Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-27
2003-08-12
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210010, C514S231500, C514S252130, C514S277000, C514S336000, C514S326000, C514S365000, C514S372000, C514S383000, C514S397000, C514S422000, C514S442000, C544S060000, C544S145000, C544S242000, C544S368000, C546S207000, C548S146000, C548S206000, C548S311100, C548S315100, C548S364100, C548S365700
Reexamination Certificate
active
06605637
ABSTRACT:
This application is a 371 of PCT/FR00/00814 filed Mar. 31, 2000.
A subject, of the present invention is new derivatives of lipoic acid, which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or are agents which allow the regeneration of antioxidants or entities which trap the reactive oxygen species (ROS) and which intervene in a more general fashion in the redox status of thiol groups. These antioxidants or entities which trap the reactive oxygen species can be of natural origin, such as for example vitamin E or glutathione, or of synthetic origin such as certain products which trap the ROS or products having both an inhibitory activity on NO-synthase enzymes and an activity which traps the ROS. Examples of such products of synthetic origin can in particular be found in the PCT Patent Applications WO 96/09653, WO 98/42696 and WO 98/58934.
Therefore, the invention relates in particular to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and/or as agents which allow the regeneration of antioxidants or entities which trap the ROS's and which intervene in a more general fashion in the redox status of thiol groups.
Given the potential role of NO and 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 and the metabolism of glutathione as well as the redox status of thiol groups are involved. In particular:
cardiovascular and cerebrovascular disorders including for example atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemias and thromboses.
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and 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.);
disorders of the skeletal muscle and neuromuscular joints (myopathy, myositis) as well as cutaneous 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 gastro-intestinal 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 for example lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nrephropathies 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 to diabetes;
all the pathologies characterized by an excessive production or a dysfunction of nitrogen monoxide and/or the metabolism of glutathione and of the redox status of the 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). This is the case in particular in Parkinson's disease which illustrates the invention (Beal M F, Excitotoxicity and nitric oxide in Parkinson's disease pathogenesis.
Ann. Neurol
. 44[Suppl 1], S110-S114, 1998; Donato et al., Gluthathione in Parkinson's disease: a link between oxidative stress and mitochondrial damage.
Ann. Neurol
. 32, S111-S115, 1992). In this context, medicaments which can inhibit the formation of nitrogen monoxide or re-establish the biological functionality of the thiol groups or glutathione can have beneficial effects.
Moreover, in earlier patents, the inventors have already described NO Synthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925) and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties (PCT Patent Application WO/09653). They have also described derivatives of amidines in PCT Patent Applications WO 98/42696 and WO 98/58934 and of the derivatives of aminopyridines in the PCT Patent Application WO 00/02860. These derivatives of amidines or aminopyridines have the characteristic of being both NO Synthase inhibitors and ROS inhibitors
A subject of the present invention is new derivatives of lipoic acid, their preparation and their use in therapeutics.
Therefore the invention relates to a product of general formula (I), characterized in that it comprises the products of sub-formulae (I)a and (I)b
in which
R
1
and R
2
represent independently a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
A represents one of the —(CH
2
)
m
—NR
3
CO(CH
2
)
n
—, —(CH
2
)
m
—CONR
3
—(CH
2
)
n
—, —(CH
2
)
m
—NR
3
—(CH
2
)
n
—, —(CH
2
)
m
—CONR
3
—(CH
2
)
p
—NR
4
—(CH
2
)
n
—, —(CH
2
)
m
—NR
3
—CO—N
4
—CH
2
)
n
— or —(CH
2
)
m
— radicals, m and n being integers from 0 to 6, p being an integer from 2 to 6, and R
3
and R
4
representing independently a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
X represents a
radical, in which the T group, which is attached to the Y group, represents a —(CH
2
)
i
— radical in which i represents an integer comprised between 0 and 6, and R
5
represents a hydrogen atom, a linear or branched alkyl radical having 1 to 6 carbon atoms or a —(CH
2
)
m
—Q radical in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylthio, alkylamino or dialkylamino radical, or also R
5
represents a heterocycle with 5 to 6 members the heterocyclic members of which are chosen from the —O—, —N(R
6
)— and —S— radicals, R
6
representing a hydrogen atom, a linear or branched alkyl having 1 to 6 carbon atoms or the bond to the phenyl ring of the X radical;
or also X represents a —(CH
2
)
q
— radical in which q represents an integer from 0 to 6;
and finally Y represents one of the
radicals in which:
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl 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, the 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, or B represents NR
8
R
9
, in which R
8
and R
9
represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or one of R
8
and R
9
represents a nitro radical while the other represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or also R
8
and R
9
together form with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain being chosen from a group composed of —CH
2
—, —NH—, —O—
Auguet Michel
Chabrier de Lassauniere Pierre-Etienne
Harnett Jeremiah
McKane Joseph K.
Muserlian Lucas and Mercanti
Small Andrea D.
Societe de Conseils de Recherches et d'Applications Scienti
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