HRP20030226A2 - 2,5-DIHYDRO-PYRAZOLO[3,4-d]PYRIMIDIN-4-ONES WITH AN ANTICONVULSIVE ACTION AND METHODS FOR PRODUCING THE SAME - Google Patents
2,5-DIHYDRO-PYRAZOLO[3,4-d]PYRIMIDIN-4-ONES WITH AN ANTICONVULSIVE ACTION AND METHODS FOR PRODUCING THE SAME Download PDFInfo
- Publication number
- HRP20030226A2 HRP20030226A2 HR20030226A HRP20030226A HRP20030226A2 HR P20030226 A2 HRP20030226 A2 HR P20030226A2 HR 20030226 A HR20030226 A HR 20030226A HR P20030226 A HRP20030226 A HR P20030226A HR P20030226 A2 HRP20030226 A2 HR P20030226A2
- Authority
- HR
- Croatia
- Prior art keywords
- pyrimidin
- dihydropyrazolo
- methyl
- phenyl
- difluorobenzyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 230000002082 anti-convulsion Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 35
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- FQXKRMCCAZDGMY-UHFFFAOYSA-N 5-benzyl-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC=2NN=CC=2C(=O)N1CC1=CC=CC=C1 FQXKRMCCAZDGMY-UHFFFAOYSA-N 0.000 claims description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 claims description 3
- DYUCRIIUUWXRGB-UHFFFAOYSA-N 2-methyl-5-[(2-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=CC=CC=C1CN1C(=O)C2=CN(C)N=C2N=C1 DYUCRIIUUWXRGB-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- WJTGTXAPWHRKJU-UHFFFAOYSA-N 5-[(2-chlorophenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound ClC1=CC=CC=C1CN1C(=O)C2=CNN=C2N=C1 WJTGTXAPWHRKJU-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical class OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000006223 tetrahydrofuranylmethyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical class 0.000 claims description 2
- RRCUCKWZTGAACQ-UHFFFAOYSA-N 2,5-bis[(2-chlorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound ClC1=CC=CC=C1CN1N=C(N=CN(CC=2C(=CC=CC=2)Cl)C2=O)C2=C1 RRCUCKWZTGAACQ-UHFFFAOYSA-N 0.000 claims description 2
- OOZQCNPEQHJQBC-UHFFFAOYSA-N 2,6-dimethyl-5-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=NC2=NN(C)C=C2C(=O)N1CC1=CC=CC=C1C(F)(F)F OOZQCNPEQHJQBC-UHFFFAOYSA-N 0.000 claims description 2
- YGIFRYMSBNDQID-UHFFFAOYSA-N 2-[(2-methyl-4-oxopyrazolo[3,4-d]pyrimidin-5-yl)methyl]benzonitrile Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1C#N YGIFRYMSBNDQID-UHFFFAOYSA-N 0.000 claims description 2
- SHFSNBRDZVHGNV-UHFFFAOYSA-N 2-benzyl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC2=NN(CC=3C=CC=CC=3)C=C2C(=O)N1CC1=CC=CC=N1 SHFSNBRDZVHGNV-UHFFFAOYSA-N 0.000 claims description 2
- AYBHOOVUHQJEJD-UHFFFAOYSA-N 2-benzyl-5-[(2-chloro-6-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(Cl)=C1CN1C(=O)C2=CN(CC=3C=CC=CC=3)N=C2N=C1 AYBHOOVUHQJEJD-UHFFFAOYSA-N 0.000 claims description 2
- MAFPHHBENANVJF-UHFFFAOYSA-N 2-butyl-5-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCCC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1F MAFPHHBENANVJF-UHFFFAOYSA-N 0.000 claims description 2
- NDXKGEYOKAKTNG-UHFFFAOYSA-N 2-butyl-5-[(2-chloro-6-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCCC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1Cl NDXKGEYOKAKTNG-UHFFFAOYSA-N 0.000 claims description 2
- FPNSKPWZRRQHRJ-UHFFFAOYSA-N 2-butyl-5-[(4-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCCC)C=C(C2=O)C=1N=CN2CC1=CC=C(C)C=C1 FPNSKPWZRRQHRJ-UHFFFAOYSA-N 0.000 claims description 2
- LWLSSXOUTGHQQK-UHFFFAOYSA-N 2-ethyl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CC)C=C(C2=O)C=1N=CN2CC1=CC=CC=N1 LWLSSXOUTGHQQK-UHFFFAOYSA-N 0.000 claims description 2
- VVIUJICXFDNDNN-UHFFFAOYSA-N 2-ethyl-5-[(4-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CC)C=C(C2=O)C=1N=CN2CC1=CC=C(C)C=C1 VVIUJICXFDNDNN-UHFFFAOYSA-N 0.000 claims description 2
