RU2001109228A - Unsaturated derivatives of hydroxy acid as inhibitors of NAD + -ADP-ribosyltransferase - Google Patents

Claims (11)

1. Unsaturated derivative of hydroxy acid of the formula (I)

where R ₁ represents a C _1-20 alkyl group, a phenyl group optionally substituted by 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, (C _1-4 -alkyl) amino group, di (C _1-4 -alkyl) amino group or di (C _1-4 -alkanoyl) amino group, in addition, R ₁ is a 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two a nitrogen atom or a sulfur atom as a heteroatom; R ₂ represents a halogen atom; or R ₁ forms together with R _{2 a} C _5-7 cycloalkyl group optionally fused to a benzene ring, Y represents a hydrogen atom, a hydroxy group, a C _1-30 alkanoyloxy group or a C _3-22 alkenoyloxy group; X is a halogen atom, a hydroxy group or an amino group; R ₃ represents C _3-7 -tsikloalkilgruppu or a group of formula -NR ₄ R ₅ wherein R ₄ and R ₅ represent, independently, a hydrogen atom, C ₁ - ₅ -alkyl, C _1-5 -alkanoilgruppu or R ₄ and R ₅ form a 5- or 6-membered saturated or unsaturated heterocyclic group with an adjacent nitrogen atom, which may also contain an oxygen atom and may be fused to a benzene ring, where the heterocyclic group and / or benzene ring may be substituted by one or two substituents selected from the group comprising a C _1-2 -alkyl group, C _1-2 - alkoxy group or halogen atom, in addition, its geometric and / or optical isomers, and / or their pharmaceutically acceptable acid addition salts. 2. The hydroxy acid derivative according to claim 1, wherein in formula I, X represents an amino group, Y represents a hydroxy group, R ₃ represents a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ where R ₄ and R ₅ are, independently of one another, a C _1-5 alkanoyl group, but one of them may also be a hydrogen atom, or R ₄ and R ₅ form, together with the adjacent nitrogen atom, a 5- or 6-membered saturated or unsaturated heterocyclic group that is condensed with benzene ring and may also contain an oxygen atom, where heterocyclic groups operated and / or the benzene ring may be substituted with one or two substituents selected from the group consisting of C _1-2 -alkyl, C _1-2 -alkoxy or halogen, and R ₁ represents a C _14-20 -alkyl group, a phenyl group, optionally substituted with 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, a (C _1-4 alkyl) amino group, di (C _1-4 alkyl) an amino group or a di (C _1-4 alkanoyl) amino group, in addition, R ₁ represents a 5- or 6-membered saturated or unsaturated heterocyclic a group containing one or two nitrogen atoms or a sulfur atom as a heteroatom, and R ₂ is a hydrogen atom or X is a halogen atom or a hydroxy group, Y is a hydrogen atom, a hydroxy group, a C _1-30 alkanoyloxy group or a C _3-22 alkenoyloxy group, R ₃ means a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ where R ₄ and R ₅ represent, independently of one another, a hydrogen atom, a C _1-5 alkyl group, a C _1-5 alkanoyl group, or R ₄ and R ₅ form together with the adjacent nitrogen atom a 5- or 6-membered saturated or unsaturated heterocyclic moieties Which may contain also an oxygen atom and can be condensed with a benzene ring, wherein the heterocyclic group and / or the benzene ring may be substituted with one or two substituents selected from the group consisting of C _1-2 -alkyl, C _1-2 -alkoxy or a halogen atom, R ₁ represents a C _1-20 alkyl group, a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, (C _{1 -4-} alkyl) amino group, di (C _1-4 -alkyl) amino group or di A (C _1-4 alkanoyl) amino group, in addition, R ₁ is a 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atoms or a sulfur atom as a hetero atom, and R ₂ is a hydrogen atom, or R ₁ forms together with R _{2 a} C _5-7 cycloalkyl group optionally fused to a benzene ring, in addition, its geometric and / or optical isomers and / or their pharmaceutically acceptable acid addition salts. 3. The hydroxy acid derivative according to claim 1, where in the formula IR ₁ is a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a methyl group, methoxy group or chlorine atom, in addition, R ₁ represents 5- or 6- a saturated or unsaturated heterocyclic group containing one or two nitrogen atoms as a heteroatom, R ₂ is a hydrogen atom, X is an amino group, Y is a hydrogen atom or a hydroxy group, R ₃ is a group of the formula —NR ₄ R ₅ , where R ₄ and R ₅ represent, independently pyr from each other, hydrogen, C _1-5 -alkyl, C _1-5 -alkanoilgruppu, or R ₄ and R ₅ form together with the adjacent nitrogen atom a 5- or 6-membered saturated or unsaturated heterocyclic group, furthermore geometric his and / or optical isomers and / or their pharmaceutically acceptable acid addition salts. 4. The hydroxy acid derivative according to claim 3, wherein, in the formula, IR ₁ represents a pyridyl group or a phenyl group optionally substituted with 1-3 methoxy groups, R ₂ represents a hydrogen atom, X represents an amino group, Y represents a hydrogen atom or hydroxy group, R ₃ means pyrrolidino , piperidino or morpholino groups, in addition, its geometric and / or optical isomers, and / or their pharmaceutically acceptable acid addition salts. 5. A method of obtaining an unsaturated derivative of hydroxy acid acid of the formula I, where R ₁ , R ₂ , R ₃ , X and Y are described in claim 1, characterized in that a) to obtain compounds of formula I, where X is an amino group, R ₁ , R ₂ , R ₃ , and Y are the same as described in the description of formula I, amidoxime of formula (II)

