NO301929B1 - 4-aryl-tiazol- eller -imidazol-derivater - Google Patents
4-aryl-tiazol- eller -imidazol-derivater Download PDFInfo
- Publication number
- NO301929B1 NO301929B1 NO921156A NO921156A NO301929B1 NO 301929 B1 NO301929 B1 NO 301929B1 NO 921156 A NO921156 A NO 921156A NO 921156 A NO921156 A NO 921156A NO 301929 B1 NO301929 B1 NO 301929B1
- Authority
- NO
- Norway
- Prior art keywords
- thiazole
- carboxamide
- phenyl
- hydroxy
- carboximidamide
- Prior art date
Links
- 150000002460 imidazoles Chemical class 0.000 title abstract description 4
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- IQGSYVPGKNJALP-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=CC(Cl)=CC=2)=C1 IQGSYVPGKNJALP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 206010019280 Heart failures Diseases 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 4
- BSTDPPPLYKJYEO-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C=C(Cl)C(Cl)=CC=2)=C1 BSTDPPPLYKJYEO-UHFFFAOYSA-N 0.000 claims description 3
- MIXLZCYFMQNQDD-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound C1=C(OC)C(OC)=CC=C1C1=CSC(C(N)=NO)=N1 MIXLZCYFMQNQDD-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- QCEMLOKIEVVRPZ-UHFFFAOYSA-N 4-(3-chloro-4,5-dimethoxyphenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical group ClC1=C(OC)C(OC)=CC(C=2N=C(SC=2)C(=N)NO)=C1 QCEMLOKIEVVRPZ-UHFFFAOYSA-N 0.000 claims description 2
- FYUWXCNELXARTI-UHFFFAOYSA-N 5-(3,4-dimethylphenyl)-N'-hydroxy-1H-imidazole-2-carboximidamide Chemical compound C1=C(C)C(C)=CC=C1C1=CNC(C(=N)NO)=N1 FYUWXCNELXARTI-UHFFFAOYSA-N 0.000 claims description 2
- KXCQDIWJQBSUJF-UHFFFAOYSA-N 4-phenyl-1,3-thiazole Chemical compound S1C=NC(C=2C=CC=CC=2)=C1 KXCQDIWJQBSUJF-UHFFFAOYSA-N 0.000 claims 1
- XHLKOHSAWQPOFO-UHFFFAOYSA-N 5-phenyl-1h-imidazole Chemical class N1C=NC=C1C1=CC=CC=C1 XHLKOHSAWQPOFO-UHFFFAOYSA-N 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011575 calcium Substances 0.000 abstract description 3
- 229910052791 calcium Inorganic materials 0.000 abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 2
- 229940124630 bronchodilator Drugs 0.000 abstract description 2
- 230000000747 cardiac effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 210000003365 myofibril Anatomy 0.000 abstract description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- -1 4-(3-chloro-4,5-dimethoxy-phenyl)-N-hydroxy-thiazole-2-carboxamide Chemical compound 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- AVYBERINYRMRTR-UHFFFAOYSA-N 5-phenyl-1h-imidazole-2-carboxamide Chemical compound N1C(C(=O)N)=NC(C=2C=CC=CC=2)=C1 AVYBERINYRMRTR-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- XHAYBUXBCCPCRL-UHFFFAOYSA-N 4-(3-chloro-4,5-dimethoxyphenyl)-1,3-thiazole-2-carboxamide Chemical compound ClC1=C(OC)C(OC)=CC(C=2N=C(SC=2)C(N)=O)=C1 XHAYBUXBCCPCRL-UHFFFAOYSA-N 0.000 description 3
- VPCNHYHCNXZJAV-UHFFFAOYSA-N 4-(3-chloro-5-methoxy-4-methylthiophen-2-yl)-1,3-thiazole-2-carboxamide Chemical compound CC1=C(OC)SC(C=2N=C(SC=2)C(N)=O)=C1Cl VPCNHYHCNXZJAV-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- LFCCVJXZLGAFGN-UHFFFAOYSA-N 2-bromo-1-(3-chloro-4,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(C(=O)CBr)=CC(Cl)=C1OC LFCCVJXZLGAFGN-UHFFFAOYSA-N 0.000 description 2
- ONOOPHIHUQNUNI-UHFFFAOYSA-N 4-(3-chloro-4,5-dimethoxyphenyl)-1,3-thiazole-2-carbonitrile Chemical compound ClC1=C(OC)C(OC)=CC(C=2N=C(SC=2)C#N)=C1 ONOOPHIHUQNUNI-UHFFFAOYSA-N 0.000 description 2
- ISHGTFOPDPGSHQ-UHFFFAOYSA-N 4-(4-chlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C=CC(Cl)=CC=2)=C1 ISHGTFOPDPGSHQ-UHFFFAOYSA-N 0.000 description 2
- VZYJYKJYUQHDMJ-UHFFFAOYSA-N 4-phenyl-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=CC=CC=2)=C1 VZYJYKJYUQHDMJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SSBLFQUOASMILG-UHFFFAOYSA-N ethyl 4-(3-chloro-4,5-dimethoxyphenyl)-1,3-thiazole-2-carboxylate Chemical compound S1C(C(=O)OCC)=NC(C=2C=C(OC)C(OC)=C(Cl)C=2)=C1 SSBLFQUOASMILG-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- RLPMSNUHOBJXND-UHFFFAOYSA-N methyl 4-(3-chloro-5-methoxy-4-methylthiophen-2-yl)-1,3-thiazole-2-carboxylate Chemical compound S1C(C(=O)OC)=NC(C2=C(C(C)=C(OC)S2)Cl)=C1 RLPMSNUHOBJXND-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- LBKPMNBCFAEPBT-UHFFFAOYSA-N 1-(3-chloro-4,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(C(C)=O)=CC(Cl)=C1OC LBKPMNBCFAEPBT-UHFFFAOYSA-N 0.000 description 1
- GJDSMXZDKYUSGO-UHFFFAOYSA-N 1-methyl-4-(3-methylphenyl)imidazole-2-carboxamide Chemical compound CC1=CC=CC(C=2N=C(N(C)C=2)C(N)=O)=C1 GJDSMXZDKYUSGO-UHFFFAOYSA-N 0.000 description 1
- FUNBQBAQDDQDOR-UHFFFAOYSA-N 4-(2,3-dichlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C(=C(Cl)C=CC=2)Cl)=C1 FUNBQBAQDDQDOR-UHFFFAOYSA-N 0.000 description 1
