MXPA00000835A - Derivatives of acyl-piperazinil-pyrimidins, preparation thereof and application as medicaments - Google Patents
Derivatives of acyl-piperazinil-pyrimidins, preparation thereof and application as medicamentsInfo
- Publication number
- MXPA00000835A MXPA00000835A MXPA/A/2000/000835A MXPA00000835A MXPA00000835A MX PA00000835 A MXPA00000835 A MX PA00000835A MX PA00000835 A MXPA00000835 A MX PA00000835A MX PA00000835 A MXPA00000835 A MX PA00000835A
- Authority
- MX
- Mexico
- Prior art keywords
- piperazinyl
- methoxy
- hydrochloride
- methoxypyrimidine
- pyrimidine
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 20
- -1 trifluorometyl Chemical group 0.000 claims abstract description 153
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000011780 sodium chloride Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 230000000147 hypnotic Effects 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 230000001624 sedative Effects 0.000 claims abstract description 8
- 210000003169 Central Nervous System Anatomy 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 4
- 239000000932 sedative agent Substances 0.000 claims abstract description 4
- 150000004885 piperazines Chemical class 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000005842 heteroatoms Chemical group 0.000 claims description 9
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 230000000202 analgesic Effects 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 125000004434 sulfur atoms Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 239000003193 general anesthetic agent Substances 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 239000003158 myorelaxant agent Substances 0.000 claims description 5
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 230000001773 anti-convulsant Effects 0.000 claims description 4
- 239000001961 anticonvulsive agent Substances 0.000 claims description 4
- 125000004429 atoms Chemical group 0.000 claims description 4
- 150000002829 nitrogen Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical class ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- CFHGBZLNZZVTAY-UHFFFAOYSA-N Lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 3
- 230000000949 anxiolytic Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 2
- 206010057668 Cognitive disease Diseases 0.000 claims description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N Phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 2
- 206010040984 Sleep disease Diseases 0.000 claims description 2
- OSLQMALCAFWODX-UHFFFAOYSA-N [4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]-phenylmethanethione Chemical compound COC1=CC=NC(N2CCN(CC2)C(=S)C=2C=CC=CC=2)=N1 OSLQMALCAFWODX-UHFFFAOYSA-N 0.000 claims description 2
- FTZPBBKANJNASG-UHFFFAOYSA-N [4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]-phenylmethanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC=CC=2)=N1 FTZPBBKANJNASG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000000954 anitussive Effects 0.000 claims description 2
- 230000001430 anti-depressive Effects 0.000 claims description 2
- 230000000561 anti-psychotic Effects 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 239000002249 anxiolytic agent Substances 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000002490 cerebral Effects 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000002995 2-(trifluoromethyl)benzoyl group Chemical group FC(C1=C(C(=O)*)C=CC=C1)(F)F 0.000 claims 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 3
- APCAJUMMGVKSCW-UHFFFAOYSA-N (4-pyrimidin-2-ylpiperazin-1-yl)-[2-(trifluoromethyl)phenyl]methanone Chemical compound FC(F)(F)C1=CC=CC=C1C(=O)N1CCN(C=2N=CC=CN=2)CC1 APCAJUMMGVKSCW-UHFFFAOYSA-N 0.000 claims 2
- 125000002999 4-(trifluoromethyl)benzoyl group Chemical group FC(C1=CC=C(C(=O)*)C=C1)(F)F 0.000 claims 2
- YUCCVPXRYJRDNZ-UHFFFAOYSA-N [4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]-(5-methylthiophen-2-yl)methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2SC(C)=CC=2)=N1 YUCCVPXRYJRDNZ-UHFFFAOYSA-N 0.000 claims 2
- 230000002460 anti-migraine Effects 0.000 claims 2
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims 2
- XEHFVPPGVYDARR-UHFFFAOYSA-N (2-aminophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C(=CC=CC=2)N)=N1 XEHFVPPGVYDARR-UHFFFAOYSA-N 0.000 claims 1
- QUKFWFGKFSRPQY-UHFFFAOYSA-N (2-fluorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C(=CC=CC=2)F)=N1 QUKFWFGKFSRPQY-UHFFFAOYSA-N 0.000 claims 1
- XAEAFOPJORAPHJ-UHFFFAOYSA-N (2-hydroxyphenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C(=CC=CC=2)O)=N1 XAEAFOPJORAPHJ-UHFFFAOYSA-N 0.000 claims 1
- SOVYNQTYKPMCQS-UHFFFAOYSA-N (2-methoxyphenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.COC1=CC=NC(N2CCN(CC2)C(=O)C=2C(=CC=CC=2)OC)=N1 SOVYNQTYKPMCQS-UHFFFAOYSA-N 0.000 claims 1
- CCZSIFVCYJSMLQ-UHFFFAOYSA-N (3-chlorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=C(Cl)C=CC=2)=N1 CCZSIFVCYJSMLQ-UHFFFAOYSA-N 0.000 claims 1
- KXBBLUDPDRZVTR-UHFFFAOYSA-N (3-chlorothiophen-2-yl)-[4-(4-ethoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.CCOC1=CC=NC(N2CCN(CC2)C(=O)C2=C(C=CS2)Cl)=N1 KXBBLUDPDRZVTR-UHFFFAOYSA-N 0.000 claims 1
- IKPTYEDWQZPHHD-UHFFFAOYSA-N (3-chlorothiophen-2-yl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C2=C(C=CS2)Cl)=N1 IKPTYEDWQZPHHD-UHFFFAOYSA-N 0.000 claims 1
- CDCBAMNRVHFHJO-UHFFFAOYSA-N (3-chlorothiophen-2-yl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.COC1=CC=NC(N2CCN(CC2)C(=O)C2=C(C=CS2)Cl)=N1 CDCBAMNRVHFHJO-UHFFFAOYSA-N 0.000 claims 1
