CN1188121C - 治疗性取代的胍类 - Google Patents
治疗性取代的胍类 Download PDFInfo
- Publication number
- CN1188121C CN1188121C CNB941926109A CN94192610A CN1188121C CN 1188121 C CN1188121 C CN 1188121C CN B941926109 A CNB941926109 A CN B941926109A CN 94192610 A CN94192610 A CN 94192610A CN 1188121 C CN1188121 C CN 1188121C
- Authority
- CN
- China
- Prior art keywords
- guanidine
- phenyl
- methyl
- ethylphenyl
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000002357 guanidines Chemical class 0.000 title abstract description 16
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 238000011282 treatment Methods 0.000 claims abstract description 26
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 412
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 204
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 204
- 150000001875 compounds Chemical class 0.000 claims description 153
- -1 N-(3-ethylphenyl)-N, N '-dimethyl-N '-(2-chloro-5-aminomethyl phenyl) guanidine Chemical compound 0.000 claims description 135
- 125000004432 carbon atom Chemical group C* 0.000 claims description 125
- 229910052799 carbon Inorganic materials 0.000 claims description 89
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
- 229910052757 nitrogen Inorganic materials 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 229940117389 dichlorobenzene Drugs 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 12
- 208000028867 ischemia Diseases 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 10
- 210000004556 brain Anatomy 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 208000006264 Korsakoff syndrome Diseases 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 239000004220 glutamic acid Substances 0.000 claims description 8
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 7
- 206010015037 epilepsy Diseases 0.000 claims description 7
- 235000013922 glutamic acid Nutrition 0.000 claims description 7
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 6
- 208000010125 myocardial infarction Diseases 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 201000010374 Down Syndrome Diseases 0.000 claims description 5
- 208000023105 Huntington disease Diseases 0.000 claims description 5
- 208000013016 Hypoglycemia Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 206010044688 Trisomy 21 Diseases 0.000 claims description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- QEJQOMLQOFCXHB-UHFFFAOYSA-N 2-(2-bromo-5-ethylphenyl)-1-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Br)C(N=C(N)NC=2C=C(SC)C=CC=2)=C1 QEJQOMLQOFCXHB-UHFFFAOYSA-N 0.000 claims description 4
- JSURYTNBXZUQAB-UHFFFAOYSA-N 2-(2-bromo-5-ethylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Br)C(N=C(N)N(C)C=2C=C(SC)C=CC=2)=C1 JSURYTNBXZUQAB-UHFFFAOYSA-N 0.000 claims description 4
- ZDZFITPKVXAGEV-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(=N)NC=2C(=CC=C(CC)C=2)Cl)=C1 ZDZFITPKVXAGEV-UHFFFAOYSA-N 0.000 claims description 4
- 206010002660 Anoxia Diseases 0.000 claims description 4
- 241000976983 Anoxia Species 0.000 claims description 4
- 206010021143 Hypoxia Diseases 0.000 claims description 4
- 206010029350 Neurotoxicity Diseases 0.000 claims description 4
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 4
- 230000007953 anoxia Effects 0.000 claims description 4
- 231100000228 neurotoxicity Toxicity 0.000 claims description 4
- 230000007135 neurotoxicity Effects 0.000 claims description 4
- 230000007310 pathophysiology Effects 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- VZVIUBVEWXHBGX-UHFFFAOYSA-N 1-(2-bromo-5-ethylphenyl)-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Br)C(N(C)C(N)=NC=2C=C(SC)C=CC=2)=C1 VZVIUBVEWXHBGX-UHFFFAOYSA-N 0.000 claims description 3
- WJBSIQJJXAAORE-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-1-methyl-2-naphthalen-1-ylguanidine Chemical compound CCC1=CC=C(Cl)C(N(C)C(=N)NC=2C3=CC=CC=C3C=CC=2)=C1 WJBSIQJJXAAORE-UHFFFAOYSA-N 0.000 claims description 3
- DIUYFKYCQGBTJD-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-3-(3-ethylphenyl)-1,3-dimethylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(CC)C=2)Cl)=C1 DIUYFKYCQGBTJD-UHFFFAOYSA-N 0.000 claims description 3
- BRPVMFSJCWOHNX-UHFFFAOYSA-N 1-(2-chloro-5-methylsulfanylphenyl)-2-naphthalen-1-ylguanidine Chemical compound CSC1=CC=C(Cl)C(NC(=N)NC=2C3=CC=CC=C3C=CC=2)=C1 BRPVMFSJCWOHNX-UHFFFAOYSA-N 0.000 claims description 3
- JHVHEDNLONERHY-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC)C=2)Cl)=C1 JHVHEDNLONERHY-UHFFFAOYSA-N 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003706 n methyl dextro aspartic acid receptor stimulating agent Substances 0.000 claims description 3
- 208000004296 neuralgia Diseases 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 3
- 108020003175 receptors Proteins 0.000 claims description 3
- FZYJTQJTUVRQQY-UHFFFAOYSA-N 1-(2-bromo-5-ethylphenyl)-2-naphthalen-1-ylguanidine Chemical compound CCC1=CC=C(Br)C(NC(=N)NC=2C3=CC=CC=C3C=CC=2)=C1 FZYJTQJTUVRQQY-UHFFFAOYSA-N 0.000 claims description 2
- HJQBESQLXUTSIF-UHFFFAOYSA-N 1-(2-bromo-5-ethylphenyl)-3-(3-ethylphenyl)-1,3-dimethylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(CC)C=2)Br)=C1 HJQBESQLXUTSIF-UHFFFAOYSA-N 0.000 claims description 2
- BTURBQFTDOLNFI-UHFFFAOYSA-N 1-(2-bromo-5-methylsulfanylphenyl)-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC)C=2)Br)=C1 BTURBQFTDOLNFI-UHFFFAOYSA-N 0.000 claims description 2
- PRMTUXISSKRAAL-UHFFFAOYSA-N 1-(2-bromo-5-methylsulfanylphenyl)-2-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC)C=2)Br)=C1 PRMTUXISSKRAAL-UHFFFAOYSA-N 0.000 claims description 2
- UCYOHHWEGXDSCQ-UHFFFAOYSA-N 1-(2-bromo-5-methylsulfanylphenyl)-2-naphthalen-1-ylguanidine Chemical compound CSC1=CC=C(Br)C(NC(N)=NC=2C3=CC=CC=C3C=CC=2)=C1 UCYOHHWEGXDSCQ-UHFFFAOYSA-N 0.000 claims description 2
- XRFRQZCSBWFMEA-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Cl)C(N(C)C(N)=NC=2C=C(SC)C=CC=2)=C1 XRFRQZCSBWFMEA-UHFFFAOYSA-N 0.000 claims description 2
- GEPMFUXMINZFQF-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-2-(3-iodophenyl)-1-methylguanidine Chemical compound CCC1=CC=C(Cl)C(N(C)C(=N)NC=2C=C(I)C=CC=2)=C1 GEPMFUXMINZFQF-UHFFFAOYSA-N 0.000 claims description 2
- AJBSFOLEPCBEFS-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-2-methyl-1-quinolin-8-ylguanidine Chemical compound CCC1=CC=C(Cl)C(N(C(N)=NC)C=2C3=NC=CC=C3C=CC=2)=C1 AJBSFOLEPCBEFS-UHFFFAOYSA-N 0.000 claims description 2
- NWMZDUHHAYCBRU-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-2-naphthalen-1-ylguanidine Chemical compound CCC1=CC=C(Cl)C(NC(=N)NC=2C3=CC=CC=C3C=CC=2)=C1 NWMZDUHHAYCBRU-UHFFFAOYSA-N 0.000 claims description 2
- XKRPLOIELSAVGL-UHFFFAOYSA-N 1-(2-chloro-5-ethylphenyl)-2-quinolin-8-ylguanidine Chemical compound CCC1=CC=C(Cl)C(NC(=N)NC=2C3=NC=CC=C3C=CC=2)=C1 XKRPLOIELSAVGL-UHFFFAOYSA-N 0.000 claims description 2
- PYRIKADMLWUBTN-UHFFFAOYSA-N 1-(2-chloro-5-methylsulfanylphenyl)-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC)C=2)Cl)=C1 PYRIKADMLWUBTN-UHFFFAOYSA-N 0.000 claims description 2
- RFYJUKZJRFTRMZ-UHFFFAOYSA-N 1-(2-chloro-5-methylsulfanylphenyl)-2-(3-iodophenyl)-1-methylguanidine Chemical compound CSC1=CC=C(Cl)C(N(C)C(N)=NC=2C=C(I)C=CC=2)=C1 RFYJUKZJRFTRMZ-UHFFFAOYSA-N 0.000 claims description 2
- FYSUHOWUXMBUBB-UHFFFAOYSA-N 1-(2-iodo-5-methylsulfanylphenyl)-2-naphthalen-1-ylguanidine Chemical compound CSC1=CC=C(I)C(NC(N)=NC=2C3=CC=CC=C3C=CC=2)=C1 FYSUHOWUXMBUBB-UHFFFAOYSA-N 0.000 claims description 2
- SLAQVNXNAGNTSK-UHFFFAOYSA-N 1-(3-bromophenyl)-2-(2-chloro-5-methylsulfanylphenyl)-1-methylguanidine Chemical compound CSC1=CC=C(Cl)C(N=C(N)N(C)C=2C=C(Br)C=CC=2)=C1 SLAQVNXNAGNTSK-UHFFFAOYSA-N 0.000 claims description 2
- BCQMAWUNJNFILR-UHFFFAOYSA-N 1-(3-bromophenyl)-2-(2-chloro-5-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=C(Cl)C(N=C(N)NC=2C=C(Br)C=CC=2)=C1 BCQMAWUNJNFILR-UHFFFAOYSA-N 0.000 claims description 2
- FMQVGRXEWWSRBA-UHFFFAOYSA-N 1-(5-ethyl-2-fluorophenyl)-2-naphthalen-1-ylguanidine Chemical compound CCC1=CC=C(F)C(NC(=N)NC=2C3=CC=CC=C3C=CC=2)=C1 FMQVGRXEWWSRBA-UHFFFAOYSA-N 0.000 claims description 2
- MXWIORYTZRUPSB-UHFFFAOYSA-N 1-(5-ethyl-2-fluorophenyl)-3-(3-ethylphenyl)-1,3-dimethylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(CC)C=2)F)=C1 MXWIORYTZRUPSB-UHFFFAOYSA-N 0.000 claims description 2
- HJEHWCOOFIHZGK-UHFFFAOYSA-N 1-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1,3-dimethyl-3-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 HJEHWCOOFIHZGK-UHFFFAOYSA-N 0.000 claims description 2
- TZNCNYDAMCIDTL-UHFFFAOYSA-N 1-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 TZNCNYDAMCIDTL-UHFFFAOYSA-N 0.000 claims description 2
- HVRDNPQSANJOLU-UHFFFAOYSA-N 1-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-2-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 HVRDNPQSANJOLU-UHFFFAOYSA-N 0.000 claims description 2
- XNJABMIJAMLXCE-UHFFFAOYSA-N 1-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-3-(3-ethylphenyl)-1,3-dimethylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 XNJABMIJAMLXCE-UHFFFAOYSA-N 0.000 claims description 2
- PBZAUITXNIYNNA-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1-methyl-2-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 PBZAUITXNIYNNA-UHFFFAOYSA-N 0.000 claims description 2
- UAVJHLUSZGEAHR-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-2-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N=C(N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 UAVJHLUSZGEAHR-UHFFFAOYSA-N 0.000 claims description 2
- DJUGXWFWOSCNBP-UHFFFAOYSA-N 2-(2-bromo-5-ethylphenyl)-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)NC=2C(=CC=C(CC)C=2)Br)=C1 DJUGXWFWOSCNBP-UHFFFAOYSA-N 0.000 claims description 2
- IUGLTEXZPZOFOP-UHFFFAOYSA-N 2-(2-bromo-5-ethylphenyl)-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(=N)NC=2C(=CC=C(CC)C=2)Br)=C1 IUGLTEXZPZOFOP-UHFFFAOYSA-N 0.000 claims description 2
- BNGOXCNBHXJYEW-UHFFFAOYSA-N 2-(2-bromo-5-methylsulfanylphenyl)-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)NC=2C(=CC=C(SC)C=2)Br)=C1 BNGOXCNBHXJYEW-UHFFFAOYSA-N 0.000 claims description 2
- MRBJNCCRYFEIKX-UHFFFAOYSA-N 2-(2-bromo-5-methylsulfanylphenyl)-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(N)=NC=2C(=CC=C(SC)C=2)Br)=C1 MRBJNCCRYFEIKX-UHFFFAOYSA-N 0.000 claims description 2
- YGXUFGUISDESJT-UHFFFAOYSA-N 2-(2-bromo-5-methylsulfanylphenyl)-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(NC(N)=NC=2C(=CC=C(SC)C=2)Br)=C1 YGXUFGUISDESJT-UHFFFAOYSA-N 0.000 claims description 2
- GGMIXZOQMFGBLV-UHFFFAOYSA-N 2-(2-bromo-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(=N)NC=2C(=CC=C(SC)C=2)Br)=C1 GGMIXZOQMFGBLV-UHFFFAOYSA-N 0.000 claims description 2
- JDFVXWCNWRNUAA-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)NC=2C(=CC=C(CC)C=2)Cl)=C1 JDFVXWCNWRNUAA-UHFFFAOYSA-N 0.000 claims description 2
- HWLMJMJSNQMMQM-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-iodophenyl)-1-methylguanidine Chemical compound CCC1=CC=C(Cl)C(NC(=N)N(C)C=2C=C(I)C=CC=2)=C1 HWLMJMJSNQMMQM-UHFFFAOYSA-N 0.000 claims description 2
- GGELCBMAEYPTAG-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-iodophenyl)guanidine Chemical compound CCC1=CC=C(Cl)C(NC(=N)NC=2C=C(I)C=CC=2)=C1 GGELCBMAEYPTAG-UHFFFAOYSA-N 0.000 claims description 2
- CAGQZDKRWKTGPU-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Cl)C(N=C(N)NC=2C=C(SC)C=CC=2)=C1 CAGQZDKRWKTGPU-UHFFFAOYSA-N 0.000 claims description 2
- PVPMXTZJNOIHPM-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CCC1=CC=C(Cl)C(N=C(N)N(C)C=2C=C(SC)C=CC=2)=C1 PVPMXTZJNOIHPM-UHFFFAOYSA-N 0.000 claims description 2
- JXZXUBTXFUTIGN-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-(3-iodophenyl)-1-methylguanidine Chemical compound CSC1=CC=C(Cl)C(NC(=N)N(C)C=2C=C(I)C=CC=2)=C1 JXZXUBTXFUTIGN-UHFFFAOYSA-N 0.000 claims description 2
- YJGWJAMJGMMWEO-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-(3-iodophenyl)guanidine Chemical compound CSC1=CC=C(Cl)C(N=C(N)NC=2C=C(I)C=CC=2)=C1 YJGWJAMJGMMWEO-UHFFFAOYSA-N 0.000 claims description 2
- WRCQAVVHFIRQLI-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(NC(N)=NC=2C(=CC=C(SC)C=2)Cl)=C1 WRCQAVVHFIRQLI-UHFFFAOYSA-N 0.000 claims description 2
- FOGWZALTLYMPPP-UHFFFAOYSA-N 2-(3-bromophenyl)-1-(2-chloro-5-methylsulfanylphenyl)-1-methylguanidine Chemical compound CSC1=CC=C(Cl)C(N(C)C(N)=NC=2C=C(Br)C=CC=2)=C1 FOGWZALTLYMPPP-UHFFFAOYSA-N 0.000 claims description 2
- IIFBJNQXQDTCQM-UHFFFAOYSA-N 2-(5-ethyl-2-fluorophenyl)-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)NC=2C(=CC=C(CC)C=2)F)=C1 IIFBJNQXQDTCQM-UHFFFAOYSA-N 0.000 claims description 2
- MUHSCVHVAFJJJQ-UHFFFAOYSA-N 2-(5-ethyl-2-fluorophenyl)-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(=N)NC=2C(=CC=C(CC)C=2)F)=C1 MUHSCVHVAFJJJQ-UHFFFAOYSA-N 0.000 claims description 2
- DGVPWFLBPUWHJP-UHFFFAOYSA-N 2-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 DGVPWFLBPUWHJP-UHFFFAOYSA-N 0.000 claims description 2
- NUJUZEHONDSNNQ-UHFFFAOYSA-N 2-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 NUJUZEHONDSNNQ-UHFFFAOYSA-N 0.000 claims description 2
- RXOVQOSPGINGLJ-UHFFFAOYSA-N 2-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(NC(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 RXOVQOSPGINGLJ-UHFFFAOYSA-N 0.000 claims description 2
- FWDBZPSACBQMDH-UHFFFAOYSA-N 2-[2-bromo-5-(trifluoromethylsulfanyl)phenyl]-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Br)=C1 FWDBZPSACBQMDH-UHFFFAOYSA-N 0.000 claims description 2