- WJABVSYZDISIKX-UHFFFAOYSA-N 4-(2,3-dichlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C(=C(Cl)C=CC=2)Cl)=C1 WJABVSYZDISIKX-UHFFFAOYSA-N 0.000 description 1
- MYQZAGARZRBMGO-UHFFFAOYSA-N 4-(2,5-dichlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C(=CC=C(Cl)C=2)Cl)=C1 MYQZAGARZRBMGO-UHFFFAOYSA-N 0.000 description 1
- QEGOMBVNYMYHIX-UHFFFAOYSA-N 4-(2,5-dichlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C(=CC=C(Cl)C=2)Cl)=C1 QEGOMBVNYMYHIX-UHFFFAOYSA-N 0.000 description 1
- HMPRQIHNQZXYHC-UHFFFAOYSA-N 4-(2-chloro-3,4-dimethoxyphenyl)-1,3-thiazole-2-carboxamide Chemical compound ClC1=C(OC)C(OC)=CC=C1C1=CSC(C(N)=O)=N1 HMPRQIHNQZXYHC-UHFFFAOYSA-N 0.000 description 1
- KABOGOJZZPBIJE-UHFFFAOYSA-N 4-(2-chlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C(=CC=CC=2)Cl)=C1 KABOGOJZZPBIJE-UHFFFAOYSA-N 0.000 description 1
- SXCPZUAMVDMADQ-UHFFFAOYSA-N 4-(2-chlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C(=CC=CC=2)Cl)=C1 SXCPZUAMVDMADQ-UHFFFAOYSA-N 0.000 description 1
- GZDXUMORPZQJNC-UHFFFAOYSA-N 4-(2-fluorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C(=CC=CC=2)F)=C1 GZDXUMORPZQJNC-UHFFFAOYSA-N 0.000 description 1
- OMDUJTZIOBPPMN-UHFFFAOYSA-N 4-(2-fluorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C(=CC=CC=2)F)=C1 OMDUJTZIOBPPMN-UHFFFAOYSA-N 0.000 description 1
- IRCUSBQJPMUTMV-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=C(Cl)C(Cl)=CC=2)=C1 IRCUSBQJPMUTMV-UHFFFAOYSA-N 0.000 description 1
- KKWWESVWJKAKNI-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-1,3-thiazole-2-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1=CSC(C(N)=O)=N1 KKWWESVWJKAKNI-UHFFFAOYSA-N 0.000 description 1
- KHHVIBQWYXORIY-UHFFFAOYSA-N 4-(3,4-dimethylphenyl)-1,3-thiazole-2-carboxamide Chemical compound C1=C(C)C(C)=CC=C1C1=CSC(C(N)=O)=N1 KHHVIBQWYXORIY-UHFFFAOYSA-N 0.000 description 1
- SMGSGRZQCIXQJY-UHFFFAOYSA-N 4-(3,4-dimethylphenyl)-1-methylimidazole-2-carboxamide Chemical compound C1=C(C)C(C)=CC=C1C1=CN(C)C(C(N)=O)=N1 SMGSGRZQCIXQJY-UHFFFAOYSA-N 0.000 description 1
- VGHLDCHCKNIJHP-UHFFFAOYSA-N 4-(3,4-dimethylphenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound C1=C(C)C(C)=CC=C1C1=CSC(C(=N)NO)=N1 VGHLDCHCKNIJHP-UHFFFAOYSA-N 0.000 description 1
- JHULMCURQXBKDK-UHFFFAOYSA-N 4-(3,4-dimethylphenyl)-N'-hydroxy-1-methylimidazole-2-carboximidamide methanesulfonic acid Chemical compound CS(O)(=O)=O.Cc1ccc(cc1C)-c1cn(C)c(n1)C(=N)NO JHULMCURQXBKDK-UHFFFAOYSA-N 0.000 description 1
- VOGOHEISVIMCPZ-UHFFFAOYSA-N 4-(3,5-dichlorophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=C(Cl)C=C(Cl)C=2)=C1 VOGOHEISVIMCPZ-UHFFFAOYSA-N 0.000 description 1
- KZLRHGOHWVOVMV-UHFFFAOYSA-N 4-(3,5-dichlorophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C=C(Cl)C=C(Cl)C=2)=C1 KZLRHGOHWVOVMV-UHFFFAOYSA-N 0.000 description 1
- WINSSLCYJRUUNN-UHFFFAOYSA-N 4-(3-bromophenyl)-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=C(Br)C=CC=2)=C1 WINSSLCYJRUUNN-UHFFFAOYSA-N 0.000 description 1
- UAIHMOAXNWZDRP-UHFFFAOYSA-N 4-(3-bromophenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound S1C(C(=N)NO)=NC(C=2C=C(Br)C=CC=2)=C1 UAIHMOAXNWZDRP-UHFFFAOYSA-N 0.000 description 1
- GPRGWIFPMCQJFT-UHFFFAOYSA-N 4-(3-chloro-4-ethoxy-5-methoxyphenyl)-1,3-thiazole-2-carboxamide Chemical compound C1=C(OC)C(OCC)=C(Cl)C=C1C1=CSC(C(N)=O)=N1 GPRGWIFPMCQJFT-UHFFFAOYSA-N 0.000 description 1
- SURKXFRHSPPOBH-UHFFFAOYSA-N 4-(3-chloro-4-ethoxy-5-methoxyphenyl)-N'-hydroxy-1,3-thiazole-2-carboximidamide Chemical compound C1=C(OC)C(OCC)=C(Cl)C=C1C1=CSC(C(=N)NO)=N1 SURKXFRHSPPOBH-UHFFFAOYSA-N 0.000 description 1
- NZGCBIOUVRMJBY-UHFFFAOYSA-N 4-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,3-thiazole-2-carboxamide Chemical compound ClC1=C(O)C(OC)=CC(C=2N=C(SC=2)C(N)=O)=C1 NZGCBIOUVRMJBY-UHFFFAOYSA-N 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
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- 230000004217 heart function Effects 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
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate 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
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- CVXGFPPAIUELDV-UHFFFAOYSA-N phenacylazanium;chloride Chemical compound [Cl-].[NH3+]CC(=O)C1=CC=CC=C1 CVXGFPPAIUELDV-UHFFFAOYSA-N 0.000 description 1
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- CYFJIBWZIQDUSZ-UHFFFAOYSA-N thioglycine Chemical class NCC(S)=O CYFJIBWZIQDUSZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
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Description
Oppfinnelsen angår 4-aryltiazol- eller -imidazolderivater som kan brukes som terapeutika, samt farmasøytiske preparater som inneholder slike derivater.