- IMSDXMGUPCGVFA-UHFFFAOYSA-N 2-methyl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=N1 IMSDXMGUPCGVFA-UHFFFAOYSA-N 0.000 claims description 2
- LZESYJSTDCRAGF-UHFFFAOYSA-N 2-methyl-5-(pyridin-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=NC=C1 LZESYJSTDCRAGF-UHFFFAOYSA-N 0.000 claims description 2
- SDQGENBCCSDKES-UHFFFAOYSA-N 2-methyl-5-[(2,4,6-trimethylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=CC(C)=CC(C)=C1CN1C(=O)C2=CN(C)N=C2N=C1 SDQGENBCCSDKES-UHFFFAOYSA-N 0.000 claims description 2
- DLKKGOVPGFVOOE-UHFFFAOYSA-N 2-methyl-5-[(2-nitrophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1[N+]([O-])=O DLKKGOVPGFVOOE-UHFFFAOYSA-N 0.000 claims description 2
- FQDACLZICMVLNJ-UHFFFAOYSA-N 2-methyl-5-[(2-phenylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1C1=CC=CC=C1 FQDACLZICMVLNJ-UHFFFAOYSA-N 0.000 claims description 2
- BAVFPCSZADUCDT-UHFFFAOYSA-N 2-methyl-5-[(3-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=CC=CC(CN2C(C3=CN(C)N=C3N=C2)=O)=C1 BAVFPCSZADUCDT-UHFFFAOYSA-N 0.000 claims description 2
- CQOHVQHTTXMVTG-UHFFFAOYSA-N 2-methyl-5-[(4-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=CC(C)=CC=C1CN1C(=O)C2=CN(C)N=C2N=C1 CQOHVQHTTXMVTG-UHFFFAOYSA-N 0.000 claims description 2
- FRSGBYWHJGCHKX-UHFFFAOYSA-N 2-methyl-5-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1C(F)(F)F FRSGBYWHJGCHKX-UHFFFAOYSA-N 0.000 claims description 2
- MHGKLUYLLRSBIX-UHFFFAOYSA-N 2-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=C(C(F)(F)F)C=C1 MHGKLUYLLRSBIX-UHFFFAOYSA-N 0.000 claims description 2
- JRFNAQLMVSMCTO-UHFFFAOYSA-N 2-phenyl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC2=NN(C=3C=CC=CC=3)C=C2C(=O)N1CC1=CC=CC=N1 JRFNAQLMVSMCTO-UHFFFAOYSA-N 0.000 claims description 2
- PWPUPHKWFDZROA-UHFFFAOYSA-N 2-propan-2-yl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C(C)C)C=C(C2=O)C=1N=CN2CC1=CC=CC=N1 PWPUPHKWFDZROA-UHFFFAOYSA-N 0.000 claims description 2
- GMMNYEDDZHEUPA-UHFFFAOYSA-N 2-propyl-5-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCC)C=C(C2=O)C=1N=CN2CC1=CC=CC=N1 GMMNYEDDZHEUPA-UHFFFAOYSA-N 0.000 claims description 2
- SQXPLWUIEHGLKW-UHFFFAOYSA-N 5-(pyridin-2-ylmethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC2=NNC=C2C(=O)N1CC1=CC=CC=N1 SQXPLWUIEHGLKW-UHFFFAOYSA-N 0.000 claims description 2
- JWNMLWPGXCYXLI-UHFFFAOYSA-N 5-(pyridin-3-ylmethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC2=NNC=C2C(=O)N1CC1=CC=CN=C1 JWNMLWPGXCYXLI-UHFFFAOYSA-N 0.000 claims description 2
- XINOYZZCYJVHAI-UHFFFAOYSA-N 5-(pyridin-4-ylmethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC2=NNC=C2C(=O)N1CC1=CC=NC=C1 XINOYZZCYJVHAI-UHFFFAOYSA-N 0.000 claims description 2
- QNYVUEWYUZKLIR-UHFFFAOYSA-N 5-[(2,4,6-trimethylphenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=CC(C)=CC(C)=C1CN1C(=O)C2=CNN=C2N=C1 QNYVUEWYUZKLIR-UHFFFAOYSA-N 0.000 claims description 2
- SICHJHQFAKVBKW-UHFFFAOYSA-N 5-[(2,4-dichlorophenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound ClC1=CC(Cl)=CC=C1CN1C(=O)C2=CNN=C2N=C1 SICHJHQFAKVBKW-UHFFFAOYSA-N 0.000 claims description 2
- NWNSBEOJBJQELV-UHFFFAOYSA-N 5-[(2,4-dichlorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=C(Cl)C=C1Cl NWNSBEOJBJQELV-UHFFFAOYSA-N 0.000 claims description 2
- QEQZIJYLCYDSEY-UHFFFAOYSA-N 5-[(2,6-dichlorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=C(Cl)C=CC=C1Cl QEQZIJYLCYDSEY-UHFFFAOYSA-N 0.000 claims description 2
- CRPNJOQSDJZOJZ-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(F)=C1CN1C(=O)C2=CNN=C2N=C1 CRPNJOQSDJZOJZ-UHFFFAOYSA-N 0.000 claims description 2
- XRVREQKBLREZSK-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2,6-dimethylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=NC2=NN(C)C=C2C(=O)N1CC1=C(F)C=CC=C1F XRVREQKBLREZSK-UHFFFAOYSA-N 0.000 claims description 2