- QFVRBMCQVTUKJK-UHFFFAOYSA-N (3-chlorothiophen-2-yl)-[4-(4-propan-2-yloxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound CC(C)OC1=CC=NC(N2CCN(CC2)C(=O)C2=C(C=CS2)Cl)=N1 QFVRBMCQVTUKJK-UHFFFAOYSA-N 0.000 claims 1
- CYSRJEZGDRYBHZ-UHFFFAOYSA-N (3-fluorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=C(F)C=CC=2)=N1 CYSRJEZGDRYBHZ-UHFFFAOYSA-N 0.000 claims 1
- GIOFVHWSBGMPJT-UHFFFAOYSA-N (3-methoxyphenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC(C(=O)N2CCN(CC2)C=2N=C(OC)C=CN=2)=C1 GIOFVHWSBGMPJT-UHFFFAOYSA-N 0.000 claims 1
- COZIABXQRYUDTN-UHFFFAOYSA-N (4-chlorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC(Cl)=CC=2)=N1 COZIABXQRYUDTN-UHFFFAOYSA-N 0.000 claims 1
- ZEHGGXZSLAIMNS-UHFFFAOYSA-N (4-chlorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC(Cl)=CC=2)=N1 ZEHGGXZSLAIMNS-UHFFFAOYSA-N 0.000 claims 1
- YGFKQKNWPIFDAT-UHFFFAOYSA-N (4-fluorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC(F)=CC=2)=N1 YGFKQKNWPIFDAT-UHFFFAOYSA-N 0.000 claims 1
- GKERILVZNUMMJN-UHFFFAOYSA-N (4-fluorophenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone;hydrochloride Chemical compound Cl.COC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC(F)=CC=2)=N1 GKERILVZNUMMJN-UHFFFAOYSA-N 0.000 claims 1
- GWOPRVSTEXYZKZ-UHFFFAOYSA-N (4-fluorophenyl)-[4-(4-propan-2-yloxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound CC(C)OC1=CC=NC(N2CCN(CC2)C(=O)C=2C=CC(F)=CC=2)=N1 GWOPRVSTEXYZKZ-UHFFFAOYSA-N 0.000 claims 1
- GEMJZJQUELTYJN-UHFFFAOYSA-N (4-methoxyphenyl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound C1=CC(OC)=CC=C1C(=O)N1CCN(C=2N=C(OC)C=CN=2)CC1 GEMJZJQUELTYJN-UHFFFAOYSA-N 0.000 claims 1
- CVTVGRRTTYVCTR-UHFFFAOYSA-N (5-chlorothiophen-2-yl)-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]methanone Chemical compound COC1=CC=NC(N2CCN(CC2)C(=O)C=2SC(Cl)=CC=2)=N1 CVTVGRRTTYVCTR-UHFFFAOYSA-N 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
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- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
- 230000000506 psychotropic Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002868 serotonin 5-HT1 receptor antagonist Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Abstract
The derivatives of acyl-piperazinil-pyrimidins having a general formula (1), wherein X is O or S, R1 is alcoxy or trifluorometyl, R2 is alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl are useful for the treatment of the central nervous system. The compounds (1) wherein X is O are obtained by reaction of a derivative of pirimidin with a derivative of piperazine or by reaction of a derivative of piperazine-pyrimidin with a carboxylic acid or a salt or derivativethereof. The compounds (1) wherein X is S can be obtain by reaction of (1) wherein X is O with the Lawesson reactive or with phosphores pentalsulfide. The compounds (1) have a sedative, anticonvulsive, hypnotic or general anesthesic activity and can be used in human and/or animal medicine.
Description
DERIVATIVES OF ACIL-PIPERAZINIL-PYRIMIDINAS, ITS PREPARATION AND ITS APPLICATION AS MEDICINES
FIELD OF THE INVENTION
The present invention relates to novel acyl-piperazinyl-pyrimidines of general formula (1), as well as to their physiologically acceptable salts, to processes for their preparation, to their application as medicaments in human and / or veterinary therapeutics and to pharmaceutical compositions. that contain them
(D) The novel compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicines.
BACKGROUND OF THE INVENTION
In our patents EP 382 637 and EP 497 659 we have described various derivatives of alkyl piperazinyl-pyrimidines, of general formula (2) with anxiolytic and / or tranquilizing properties.
( 2 )
European Patent EP-0 115 713 refers to (piperazinyl-1) -2-pyrimidines, with substituents at the 4-position of piperazine, consisting of an alkylcarbonyl group, alkylcarbonyl substituted by an amino or substituted amino group, an alkylcarboxylic group or alkylcarboxylate, or a substituted carbonylalkyl group, which has psychotropic activity by a dopaminergic mechanism. The PCT application WO 94/14779 refers to (piperazinyl-1) -4-pyrimidines, with substituents at the 4-position of piperazine, consisting only of linear or branched alkyl chains of up to 4 carbon atoms, optionally ending with a phenyl group which can be substituted, having 5-HT 1 receptor antagonist activity and which can be used in the treatment or prevention of disorders related to excessive vasodilation. U.S. Patent 4,547,505 relates to novel pharmacologically active compounds, the general formulation of which includes a piperazine, wherein one of the nitrogen atoms is replaced by the groups called pyrimidine or others, and the other nitrogen atom is replaced by a group substituted acyl, and which has analgesic activity. We have now discovered that the introduction of a substituent at the 4-position of the pyrimidine and the substitution of an alkyl radical with an acyl radical gives rise to the novel compounds of the general formula (1). Said compounds have useful biological properties and make them especially useful for their use in human and / or veterinary therapeutics. The compounds object of this invention are useful as agents with activity in the central nervous system in mammals including man. In particular, the new compounds are useful as sedatives, anticonvulsants, hypnotics and general anesthetics.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the results of the sedative activity of some compounds of this invention, determined by a decrease in locomotor activity.
