infractions of ischemic or haemorrhagic origin, ischemias and thromboses;
disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where cerebral infarctions, sub-arachnoid haemorrhage, ageing, senile dementia, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Freidreich's ataxia, Creutzfeld-Jacob's disease and prion diseases, amyotrophic lateral sclerosis, but also pain, cerebral or bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleeping disorders, eating disorders (anorexia, bulimia, etc.) can be mentioned in particular;
disorders of the skeletal muscle and of the neuromuscular junctions (myopathy, myositis) as well as skin diseases;
proliferative and inflammatory diseases such as, for example, atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastrointestinal system (colitis, Crohn's disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities;
organ transplants;
auto-immune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies;
cancer;
autosomal genetic diseases such as Unverricht-Lundborg disease;
neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson's disease)
impotence linked with diabetes;
all the pathologies characterized by a production or a dysfunction of nitrogen monoxide and/or ROS or the metabolism of glutathione and of the redox status of thiol groups.
In all these pathologies, there is experimental evidence demonstrating the involvement of nitrogen monoxide or of a dysfunction of the metabolism of glutathione (Kerwin et al., Nitric oxide: a new paradigm for second messengers,
J. Med. Chem
. 38, 4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant,
Free Radical Biology
&
Medicine
19, 227-250, 1995). In this context, medicaments which can inhibit the formation of nitrogen monoxide, trap the ROS's or re-establish the biological functionality of the thiol groups or glutathione can have beneficial effects.
Compounds comprising both inhibitory properties of the NO-synthases and ROS trapping properties have already been described by the Applicant in earlier patent applications (cf. PCT Applications WO 98/42696, WO 98/58934, WO 00/02860, WO 00/17190 and WO 00/17191). More recently derivatives of lipoic acid having both inhibitory properties of the NO-synthases and regenerating properties of antioxidants or of ROS traps and more generally have an influence on the redox status of thiol groups have also been described more recently in the PCT Application WO 00/59899
The compounds of the invention correspond to general formula (I)
in which
R
1
represents a hydrogen atom or an alkyl radical;
A and A′ represent a hydrogen atom or one of the following radicals:
a
radical, in which R
2
, R
3
, R
4
, R
5
, R
6
represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or NR
8
R
9
radical,
R
8
and R
9
representing, independently, a hydrogen atom, an alkyl radical or a —COR
10
group,
or R
8
and R
9
form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R
10
representing a hydrogen atom, an alkyl, alkoxy or NR
11
R
12
radical,
R
11
and R
12
representing, independently, a hydrogen atom or an alkyl radical,
or R
11
and R
12
forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R
7
represents a hydrogen atom, an alkyl radical or a —COR
13
group,
R
13
representing a hydrogen atom, an alkyl or alkoxy or NR
14
R
15
radical,
R
14
and R
15
representing independently, a hydrogen atom or an alkyl radical, or R
14
and R
15
forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
and &OHgr; does not exist, or represents a bond, O or S or also an NR
16
radical, in which R
16
represents a hydrogen atom or an alkyl radical;
or a
radical, in which R
17
, R
18
and R
19
represent, independently, a hydrogen, a halogen, the OH or SR
20
group or an alkyl, alkenyl or alkoxy radical or an NR
21
R
22
radical,
R
20
representing a hydrogen atom or an alkyl radical,
R
21
and R
22
representing, independently, a hydrogen atom, an alkyl radical or a —COR
23
group,
or R
21
and R
22
forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R
23
representing a hydrogen atom, an alkyl, alkoxy or NR
24
R
25
radical,
R
24
and R
25
representing, independently, a hydrogen atom or an alkyl radical, or R
24
and R
25
forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom alr
Auvin Serge
Chabrier de Lassauniere Pierre-Etienne
Harnett Jeremiah
Habte Kahsay
Muserlian Lucas and Mercanti
Raymon Richard L
Societe de Conseils de Recherchet et E'Applications Scienti
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