- CGZHZRXOEAEINF-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-(pyridin-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(F)=C1CN1C(=O)C2=CN(CC=3N=CC=CC=3)N=C2N=C1 CGZHZRXOEAEINF-UHFFFAOYSA-N 0.000 claims description 2
- NSPYEGLHZGCGBZ-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-ethylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1F NSPYEGLHZGCGBZ-UHFFFAOYSA-N 0.000 claims description 2
- PZECXTOQFHTQGG-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1F PZECXTOQFHTQGG-UHFFFAOYSA-N 0.000 claims description 2
- QQMKAIDOVGURLP-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-phenylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(F)=C1CN1C(=O)C2=CN(C=3C=CC=CC=3)N=C2N=C1 QQMKAIDOVGURLP-UHFFFAOYSA-N 0.000 claims description 2
- TTYRJAIPAMKAMB-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C(C)C)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1F TTYRJAIPAMKAMB-UHFFFAOYSA-N 0.000 claims description 2
- CWTAITURROZLHW-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-2-propylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1F CWTAITURROZLHW-UHFFFAOYSA-N 0.000 claims description 2
- YWFMREGPHUYEDV-UHFFFAOYSA-N 5-[(2,6-difluorophenyl)methyl]-6-methyl-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=NC2=NNC=C2C(=O)N1CC1=C(F)C=CC=C1F YWFMREGPHUYEDV-UHFFFAOYSA-N 0.000 claims description 2
- DRHFWRPPGZQMBW-UHFFFAOYSA-N 5-[(2-chloro-6-fluorophenyl)methyl]-2-ethylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1Cl DRHFWRPPGZQMBW-UHFFFAOYSA-N 0.000 claims description 2
- ADFTXDJWLDNODQ-UHFFFAOYSA-N 5-[(2-chloro-6-fluorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1Cl ADFTXDJWLDNODQ-UHFFFAOYSA-N 0.000 claims description 2
- JTMWHJOJHIAEPF-UHFFFAOYSA-N 5-[(2-chloro-6-fluorophenyl)methyl]-2-phenylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(Cl)=C1CN1C(=O)C2=CN(C=3C=CC=CC=3)N=C2N=C1 JTMWHJOJHIAEPF-UHFFFAOYSA-N 0.000 claims description 2
- VNVIZFKRIWSZNQ-UHFFFAOYSA-N 5-[(2-chloro-6-fluorophenyl)methyl]-2-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C(C)C)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1Cl VNVIZFKRIWSZNQ-UHFFFAOYSA-N 0.000 claims description 2
- HJFPDZQDSAWCRK-UHFFFAOYSA-N 5-[(2-chloro-6-fluorophenyl)methyl]-2-propylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCC)C=C(C2=O)C=1N=CN2CC1=C(F)C=CC=C1Cl HJFPDZQDSAWCRK-UHFFFAOYSA-N 0.000 claims description 2
- KMRGXJWVFHNMSQ-UHFFFAOYSA-N 5-[(2-chlorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1Cl KMRGXJWVFHNMSQ-UHFFFAOYSA-N 0.000 claims description 2
- CFARRBFGZHWBSW-UHFFFAOYSA-N 5-[(2-iodophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1I CFARRBFGZHWBSW-UHFFFAOYSA-N 0.000 claims description 2
- FWXXCWYDEOBULT-UHFFFAOYSA-N 5-[(2-methoxyphenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound COC1=CC=CC=C1CN1C(=O)C2=CNN=C2N=C1 FWXXCWYDEOBULT-UHFFFAOYSA-N 0.000 claims description 2
- HLISVYKYHKEOQW-UHFFFAOYSA-N 5-[(2-methoxyphenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound COC1=CC=CC=C1CN1C(=O)C2=CN(C)N=C2N=C1 HLISVYKYHKEOQW-UHFFFAOYSA-N 0.000 claims description 2
- DCGCRXMPVSXOJY-UHFFFAOYSA-N 5-[(2-methylphenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=CC=CC=C1CN1C(=O)C2=CNN=C2N=C1 DCGCRXMPVSXOJY-UHFFFAOYSA-N 0.000 claims description 2
- FGYHLTKHSYGQMJ-UHFFFAOYSA-N 5-[(3-chlorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC(Cl)=C1 FGYHLTKHSYGQMJ-UHFFFAOYSA-N 0.000 claims description 2
- WYYUYPJVUXFPPM-UHFFFAOYSA-N 5-[(4-chlorophenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=CC(Cl)=CC=C1CN1C(=O)C2=CNN=C2N=C1 WYYUYPJVUXFPPM-UHFFFAOYSA-N 0.000 claims description 2
