CN1083065A - N-磺酰基-四氢-[1，3-二噁庚并[5，6-b]-氮杂环丙烯的制备方法 - Google Patents
N-磺酰基-四氢-[1，3-二噁庚并[5，6-b]-氮杂环丙烯的制备方法 Download PDFInfo
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- CN1083065A CN1083065A CN92109428A CN92109428A CN1083065A CN 1083065 A CN1083065 A CN 1083065A CN 92109428 A CN92109428 A CN 92109428A CN 92109428 A CN92109428 A CN 92109428A CN 1083065 A CN1083065 A CN 1083065A
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- Prior art keywords
- formula
- aziridine
- general formula
- tetrahydrochysene
- alkylsulfonyl
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 6
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 24
- -1 tetramethylene, pentamethylene Chemical group 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 5
- 239000013067 intermediate product Substances 0.000 abstract description 4
- NTVCIOGUJHBVBO-UHFFFAOYSA-N 4,5-dihydro-3h-dioxepine Chemical compound C1COOC=CC1 NTVCIOGUJHBVBO-UHFFFAOYSA-N 0.000 abstract 1
- 229940088623 biologically active substance Drugs 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000008280 blood Substances 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 0 C*c1ccc(*(C)C)cc1 Chemical compound C*c1ccc(*(C)C)cc1 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DZLOHEOHWICNIL-QGZVFWFLSA-N (2R)-2-[6-(4-chlorophenoxy)hexyl]-2-oxiranecarboxylic acid ethyl ester Chemical compound C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)OCC)CO1 DZLOHEOHWICNIL-QGZVFWFLSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- OSLWHOALCCNLIC-KFURWHPZSA-N (e)-n-[2-[4-(3-cyclohexyl-2-iminoimidazolidin-1-yl)sulfonylphenyl]ethyl]but-2-enamide Chemical compound C1=CC(CCNC(=O)/C=C/C)=CC=C1S(=O)(=O)N1C(=N)N(C2CCCCC2)CC1 OSLWHOALCCNLIC-KFURWHPZSA-N 0.000 description 1
- OPPLDIXFHYTSSR-GLECISQGSA-N (ne)-n-(1-methylpyrrolidin-2-ylidene)-n'-phenylmorpholine-4-carboximidamide Chemical compound CN1CCC\C1=N/C(N1CCOCC1)=NC1=CC=CC=C1 OPPLDIXFHYTSSR-GLECISQGSA-N 0.000 description 1
- XIJZRXDBTDOULF-UHFFFAOYSA-N 2-phenyl-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound S1C2=CC=CC=C2NC(=O)CC1C1=CC=CC=C1 XIJZRXDBTDOULF-UHFFFAOYSA-N 0.000 description 1
- MCNQDGXBYQRUGL-UHFFFAOYSA-N 2-sulfonylimidazole Chemical class O=S(=O)=C1N=CC=N1 MCNQDGXBYQRUGL-UHFFFAOYSA-N 0.000 description 1
