RU2000104007A

RU2000104007A - DERIVATIVES OF ACYLPIPERASINYLPYRIMIDINES, THEIR RECEIVING AND USING AS MEDICINES

Info

Publication number: RU2000104007A
Application number: RU2000104007/04A
Authority: RU
Inventors: АРХОНА Хорди КОРБЕРА; ДОМЕНЕЧ Давид ВАНЬО; КОНСТАНСА Хорди ФРИГОЛА
Original assignee: Лабораторьос Дель Др.Эстев, С.А.
Priority date: 1997-07-21
Filing date: 1998-07-21
Publication date: 2001-10-27

Claims

1. Derived acylpiperidazine pyrimidine General formula

where X represents an oxygen or sulfur atom;
R ₁ is C _1-4 -alkoxy or a trifluoromethyl radical;
R ₂ is a C _1-6 alkyl radical; saturated C _3-6 cycloalkyl; heterocycloalkyl consisting of a ring of 3-6 atoms, the heteroatom of which is chosen from an oxygen, sulfur or nitrogen atom, optionally N-substituted with C ₁ -C ₆ alkyl; phenyl, optionally substituted with 1, 2 or 3 identical or different substituents selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl consisting of a C _1-3 alkyl group substituted by a phenyl radical, optionally substituted with 1, 2 or 3 identical or different substituents selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; a heteroaryl consisting of a 5- or 6-membered heteroaromatic ring, optionally substituted, or of fused heteroaromatic systems, optionally substituted and containing 9 or 10 atoms, 1 or 2 of which are heteroatoms selected from oxygen, sulfur and nitrogen, and the above substituents are selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and heteroarylalkyl consisting of an alkyl group containing from 1 to 3 carbon atoms and substituted by a heteroaryl radical, consisting of a 5- or 6-membered heteroaromatic ring, optionally substituted, or of fused 9-or 10-membered heteroaromatic systems, optionally substituted, with 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, with the aforementioned substituents being selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and its physiologically acceptable salts.

2. The compound according to claim 1, where R ₁ is methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy.

3. The compound according to claim 1, where R ₂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.

4. The compound according to claim 1, where R ₂ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

5. The compound according to claim 1, wherein R ₂ is 2-aziridinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3- piperidinyl or 4-piperidinyl.

6. The compound according to claim 1, wherein R ₂ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitrophenyl 3-nitrophenyl, 4-nitrophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- ( trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2, 3-dibromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimeti lphenyl, 2,4-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl.

7. The compound according to claim 1, where R ₂ is phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, optionally substituted on the aromatic ring.

8. The compound according to claim 1, where R ₂ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-tinyl, 5-methyl-2-thienyl, 3-methoxy-2- thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-indolyl, 3-indolyl, 2-benzo [ b] thienyl, 3-benzo [b] thienyl, 3-chloro-2-benzo [b] thienyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, quinolyl, oxazolyl, or thiazolyl.

9. The compound according to claim 1, where R ₂ is 2-thienylmethyl, 2-benzo [b] thienmethyl or 3- (4-chloropyrazolyl) propyl.

10. The compound according to claim 1, selected from the following group:
2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
2- (4-acetyl-3-piperazinyl) -4-methoxypyrimidine,
2- {4- [4- (4-chloropyrazolyl) butanoyl] -1-piperazinyl} -4-methoxypyrimidine,
2- {4- [4- (4-chloropyrazolyl) butanoyl] -1-piperazinyl} -4-methoxypyrimidine hydrochloride,
2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine,
2- (4-cyclopropylcarbonyl-1-piperazinyl) -4-methoxypyrimidine,
2- [4- (2-furylcarbonyl) -1-piperazinyl] -4- (trifluoromethyl) pyrimidine,
2- [4- (2-thienylcarbonyl) -1-piperazinyl] -4- (trifluoromethyl) pyrimidine,
4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (2-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-chloro-2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-chloro-2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (2-pyrrolylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (2-pyrrolylcarbonyl] -1-piperazinyl) pyrimidine hydrochloride,
4-methoxy-2- [4- (2-thienylacetyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (2-thienylacetyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (3-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (3-Indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-benzo [b] thienylacetyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (5-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (5-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
4-methoxy-2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (4-fluoro-benzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (3-Fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (3-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (2- (fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2- (fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (2- (chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2- (chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (2-tetrahydrofurylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine,
4-methoxy-2- [4- (2-tetrahydrofurylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine hydrochloride,
2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine,
4-methoxy-2- {4- [4- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine,
4-methoxy-2- {4- [4- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride,
4-methoxy-2- {4- [3- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine,
4-methoxy-2- {4- [3- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride,
4-methoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine,
4-methoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride,
4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine,
4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine dihydrochloride,
2- (4-isonicotinoyl-1-piperazinyl) -4-methoxypyrimidine,
2- (4-isonicotinoyl-1-piperazinyl) -4-methoxypyrimidine dihydrochloride,
2- [4- (1-imidazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (1-imidazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- (4-nicotinoyl-1-piperazinyl) -4- (trifluoromethyl) pyrimidine,
2- (4-nicotinoyl-l-piperidazinyl) -4- (trifluoromethyl) pyrimidine hydrochloride,
4-methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine,
4-methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine,
4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-ethoxypyrimidine,
2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-ethoxypyrimidine hydrochloride,
4-ethoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine,
4-ethoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride,
2- [4- (2-methylbenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-methylbenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (4-Fluorobenzoyl) -1-piperazinyl] -4-isopropoxypyrimidine,
2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-isopropoxypyrimidine hydrochloride,
4-isopropoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine,
4-isopropoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride,
2- [4- (3-chloro-2-thienocarbonyl) -1-piperazinyl] -4-isopropoxypyrimidine,
2- [4- (3-chloro-2-thienocarbonyl) -1-piperazinyl] -4-isopropoxypyrimidine hydrochloride,
2- [4- (cyclohexylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (cyclohexylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-ethoxy-2- [4- (4-fluorobenzoyl) -1-piperazinyl] pyrimidine,
4-ethoxy-2- [4- (4-fluorobenzoyl) -1-piperazinyl] pyrimidine hydrochloride,
2- [4- (2-thiazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-aminobenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-aminobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (3-fluoro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (3-fluoro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
2- [4- (4-methoxy-2-pyrimidinyl) -1-piperazinylcarbonyl] benzoic acid,
2- [4- (2-acetoxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (2-hydroxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine,
2- [4- (4-methoxy-2-pyrimidinyl) -1-piperazinylcarbonyl] sodium benzoate,
2- [4- (2-hydroxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride,
4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine and
4-ethoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine.