- NELANVCEROTAHV-UHFFFAOYSA-N 2-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1-(3-ethylphenyl)-1-methylguanidine Chemical compound CCC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 NELANVCEROTAHV-UHFFFAOYSA-N 0.000 claims description 2
- UXNCDBZZDNOUKK-UHFFFAOYSA-N 2-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1-(3-ethylphenyl)guanidine Chemical compound CCC1=CC=CC(NC(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 UXNCDBZZDNOUKK-UHFFFAOYSA-N 0.000 claims description 2
- GHFVEHZERRLUOZ-UHFFFAOYSA-N 2-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(NC(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 GHFVEHZERRLUOZ-UHFFFAOYSA-N 0.000 claims description 2
- CLLJCGXNPWKSMU-UHFFFAOYSA-N 2-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 CLLJCGXNPWKSMU-UHFFFAOYSA-N 0.000 claims description 2
- 108091006146 Channels Proteins 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 208000029028 brain injury Diseases 0.000 claims description 2
- 230000035945 sensitivity Effects 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims 2
- 210000000278 spinal cord Anatomy 0.000 claims 2
- PTABCVAMJOAPHA-UHFFFAOYSA-N 1-(2-chloro-5-methylsulfanylphenyl)-1-methyl-2-naphthalen-1-ylguanidine Chemical compound CSC1=CC=C(Cl)C(N(C)C(N)=NC=2C3=CC=CC=C3C=CC=2)=C1 PTABCVAMJOAPHA-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
- 239000000460 chlorine Substances 0.000 description 157
- 238000005160 1H NMR spectroscopy Methods 0.000 description 75
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 64
- 239000007787 solid Substances 0.000 description 62
- 239000003513 alkali Substances 0.000 description 60
- 238000004458 analytical method Methods 0.000 description 60
- 238000004364 calculation method Methods 0.000 description 59
- 238000004809 thin layer chromatography Methods 0.000 description 58
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 20
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 20
- 239000000376 reactant Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 15
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 108010063843 Phencyclidine Receptors Proteins 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000000547 substituted alkyl group Chemical group 0.000 description 12
- 229910004298 SiO 2 Inorganic materials 0.000 description 11
- 125000004414 alkyl thio group Chemical group 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 210000002418 meninge Anatomy 0.000 description 10
- 108010085082 sigma receptors Proteins 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 9
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229960002989 glutamic acid Drugs 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 210000002569 neuron Anatomy 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- KCTJOEASAHXBBW-UHFFFAOYSA-N 3-methylamphetamine Chemical compound CC(N)CC1=CC=CC(C)=C1 KCTJOEASAHXBBW-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 description 6
- 208000006011 Stroke Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 230000030833 cell death Effects 0.000 description 6
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000004744 fabric Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 210000003739 neck Anatomy 0.000 description 5
- 229920001021 polysulfide Polymers 0.000 description 5
- 239000005077 polysulfide Substances 0.000 description 5
- 150000008117 polysulfides Polymers 0.000 description 5
- 239000002287 radioligand Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 4
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 102000004310 Ion Channels Human genes 0.000 description 4
- 108090000862 Ion Channels Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000001589 carboacyl group Chemical group 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- JZPLZDDBGXHLIM-UHFFFAOYSA-N (3-ethylphenyl)-methylcyanamide Chemical compound CCC1=CC=CC(N(C)C#N)=C1 JZPLZDDBGXHLIM-UHFFFAOYSA-N 0.000 description 3
- KCHLDNLIJVSRPK-UHFFFAOYSA-N 3-methylsulfanylaniline Chemical compound CSC1=CC=CC(N)=C1 KCHLDNLIJVSRPK-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 3
- 230000000324 neuroprotective effect Effects 0.000 description 3
- 230000002887 neurotoxic effect Effects 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000000700 radioactive tracer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 210000000225 synapse Anatomy 0.000 description 3
- UPZYTGCPTDSRFV-UHFFFAOYSA-N (2-chloro-5-ethylphenyl)cyanamide Chemical compound CCC1=CC=C(Cl)C(NC#N)=C1 UPZYTGCPTDSRFV-UHFFFAOYSA-N 0.000 description 2
- WRTAZRGRFBCKBU-UHFFFAOYSA-N 2,5-dibromoaniline Chemical compound NC1=CC(Br)=CC=C1Br WRTAZRGRFBCKBU-UHFFFAOYSA-N 0.000 description 2
- AVYGCQXNNJPXSS-UHFFFAOYSA-N 2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC=C1Cl AVYGCQXNNJPXSS-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000001738 Nervous System Trauma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- HBCFTQKFAADPMS-UHFFFAOYSA-N carbamimidoylazanium;methanesulfonate Chemical compound NC(N)=N.CS(O)(=O)=O HBCFTQKFAADPMS-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000013172 carotid endarterectomy Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 229960000956 coumarin Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 230000002461 excitatory amino acid Effects 0.000 description 2
- 239000003257 excitatory amino acid Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 208000028412 nervous system injury Diseases 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 150000003512 tertiary amines Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- YVJXKCCZOVMOTD-UHFFFAOYSA-N (3-ethylphenyl)cyanamide Chemical compound CCC1=CC=CC(NC#N)=C1 YVJXKCCZOVMOTD-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- LUKSDHOQKVTGGT-UHFFFAOYSA-N 1-(3-amino-4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C(N)=C1 LUKSDHOQKVTGGT-UHFFFAOYSA-N 0.000 description 1
- AFQSOFCFZWCFCI-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-1,3-dimethyl-3-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 AFQSOFCFZWCFCI-UHFFFAOYSA-N 0.000 description 1
- MOKMFHNQVNRSFB-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethylsulfanyl)phenyl]-3-(3-ethylphenyl)-1,3-dimethylguanidine Chemical compound CCC1=CC=CC(N(C)C(=N)N(C)C=2C(=CC=C(SC(F)(F)F)C=2)Cl)=C1 MOKMFHNQVNRSFB-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- JXTCVZXLUKTIGE-UHFFFAOYSA-N 2-(2-chloro-5-ethylphenyl)-1-(3-ethylphenyl)guanidine;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCC1=CC=CC(NC(N)=NC=2C(=CC=C(CC)C=2)Cl)=C1 JXTCVZXLUKTIGE-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- WJGFDDCMTMHZMN-UHFFFAOYSA-N 2-bromo-5-methylsulfanylbenzoic acid Chemical compound CSC1=CC=C(Br)C(C(O)=O)=C1 WJGFDDCMTMHZMN-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 235000004237 Crocus Nutrition 0.000 description 1
- 241000596148 Crocus Species 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 244000044425 Quisqualis indica Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000010692 aromatic oil Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 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 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- GSGSSRVLLAXORZ-UHFFFAOYSA-N n-methyl-3-methylsulfinylaniline Chemical compound CNC1=CC=CC(S(C)=O)=C1 GSGSSRVLLAXORZ-UHFFFAOYSA-N 0.000 description 1
- ZPOPWKYXLPVDKF-UHFFFAOYSA-N n-methyl-3-methylsulfinylaniline;hydrochloride Chemical compound Cl.CNC1=CC=CC(S(C)=O)=C1 ZPOPWKYXLPVDKF-UHFFFAOYSA-N 0.000 description 1
- CYSBKMAGWFJGLN-UHFFFAOYSA-N n-methyl-3-methylsulfonylaniline Chemical compound CNC1=CC=CC(S(C)(=O)=O)=C1 CYSBKMAGWFJGLN-UHFFFAOYSA-N 0.000 description 1
- RTRJWBAHAZCNKJ-UHFFFAOYSA-N n-methyl-3-methylsulfonylaniline;hydrochloride Chemical compound Cl.CNC1=CC=CC(S(C)(=O)=O)=C1 RTRJWBAHAZCNKJ-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SYNRNTWNYBCYHF-UHFFFAOYSA-N naphthalen-1-ylcyanamide Chemical compound C1=CC=C2C(NC#N)=CC=CC2=C1 SYNRNTWNYBCYHF-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001769 paralizing effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000767 polyaniline Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/42—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
- C07C323/44—X or Y being nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
Abstract
本发明提供了有治疗用途的式I的取代的胍类和使用它们的治疗方法以及包含一种或多种这类胍的药物组合物。
Description
本发明涉及某些取代的胍类,及利用它们的治疗方法和含有一种或多种这种胍类的药物组合物。
许多取代的胍类已经被报道。参见,例如,美国专利
1,411,731,1,422,506,1,597,233,1,642,180,1,672,431,1,730,388,1,756,315,1,795,739,1,850,682,2,145,214,2,254,009,2,633,474,3,117,994,3,140,231,3,159,676,3,228,975,3,248,426,3,252,816,3,283,003,3,270,054,3,301,755,3,320,229,3,301,775,3,409,669,3,479,437,3,547,951,3,639,477,3,681,457,3,769,427,3,784,643,3,803,324,3,908,013,3,949,089,3,975,533,3,976,787,4,060,640,4,014,934,4,161,541,4,709,094,4,906,779,5,093,525,5,190,976 and 5,262,568;和PCT申请WO90/12575,WO91/12797,WO91/18868,和WO92/14697;和H.W.Geluk,et al.,J.Med.Chem.,12:712(1969)。
氨基酸L-谷氨酸广泛被认为在中枢神经系统中的兴奋性突触上起化学传递物质作用。神经元对谷氨酸的响应是复杂的并且似乎是由至少三种不同受体类型即KA,QA和NMDA亚型介导的,每个受体都是用其相对特异性配体命名的,即分别为红藻氨酸,使君子酸和N-甲基-D-天冬氨酸。活化一个或多个这些受体类型的氨基酸被称为兴奋性氨基酸(EAA)。
在大脑中,兴奋性氨基酸受体的NMDA亚型在正常兴奋性突触传递期间被活化。正常条件下NMDA受体的活化是在兴奋性突触上长期强化现象和类记忆现象的原因。神经过度兴奋发生在癫痫发作时,而且已经证明NMDA受体的过分活化对癫痫病理生理学起作用。
NMDA受体还强烈地与神经细胞死亡有关,该死亡发生在脑脊髓缺血之后。当局部缺血脑损伤如中风或心脏病发作时,内生谷氨酸过度释放,造成NMDA受体受到过分刺激。与NMDA受体有关的是离子通道。识别位点即NMDA受体在离子通道外表。当谷氨酸与NMDA受体相互作用时将引起离子通道打开,因此使阳离子流穿过细胞膜,例如,Ca2+和Na+进入细胞,K+流出细胞。可以相信,这种由谷氨酸与NMDA受体相互作用引起的离子流,特别是Ca2+离子流,对神经细胞死亡起着重要作用。参见,例如,S.M.Rothman,et al.,Trends in Neurosci.,10(7):299-302(1987)。
因此,阻碍对NMDA受体活化响应的制剂在神经性疾病如癫痫治疗方面具有治疗用途,并可预防因缺氧或低血糖或脑缺血(发生于中风,损伤和心脏病发作期间)造成的神经细胞死亡。一些神经系统疾病与NMDA受体过分活化引起的神经变性有关。因此,NMDA受体传递响应拮抗剂具有治疗这类疾病如阿尔茨海默病,帕金森病,亨廷顿病,肌萎缩性侧索硬化,唐氏综合症和科尔萨科夫病的能力。
对NMDA受体-离子通道复合物的研究已使被认为是PCP受体的离子通道中的受体位点得以确定。参见
J.P.Vincent,et al.,Proc.Natl.Acad.Sci.USA,76:4678-4682(1979);S.R.Zukin,et al.,Proc.Natl.Acad.Sci.USA,76:5372-5376(1979);M.S.Sonders,et al.,Trends in Neurosci.,11(1):37-40(1988);and N.A.Anis,et al.,Br.J.Pharmacol.,79:565-575(1983).
结合到PCP受体上的化合物可以作为离子通道阻断剂,它可以中断通过细胞膜的离子流。以此方式,与PCP受体相互作用的制剂作为非竞争性拮抗剂来降低NMDA受体上的谷氨酸的激动剂作用。
已知的PCP受体配体包括PCP,即苯环哌啶,类似物有1-〔1-(2-噻吩基)-环己基〕-哌啶(TCP),苯并吗吩烷(sigma)鸦片制剂,和(+)-5-甲基-10,11-二氢-5H-二苯并〔a,d〕环庚烯-5,10-亚胺(即药物MK-801,见美国专利4,399,141)。另见E.H.F.Wong,et al.,Proc.Natl.Acad.Sci.USA,83:7104-7108(1986)和W.J.Thompson,et al.,J.Med.Chem.,33:789-808(1990)。
本发明提供式I取代的胍类及其药物上可接受的盐:
其中R,R1和R2分别代表氢,具有1-20个碳原子的取代或未取代烷基,具有2-20个碳原子的取代或未取代链烯基,具有2-20个碳原子的取代或未取代炔基,具有1-20个碳原子的取代或未取代烷氧基,具有1-20个碳原子的取代或未取代烷硫基,具有1-20个碳原子的取代或未取代氨基烷基,具有至少6个环碳原子的取代或未取代碳环芳基,具有至少6个环碳原子的取代或未取代芳烷基,或具有1-3个环和1-3个杂原子的取代或未取代杂芳香基或杂脂环基,每个环为3-8元环;
R3和R4分别代表卤素,羟基,叠氮基,具有1-20个碳原子的取代或未取代烷基,具有2-20个碳原子的取代或未取代链烯基,具有2-20个碳原子的取代或未取代炔基,具有1-20个碳原子的取代或未取代烷氧基,具有1-20个碳原子的取代或未取代烷硫基,具有1-20个碳原子的取代或未取代氨基烷基,具有至少6个环碳原子的取代或未取代碳环芳基,或具有至少6个环碳原子的取代或未取代芳烷基;
每个R5取代基分别代表卤素,羟基,叠氮基,具有1-20个碳原子的取代或未取代烷基,具有2-20个碳原子的取代或未取代链烯基,具有2-20个碳原子的取代或未取代炔基,具有1-20个碳原子的取代或未取代烷氧基,具有1-20个碳原子的取代或未取代烷硫基,具有1-20个碳原子的取代或未取代氨基烷基,具有至少6个环碳原子的取代或未取代碳环芳基,或具有至少6个环碳原子的取代或未取代芳烷基;
n是整数1-3。
另一方面,本发明提供式II化合物或其药物上可接受的盐:
其中R,R1和R2分别代表氢,具有1-20个碳原子的取代或未取代烷基,具有2-20个碳原子的取代或未取代链烯基,具有2-20个碳原子的取代或未取代炔基,具有1-20个碳原子的取代或未取代烷氧基,具有1-20个碳原子的取代或未取代烷硫基,具有1-20个碳原子的取代或未取代烷基亚磺酰基,具有1-20个碳原子的取代或未取代烷基磺酰基,具有1-20个碳原子的取代或未取代氨基烷基,具有至少6个环碳原子的取代或未取代碳环芳基,具有至少6个环碳原子的取代或未取代芳烷基,或具有1-3个环和1-3个杂原子的取代或未取代杂芳香基或杂脂环基,每个环为3-8元环;
R3,R4和每个R5取代基分别代表卤素,羟基,叠氮基,具有1-20个碳原子的取代或未取代烷基,具有2-20个碳原子的取代或未取代链烯基,具有2-20个碳原子的取代或未取代炔基,具有1-20个碳原子的取代或未取代烷氧基,具有1-20个碳原子的取代或未取代烷硫基,具有1-20个碳原子的取代或未取代烷基亚磺酰基,具有1-20个碳原子的取代或未取代烷基磺酰基,具有1-20个碳原子的取代或未取代氨基烷基,具有至少6个环碳原子的取代或未取代碳环芳基,或具有至少6个环碳原子的取代或未取代芳烷基;n是整数0-3。因此,除了式II的R,R1,R2,R3,R4,R5还可以分别选自具有1-20个碳原子的取代或未取代烷基亚砜和具有1-20个碳原子的取代或未取代烷基磺酰基外,式II的定义与式I的相同。
式I和II的优选化合物显示出对PCP受体的高亲和力。这里所用短语“对PCP受体的高亲和力”表示该化合物在典型PCP受体结合力测定中表现的IC50为1μM或更少,如下面实施例74所述,更优选地,在这种PCP受体测定中IC50为0.5μM或更少。由于下面讨论的原因,至少在某些治疗应用方面,进一步优选的是那些对PCP受体具有这样的高亲和力以及对σ受体也具有高亲和力的式I和II化合物。这里所用短语“对σ受体的高亲和力”表示该化合物在典型σ受体结合力测定中表现的IC50为1μM或更少,如下面实施例75所述,更优选地,在这种σ受体测定中IC50为0.5μM或更少。
本发明取代的胍类有利于多种治疗应用。因此,本发明包括治疗和/或预防神经性疾病如癫痫,神经变性疾病和/或如由于缺氧,低血糖,脑脊髓缺血,脑脊髓创伤等等造成的神经细胞死亡的方法。式I和II化合物对治疗和/或预防多种神经变性疾病也是有用的,例如帕金森病,亨廷顿病,肌萎缩性侧索硬化,阿尔茨海默病,唐氏综合症和科尔萨科夫病。总之,本发明的方法包括施用治疗有效量的式I或式II的一种或多种化合物于动物,包括哺乳动物,特别是人。
本发明还提供含有一种或多种式I或式II化合物和适宜载体的药物组合物。
本发明的其它方面公开如下。
如上定义的式I和II化合物(即本发明化合物)的适宜的卤素取代基包括F,Cl,Br和I。这里对式I和II的引证,或对本发明化合物的引证,同样适用于如在此定义的式Ia,Ib,Ic,IIa,IIb和IIc。因此,这里认可的式I和II的适宜的和优选的取代基同样也是式Ia,Ib,Ic,IIa,IIb和IIc化合物的适宜的和优选的取代基。式I和II化合物的烷基优选具有1-12个碳原子,更优选1-8个碳原子,再优选1-6个碳原子,更进一步优选的是1,2,3或4个碳原子。甲基,乙基和包括异丙基的丙基是特别优选的烷基。这里所用的术语烷基,除非另有说明,是指环基和非环基,当然,该环基应至少含有3个碳环成员。一般直链或支链非环烷基比环基更优选。本发明化合物优选的链烯基和炔基具有一个或多个不饱和键及2-12个碳原子,更优选2-8个碳原子,再优选2-6个碳原子,更进一步优选的是1,2,3或4个碳原子。这里所用的术语链烯基和炔基涉及环基和非环基,尽管通常更优选直链或支链非环基。式I和II化合物优选的烷氧基包括具有一个或多个氧键和1-12个碳原子的基团,更优选1-8个碳原子,再优选1-6个碳原子,更进一步优选的是1,2,3或4个碳原子。式I和II化合物优选的烷硫基包括具有一个或多个硫醚键和1-12个碳原子的基团,更优选1-8个碳原子,再优选1-6个碳原子。具有1,2,3或4个碳原子的烷硫基是特别优选的。本发明化合物优选的烷基亚磺酰基包括具有一个或多个亚砜(SO)基团和1-1 2个碳原子的基团,更优选1-8个碳原子,再优选1-6个碳原子。具有1,2,3或4个碳原子的烷基亚磺酰基是特别优选的。本发明化合物优选的烷基磺酰基包括具有一个或多个磺酰基(SO2)和1-12个碳原子的基团,更优选1-8个碳原子,再优选1-6个碳原子。具有1,2,3或4个碳原子的烷基磺酰基是特别优选的。优选的氨基烷基包括具有一个或多个伯,仲和/或叔胺基和1-12个碳原子的基团,更优选1-8个碳原子,再优选1-6个碳原子,更进一步优选的是1,2,3或4个碳原子。仲和叔胺基团一般比伯胺基团更优选。式I和式II化合物适宜的杂芳香基含有一个或多个N,O或S原子并包括,例如,包括8-香豆素基在内的香豆素基,包括8-喹啉基在内的喹啉基,吡啶基,吡嗪基,嘧啶基,呋喃基,吡咯基,噻吩基,噻唑基,噁唑基,咪唑基,吲哚基,苯并呋喃基和苯并噻唑基。式I和式II化合物适宜的杂脂环基含有一个或多个N,O或S原子并包括,例如,四氢呋喃基,四氢吡喃基,哌啶基,吗啉代和吡咯烷基。式I和式II化合物适宜的碳环芳基包括单和多环化合物,包括含有分开和/或稠合的芳基的多环化合物。典型的碳环芳基含有1-3个分开或稠合环,并有6-18个碳环原子。具体优选的碳环芳基包括苯基有3-取代的苯基,2,5-取代的苯基,2,3,5-取代的和2,4,5-取代的苯基,特别是其中的苯基取代基分别选自相同的上面定义的R3-R5;萘基有1-萘基和2-萘基;联苯基;菲基和蒽基。式I和式II化合物的适宜的芳烷基包括单和多环化合物,包括含有分离和/或稠合芳基的多环化合物。典型的芳烷基含有1-3个分开和/或稠合环以及6-18个碳环原子。优选的芳烷基包括苄基和亚甲基萘基(-CH2-萘基)。