- XMCDIPCCKOAIGJ-UHFFFAOYSA-N 5-[(4-chlorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=C(Cl)C=C1 XMCDIPCCKOAIGJ-UHFFFAOYSA-N 0.000 claims description 2
- FKBKIVNNAZQFJJ-UHFFFAOYSA-N 5-[(4-fluorophenyl)methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1CN1C(=O)C2=CNN=C2N=C1 FKBKIVNNAZQFJJ-UHFFFAOYSA-N 0.000 claims description 2
- QKIHDGHCVXBFAQ-UHFFFAOYSA-N 5-[(4-fluorophenyl)methyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=C(F)C=C1 QKIHDGHCVXBFAQ-UHFFFAOYSA-N 0.000 claims description 2
- QPFNXNKOHWYGCQ-UHFFFAOYSA-N 5-[(4-methylphenyl)methyl]-2-phenylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=CC(C)=CC=C1CN1C(=O)C2=CN(C=3C=CC=CC=3)N=C2N=C1 QPFNXNKOHWYGCQ-UHFFFAOYSA-N 0.000 claims description 2
- VJKPHMHEDAHJLB-UHFFFAOYSA-N 5-[(4-methylphenyl)methyl]-2-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C(C)C)C=C(C2=O)C=1N=CN2CC1=CC=C(C)C=C1 VJKPHMHEDAHJLB-UHFFFAOYSA-N 0.000 claims description 2
- XDHXOGLSOZJJMC-UHFFFAOYSA-N 5-[(4-methylphenyl)methyl]-2-propylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(CCC)C=C(C2=O)C=1N=CN2CC1=CC=C(C)C=C1 XDHXOGLSOZJJMC-UHFFFAOYSA-N 0.000 claims description 2
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- MRGMAASWWFCZMM-UHFFFAOYSA-N 5-benzyl-2-methylpyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=CC=C1 MRGMAASWWFCZMM-UHFFFAOYSA-N 0.000 claims description 2
- MAYUCBCSAVDUKG-UHFFFAOYSA-N orthoacetic acid Chemical class CC(O)(O)O MAYUCBCSAVDUKG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 4
- KOPLPJUAZXSGGH-UHFFFAOYSA-N 5-[(2-chlorophenyl)methyl]-2-(oxolan-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound ClC1=CC=CC=C1CN1C(=O)C2=CN(CC3OCCC3)N=C2N=C1 KOPLPJUAZXSGGH-UHFFFAOYSA-N 0.000 claims 1
- QZOHLMMPYFVKJL-UHFFFAOYSA-N 5-[(2-chlorophenyl)methyl]-6-methyl-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound CC1=NC2=NNC=C2C(=O)N1CC1=CC=CC=C1Cl QZOHLMMPYFVKJL-UHFFFAOYSA-N 0.000 claims 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 230000001773 anti-convulsant effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
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- 229960003965 antiepileptics Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- LEFSNWUSTYESGC-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carboxamide Chemical compound NC(=O)C1=CNN=C1N LEFSNWUSTYESGC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 2
- JZPHAJFIZZEAEK-UHFFFAOYSA-N 3-chloro-6-methoxy-2h-indazole Chemical compound COC1=CC=C2C(Cl)=NNC2=C1 JZPHAJFIZZEAEK-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- -1 pyrazolopyramides Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
- STLFDTKIWQNYHR-UHFFFAOYSA-N 2-benzyl-5-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC1=CC=CC(F)=C1CN1C(=O)C2=CN(CC=3C=CC=CC=3)N=C2N=C1 STLFDTKIWQNYHR-UHFFFAOYSA-N 0.000 description 1
- RMABPCNSXXKDLU-UHFFFAOYSA-N 2-benzyl-5-[(4-methylphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=CC(C)=CC=C1CN1C(=O)C2=CN(CC=3C=CC=CC=3)N=C2N=C1 RMABPCNSXXKDLU-UHFFFAOYSA-N 0.000 description 1
- GIZUAZUUKUGDLI-UHFFFAOYSA-N 5-(2-phenylethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC=2NN=CC=2C(=O)N1CCC1=CC=CC=C1 GIZUAZUUKUGDLI-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FJWLWIRHZOHPIY-UHFFFAOYSA-N potassium;hydroiodide Chemical compound [K].I FJWLWIRHZOHPIY-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Područje tehnike
Izum se odnosi na 2,5-dihidropirazolo[3,4-d]pirimidin-4-one i njihove tautomere koji sadrže jedan ar(alkil) radikal na 2-poziciji, vodik ili jedan ar(alkil) radikal i njihovu uporabu kao lijekova, posebice za liječenje različitih oblika padavice.
Poradi strukturnih sličnosti s adeninom, pirazolo[3,4-d]pirimidini su spojevi od farmakološkog interesa.