11. A method of obtaining a compound of the general formula (1) where X represents an oxygen atom according to claim 1, which comprises reacting the chloropyrimidine derivative of formula (III)

where R ₁ matter defined in claim 1,
with a piperazine derivative of the general formula (IV)

where R ₂ is as defined in claim 1, and X represents an oxygen atom, and if necessary, the obtained compound of formula I, where X represents an oxygen atom, by reaction with a Lausson reagent (2,4-bis (4-methoxyphenyl) - 1,3,2,4-dithiadifosphaethano-2,4-disulfonate) or with phosphorus pentasulfide, is converted into a compound of formula I, where X represents a sulfur atom and, optionally, any of the obtained compounds of general formula (I) is converted into its physiologically acceptable salt by reaction with a mineral acid or an organic acid in a suitable solvent e.

12. The method of obtaining compounds of General formula (1) according to claim 1, where X represents an oxygen atom that includes the interaction of the amine of formula (V)

where R ₁ has the meanings defined in claim 1, with a carboxylic acid of the formula R ₂ COOH (VI) or with a salt of the mentioned acid, where R ₂ has the meanings defined in claim 1, and if necessary, the resulting compound of formula I, where X represents an oxygen atom, by reaction with a Lausson's reagent, (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphaethano-2,4-disulfuride) or with phosphorus pentasulfide, is converted to a compound of formula I, where X represents a sulfur atom and, optionally, any of the compounds of the general formula (I) obtained is converted into its physiologically acceptable salt with a mineral acid or organic acid in a suitable solvent.

13. The method of obtaining compounds of General formula (1) according to claim 1, where X represents an oxygen atom that includes the interaction of the amine of formula (V)

where R ₁ has the values defined in claim 1, with the reagent R ₂ COY (VII), where R ₂ has the values defined in paragraph 1, and Y represents a halogen atom, an azide group, an imidazolyl group, an O- group CO-R ₄ , where R ₄ is an alkyl radical containing from 1 to 6 carbon atoms, or an aryl radical, optionally substituted with one or more halogen atoms, or the OR ₅ group, where R ₅ represents an aromatic group or one or two rings substituted one or more halogen atoms or nitro radicals, or N-succinimide, and if necessary, to obtain This compound of formula I, where X represents an oxygen atom, is converted by reaction with a Lausson reagent, (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphaethane-2,4-disulfuride) or with phosphorus pentasulfide. to a compound of formula I, where X represents a sulfur atom and, optionally, any of the compounds obtained by the general formula (I) is converted into its physiologically acceptable salt by reaction with a mineral acid or an organic acid in a suitable solvent.

14. A pharmaceutical composition, characterized in that it contains as an active ingredient an effective amount of at least one compound of general formula (I) or one of its physiologically acceptable salts according to any one of claims 1 to 10, in combination with a pharmaceutically acceptable excipient.

15. The compound of General formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 10 for the manufacture of a drug that is active against the Central nervous system of mammals, including humans.

16. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament having a sedative, anticonvulsant, analgeiating, relaxing muscle, antitusigenic, anxiolytic, antipsychotic, antidepressant, antiischemic for the brain, antimigraine activity and for the manufacture of a medicament for the treatment of sleep disorders, neurodegenerative diseases, cognitive disorders and Alzheimer's disease, sleep induction or general anesthesia for mammals, including humans.