PETAL DESCRIPTION OF THE INVENTION
The present invention provides new compounds capable of causing conscious sedation, of acting as hypnotic agents, anticonvulsants, analgesics, muscle relaxants, antitussives, anxiolytics, antipsychotics, antidepressants, cerebral anti-ischemic agents, antimigraine agents, useful agents for sleep disorders, agents for diseases neurodegenerative, for cognitive disorders and Alzheimer's disease, and agents capable of inducing or maintaining general anesthesia, attending to the dose and route of administration. The compounds object of the present invention correspond to the general formula (1)
(1) where X is an oxygen or sulfur atom; Ri is a C.sub.1 -C or trifluoromethyl alkoxy radical; R2 is a C-C6 alkyl radical; C3-C saturated cycloalkyl; heterocycloalkyl consisting of a ring of 3 to 6 atoms comprising a heteroatom selected from an oxygen, sulfur and nitrogen atom, optionally N-substituted; phenyl optionally substituted by 1, 2 or 3 identical or different substituents selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl constituted by a C3 alkyl group substituted by a phenyl radical optionally substituted by 1, 2 or 3 equal or different substituents selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy;
heteroaryl consisting of an optionally substituted 5-membered or 6-membered heteroaromatic ring or fused, optionally substituted heteroaromatic systems of 9 to 10 members consisting of 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, said substituents being selected from fluorine, chlorine , bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and heteroarylalkyl constituted by an alkyl group of 1 to 3 carbon atoms substituted by a heteroaryl radical consisting of an optionally substituted heteroaromatic ring; of 5 or 6 members or by fused heteroaromatic systems, optionally substituted, from 9 to 10 members consisting of 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, said substituents being selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl , trifluoromethyl and methoxy; and their pharmaceutically acceptable salts. In the present invention the term, "alkoxy" C.-C represents a radical OR3 in which R3 is a straight or branched saturated carbon chain of 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy , sec-butoxy or tert-butoxy. The term "alkyl" represents a radical derived from a straight or branched chain saturated hydrocarbon. The term "alkyl" C.-C6 represents a straight or branched chain alkyl radical including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl, neopentyl and hexyl.
The term "C3-Cβ saturated cycloalkyl" represents a saturated 3 to 6 carbon ring, such as for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "heterocycloalkyl" represents a ring of 3 to 6 atoms including a heteroatom such as an oxygen atom or a sulfur atom, such as for example a radical 2-aziridinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, -tetrahydrothienyl, 3-tetrahydrothienyl, or an N-substituted or unsubstituted nitrogen atom, such as for example 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinolyl, 3-piperidinyl or 4-piperidinyl. The term "aryl" represents a phenyl radical unsubstituted or substituted by 1, 2 or 3 same or different substituents such as fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy, such as 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-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- (thluoromethyl) phenyl, - (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,3-difluorophenyl, 3 , 4-difluorophenyl, 2,4-difluorophenyl, 2,3-dibromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,3 -methoxyphenyl, 3,4-dimethoxy phenyl or 2,4-dimethoxyphenyl. The term "arylalkyl" represents a straight or branched chain of 1 to 3 carbon atoms and which is substituted by an aryl radical, defined above as the term "aryl", and which includes substituents such as phenylmethyl, 1-phenylethyl, 2-phenylethyl , 3-phenylpropyl, as well as other radicals in which the aromatic ring is substituted by groups such as fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy. The term "heteroaryl" represents a substituted or unsubstituted heteroaromatic ring of 5 or 6 members or substituted or unsubstituted fused heteroaromatic systems of 9 to 10 members consisting of 1 or 2 heteroatoms such as nitrogen, oxygen or sulfur, the substituents being such groups as fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy, such as 2-fuhlo, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 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-benzo [b] thienyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, quinolyl, oxazolyl and thiazolyl. The term "heteroarylalkyl" represents an alkyl group of 1 to 3 carbon atoms and is substituted by a heteroaryl radical, defined above as a term "heteroaryl" and which includes substituents such as 2-thienylmethyl, 2-benzo [b] thienylmethyl and 3- (4-chloropyrazolyl) propyl. The new compounds of general formula (1) may possess an asymmetric carbon atom and can therefore be prepared as optical isomers or recemates. The racemates of the compounds (1) can be resolved in their optical isomers by conventional methods, such as for example separation by chiral chromatography or by fractional crystallization of their diastereomeric salts. Likewise, they can also be obtained by asymmetric synthesis using chiral precursors. The present invention also relates to the physiologically acceptable salts of the compounds of the general formula (1), in particular the addition salts of mineral acids such as hydrochloric, bromohydric, phosphoric, sulfuric, nitric acid and with organic acids such as p-toluenesulfonic or methanesulfonic acid. The new derivatives of the general formula (1), in which X is an oxygen atom and R. and R2 have the meaning indicated above, can be prepared according to the methods A or B indicated below:
Method A: The compounds of general formula (1) can be prepared by reaction of the chloropyrimidine derivative (3), where R has the meaning indicated above, with a piperazine derivative of general formula (4), wherein X and R2 they have the meaning indicated above.