所说式I或式II的取代的R,R1,R2,R3,R4和R5基团(以及下面将说明的式Ia-Ic和IIa-IIc的取代基团)可以在一个或多个适宜的位置被一个或多个适当基团取代,例如,卤素如氟,氯,溴和碘;氰基;羟基;硝基;叠氮基;烷酰基如C1-6烷酰基如乙酰基等等;氨基甲酰基;烷基包括具有1-12个碳原子,或1-6个碳原子,更优选1-3个碳原子的烷基;链烯基和炔基包括具有一个或多个不饱和键和2-12个或2-6个碳原子的那些基团;烷氧基包括具有一个或多个氧键和1-12个或1-6个碳原子的那些基团;芳氧基如苯氧基;烷硫基包括具有一个或多个硫醚键和1-12个或1-6个碳原子的那些基团;氨基烷基如具有一个或多个N原子和1-12个或1-6个碳原子的那些基团。
应该理解,上述烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基和氨基烷基取代基包括其中杂原子直接连接在环系上的那些基团,如碳环芳基或杂环基,以及其中杂原子被亚烷基键与环系隔开的那些基团,例如,1-4个碳原子的那些基团。
式I和式II优选的苯环取代基R3,R4和R5(以及下面将说明的式Ia-Ic和IIa-IIc的苯环取代基)包括卤素,特别是F,Cl和Br,羟基,叠氮基,取代或未取代的烷基包括卤代烷基,取代或未取代的烷氧基包括卤代烷氧基,取代或未取代的烷硫基。典型优选的苯环取代基具有1-4个碳原子,且甲基,乙基和包括异丙基在内的丙基是特别优选的。卤素取代的烷基和烷氧基也是特别优选的,包括具有1,2,3或4个碳原子的氟代烷基,如三氟甲基,以及具有1,2,3或4个碳原子的氟取代的烷氧基,如三氟甲氧基(-OCF3)。甲硫基(-SCH3)和乙硫基(-SCH2CH3)也是特别优选的苯环取代基。
本发明优选的化合物包括三取代化合物,其中上面定义的结构式中的胍取代基R,R1和R2之一(或下面将说明的式Ia-Ic和IIa-IIc的相应的胍取代基)是氢,而另外两个取代基不能是氢,优选其中R或R1是杂环芳基或碳环芳基,更优选其中R是取代或未取代的杂环芳基,或取代或未取代的碳环芳基,且R1和R2之一是氢而另一个是取代或未取代的烷基。也优选N,N′-二取代化合物,即式I或II的R和R1之一(或式Ia-Ic和IIa-IIc的相应的胍取代基)是氢且R2是氢,优选其中R是取代或未取代的杂环芳基或取代或未取代的碳环芳基,且R1和R2是氢。还优选N,N,N′,N′-四取代化合物,即式I或II的各取代基R,R1和R2(或式Ia-Ic和IIa-IIc的相应的胍取代基)不是氢且R2是氢,优选其中R或R1是取代或未取代的杂环芳基,或取代或未取代的碳环芳基,更优选其中R是取代或未取代的杂环芳基,或取代或未取代的碳环芳基,且R1和R2分别为取代或未取代烷基。在任何情况下,一般至少式I或II化合物的取代基R和R1之一不是氢。
式II化合物的优选的R3,R4和R5烷基亚磺酰基(以及下面将说明的式IIa-IIc化合物的苯环烷基亚磺酰基)典型地具有一个或多个亚砜基团,更典型的是具有1-2个亚砜基团和1-8个碳原子,更优选1-6个碳原子,再优选的是1-3个碳原子。甲基亚磺酰基(-S(O)CH3)和乙基亚磺酰基(-S(O)CH2CH3)是特别优选的R3,R4和R5烷基亚磺酰基。优选的取代的烷基亚磺酰基包括含有一个或多个F,Cl,Br或I原子的卤代烷基亚磺酰基,优选一个或多个F原子和1-3个碳原子,更优选1或2个碳原子。具体优选的基团包括氟甲基亚磺酰基,特别是三氟甲基亚磺酰基(-S(O)CF3),和氟乙基亚磺酰基如2-三氟乙基亚磺酰基(-S(O)CH2CF3)和五氟乙基亚磺酰基(-S(O)CF2CF3)。
式II化合物的优选的R3,R4和R5烷基磺酰基(以及下面将说明的式IIa-IIc化合物的苯环烷基磺酰基)典型地具有一个或多个磺酰基(SO2),更典型的是具有一个磺酰基和1-8个碳原子,更优选1-6个碳原子,再优选的是1-3个碳原子。甲基磺酰基(-S(O)2CH3)和乙基磺酰基(-S(O)2CH2CH3)是特别优选的R3和R4磺酰基烷基。优选的取代的烷基磺酰基包括含有一个或多个F,Cl,Br或I原子的卤代烷基磺酰基,优选一个或多个F原子和1-3个碳原子,更优选1或2个碳原子。具体优选的基团包括氟甲基磺酰基,特别是三氟甲基磺酰基(-S(O)2CF3),和氟乙基磺酰基如2-三氟乙基磺酰基(-S(O)2CH2CF3)和五氟乙基磺酰基(-S(O)2CF2CF3)。
特别优选的R和R1基团包括至少在2,5环位上取代的苯基。例如,优选下列式Ia化合物及其药物上可接受的盐:
其中R和R2如式I定义;各R3,R4,R5,R3′,R4′和R5′取代基分别选自相同的式I中定义的R3-R5取代基;m和n分别为整数0-3。优选的式Ia化合物包括至少R和R2其中之一不是杂环芳基或碳环芳基的那些化合物,例如,至少R和R2其中之一是氢或取代或未取代的烷基,特别优选具有1,2,3或4个碳原子的取代或未取代的烷基。式Ia中m和n的优选值为0和1。
另外优选的是式IIa化合物,定义同上述式Ia,但其中的每个取代基,特别是R3,R4,R5,R3′,R4′和R5′取代基可以分别为具有1-20个碳原子的烷基亚磺酰基或具有1-20个碳原子的烷基磺酰基。式Ha优选的化合物包括至少R和R2其中之一不是杂环芳基或碳环芳基的那些化合物,例如,至少R和R2其中之一是氢或取代或未取代的烷基,特别优选具有1,2,3或4个碳原子的取代或未取代的烷基。式IIa中m和n的优选值为0和1。
式I进一步优选的化合物包括那些其中n等于1的化合物,特别是n等于1且苯环在3-或4-位被R5取代,即苯环是2,3,5-取代的或2,4,5-取代的。
这样的式II化合物也是优选的,即n等于1的式II化合物,特别是n等于1且苯环在3-或4-位被R5取代,即苯环是2,3,5-取代的或2,4,5-取代的。
式I特别优选的化合物是那些其中n等于0的化合物(即苯环的3,4和6位上被氢取代),特别是下列式Ib化合物及其药物上可接受的盐:
其中R至R4如上述式I中定义;特别优选的式Ib化合物包括其中R是取代或未取代的杂环芳基或取代或未取代的碳环芳基如取代或未取代的苯基或萘基,以及至少R1和R2其中之一不是杂环芳基或碳环芳基的那些化合物,例如,至少R1和R2其中之一是氢或取代或未取代的烷基,特别优选具有1,2,3或4个碳原子的取代或未取代的烷基的化合物。
另外优选的是式IIb化合物,定义同上述式Ib,但其中的每个取代基,特别是R3和R4取代基可以分别为具有1-20个碳原子的烷基亚磺酰基或具有1-20个碳原子的烷基磺酰基。特别优选的式IIb化合物包括那些其中R是取代或未取代杂环芳基或取代或未取代碳环芳基的化合物如取代或未取代的苯基或萘基,以及至少R1和R2其中之一不是杂环芳基或碳环芳基,例如,至少R1和R2其中之一是氢或取代或未取代的烷基,特别是具有1,2,3或4个碳原子的取代或未取代的烷基的化合物。
本发明进一步优选的化合物除了2,5-位被取代的苯基部分之外,还具有至少一个胍取代基(即式I或II的R,R1或R2),即在3-位被取代的苯基,优选在其它环位没有取代。特别优选的是下式Ic的N-(3-取代苯基)-N′-(2,5-二取代苯基)胍及其药物上可接受的盐:
其中R和R2如上述式I中定义;各R3′,R4′,R5′和R3″取代基分别选自相同的式I中定义的R3、R4和R5取代基;n是整数0-3。特别优选的式Ic化合物包括至少R和R2其中之一不是杂环芳基或碳环芳基的那些化合物,例如,至少R和R2其中之一是氢或取代或未取代的烷基,特别是具有1-4个碳原子的取代或未取代的烷基。特别优选的式Ic化合物是R和R2其中之一是氢,而另一个是具有1,2,3或4个碳原子的取代或未取代的烷基,更优选的是其中R为甲基,乙基或丙基,而R2为氢的化合物。式Ic的优选n值为0和1。
另外优选的是式IIc化合物,定义同上述式Ic,但其中的每个取代基,特别是R3′,R4′,R5′和R3″取代基可以分别为具有1-20个碳原子的烷基亚磺酰基或具有1-20个碳原子的烷基磺酰基。优选的式IIc化合物包括那些R和R2其中之一不是杂环芳基或碳环芳基的化合物,例如,至少R1和R2其中之一是氢或取代或未取代的烷基,特别是具有1,2,3或4个碳原子的取代或未取代的烷基的化合物。特别优选的式IIc化合物是R和R2其中之一是氢,而另一个是具有1-4个碳原子的取代或未取代的烷基,更优选的是其中R为甲基,乙基或丙基,而R2为氢的化合物。式IIc的优选n值为0和1。
式I和II优选化合物表现出对PCP受体高的亲和力。至少对于一些治疗应用,对PCP受体和σ受体表现高亲和力的式I或II化合物可以优选。然而,不要被理论束缚,可以想见,对PCP受体和σ受体具有高亲和力的药剂能够给予上述疾病以有效的治疗,而没有一些以前NMDA受体拮抗剂所表现出的液泡损伤的危险。例如,参见Olnoy et al.,Science,244:1360-1364(1989)。
不希望被理论所束缚,含有烷基亚磺酰基和/或烷基磺酰基的本发明化合物实际上可以作为“药物前体”,在给患者服用该化合物之后,亚磺酰基或磺酰基在体内被代谢(还原)成相应的硫醚部分。特别是,具有芳基取代基且其环上被一个或多个烷基亚磺酰基和/或烷基磺酰基取代的本发明化合物可以是有效的药物前体。因此,式II优选化合物包括那些含有碳环或杂环基的化合物,如被一个或多个具有1-4个碳原子的烷基亚磺酰基或烷基磺酰基取代的萘基或苯基。
本发明特别优选的化合物包括下列化合物及其药物上可接受的盐:
N-(3-乙基苯基)-N,N′-二甲基-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N′-(2,5-二氯苯基)-N′-甲基胍;
N-(3-乙基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N′-(2,5-二溴苯基)-N′-甲基胍;
N-(3-乙基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氟-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲硫基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-甲硫基)胍;
N-(1-萘基)-N′-(2-溴-5-乙基苯基)胍;
N-(1-萘基)-N′-(2-氟-5-乙基苯基)胍;
N-(1-萘基)-N′-(2,5-二氯苯基)胍;
N-(1-萘基)-N′-(2-氟-5-甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,4,5-三氯苯基)胍;
N-(3-乙基苯基)-N′-(2,4,5-三氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,3,5-三氯苯基)胍;
N-(3-乙基苯基)-N′-(2,3,5-三氯苯基)胍;
N-(1-萘基)-N′-(2,4,5-三氯苯基)胍;
N-(1-萘基)-N′-(2,3,5-三氯苯基)胍;
N-(1-萘基)-N′-(2,5-二氯苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2-氯-5-甲基苯基)胍;
N-(1-萘基)-N′-(2,5-二甲基苯基)胍;
N-(1-萘基)-N′-(2,5-二溴苯基)胍;
N-(1-萘基)-N′-(2-氯-5-甲基苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2,5-二甲基苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2,5-二溴苯基)-N-甲基胍;
N-(1-萘基)-N′-(2,5-二溴苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2-氯-5-硫甲基苯基)胍;
N-(1-萘基)-N′-(2-氟-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-溴-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-硫甲基-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-甲氧基-5-甲基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-乙基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-乙基苯基)-N′-甲基胍;
N-(1-萘基)-N′-甲基-N′-(2-氯-5-硫甲基苯基)胍;
N-(8-喹啉基)-N′-(2-氯-5-甲基苯基)胍;
N-(8-喹啉基)-N′-(2-氯-5-乙基苯基)胍;
N-(8-喹啉基)-N′-甲基-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲硫基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-溴苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-溴苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-溴苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲氧基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲氧基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲氧基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲基磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基磺酰基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基磺酰基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-甲基亚磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基亚磺酰基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基亚磺酰基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-碘苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-碘苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-碘苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(1-萘基)-N′-(2-碘-5-甲硫基苯基)胍;
N-(1-萘基)-N′-(2-溴-5-甲硫基苯基)胍。
还有特别优选的是上面特别指定的并具有一个或多个不是氢的附加胍取代基(即式I或II的R,R1或R2取代基)的化合物,特别是一个或多个附加取代基是取代或未取代的烷基,尤其是未取代的甲基,乙基,丙基,丁基,戊基或己基,更优选的是未取代的甲基,乙基或丙基。例如,四取代化合物是特别优选的,如二烷基-,二芳基取代的化合物如N-(3-乙基苯基)-N,N′-二甲基-N′-(2,5-二溴苯基)胍,N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲基苯基)胍等等。
本发明更进一步提供式II′化合物,其定义同上述式II,但其中每个取代基R3,R4和每个R5也可以分别为硝基,氰基,取代或未取代的烷酰基或取代或未取代的羧基。这里公开的式II化合物的适宜和优选的取代基也是式II′适宜和优选的取代基。式II适宜的烷酰基具有1-8个碳原子,更优选1-4个碳原子。乙酰基是特别适宜的烷酰基。式II′的羧基包括式-(CH2)nCOOY的酸和酯基,其中n是整数0-8,更优选1,2,3或4,Y是氢或取代或未取代的烷基,优选具有1-6个碳原子,或1-3个碳原子。式II′化合物可以按此处公开的式I和II化合物的合成方法制备。本发明还包括式II′化合物在所公开的治疗方法中的用途,其中式II′化合物以与式I和II相同的方式说明。
式I和II化合物可以很容易地通过胺反应来制备,典型地是通过胺盐如胺盐酸盐与预先制备的烷基或芳基氨腈(见S.R.Safer,etal.,J.Org.Chem.,13:924(1948))或相应的N-取代的烷基或芳基氨腈进行反应。这是制备N,N′-二芳基-N′-烷基胍特别适宜的方法,其中取代基不相同。对于不对称胍类的合成,见G.J.Durant,et al.,J.Med.Chem.,28:1414(1985),和C.A.Maryanoff,et al.,J.Org.Chem.,51:1882(1986),在此引作参考。对胍类合成的其它讨论见PCT申请WO 91/12797和美国专利5,093,525,5,262,568和5,265,568,在此全部引作参考。另见H.W.J.Cressman,Org.Syn.Coll.,3:608-609(1955);M.P.Kavanaugh,et al.,Proc.Natl.Acad.Sci.USA,83:8784-8788(1986),在此也全部引作参考。
更具体地,式(I)和式(II)化合物可以通过适宜的胺盐如胺盐酸盐与少量摩尔过量(例如1.1摩尔当量)的取代的氨腈在适宜的溶剂如甲苯或氯苯和惰性气氛如氩气或氮气下反应来制备。然后将反应溶液从110℃到120℃加热2-16小时直到反应完成,例如用薄层色谱法监视。将反应溶液冷却至室温,然后最好用溶剂如无水乙醇稀释。减压除去溶剂得到所需的取代胍。粗产物可以用重结晶和/或快速色谱法纯化,例如,在硅胶(60-200目,50xw/w)上用5-25%甲醇的乙酸乙酯洗脱。适宜的重结晶溶剂包括乙醇/乙酸乙酯混合物或乙醇/乙醚混合物。具有适当取代基(即,R,R1,R2和R3,R4,R5-取代的苯基取代基)的氨腈和胺试剂为商品或容易地用已知方法制备。例如,氨腈起始原料可以用溴化氰(BrCN)在适宜的溶剂如无水乙醚中处理相应的取代胺来合成。胺盐酸盐可由用过量的HCl处理适宜的胺得到。例如,2,5-取代的苯胺盐酸盐可通过加入甲醇的HCl至冷却的取代的苯胺溶液中然后在室温搅拌30分钟来制备。烷基亚磺酰基取代的或烷基磺酰基取代的试剂(它们能提供如上所述的本发明的相应的取代的化合物)通过氧化(例如,H2O2)烷硫基取代的试剂来得到。参见,例如,下列实施例5。
如上所述,本发明包括治疗或预防某些神经性疾病,包括脑中风或创伤损伤,癫痫或神经变性疾病的方法,该方法包括根据治疗需要将有效量的一种或多种式I或II的胍类给药于患者包括哺乳动物,特别是人。特别是,本发明提供治疗和/或预防由,比如,缺氧,低血糖,脑脊髓缺血,脑脊髓创伤,中风,心脏病发作或溺水造成的神经细胞死亡的方法。典型的待治患者包括,比如,心脏病发作,中风,脑脊髓损伤患者,经过重大手术如心脏手术的患者,此时脑缺血是潜在的并发症,以及由于血流中气泡栓存在而患有减压症的的患者如潜水员。
特别地,本发明提供治疗方法,即给那些经历手术或其它治疗,而脑脊髓缺血是潜在危险的病人服用本发明的一种或多种化合物。例如,颈动脉内膜切除术是用于校正颈动脉粥样硬化的外科手术。与该治疗相关的主要危险包括手术中气栓和随大脑血流增加产生的脑部高血压的危险,它们可以导致动脉瘤或出血。因此,手术前或手术中应服用有效量的本发明的一种或多种化合物以减小伴随颈动脉内膜切除术产生的那些危险。
本发明还包括预防由冠状动脉旁路移植和主动脉阀更换手术引起的神经性疾病的方法。这些方法应包括给经历这些外科手术的病人服用有效量的本发明的一种或多种化合物,典型地是在手术前或手术中服用。
本发明还提供预防经过可能造成有损于病人的局部缺血的手术的心肌梗塞病人患神经性损伤的方法。这些方法应包括给经历这些外科手术的病人服用有效量的本发明的一种或多种化合物,典型地是在手术前或手术中服用。
本发明还提供治疗或预防神经疼痛的方法,如癌症病人,糖尿病患者,截肢病人和其他可能经历神经疼痛的人。这些治疗方法包括根据治疗需要给病人服用有效量的式I或II的一种或多种化合物。
进一步提供的是改善由谷氨酸与神经细胞的NMDA受体相互作用引起的神经毒性作用的方法,包括给表现这种神经毒性症状或对神经毒性作用敏感的患者如哺乳动物,特别是人,服用能改善神经毒性作用的有效量的式I或II的一种或多种化合物。
本发明还提供抑制与NMDA受体离子通道有关的神经毒性的方法,包括根据治疗需要给患者如哺乳动物,特别是人,服用能抑制或防止这种神经毒性的有效量的式I或II的一种或多种化合物。
本发明进一步提供治疗科尔萨科夫病,慢性酒精中毒引起的疾病的方法,包括给患者包括哺乳动物,特别是人,服用能治疗这种疾病的有效量的式I或II的一种或多种化合物。用NMDA拮抗剂MK-801(Merck Index,monograph 3392,11th ed.,1989)对动物的预治疗明显减弱科尔萨科夫病大鼠模型中细胞丧失的程度,出血和氨基酸的变化。见P.J.Langlais,et aL.,Soc.Neurosci.Abstr.,14:774(1988)。因此,本发明化合物具有减弱伴随科尔萨科夫病而来的细胞丧失,出血和氨基酸改变的用途。
本发明还提供确定本发明化合物结合活性,例如,对NMDA受体的结合活性的方法,以及用一种或多种式I或II的放射性示踪化合物,例如,用125I,3H,32P,99Tc等等,优选125I,示踪的本发明化合物在体外或体内结合活性的诊断方法。例如,具有苯基取代基,即环上被一个或多个125I取代的本发明化合物可以用于哺乳动物,然后对对象进行扫描以检查该化合物与NMDA受体的结合情况。具体讲,单光子发射计算X射线断层照相(“SPECT”)能用于检测这种结合。这种哺乳动物的分析方法例如有助于急性大脑缺血的诊断和治疗。
因此,本发明包括含有放射性示踪元素如125I,3H,32P,99Tc等等,优选125I,的式I或II化合物。这些放射性示踪化合物可以用合成领域中已知的方法很容易地制备。例如,具有芳香基如苯基,带有溴或氯环取代基的本发明化合物可以用于示踪反应的交换以得到相应的含有125I环取代基的化合物。
式I和II化合物的某些药物活性可以通过,比如,下列方法确定:(a)通过氚标记的MK-801的竞争性置换确定对于PCP受体的结合亲和力;(b)通过测量该化合物防止由于暴露于谷氨酸而引起的神经细胞死亡的能力在体外进行细胞毒性研究;(c)用动物模型确定体内神经保护能力。
用放射性配体结合力测定法很适宜进行对式I和II化合物对于PCP受体结合活性的评价。对这些化合物进行试验以确定它们置换氚示踪的MK-801的能力,MK-801用于标记PCP受体。用于评价竞争性置换的结合数据的优选的化合物是那些对PCP受体表现出高亲和力(即低IC50值)的化合物。在这些PCP结合活性的研究中,IC50值至多为1μM,优选至多为0.5μM时,表示高结合亲和力。
如上所述,在σ结合研究中,IC50值小于1μM即表示化合物对σ受体具有高结合亲和力。σ受体结合测定,优选对比3H-DTG,可以用E.Weber,et al.,Proc.Natl.Acad.Sci.(USA),83:8784-8788(1986)上公开的方法进行,该文在此引作参考。
式I和II化合物可以与其它药物一起用于治疗。例如,对于中风患者的治疗,式I或II的一种或多种化合物可适当地与作为血液凝固机制相互作用目标的药物如链激酶,tPA,尿激酶和其它溶解血块的药剂一起服用。
如上所述,优选的式I和II胍类表现出对PCP受体高的亲和力。因此,除了治疗上面讨论的神经变性和的有关的疾病外,本发明的胍类还可以用作在动物模型中进行潜在PCP受体配体检查的药物工具。
本发明化合物可以鼻内,口服或注射如肌肉,腹膜内,皮下或静脉注射给药,或通过透皮,眼内或肠内方式给药。最佳剂量可以通过常规方法确定。本发明胍类适合于以质子化和水溶性形式施用于患者,例如,药物上可接受的有机或无机酸盐形式如盐酸盐,硫酸盐,半硫酸盐,磷酸盐,硝酸盐,乙酸盐,草酸盐,柠檬酸盐,马来酸盐等等。
本发明化合物既可以单独使用,也可以同一种或多种上述其它的治疗剂结合使用,如与常规赋形剂,即,不与活性化合物进行有害反应的并对接受者本身无害的适合于肠外,肠内或鼻内使用的药物上可接受的有机或无机载体混合成药物组合物。适宜的药物上可接受的载体包括(但不限于)水,盐溶液,醇,蔬菜油,聚乙二醇,明胶,乳糖,直链淀粉,硬脂酸镁,滑石,硅酸,粘性石蜡,芳香油,脂肪酸甘油一酯和甘油二酯,石油醚脂肪酸酯,羟甲基纤维素,聚乙烯吡咯烷酮等等。药物制剂可以采用灭菌消毒和,如果需要,与不会与活性化合化剂,影响渗透压力的盐,缓冲剂,着色剂,调味剂和/或芳香族物质等等混合。
为肠外使用,特别适合的是溶液,优选油或水溶液,以及悬浮液,乳浊液或植入剂包括栓剂。安瓿是常规单位剂型。
对肠内使用,特别适合的是片剂,糖衣丸或用滑石和/或碳水化合物载体作为结合剂的胶囊等等,优选的载体有乳糖和/或玉米淀粉和/或马铃薯淀粉。糖浆,酏剂等等都可以使用,其中可使用甜味载体。缓释组合物可用于制剂,包括其中活性组分被不同可崩解包衣保护,保护方式包括,例如,装入微胶囊,多包衣等等。
静脉或肠外给药如皮下,腹膜内或肌肉内给药是优选的。本发明化合物对治疗哺乳动物如人特别有价值,其中所患疾病的病理生理学涉及由NMDA受体激动剂引起的神经细胞过度兴奋。典型的患者包括那些患有神经变性疾病如帕金森病,亨廷顿病,肌萎缩性侧索硬化,阿尔茨海默病,唐氏综合症和科尔萨科夫病的患者。还适合于治疗那些患有或可能患有由,例如,癫痫或缺血,低血糖,脑脊髓缺血或脑脊髓创伤造成的神经细胞变性而引起的神经系统机能不良的病人。综上所述,典型的治疗患者是心脏病发作,中风,脑脊髓损伤病人,经历重大外科手术,其时脑脊髓缺血是潜在的并发症的病人,以及由于血流中气泡栓存在而患有减压症的病人如潜水员。
应该认识到,用于给定治疗的活性化合物的实际优选剂量将根据所用的具体化合物,用于制剂的特定组合物,使用方式,给药的特定部位等等而变化。对于给定给药的最佳给药率可以由本领域技术人员很容易地利用针对前述指导进行的常规剂量测定试验来确定。合适的一种或多种式I或式II化合物,特别是当使用药效更强式I合适的一种或多种式I或式II化合物,特别是当使用药效更强式I或II化合物时的有效剂量一般在每天每公斤接受者体重0.01-100毫克范围,优选范围为0.01-20mg/kg/天,更优选0.05-4mg/kg/天。所需的剂量适宜的给药方式为每天一次,或分成几次如2-4次,以每天合适的间隔或按其它适当的安排给药。这种分次给药可以单位药剂形式给药,例如,每单位制剂含有0.05-10mg,优选0.2-2mg式I或II化合物。
如同以前的胍类,如美国专利1,411,713记载的那些,本发明胍类也应该具有作为摩擦加速剂的用途。
以上和以下引证的所有申请,专利和公开的全文在此均引作参考。
下列非限制性实施例用于说明本发明。
在下列实施例中,熔点(mp)是在Thomas-Hoover仪(化合物熔点<230℃)上在开口毛细管中测定的,并且没有修正。所有化合物的NMR谱记录于General Electric QE-300或Bruker 300上,化学位移用相对于氚化溶剂的残留信号的ppm表示(CHCl3,7.26ppm;HCD2OD,3.30ppm;TMS,0.00ppm)。IR谱在有或无CHCl3情况下记录于Nicolet 5DXB FT-IR或1420型Perkin-Elmer上。所有化合物的IR和NMR谱与它们的指定结构一致。元素分析由M-H-W Laboratories(Phoenix,AZ)或Galbraith Laboratorics(Knoxvillc,TN)完成。1-萘基胺,溴化氰,3-乙基苯胺和氯苯从Aldrich Chemi-cal Company得到并按收到的那样使用。所有其它溶剂均为试剂级。可用来制备实施例27-46和51的化合物的1-萘基氨腈适宜通过下述过程制备:在0℃将17.5mL(87.5mMol)BrCN(5.0M的CH3CN;Aldrich)溶液通过套管加到20.0g(140mMol)1-萘基胺的乙醚溶液中。0.5小时后移去冷却浴并将混合物在室温搅拌过夜(14小时)。胺·HBr的结晶沉淀形成,吸滤除去该沉淀,用乙酸乙酯(15mL×3)洗涤。真空浓缩滤液,得到12.5g粗氨腈的红紫色固体,其TLC表示尚有少量氢溴酸胺盐存在。将该粗固体用水(200mL)搅拌1小时,吸滤之后留下粉红色固体,真空干燥过夜,得到9.2g(78.3%)纯1-萘基氨腈。
实施例1 N-(3-乙基苯基)-N-甲基-N′-(2,5-二氯苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=R4=Cl,n=0的盐酸盐)的制备。
部分1:N-(3-乙基苯基)-N-甲基氨腈的制备
步骤A:3-乙基苯基氨腈
在4℃将溴化氰(11.36g,107mmol)的无水乙醚(50mL)溶液缓慢加到搅拌着的3-乙基苯胺(20.8g,171mmol)的乙醚溶液中。之后将反应混合物在24℃搅拌12小时使之成为带有白色沉淀的棕色溶液。滤除沉淀;将滤液用含水HCl(1N,3×150mL)和盐水(60mL)洗涤。然后将此醚化溶液在MgSO4上干燥,过滤,浓缩得到浓液体。将该粗产物用色谱法(SiO2,己烷,己烷/CH2Cl2,CH2Cl2)进一步纯化,得到3-乙基苯基氨腈液体(11.6g,76%产率)。
步骤B:N-(3-乙基苯基)-N-甲基氨腈
将3-乙基苯基氨腈(4.65g,31.8mmol)和氢化钠(2.55g,80%NaH于矿物油中的悬浮液,63.6mmol的NaH)于无水THF中的悬浮液加热回流3小时。将反应混合物在冰浴中冷却,然后搅拌着滴加甲基碘(11.28g,79.5mmol)。将反应混合物搅拌15小时,接着再加入MeOH(10mL)。将反应混合物浓缩至干,得到粗产物。在粗产物中加入蒸馏水(40mL),然后用CH2Cl2(4×40mL)萃取。合并的有机萃取液用水(3×30mL)洗涤,然后用MgSO4干燥。除去溶剂,得到的粗产物为琥珀色浆状物。将粗产物用快速色谱法(SiO2,CH2Cl2)纯化,得到4.2g(75%产率)所需产品。
部分2:2,5-二氯苯胺盐酸盐的制备
在4℃将甲醇盐酸(1M,30mL)加入2,5-二氯苯胺(Aldrich,1.5g,9mmol)的甲醇(10mL)溶液中,然后将反应混合物在25℃搅拌30分钟。将所得溶液蒸发并真空干燥,得到1.6g 2,5-二氯苯胺盐酸盐(88%产率)。
部分3:胍的合成
将N-(3-乙基苯基)-N-甲基氨腈(520mg,3.3mmol),2,5-二氯苯胺(600mg,3mmol)和氯苯(2mL)的混合物在氮气下在装有水冷凝器的干燥圆底颈瓶中混合,然后将其放入预热的油浴中(150-160℃)。将反应混合物加热4小时。冷却后将反应粗产物通过从氯苯/乙醚结晶来纯化。过滤收集晶体,用乙醚洗涤,在真空炉中干燥(40℃,15小时),得到标题化合物N-(3-乙基苯基)-N-甲基-N′-(2,5-二氯苯基)胍盐酸盐为白色固体(760mg,72%产率)。
TLC:Rf=0.45(10% MeOH/CH2Cl2);mp:162-163℃;1H NMR(CD3OD):δ7.53-7.23(m,7H,Ar-H),3.48(s,3H,CH3),2.70(q,J=7.6Hz,2H,CH2),1.26(t,J=7.6Hz,3H,CH3);MS(EI):m/e 322(M+游离碱;元素分析:C16H17Cl2N3·HCl;计算值(%):C:53.57,H:5.05,N:11.71;实测值(%):C:53.66,H:5.20,N:11.71.