Beslektede derivater er kjent. Syntesen av 4-(4-klor-fenyl)-tiazol-2-karboksamid er beskrevet av J. Kosary, Magy. Kem, Foly, 1980, 86(6), 282 (Chem. Abstr., 1981, (94), 47247s). Det er imidlertid ikke omtalt noen farmakologisk aktivitet. I Belgisk patentsøknad BE 822 030 omtales 4-fenyl-tiazol-2-karboksamid som et medikament for å hemme mavesaft-sekresjon, behandle ulcerasjoner og bekjempe inflammatoriske prosesser.
Forbindelsene i henhold til oppfinnelsen, øker hjerte-myofibrillenes følsomhet for kalsium. En økning i kalsium-følsomhet bedrer hjertefunksjonen på en energetisk gunstig måte hos hjertesviktpasienter uten fare for samtidig å gi kalsium-overbelastning i myokardiecellene. Forbindelsene har også fosfodiesterase-hemmende aktivitet og bronkodilaterende aktivitet og er egnet til behandling av pasienter som lider av astma. Foreliggende oppfinnelse tilveiebringer således også farmasøytiske preparater som inneholder én eller flere av forbindelsene i henhold til oppfinnelsen, og disse kan benyttes til behandling av hjertesvikt og astma hos pattedyr.
Oppfinnelsen angår et 4-aryltiazol- eller -imidazol-derivat med formel
hvor X er O eller NOH,
Y er S eller NR3,
Ar er fenyl,
R er én til fire substituenter uavhengig av hverandre, valgt fra hydrogen, hydroksy, C^- Cg-alkyl, C-L-Cg-alkoksy, Ci-Cg-tio alkyl, C5-C7-cykloalkyl, halogen, CF3og NC>2og R3er hydrogen eller Cx-Cs-alkyl; eller et farmasøytisk akseptabelt salt derav, med det forbehold at 4-(4-klorfenyl)-tiazol-2-karboksamid og 4(5)-fenylimidazol-2-karboksamid ikke inngår.
Spesifikt egnede forbindelser er 4-(3-klor-4,5-dimetoksy-fenyl)-N-hydroksy-tiazol-2-karboksamid, 4-(3,4-diklorfenyl)-N-hydroksy-tiazol-2-karboksimidamid, N-hydroksy-4-(4,5-dimetoksyfenyl)-tiazol-2-karboksimidamid og N-hydroksy-4-(3,4-dimetylfenyl)-lH-imidazol-2-karboksimidamid, eller farmasøytisk akseptable salter derav.
Derivater hvor Y er NR^(imidazoler) oppviser i alminnelighet bedre oppløselighet i vann enn derivater hvor Y er S (tiazoler), hvilket gjør førstnevnte forbindelser særlig egnet for bruk i injeksjonspreparater. Foretrukne imidazoler har hydrogen som R^.
Betegnelsen C^-Cg-alkyl står her for en forgrenet- eller uforgrenet alkylgruppe som har 1-6 karbonatomer, så som metyl, etyl, propyl, isopropyl, butyl, tert-butyl, pentyl, heksyl og lignende. Foretrukket er alkylgrupper som har 1-4 karbonatomer, særlig metylgruppen.
Alkylgruppen som forekommer på lavere alkoksy- og lavere tioalkylgrupper har samme betydning som definert ovenfor for Ci-Cg-alkyl.
Betegnelsen C5-C7-cykloalkyl står for en cykloalkylgruppe som har 5-7 karbonatomer, så som cyklopentyl eller cyklo-heksyl.
Med betegnelsen halogen, benyttet ved definisjonene av formel I, menes fluor, klor, brom eller jod. Klor er det foretrukne halogen.
De nye forbindelsene med formel I kan isoleres fra reaksjonsblandingen i form av et farmasøytisk akseptabelt salt. Farmasøytisk akseptable salter kan også oppnås ved å behandle den frie base I med en uorganisk eller organisk syre, så som HC1, HBr, HI, H2S04, H3P04, eddiksyre, propionsyre, glykolsyre, maleinsyre, malonsyre, metansulfonsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, benzosyre eller ascorbinsyre.
4-fenyl-tiazol- eller -imidazolderivatet i henhold til oppfinnelsen, kan fremstilles etter kjente fremgangsmåter. En egnet fremgangsmåte for fremstillingen av disse forbindelsene karakteriseres ved at et 4-fenyl-tiazol- eller -imidazol-derivat med formel II
hvor R, Ar og Y har de tidligere angitte betydninger og L er en utgående gruppe, så som hydroksy, halogen (fortrinnsvis klor eller brom) eller alkoksy (fortrinnsvis metoksy), kondenseres med ammoniakk for å gi derivatet med formel I, hvori X = 0, hvoretter det oppnådde derivat eventuelt kan omdannes til derivatet med formel I, hvori X = NOH og/eller omdannes til et farmasøytisk akseptabelt salt.
4-fenyl-tiazol- eller -imidazolderivater med formel II, kan fremstilles etter vanlige syntesemetoder, for eksempel ved kondensasjon av aminotioacetatestere og passende aromatiske ketoner, hvilket er mer spesifikt illustrert i eksemplene.