(3) (4) (1) The reaction is carried out in an organic solvent, such as for example a chlorinated organic hydrocarbon such as dichloromethane or chloroform, a linear or cyclic ether such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aprotic polar solvent such as pyridine, dimethisulfoxide or dimethylformamide or any other suitable solvent to effect a nucleophilic aromatic substitution reaction. The reaction can be carried out in the presence of a mineral or organic base such as an aliphatic amine, preferably triethylamine or N-methylmorpholine and is stirred at a temperature between room temperature and the boiling point of the solvent for a period between ten minutes and twenty-four hours, with the period between thirty minutes and five hours being the preferred conditions.
Method B: By reaction of the amine of formula (5):
(5) in which R. has the meaning indicated above with a carboxylic acid of the general formula R2COOH (6), in which R2 has the meaning indicated above, either with a salt of this same acid or also with a reactive derivative R2COY (7).
(5) (1)
Examples of salts include alkali metal salts such as the sodium salt and the potassium salt, alkaline earth salts such as the calcium salt and the magnesium salt, the ammonium salt, and salts of organic bases such as triethylamine, trimethylamine, pyridine and picoline. Examples of reactive derivatives of the general formula R2COY (7) in which Y is a halogen atom, preferably a chlorine atom or a bromine atom, an azido group (-N3), a 1-imidazolyl group, an O- group CO-R, wherein R can be an alkyl radical of 1 to 6 carbon atoms or aryl, preferably substituted by one or more halogen atoms, or a group OR 5 where R 5 represents an aromatic group of one or two rings substituted by one or more halogen atoms or nitro radicals, with 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl, pentafluorophenyl, 1-benzotriazolyl or N-succinimide being preferred. Also, instead of using the mentioned reactive derivatives mentioned above, the compounds of general formula (1) can be prepared directly by reaction of the amine (5) with the carboxylic acid of the general formula R2COOH (7), preferring in this case that the The reaction proceeds in the presence of activating reagents of carbonyl groups such as N.N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide or 3- (3-dimethylamino) propyl-1-ethylcarbodiimide. This reaction can also be carried out using the carbodiimides mentioned in the presence of 1-benzotriazole or N-hydroxysuccinimide. The acids of the general formula (7) and the amine of the formula (5) also react directly in the presence of N, N'-carbonyldiimidazole or of the propanephosphonic acid anhydride. The reaction is carried out in an organic solvent, such as for example a chlorinated organic hydrocarbon such as dichloromethane or chloroform, a linear or cyclic ether such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a polar aprotic solvent such as pyridine, dimethylsulfoxide or dimethylformamide or any other suitable solvent. The reaction can be carried out in the presence of a mineral or organic base such as an aliphatic amine, preferably triethylamine or N-methylmorpholine and is stirred at a temperature between room temperature and the boiling point of the solvent for a period between ten minutes and twenty-four hours, with the period between thirty minutes and five hours being the preferred conditions.
Method C: The new derivatives of general formula (1), in which X is a sulfur atom and R. and R2 have the meaning indicated above, can be prepared according to the following method: By treatment of a compound of general formula (1), in which Ri and R2 have the meaning indicated above and in which X is an oxygen atom, with Lawesson's reagent (2,4-bis (4-methoxyphenol) -1, 3,2,4-dithiadiphosphaetane-2,4-disulfide) or with phosphorus pentasulfide, the corresponding thioamides are obtained in which X is a sulfur atom:
The reaction is carried out in an organic solvent such as toluene, benzene, heptane, pyridine or tetrahydrofuran. The reaction is maintained under stirring at a temperature between room temperature and the boiling point of the solvent for a period of between one hour and twenty-four hours, it being preferable to carry out the reaction at 80 ° C and for a period of between one hour and sixteen hours
Method D: The salts of the compounds of general formula (1) are prepared by reaction with a mineral acid such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acid or with an organic acid such as p-toluenesulfonic acid or meta nsulf ion in an appropriate solvent such as methanol, ethanol, ethyl ether, ethyl acetate, acetonitrile or acetone obtaining the corresponding salts with the usual precipitation or crystallization techniques. The invention provides pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable excipient, at least one compound of general formula (1) or one of its physiologically acceptable salts. The invention also relates to the use of a compound of general formula (1) and its physiologically acceptable salts in the preparation of a medicament with activity on the central nervous system in mammals, including man, particularly in the manufacture of a medicament with sedative, anticonvulsant, hypnotic and general anesthetic activity. In the following examples, the preparation of new compounds according to the invention is indicated. Some typical forms of use are also described for the different fields of application, as well as galenic formulas applicable to the compounds of the invention.
Method A:
EXAMPLE 1 Preparation of 2-r4- (2-furcarbonyl) -1-piperazinyl-4-mexoti-pyrimidine
A solution of 1.0 g (6.92 mol) of 2-chloro-4-methoxypyrimidine, 1.49 g (8.30 mmol) of 1- (2-fuhlcarbonyl) piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 ml of n-butanol was added. Maintains gentle reflux overnight. The solvent is evaporated under pressure and the resulting crude is diluted in chloroform and washed with water. The organic phase is dried with S0 Na2 and evaporated to dryness obtaining a crude product which is purified by chromatography on silica gel using ethyl acetate / petroleum ether 70:30 as eluent, yielding an oil that solidifies on standing. The solid is suspended in petroleum ether to obtain 1.4 g (4.86 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine. p.f. = 85-86 ° C.