实施例2 N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)的制备
部分1:2,5-二溴苯胺盐酸盐的制备
在4℃将甲醇盐酸(1M,30mL)加入2,5-二溴苯胺(Aldrich,1.5g,6mmol)的甲醇(5mL)溶液中,然后将反应混合物在25℃搅拌30分钟。该反应混合物变成带有白色沉淀的浅棕色溶液。过滤收集沉淀,用乙醚(2mL)洗涤,真空干燥,得到1.6g 2,5-二溴苯胺盐酸盐(93%产率)。
部分2:胍的合成
将N-(3-乙基苯基)-N-甲基氨腈(520mg,3.3mmol),2,5-二溴苯胺盐酸盐(861mg,3mmol)和氯苯(2mL)的混合物在氮气下在装有水冷凝器的干燥圆底颈瓶中混合,然后将其放入预热的油浴中(150-160℃)。将反应混合物加热3小时。冷却后将反应粗产物通过从氯苯/乙醚结晶来纯化。过滤收集晶体,用乙醚洗涤,在真空炉中干燥(40℃,15小时),得到标题化合物N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐为白色固体(780mg,59%产率)。
TLC:Rf=0.5(10% MeOH/CH2Cl2);mp:217-218℃;1H NMR(CD3OD):δ7.56-7.20(m,7H,Ar-H),3.41(s,3H,CH3),2.62(q,J=7.7Hz,2H,CH2),1.18(t,J=7.7Hz,3H,CH3);MS(EI):m/e 411(M+游离碱;元素分析:C16H17Br2N3·HCl;计算值(%):C:42.93,H:4.05,N:9.39;实测值(%):C:42.90,H:4.01,N:9.13.
实施例3 N-(3-乙基苯基)-N′-(2,5-二氯苯基)胍甲磺酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=R4=Cl,n=0的甲磺酸盐)的制备
部分1:2,5-二氯苯基氨腈的制备
在4℃将固体BrCN(1.22g,11.3mmol)缓慢加入2,5-二氯苯胺(3.0g,18.5mmol)的60mL水的不均匀浆液中。5分钟后移去冷却浴,将非均匀反应混合物在室温搅拌24小时,得到水悬浮液中的产物。过滤收集该产物,用水(100mL)洗涤,真空干燥,得到粗产物(2g,60%产率)。
部分2:3-乙基苯胺甲磺酸盐的制备
在4℃将甲磺酸(4.4g,45mmol)加入3-乙基苯胺(Aldrich,4.84g,40mmol)的甲醇(10mL)溶液中,然后将反应混合物在25℃搅拌30分钟,得到带有白色沉淀的溶液。过滤收集该沉淀,用乙醚洗涤,真空干燥,得到7.7g 3-乙基苯胺甲磺酸盐(7.7g,91%产率)。
部分3:胍的合成
将2,5-二氯苯基氨腈(1.02g,5.5mmol),3-乙基苯胺甲磺酸盐(1.1g,5mmol)和氯苯(15mL)的混合物在氮气下在装有水冷凝器的干燥圆底颈瓶中混合,然后将其放入预热的油浴(150-160℃)中。将反应混合物加热2小时。冷却后将反应粗产物通过从氯苯/乙醚结晶来纯化。过滤收集晶体,用乙醚洗涤,在真空炉中干燥(40℃,15小时),得到标题化合物N-(3-乙基苯基)-N′-(2,5-二氯苯基)胍甲磺酸盐为白色固体(1.5g,75%产率)。
TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:220-221℃;1H NMR(300MHz,CD3OD):δ7.58-7.17(m,7H,Ar-H),2.68(s,3H,SO3CH3),2.68(m,2H,CH3),1.24(t,J=7.6Hz,CH3)元素分析C16H19Cl2N3O3;计算值(%):C:47.83,H:4.74,N:10.39;实测值(%):C:47.44,H:4.64,N:10.27.
实施例4 N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍甲磺酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Cl,R4=CH2CH3,n=0的甲磺酸盐)的制备
部分1:2-氯-5-乙基苯基氨腈的制备
在4℃将固体BrCN(0.848g,8mmol)缓慢加入2-氯-5-乙基苯胺(1.6g,10mmol)的60mL水的不均匀浆液中。5分钟后移去冷却浴,将非均匀反应混合物在室温搅拌24小时,得到水悬浮液中的产物。过滤收集该沉淀,用水(100mL)洗涤,真空干燥,得到纯标题化合物(1.45g,80%产率)。
部分2:胍的合成
将2-氯-5-乙基苯基氨腈(0.6g,3.08mmol),3-乙基苯胺甲磺酸盐(0.64g,2.93mmol)和氯苯(12mL)的混合物在氮气下在装有水冷凝器的干燥圆底颈瓶中混合,然后将其放入预热的油浴(150-160℃)中。将反应混合物加热3小时。冷却后将反应粗产物通过从氯苯/乙醚结晶来纯化。过滤收集晶体,用乙醚洗涤,在真空炉中干燥(40℃,15小时),得到标题化合物N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍甲磺酸盐为白色固体(1.1g,91%产率)。
TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:162-163℃;1H NMR(300MHz,CD3OD):δ7.48-7.17(m,7H,Ar-H),2.69(s,3H,SO3CH3),2.67(q,J=7.6Hz,4H),(H2),1.24(t,J=7.5Hz,6H,CH3);元素分析C18H24ClN3SO3;计算值(%):C:54.33,H:6.08,N:10.56;实测值(%):C:53.98,H:6.14,N:10.40.
实施例5
适合与适当的氨腈化合物反应以得到上述本发明化合物的其它取代苯胺中间体既是商品,也可以用本合成领域技术人员都知道的方法来制备。下列实施例5a-5d公开了制备4种不同的取代苯胺化合物的方法,这些化合物适用于制备本发明化合物,如下列实施例23,58,64,69和70中的化合物。
实施例5a 2-溴-5-甲硫基苯胺盐酸盐的制备
将三乙胺(1.05mL,7.28mmol)加入搅拌的(冷却至16-19℃)2-溴-5-(甲硫基)苯甲酸(1.5g,6.07mmol,用Kuenzle,F.,etal.,Helv.Chim.Acta.,52(3):622-628(1969)所述方法制备)的DMF(17mL)溶液中。简单搅拌后在15分钟内通过加液漏斗加入二苯基磷酰基叠氮化物(1.7mL,7.59mmol)。常温搅拌2小时后薄层色谱法(SiO2,环己烷/乙酸乙酯8∶1)显示该反应已完成。向该溶液内加入蒸馏水(7mL),然后将混合物加热至65℃2小时。
将反应混合物在45℃真空浓缩,得到浅黄色浆状剩余物。在剩余物中加水(50mL)后加入饱和碳酸钾直至pH9。混合物用40mL二氯甲烷萃取两次。合并的萃取液用盐水洗涤,MgSO4干燥并真空浓缩,得到黄色状物油。将黄色油状物溶解于10mL乙醚并加入HCl/乙醚(10mL,1N),得到白色沉淀。过滤收集固体并用柱色谱法(SiO2,己烷/EtOAc:100%-80%)进一步纯化。最终产物为白色固体(0.6g,39%产率)。
1H NMR(CD3OD):δ(ppm)7.76(d,1H,8.5Hz),7.20(s,1H),7.18(d,1H),2.50(s,3H,CH3)元素分析C7H8BrNS·HCl;计算值(%):C:33.03,H:3.56,N:5.50;实测值(%):C:33.00,N:3.52,N:5.59.
实施例5b N-甲基-3-甲基亚磺酰基苯胺盐酸盐的制备
部分1:N-甲基-(3-甲硫基苯基)胺
将3-甲基巯基苯胺(5g,34.8mmol)溶解于甲酸(1.92mL,49mmol)并在氩气中加热至100-105℃过夜。将反应混合物冷却至室温并用CH2Cl2(75mL)萃取。有机相用饱和Na2CO3(30mL)洗涤三次并用MgSO4干燥,过滤除去MgSO4并浓缩溶液,得到甲酰胺。在氩气中将甲酰胺溶解于无水THF(30mL)。在0-5℃向该溶液中缓慢加入LiAlH4的THF(50mL,1M)。将反应升至室温并搅拌20小时。向该反应混合物中加入50mL饱和MgSO4水溶液。保存有机相。将水相用乙酸乙酯(50mL)萃取三次并将合并的有机溶液用H2O(50mL)和盐水(50mL)洗涤,MgSO4干燥。过滤溶液除去MgSO4,然后浓缩得到粗产物,通过柱色谱法(己烷/EtOAc:8/1)进一步纯化。将含有产物的部分收集并浓缩,真空干燥,得到纯N-甲基-(3-甲硫基苯基)胺(5.25g,98%产率)。
部分2:N-甲基-3-甲基亚磺酰基苯胺盐酸盐
在0-5℃将过氧化氢(30%水溶液,10.22mL,1mol,Aldrich)加入N-甲基-3-甲基巯基苯胺(3.0g,19.6mmol)的丙酮(17mL)溶液中。反应搅拌过夜,然后除去丙酮。加入1N NaOH水溶液直至pH12,然后用乙醚(30mL)萃取三次。将合并的有机相用MgSO4干燥,然后过滤除去MgSO4,将所得溶液浓缩得到标题化合物的粗产物,通过柱色谱法(硅胶,用EtOAc/MeOH:100%-90%洗脱)纯化,得到N-甲基-3-甲基亚磺酰基苯胺,然后将其进一步转化成盐酸盐(1.82g,45%产率)。
1H NMR(CD3OD):δ(ppm)7.90-7.55(m,Ar-H,4H),3.11(s,NCH3,3H),2.85(s,SOCH3,3H);MS(EI):m/e 169(M+游离碱;TLC:Rf=0.29(SiO2,EtOAc);M.P.:137-138℃.
实施例5c N-甲基-3-甲基磺酰基苯胺盐酸盐的制备
在0-5℃将过氧化氢(30%水溶液,10.22mL,1mol,Aldrich)加入N-甲基-3-甲基巯基苯胺(3.0g,19.6mmol)的丙酮(17mL)溶液中。反应搅拌过夜,然后除去丙酮。加入1N NaOH水溶液直至pH12,然后用乙醚(30mL)萃取三次。将合并的有机相用MgSO4干燥,然后过滤除去MgSO4,将所得溶液浓缩得到标题化合物的粗产物,通过柱色谱法(硅胶,用EtOAc/MeOH:100%-90%洗脱)纯化,得到N-甲基-3-甲基磺酰基苯胺,然后将其进一步转化成盐酸盐(1.8g,42%产率)。
1H NMR(CD3OD):δ(ppm)7.90-7.50(m,Ar-H,4H),3.16(s,SO2CH3,3H),3.05(s,NCH3,3H);MS(EI):m/e 185(M+:C8H11NSO2);TLC:Rf=O.81(SiO2,EtOAc);M.P.:169-170℃.
实施例5d 2-氟-5-乙基苯胺的制备
部分1:3-硝基-4′-氟代乙酰苯
在-10℃在10分钟内将4′-氟代乙酰苯(Aldrich,75g,54.3mmol)滴加到搅拌的预冷却的发烟硝酸(40mL)中。将温度严格保持在-9--10℃总共8小时。然后将反应混合物烧瓶转移至冰箱(-10℃)存储过夜。早晨将反应混合物倒在冰(1.5kg)上。将所得混合物用乙醚(400mL)萃取三次。有机相用NaOH(1N,300mL)和盐水洗涤四次。真空浓缩得到一黄色液体,薄层色谱(SiO2,环己烷/乙酸乙酯:2/1)显示有一个主产物和两个副产物。将粗产物在600克230-240目硅胶上纯化,用10∶1至3∶1梯度的己烷/乙酸乙酯洗脱。浓缩含有产物的部分,得到浅黄色液体(27.6克)。
部分2:3′-氨基-4′-氟代乙酰苯
将氯化亚锡(II)盐酸盐(37克)分批加入搅拌的3′-硝基-4′-氟代乙酰苯(10.04g,55mmol)的72mL浓盐酸混合物中。加入1/3原料后,迅速提高内部反应温度(至95℃)。然后将混合物加热回流10分钟,使所有固体溶解,得到溶液。然后将混合物冷却至室温并倒在冰/水混合物(150g)上。然后将混合物在冰浴中进一步冷却,同时加入50%氢氧化钠直至pH12。水相用乙醚(50mL)萃取两次。合并的有机萃取液用盐水洗涤,然后用硫酸镁干燥。除去干燥剂并真空浓缩滤液,得到橘黄色油状物(8.73g),将其放置重结晶。该原料的纯度足以直接用于下一步(部分3)。
部分3:2-氟-5-乙基苯胺
将4.94g氢氧化钠加入搅拌的3′-氨基-4′-氟代乙酰苯(7.56g,49.4mmol)的三甘醇(60mL)混合物中。通过注射器将纯水合肼(7.2mL)一次注入混合物中。该添加过程产生轻微的放热(温度在50℃左右)。给反应瓶(三颈,配有克莱森接管和接受瓶)罩上加热罩,将反应加热至100℃1小时,然后至150℃。在高温下馏出液开始在接受瓶中收集。150℃1小时后将反应混合物加热至180℃,同时继续收集馏出液。180℃45分钟后薄层色谱显示起始原料已完全消失且单一主要产物出现。用冰浴使反应混合物冷却至室温并将其倒入100mL水中。用乙醚(125mL)萃取混合物水溶液三次,合并的有机萃取液用水洗一次,用盐水洗一次,然后用碳酸钾干燥。真空浓缩有机萃取液,得到2-氟-5-乙基苯胺(6.82g)为琥珀色液体。该原料用柱色谱法(硅胶,己烷/乙酸乙酯:2/1)进一步纯化,得到7.11克产物为粘性液体。
1H NMR(CDCl3):δ(ppm)8.0-7.0(m,Ar-H),2.52(q,CH2),1.20(t,CH3);MW:139.18 游离碱 元素分析:C8H10NF;计算值(%):C:69.04,H:7.24,N:10.07;实测值(%):C:69.03;N:7.49,N:9.89.
实施例6-73
用类似于上述实施例1-5所用方法,但采用适宜的取代胺盐酸和氨腈试剂,制备下列具有特定物理性质的式I和II化合物。
实施例6 N-(3-乙基苯基)-N-甲基-N′-(2,5-二氯苯基)-N′-甲基胍盐酸盐(式I:R=3-乙基苯基,R1=R2=CH3,R3=R4=Cl,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:161-162℃;1H NMR(300MHz,CD3OD):δ7.38-7.09(m,7H,Ar-H),3.44(s,3H,CH3),3.38(s,3H,CH3),2.51(q,J=7.6Hz,2H,CH2),1.16(t,J=7.6Hz,3H,CH3);元素分析(C17H19Cl2N3·HCl·H2O);计算值(%):C:52.26,H:5.68,N:10.75;实测值(%):C:51.94,H:5.59,N:10.44.
实施例7 N-(3-乙基苯基)-N′-(2,5-二氯苯基)-N′-甲基胍盐酸盐(式I:R=3-乙基苯基,R1=H,R2=CH3,R3=R4=Cl,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp=92-93℃,1HNMR(300MHz,CD3OD):δ7.76-7.12(m,7H,Ar-H),3.44(s,3H,CH3),2.68(q,J=7.6Hz,2H,CH2),1.24(t,J=7.6Hz,3H,CH3);元素分析(C16H17Cl2N3·HCl),计算值(%)C:53.58,H:5.06,N:11.91;实测值(%):C:53.49,H:5.20,N:11.92;MS(EI)=m/e 321(M+游离碱)
实施例8 N-(3-乙基苯基)-N′-(2,5-二氯苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=R4=Cl,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:111-112℃;1H NMR(300MHz,CD3OD):δ7.58-7.15(m,7H,Ar-H),2.68(q,J=7.6Hz,2H,CH2),1.24(t,J=7.6Hz,3H,CH3);MS(EI):m/e 308(M+游离碱 元素分析:(C15H15Cl2N3·HCl);计算值(%):C:52.27,H:4.68,N:12.19;实测值(%):C:52.17,H:4.76,N:12.25.