Omdannelsen av karboksamid-derivatene med formel I
(X = 0) til N-hydroksykarboksamid-derivatene med formel I (X = NOH), skjer via et nitril med formel III
hvor R, Ar og Y har de tidligere angitte betydninger. Nitril-derivatene med formel III kan også fremstilles fra andre utgangsmaterialer enn karboksamidene med formel I, for eksempel fra tilsvarende aldehyder, som etter velkjente metoder innenfor den organiske kjemi, kan omdannes til
nitriler via et oksim.
Det er mulig å omdanne produktene oppnådd gjennom én av de foran nevnte fremgangsmåter til en annet produkt i henhold til oppfinnelsen. Ved hjelp av alminnelig kjente metoder er det for eksempel mulig å omdanne substituenter på fenylgruppen til andre substituenter. Alkoksysubstituenter kan behandles med sterke syrer, så som BBr^, for å gi hydroksysubstituenten. Hydroksy-substituerte forbindelser kan kondenseres med lavere alkoholer i surt miljø for å gi alkoksyderivater, med lavere tioalkoholer for å gi alkyltioderivater.
Forbindelsene ifølge oppfinnelsen, kan administreres enteralt eller parenteralt, og til mennesker fortrinnsvis i en døgndose på 0,001-10 mg per kg legemsvekt. Blandet med farmasøytisk egnede hjelpestoffer, kan forbindelsene presses til faste enhetsdoser, så som piller eller tabletter, eller innarbeides i kapsler, suppositorier eller nebulisatorer. Ved hjelp av farmasøytisk egnede væsker, kan forbindelsene også benyttes som injeksjonspreparater i form av en oppløsning, suspensjon, emulsjon eller som spray, f.eks. nesespray.
Også 4-(4-klorfenyl)-tiazol-2-karboksamid, hvis syntese er beskrevet av J. Kosary, Magy. Kem. Foly, 1980, 86(6), 282 (Chem. Abstr., 1981 (94), 47247s), kan blandes med farmasøytisk egnede hjelpestoffer og benyttes terapeutisk eller for å fremstille et medikament for behandling av pasienter som lider av hjertesvikt eller astma.
Oppfinnelsen er ytterligere illustrert gjennom de følgende eksempler.
Eksempel 1
4 -( 3- klor- 4, 5- dimetoksyfenyl)- tiazol- 2- karboksamid
a) 1-(3-klor-4 , 5-dimetoksyfenyl)-etanon (31,6 g) ble oppløst i kloroform (140 ml) og oppløsningen omrørt ved romtemperatur
og behandlet dråpevis med en oppløsning av brom (7,9 ml) i kloroform (60 ml). Etter ytterligere 45 minutter ble blandingen nøytralisert med vandig kaliumbiokarbonat-opp-løsning. Det organiske lag ble fraskilt og vasket med natrium-
klorid-oppløsning, tørket over natriumsulfat, deretter filtrert og inndampet til tørrhet. Den resulterende olje
(42,8 g) ble krystallisert fra eter-heksan for å gi 2-brom-l-(3-klor-4,5-dimetoksyfenyl)-etanon (32,0 g), smp. 76,5-78°C. b) Til en oppløsning av etylaminotioksoacetat (16,2 g) i etanol (80 ml), omrørt under nitrogen under tilbakeløps-kjøling, ble det dråpevis i løpet av 10 minutter tilsatt en varm oppløsning av 2-brom-l-(3-klor-4 , 5-dimetoksyfenyl)-etanon (31,9 g) i etanol (180 ml). Blandingen ble kokt under tilbake-løpskjøling i 4 timer og deretter avkjølt til romtemperatur. Det utfelte bunnfall ble oppsamlet ved filtrering og tørket under vakuum ved 60°C. Omkrystallisasjon fra etanol ga etyl 4-(3-klor-4,5-dimetoksyfenyl)-tiazol-2-karboksylat som et hvitt faststoff (21,9 g), smp. 92-94°C. c) En oppløsning av etyl 4-(3-klor-4,5-dimetoksyfenyl)-tiazol-2-karboksylat (21,8 g) i 1,2-etandiol (150 ml) ble ved
120°C behandlet med ammoniakkgass i 25 minutter. Blandingen ble avkjølt i et isbad og den resulterende suspensjonen filtrert, vasket med metanol og tørket ved 60°C under vakuum for å gi 4-(3-klor-4,5-dimetoksyfenyl)-tiazol-2-karboksamid (18,7 g), smp. 178-180°C.
Eksempel 2
Analogt med fremgangsmåten beskrevet i Eksempel 1, ble det fremstillet:
4-(4-metoksyf enyl)-tiazol-2-karboksamid.
Smp.: 223-225°C
4-(2-klor-3,4-dimetoksyfenyl)-tiazol-2-karboksamid.
Smp.: 201-203°C
4-(3-klor-4-etoksy-5-metoksyfenyl)-tiazol-2-karboksamid Smp.: 186-188°C
4-(4-hydroksy-3-metoksyfenyl)-tiazol-2-karboksamid.
Smp.: 137-142°C
4- (3-metoksy-4-metyltiofenyl)-tiazol-2-karboksamid.
Smp.: 200-202°C
4-(3-klor-5-metoksy-4-metyltiofenyl)-tiazol-2-karboksamid. Smp.: 201-203°C
4-(3,4-dimetoksyfenyl)-tiazol-2-karboksamid.
Smp.: 190-191°C
4-(3-klor-4-hydroksy-5-metoksyfenyl)-tiazol-2-karboksamid. Smp.:234-236°C
4-(3-klorfenyl)-tiazol-2-karboksamid.
Smp.: 155-156°C
4-(2-klorfenyl)-tiazol-2-karboksamid.
Smp.:125-127°C
4-fenyl-tiazol-2-karboksamid.
Smp.: 144-145°C
4- (3-metyltiofenyl)-tizol-2-karboksamid.
Smp.: 13 6-13 8°C
4-(3-nitrofenyl)-tiazol-2-karboksamid.
Smp.: 247-248°C
4-(2-fluorfenyl)-tiazol-2-karboksamid.
Smp.:155-157°C
4-(3-fluorfenyl)-tiazol-2-karboksamid.