Stanje tehnike
Dosad su bili opisani samo 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on i 5-fenetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on [Sochneva, E.O.; Solov’eva, N.P.; Granik, V.G., Khim. Geterotsikl. Soedin. 1978, (12), 1671-6; Granik, V.G.; Sochneva, E.O.; Solov’eva, N.P.: Shvarts, G. Ya.; Syubaev, R.D.; Mashkovskii, M.D., Khim.-Farm. Zh. 1980, 14(6), 36-40]. Ovi spojevi ispitani su za protuupalno djelovanje; antikonvulzivno djelovanje nije spomenuto nit naznačeno.
5-arilmetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-oni [sic] koji imaju daljnji supstituent u pirazolovom prstenu nisu poznati.
Poznata antikonvulzivna sredstva u jednu ruku imaju nedostatke u smislu nepoželjnih nuspojava, poput neurotoksičnosti i idiosinkrazija, do kojih dolazi, a s druge strane nisu aktivni kod izvjesnih oblika epilepsije.
Izum se stoga temelji na omogućavanju spojeva poželjnih farmakoloških svojstava s antikonvulzivnim djelovanjem, koji se mogu primijeniti kao lijekovi, posebice za liječenje epilepsije.
Opis izuma
U skladu s predmetnim izumom, rečeni novi spojevi su 2,5-dihidropirazolo[3,4-d]pirimidin-4-oni opće formule 1
[image]
ili njihovi tautomeri, gdje
R = CH2-fenil, u kojem fenil može biti mono- ili polisupstituiran halogenom,
C1-C3-alkilom, ravnog ili razgrananog lanca, po izboru mono- ili polisupstituiran, halogenom,
C1-C3-alkiloksijem, ravnog ili razgrananog lanca, fenilom, NO2, CN;
CH2-piridinilom;
R1 = H; C1-C4-alkil; fenil; CH2-fenil, u kojem fenil po izboru može biti supstituiran halogenom; CH2-piridinil; tetrahidrofuranilmetil.
R2 = H, metil,
isključujući spoj u kojem R jest CH2-fenil, a R1 je vodik.
Primjeri spojeva opće formule 1 koji ovdje mogu biti spomenuti su:
5-(2-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-fluorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4-diklorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metilbenziI)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metoksibenziI)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4,6-trimetilbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-benzil-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metoksibenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-trifluormetilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-fenilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-diklorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-nitrobenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4-diklorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-jodobenziI)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-cijanobenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-fIuorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4,6-trimetilbenzil)-2metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-piridinilmetil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fIuorbenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fIuorbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenziI)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
2,5-bis-(2-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-piridin-2-ilmetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-2-tetrahidrofuran-2-ilmetil-2,5-dihidropirazol[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-6-metil-2,5-dihidropirazol[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-6-metil-2,5-dihidropirazol[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2,6-dimetil-2,5-dihidropirazol[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2,6-dimetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on.
Postupak za pripravu spojeva formule 1 i njihovih tautomera počinje od poznatih estera 3-aminopirazol-4-karboksilne kiseline (spojeva opće formule 2) ili 3-aminopirazol-4-karboksamida (spojevi opće formule 3) [P. Schmidt, J. Druey, Helv. Chim. Acta. 1956, 39, 986-991; K. Eichenberger, P. Schmidt, M. Wilhelm, J. Druey; Helv. Chim. Acta 1959, 42, 349-359; J. K. Chakrabarti, T.M. Hotten, I.A. Pullar, N.C. Nicholas, J. Med. Chem. 1989, 32 (12), 2573-2582],
[image]
gdje
R1 = H, C1-C4-alkil; fenil; CH2-fenil, u kojem fenil po izboru može biti supstituiran halogenom; CH2-piridinil, tetrahidrofuranilmetil,
a Et je alkilni radikal.
Ovi spojevi opće formule 2 ili opće formule 3 su u jednu ruku ciklirani uporabom formamida (R2 = H) ili acetamida (R2 = metil) na relativno visokim temperaturama, alternativno, spojevi opće formule 3 su ciklirani uporabom estera orto-mravlje kiseline i/ili smjesama mravlje kiseline/octenog anhidrida (R2 = H) ili uporabom estera orto-mravlje kiseline i/ili octenog anhidrida (R2 = metil), a potom reagiraju s R-halidima, pri čemu R ima gore navedeno značenje, kako bi se dobili spojevi opće formule 1 (Metoda B).
U drugu ruku, spojevi opće formule 3, reagiraju s dimetilformamid dimetil acetalom (R2 = H) ili dimetilacetamid dimetil acetalom (R2 = metil), a tako dobiveni proizvod reagira s R-aminima, pri čemu R ima gore spomenuto značenje, kako bi se dobili spojevi opće formule 1 (Metoda A).