实施例9 N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)-N′-甲基胍盐酸盐(式I:R=3-乙基苯基,R1=R2=CH3,R3=R4=Br,n=0的盐酸盐)。
白色固体;TLC:Rf=0.3(10% MeOH/CH2Cl2);mp:179-180℃;1H NMR(300MHz,CD3OD):δ7.48-7.10(m,7H,Ar-H),3.45(s,3H,CH3),3.38(s,3H,CH3),2.52(q,J=7.7Hz,2H,CH2),1.18(t,J=7.7Hz,3H,CH3);MS(EI):m/e 425(M+ 游离碱 元素分析:(C17H19Br2N3·HCl);计算值(%):C:44.23,H:4.37,N:9.10;实测值(%):C:44.00,H:4.57,N:9.04.
实施例10 N-(3-乙基苯基)-N′-(2,5-二溴苯基)胍盐酸盐(式1:R=3-乙基苯基,R1=R2=H,R3=R4=Br,n=0的盐酸盐)。
白色固体;TLC:Rf=0.54(10% MeOH/CH2Cl2);mp:76-77℃;1H NMR(300MHz,CD3OD):δ7.70-7.15(m,7H,Ar-H),2.67(q,J=7.6Hz,2H,CH2),1.24(t,J=7.6Hz,3H,CH3);MS(EI):m/e 397(M+游离碱);HRMS:394.9618(394.9632 calculated forC15H15Br2N3).
实施例11 N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Cl,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10% MeOH/CH2Cl2);mp:180-181℃;1H NMR:δ7.76-7.25(m,7H,Ar-H),3.53(s,3H,CH3),2.70(q,J=7.5Hz,2H,CH2),1.26(t,J=7.5Hz,3H,CH3);MS(EI):m/e 355(M+ 游离碱 元素分析.:(C17H17ClF3N3·HCl);计算值(%):C:52.05,H:4.63,N:10.71;实测值(%):C:52.15,H:4.53,N:10.72.
实施例12 N-(3-乙基苯基)-N′-(2-氯-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Cl,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:73-74℃;1H NMR:δ7.55-7.16(m,7H,Ar-H),2.60 (q,J=7.6Hz,2H,CH2),1.21(t,J=7.6Hz,3H,CH3);MS(EI):m/e 341(M+游离碱);HRMS:341.0907(341.0917 calculated for C16H15ClF3N3).
实施例13 N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Br,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10%MeOH/CH2Cl2);mp:184-185℃;1H NMR:δ7.93-7.28(m,7H,Ar-H),3.50(s,3H,CH3),2.70(q,J=7.6Hz,2H,CH2),1.25(t,J=7.6Hz,3H,CH3);MS(EI):m/e 400(M+游离碱 元素分析:(C17H17BrF3N3·HCl);计算值(%):C:46.76,H:4.15,N:9.62;实测值(%):C:46.57,H:4.12,N:9.36
实施例14 N-(3-乙基苯基)-N′-(2-溴-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Br,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:109-110℃;1H NMR:δ7.77-7.17(m,7H,Ar-H),2.61(q,J=7.7Hz,2H,CH2);MS(EI):m/e 386(M+游离碱);HRMS:385.0391(385.0401calculated for C16H15BrF3N3).
实施例15 N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=F,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10% MeOH/CH2Cl2);mp:158-159℃;1H NMR:δ8.20-7.20(m,7H,Ar-H),3.43(s,3H,CH3),2.61(q,J=7.6Hz,2H,CH2),1.17(t,J=7.6Hz,3H,CH3);MS(EI):m/e 339(M+游离碱 元素分析:(C17H17F4N3·HCl);计算值(%):C:54.33,H:4.83,N:11.18;实测值(%):C:54.20,H:4.90,N:11.04.
实施例16 N-(3-乙基苯基)-N′-(2-氟-5-三氟甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=F,R4=CF3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:105-106℃;1H NMR:δ7.25-6.85(m,7H,Ar-H),2.60(q,J=7.7Hz,2H,CH2),1.21(t,J=7.6Hz,3H,CH3);MS(EI):m/e 325(M+游离碱);HRMS:325.1212(325.1202,C16H15N3F4计算值).
实施例17 N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)-N′-甲基胍盐酸盐(式I:R=3-乙基苯基,R1=R2=CH3,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.3(10% MeOH/CH2Cl2);mp:129-130℃;1H NMR(300MHz,CD3OD):δ7.28-7.01(m,7H,Ar-H),3.42(s,3H,CH3),3.39(s,3H,CH3),2.49(q,J=7.6Hz,2H,CH2),2.34(q,J=7.6Hz,2H,CH2),1.13(t,J=7.7Hz,3H,CH3),1.05(t,J=7.7Hz,3H,CH3);MS(EI):m/e 330(M+游离碱).
实施例18 N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:190-191℃;1H NMR(300MHz,CD3OD):δ7.44-7.20(m,7H,Ar-H),3.48(s,3H,CH3),2.71(q,J=7.6Hz,2H,CH2),2.65(J=7.6Hz,2H,CH2),1.27(t,J=7.7Hz,3H,CH3),1.23(t,J=7.7Hz,3H,CH3);MS(EI):m/e 315(M+游离碱 元素分析nal.:(C18H22ClN3·HCl);计算值(%):C:61.36,H:6.58,N:11.93;实测值(%):C:61.09,H:6.37,N:11.86.
实施例19 N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10%MeOH/CH2Cl2);mp:77-78℃;1H NMR(300MHz,CD3OD):δ7.49-7.18(m,7H,Ar-H),2.69(q,J=7.6Hz,4H,CH2),1.24(t,J=7.6Hz,6H,CH3);MS(EI):m/e 301(M+游离碱 元素分析:(C17H20ClN3·HCl);计算值(%):C:60.36,H:6.26,N:12.42;实测值(%):C:60.33,H:6.42,N:12.37.
实施例20 N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:189-190℃;1H NMR(300MHz,CD3OD):δ7.62-7.18(m,7H,Ar-H),3.49(s,3H,CH3),2.71(q,J=7.6Hz,2H,CH2),2.64(q,J=7.6Hz,2H,CH2),1.26(t,J=7.6Hz,3H,CH3),1.23(t,J=7.7Hz,3H,CH3);MS(EI):m/e 360(M+游离碱 元素分析:(C18H22BrN3·HCl);计算值(%):C:54.49,H:5.84,N:10.59;实测值(%):C:54.46,H:5.95,N:10.62.
实施例21 N-(3-乙基苯基)-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.54(10% MeOH/CH2Cl2);mp:70-71℃;1H NMR(300MHz,CD3OD):δ7.62-7.10(m,7H,Ar-H),2.71-2.62(m,4H,CH2),1.27(t,J=7.6Hz,3H,CH3),1.22(t,J=7.7Hz,3H,CH3);元素分析(C17H20BrN3·HCl);计算值(%):C:53.35,H:5.53,N:10.98;实测值(%):C:53.61,H:5.56,N:11.04;MS(EI):m/e 345(M+游离碱)
实施例22 N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=F,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:171-172℃;1H NMR(300MHz,CD3OD):δ7.45-7.14(m,7H,Ar-H),3.48(s,3H,CH3),2.70(q,J=7.6Hz,2H,CH2),2.64(q,J=7.5Hz,2H,CH2),1.26(t,J=7.7Hz,3H,CH3),1.22(t,J=7.5Hz,3H,CH3);MS(EI):m/e 299(M+游离碱 元素分析:(C18H22FN3·HCl);计算值(%):C:64.37,H:6.90,N:12.51;实测值(%):C:64.49,N:7.01,N:12.45.
实施例23 N-(3-乙基苯基)-N′-(2-氟-5-乙基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=F,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.3(10% MeOH/CH2Cl2);mp=52.53℃;1H NMR(300MHz,CD3OD):δ7.34-7.11(m,7H,Ar-H),2.70-2.61(m,4H,CH2),1.26-1.20(m,6H,CH3)元素分析(C17H20FN3·HCl);计算值(%):C:63.45,H:6.58,N:13.06;实测值(%):C:63.52,H:6.77,N:13.32;MS(EI):m/e 285(M+游离碱).
实施例24 N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Cl,R4=CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.45(10% MeOH/CH2Cl2);mp:204-205℃;1H NMR(300MHz,CD3OD):δ7.46-7.16(m,7H,Ar-H),3.48(s,3H,CH3),2.70(q,J=7.6Hz,2H,CH2),2.33(s,3H,CH3),1.26(t,J=7.6Hz,3H,CH3);MS(EI):m/e 302(M+游离碱 元素分析:(C17H20ClN3·HCl);计算值(%):C:60.36,H:6.26,N:12.42;实测值(%):C:60.23,H:6.50,N:12.32.
实施例25 N-(3-乙基苯基)-N′-(2-氯-5-甲基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Cl,R4=CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.35(10% MeOH/CH2Cl2);mp:88-89℃;1H NMR(300MHz,CD3OD):δ7.45-7.18(m,7H,Ar-H),2.69(q,J=7.7Hz,2H,CH2),2.37(s,3H,CH3),1.25(t,J=7.7Hz,3H,CH3);MS(EI):m/e 288(M+游离碱 元素分析:(C16H18ClN3·HCl·0.5H2O);计算值(%):C:57.66,H:6.05,N:12.61;实测值(%):C:57.36,H:6.08,N:12.46.
实施例26 N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.45(10% MeOH/CH2Cl2);mp:198-199℃;MS(EI):m/e 333(M+游离碱);1H NMR(CD3OD):δ7.45-7.20(m,7H,Ar-H),3.49(s,3H,CH3),2.70(q,J=7.5Hz,2H,CH2),2.49(s,3H,SCH3),1.26(t,J=7.5Hz,3H,CH3);元素分析(C17H20ClN3S·HCl);计算值(%):C:55.14,H:5.72,N:11.35;实测值(%):C:54.99,H:5.63,N:11.23.
实施例27 N-(3-乙基苯基)-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.45(10% MeOH/CH2Cl2);mp=132-133℃;1H NMR(CD3OD):δ7.50-7.18(m,7H,Ar-H),2.69(q,J=7.6Hz,2H,CH2),2.51(s,3H,CH3),1.25(t,J=7.6Hz,3H,CH3);元素分析(C16H18ClN3S·HCl);计算值(%):C:53.93,N:11.79,H:5.37;实测值(%):C:54.09,N:11.72,H:5.44.
实施例28 N-(1-萘基)-N′-(2-氟-5-甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=F,R4=CH3,n=0的盐酸盐)。
白色固体;mp 194℃;1H NMR(300MHz,CD3OD):δ7.98-8.15(m,2,Ar-H),7.57-7.68(m,3,Ar-H)7.15-7.24(d,5,Ar-H);2.35(s,3,CH3);MS(EI);m/e 293(M+游离碱).
实施例29 N-(1-萘基)-N′-(2,5-二氯苯基)-N′-甲基胍盐酸盐(式I:R=1-萘基,R1=H,R2=CH3,R3=R4=Cl,n=0的盐酸盐)。
白色固体;mp 210℃,1H NMR(300MHz,CD3OD):δ7.96-8.02(m,3,Ar-H),7.48-7.64(m,7,Ar-H);3.52(s,3,N-CH3);MS(EI):m/e 344(M+游离碱 元素分析:(C18H15Cl2N3·HCl·0.25H2O);计算值(%):C:56.13,H:4.32,N:10.91;实测值(%):C:56.02,H:4.60,N:10.73.
实施例30 N-(1-萘基)-N′-(2-氯-5-甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Cl,R4=CH3,n=0的盐酸盐)。
白色固体;mp 125℃;1H NMR(300MHz,CD3OD):δ7.95-8.10(m,3,Ar-H),7.52-7.70(m,6,Ar-H);7.41-7.48(d,1,Ar-H);7.30-7.35(s,1,Ar-H);7.20-7.25(m,2,Ar-H);2.37(s,3,Ar-CH3);MS(EI):m/e 310(M+游离碱 元素分析:(C18H16ClN3·HCl);计算值(%):C:62.44,H:4.95,N:12.14;实测值(%):C:62.52,H:5.04,N:11.96.
实施例31 N-(1-萘基)-N′-(2,5-二甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=R4=CH3,n=0的盐酸盐)。
白色固体;mp 122-123℃;1H NMR(300MHz,CD3OD):δ7.95-8.08(m,3,Ar-H),7.55-7.71(m,4,Ar-H);7.10-7.28(m,3,Ar-H);2.32(s,6,2 Ar-CH3);MS(EI):m/e 289(M+游离碱 元素分析:(C19H19N3·HCl);计算值(%):C:70.04,H:6.19,N:12.90;实测值(%):C:70.02,H:6,20,N:12.87.
实施例32 N-(1-萘基)-N′-(2,5-二溴苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=R4=Br,n=0的盐酸盐)。
白色固体;mp 231-232℃;1H NMR(300MHz,CD3OD):δ7.97-8.13(m,3,Ar-H),7.48-7.72(m,7,Ar-H);MS(EI):M/e 419(M+游离碱).
实施例33 N-(1-萘基)-N′-(2-氯-5-甲基苯基)-N′-甲基胍盐酸盐(式I:R=1-萘基,R1=H,R2=CH3,R3=Cl,R4=CH3,n=0的盐酸盐)。
白色固体;mp 228-229℃;1H NMR(300MHz,CD3OD):δ7.96-7.99(m,3,Ar-H),7.48-7.61(m,6,Ar-H);7.26-7.30(d,1,Ar-H);3.50(s,3,N-CH3);2.39(s,3,Ar-CH3)1 MS(EI):m/e 324(M+游离碱;元素分析(C19H18ClN3·HCl);计算值(%):C:63.34,H:5.32,N:11.66;实测值(%):C:63.20,H:5.43,N:11.66.
实施例34 N-(1-萘基)-N′-(2,5-二甲基苯基)-N′-甲基胍盐酸盐(式I:R=1-萘基,R1=H,R2=CH3,R3=R4=CH3,n=0的盐酸盐)。
白色固体;mp 216-217℃;1H NMR(300MHz,CD3OD):δ7.95-8.00(m,2,Ar-H),7.5-7.7(m,4,Ar-H);7.18-7.38(m,4,Ar-H);3.5(br s,3,N-CH3);2.38 (s,3,Ar-CH3);MS(EI):m/e 303(M+游离碱元素分析:(C20H21N3·HCl);计算值(%):C:70.68,H:6,52,N:12.36;实测值(%):C:70.51,H:6,46,N:12.18.
实施例35 N-(1-萘基)-N′-(2,5-二溴苯基)-N-甲基胍盐酸盐(式I:R=1-萘基,R1=H,R2=CH3,R3=R4=Br,n=0的盐酸盐)。
白色固体;mp 213℃;1H NMR(300MHz,CD3OD):δ7.94-8.06(m,3,Ar-H),7.54-7.74(m,6,Ar-H);7.2-7.38(m,1,Ar-H);3.5(br,s,N-CH3);MS(EI):m/e 433(M+游离碱 元素分析:(C18H15Br2N3·HCl);计算值(%):C:46.04,H:3.43,N:8.95;实测值(%):C:46.15,H:3.33,N:8.89.
实施例36 N-(1-萘基)-N′-(2-氯-5-硫甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
白色固体;mp 175℃;1H NMR(300MHz,CD3OD):δ7.95-8.10(m,3,AR-H),7.55-7.70(m,4,Ar-H);7.46-7.51(d,J=8Hz;1,Ar-H);7.34-7.39(s,1,Ar-H);7.25-7.32(dd,1,Ar-H);2.51(s,3,S-CH3);MS(EI):m/e 342(M+游离碱 元素分析:(C18H16ClN3S·HCl·EtOH);计算值(%):C:56.61,H:5.23,N:9.90;实测值(%):C:56.71,H:5.21,N:10.19.
实施例37 N-(1-萘基)-N′-(2-氟-5-三氟甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=F,R4=CF3,n=0的盐酸盐)。
V白色固体;mp 149℃;1H NMR(300MHz,CD3OD):δ7.97-8.07(m,3,Ar-H),7.48-7.85 (m,7,Ar-H);MS(EI):m/e 347(M+for游离碱 元素分析:(C18H13F4N3·HCl);计算值(%):C:56.33,H:3.68,N:10.95;实测值(%):C:55.91,H:3.69,N:10.79.
实施例38 N-(1-萘基)-N′-(2-氯-5-三氟甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Cl,R4=CF^{角标=2}3,n=0的盐酸盐)。
白色固体;mp 198℃;1H NMR(300MHz,CD3OD):δ8.07-8.09(d,J=8.5Hz,1,Ar-H),7.98-8.01(m,2,Ar-H);7.56-7.86(m;7,Ar-H);MS(EI):m/e 364(M+游离碱 元素分析:(C18H13ClF3N3·HCl);计算值(%):C:54.02,H:3.53,N:10.50;实测值(%):C:54.16,H:3.52,N:10.35.
实施例39 N-(1-萘基)-N′-(2-溴-5-三氟甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Br,R4=CF3,n=0的盐酸盐)。
白色固体;mp 234℃;1H NMR(300MHz,CD3OD):δ8.10-8.12(d,J=9Hz,1,Ar-H),7.97-8/01(m,3,Ar-H);7.86(s,1,Ar-H);7.56-7.70(m,5,Ar-H);MS(EI):m/e 408(M+游离碱 元素分析.:(C18H13BrF3N3·HCl);计算值(%):C:48.62,H:3.17,N:9.45;实测值(%):C:48.49,H:3.11,N:9.18.
实施例40 N=(1-萘基)-N′-(2-硫甲基-5-三氟甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=SCH3,R4=CF3,n=0的盐酸盐)。
白色固体;mp 210℃;1H NMR(300MHz,CD3OD):δ8.11-8.14(d,J=8Hz,1,Ar-H),7.98-8.01(d,J=7Hz;2,Ar-H);7.55-7.73(m,7,Ar-H);2.62(3,s,S-CH3);MS(EI):m/e 375(M+游离碱);元素分析(C19H16F3N3S·HCl);计算值(%):C:55.41,H:4.16,N:10.20;实测值(%):C:55.27,H:4.18,N:10.90.
实施例41 N-(1-萘基)-N′-(2-甲氧基-5-甲基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=OCH3,R4=CH3,n=0的盐酸盐)。
白色固体;mp 194℃;1H NMR(300MHz,CD3OD):δ8.06-8.09(d,J=8Hz,1,Ar-H),7.96-8.00(m,2,Ar-H);7.52-7.69(m,4,Ar-H);7.14-7.20(m,2,Ar-H);7.02-7.05(dd,J=8.5Hz;1,Ar-H);3.94(s,3,OCH3);2.29(3,s,Ar-CH3);元素分析(C19H19N3O·HCl);计算值(%):C:66.76,H:5.90,N:12.29;实测值(%):C:66.25,H:5.89,N:12.23.
实施例42 N-(1-萘基)-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;mp 154℃;1H NMR(300MHz,CD3OD):δ8.07-8.10(d,J=9Hz,1,Ar-H),7.97-8.01(m,2,Ar-H);7.57-7.69(m,4,Ar-H);7.47-7.50(d,J=8Hz,1,Ar-H);7.13-7.35(m,2,Ar-H);2.63-2.71(q,J=7.5Hz,2,CH2);1.21-1.26(t,J=8Hz,3,CH3);MS(EI):m/e 324(M+游离碱).
实施例43 N-(1-萘基)-N′-(2-氯-5-乙基苯基)-N′-甲基胍盐酸盐(式I:R=1-萘基,R1=H,R2=CH3,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;mp 233℃;1H NMR(300MHz,CD3OD):δ7.97-8.02(m,3,Ar-H),7.52-7.63(m,6,Ar-H);7.31-7.34(d,J=8Hz,1,Ar-H);3.51(br s,3,N-CH3);2.67-2.74(q,J=7.5Hz,2,CH2);1.24-1.29(t,J=8Hz,3,CH3);MS(EI):m/e 338(M+游离碱 元素分析:(C20H20ClN3·HCl);计算值(%):C:64.18,H:5.65,N:11.23;实测值(%):C:63.96,H:5.83,N:11.25.
实施例44 N-(1-萘基)-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10% MeOH/CH2Cl2);1H NMR(300MHz,CD3OD):δ8.09-7.22(m,10H,Ar-H),2.67(q,J=7.5Hz,2H,CH2),1.24(t,J=7.5Hz,3H,CH3).
实施例45 N-(1-萘基)-N′-(2-氟-5-乙基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=F,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10% MeOH/CH2Cl2);1H NMR(300MHz,CD3OD):δ8.05-7.19(m,10H,Ar-H),2.65 (q,J=7.5Hz,2H,CH2),1.23(t,J=7.5Hz,3H,CH3).