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 241000612153 Cyclamen Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 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 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 150000001542 azirines Chemical class 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 1
- 229950009226 ciglitazone Drugs 0.000 description 1
- 229930186364 cyclamen Natural products 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950006213 etomoxir Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- OTGHWLKHGCENJV-UHFFFAOYSA-N glycidic acid Chemical class OC(=O)C1CO1 OTGHWLKHGCENJV-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229950004872 linogliride Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000004579 marble Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AWXXNBQGZBENFO-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1.C1COCCN1 AWXXNBQGZBENFO-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-
氮杂环丙烯及其制备中所用中间产物的制备方法。
从顺-2-丁烯-1，4-二醇开始，通过4，7-二氢
-1，3-二噁庚和反-6-酰氨基-5-氯代-1，3-二氧杂
环庚烷，合成新的四氢-[1，3]-二噁庚并[5，6-b]-氮
杂环丙烯，由此得到新的具有降血糖活性的N-磺酰
基-四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙烯。这些
产物亦是合成其它生物活性物质的有价值的中间
体。
Description
本发明是关于新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯（N-sulfonyl-tetrahydro-[1，3]-dioxepino[5，6-b]-azirines）及其制备时所用中间产物的制备方法的;这些化合物可用作降血糖剂。
已知非胰岛素依赖性Ⅱ型糖尿病（非胰岛素依赖性糖尿病，NIDDM）的临床治疗目前只依靠两类降血糖化合物：磺酰尿类和双胍类。[R.SARGES，Progr.Med.Chem.18，191（1981）;A.C.ASMAL和A.MARBLE，Drugs，28，62（1984）;L.P.KRALL in：Joslin′s Diabetes Mellitus，12th Ed.，Lea & Febiger，Philadelphia，1985，p.412]。
亦已知，已对各种类型化合物中有代表性的化合物，如噻唑啉二酮（ciglitazone，pioglitazone，CP-72467），磺酰基咪唑啉（CGP 11112），羧基脒（linogliride），环氧乙烷羧酸类（etomoxir），piridyl-乙基咪唑啉（DG 5128），多糖类（阿卡糖）等等的降血糖活性进行了临床试验，但因功效不足或其它原因，尚无一种在市场上出售[R.J.MOHRBACHER等人，Ann.Rep.Med.Chem.22，213（1987）;E.R.LARSON等人，Ann.Rep.Med.Chem.25，205（1989）;K.E.STEINER和E.L.LIEN，Prog.Med.Chem，24，209（1987）;S.C.STINSON，Chem.Eng.News.Sept.30，1991]。
据发明人对现有技术进行的检索表明，下面通式Ⅰ的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯代表了一类新的杂环化合物和一类新的有效的降血糖剂。
本发明的目的是制备通式为Ⅰ的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯
式中R1和R2可以是氢原子，直链或支链的C1-4的烷基，或苯基，R1+R2可以是亚烷基，如四亚甲基，五亚甲基或六亚甲基，R3可以是烷基，如甲基或三氟甲基或对位取代的苯基
式中X可以是氢原子，直链或支链的C1-4烷基，或卤原子如氟、氯、溴或碘，或硝基，氨基，或酰氨基如乙酰氨基，或烷氧基如甲氧基，
据通常公知的合成N-磺酰基-氮杂环丙烯的下列反应（方案1-4）之一
[O.C.Dermer，G.E.Ham，Ethyleneimine and Other Aziridines，Chemistry and Applications，Academic Press，New York，London，1969;P.E.Fanta，in：A.Weissberger（Ed），The Chemistry of Heterocyclic Compounds，Vol.19，Part 1，Interscience Publishers，New York，London，Sydney，1964.，p.524]尤其是根据上述方案（1），先用易于从市场上得到的顺-2-丁烯-1，4-二醇与通式Ⅱ的醛或酮反应
