RU2002127729A - NEW HETEROCYCLIC AND BENZENE DERIVATIVES OF LIPOIC ACID, THEIR PRODUCTION AND APPLICATION AS MEDICINES - Google Patents

Claims (13)

1. The product of General formula (I), including the products of formulas (I) a and (I) b

in which n represents an integer from 0 to 6; R ₁ and R ₂ independently represent a hydrogen atom or a linear or branched alkyl radical consisting of 1-6 carbon atoms; XY represents —O— (CH ₂ ) _r -, —N (R ₃ ) - (CH ₂ ) _r -, —CO (CH ₂ ) _r -, —CO — N (R ₃ ) - (CH ₂ ) _r - , -N (R ₄ ) -CO- (CH ₂ ) _r - or -N (R ₃ ) -CO-N (R ₄ ) - (CH ₂ ) _r -; X'-Y 'represents - (CH ₂ ) _r , - (CH ₂ ) _r -O- (CH ₂ ) _r -, - (CH ₂ ) _r -N (R ₃ ) - (CH ₂ ) _r -, - (CH ₂ ) _r -CO (CH ₂ ) _r -, - (CH ₂ ) _r -CO-N (R ₃ ) - (CH ₂ ) _r -, - (CH ₂ ) _r -N (R ₄ ) -CO - (CH ₂ ) _r - or - (CH ₂ ) _r -N (R ₃ ) -CO-N (R ₄ ) - (CH ₂ ) _r -; R ₃ and R ₄ independently represent, each time they occur, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkoxycarbonyl radical; r independently represents each time it occurs, an integer from 0 to 6; Ω represents an aromatic b or 6 membered heterocycle, a non-aromatic 4-7 membered heterocycle or phenylene radical substituted with an R ₅ radical, R ₅ represents a hydrogen atom, a linear or branched alkyl radical containing 1-6 carbon atoms, or a radical - (CH ₂ ) _{m is a} Q radical in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylamino or dialkylamino radical, m represents an integer from 0 to 6; P represents - (CH ₂ ) _g -, g represents an integer from 0 to 6, or P also represents a radical,

in which R ₆ represents a hydrogen atom, a linear or branched alkyl radical consisting of 1-6 carbon atoms, or the radical - (CH ₂ ) _n -Q, in which Q represents a halogen atom or trifluoromethyl, hydroxy, amino, cyano -, alkoxycarbonylamino, aralkoxycarbonylamino, alkoxy, alkylthio, alkylamino or dialkylamino radical, and n represents an integer from 0 to 6, or R ₆ also represents an aromatic or non-aromatic 5 or 6 membered heterocycle, the heterocyclic members of which are selected from the radicals - O-, —N (R ₇ ) - and —S—, R ₇ represents a water atom kind or linear or branched alkyl containing from 1 to 6 carbon atoms; and finally A represents a radical,

in which B represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms, a carbocyclic or heterocyclic aryl 5 or 6 membered radical containing from 1 to 4 heteroatoms selected from O, S and N and, in particular, thiophene radicals, furan, pyrrole or thiazole, wherein the aryl radical is optionally substituted with one or more groups selected from a linear or branched alkyl, alkenyl or alkoxy radical containing from 1 to 6 carbon atoms, or B is NR ₈ R ₉ in which R ₈ and R ₉ introducing independently a hydrogen atom or a linear or branched alkyl radical containing from 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 containing from 1 to 6 carbon atoms, or R ₈ and R ₉ taken together form a non-aromatic 5 or 6 membered heterocycle with the nitrogen atom, the chain elements being selected from the group consisting of —CH ₂ -, —NH—, —O— or —S—, or also B represents an SR ₁₀ radical in which R ₁₀ represents a hydrogen atom or whether eyny or branched alkyl radical containing from 1 to 6 carbon atoms, or a salt of a product of general formula (I). 2. The product according to claim 1, which is one of the group comprising the following compounds: N ’- (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide; N ’- (4- {4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide; N ’- [3 - ({4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide; N ’- [3 - ({4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} phenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} -2-methylphenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} -3-methylphenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} -2-methoxyphenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} -3-methoxyphenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} -2-cyanophenyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; 4- (3 - {[amino (2-thienyl) methylidene] amino} benzyl) -N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; N ’- (3- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide; tert-butyl 5 - {[amino (2-thienyl) methylidene] amino} -2- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} benzyl carbamate; N ’- (3- (aminomethyl) -4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide; tert-butyl 3 - {[amino (2-thienyl) methylidene] amino} benzyl {1- [5- (1,2-dithiolan-3-yl) pentanoyl] -4-piperidinyl} carbamate; N ’- {3 - [({1- [5- (1,2-dithiolan-3-yl) pentanoyl] -4-piperidinyl} amino) methyl] phenyl} -2-thiophenecarboximidamide; N- [2- (4 - {[amino (2-thienyl) methylidene] amino} phenyl) ethyl] -4 - {[5- (1,2-dithiolan-3-yl) pentanoyl] amino} benzamide, or one from their salts. 3. A method for producing a compound of general formula (I) according to claim 1, comprising reacting a compound of general formula (II)