实施例46 N-(1-萘基)-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10%MeOH/CH2Cl2);mp:145-146℃;1H NMR(300MHz,CD3OD):δ8.09-7.22(m,10H,Ar-H),2.67(q,J=7.5Hz,2H,CH2),1.24(t,J=7.5Hz,3H,CH3);MS(EI):m/e 367(M+游离碱).
实施例47 N-(1-萘基)-N′-(2-氟-5-乙基苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=F,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.5(10%MeOH/CH2Cl2);mp:100-101℃;1H NMR(300MHz,CD3OD):δ8.05-7.19(m,10H,Ar-H),2.65(q,J=7.5Hz,2H,CH2),1.23(t,J=7.5Hz,3H,CH3);MS (EI):m/e 307.1(M+游离碱 元素分析:(C19H18FN3·HCl);计算值(%):C:66.37,H:5.57,H:12.22;实测值(%):C:66.21,H:5.50,N:12.17.
实施例48 N-(8-喹啉基)-N′-(2-氯-5-甲基苯基)胍盐酸盐(式I:R=8-喹啉基,R1=R2=H,R3=Cl,R4=CH3,n=0的盐酸盐)。
淡黄色固体;mp 150℃;1H NMR(300MHz,CD30D):δ8.98-8.00(dd,1,Ar-H),8.40-8.44(dd,1,Ar-H);7.93-7.96(d,1,Ar-H);7.82-7.84(d,1,Ar-H);7.61-7.68(m,2,Ar-H);7.38-7.44(m,3,Ar-H);7.21-7.22(d,1,Ar-H);3.30(s,3,CH3);MS(EI):m/e 310(M+游离碱
实施例49 N-(8-喹啉基)-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=8-喹啉基,R1=R2=H,R3=Cl,R4=CH2C3,n=0的盐酸盐)。
棕色固体;mp 167℃;1H NMR(300MHz,CD3OD):δ8.40-9.25(m,2,Ar-H),7.27-8.34(m,7,Ar-H);2.65-2.72(q,2,CH2);1.22-1.27(t,3,CH3);MS(EI):m/e 324(M+游离碱).
实施例50 N-(3-乙基苯基)-N-甲基-N′-(2,4,5-三氯苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=R4=Cl,R5=4-Cl,n=1的盐酸盐)。
白色固体;TLC:Rf=0.3(10% MeOH/CH2Cl2);mp:164-165℃;1H NMR(300MHz,CD3OD):δ7.79-7.23(m,6H,Ar-H),3.49(s,3H,CH3),2.70(q,J=7.6Hz,2H,CH2),1.26(t,J=7.6Hz,3H,CH3);MS(EI):m/e 335.0(M+游离碱 元素分析:(C16H16Cl3N3·HCl·1/2H2O);计算值(%):C:47.78,H:4.51,N:10.45;实测值(%):C:47.93,H:4.63,N:10.33.
实施例51 N-(3-乙基苯基)-N′-(2,4,5-三氯苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=R2=H,R3=R4=Cl,R5=4-Cl,n=1的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:82-83℃;1HNMR(300MHz,CD3OD):δ7.63-7.18(m,6H,Ar-H),2.63(q,J=7.6Hz,2H,CH2),1.22(t,J=7.6Hz,3H,CH3);MS(EI):m/e 341(M+游离碱).
实施例52 N-(1-萘基)-N′-(2,4,5-三氯苯基)胍盐酸盐(式I:R=1-萘基,R1=R2=H,R3=R4=Cl,R5=4-Cl,n=1的盐酸盐)。
白色固体;TLC:Rf=0.4(10% MeOH/CH2Cl2);mp:238-239℃;1H NMR(300MHz,CD3OD):δ8.08-7.58(m,10H,Ar-H);MS(EI):m/e363(M+游离碱 元素分析.:(C17H12Cl3N3·HCl);计算值(%):C:50.9,H:3.29,N:10.48;实测值(%):C:51.11,H:3.33,N:10.63.
实施例53 N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍盐酸盐(式I:R=3-乙基苯基,R1=CH3,R2=H,R3=Br,R4=CH3S,n=0的盐酸盐)。
TLC:Rf=0.5(SiO2,CH2Cl2/MeOH=10/1);M.P.:90-92℃;1HNMR(CD3OD):δ(ppm)7.64-7.15(m,Ar-H,7H),3.49(s,CH3,3H),2.70(q,J=7.4Hz,2H,CH2),2.47(s,SCH3,3H),1.25(t,J=7.5Hz,3H,CH3);MS(EI):m/e 377(M+:C17H20N3Br1S1);元素分析(C17H20N3Br1S1·HCl);计算值(%):C:49.23,H:5.1,N:10.13;实测值(%)C:49.30,H:5.28,N:10.28.
实施例5 4 N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二氯苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=R4=Cl,n=0的盐酸盐)。
TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:200-201℃;1H NMR(300MHz,CD3OD):δ(ppm)7.55-7.15(m,7H,Ar-H),3.49(s,3H,NCH3),2.52(s,3H,SCH3);MS(EI):m/e 339(M+游离碱);元素分析(C15H15Cl2N3S·HCl);计算值(%):C:47.82,H:4.28,N:11.15;实测值(%):C:47.66,H:4.26,N:11.34.
实施例55 N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)。
TLC:Rf=0.4(10% MeOH/CH2Cl2);MP:239-240℃;1H NMR:δ(ppm)7.70-7.20(m,7H,Ar-H),3.49(s,3H,NCH3),2.53(s,3H,SCH3);MS(EI):m/e 429(M+游离碱 元素分析(C15H15Br2N3S·HCl);计算值(%):C:38.69,H:3.46,N:9.02;实测值(%):C:38.65,H:3.60,N:8.98.
实施例56 N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:212-213℃;1H NMR(300MHz,CD3OD):δ(ppm)7.45-7.19(m,7H,Ar-H),3.49(s,3H,CH3),2.68(q,J=7.5Hz,2H,CH2),2.51(s,3H,SCH3),1.22(t,J=7.5Hz,3H,CH3);MS(EI):m/e 333(M+游离碱 元素分析(C17H20ClN3S·HCl);计算值(%):C:55.14,H:5.72,N:11.35;实测值(%):C:55.29,H:5.81,N:11.36.
实施例57 N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
TLC:Rf=0.25(10% MeOH/CH2Cl2);MP:203-204℃;1H NMR(300MHz,CD3OD):δ(ppm)7.50-7.18(m,7H,Ar-H),3.49(s,3H,CH3),2.52(s,3H,SCH3),2.49(s,3H,SCH3);MS(EI):m/e 351(M+for游离碱 元素分析.(C16H18ClN3S2·HCl);计算值(%):C:49.48,H:4.93,N:10.82;实测值(%):C:49.41,H:5.07,N:10.81.
实施例58 N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=Br,R4=SCH3,n=0的盐酸盐)。
TLC:Rf=0.43(SiO2,CH2Cl2/MeOH=10/1);M.P.:174-175℃;1HNMR(CD3OD):δ(ppm)7.65-7.15(m,Ar-H,7H),3.49(s,CH3,3H),2.52(s,SCH3,3H),2.49(s,SCH3,3H);HRMS:395.0120(Calcd.:395.0126 for C16H18N3BrS2);HPLC:98.47%.
实施例59 N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=3-甲硫基苯基,R1=CH3,R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:199-200℃;1H NMR(300MHz,CD3OD):δ(ppm)7.65-7.15(m,7H,Ar-H),3.49(s,3H,CH3),2.64 (q,J=7.5Hz,2H,CH2),2.52(s,3H,SCH3),1.23(t,J=7.5Hz,3H,CH3);MS(EI):m/e 378(M+游离碱 元素分析(C17H20BrN3S·HCl);计算值(%):C:49.23,H:5.10,N:10.13;实测值(%):C:49.39,H:5.01,N:10.02.
实施例60 N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二氯苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=R4=Cl,n=0的盐酸盐)。
TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:209-210℃;1H NMR:δ(ppm)7.86-7.39(m,7H,Ar-H);3.54(s,3H,CH3);MS(EI):m/e 361(M+游离碱 元素分析.(C15H12Cl2F3N3·HCl);计算值(%):C:45.19,H:3.29;N:10.54;实测值(%):C:45.31,H:3.50,N:10.61.
实施例61 N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)。
TLC:Rf=0.5(10% MeOH/CH2Cl2);MP:233-234℃;1H NMR:δ(ppm)7.90-7.45(m,7H,Ar-H);3.54(s,3H,CH3);MS(EI):m/e 449(M+游离碱 元素分析.(C15H12Br2F3N3·HCl);计算值(%):C:36.93,H:2.69,N:8.62;实测值(%):C:37.00,H:2.70,N:8.56.
实施例62 N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:156-157℃;1H NMR(300MHz,CD3OD):δ(ppm)7.90-7.20(m,7H,Ar-H),3.53(s,3H,CH3),2.49(s,3H,SCH3);MS(EI):m/e 373(M+游离碱);元素分析(C16H15ClF3N3S2·HCl);计算值(%):C:46.84,H:3.93,N:10.24;实测值(%):C:46.78,H:4.07,N:10.12.
实施例63 N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
TLC:Rf=0.3(10% MeOH/CH2Cl2);MP:164-165℃;1H NMR(300MHz,CD3OD):δ(ppm)7.83-7.19(m,7H,Ar-H),3.53(s,3H,CH3),2.65(q,J=7.5Hz,2H,CH2),1.22(t,J=7.5Hz,3H,CH3);MS(EI):m/e 355(M+游离碱 元素分析.(C17H17ClF3N3·HCl);计算值(%):C:52.06,H:4.63,N:10.71;实测值(%):C:52.14,H:4.79,N:10.66.
实施例64 N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=Br,R4=SCH3,n=0的盐酸盐)。
TLC:Rf=0.5(10% MeOH/CH2Cl2);MP:121-122℃;1H NMR(300MHz,CD3OD):δ(ppm)7.87-7.15(m,7H,Ar-H),3.53(s,3H,CH3),2.49(s,3H,CH3);MS(EI):m/e 419(M+游离碱 元素分析(C16H15BrF3N3S·HCl);计算值(%):C:42.26,H:3.5,N:9.24;实测值(%):C:42.27,H:3.70,N:9.06.
实施例65 N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍盐酸盐(式I:R=3-三氟甲基苯基,R1=CH3,R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
TLC:Rf=0.5(10% MeOH/CH2Cl2);MP:95-96℃;1H NMR(300MHz,CD3OD):δ(ppm)7.70-6.75(m,7H,Ar-H),3.47(s,3H,CH3),2.58(q,J=7.5HZ,2H,CH2),1.22(t,J=7.5Hz,3H,CH3);MS(EI):m/e401(M+游离碱 元素分析.(C17H17BrF3N3·HCl);计算值(%):C:46.76,H:4.15,N:9.62;实测值(%):C:46.57,H:4.43,N:9.38.
实施例66 N-(3-溴苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-溴苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
TLC:Rf=0.5(10% MeOH/CH2Cl2);MP:244-245℃;1H NMR(300MHz,CD3OD):δ(ppm)7.80-7.20(m,7H,Ar-H),3.53(s,3H,CH3),2.49(s,3H,SCH3);MS(EI):m/e 385(M+游离碱);元素分析(C15H15BrClN3S·HCl);计算值(%):C:42.78,H:3.83,N:9.98;实测值(%):C:42.85,H:3.99,N:9.80.
实施例67 N-(3-三氟甲氧基苯基)-N′-(2-溴-5-乙基苯基)-N-甲基胍盐酸盐(式I:R=3-三氟甲氧基苯基,R1=CH3,R2=H,R3=Br,R4=CH2CH3,n=0的盐酸盐)。
TLC:Rf=0.36(SiO2,CH2Cl2/MeOH=10/1);MP:74-75℃;1HNMR(CD3OD):δ(ppm)7.63-7.15(m,Ar-H,7H),3.30(s,CH3,3H),2.64(m,CH2,2H),1.23(t,CH3,J=7.45Hz,3H);MS(EI):m/e 416.0(M+:C17H17N3BrOF3)元素分析C17H17N3BrOF3·HCl);计算值(%):C:45.10,H:4.01,N:9.28;实测值(%):C:45.31,H:4.15,N:9.09.
实施例68 N-(3-三氟甲氧基苯基)-N′-(2,5-二溴苯基)-N-甲基胍盐酸盐(式I:R=3-三氟甲氧基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)。
TLC:Rf=0.55(SiO2,CH2Cl2/MeOH=10/1);MP:188-189℃;1HNMR(CD3OD):δ(ppm)7.80-7.40(m,Ar-H,7H),3.52(s,CH3,3H);MS(EI):m/e 467.80(M+:C15H12N3Br2OF3)元素分析C15H12N3Br2OF3·HCl);计算值(%):C:35.78,H:2.60,N:8.34;实测值(%):C:35.72,H:2.75,N:8.26.
实施例69 N-(3-甲基磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐(式II:R=3-甲基磺酰基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)。
TLC:Rf=0.47(SiO2,CH2Cl2/MeOH=10/1);MP:245-246℃;1HNMR(CD3OD):δ(ppm) 8.15-7.45(m,Ar-H,7H),3.56(s,CH3,3H),3.17(s,CH3,3H);MS(EI):m/e 462(M+:C15H15N3Br2SO2);元素分析(C15H15N3Br2SO2·HCl);计算值(%):C:36.20,H:3.24,N:8.44;实测值(%):C:35.98,H:3.11,N:8.36.
实施例70 N-(3-甲基亚磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍盐酸盐(式II:R=3-甲基亚磺酰基苯基,R1=CH3,R2=H,R3=R4=Br,n=0的盐酸盐)。
TLC:Rf=0.52(SiO2,CH2Cl2/MeOH=10/1);MP:169-170℃;1HNMR(CD3OD):δ(ppm)7.90-7.45(m,Ar-H,7H),3.55(s,CH3,3H),2.85(s,CH3,3H);MS(EI):m/e 446(M+:C15H15N3Br2SO);元素分析(C15H15N3Br2SO·HCl);计算值(%):C:37.41,H:3.35,N:8.72;实测值(%):C:37.15,H:3.46,N:8.38.
实施例71 N-(3-碘苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍盐酸盐(式I:R=3-碘苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
M.P.:61-63℃。
实施例72 N-(2-氯-5-乙基苯基)-N′-(3-碘苯基)胍盐酸盐(式I:R=3-碘苯基,R1=R2=H,R3=Cl,R4=CH2CH3,n=0的盐酸盐)。
白色固体;mp 76-77℃;Rf=0.28(10∶1 CHCl3/MeOH):1H NMR(300MHz,CD3OD):δ(ppm)7.76-7.78(m,1H,Ar-H),7.52-7.56(m,1H,Ar-H),7.39-7.42(d,J=6Hz,1H,Ar-H),7.31-7.36(m,1H,Ar-H),7.08-7.22(m,3H,Ar-H),3.30(q,2H,CH2),1.20-1.30 It,3H,CH3);MS(EI):m/e 400(M+游离碱 元素分析:(C15H16Cl2lN3·HCl);计算值(%):C:41.31,H:3.70,N:9.63;实测值(%):c:44.60,H:3.96,N:9.59.
实施例73 N-(2-氯-5-硫甲基苯基)-N′-(3-碘苯基)-N′-甲基胍盐酸盐(式I:R=3-碘苯基,R1=CH3,R2=H,R3=Cl,R4=SCH3,n=0的盐酸盐)。
棕色固体;mp 61-63℃;Rf=0.24(10∶1)CHCl3/MeOH);1HNMR(300MHz,CD3OD):δ7.74-7.75(3,1H,Ar-H),7.58-7.62(dt,1H,Ar-H),7.30-7.37(m,2H,Ar-H),7.14-7.19(t,1H,Ar-H),6.92-6.97(m,2H,Ar-H),3.36(s,3H,N-CH3),2.46 (s,3H,SCH3);MS(EI):m/e 432(M+游离碱 元素分析(C15H15ClN3S·HCl·Et2O);计算值(%):C:40.76,H:4.33,N:8.20;实测值(%):C:44.37,H:4.69,N:8.58.