式中R1和R2的定义同上，生成通式Ⅲ的4，7-二氢-1，3-二噁庚（4，7-dihydro-1，3-dioxepins）
式中R1和R2的定义同上，再使该化合物在通式Ⅳ的有机腈中与氯化腈反应
式中R4表示直链或支链的C1-4烷基或苄基，使得到的通式Ⅴ的反-酰氨基-氯代-二氧杂环庚烷（Trans-acylamino-chlorodioxepans）
（式中R1、R2和R4的定义同上）脱卤化氢环化生成通式Ⅵ的四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯
式中R1和R2的定义同上，该化合物与通式Ⅶ的磺酰氯反应，
式中R3的定义同上，生成通式Ⅰ的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙烯，该通式Ⅰ中，R1，R2和R3的定义同上，R3表示4-酰氨基苯基如4-乙酰氨基苯基，最后，再使该化合物在生成通式Ⅰ中R1和R2定义同上，R3为4-氨基苯基的新化合物的条件下，进行碱催化的水解反应（方案5）。
采用文献[C.E：Pawloshy，Dloxeplns and Trioxepins，in：A.Weissberger，E.C.Taylor（Eds.），The Chemietry of Heterocyclic Compounds，Vol.26，Wiley Interscience，New York，1972.，p.319]中公开的方法，根据上述方案5，很容易得到通式Ⅲ的二噁庚。
据文献资料[M.Dumic，M.V.Prostenik，I.Butula，Croat.Chem.Acta.51，259，（1978）;M.Dumic，Maiser Thesis，Faculty of Technology，Zagreb University，1977]，很容易得到通式Ⅴ的反-酰氨基-氯代二氧杂环庚烷。
据申请人的研究，通式Ⅵ的二噁庚并氮杂环丙烯不是公知的，但在生成氮杂环丙烯的反应条件下（100℃的苏打水溶液，或氢氧化钾的热乙醇溶液），通式Ⅴ的潜在的前体（potential precursors）生成邻位的酰氨基-二噁烷醇[M.SOVAK，R.RANGANATHAN，US4389526（1983.6.21），或二噁庚并-唑啉（dcoxepino-oxazolines）（M.DUMIC等人，Org.Prep.Proc.Int.24，545（1992）in press]。
现已意外发现，在20℃-150℃，优选50℃-100℃的范围内，在碱性氢氧化物如钠或钾的氢氧化物水溶液中，用等摩尔比反应物且碱性氢氧化物过量直到5倍摩尔，优选过量1.5-2.5摩尔条件下，可将通式Ⅴ的化合物转变制成通式Ⅵ的二噁庚并-氮杂环丙烯。
通式Ⅵ的化合物与通式Ⅶ的磺酰氯的反应可按文献中公知的条件进行，如按化学计量的摩尔比，或按磺酰氯（Ⅴ）过量1.1-2.0，优选1.1-1.3摩尔，用或不用惰性有机溶剂，如选自甲苯或二甲苯的芳烃溶剂，选自二氯甲烷、氯仿或1，2-二氯乙烷的氯代烃溶剂，更进一步地在乙酸乙酯、二噁烷、二甲基甲酰胺或二甲亚砜中，在等摩尔量或过量1.1-2.0，优选1.1-1.3摩尔有机碱如吡啶，三乙胺或吗啉（morpholine）存在下，或在用作溶剂的碱中反应。该反应亦可在通式Ⅵ的氮杂环丙烯过量2-5，最好2-3摩尔条件下进行，其中该通式化合物用作碱以除掉反应期间产生的氯化氢。
采用常规水解法，在碱介质中，可使通式Ⅰ中R3＝4-酰氨基苯基如4-乙酰基苯基的化合物脱酰而成通式Ⅰ中R3＝4-氨基苯基的化合物。
新的通式Ⅵ的四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙烯适宜用作合成生物活性物质，尤其是降血糖剂的中间产物。
通式Ⅰ的化合物可用作合成生物活性物质，尤其是降血糖剂的中间产物。
通式Ⅰ的化合物可作为活性成份，用于制备具有降血糖活性的药剂。
意外发现按本发明得到的通式Ⅰ的化合物，在阿脲诱发（alloxan-induced）小鼠和大鼠糖尿病的实验模型中，不管用药方式如静脉、皮下注射或口服，都显示出明显的，或者说甚至是非常强烈的降血糖活性。举例言之，按10mg/kg剂量给小鼠皮下用Ⅰa 4hr后，与患糖尿病但未给药的动物相比，血中葡萄糖（糖）浓度降低37%，即血糖浓度为63%。按20mg/kg剂量给小鼠静脉用Ⅰa 40min后，血中葡萄糖甚至降到患糖尿病但未给药的动物的血糖值的33%。按20mg/kg剂量给小鼠口服化合物Ⅰa 6hr后，血中葡萄糖降至起始浓度的60%。在一类似实验中，按20mg/kg剂量给糖尿病患鼠（大鼠）皮下用化合物Ⅰa 4hr后，血中葡萄糖浓度降至起始浓度的67%。
对降血糖活性的评价实验，在体重20-25g的CBA种小鼠和体重160-200g的Fischer种大鼠身上进行。将这些鼠置于笼内，按12hr光照：12hr无光照的日程，隋意喂食食物和水。将阿脲四水合物（65mg/kg;Merck）一次注入尾静脉，使诱发高血糖症（C.C.RERUP，Pharmacol.Rev.22，485（1970））。注射阿脲48hr后对受试动物进行测试。从尾静脉取出第一次血样（0.025ml）后，立即将试验药物（通式Ⅰ的化合物，溶于最少量的DMSO中，且用盐水-9.0%NaCl稀释）通过皮下或静脉或通过胃饲管（经口）一次注入。根据用药剂量和给药方式，在不同时间间隔（1-24hr.）抽取其它血样。用酶法（P.TRINDER，Ann.Clin.Biochem.6，24（1969））分析血中葡萄糖。计算结果时，血糖用mmol/l全血表示。第一次血样作为对照值，表示为100%。