Smp.: 175-178°C
4-(3-bromfenyl)-tiazol-2-karboksamid.
Smp.: 157-158°C
4-[3-(trifluormetyl)fenyl]-tiazol-2-karboksamid. Smp.: 155-158°C
4-(4-fluorfenyl)-tiazol-2-karboksamid.
Smp.: 165-170°C
4-(4-bromfenyl)-tiazol-2-karboksamid.
Smp.: 206-207°C
4-[4-(trifluormetyl)fenyl]-tiazol-2-karboksamid. Smp.: 195-197°C
4-(2,3-diklorfenyl)-tiazol-2-karboksamid.
Smp.: 215-217°C
4-(3,4-diklorfenyl)-tiazol-2-karboksamid.
Smp.: 215°C
4-(3 , 5-diklorfenyl)-tiazol-2-karboksamid.
Smp.: 167-170°C
4-(2,5-diklorfenyl)-tiazol-2-karboksamid. Smp.:223-224°C
4-(3-metylfenyl)-tiazol-2-karboksamid.
Smp.: 118-120°C
4-(4-metylfenyl)-tiazol-2-karboksamid.
Smp.: 205-206°C
4-(3,4-dimetylfenyl)-tiazol-2-karboksamid. Smp.: 172-174°C
Eksempel 3
4-( 3- klor- 4, 5- dimetoksvfenyl)- N- hvdroksy- tiazol- 2- karboksimid-amid
a) En oppløsning av 4 -(3-klor-4,5-dimetoksyfenyl)-tiazol-2 - karboksamid (1,58 g) (Eksempel lc) i pyridin (9 ml) ble av-kjølt til 0°C og behandlet med trifluoreddiksyreanhydrid
(4ml) mens den innvendige temperatur ble holdt lavere enn 10°C. Blandingen ble omrørt ved romtemperatur i 10 minutter, deretter avkjølt og behandlet dråpevis med vann (45 ml) mens den innvendige temperatur ble holdt lavere enn 30°C. Det utfelte faststoff ble oppsamlet ved filtrering og tørket under vakuum ved 60°C. Omkrystallisasjon fra diklormetan-eter førte til 4-(3-klor-4,5-dimetoksyfenyl)-tiazol-2-karbonitril (1,25 g), smp. 147-149°C. b) Natriummetall (3,9 g) ble skåret opp i små biter og tilsatt til metanol (200 ml) omrørt under nitrogenatmosfære.
Etter at alt natriumet var oppløst, ble den varme blandingen behandlet med en varm oppløsning av hydroksylamin-hydroklorid (11,6 g) i metanol (200 ml). Etter 15 minutter ble den hvite natriumklorid-suspensjonen filtrert og filtratet tilsatt til 4-(3-klor-4,5-dimetoksyfenyl)-tiazol-2-karbonitril (15,4 g). Det ble oppnådd en oppløsning, som etter 10 minutter ble etterfulgt av utfelling av et farveløst faststoff. Etter ytterligere 1,5 timer, ble reaksjonsblandingen konsentrert til et lite volum ved inndampning, avkjølt og fortynnet med vann (700 ml) . Faststoffet ble frafiltrert, tørket ved 60°C under vakuum og omkrystallisert fra metanol-vann for å gi 4-(3-klor-4,5-dimetoksyfenyl)-N-hydroksy-tiazol-2-karboksimidamid
(15,3 g), smp. 169-170°C.
Eksempel 4
Analogt med beskrivelsen i Eksempel 3, ble det fremstillet:
N-hydroksy-4-fenyl-tiazol-2-karboksimidamid.
Smp.: 145-146°C
N-hydroksy-4-(4-metoksyfenyl)-tiazol-2-karboksimidamid.
Smp.: 192-194°C
N-hydroksy-4-(4-hydroksyfenyl)-tiazol-2-karboksimidamid
Smp.: 195-197°C
N-hydroksy-4-(3,4-dimetoksyfenyl)-tiazol-2-karboksimidamid Smp.: 192-202°C
4-(2-klor-3,4-dimetoksyfenyl)-N-hydroksy-tiazol-2-karboksimid-amid.
Smp.: 180-183°C
4-(3-klor-4-etoksy-5-metoksyfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 177-179°C
N-hydroksy-4-(4-hydroksy-3-metoksyfenyl)-tiazol-2-karboksimid-amid.
Smp.: 188-191°C
N-hydroksy-4-(3-metoksy-4-metyltiofenyl)-tiazol-2-karboksimid-amid.
Smp.: 215-219°C
4-(3-klor-5-metoksy-4-metyltiofenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 200-202°C
4-(3-klorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 189-191°C
4-(4-klorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 205-207°C
4-(2-klorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 176-178°C 4-(3-klor-4-hydroksy-5-metoksyfenyl)-N-hydroksy-tiazbl-2-karboksimidamid.
Smp.: 207-211°C
N-hydroksy-4-[3-(metyltio)fenyl]-tiazol-2-karboksimidamid.
Smp.: 165-166°C
N-hydroksy-4- (3-nitrofenyl) -tiazol-2-karboksimidamid.
Smp.: 227-230°C
4-(2-fluorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 168-169°C
4-(3-fluorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 179-180°C
4- (4-fluorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 171-176°C
4- (3-bromfenyl) -N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 206-207°C
4-(4-klorfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 205-207°C
4-(4-bromfenyl)-N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 215-218°C
N-hydroksy-4-[3-(trifluormetyl)fenyl]-tiazol-2-karboksimid-amid.
Smp.: 186-187°C
N-hydroksy-4-[4-(trifluormetyl)fenyl]-tiazol-2-karboksimid-amid.
Smp.: 224-228°C 4-(2,3-diklorfenyl)-N-hydroksy-tiazol-2-karboksimidamid. Smp.: 190-191°C
4-(3,4-diklorfenyl)-N-hydroksy-tiazol-2-karboksimidamid. Smp.: 224-226°C
4-(3,5-diklorfenyl)-N-hydroksy-tiazol-2-karboksimidamid. Smp.: 223-225°C
4-(2,5-diklorfenyl) -N-hydroksy-tiazol-2-karboksimidamid.