实施例74 PCP放射性配体结合力测定
PCP受体结合力测定是用大鼠脑膜作为受体源进行的。用于标记PCP受体的放射性配体是〔3H〕MK-801。
〔3H〕MK-801的合成和PCP受体结合力测定方案刊登在J.F.W.Keana,et al.,Life Sci.,43:965-973(1988)上。简要地说,在测定方案中,大鼠脑膜是依照“去污剂处理的膜(detergent-treatedmembranes)”所述方法制备和使用的(见D.E.Murphy,et al.,J.Pharmacol.Exp.Ther.,240:778-784(1987)),并以10mg/ml蛋白质浓度存储于-70℃。观察表明,该膜存放在-70℃一个月对受体的数量或对〔3H〕MK-801的亲和力没有影响。
对于用大鼠脑膜的测定,先将解冻的大鼠脑膜在32℃以1mg/ml浓度用0.01%Triton X-100培养15分钟,然后用离心法洗涤三次以减弱内生氨基酸浓度,最后重新悬浮于缓冲液中以待测定。将甘氨酸和1-谷氨酸相继加入最终浓度为1μM的培养液中以最大限度地激发〔3H〕MK-801的结合。测定采用400μL脑膜,50μL缓冲液或未标记的药物。
对于〔3H〕K-801结合力的测定,可用200μg/ml大鼠脑膜在室温下培养1nm放射性配体4小时。所有测定被真空下的迅速过滤终止,过滤是用Brandel 48孔的细胞收获器(Brandel,Gaithersburg,MD)通过预泡在0.05%聚乙烯亚胺中的Whatman GF/B玻璃纤维滤布进行的。将滤布用5ml冷5mM Tris-HCl(pH=7.4)洗涤三次,再将每个滤布悬放在10ml Cytoscint(ICN Biomedicals,Costa Mesa,CA)中,用计数率为50%的液闪谱仪测量其放射性。非特异性结合被定义为在10μM MK-801或100μM PCP存在下保持的结合力。
饱和度数据的评价和1C50值的确定依照J.B.Fischer和A.Schonbrunn所述方法(J.Biol.Chem.,263:2808-2816(1988))进行。Ki值是依照Cheng et al.,Biochem.Pharmacol.,22:3099-3108(1973)所述方法从IC50值得到的。
测定的结果列于实施例75后面的表I中,其中试验化合物(即化合物序号1-83指定的化合物)的通式示于表I顶部,同时在表中列出每个化合物的具体取代基。
实施例75 σ受体结合力的测定
方法
用豚鼠脑膜匀浆和放射性配体〔3H〕DTG测定的σ受体结合力是按E.Weber,et al.,P.N.A.S.(USA),83:8784-8788(1986)所述方法进行的。简单地说,将冷冻的整个豚鼠脑(Biotrol,Indi-anapolis,IN)在10体积(w/v)冰冷的320mM蔗糖中用Brinkmanpolytron均匀化。在4℃将匀浆以1,000×g离心20分钟。在4℃将上层清液以20,000×g离心20分钟。将所得丸粒重新悬浮于10倍初始体积的pH7.4的50mM Tris/HCl缓冲液中,并在4℃以20,000×g离心20分钟。再将所得丸粒重新悬浮于5倍初始体积的冰冷的50mM Tris/HCl(pH7.4)中,最终体积调整到蛋白质浓度为3mg/ml。20ml的等分试样存储于-70℃直到使用,未见结合力损失。
对于〔3H〕DTG结合力的测定,是将冷冻的脑膜悬浮液解冻并用1∶3的50mM Tris/HCl(pH7.4)稀释。将0.8ml稀释的脑膜悬浮液和0.1ml〔3H〕DTG(Dupont/NEN)加到12×75mm的聚苯乙烯试管中,最终浓度为1.4nM并加入0.1ml未标记的药物或缓冲液。在1ml最终培养体积中蛋白质浓度是800μg/ml,相应于32mg脑组织(原始湿重)和特异性结合力的线性范围之内的组织浓度。非特异性结合被定义为在10μM氟哌啶醇存在下保持的结合力。在室温下添加4ml冰冷的50mM Tris/HCl(pH7.4)和通过Whatman GF/B玻璃纤维滤布在真空下用48孔细胞收获器(Brandel)迅速过滤脑膜悬浮液之后90分钟,培养被终止。滤布用4ml 50mM Tris/HCl(pH7.4)洗涤两次。将每个滤布悬放在10ml Cytoscint(ICI)中,用计数率为50%的液闪谱仪测量其放射性。IC50值用非线性回归分析确定。具有特定结构的每个试验化合物的结果列于下列表I中。在表I中,标记“NT”表示该化合物未在规定的测定中试验。
表I
化合物序号 | R | R1 | R2 | R3 | R4 | [3H-MK801] | [3H·DTG]IC50(nM) | |
IC50(nM) | Ki(nM) | |||||||
1 | 3-乙基苯基 | H | H | Cl | Cl | 88 | 67.7 | 11.8 |
2 | 3-乙基苯基 | H | H | Cl | Br | 87.5 | 67.3 | 18.2 |
3 | 3-乙基苯基 | H | H | H | Cl | 146 | 112 | 15.5 |
4 | 3-乙基苯基 | H | H | Br | CF3 | 86.9 | 66.8 | 10.3 |
5 | 3-乙基苯基 | H | H | F | CF3 | 98.9 | 76.0 | 14.8 |
6 | 3-乙基苯基 | H | H | Cl | CF3 | 57.1 | 43.9 | 14.2 |
7 | 3-乙基苯基 | H | H | Cl | CH3 | 100 | 76.9 | 30.6 |
8 | 3-乙基苯基 | H | H | Cl | CH2CH3 | 45.2 | 34.7 | 2.04 |
9 | 3-乙基苯基 | H | H | H | CH2CH3 | 168 | 129 | 8.0 |
10 | 3-乙基苯基 | CH3 | H | Cl | Cl | 84.6 | 65.0 | 28.5 |
11 | 3-乙基苯基 | CH3 | H | Br | Br | 47.6 | 36.6 | 40.2 |
12 | 3-乙基苯基 | CH3 | H | H | Cl | 646 | 497 | 43.5 |
13 | 3-乙基苯基 | CH3 | H | Br | CF3 | 102 | 78.4 | 208 |
14 | 3-乙基苯基 | CH3 | H | F | CF3 | 252 | 194 | 85 |
15 | 3-乙基苯基 | CH3 | H | Cl | CF3 | 131 | 101 | 120 |
16 | 3-乙基苯基 | CH3 | H | Cl | CH3 | 101 | 77.6 | 45.3 |
17 | 3-乙基苯基 | CH3 | H | Cl | CH2CH3 | 53 | 40.7 | 115 |
18 | 3-乙基苯基 | CH3 | H | H | CH2CH3 | 213 | 164 | 81.8 |
19 | 3-乙基苯基 | CH3 | H | H | Br | 105 | 80.7 | 40 |
表I(续)
化合物序号 | R | R1 | R2 | R3 | R4 | [3H-MK801] | [3H-DTG]IC50(nM) | |
IC50(nM) | Ki(nM) | |||||||
20 | 3-乙基苯基 | CH3 | H | F | CH2CH3 | 126 | 96.9 | 112.5 |
21 | 3-乙基苯基 | H | H | F | CH2CH3 | 64.8 | 49.8 | 7.4 |
22 | 3-乙基苯基 | CH3 | H | Br | CH2CH3 | 16.7 | 12.8 | 203 |
23 | 3-乙基苯基 | H | H | Br | CH2CH3 | 38.3 | 24.9 | 5.07 |
24 | 3-乙基苯基 | CH3 | H | Cl | SCH3 | 6.7 | 5.1 | 309.5 |
25 | 3-乙基苯基 | H | H | Cl | SCH3 | 15.4 | 11.8 | 15.8 |
26 | 3-乙基苯基 | CH3 | CH3 | Cl | Cl | 93.7 | 72.0 | 39.3 |
27 | 3-乙基苯基 | CH3 | CH3 | Br | Br | 35.5 | 27.3 | 380 |
28 | 3-乙基苯基 | CH3 | CH3 | Cl | CH2CH3 | 145 | 112 | 240.5 |
29 | 2-氯-5-乙基苯基 | H | H | Cl | CH3 | 54.7 | 42.1 | 36.1 |
30 | 2-氯-5-乙基苯基 | H | H | Br | Br | 66.4 | 51.0 | 186 |
31 | 1-萘基 | H | H | Cl | Cl | 41 | 31.5 | 25 |
32 | 1-萘基 | H | H | Br | Br | 48.6 | 37.3 | 37.6 |
33 | 1-萘基 | H | H | CH3 | CH3 | 79.2 | 60.9 | 27.4 |
34 | 1-萘基 | H | H | F | CH3 | 86 | 66.1 | 69 |
35 | 1-萘基 | H | H | Cl | CH3 | 31.2 | 24.0 | 43 |
36 | 1-萘基 | H | H | OCH3 | CH3 | 61.5 | 47.3 | 161 |
37 | 1-萘基 | H | H | H | Cl | 371 | 285 | 33 |
38 | 1-萘基 | H | H | H | CH3 | 192 | 148 | 75 |
39 | 1-萘基 | H | H | F | CF3 | 38.4 | 29.5 | 79.4 |
40 | 1-萘基 | H | H | Cl | CF3 | 38.6 | 29.6 | 52.5 |
41 | 1-萘基 | H | H | Br | CF3 | 51.1 | 39.3 | 49.6 |
42 | 1-萘基 | H | H | SCH3 | CF3 | 170 | 131 | 418 |
43 | 1-萘基 | H | H | H | CF3 | 129 | 99.2 | 238 |
44 | 1-萘基 | H | H | Cl | CH2CH3 | 20.6 | 15.8 | 4.94 |
45 | 1-萘基 | H | H | H | CH2CH3 | 39 | 30.0 | 53.8 |
46 | 1-萘基 | H | H | Cl | SCH3 | 43 | 33.2 | 25.4 |
47 | 1-萘基 | H | H | H | SCH3 | 124 | 95.3 | 27 |
48 | 8-喹啉基 | H | H | Cl | CH3 | 32 | 24.4 | 989 |
49 | 8-喹啉基 | H | H | Cl | CH2CH3 | 4.2 | 3.2 | 322 |
50 | 1-萘基 | H | CH3 | Cl | Cl | 62 | 47.6 | 1318 |
51 | 1-萘基 | H | CH3 | Br | Br | 65 | 49.9 | 1250 |
52 | 1-萘基 | H | CH3 | H | Cl | 107 | 82.3 | 2982 |
表I(续)
化合物序号 | R | R1 | R2 | R3 | R4 | [3H-MK801] | [3H-DTG]IC50(nM) | |
IC50(nM) | Ki(nM) | |||||||
53 | 1-萘基 | H | CH3 | H | Br | 54 | 41.6 | 2759 |
54 | 1-萘基 | H | CH3 | CH3 | CH3 | 79 | 60.8 | 1554 |
55 | 1-萘基 | H | CH3 | Cl | CH3 | 41 | 31.6 | 2425 |
56 | 1-萘基 | H | CH3 | H | CH3 | 85 | 65.4 | 1262 |
57 | 1-萘基 | H | CH3 | Cl | CH2CH3 | 32.8 | 25.2 | 136 |
58 | 1-萘基 | H | CH3 | H | CH2CH3 | 37.5 | 28.8 | 2535 |
59 | 3-乙基苯基 | CH3 | H | Br | CH3 | 3.19 | 2.45 | 240 |
60 | 3-甲硫基苯基 | CH3 | H | Cl | SCH3 | 2.43 | 1.84 | 480 |
61 | 3-甲硫基苯基 | CH3 | H | Cl | CH2CH3 | 12.6 | 9.69 | 178 |
62 | 3-甲硫基苯基 | CH3 | H | Cl | Cl | 59.3 | 45.6 | 130 |
63 | 3-甲硫基苯基 | CH3 | H | Br | SCH3 | 2.15 | 1.65 | NT |
64 | 3-甲硫基苯基 | CH3 | H | Br | CH2CH3 | 5.09 | 3.92 | 180 |
65 | 3-甲硫基苯基 | CH3 | H | Br | Br | 5.38 | 4.13 | 113 |
66 | 3-三氟甲基苯基 | CH3 | H | Cl | SCH3 | 8.47 | 6.92 | 421 |
67 | 3-三氟甲基苯基 | CH3 | H | Cl | CH2CH3 | 77.0 | 59.2 | 200 |
68 | 3-三氟甲基苯基 | CH3 | H | Cl | Cl | 201 | 155 | 110 |
69 | 3-三氟甲基苯基 | CH3 | H | Br | SCH3 | 5.55 | 4.27 | 631 |
70 | 3-三氟甲基苯基 | CH3 | H | Br | CH2CH3 | 20.4 | 15.7 | 166 |
71 | 3-三氟甲基苯基 | CH3 | H | Br | Br | 34.0 | 26.1 | 224 |
72 | 3-溴苯基 | CH3 | H | Cl | SCH3 | 4.65 | 3.58 | NT |
73 | 3-三氟甲氧基苯基 | CH3 | H | Br | Br | 25.6 | 19.7 | NT |
74 | 3-三氟甲氧基苯基 | CH3 | H | Br | CH2CH3 | 16.0 | 12.3 | NT |
75 | 3-甲基磺酰基苯基 | CH3 | H | Br | Br | 530 | 408 | NT |
76 | 3-甲基亚磺酰基苯基 | CH3 | H | Br | Br | 322 | 248 | NT |
77 | 3-碘苯基 | CH3 | H | Cl | SCH3 | 2.11 | 1.62 | NT |
78 | 3-碘苯基 | H | H | Cl | CH2CH3 | 13.7 | 10.5 | NT |
79 | 8-喹啉基 | CH3 | H | Cl | SCH3 | 22.3 | 17 | 542 |
实施例76对由NMDA诱导的对中枢神经系统兴奋性损伤的保护作用的体内测定
本发明化合物的体内效力以汇总于表II的数据为代表且依据下列方案得到。将新生7天的大鼠用matophane吸入麻醉剂麻醉4-6分钟,插入定向仪并在纹状体内(intrastriatally)注射0.5μl 50mMNMDA(N-甲基-D-天冬氨酸盐)。注射NMDA 15分钟后给大鼠幼崽腹膜内注射10,30或60μmol/kg的表II中规定结构的NMDA拮抗剂。将动物放归它们的母亲,并观察它们的痛苦迹象(例如,呼吸抑制)。5天后,动物用CO2麻醉后断头;取出大脑并称重以确定神经保护的程度。由于注射NMDA造成大脑生长迟缓(包括坏死),因此可根据注射和未注射的脑半球重量来检查试验的效果。两组大鼠幼崽分别使用了三种剂量的化合物以获得神经保护剂量-响应曲线。每个试验化合物的化学结构用下面表II顶部的通式表示,其具体取代基标在表内。表II公开了1)每个试验化合物的ED80,即对中枢神经系统损伤提供80%最大保护的化合物剂量;2)由所示剂量(用每公斤试验对象体重μmol表示)提供的对中枢神经系统损伤最大保护的百分比(%)。
表II
化合物序号 | R | R1 | R2 | R3 | R4 | ED80μmol/kg | 每剂量(μmol/kg)最大保护(%) |
1 | 3-乙基苯基 | CH3 | H | Cl | Cl | 36.4 | 88.8@60 |
2 | 3-乙基苯基 | CH3 | H | Br | Br | 13.4 | 93.8@60 |
3 | 3-乙基苯基 | H | H | F | CF3 | 15.2 | 76.6@60 |
4 | 3-乙基苯基 | CH3 | H | Cl | C2H5 | 19.8 | 77.8@60 |
5 | 1-萘基 | H | CH3 | Cl | C2H5 | 22.3 | 92.2@60 |
6 | 1-萘基 | H | CH3 | Br | Br | 26.9 | 85.7@60 |
7 | 1-萘基 | H | CH3 | CH3 | CH3 | 22.5 | 86.0@30 |
8 | 1-萘基 | H | H | F | CF3 | 28.8 | 96.0@60 |
9 | 1-萘基 | H | H | Cl | SCH3 | 10.8 | 92.7@60 |
10 | 1-萘基 | H | H | Cl | CH3 | 45.8 | 96.4@60 |
11 | 8-喹啉基 | H | H | Cl | C2H5 | 14.2 | 94.5@30 |
上文已经通过优选实例详细说明了本发明。然而本领域技术人员能够理解,根据本公开可能作出的任何修饰和改进均在本发明范围之内。
Claims (31)
2.权利要求1的化合物,所述化合物是N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍或其药物上可接受的盐。
3.权利要求1的化合物,所述化合物是N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)胍或其药物上可接受的盐。
4.权利要求1的化合物,其中R和R2均为氢。
5.权利要求1的化合物,其中R和R2中至少一个不为氢。
6.权利要求4或5的化合物,其中R和R2为氢或具有1-4个碳原子的烷基。
7.下列的权利要求1的化合物或其药物上可接受的盐:
N-(3-乙基苯基)-N,N′-二甲基-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N′-(2,5-二氯苯基)-N′-甲基胍;
N-(3-乙基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N′-(2,5-二溴苯基)-N′-甲基胍;
N-(3-乙基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氟-5-三氟甲基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氟-5-乙基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-甲基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-甲硫基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-甲硫基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,4,5-三氯苯基)胍;
N-(3-乙基苯基)-N′-(2,4,5-三氯苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2,3,5-三氯苯基)胍;
N-(3-乙基苯基)-N′-(2,3,5-三氯苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲硫基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N′-(2,5-二氯苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-甲硫基苯基)胍;
N-(3-溴苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-溴苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-溴苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-三氟甲氧基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-三氟甲氧基苯基)-N-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲氧基苯基)-N′-甲基-N′-(2-溴-5-乙基苯基)胍;
N-(3-三氟甲氧基苯基)-N′-(2-溴-5-乙基苯基)胍;
N-(3-碘苯基)-N-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(3-碘苯基)-N-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-碘苯基)-N′-甲基-N′-(2-氯-5-乙基苯基)胍;
N-(3-碘苯基)-N′-(2-氯-5-乙基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-氯-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-溴-5-乙硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N,N-二甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-乙基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲硫基苯基);
N-(3-甲硫基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-甲硫基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-氯-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;
N-(3-三氟甲基苯基)-N′-甲基-N′-(2-溴-5-三氟甲硫基苯基)胍;或
N-(3-三氟甲基苯基)-N,N′-二甲基-N′-(2-溴-5-三氟甲硫基苯基)胍。
8.下式所示化合物或其药物上可接受的盐:
其中R是萘基或喹啉基;R1和R2各自独立地代表氢或C1-20烷基;
R3,R4和每个R5取代基各自独立地代表卤素,羟基,叠氮基,任选取代的C1-20烷基,任选取代的C2-20链烯基,任选取代的C2-20炔基,任选取代的C1-20烷氧基,任选取代的C1-20烷硫基,任选取代的C1-20氨基烷基,任选取代的具有至少6个环碳原子的碳环芳基,或任选取代的具有至少6个环碳原子的芳烷基;n是整数0-3。
9.权利要求8的化合物,所述化合物是:
N-(1-萘基)-N′-(2-溴-5-乙基苯基)胍;
N-(1-萘基)-N′-(2-氟-5-乙基苯基)胍;
N-(1-萘基)-N′-(2,5-二氯苯基)胍;
N-(1-萘基)-N′-(2,4,5-三氯苯基)胍;
N-(1-萘基)-N′-(2,3,5-三氯苯基)胍;
N-(1-萘基)-N′-(2,5-二氯苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2-氯-5-甲基苯基)胍;
N-(1-萘基)-N′-(2,5-二甲基苯基)胍;
N-(1-萘基)-N′-(2,5-二溴苯基)胍;
N-(1-萘基)-N′-(2-氯-5-甲基苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2,5-二甲基苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2,5-二溴苯基)-N-甲基胍;
N-(1-萘基)-N′-(2,5-二溴苯基)-N′-甲基胍;
N-(1-萘基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(1-萘基)-N′-(2-氟-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-溴-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-甲硫基-5-三氟甲基苯基)胍;
N-(1-萘基)-N′-(2-甲氧基-5-甲基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-乙基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-乙基苯基)-N′-甲基胍;
N-(1-萘基)-N′-甲基-N′-(2-氯-5-甲硫基苯基)胍;
N-(8-喹啉基)-N′-(2-氯-5-甲基苯基)胍;
N-(8-喹啉基)-N′-(2-氯-5-乙基苯基)胍;
N-(8-喹啉基)-N′-甲基-(2-氯-5-乙基苯基)胍;
N-(1-萘基)-N′-(2-氟-5-甲基苯基)胍;
N-(1-萘基)-N′-(2-氯-5-甲硫基苯基)胍;
N-(1-萘基)-N′-(2-碘-5-甲硫基苯基)胍;或
N-(1-萘基)-N′-(2-溴-5-甲硫基苯基)胍。
11.权利要求10的化合物,其中R1和R2中一个是氢,R1和R2中另一个是C1-20烷基。
12.权利要求10的化合物,其中R1和R2分别是C1-20烷基。
13.下式所示的化合物或其药物上可接受的盐:
其中R1和R2分别代表氢或C1-20烷基;
R是任选取代的苯基、萘基或喹啉基;
R3,R4,每个R5分别代表卤素,羟基,叠氮基,任选取代的C1-20烷基,任选取代的C2-20链烯基,任选取代的C2-20炔基,任选取代的C1-20烷氧基,任选取代的C1-20烷硫基,任选取代的C1 -20氨基烷基,任选取代的具有至少6个环碳原子的碳环芳基,或任选取代的具有至少6个环碳原子的芳烷基;n是整数0-3。
14.权利要求13的化合物,其中R是喹啉基。
15.下式所示的化合物或其药物上可接受的盐:
其中R为在3-位上被如R3、R4和R5所述的取代基取代的苯基,R1和R2分别代表氢或C1-20烷基;
R3,R4和每个R5分别代表卤素,羟基,叠氮基,任选取代的C1-20烷基,任选取代的C2-20链烯基,任选取代的C2-20炔基,任选取代的C1-20烷氧基,任选取代的C1-20烷硫基,任选取代的C1 -20烷基亚磺酰基,任选取代的C1-20烷基磺酰基,任选取代的C1 -20氨基烷基,任选取代的具有至少6个环碳原子的碳环芳基,或任选取代的具有至少6个环碳原子的芳烷基;R3、R4和R5中至少一个是任选取代的烷基亚磺酰基或任选取代的烷基磺酰基;n是整数0-3。
16.下列的权利要求15的化合物或其药物上可接受的盐:
N-(3-甲基磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基磺酰基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍。
N-(3-甲基磺酰基苯基)-N′-(2,5-二溴苯基)胍;
N-(3-甲基亚磺酰基苯基)-N-甲基-N′-(2,5-二溴苯基)胍;
N-(3-甲基亚磺酰基苯基)-N′-甲基-N′-(2,5-二溴苯基)胍;或
N-(3-甲基亚磺酰基苯基)-N′-(2,5-二溴苯基)胍。
17.权利要求8,10,13和15中任一项所述的化合物或其药物上可接受的盐在制备用于治疗或预防精神系统疾病的药物中的用途,其中疾病的病理生理学涉及由NMDA受体激动剂造成的神经细胞过度兴奋。
18.权利要求17的用途,其中R1和R2中一个是氢,R1和R2中另一个是C1-20烷基。
19.权利要求17的用途,其中R1和R2分别是C1-20烷基。
20.权利要求17的用途,其中所说疾病是阿尔茨海默病,帕金森病,亨廷顿病,肌萎缩性侧索硬化,唐氏综合症或科尔萨科夫病,或所述障碍是癫痫。
22.权利要求21的用途,其中R1和R2中一个是氢,R1和R2中另一个是C1-20烷基。
23.权利要求21的用途,其中R1和R2分别是C1-20烷基。
24.权利要求21的用途,其中所说神经毒性是由于缺血,低血糖,脑或脊髓缺血或脑或脊髓创伤发生之后内生谷氨酸过度释放引起的。
25.权利要求21所述的化合物用途,所述用途是制备用于治疗脑或脊髓损伤、脑或脊髓缺血、心脏病发作、缺氧、低血糖的患者、经过手术而脑缺血是潜在的并发症的患者、或减压症的药物。
26.权利要求21所述的化合物用途,所述用途是制备用于治疗神经变性疾病的药物。
27.权利要求21所述的化合物用途,所述用途是制备用于治疗帕金森病,亨廷顿病,肌萎缩性侧索硬化,阿尔茨海默病,唐氏综合症或科尔萨科夫病的药物。
29.权利要求28的用途,其中R1和R2中一个是氢,R1和R2中另一个是C1-20烷基。
30.权利要求28的用途,其中R1和R2分别是C1-20烷基。
31.权利要求1所述的化合物或其药物上可接受的盐在制备用于治疗或预防精神系统疾病的药物中的用途,其中疾病的病理生理学涉及由NMDA受体激动剂造成的神经细胞过度兴奋。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6852293A | 1993-05-27 | 1993-05-27 | |
US08/068,522 | 1993-05-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1126434A CN1126434A (zh) | 1996-07-10 |
CN1188121C true CN1188121C (zh) | 2005-02-09 |
Family
ID=22083114
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB941926109A Expired - Fee Related CN1188121C (zh) | 1993-05-27 | 1994-05-27 | 治疗性取代的胍类 |
Country Status (13)
Country | Link |
---|---|
US (2) | US6147063A (zh) |
EP (1) | EP0705100B1 (zh) |
JP (2) | JP3610368B2 (zh) |
KR (1) | KR20030097618A (zh) |
CN (1) | CN1188121C (zh) |
AT (1) | ATE245977T1 (zh) |
CA (1) | CA2163361C (zh) |
DE (1) | DE69432984T2 (zh) |
DK (1) | DK0705100T3 (zh) |
ES (1) | ES2204920T3 (zh) |
PT (1) | PT705100E (zh) |
WO (1) | WO1994027591A1 (zh) |
ZA (1) | ZA943744B (zh) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0751767A4 (en) * | 1994-02-03 | 1997-12-10 | Cambridge Neuroscience Inc | GUANIDINE FOR THERAPEUTIC USE |
US6787569B1 (en) | 1994-02-03 | 2004-09-07 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
US6143791A (en) * | 1994-02-03 | 2000-11-07 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
US7351743B1 (en) | 1994-02-03 | 2008-04-01 | Wyeth | Therapeutic guanidines |
US6025355A (en) | 1997-05-19 | 2000-02-15 | Cambridge Neuroscience, Inc. | Pharmaceutically active compounds and methods of use |
US6756389B2 (en) * | 1996-08-09 | 2004-06-29 | Cambridge Neuroscience, Inc. | Pharmaceutically active compounds and methods of use |
CA2306276A1 (en) * | 1997-10-10 | 1999-04-22 | James B. Fischer | Pharmaceutically active compound and methods of use |
US6774263B1 (en) | 1997-10-10 | 2004-08-10 | Cambridge Neuroscience, Inc. | Pharmaceutically active compound and methods of use |
US7041702B1 (en) | 1997-10-21 | 2006-05-09 | Scion Pharmaceuticals, Inc. | Pharmaceutically active compounds and methods of use |
US20030199574A1 (en) | 2000-03-02 | 2003-10-23 | Vitreo-Retinal Technologies, Inc. | Treatment of ophthalmic disorders using urea and urea derivatives |
EP1480678B1 (en) * | 2002-02-13 | 2009-04-15 | Vitreo-Retinal Technologies, Inc. | Treatment of ophthalmic disorders using urea and urea derivatives |
GB0216621D0 (en) * | 2002-07-17 | 2002-08-28 | Imaging Res Solutions Ltd | Imaging compounds |
CN1926098A (zh) * | 2004-03-29 | 2007-03-07 | 神经研究公司 | 新的脲衍生物及其医药应用 |
AU2006304787A1 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
JP2009536667A (ja) | 2006-05-09 | 2009-10-15 | ブレインセルス,インコーポレイティド | 5ht受容体介在性の神経新生 |
EP2021000A2 (en) | 2006-05-09 | 2009-02-11 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