Method B:
EXAMPLE 3 Preparation of 4-methoxy-2-f4- (2-thienylcarbonyl) -1-piperazine-pyrimidine
A solution of 1.0 g (5.15 mmol) of 4-methoxy-2- (1-piperazinyl) pyrimidine and 1 ml (7.18 mmol) of triethylamine in 30 ml of CH2Cl2 is cooled to 0 ° C and 0.76 g is slowly added ( 5.18 mmol) of 2-thienylcarbonyl chloride. The solution is kept at 0 ° C for one hour and allowed to rise to room temperature. The organic phase is washed with H2O, dried under Na 2 SO and the solvent is removed under reduced pressure. The resulting crude is dissolved in ethyl ether by crystallizing 1.0 g (3.28 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine. p.f. = 71-73 ° C
EXAMPLE 12 Preparation of 4-methoxy-2-r4- (3-thienylcarbonyl) -1-piperazinnillpyrimidine
To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 ml (7.86 mmol) of triethylamine in 30 ml of CH2Cl2 cooled to 0 ° C is added 0.84 g (7.81 mmol) of ethyl chloroformate. The mixture is kept at 0 ° C for 20 minutes and 1.5 g (7.81 mmol) of 4-methoxy-2- (1-piperazinyl) pyrimidine dissolved in 10 ml of CH 2 Cl 2 is added thereto. Allow to rise to room temperature and keep stirring for 2 hours and the organic phase is washed with H20, dried with SO4Na2 and the solvent is evaporated under reduced pressure. The resulting oil is treated with ethyl ether yielding a solid which is recrystallized from ethanol / H2O to obtain 0.8 g (2.63 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pihmidine. p.f. = 90-92 ° C.
EXAMPLE 20 Preparation of 2-r4- (2-indolylcarbonyl) -1 -pinerazinyl-4-methoxypyrimidine
To a solution of 0.83 g (5.15 mmol) of the indole-2-carboxylic acid in 15 ml of dry THF is added 0.83 g (5.15 mmol) of N, N'-carbonyldiimidazole. After 30 minutes a solution of 1.0 g (5.15 mmol) of 4-methoxy-2- (1-piperazinyl) pihmidine is added and left stirring at room temperature overnight. The solvent is removed under reduced pressure and H2O is added, forming a precipitate that is filtered and dried, yielding 1.7 g (5.04 mmol) of 2- [4- (2-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine. p.f. = 202-203 ° C.
Method C
EXAMPLE 54 Preparation of 4-methoxy-2- (4-thiobenzoyl-1-piperazine-D-pyrimidine
Dissolve 0.56 g (1.9 mmol) of 2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine in 25 mL of dry toluene, add 0.46 g (1.14 mmol) of Lawesson's reagent (2,4-bis) (4-methoxyphenyl) -1,2,2,4-dithiadiphosphaetane-2,4-disulfide) and the mixture is heated at 80-90 ° C for 16 hours. Ethyl ether is added, washed with basic H 2 O and the organic extract is dried with SO 4 Na 2 and evaporated under reduced pressure. The resulting crude is crystallized with ethyl ether-petroleum ether to obtain 160 mg (0.5 mmol) of 2- (4-thiobenzoyl-1-piperazinyl) -4-methoxypyrimidine. m.p. = 125-129 ° C.
Method D
EXAMPLE 2 Preparation of 2-r4- (2-furylcarbonyl) -1-piperazinyl-4-methoxypyrimidine hydrochloride
Dissolve 1.0 g (3.47 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxy-pyrimidine in ethyl acetate and add a few drops of ethyl ether / hydrochloric acid solution. obtaining a precipitate that is filtered and dried, yielding 1.07 9 (3.29 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride. p.f. = 162-164 ° C.
EXAMPLE 4 Preparation of 4-methoxy-2-r4- (2-thienylcarbonyl) -1- piperazinylpyrimidine hydrochloride
Dissolve 1.0 g (3.29 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine in acetone and add a few drops of ethanol / hydrochloric acid solution, obtaining a precipitate which filter and dry, yielding 1.05 g (3.08 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride. mp = 143-145 ° C.
EXAMPLE 13 Preparation of 4-methoxy-2-r4- (3-thienylcarbonyl) -1- piperazinylpyrimidine hydrochloride
0.8 g (2.63 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-pperazinyl] pyrimidine are dissolved in ethanol, a few drops of ethanol / HCl and ethyl ether are added forming a precipitate which it is filtered and dried, obtaining 0.6 g (1.76 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride. p.f. = 154-156 ° C.
NJ
NJ
NJ CTi
NJ
4- > OR
Hypnotic activity in mice The hypnotic activity of the products of the invention has been studied by determining their ability to potentiate the sleep time induced by barbital, according to a modification of the method described by David Sudgen (J. Pharmacol. Exp. Ther. , 1983, 227, 3). After fifteen minutes of administration of barbital (150 mg / kg, i.v.), the mice were treated with the product under study at an initial dose of 100 mg / kg (i.p.). Of the most active products, the effective dose 50 (ED50) was determined. Table 2 shows the results of some of the products object of this invention taking the meprobamate as reference standard.
TABLE 2: Potentiation of barbital-induced hypnosis
Example% Activity (hypnosis) DE5Q Dose 100 mg / kg a a /
2 93 14.4 4 100 8.7 8 97 9.7 9 67 28.1 10 74 11.6 11 89 10.5 13 77 41.3 15 86 8.2 17 56 84.2 18 82 27.3 22 57 75 24 69 41.5 26 60 74.1 30 75 37.2 32 73 56.5 34 98 7 55 70 31 57 100 1,6 59 101 14 61 102 4,5 63 103 4 65 100 7,7 67 96 15 69 97 10 73 98 9,5 81 99 8,3 83 100 5,3 87 101 10 89 102 8 91 81 10 92 98 8 94 84 5.2 96 97 3
Meprobamate 54 84.5 General anesthetic activity General anesthetic activity was studied in mice, injecting the product under study into the caudal vein. The onset and duration of sleep time was determined. The results for some of the products covered by this patent are shown in Table 3 and are shown to have a clear anesthetic activity in relation to the reference standard (Propofol), with subsequent recovery of the animals.