Smp.: 189-190°C
N-hydroksy-4-(3-metylfenyl)-tiazol-2-karboksimidamid.
Smp.: 190-192°C
N-hydroksy-4-(4-metylfenyl)-tiazol-2-karboksimidamid.
Smp.: 196-200°C
N-hydroksy-4-(3,4-dimetylfenyl)-tiazol-2-karboksimidamid. Smp.: 206-210°C
4-cykloheksylfenyl-N-hydroksy-tiazol-2-karboksimidamid.
Eksempel 5
4-( 4- hydroksyfenyl)- tiazol- 2- karboksamid
Bortribromid (3,7 ml) ble tilsatt dråpevis under nitrogen til en suspensjon av 4-(4-metoksyfenyl)-tiazol-2-karboksamid (3 g) i diklormetan (45 ml). Blandingen ble omrørt ved romtemperatur i 2 timer, deretter under tilbakeløpsbehandling i 2 timer og deretter avkjølt, hvoretter vann (60 ml) ble forsiktig tilsatt. Bunnfallet ble frafiltrert og det opp-samlede bunnfall tørket under vakuum ved 50°C og omkrystallisert fra metanol for å gi 4-(4-hydrosyfenyl)-tiazol-2-karboksamid (2,03 g), smp. 223-227°C.
Eksempel 6
4-( 3- klor- 5- metoksy- 4- metyltiofenyl)- tiazol- 2- karboksamid
a) Etyl 4-[3-klor-4-[[(dimetylamino)karbonyl]tio]-5-metoksy-fenyl]-tiazol-2-karboksylat (27,3 g) ble tilsatt til en opp-løsning av kaliumhydroksyd (24,75 g) i dietylenglykol (250 ml) og omrørt ved 120°C under nitrogen i 1 time. Til den avkjølte blandingen ble det tilsatt jodmetan (25 ml). Etter omrøring i 1 time ved romtemperatur ble blandingen helt over i vann
(1,2 1) og justert til pH 1 ved tilsetning av 5N saltsyre. Bunnfallet ble frafiltrert, vasket med vann og tørket ved 4 0°C under vakuum for å gi et faststoff som ble oppløst i N,N-dimetylformamid, hvorpå kaliumkarbonat (12 g) og jodmetan (10 ml) ble tilsatt. Etter omrøring i 1,5 timer ble suspensjonen helt over i vann (800 ml). Bunnfallet ble frafiltrert, vasket med vann og tørket ved 50°C under vakuum for å gi metyl 4-(3-klor-5-metoksy-4-metyltiofenyl)-tiazol-2-karboksylat (20 g). b) Analogt med beskrivelsen i Eksempellc, ble 4-(3-klor-5-metoksy-4-metyltiofenyl)-tiazol-2-karboksamid, smp. 201-203°C,
fremstillet fra metyl 4-(3-klor-5-metoksy-4-metyltiofenyl) - tiazol-2-karboksylat.
Eksempel 7
4 - fenyl- 1H- imidazol- 2- karboksamid
a) En oppløsning av etyl-aminotioksoacetat (7,4 g) i 74 ml diklormetan ble omrørt i et vannbad ved romtemperatur og
behandlet dråpevis med trietyloksonium-tetrafluorborat i diklormetan (1,0M, 74 ml). Blandingen ble omrørt i 16 timer og deretter inndampet til tørrhet for å gi en gul olje. Vannfritt natriumacetat (9,10 g), 2-aminoacetofenon-hydroklorid (9,54 g) og iseddik (110 ml) ble tilsatt til oljen og blandingen omrørt og oppvarmet til 75°C under nitrogenatmosfære. Etter 2 timer
ble reaksjonsblandingen inndampet og residuet suspendert i vann (50 ml) , gjort langsomt basisk med kaliumkarbonat og
deretter ekstrahert med etylacetat. De organiske ekstraktene ble vasket med vann og saltvann, tørket over magnesiumsulfat og inndampet til tørrhet. Residuet ble krystallisert fra diklormetan-dietyleter for å gi 7,63 g 4-fenyl-lH-imidazol-2-karboksylsyre-etylester. b) Etter fremgangsmåten beskrevet i Eksempel lc, ble den ovennevnte etylester omdannet til 4-fenyl-lH-imidazol-2-karboksamid, smp. 210-211°C.
Eksempel 8
Analogt med beskrivelsen i Eksempel 7, ble det fremstillet: 4-fenyl-lH-imidazol-2-karboksamid, smp.: 210-211°C
4-(3-metylfenyl)-lH-imidazol-2-karboksamid.
Smp.: 270-271°C
4-(3,4-dimetylfenyl)-lH-imidazol-2-karboksamid.
Smp.: 266-267°C
4-(3-fluorfenyl)-lH-imidazol-2-karboksamid.
Smp.: 237-238°C
Eksempel 9
l- metvl- 4-( 3- metylfenyl)- lH- imidazol- 2- karboksamid
En blanding av 9,79 g 4-(3-metylfenyl)-lH-imidazol-2-karboksylsyre-etylester (oppnådd etter fremgangsmåten i Eksempel 7), finmalt vannfritt kaliumkarbonat (7,05 g) og dimetylformamid (50 ml) ble omrørt ved romtemperatur i 15 minutter, hvorpå jodmetan (4,0 ml) ble tilsatt i en porsjon. Etter ytterligere 3 0 minutter ble reaksjonsblandingen helt over i omrørt vann og bunnfallet frafiltrert, vasket med vann og tørket ved 50°C under vakuum for å gi 10,0 g 1-metyl-4-(3-metylfenyl)-lH-imidazol-2-karboksylsyre-etylester, som ble omdannet på samme måte som beskrevet i Eksempel lc, til 1-
metyl-4-(3-metylfenyl)-lH-imidazol-2-karboksamid,
smp. 176-177°C.
Eksempel 10
Analogt med beskrivelsen i Eksempel 9, ble det fremstillet:
l-metyl-4-(3,4-dimetylfenyl)-lH-imidazol-2-karboksamid.