in which n, X, Y, Ω, X ', Y' and P have the same meanings as in the general formula (I), a) with a compound of the general formula (I.i)

in which B has the same meaning as in the general formula (I), and L represents a leaving group, for example, an alkoxy, alkylthio, sulfonic acid, halide, aryl alcohol radical or tosyl radical, b) or with a compound of the general formula (I.ii)

in which L represents a leaving group, for example, an alkoxy, alkylthio, sulfonic acid, halogen, aryl alcohol radical or a tosyl radical, c) or with a compound of the general formula (I.iii)

in which L represents a leaving group, for example, an alkoxy, alkylthio, sulfonic acid, halogen, aryl alcohol or tosyl radical, and Gp represents a carbamate-type protecting group, for example a tert-butoxycarbonyl group, if a compound of the general formula (I.iii) is selected for this reaction, then hydrolysis is carried out in the presence of a strong acid, for example trifluoroacetic acid, for this reaction, d) or with a derivative of a compound of formula (I.iv) (N-methyl-N’-nitro-N-nitrosoguanidine)

e) or, finally, with a derivative of a compound of formula (I.v) in which Gp represents a protecting group

4. The method of obtaining the product of General formula (I) according to claim 1, in which XY is —CO-N (R ₃ ) - (CH ₂ ) _r , comprising reacting an acid of general formula (I.vi),

in which n has the same meaning as in general formula (I) of claim 1, with an amine of general formula (X) or (Xa),

in which r, R ₃ , Ω, X ', Y', P and A have the same meaning as in the general formula (I) of claim 1, wherein the compound of the general formula (Xa) is such that its Ω heterocycle contains an atom nitrogen. 5. Intermediates in the synthesis having the general formulas (II), (III) and (IV) as new industrial products

in which n, X ’, Y’, P, A, Ω and X-Y have the same meaning as in general formula (I) of claim 1; and Gp is a carbamate type protecting group. 6. The product of General formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, used as a medicine. 7. A pharmaceutical composition comprising, as an active ingredient, at least one product according to claim 1 or 2, or a pharmaceutically acceptable salt of said product. 8. The use of a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the preparation of a medicament for inhibiting NO synthase. 9. The use of a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the preparation of a medicament for the regeneration of antioxidants. 10. The use of the product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the preparation of a medicament exhibiting inhibitory activity against NO synthase and the ability to regenerate antioxidants. 11. The use of a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the manufacture of a medicament for the treatment of a number of pathologies associated with the synthesis of nitric oxide and / or the redox state of thiol groups, pathologies such as disorders of the central or peripheral nervous system, in particular, adequately represented by Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, se cal shock, pathologies resulting from radioactive radiation, solar radiation or organ transplants, autoimmune and autosomal diseases, cancer and all the pathologies characterized by synthesis of nitric oxide or dysfunction of nitric oxide and / or the redox status of thiol groups. 12. The use of a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the manufacture of a medicament for the treatment of cerebrovascular disorders such as migraine, ischemic or hemorrhagic cerebral infarction, ischemia and thrombosis. 13. The use of a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt of this product for the manufacture of a medicament for the treatment of disorders of the central or peripheral nervous system, such as, for example, neurodegenerative disorders, pain and fibromyalgia, head trauma and the spinal cord, diabetes and related complications, including retinopathy, nephropathy and polyneuropathy, addiction to drugs, alcohol and certain chemicals, erectile dysfunction and reproductive disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleep and digestion disorders.