由小鼠所得结果示于下面表1中：
另一方面，通式Ⅰ的化合物并未降低健康（无糖尿病的对照组）的动物的血糖浓度。Ⅰa在健康小鼠和大鼠身上的试验结果示于下面表2。
综上所述，通式为Ⅰ的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯代表了一类有效的降血糖剂，可通过常规制药技术，制成适用的、具有短期或长期活性的治疗糖尿病的药物剂型，如片剂，丸剂、粉剂、锭剂、胶囊、颗粒，溶液等等。
下面通过实施例进一步说明本发明，但决非作任何限制。
实施例1
使由10.0g氯酰胺V（R1＝R2＝H，R4＝CH3），7.2g氢氧化钾和150cm3水组成的混合物在回流冷凝器下沸腾90min，冷却到室温后用氯仿萃取。蒸出氯仿，蒸馏残余物经过硅胶柱色谱，用氯仿/甲醇混合物（25∶1）洗提，得到浅黄油状二噁庚并-氮杂环丙烯Ⅵa（R1＝R2＝H）。
B.p.90-93℃/2.1KPa。
类似地，用相应氯酰胺Ⅴ制出下面的四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙烯Ⅵ：
表3
实施例2
在室温下，搅拌由0.120g二噁庚并-氮杂环丙烯Ⅵa（R1＝R2＝H），0.260g 4-乙酰氨基苯基-磺酰氯，0.17g吡啶和5.0cm3二氯甲烷组成的混合物60min。另外加20cm3二氯甲烷后，将2×10cm3氢氧化钠溶液（1∶1）混入混合物，分离有机层，用10cm3水洗后，经稀盐酸中和至pH＝6，再用10cm3水洗一次，置无水硫酸钠上干燥。蒸出二氯甲烷，得到粗制的色谱纯（Rf＝0.57;洗提液∶乙酸乙酯/甲醇＝20∶1;检测：UV254nm，硅胶板Merck 60 F254）磺酰基氮杂环丙烯Ⅰa（R1＝R2＝H，R3＝4-乙酰氨基苯基）。M.p.210-212℃（乙酸乙酯/甲醇＝1∶1）。
用相应的氮杂环丙烯Ⅵ和磺酰氯Ⅶ，合成出下列磺酰基氮杂环丙烯Ⅰ：
表4
实施例3
使由0.313g磺酰基氮杂环丙烯Ⅰa（R1＝R2＝H，R3＝4-乙酰基-氨基苯基），0.140g氢氧化钾和3cm3水组成的混合物回流沸腾30min，浓缩成稠浆，用氯仿提取。蒸出氯仿。蒸馏残余物经过色谱硅胶柱，用乙酸乙酯/甲醇＝20∶1混合物洗提，得到色谱纯（硅胶Merck 60F254，;洗提液∶乙酸乙酯/甲醇＝20∶1;检测：UV254nm;碘蒸气∶棕色;水合茚三酮溶液∶仙客来属红色;Rf＝0.65）磺酰基氮杂环丙烯Ⅰv（R1＝R2＝H，R3＝4-氨基苯基），该物为浅黄-淡红色的。
类似水解通式Ⅰ的相应的N-（4-乙酰氨基-苯磺酰基）-氮杂环丙烯，得到下列N-（4-氨基-苯磺酰基）-氮杂环丙烯Ⅰ：
表5
Claims (2)
1、一种制备通式为Ⅰ的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯的方法，
式中R1和R2可以是氢原子，直链或支链的C1-4的烷基，或苯基，R1+R2可以是亚烷基，如四亚甲基，五亚甲基或六亚甲基，R3可以是烷基如甲基或三氟甲基或对位取代的苯基
式中X可以是氢原子，直链或支链的C1-4烷基，或卤原子如氟、氯、溴或碘，或硝基，氨基，或酰氨基如乙酰氨基，或烷氧基如甲氧基；
其特征在于按下列通常公知的合成N-磺酰基-氮杂环丙烯的反应(方案1-4)之一进行制备：
2、如权利要求1所述的通式为Ⅰ的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯的方法，其特征在于使顺-2-丁烯-1，4-二醇与通式Ⅱ的醛或酮反应，
式中R1和R2的定义同上，生成通式Ⅲ的4，7-二氢-1，3-二噁庚，
式中R1和R2的定义同上，再使该化合物在通式Ⅳ的有机腈中与氯化腈反应
式中R4表示直链或支链的C1-4烷基或苄基，使得到的通式Ⅴ的反-酰氨基-氯代-二氧杂环庚烷
式中R1、R2和R4定义同上，
脱卤化氢环化生成通式Ⅵ的四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙烯
式中R1和R2定义同上，
该化合物与通式Ⅶ的磺酰氯反应，
式中R3定义同上，生成通式Ⅰ中R1和R2定义同上，R3为4-酰氨基苯基如4-乙酰氨基苯基的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙烯，最后，再使该化合物在生成通式Ⅰ中R1，R2和R3定义同上，R3为4-氨基苯基的新化合物条件下，进行碱催化的水解反应。
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9111433A SI9111433B (sl) | 1991-08-22 | 1991-08-22 | Novi N-sulfonil-tetrahidro-/1,3/-dioksepino/5,6-b/azirini, postopek priprave, intermediati za njihovo pripravo in uporaba |
| PCT/EP1992/001913 WO1993004067A1 (en) | 1991-08-22 | 1992-08-20 | Hypoglycemic n-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines |
| CA002115269A CA2115269A1 (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines, methods and intermediates for their preparation, and their use |