Spojevi u skladu s izumom, upravo kao i već opisani spoj 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on, ili njihove farmaceutski uporabljive soli prikladne su za proizvodnju farmaceutskih pripravaka. Farmaceutski pripravci ili lijekovi mogu sadržavati jedan ili više spojeva u skladu s predmetnim izumom. Uobičajeni farmaceutski vehikuli i ekscipiensi mogu se rabiti za proizvodnju farmaceutskih pripravaka. Lijekovi se mogu primjenjivati, na primjer, parenteralno (npr. intravenski, intramuskularno, subkutano) ili oralno.
Oblici za primjenu se mogu pripraviti procesima koji su općenito poznati i uobičajeni u farmaceutskoj praksi.
Spojevi u skladu s predmetnim izumom imaju snažno antikonvulzivno djelovanje, poput već opisanog spoja 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-ona.
Antikonvulzivno djelovanje
Spojevi u skladu s predmetnim izumom testirani su na njihovo antikonvulzivno djelovanje in vivo nakon i.p. primjene na miševe u skladu s uobičajenim međunarodnim standardima (Pharmac. Weekblad, Sc. Ed. 14, 132 (1992) i Antiepileptic Drugs, Third Ed., Raven Press, New York 1989) (Tablica 1).
Tablica 1. Antikonvulzivno djelovanje odabranih 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona
[image] [image]
[image]
Bilješke za Tablicu 1:
1. Numeriranje spojeva u skladu s primjerima u Tablici 2
2. Koeficijent podjele Oktanol/voda
3. Miš i.p.: MES = maksimalni elektrošok, PTZ= s.c. pentetrazol
4. u mg/kg
5. u % zaštićenih životinja
Analogni rezultati dobiveni su za oralno djelovanje.
Na primjer, za spoj 1, (5-(2-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on), u štakora uz maksimalni elektrošok, utvrđeno je da ED50 (p.o.) iznosi 18 mg/kg, a za neurotoksičnost NT50 iznosi > 500 mg/kg. Ovaj spoj je također aktivan na modelima konvulzije uporabom bikukulina i pikrotoksina kao sredstva-uzročnika za poticanje konvulzije. Spoj 14 (5-(2-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on) je također snažni antikonvulzant sa širokim terapijskim učinkom (ED50 (štakor p.o.) = 9 mg/kg, NT50 > 300 mg/kg). Spoj 21 ima sličan farmakološki profil (ED50 (štakor p.o.) = 3 mg/kg, NT50 > 300 mg/kg).
Radni primjeri
Sljedeći primjeri služe za daljnju ilustraciju izuma bez ograničavanja istog.
Opći postupak za pripravu spojeva formule 1 i njihovih tautomera kao u Tablici 2 (Metoda A)
50 mmola 3-aminopirazol-4-karboksamida reagira s dimetilformamid dimetil acetalom (R2 = H) ili dimetilacetamid dimetil acetalom (R2 = metil) na relativno visokoj temperaturi, poželjno je 90-130ºC, u/ili bez organskog otapala. Nakon 12-40 sati, višak otapala i reagensa se [sic] u potpunosti uklanja. 50 mmola R-amina, u kojem R ima gore spomenuto značenje, dodaje se u ostatak i, ako je prikladno, inertno organsko otapalo, poželjno je ksilen, klorobenzen, itd. Reakcijska smjesa reagira pri relativno visokoj temperaturi, poželjno je 100-180ºC. Nakon 10-35 sati, otapalo je uklonjeno i dobiven je čisti spoj formule 1 putem ponovne kristalizacije iz organskog otapala, poželjno je DMF-a, etanola, metanola ili acetona, ili alternativno kromatografijom.
Opći postupak za pripravu spojeva formule 1 i njihovih tautomera kao u Tablici 2 (Metoda B)
I. korak
50 mmola ester/amida 3-aminopirazol-4-karboksilne kiseline reagira na relativno visokim temperaturama (100-200ºC) 3-15 sati u formamidu (R2 = H) ili acetamidu (R2 = metil). Nakon završetka reakcije, proizvodi (pirazolopiramidini) su ili izolirani filtracijom, ili izdvojeni kromatografijom nakon uklanjanja otapala.
Alternativno, 50 mmola 3-aminopirazol-4-karboksamida reagira s esterom orto-mravlje kiseline i/ili smjesom mravlje kiseline/octenog anhidrida i/ili s octenim anhidridom (R2 = H) ili s esterima orto-octene kiseline i/ili octenim anhidridom (R = metil) tijekom 10-50 sati na relativno visokoj temperaturi, poželjno je 80-120ºC. Nakon završetka reakcije, proizvodi (pirazolopirimidini) su ili izolirani filtracijom, ili izdvojeni kromatografijom nakon uklanjanja otapala.
II. korak
20 mmola pirazolopirimidina razrjeđeno je u DMF-u, tretirano s neorganskom bazom, poželjno je natrijem, kalijem ili kalcij karbonatom i natrij/kalij jodom i reagira s 25-40 mmola R-halida, gdje R ima gore spomenuto značenje, na relativno visokoj temperaturi, poželjno je 50-140ºC. Nakon 5-40 sati, reakcijska smjesa je filtrirana, a spoj iz formule 1 je ili izoliran filtracijom, ili izdvojen kromatografijom nakon uklanjanja otapala. Tako dobiveni sirovi proizvodi su ponovno kristalizirani iz organskog otapala, poželjno je DMF, etanol, metanol ili aceton.