TABLE 3 Anesthetic activity in mice. Administration i.v.
Sedative activity Sedative activity has been studied by the effect of some products on locomotor activity in mice at different doses. The technique described by T.G. Heffneren J. Pharm. Exp. Ther., 1989, 251, 105-112. The measurement of the locomotor activity was carried out by placing the mice in groups of four and automatically determining the movement of the animals through a video installation and the SMART program (Leticia S.A.) of image analysis. The measurement of the activity was started 5 minutes after the administration of the product by i.p. and it was carried out for 20 minutes. The results (figure 1) demonstrate the sedative effect of the compounds tested.
Muscle relaxing activity The muscle relaxant activity of the products of the invention has been studied by assessing their effect on the body tone and abdominal tone of the rats, following the method described by S. IRWING (Gordon Res. Conf. On Medicinal Chem, 1959, p 133). The rats received the products under study at the dose of 80 mg / kg, ip, and at different times after administration (1/2, 1, 2, 3, 4 and 5 hours) body tone and tone were evaluated. abdominal assessing muscle tension compared to control animals. The results reported in Table 4 show that many of the products have a remarkable muscle relaxant activity, this effect being longer than that of propofol or zolpidem, taken as reference products.
TABLE 4 Myorelaxant activity in the rat Irwing test.
GDOSIS = 80 mg / kq, i.p.l
Muscle Relaxation% to an Example time of 1 / 2H. 1 HOUR. 2H. 3H. 4H. 5H. 4 100 90 10 0 0 0 34 60 70 80 85 40 40 57 100 100 100 80 55 0 63 100 100 90 75 20 0 71 100 100 100 40 10 0 73 100 100 100 0 0 0 75 100 100 100 80 80 60 77 100 100 100 60 0 0 79 100 100 100 65 0 0 83 90 90 90 70 50 0 92 100 100 100 0 0 0 Propofol 100 100 70 0 0 0
Analgesic activity The analgesic activity of the products object of the invention has been studied by evaluating their effect in the test of contortions induced by phenylbenzoquinone in mouse, following the method described by Siegmund, E., et al. (Prog. Soc. Exp. Med. 1957, 95: 729-731). The mice received the products under study, at different dose levels, and 1 hour later they received an i.p. of 5 mg / kg of phenylbenzoquinone. The contortions of the mice were recorded during the following 15 minutes and compared with the contorsions of the control group. Table 5 shows that of DE-50 (effective dose 50) of the compound of example 4, which showed a greater analgesic activity than aspirin, whether administered subcutaneously or orally.
TABLE 5. Analgesic activity. Protection of the contorsions induced by phenylbenzoquinone in mice.
Example De-50 (mq / kq s.c.) DE-50 (mq / kq, p.o.) Aspirin 84 120 4 48 72
Pharmaceutical formulations 1. Injectable route (im / iv):
Example compound 4 5 mg Sodium chloride is. 0.1 N HCl 0.1 N NaOH is. Water for injection c.s.p 3 ml
2. - Capsules
Compound of Example 4 0.5 to 4.0 mg Colloidal Silicon Dioxide 0.5 mg Magnesium Stearate 1.0 mg Lactose c.s.p. 100 mg
3. Tablets
Compound of Example 4 0.5 to 4.0 mg
Colloidal Silicon Dioxide 0.5 mg Magnesium stearate 1.0 mg Croscarmellose sodium 60 mg Lactose c.s.p 100 mg
Formula B / wet granulation)
Example compound 4 0.5 to 4.0 mg
Colonial Silicon Dioxide 0.5 mg
Magnesium stearate 1.0 mg
Povidone K-30 5.0 mg Carboxymethyl 2 sodium starch 5.0 mg Microcrystalline cellulose 20 mg
Lactose c.s.p 100 mg
Claims (18)
1. - An acyl-piperazinyl-pyrirmidine derivative of the general formula (1) (1 ) where X is an oxygen or sulfur atom; R. is an alkoxy C radical. - C or trifluoromethyl; R 2 is a C 6 C alkyl radical; saturated C3-C6 cycloalkyl; heterocycloalkyl consisting of a ring of 3 to 6 atoms comprising a heteroatom selected from an oxygen, sulfur and nitrogen atom, optionally N-substituted; phenyl optionally substituted by 1, 2, or 3 equal or different substituents selected from fluorine, chlorine, bromine, amino, acetamino, nitro, methyl, trifluoromethyl and methoxy; arylalkyl constituted by a C-C3 alkyl group substituted by a phenyl radical optionally substituted by 1, 2, or 3 equal or different substituents selected from fluorine, chlorine, bromine, amino, acetamino, nitro, methyl, trifluoromethyl and methoxy; heteroaryl consisting of a heteroaromatic ring, optionally substituted, of 5 or 6 members or by fused heteroaromatic systems, optionally substituted, of 9 to 10 members consisting of 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, heteroatoms selected from oxygen, sulfur and nitrogen, said substituents being selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and heteroarylalkyl constituted by an alkyl group of 1 to 3 carbon atoms substituted by a heteroaryl radical consisting of a heteroaromatic ring, optionally substituted, of 5 or 6 members or by fused heteroaromatic systems, optionally substituted, from 9 to 10 members constituted by 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, said substituents being selected from fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and their physiologically acceptable salts.