Smp.: 194-203°C.
l-metyl-4-(3-fluorfenyl)-lH-imidazol-2-karboksamid.
Smp.: 149-150°C.
Eksempel 11
N- hvdroksv- 4 - fenyl- 1H- imidazol- 2- karboks imidamid
En suspensjon av 4,55 g 4-fenyl-1H-imidazol-2-karboksamid i pyridin (3 0 ml) ble omrørt og avkjølt til -20°C og behandlet dråpevis med fosfor-oksyklorid (2,3 ml), hvorunder den innvendige temperatur ble holdt lavere enn 0°C. Etter 40 minutter ble reaksjonsblandingen avkjølt til -25°C og langsomt tilsatt vann (5 ml). Den resulterende suspensjonen ble helt over i omrørt vann, forsiktig gjort basisk med kaliumkarbonat og deretter filtrert. Det frafiltrerte faststoffet ble oppløst i diklormetan og sendt gjennom en kort kolonne av fin silika. Kolonnen ble eluert med diklormetan-etylacetat (9:1), passende fraksjoner oppsamlet og inndampet for å gi 4-fenyl-lH-imidazol-2-karbonitril (2,02 g), som ble behandlet på samme måte som beskrevet i Eksempel 3b og omdannet med metansulfonsyre til N-hydroksy-4-fenyl-lH-imidazol-2-karboksimidamid-metansulfonat (1:2) ,
smp. 151-153°C.
Eksempel 12
Analogt med beskrivelsen i Eksempel 11 ble det fremstillet: N-hydroksy-4-(3-metylfenyl)-lH-imidazol-2-karboksimidamid-metansulfonat (1:2). Smp.: 143-144°C.
N-hydroksy-4-(3,4-dimetylfenyl)-lH-imidazol-2-karboksimidamid-metansulfonat (1:2). Smp.: 145-150°C.
N-hydroksy-4-(3-fluorfenyl)-lH-imidazol-2-karboksimidamid-metansulfonat (1:2). Smp.: 149-151°C
N-hydroksy-l-metyl-4-(3-metylfenyl)-1H-imidazol-2-karboksimid-amid-metansulfonat (1:2). Smp.: 163-166°C.
N-hydroksy-l-metyl-4-(3,4-dimetylfenyl)-lH-imidazol-2-karboksimidamid-metansulfonat (1:2). Smp.: 179-185°C.
N-hydroksy-l-metyl-4-(3 -fluorfenyl)-1H-imidazol-2-karboksimid-amid-metansulf onat (1:2). Smp.: 180-182°C.
Claims (5)
1. 4-fenyl-tiazol- eller -imidazol-derivat,karakterisert vedformel I
hvor X er 0 eller NOH,
Y er S eller NR^,
Ar er fenyl,
R er én til fire substituenter uavhengig av hverandre, valgt fra hydrogen, hydroksy, C^-Cg-alkyl, C^-Cg-alkoksy, C^-Cg-tioalkyl, C5-C7-cykloalkyl, halogen, CF3 og N02 og
R3er hydrogen eller Ci-Cg-alkyl; eller et farmasøytisk akseptabelt salt derav, med det forbehold at 4-(4-klorfenyl)-tiazol-2-karboksamid og 4(5)-fenylimidazol-2-karboksamid ikke inngår.
2. Forbindelse ifølge krav 1,karakterisertved at den er 4-(3-klor-4,5-dimetoksyfenyl)-N-hydroksy-tiazol-2-karboksimidamid, 4-(3,4-diklorfenyl)-N-hydroksy-tiazol-2-karboksimidamid, N-hydroksy-4-(4,5-dimetoksyfenyl) - tiazol-2-karboksimidamid eller N-hydroksy-4-(3,4-dimetyl-fenyl)-1H-imidazol-2-karboksimidamid, eller et farmasøytisk akseptabelt salt derav.
3. Farmasøytisk preparat,karakterisertved at det omfatter 4-fenyl-tiazol- eller -imidazol-derivatet ifølge krav 1, eller 4-(4-klorfenyl)-tiazol-2-karboksamid eller farmasøytisk akseptable salter derav, i blanding med farmasøytisk akseptable hjelpestoffer.
4. Kjemisk forbindelse til bruk som terapeutikum,karakterisert vedat den er 4-fenyl-tiazol-eller -imidazol-derivatet ifølge krav 1 eller 4-(4-klorfenyl)-tiazol-2-karboksamid eller et farmasøytisk akseptabelt salt derav.