Alternativno, pročišćavanje se može izvesti kromatografijom.
Tablica 2: Pirazolo[3,4-d]pirimidini
[image] [image]
1. Uporabljene skraćenice: Me = CH3, Et = C2H5, Pro = C3H7, i-Pro = i-C3H7, Bu = C4H9, Ph = C6H5, Bn = -CH2-C6H5, Py = C8H4N, THF = C4H8O.
Claims (11)
1. Novi spoj opće formule 1
[image]
ili njegovi tautomeri, naznačen time da
R = CH2-fenil, u kojem fenil može biti mono- ili polisupstituiran
halogenom,
C1-C3-alkilom, ravnog ili razgrananog lanca, po izboru mono- ili polisupstituiran
halogenom,
C1-C3-alkiloksijem, ravnim ili razgrananim,
fenilom,
NO2,
CN,
CH2-piridinil;
R1 = H; C1-C4-alkil; fenil; CH2-fenil, u kojem fenil može po izboru biti supstituiran halogenom; CH2-piridinil; tetrahidrofuranilmetil;
R2 = H, metil,
isključujući spoj u kojem R jeste CH2-fenil, a R1 je vodik.
2. Spoj opće formule 1, naznačen time, da je
5-(2-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-fluorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4-diklorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metilbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metoksibenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4,6-trimetilbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-piridinilmetil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-benzil-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-metoksibenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(3-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-trifluormetilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-fenilbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-diklorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-nitrobenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-klorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4-diklorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-jodobenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-cijanobenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-fIuorbenzil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,4,6-trimetilbenzil)-2metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-piridinilmetil)-2-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-etil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorobenzil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-propil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-izopropil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-butil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-fenil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klor-6-fluorbenzil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(4-metilbenzil)-2-benzil-2,5-dihidropirazo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-benzil-2,5-dihidropirazo[3,4-d]pirimidin-4-on;
5-(2-piridinilmetil)-2-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
2,5-bis(2-klorbenzil)-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2-piridin-2-ilmetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-2-tetrahidrofuran-2-ilmetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-klorbenzil)-6-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-6-metil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2-trifluormetilbenzil)-2,6-dimetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
5-(2,6-difluorbenzil)-2,6-dimetil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on;
3. Postupak za pripravu 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona opće formule 1, naznačen time, da se sastoji od reakcijskih spojeva opće formule 3, s dimetilformamid dimetil acetalom ili s dimetilacetamid dimetil acetalom, a potom ciklira s R-aminima, pri čemu R ima gore spomenuto značenje (Metoda A).
[image]
4. Postupak za pripravu 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona opće formule 1, naznačen time, da sadrži ciklirane spojeve opće formule 2, pri čemu je Et alkil radikal, ili opće formule 3 s formamidom ili acetamidom, a potom reagira s R-halidima, pri čemu R ima gore spomenuto značenje (Metoda B).
[image]
5. Postupak prema zahtjevu 4, naznačen time, što se za cikliranje spojeva opće formule 3 koriste esteri orto-mravlje kiseline i/ili smjese mravlje kiseline/octenog anhidrida ili esteri orto-octene kiseline i/ili octeni anhidrid.
6. Farmaceutski pripravak, naznačen time, što sadrži jedan ili više 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona opće formule 1 prema zahtjevu 1 ili njihove farmaceutski uporabljive soli kao aktivne spojeve u dodatku jednom ili više fiziološki prihvatljivih ekscipijensa i/ili vehikula i, ako je primjereno, razrjeđivača.
7. Farmaceutski pripravak, naznačen time, što sadrži jedan ili više 2,5-dihidropirazolo [3,4-d]pirimidin-4-ona iz zahtjeva 2 ili njihovih farmaceutski uporabljivih soli kao aktivnih spojeva u dodatku jednom ili više fiziološki prihvatljivih ekscipijensa i/ili vehikula i, ako je primjereno, razrjeđivača.
8. Farmaceutski pripravak, naznačen time, što sadrži 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on iz zahtjeva 2 ili njegove farmaceutski uporabljive soli kao aktivne spojeve u dodatku jednom ili više fiziološki prihvatljivih ekscipijensa i/ili vehikula i, ako je primjereno, razrjeđivača.
9. Farmaceutski pripravak, naznačen time, što sadrži 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-on i jedan ili više 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona iz zahtjeva 1 ili 2, ili njihove farmaceutski uporabljive soli kao aktivnih spojeva u dodatku jednom ili više fiziološki prihvatljivih ekscipijensa i/ili vehikula i, ako je primjereno, razrjeđivača.