where R ₁ and R ₂ described above, reacts with a reagent of formula (III)

where Z is a leaving group, preferably a halogen atom; Y is described above, or b) to obtain compounds of formula I, where X is an amino group, Y is a hydroxy group, R ₁ , R ₂ and R ₃ are indicated in the description of formula I, a reagent of formula III, where Z is a leaving group, preferably a chlorine atom, and Y is described above, reacts with a base, and the resulting oxirane derivative of formula (V)

where R ₃ described above, reacts with an amidoxime of formula II, where R ₁ and R _{2 are} described above, or c) to obtain compounds of formula I, where X is an amino group, R ₁ , R ₂ , R ₃ and Y are indicated in the description of formula I, a carboxyl nitrile of formula (IV)

where R ₁ and R ₂ described above, reacts with a hydroxylamine derivative of the formula (VI)

where R ₃ and Y are described above, or d) to obtain compounds of formula I, where X is an amino group, R ₁ , R ₂ , R ₃ and Y are indicated in the description of formula I, a reactive derivative of a carboxylic acid of formula (VII)

where V is a leaving group, R ₁ and R _{2 are} described above, reacts with a hydroxylamine derivative of formula VI, where R ₃ and Y are described above, or e) to obtain compounds of the formula I, where X is an amino group, Y is a hydroxy group, R _{3 is a} group of the formula —NR ₄ R ₅ , where R ₁ , R ₂ , R ₄ and R ₅ are indicated in the description of the formula I, amidoxime of the formula II, where R ₁ and R _{2 are} described above, reacts with epichlorohydrin in the presence of a base, and the resulting epoxide of formula (VIII)

where R ₁ and R ₂ described above, reacts with an amine of the formula HNR ₄ R ₅ where R ₄ and R _{5 are} described above, or f) to obtain compounds of formula I, where X represents a halogen atom, R ₁ , R ₂ , R ₃ and Y are indicated in the description of formula I, an oxygen-substituted oxime of formula (IX)