5. Anvendelse av 4-fenyl-tiazol- eller -imidazol-derivatet ifølge krav 1 eller 4-(4-klorfenyl)-tiazol-2-karboksamid, eller farmasøytisk akseptable salter derav, for fremstilling av et medikament for behandling av hjertesvikt og astma.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91302573 | 1991-03-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO921156D0 NO921156D0 (no) | 1992-03-24 |
| NO921156L NO921156L (no) | 1992-09-28 |
| NO301929B1 true NO301929B1 (no) | 1997-12-29 |
Family
ID=8208225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO921156A NO301929B1 (no) | 1991-03-25 | 1992-03-24 | 4-aryl-tiazol- eller -imidazol-derivater |
Country Status (17)
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| US (2) | US5254575A (no) |
| EP (1) | EP0506194B1 (no) |
| JP (1) | JPH0597816A (no) |
| KR (1) | KR920018037A (no) |
| AT (1) | ATE141597T1 (no) |
| AU (1) | AU648394B2 (no) |
| CA (1) | CA2063172A1 (no) |
| DE (1) | DE69212870T2 (no) |
| DK (1) | DK0506194T3 (no) |
| ES (1) | ES2093765T3 (no) |
| FI (1) | FI921262A (no) |
| GR (1) | GR3021260T3 (no) |
| IE (1) | IE73235B1 (no) |
| MX (1) | MX9203810A (no) |
| NO (1) | NO301929B1 (no) |
| NZ (1) | NZ242095A (no) |
| ZA (1) | ZA921781B (no) |
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| US5922751A (en) * | 1994-06-24 | 1999-07-13 | Euro-Celtique, S.A. | Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same |
| US5874437A (en) * | 1996-11-01 | 1999-02-23 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| US6331543B1 (en) | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
| USRE37234E1 (en) | 1996-11-01 | 2001-06-19 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses |
| AU722480B2 (en) * | 1996-11-01 | 2000-08-03 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| US5958926A (en) | 1996-11-01 | 1999-09-28 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| AU6030098A (en) * | 1997-01-16 | 1998-08-07 | Neorx Corporation | Phalloidin derivatives and analogs to treat congestive heart failure |
| US6472425B1 (en) | 1997-10-31 | 2002-10-29 | Nitromed, Inc. | Methods for treating female sexual dysfunctions |
| IL147688A0 (en) | 1999-08-21 | 2002-08-14 | Byk Gulden Lomberg Chem Fab | Synergistic combination |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| KR20050115331A (ko) | 2003-04-01 | 2005-12-07 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | 불임증 포스포디에스터라제의 억제제 |
| AU2004232936B2 (en) * | 2003-04-18 | 2008-10-30 | Merck & Co., Inc. | Biaryl substituted thiazoles, oxazoles and imidazoles as sodium channel blockers |
| SA04250288B1 (ar) * | 2003-09-19 | 2008-07-19 | سولفاي فارماسوتيكالز بي . في | مشتقات ثيازول thiazole كمعدلات لمستقبل المكونات الكيميائية للقنب cannabinoid |
| PE20070530A1 (es) * | 2005-10-26 | 2007-05-31 | Smithkline Beecham Corp | Compuestos derivados de tiazoles sustituidos como agentes de apertura de canales de potasio activados por calcio de alta conductancia |
| WO2008151257A2 (en) | 2007-06-04 | 2008-12-11 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| AU2009256157B2 (en) | 2008-06-04 | 2014-12-18 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EA201391254A1 (ru) | 2011-03-01 | 2014-02-28 | Синерджи Фармасьютикалз Инк. | Способ получения агонистов гуанилатциклазы c |
| CA2902348C (en) | 2013-02-25 | 2021-11-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| AU2014235209B2 (en) | 2013-03-15 | 2018-06-14 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists combined with other drugs |
| WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| US20160184387A1 (en) | 2013-08-09 | 2016-06-30 | Dominique Charmot | Compounds and methods for inhibiting phosphate transport |
| CN114340631A (zh) | 2019-05-21 | 2022-04-12 | 阿德利克斯股份有限公司 | 用于降低患者的血清磷酸盐的组合 |
Family Cites Families (4)
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|---|---|---|---|---|
| HU168036B (no) * | 1973-11-09 | 1976-02-28 | ||
| FR2261756A1 (en) * | 1974-02-27 | 1975-09-19 | Roussel Uclaf | 2-Thiazole-N-(Piperazino or piperidino) alkyl carboxamides - as hypotensive and anti-hypertensive agents of low toxicity |
| EP0199968B1 (en) * | 1985-03-27 | 1990-02-28 | Zenyaku Kogyo Kabushiki Kaisha | Thiazole derivatives |
| JPH02262562A (ja) * | 1988-10-20 | 1990-10-25 | Ishihara Sangyo Kaisha Ltd | イミダゾール系化合物 |
-
1992
- 1992-03-06 IE IE920734A patent/IE73235B1/en not_active IP Right Cessation
- 1992-03-10 ZA ZA921781A patent/ZA921781B/xx unknown
- 1992-03-13 AU AU12915/92A patent/AU648394B2/en not_active Ceased
- 1992-03-17 CA CA002063172A patent/CA2063172A1/en not_active Abandoned
- 1992-03-23 DE DE69212870T patent/DE69212870T2/de not_active Expired - Fee Related
- 1992-03-23 NZ NZ242095A patent/NZ242095A/en unknown
- 1992-03-23 ES ES92200825T patent/ES2093765T3/es not_active Expired - Lifetime
- 1992-03-23 DK DK92200825.5T patent/DK0506194T3/da active
- 1992-03-23 KR KR1019920004745A patent/KR920018037A/ko not_active Application Discontinuation
- 1992-03-23 AT AT92200825T patent/ATE141597T1/de not_active IP Right Cessation
- 1992-03-23 EP EP92200825A patent/EP0506194B1/en not_active Expired - Lifetime
- 1992-03-24 FI FI921262A patent/FI921262A/fi not_active Application Discontinuation
- 1992-03-24 NO NO921156A patent/NO301929B1/no unknown
- 1992-03-25 JP JP4067491A patent/JPH0597816A/ja active Pending
- 1992-03-25 US US07/857,526 patent/US5254575A/en not_active Expired - Fee Related
- 1992-06-29 MX MX9203810A patent/MX9203810A/es unknown
-
1993
- 1993-10-14 US US08/136,530 patent/US5462959A/en not_active Expired - Fee Related
-
1996
- 1996-10-04 GR GR960402611T patent/GR3021260T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR3021260T3 (en) | 1997-01-31 |
| US5254575A (en) | 1993-10-19 |
| CA2063172A1 (en) | 1992-09-26 |
| FI921262A0 (fi) | 1992-03-24 |
| MX9203810A (es) | 1992-07-31 |
| DK0506194T3 (da) | 1996-12-23 |
| EP0506194A1 (en) | 1992-09-30 |
| ES2093765T3 (es) | 1997-01-01 |
| ATE141597T1 (de) | 1996-09-15 |
| AU1291592A (en) | 1992-10-01 |
| DE69212870T2 (de) | 1997-01-16 |
| EP0506194B1 (en) | 1996-08-21 |
| AU648394B2 (en) | 1994-04-21 |
| FI921262A (fi) | 1992-09-26 |
| NO921156L (no) | 1992-09-28 |
| DE69212870D1 (de) | 1996-09-26 |
| ZA921781B (en) | 1992-11-25 |
| US5462959A (en) | 1995-10-31 |
| NZ242095A (en) | 1994-04-27 |
| JPH0597816A (ja) | 1993-04-20 |
| NO921156D0 (no) | 1992-03-24 |
| IE920734A1 (en) | 1992-10-07 |
| KR920018037A (ko) | 1992-10-21 |
| IE73235B1 (en) | 1997-05-21 |
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