| US07/932,482 US5286744A (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-biazirines, intermediates for their preparation and their use |
| SK210-94A SK21094A3 (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-/1,3/-dioxepino/5,6-b/azirines, methods and intermediates of their preparation and use |
| HU9402713A HUT70948A (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirine derivatives pharmaceutical compositions containing them and process for preparing them |
| RU94043428A RU2118324C1 (ru) | 1991-08-22 | 1992-08-20 | N-сульфонилтетрагидро-[1,3]-диоксепино[5,6-b] азирины и промежуточные продукты для их получения |
| JP5504124A JPH08506565A (ja) | 1991-08-22 | 1992-08-20 | Ｎ−スルホニルテトラヒドロ−〔１，３〕−ジオキセピノ−〔５，６−ｂ〕−アジリン類、その調製のための方法と中間体および用途 |
| EP92917719A EP0641345A1 (en) | 1991-08-22 | 1992-08-20 | Hypoglycemic n-sulfonyl-tetrahydro- 1,3]-dioxepino 5,6-b]azirines |
| CS94392A CZ39294A3 (en) | 1991-08-22 | 1992-08-20 | N-SULFONYL-TETRAHYDRO-/1,3/-DIOXEPINO/5,6-b/AZIRINES, PROCESSES AND INTERMEDIATES OF THEIR PREPARATION AND THEIR USE |
| CN92109428A CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
| HR930891A HRP930891A2 (en) | 1991-08-22 | 1993-05-13 | NEW N-SULFONIL-TETRAHIDRO-/1,3/-DIOKSEPINO/5,6-b/ AZYRINES, METHODS, PREPARATIONS, INTERMEDIATES AND USE |
| BG98627A BG61570B1 (en) | 1991-08-22 | 1994-03-01 | N-sulphonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines,methods and means for their preparation and their usage |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU143391 | 1991-08-22 | ||
| CN92109428A CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
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| CN1083065A true CN1083065A (zh) | 1994-03-02 |
| CN1035766C CN1035766C (zh) | 1997-09-03 |
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| CN92109428A Expired - Fee Related CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5286744A (zh) |
| EP (1) | EP0641345A1 (zh) |
| JP (1) | JPH08506565A (zh) |
| CN (1) | CN1035766C (zh) |
| BG (1) | BG61570B1 (zh) |
| CA (1) | CA2115269A1 (zh) |
| CZ (1) | CZ39294A3 (zh) |
| HR (1) | HRP930891A2 (zh) |
| HU (1) | HUT70948A (zh) |
| RU (1) | RU2118324C1 (zh) |
| SI (1) | SI9111433B (zh) |
| SK (1) | SK21094A3 (zh) |
| WO (1) | WO1993004067A1 (zh) |