2. A compound according to claim 1, wherein R. is a methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy.
3. A compound according to claim 1, wherein R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.
4. A compound according to claim 1, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
5. A compound according to claim 1, wherein R2 is 2-aziridinyl, 2-tetrahydrofluoryl, 3-tetrahydrofuryl, 2-tetrahydrothieno, 3-tetrahydrothienyl, 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl , 2-piperidinyl, 3-piperidinyl or 4-piperidinyl.
6. - A compound according to claim 1, wherein R2 is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, -aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acothamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenium , 3-methylphenyl, 4-methylphenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 3, 4-dichlorophenyl, 2,4-dichlorophenyl, 2,3-difluorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 2,3-dibromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,3- dimethylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl or 2,4-dimethoxyphenyl.
7. A compound according to claim 1, wherein R2 is phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, optionally substituted on the aromatic ring.
8. A compound according to claim 1, wherein R2 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 3-methoxyl. -2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pihodyl, 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. A compound according to claim 1, wherein R2 is 2-thienylmethyl, 2-benzo [b] thienylmethyl or 3- (4-chloropyrazolyl) propyl.
10. - A compound according to claim 1, selected from the following group: * 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypihmidine, 2- [4- (2-furylcarbonyl) hydrochloride ) -1-piperazinyl] -4-methoxypyrimidine, * 4-methoxy-2- [4- (2-t-phenylcarbonyl) -1-piperazinyl] pyrimidine, * 4-methoxy-2-hydrochloride [4- (2-thienylcarbonyl) -1-piperazinylpi midina, * 2- (4-acetyl-1-piperazinyl) -4-methoxypyrimidine, * 2-. { 4- [4- (4-chloropyrazolyl) butanoyl} -1-piperazinyl} 4-methoxypyrimidine, 2- hydrochloride. { 4- [4- (4-chloropyrazolyl) butanoyl] -1-piperazinyl} -4-methoxy-pyrimidine, * 2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine, * 2- (4-cyclopropylcarbonyl-1-piperazinyl) -4-methoxy-pyrimidine, * 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4- (trifluoromethyl) pihmidine, * 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazine] pihminidine, * 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyljpyrimidine hydrochloride, * 2- [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, Allohydrate 2 - [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, * 4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyljpihmidine, * hydrochloride 4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyljpyrimidine, * 2- [4- (2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, * hydrochloride 2- [4- (2-Benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, * 2- [4- (2-indolylcarbonyl) -1-piperazinyl] -4-methoxy-phemidine, * 2- [ 4- (3-chloro-2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyridine, 2- [4- (3-chloro-2-benzo [b] thienylcarbonyl) hydrochloride) -1-pipera zinyl] -4-methoxypyrimidine, * 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] pihmidine, * 4-methoxy-2- [4- (2-thienylacetyl) -1-piperazinyljpyrimidine hydrochloride, * 2- [4- (3-methyl-2-thienylcarbonyl ) -1-piperazinyl) -4-methoxy-phemidine, 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-yl); ndolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, * 2- [4- (3-benzo [b] thienylacetyl) -1-piperazinyl] -4-methoxypymidine, * 2- [4- (5-chloro- 2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (5-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxyphemidine hydrochloride, * 4- methoxy-2- [4- (4-methoxybenzoyl) -1-piperazinyl] pyrimidine, * 4-methoxy-2- [4- (4-methoxybenzoyl) -1-piperazinyljpyrimidine hydrochloride, * 2 - [4- (4-fluorobenzoyl) -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-methoxy-pyrimidine hydrochloride, * 4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyl] pyrimidine, * 4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyljpyrimidine hydrochloride, * 2- [4- (33-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-pperazinyl] -4-methoxypyrimidine hydrochloride, * 4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pihmidine, * 4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pyrimidine hydrochloride, * 2- [4- (2-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, * hydrochloride 2- [4- (2-fluorobenzoyl) -1-piperazinyl] -4-methoxy-pyrimidine, * 2- [4- (2-chlorobenzoyl) -1-p-piperazinyl] -4-methoxypyr Mdina, 2- [4- (2-chlorobenzoyl) -1- piperazinyl] -4-methoxypyrimidine hydrochloride, * 4-methoxy-2- [4- (2-tetrahydrofurylcarbonyl) -1- piperazinyljpyrimidine, * 4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine, * 4-methoxy-2- [4- (2-tetrahydrofurylcarbonyl) -1-piperazinyljpyrimidine hydrochloride, 4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine hydrochloride, 2- (2-hydrochloride 4-benzoyl-1-piperazinyl) -4-methoxypyrimidine, * 4-methoxy-2-. { 4- [4- (trifluoromethyl) benzoyl] -1-piperazinyl] pyrimidine, * 4-methoxy-2- hydrochloride. { 4- [4- (Trifluoromethyl) benzoyl] -1-piperizinyl) pyrimidine, * 4-methoxy-2-. { 4- [3- 8-trifluoromethyl) benzoyl} -1-piperazinyl} pihmidine, * 4-methoxy-2-hydrochloride. { 4- [3- (thfluorotomethyl) benzoyl] -1-piperazinyl} pyrimidine, * 4-methoxy-2-. { 4-. { 2- (Trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine, * 4-methoxy-2-hydrochloride. { 4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine, * 4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine, * d 