10. Uporaba 2,5-dihidropirazolo[3,4-d]pirimidin-4-ona kao u formuli 1, naznačena time što se koristi za proizvodnju lijekova za liječenje bolesti [lacuna] različitih oblika epilepsije.
11. Uporaba 5-benzil-2,5-dihidropirazolo[3,4-d]pirimidin-4-ona, naznačena time, što se koristi za proizvodnju lijekova za liječenje bolesti [lacuna] različitih oblika epilepsije.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10042092A DE10042092A1 (de) | 2000-08-26 | 2000-08-26 | Antikonvulsiv wirkende 2,5-Dihydro-pyrazolo(3,4-d)pyrimidin-4-one und Verfahren zu deren Darstellung |
| PCT/EP2001/009811 WO2002018387A1 (de) | 2000-08-26 | 2001-08-24 | Antikonvulsiv wirkende 2,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one und verfahren zu deren darstellung |
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| HR20030226A HRP20030226A2 (en) | 2000-08-26 | 2003-03-24 | 2,5-DIHYDRO-PYRAZOLO[3,4-d]PYRIMIDIN-4-ONES WITH AN ANTICONVULSIVE ACTION AND METHODS FOR PRODUCING THE SAME |
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| NO (1) | NO20030687D0 (hr) |
| RU (1) | RU2003108258A (hr) |
| WO (1) | WO2002018387A1 (hr) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3165520A (en) * | 1965-01-12 | Certificate of correction | ||
| US3939161A (en) * | 1973-10-29 | 1976-02-17 | Abbott Laboratories | 1,3-Dimethyl- 1H-pyrazolo(4,3-D) pyrimidine-7 (6H)-ones |
| US5721356A (en) * | 1989-09-15 | 1998-02-24 | Gensia, Inc. | Orally active adenosine kinase inhibitors |
| US5763596A (en) * | 1989-09-15 | 1998-06-09 | Metabasis Therapeutics, Inc. | C-4' modified adenosine kinase inhibitors |
| EP0729758A3 (en) * | 1995-03-02 | 1997-10-29 | Pfizer | Pyrazolopyrimidines and pyrrolopyrimidines to treat neuronal disorders and other diseases |
| DE19827679A1 (de) * | 1998-06-22 | 1999-12-23 | Dresden Arzneimittel | Adenosinrezeptoraffine, antikonvulsiv und antiallergisch/antiasthmatisch wirkende Pyrazolo[3,4-d]pyrimidine und Verfahren zu deren Herstellung |
-
2000
- 2000-08-26 DE DE10042092A patent/DE10042092A1/de not_active Withdrawn
-
2001
- 2001-08-24 CA CA002420288A patent/CA2420288A1/en not_active Abandoned
- 2001-08-24 RU RU2003108258/04A patent/RU2003108258A/ru not_active Application Discontinuation
- 2001-08-24 US US10/333,504 patent/US20030186997A1/en not_active Abandoned
- 2001-08-24 CN CN01814655A patent/CN1449397A/zh active Pending
- 2001-08-24 IL IL15407001A patent/IL154070A0/xx unknown
- 2001-08-24 AU AU2001282124A patent/AU2001282124A1/en not_active Abandoned
- 2001-08-24 JP JP2002523902A patent/JP2004507547A/ja active Pending
- 2001-08-24 KR KR10-2003-7002753A patent/KR20030036734A/ko not_active Application Discontinuation
- 2001-08-24 EP EP01960709A patent/EP1311510A1/de not_active Withdrawn
- 2001-08-24 EE EEP200300078A patent/EE200300078A/xx unknown
- 2001-08-24 BR BR0113517-1A patent/BR0113517A/pt not_active Application Discontinuation
- 2001-08-24 WO PCT/EP2001/009811 patent/WO2002018387A1/de not_active Application Discontinuation
-
2003
- 2003-02-12 NO NO20030687A patent/NO20030687D0/no unknown
- 2003-02-14 BG BG107561A patent/BG107561A/xx unknown
- 2003-03-24 HR HR20030226A patent/HRP20030226A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE10042092A1 (de) | 2002-03-07 |
| BR0113517A (pt) | 2003-07-29 |
| JP2004507547A (ja) | 2004-03-11 |
| BG107561A (en) | 2003-10-31 |
| WO2002018387A1 (de) | 2002-03-07 |
| NO20030687L (no) | 2003-02-12 |
| KR20030036734A (ko) | 2003-05-09 |
| CA2420288A1 (en) | 2002-03-07 |
| AU2001282124A1 (en) | 2002-03-13 |
| NO20030687D0 (no) | 2003-02-12 |
| RU2003108258A (ru) | 2005-01-27 |
| EP1311510A1 (de) | 2003-05-21 |
| IL154070A0 (en) | 2003-07-31 |
| US20030186997A1 (en) | 2003-10-02 |
| EE200300078A (et) | 2004-12-15 |
| CN1449397A (zh) | 2003-10-15 |
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