US7998971B2 (en) * | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
EP1908464A1 (en) * | 2006-10-04 | 2008-04-09 | Centre National De La Recherche Scientifique (Cnrs) | Use of chlorine guanabenz derivatives for treating polyglutamine expansion associated diseases |
WO2010048164A2 (en) * | 2008-10-20 | 2010-04-29 | University Of South Florida | N,n'-di-p-bromophenyl guanidine treatment for stroke at delayed timepoints |
WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
GB201008047D0 (en) | 2010-05-14 | 2010-06-30 | Ge Healthcare Ltd | Method of synthesis |
NL2006875C2 (en) * | 2011-05-31 | 2012-12-03 | Vereniging Voor Christelijk Hoger Onderwijs | N,n-substituted guanidine compound. |
GB201117785D0 (en) | 2011-10-14 | 2011-11-30 | Ge Healthcare Ltd | Improved radiosynthesis method |
GB201117786D0 (en) | 2011-10-14 | 2011-11-30 | Ge Healthcare Ltd | Eluent vial |
WO2015002150A1 (ja) | 2013-07-03 | 2015-01-08 | 株式会社新日本科学 | 新規化合物,有機カチオントランスポーター3の検出剤及び活性阻害剤 |
CN111548313A (zh) * | 2019-02-11 | 2020-08-18 | 绍兴从零医药科技有限公司 | 预防和治疗慢性疼痛药物的胍类化合物 |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1677235A (en) * | 1928-07-17 | Balph v | ||
US1730388A (en) * | 1929-10-08 | Winfield scott | ||
US2145214A (en) * | 1939-01-24 | Parasiticide | ||
US1422506A (en) * | 1921-07-02 | 1922-07-11 | Dovan Chemical Corp | Process of making diphenylguanidine |
US1642180A (en) * | 1922-11-27 | 1927-09-13 | Du Pont | Di-para-xylylguanidine |
US1597233A (en) * | 1923-02-27 | 1926-08-24 | Albert C Burrage | Vulcanization of rubber |
GB223410A (en) * | 1923-11-01 | 1924-10-23 | British Dyestuffs Corp Ltd | Improvements in the manufacture of diarylguanidines |
GB224376A (en) * | 1923-11-01 | 1924-11-13 | British Dyestuffs Corp Ltd | Improvements in the manufacture of triarylguanidines |
GB258203A (en) * | 1925-09-23 | 1926-09-16 | Silesia Ver Chemischer Fabrike | An improved process for the production of symmetrical di-arylguanidines |
US1672431A (en) * | 1925-11-30 | 1928-06-05 | Firm Chem Fab Auf Actien Vorma | Symmetrical diarylized guanidine compounds |
US1795398A (en) * | 1925-12-21 | 1931-03-10 | Huguenin Albert | Elevator for boats with constant draft |
US1850682A (en) * | 1927-01-10 | 1932-03-22 | Ig Farbenindustrie Ag | Substituted guanidines |
DE514248C (de) * | 1927-09-13 | 1930-12-10 | Schering Kahlbaum Akt Ges | Verfahren zur Darstellung substituierter Guanidine |
US1756315A (en) * | 1927-11-28 | 1930-04-29 | Rubber Service Lab Co | Rubber vulcanization process |
US1915922A (en) * | 1931-03-02 | 1933-06-27 | American Cyanamid Co | Mothproofing |
GB478525A (en) * | 1936-02-13 | 1938-01-20 | Georg Knoth | Process for the preparation of diphenylguanidine |
US2254009A (en) * | 1940-04-24 | 1941-08-26 | American Cyanamid Co | Symmetrical di-2-octyl-guanidine |
US2274476A (en) * | 1940-08-23 | 1942-02-24 | American Cyanamid Co | Insecticide and moth larvae repellent |
US2362915A (en) * | 1940-12-24 | 1944-11-14 | Courtaulds Ltd | Process for improving the fastness to washing of dyed cellulosic textile materials |
US2289541A (en) * | 1941-01-18 | 1942-07-14 | American Cyanamid Co | Insecticide |
US2704710A (en) * | 1950-04-18 | 1955-03-22 | Gen Aniline & Film Corp | Precipitation of azo dyes in silver halide emulsions by means of guanidine and biguanide compounds containing long alkyl chains |
US2633474A (en) * | 1951-07-21 | 1953-03-31 | Monsanto Chemicals | 1, 3-bis (o-ethylphenyl) guanidine |
US3117994A (en) * | 1959-12-03 | 1964-01-14 | Monsanto Canada Ltd | Nu, nu', nu'-trisubstituted guanidines |
CA940537A (en) * | 1959-12-23 | 1974-01-22 | Wellcome Foundation Limited (The) | Benzyl guanidines, and a process of production |
GB952194A (en) * | 1960-12-23 | 1964-03-11 | Smith Kline French Lab | New guanidine derivatives and processes for preparing the same |
US3140231A (en) * | 1961-08-14 | 1964-07-07 | Rohm & Haas | T-octylguanidines as antihypertensive agents |
US3159676A (en) * | 1962-02-07 | 1964-12-01 | Smith Kline French Lab | Naphthyl containing guanidines |
US3248426A (en) * | 1962-03-01 | 1966-04-26 | American Home Prod | Nu-(1-naphthylmethyl)-guanidine and acid addition salt thereof |
US3301755A (en) * | 1962-04-18 | 1967-01-31 | Ciba Geigy Corp | Allylic guanidines |
CH433246A (de) * | 1962-06-25 | 1967-04-15 | Ciba Geigy | Verfahren zur Herstellung von Guanidinverbindungen |
US3479437A (en) * | 1963-08-26 | 1969-11-18 | Stauffer Chemical Co | Guanidine complexes as fungicides |
US3320229A (en) * | 1963-08-26 | 1967-05-16 | Stauffer Chemical Co | Complexes of guanidines with completely halogenated acetones |
GB1110947A (en) * | 1963-12-13 | 1968-04-24 | Evans Medical Ltd | Guanidines |
US3228975A (en) * | 1964-04-10 | 1966-01-11 | American Cyanamid Co | Akyl-substituted cyclohexyl guanidines and biguanides |
NL125066C (zh) * | 1964-07-31 | |||
US3391189A (en) * | 1966-01-13 | 1968-07-02 | Ciba Geigy Corp | Nu-allyl-guanidines and salts thereof |
US3639477A (en) * | 1968-06-17 | 1972-02-01 | Parke Davis & Co | Novel propoxyguanidine compounds and means of producing the same |
US3803324A (en) * | 1968-07-09 | 1974-04-09 | Boehringer Mannheim Gmbh | Amino-guanidine derivatives useful for regulating blood pressure |
GB1208252A (en) * | 1969-01-01 | 1970-10-14 | American Cyanamid Co | Use of alkylguanidine salts as viricides |
US3547951A (en) * | 1969-06-17 | 1970-12-15 | Waldo R Hardie | 1,3-dioxolan-4-yl-alkyl guanidines |
AU1592270A (en) * | 1969-06-17 | 1971-12-09 | Imperial Chemical Industries Limited | Antiviral processes and compositions |
US3949089A (en) * | 1969-06-23 | 1976-04-06 | Burroughs Wellcome Co. | Substituted guanidine compounds as antifibrillatory agents |
US3975533A (en) * | 1970-04-29 | 1976-08-17 | Shell Oil Company | Therapeutic agents |
US4060640A (en) * | 1970-04-29 | 1977-11-29 | Shell Oil Company | Therapeutic agents |
US3968243A (en) * | 1970-06-05 | 1976-07-06 | Burroughs Wellcome Co. | Substituted guanidine compounds in the treating of arrythmias |
NL7011683A (zh) * | 1970-08-07 | 1972-02-09 | ||
US3908013A (en) * | 1970-09-17 | 1975-09-23 | Armour Pharma | Pharmaceutical aromatic guanidine compositions and methods of using same |
US3681459A (en) * | 1970-10-01 | 1972-08-01 | Armour Pharma | Guanidine compounds and use of same |
US3769427A (en) * | 1970-10-01 | 1973-10-30 | Armour Pharma | Pharmaceutical compositions and methods of using same |
US3976787A (en) * | 1970-11-10 | 1976-08-24 | Armour Pharmaceutical Company | Pharmaceutical guanidine preparations and methods of using same |
US3784643A (en) * | 1970-12-11 | 1974-01-08 | Colgate Palmolive Co | Aryloxyalkylguanidines |
DE2133056C3 (de) * | 1971-07-02 | 1980-10-23 | Vsesojuznyj Nautschno-Issledovatelskij Institut Chimitscheskich Sredstv Zaschtschity Rastenij, Moskau | Verwendung von NJS-di-alkyl-N'arylsubstituierten Guanidinen zur Bekämpfung von Mehltaupilzen und Grauschimmel der Pflanzen |
US3976643A (en) * | 1973-07-13 | 1976-08-24 | William H. Rorer, Inc. | Guanidines |
NL7315350A (nl) * | 1973-11-09 | 1975-05-13 | Akzo Nv | Nieuwe aminoguanidine verbindingen. |
US4007181A (en) * | 1974-02-11 | 1977-02-08 | The Upjohn Company | Adamantyl containing guanidines |
US4052455A (en) * | 1974-04-08 | 1977-10-04 | Mead Johnson & Company | Styrylamidines |
US4014934A (en) * | 1974-04-15 | 1977-03-29 | Armour Pharmaceutical Company | Substituted 4'-hydroxyphenyl guanidines and methods of using the same |
US4109014A (en) * | 1974-10-29 | 1978-08-22 | Armour Pharmaceutical Company | Pharmaceutical, compositions containing substituted 4'-hydroxyphenyl guanidines and methods of using same |
US4130663A (en) * | 1975-08-04 | 1978-12-19 | Mead Johnson & Company | Styrylamidines |
US4169154A (en) * | 1976-04-15 | 1979-09-25 | Hoffmann-La Roche Inc. | Method of treating depression with thiourea derivatives |
US4051256A (en) * | 1976-09-19 | 1977-09-27 | Imperial Chemical Industries Limited | Guanidine derivatives |
US4101659A (en) * | 1977-08-29 | 1978-07-18 | Mcneil Laboratories, Incorporated | Benzhydryl guanidines |
US4172204A (en) * | 1977-10-07 | 1979-10-23 | Syntex (U.S.A.) Inc. | Method for preparing 4,5-dihydro-2-alkoxycarbonylamino-5-carbocyclic aryl imidazoles and intermediates thereof |
PH17019A (en) * | 1980-03-01 | 1984-05-11 | Wyeth John & Brother Ltd | 4-piperidyl-or dehydropiperidyl-urea derivatives and method of use |
DE3108564A1 (de) * | 1981-03-06 | 1982-11-18 | Bayer Ag, 5090 Leverkusen | N-tert-butyl-phenyl-n'-cyclohexyl-quanidine, verfahren zu ihrer herstellung sowie ihre verwendung als fungizide |
US4393077A (en) * | 1981-07-02 | 1983-07-12 | William H. Rorer, Inc. | 1-Methylene-1-phenylguanidine compounds |
FR2509724B1 (fr) * | 1981-07-15 | 1985-10-25 | Centre Nat Rech Scient | Nouvelles guanidines a fort encombrement sterique et procedes pour leur preparation |
US4742054A (en) * | 1982-11-23 | 1988-05-03 | Naftchi Nosrat E | Treatment of mammals suffering from damage to the central nervous system |
US4663263A (en) * | 1984-10-19 | 1987-05-05 | Canon Kabushiki Kaisha | Toner, charge-imparting material and composition containing substituted guanidine compound for electrophotography |
DE3501383A1 (de) * | 1985-01-17 | 1986-07-17 | Akzo Gmbh, 5600 Wuppertal | Verfahren zur herstellung von n,n'-disubstituierten guanidinen |
EP0259371B1 (en) * | 1986-01-28 | 1992-05-13 | JOHN WYETH & BROTHER LIMITED | Preparation of 3-dimethylamino-7-methyl-1,2,4-benzotriazine-1-oxide and azapropazone |
US5093525A (en) * | 1986-07-10 | 1992-03-03 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists |
US4709094A (en) * | 1986-07-10 | 1987-11-24 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | Sigma brain receptor ligands and their use |
US5190976A (en) * | 1986-07-10 | 1993-03-02 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And University Of Oregon | N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists |
US4906779A (en) * | 1986-07-10 | 1990-03-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists |
US5385946A (en) * | 1986-07-10 | 1995-01-31 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | Method for treating hypertension with disubstituted granidine compounds |
US5312840A (en) * | 1986-07-10 | 1994-05-17 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education | Substituted guanidines having high binding to the sigma receptor and the use thereof |
US4837218A (en) * | 1987-10-23 | 1989-06-06 | Washington University | Alkylated bicycloalkaneamines for treatment of neurotoxic injury |
US4891185A (en) * | 1988-01-22 | 1990-01-02 | Goldin Stanley M | High resolution monitoring device |
US5011834A (en) * | 1989-04-14 | 1991-04-30 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
DK0473671T3 (da) * | 1989-05-02 | 1994-09-19 | Oregon State | Anvendelse af sigma-receptorligander til fremstilling af et anxiolytisk middel |
CA2076664C (en) * | 1990-03-02 | 2004-01-13 | Eckard Weber | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
US5262568A (en) * | 1990-03-02 | 1993-11-16 | State Of Oregon | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
US5336689A (en) * | 1990-03-02 | 1994-08-09 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
US5574070A (en) * | 1990-05-25 | 1996-11-12 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Substituted guanidines having high binding to the sigma receptor and the use thereof |
AU671071B2 (en) * | 1990-08-30 | 1996-08-15 | State of Oregon, acting by and through The Oregon State Board of Higher Education, acting for and on behalf of The Oregon Health Sciences University, Portland, Oregon, and The University of Oregon, Eugene, Oregon, Johnson Hall, | Substituted amidines having high binding to the sigma receptor and the use thereof |
PT100115B (pt) * | 1991-02-08 | 1999-06-30 | Cambridge Neuroscience Inc | Guanidinas substituidas e seus derivados uteis como moduladores de libertacao de neurotransmissores e ensaios de rastreio para de bloqueadores de libertacao de neurotransmissores |
US5298657A (en) * | 1992-03-20 | 1994-03-29 | Cambridge Neuroscience Inc. | Preparation of substituted guanidines |
DK41193D0 (da) * | 1993-04-07 | 1993-04-07 | Neurosearch As | Ionkanalaabnere |
EP0751767A4 (en) * | 1994-02-03 | 1997-12-10 | Cambridge Neuroscience Inc | GUANIDINE FOR THERAPEUTIC USE |
-
1994
- 1994-05-27 ZA ZA943744A patent/ZA943744B/xx unknown
- 1994-05-27 CN CNB941926109A patent/CN1188121C/zh not_active Expired - Fee Related
- 1994-05-27 PT PT94919275T patent/PT705100E/pt unknown
- 1994-05-27 ES ES94919275T patent/ES2204920T3/es not_active Expired - Lifetime
- 1994-05-27 WO PCT/US1994/006008 patent/WO1994027591A1/en active IP Right Grant
- 1994-05-27 JP JP50098895A patent/JP3610368B2/ja not_active Expired - Fee Related
- 1994-05-27 DE DE69432984T patent/DE69432984T2/de not_active Expired - Fee Related
- 1994-05-27 AT AT94919275T patent/ATE245977T1/de not_active IP Right Cessation
- 1994-05-27 DK DK94919275T patent/DK0705100T3/da active
- 1994-05-27 CA CA002163361A patent/CA2163361C/en not_active Expired - Fee Related
- 1994-05-27 EP EP94919275A patent/EP0705100B1/en not_active Expired - Lifetime
- 1994-05-27 KR KR1020027015816A patent/KR20030097618A/ko not_active Application Discontinuation
-
1995
- 1995-06-02 US US08/458,741 patent/US6147063A/en not_active Expired - Fee Related
- 1995-06-02 US US08/458,803 patent/US6153604A/en not_active Expired - Fee Related
-
2004
- 2004-05-11 JP JP2004140658A patent/JP2004285073A/ja not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
DK0705100T3 (da) | 2003-11-17 |
JP3610368B2 (ja) | 2005-01-12 |
ATE245977T1 (de) | 2003-08-15 |
AU695337B2 (en) | 1998-08-13 |
WO1994027591A1 (en) | 1994-12-08 |
DE69432984T2 (de) | 2004-05-27 |
JPH08510754A (ja) | 1996-11-12 |
PT705100E (pt) | 2003-12-31 |
AU7047394A (en) | 1994-12-20 |
DE69432984D1 (de) | 2003-09-04 |
ES2204920T3 (es) | 2004-05-01 |
EP0705100B1 (en) | 2003-07-30 |
US6147063A (en) | 2000-11-14 |
ZA943744B (en) | 1995-04-26 |
CA2163361C (en) | 2008-06-17 |
US6153604A (en) | 2000-11-28 |
EP0705100A1 (en) | 1996-04-10 |
CN1126434A (zh) | 1996-07-10 |
KR20030097618A (ko) | 2003-12-31 |
CA2163361A1 (en) | 1994-12-08 |
JP2004285073A (ja) | 2004-10-14 |
EP0705100A4 (en) | 1996-05-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1188121C (zh) | 治疗性取代的胍类 | |
CN1078889C (zh) | 非肽类速激肽受体拮抗剂 | |
CN1102580C (zh) | 芳基乙烯基磺酰胺衍生物及其医药组合物 | |
CN1237055C (zh) | 三唑衍生物 | |
CN101031565A (zh) | 取代的2h-1,3-苯并噁嗪-4(3h)-酮 | |
CN1143854C (zh) | 新的2-(亚氨基甲基)氨基-苯基衍生物,其制备方法、作为药物的应用及其药物组合物 | |
CN1113236A (zh) | 非肽基速激肽受体拮抗剂 | |
CN1656075A (zh) | 喹啉衍生物和其作为5-ht6配体的用途 | |
CN1080919A (zh) | 作为酰基辅酶a-胆固醇酰基转移酶抑制剂的、新的n-芳基和n-杂芳基脲类衍生物 | |
CN101056845A (zh) | 取代的苯胺衍生物 | |
CN1649820A (zh) | 调节ppar活性的化合物及其制备方法 | |
CN1522244A (zh) | 邻氨基苯甲酰胺类化合物、其制备方法、其作为抗心律不齐剂的应用及其药物制剂 | |
CN1040755C (zh) | 杂环化合物的制备方法 | |
CN1094037A (zh) | N-苯甲酰苯胺衍生物 | |
CN1009831B (zh) | 杂环氧代-2,3-二氮杂萘基乙酸的制备方法 | |
CN1886133A (zh) | 吲哚化合物 | |
CN1653067A (zh) | 咔唑衍生物及其作为神经肽y5受体拮抗剂的应用 | |
CN101062916A (zh) | 三取代1h-吡唑化合物、其制备方法、药物组合物及其制药用途 | |
CN1028521C (zh) | 治疗剂 | |
CN1478081A (zh) | 取代的2-苯胺基苯并咪唑及其作为nhe抑制剂的用途 | |
CN1138037A (zh) | 粘连受体拮抗剂 | |
CN1617856A (zh) | 取代的4-苯基四氢异喹啉、其制备方法、其用作药物的用途以及含有它们的药物 | |
CN1149195C (zh) | 5-ht1f激动剂 | |
CN1196721A (zh) | 杂芳基取代的丙烯酰胍衍生物及其医药组合物 | |
CN1845924A (zh) | 芳基胺取代的喹唑啉酮化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050209 Termination date: 20100527 |