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| EP0669335A1 (en) * | 1994-02-21 | 1995-08-30 | PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija, dionicko drustvo | N-sulfonyl-tetrahydro-[1,3]-dioxepino [5,6] azirines with hypoglycemic activity |
| HRP940123A2 (en) * | 1994-02-21 | 1997-04-30 | Sour Pliva | New hydroxylamines with hypoglycemic activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CH497431A (de) * | 1968-03-14 | 1970-10-15 | Geigy Ag J R | Verfahren zur Herstellung von neuen Derivaten des Benzolsulfonamids |
| US4389526A (en) * | 1981-08-03 | 1983-06-21 | The Regents Of The University Of California | Intermediates and synthesis of 2-amino-2-deoxytetritols |
| CA1219865A (en) * | 1982-05-14 | 1987-03-31 | Leo Alig | Aziridine phenethanolamine derivatives |
| DE3624912A1 (de) * | 1986-07-23 | 1988-02-04 | Studiengesellschaft Kohle Mbh | Optisch reine 1,3-dioxenone, verfahren zu ihrer herstellung und ihre verwendung |
-
1991
- 1991-08-22 SI SI9111433A patent/SI9111433B/sl unknown
-
1992
- 1992-08-20 CA CA002115269A patent/CA2115269A1/en not_active Abandoned
- 1992-08-20 WO PCT/EP1992/001913 patent/WO1993004067A1/en not_active Application Discontinuation
- 1992-08-20 HU HU9402713A patent/HUT70948A/hu unknown
- 1992-08-20 JP JP5504124A patent/JPH08506565A/ja active Pending
- 1992-08-20 SK SK210-94A patent/SK21094A3/sk unknown
- 1992-08-20 EP EP92917719A patent/EP0641345A1/en not_active Withdrawn
- 1992-08-20 RU RU94043428A patent/RU2118324C1/ru active
- 1992-08-20 CZ CS94392A patent/CZ39294A3/cs unknown
- 1992-08-20 US US07/932,482 patent/US5286744A/en not_active Expired - Fee Related
- 1992-08-22 CN CN92109428A patent/CN1035766C/zh not_active Expired - Fee Related
-
1993
- 1993-05-13 HR HR930891A patent/HRP930891A2/xx not_active Application Discontinuation
-
1994
- 1994-03-01 BG BG98627A patent/BG61570B1/bg unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993004067A1 (en) | 1993-03-04 |
| CA2115269A1 (en) | 1993-03-04 |
| BG98627A (bg) | 1995-06-30 |
| JPH08506565A (ja) | 1996-07-16 |
| RU94043428A (ru) | 1996-06-20 |
| SK21094A3 (en) | 1995-08-09 |
| HRP930891A2 (en) | 1996-04-30 |
| CZ39294A3 (en) | 1995-01-18 |
| RU2118324C1 (ru) | 1998-08-27 |
| US5286744A (en) | 1994-02-15 |
| HUT70948A (en) | 1995-11-28 |
| SI9111433A (sl) | 1998-04-30 |
| CN1035766C (zh) | 1997-09-03 |
| BG61570B1 (en) | 1997-12-30 |
| SI9111433B (sl) | 1999-02-28 |
| EP0641345A1 (en) | 1995-03-08 |
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