4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine hydrochloride, * 2- (4-isonicotinoyl- 1-piperazinyl) -4-methoxypyrimidine, * 2- (4-isonicotinoyl-1-piperazinyl) -4-methoxypyrimidine dihydrochloride, * 2- [4 - (- imidazolylcarbonyl) -1-piperazinyl] -4-methoxy-pyrimidine, * 2- (4-nicotinoyl) -1-piperazinyl) -4- (trifluoromethyl) pyrimidine, 2- (4-nicotinoyl-1-piperazinyl) -4- (trifluoromethyl) pyrimidine hydrochloride, * 4-methoxy-2- [4- ( 2-pyridylcarbonyl) -1-piperazinyljpyrimidine, * 4-methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyljpyrimidine dihydrochloride, * 4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl ] pyrimidine, 4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, * 2- [4- (3-chloro-2-thienficarbonyl) -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- hydrochloride. { 4- [2- (trifluoromethyl] benzoyl] -1-piperazinyl} pyrimidine, * 2- [4- (2-methylbenzoyl) -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-piperazinyljpirimide, * 4-iopropoxy-2- orhidrate. { 4- [2- (trifluoromethyl) benzoyl] -1-piperazinyljpyridine, * 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-isopropoxy pyrimidine, * 2- [4- (hydrochloride 3-Chloro-2-thienylcarbonyl) -1-piperazinyl] -4-isopropoxypyrimidine, * 2- [4- (cyclohexylcarbonyl) -1-piperazinyl] -4-methoxy-phemidine, * 2- [4- (cyclohexylcarbonyl) hydrochloride] -1-piperazinyl] -4-methoxypyrimidine, * 4-ethoxy-2- [4- (4-flurobenzoyl) -1-piperazinyl] pyrimidine, * 4-ethoxy-2- [4- (4-fluorobenzoyl) hydrochloride - 1-piperazinyljpyrimidine, * 2- [4- (2-thazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, * 2- [4- (2-aminobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, * dihydrochloride of 2 - [4- (2-aminobenzoyl) -1-p-piperazinyl] -4-methoxypyrimidine, * 2- [4- (3-fluro-2-thienylcarbonyl) -1-piperazinyl] -4- methoxypyrimidine, 2- [4- (3-fluro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-methoxy-2-pyrimidine)] nl) -1-piperazinylcarbonylbenzoic acid, * 2- [4- (2-acetoxybenzoyl) -1-piperazinyl] -4-methoxypropylene, * 2- [4- (2-hydroxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine, sodium 2- [4- (4-methoxy-2-pyridimidinyl] -1-piperazinylcarbonyl] benzoate, 2- [4- (2-hydroxybenzoyl) hydrochloride) -1-piperazinyl] -4-methoxypihmidine, 4-methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, 4-methoxy-2- [4- ( 2-methoxybenzoyl) -1-p-piperazinyl] pyrimidine, 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine nitrate, and * 4-ethoxy -2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine.
11. Process for the preparation of a compound of general formula (1), wherein X represents an oxygen atom, according to claim 1, which consists of reacting a chloropyrimidine derivative of formula (3) (3) where R. has the meaning indicated in claim 1, with a piperazine derivative of the general formula (4) (4) where R2 has the meaning indicated in claim 1, and X represents an oxygen atom.
12. Process for the preparation of a compound of general formula (1) in which X represents an oxygen atom, according to claim 1, which consists in reacting an amine of formula (5) (5) where R. has the meaning indicated in claim 1, with a carboxylic acid of formula R2COOH (6) or with a salt of this same acid, in which R2 has the meaning indicated in claim 1.
13.- Procedure for the preparation of a compound of general formula (1) in which X represents an oxygen atom, according to claim 1, which consists in reacting an amine of formula (5) where R. has the meaning indicated in claim 1, with a reactive derivative R2COY (7), wherein R2 has the meaning indicated in claim 1 and Y represents a halogen atom, an azido group, a 1-imidazolyl group , a group O-CO-R, where R represents an alkyl radical of 1 to 6 carbon atoms or an aryl radical, optionally substituted by one or more halogen atoms, or an OR group where R5 represents an aromatic group of one or two rings substituted by one or more halogen atoms or nitro radicals, or N-succinimide.
14. - Process for the preparation of a compound of general formula (1) in which X represents a sulfur atom, according to claim 1, which consists of reacting a compound of general formula (1) in which X represents an atom of oxygen, with Lawesson's reagent, (2,4bis (4-methoxyphenyl) -1, 3,2,4-dithiadiphosphaetane-2-4-disulfide), or with phosphorus pentasulfide.
15. Process for the preparation of physiologically acceptable salts of the compounds of general formula (1), according to claim 1, which consists in reacting a compound of general formula (1) with a mineral acid or with an organic acid in the breast of an appropriate solvent.
16. A pharmaceutical composition characterized in that it contains, in addition to a pharmaceutically acceptable excipient, at least one compound of the general formula (1) or one of its physiologically acceptable salts, according to claims 1 to 10.
17.- The use of a compound of general formula (1) or its pharmaceutically acceptable salts according to any of claims 1 to 10, in the manufacture of a medicament with activity on the central nervous system in mammals, including man.
18. The use of a compound of general formula (1) or its pharmaceutically acceptable salts, according to any of claims 1 to 10, in the preparation of a medicament with sedative, anticonvulsant, analgesic, muscle relaxant, antitussive, anxiolytic, antipsychotic, antidepressant, cerebral anti-migraine, anti-migraine, in sleep disorders, in neurodegenerative diseases, in cognitive disorders and in Alzheimer's disease, hypnotic or general anesthetic, in mammals, including man.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9701627 | 1997-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00000835A true MXPA00000835A (en) | 2001-11-21 |
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