where R ₁ , R ₂ and R ₃ described above, reacts with a halogenating agent, and, if desired, the resulting compound of formula I, where X is an amino group, R ₁ , R ₂ , R ₃ and Y are described in the description of formula I, is converted into the corresponding compound of formula I, where X is a halogen atom, by diazotization and decomposition of the obtained diazonium salt in the presence of hydrogen halide or the obtained compound of formula I, where X is an amino group, R ₁ , R ₂ , R ₃ and Y are described in the description of formula I, is converted by diazotization and decomposition of the obtained diazonium salt in the presence of phosphoric acid into a compound of the formula I, where X is hydroxy group pa, and / or the resulting compound of formula I, where Y is a hydroxy group, R ₁ , R ₂ , R ₃ and Y are described in the description of formula I, is reacted with an acylating agent to obtain a compound of formula I, where Y is C ₁ - ₃₀ -alkanoiloksigruppu or C ₃ - ₂₂ -alkenoiloksigruppu and / or a resultant base of the formula I is reacted with an inorganic or organic acid to give a pharmaceutically acceptable acid addition salt or a base of the formula I is freed from its acid addition salt with a base. 6. A pharmaceutical composition containing an unsaturated hydroxy acid derivative of the formula I, wherein R ₁ is a C ₁ - ₂₀ alkyl group, a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a C ₁ - ₂ alkyl group, C ₁ - ₂ alkoxy group, halogen atom, amino group, (C _1-4 alkyl) amino group, di (C _1-4 alkyl) amino group or di (C _1-4 alkanoyl) amino group, in addition, R ₁ represents 5- or 6 a membered, saturated or unsaturated heterocyclic group containing one or two nitrogen atoms or a sulfur atom in as a heteroatom, and R ₂ represents a hydrogen atom, or R ₁ forms together with R _{2 a} C _5-7 cycloalkyl group optionally fused to a benzene ring, Y represents a hydrogen atom, a hydroxy group, a C _1-30 alkanoyloxy group or C _3-22 - an alkenyloxy group, X is a halogen atom, a hydroxy group or an amino group, R ₃ represents a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ , where R ₄ and R ₅ are independently a hydrogen atom, C _1-5 -alkyl group, C _1-5 alkanoyl group, or R ₄ and R ₅ form together with the adjacent nitrogen atom a 5- or 6-membered saturated a given or unsaturated heterocyclic group, which may also contain an oxygen atom and may be fused to a benzene ring, where the heterocyclic group and / or benzene ring may be substituted with one or two substituents selected from the group consisting of a C _1-2 alkyl group, C _{1 A -2-} alkoxy group or a halogen atom, or its geometric and / or optical isomers or their pharmaceutically acceptable acid addition salt as an active ingredient and one or more conventional carriers. 7. The pharmaceutical composition according to claim 6, containing a hydroxy acid derivative of the formula I, wherein X is an amino group, Y is a hydroxy group, R ₃ is a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ , where R ₄ and R ₅ independently, C _1-5 alkanoyl group, but one of them may also be a hydrogen atom, or R ₄ and R ₅ form, together with the adjacent nitrogen atom, a 5- or 6-membered saturated or unsaturated heterocyclic group that is condensed with a benzene ring and may also contain an acid sour ode, wherein the heterocyclic group and / or the benzene ring may be substituted with one or two substituents selected from the group consisting of C _1-2 -alkyl, C _1-2 -alkoxy or halogen, and R ₁ represents a C ₁₄ - ₂₀ - an alkyl group, a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, a (C _1-4 alkyl) amino group, di (C _{1- A 4-} alkyl) amino group or a di (C _1-4 alkanoyl) amino group, in addition, R ₁ represents a 5- or 6-membered saturated or an unsaturated heterocyclic group containing one or two nitrogen atoms or a sulfur atom as a heteroatom, and R ₂ is a hydrogen atom or X is a halogen atom or a hydroxy group, Y is a hydrogen atom, a hydroxy group, a C _1-30 alkanoyloxy group or C _3-22 is an alkenoyloxy group, R ₃ is a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ where R ₄ and R ₅ are independently hydrogen, a C _1-5 alkyl group, a C _1-5 alkanoyl group or r ₄ and r ₅ form together with the adjacent nitrogen atom a 5- or 6-membered saturated or unsaturated r terotsiklicheskuyu moiety, which may also contain an oxygen atom and can be condensed with a benzene ring, wherein the heterocyclic group and / or the benzene ring may be substituted with one or two substituents selected from the group consisting of C _1-2 -alkyl, C _1-2 -alkoxy or a halogen atom, R ₁ represents a C _1-20 alkyl group, a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, (C _1-4 -alkyl) amino group, di ( A C _1-4 alkyl) amino group or di (C _1-4 alkanoyl) amino group, in addition, R ₁ is a 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atoms or a sulfur atom as heteroatoms, and R ₂ represents a hydrogen atom, or R ₁ forms together with R ₂ C _{3-5 a} cycloalkyl group optionally fused to a benzene ring, or its geometric isomer and / or optical isomer or their pharmaceutically acceptable acid addition salt as an active ingredient . 8. The pharmaceutical composition according to claim 7, containing a hydroxy acid derivative of the formula I, wherein R ₁ is a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of methyl group, methoxy group or chlorine atom, in addition, R ₁ is 5 or a 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atoms as a heteroatom, R ₂ is a hydrogen atom, X is an amino group, Y is a hydrogen atom or a hydroxy group, R ₃ is a group of the formula —NR ₄ R ₅ , where R ₄ and R ₅ represent, independently of each other, a hydrogen atom, a C _1-5 alkyl group, a C _1-5 alkanoyl group, or R ₄ and R ₅ form together with an adjacent nitrogen atom a 5- or 6-membered a saturated or unsaturated heterocyclic group, or its geometric isomer, and / or optical isomer, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient. 9. The pharmaceutical composition of claim 8, containing a hydroxy acid derivative of the formula I, wherein R ₁ is a pyridyl group or a phenyl group optionally substituted with 1 to 3 methoxy groups, R ₂ is a hydrogen atom, X is an amino group, Y is a hydrogen atom or a hydroxy group, R ₃ denotes a pyrrolidino, piperidino or morpholino group, or its geometric isomer, and / or optical isomer, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient. 10. The use of unsaturated derivatives of hydroxy hydroxy acid of formula I in pharmaceuticals, namely, that a patient suffering from a condition associated with a deficiency of cell energy caused by inhibition of NAD ⁺ -ADP-ribosyltransferase, diabetes complications, conditions of oxygen starvation of the heart and brain, neurodegenerative a disease, an autoimmune or viral disease, a non-toxic amount of an unsaturated hydroxy acid derivative of formula I is prescribed, wherein R ₁ is a C _1-20 alkyl group, phenyl group, optionally optionally substituted by 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, a (C _1-4 alkyl) amino group, di (C _1-4 alkyl) an amino group or a di (C _1-4 alkanoyl) amino group, in addition, R ₁ is a 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atoms or a sulfur atom as a hetero atom, and R ₂ is an atom hydrogen, or R ₁ forms together with R ₂ C _5-7 -tsikloalkilgruppu optionally condensed with a benzene ring, Y Symbol a hydrogen atom, a hydroxy group, C _1-30 or C _3-22 -alkanoiloksigruppu -alkenoiloksigruppu, X - a halogen atom, a hydroxy group or an amino group, R ₃ represents C _3-7 -tsikloalkilgruppu or a group of formula -NR ₄ R _5, where R ₄ and R ₅ represent, independently of each other, a hydrogen atom, a C _1-5 alkyl group, a C _1-5 alkanoyl group, or R ₄ and R ₅ form, together with the adjacent nitrogen atom, a 5- or 6-membered saturated or unsaturated heterocyclic a group that may also contain an oxygen atom and can be condensed with a benzene ring, where the heterocycle nical group and / or the benzene ring may be substituted with one or two substituents selected from the group consisting of C _1-2 -alkyl, C _1-2 -alkoxy or halogen atom, or a geometrical isomer and / or optical isomer or a pharmaceutically acceptable acid addition salt. 11. The use of an unsaturated hydroxy acid derivative of the formula I, wherein R ₁ is a C _1-20 alkyl group, a phenyl group optionally substituted with 1-3 substituents selected from the group consisting of a C _1-2 alkyl group, a C _1-2 alkoxy group, a halogen atom, an amino group, a (C _1-4 alkyl) amino group, a di (C _1-4 alkyl) amino group or a di (C _1-4 alkanoyl) amino group, in addition, R ₁ represents a 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atom or a sulfur atom as the heteroatom, and R ₂ is about Starting hydrogen atom, or R ₁ forms together with R ₂ C _5-7 -tsikloalkilgruppu optionally condensed with a benzene ring, Y represents a hydrogen atom, a hydroxy group, C _1-30 or C _3-22 -alkanoiloksigruppu -alkenoiloksigruppu, X - a halogen atom , hydroxy group or amino group, R ₃ represents a C _3-7 cycloalkyl group or a group of the formula —NR ₄ R ₅ where R ₄ and R ₅ represent, independently of each other, a hydrogen atom, a C _1-5 alkyl group, C _{1- 5-} alkanoyl group, or R ₄ and R ₅ form together with the adjacent nitrogen atom a 5- or 6-membered saturated or unsaturated hetero an icyl group, which may also contain an oxygen atom and can be condensed with a benzene ring, where the heterocyclic group and / or benzene ring can be substituted with one or two substituents selected from the group consisting of a C _1-2 alkyl group, C _1-2 an alkoxy group or an atom of a halogen, or a geometric isomer thereof, and / or an optical isomer, or a pharmaceutically acceptable acid addition salt thereof, to obtain a pharmaceutical composition suitable for treating a condition associated with en-deficiency cell energy caused by inhibition of NAD ⁺ -ADP-ribosyltransferase, diabetes complications, conditions of oxygen starvation of the heart and brain, neurodegenerative diseases, autoimmune and / or viral diseases.