CN86100736A - 4,4-二烷基-2-氮杂环丁酮类化合物的制备方法 - Google Patents
4,4-二烷基-2-氮杂环丁酮类化合物的制备方法 Download PDFInfo
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- CN86100736A CN86100736A CN86100736.0A CN86100736A CN86100736A CN 86100736 A CN86100736 A CN 86100736A CN 86100736 A CN86100736 A CN 86100736A CN 86100736 A CN86100736 A CN 86100736A
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- Prior art keywords
- amino
- compound
- structural formula
- oxygen base
- butoxy carbonyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 22
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 31
- -1 nitro benzyloxycarbonyl Chemical group 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000006277 sulfonation reaction Methods 0.000 claims description 8
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000006884 silylation reaction Methods 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 239000002585 base Substances 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
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- 239000001103 potassium chloride Substances 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical class CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- IGWGXZKGWFYOHE-UHFFFAOYSA-N 4,4-dimethylazetidin-2-one Chemical compound CC1(C)CC(=O)N1 IGWGXZKGWFYOHE-UHFFFAOYSA-N 0.000 description 1
- DQFMBUWNEAQLHL-UHFFFAOYSA-N CN(C)C.OS(Cl)(=O)=O Chemical compound CN(C)C.OS(Cl)(=O)=O DQFMBUWNEAQLHL-UHFFFAOYSA-N 0.000 description 1
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- QUUCYKKMFLJLFS-UHFFFAOYSA-N Dehydroabietan Natural products CC1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 QUUCYKKMFLJLFS-UHFFFAOYSA-N 0.000 description 1
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- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 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
- 239000008259 solid foam Substances 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/18—Salts thereof
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本专利在此公开一类适于药用的〔3S(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸盐和这类盐的实用制备方法。
Description
1982年6月29日发布的美国专利4,337,197号描述了具有抗菌活性的O-硫酸化β-内酰胺氧肟酸,本专利公开的此类化合物中的最佳者具有如下结构式:其中,R′1,为酰基,R′3与R′4相同或不同,各为氢或烷基,M为氢或一个正离子。
本专利介绍了,制备上述化合物的数种方法其中包括一种利用具有以下结构式的中间体的制备方法。其中,A′为一个氮的保护基,γ′为苯甲基或三甲基乙酰。本专利指出,上述中间体的羟基可利用、例如一种经典试剂(如甲磺酰氯)来转化为易失去基团。该被充分保护的化合物有如下结构式(L′为一个易失去基团):该化合物可经碱(如碳酸钾)处理而环化,生成具有如下结构式的化合物。
现已发现〔3S(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸盐是一种适于药用的优良抗菌剂,其结构式如下:
为制备〔3硫(2)〕-2-〔〔〔-1-(2-氨基-4-噻唑基)-2-〔〔2,2一二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸,本专利企图改进了美国专利4,337,197所介绍的方法。
在通式II、III和IV及整个说明书中所用符号定义如下:
A为苄氧基羰基、对-硝基苄氧基羰基特丁氧基羰基、邻一硝基苯亚磺酰或三苯甲基;
R1、R2为相同或不同的碳原子数是1至4个的烷基;
R3为苄基、对一硝基苄基、苄氧基甲基、2-甲氧基-2-丙基、2-乙氧基-2-丙基、四氢吡喃-2-基、2-三甲基甲硅烷基乙基、特丁基二甲基甲硅烷基或特丁基二苯基甲硅烷基;
适于药用的通式I化合物的盐类包括由式I化合物与有机和无机阳离子形成的碱式盐。它们是铵盐、碱金属盐(如钠盐、钾盐)、碱土金属盐(如钙盐、镁盐)以及从有机碱,例如双环己胺、N,N′-二苄基乙二胺、N,N′-双(脱氢枞酸基)乙二胺、N-甲基-D-葡糖胺衍生的盐。
通式I、VI和IX的化合物图示作酸,但它们也可作为两性离子(内盐)存在,这些也包括在“适于药用的盐”定义内,均属本发明的范畴。
适于药用的〔3S(2)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕-氨基〕氧基〕乙酸盐与其他O-硫酸化β-内酰胺氧肟酸相比,是料想不到的优良抗菌剂,更明确地讲,本发明的盐类,具有可被哺乳动物口服吸收的优良特性,与其对β-内酰胺酶的良好稳定性相结合,在临床上具有可靠的对β-内酰胺的稳定性;它还具有良好的化学稳定性。
适于用药的通式I化合物的盐可用于治疗哺乳动物,例如家畜(如狗、猫、马及其他哺乳动物)和人类的格兰氏阴性细菌感染,该盐类特别适于口服,而过去青霉素和头孢霉菌素施用在感染部位的所有方式也可期望。
治疗哺乳动物机体中的格兰氏阴性细菌感染时,适于药用的通式I化合物的盐的剂量,约为1毫克/公斤体重/天至350毫克/公斤体重/天,最佳量约为10毫克/公斤体重/天至100毫克/公斤体重/天。
适于药用的通式I化合物的盐用于口服时,可制成片剂、胶囊剂、溶液或水悬浮液。
在具有如下结构式(II)的化合物中:因它是叔丁醇,所以其中的羟基转化为易失去基团变得复杂化。业已发现,如果一个通式II化合物用具有如下结构式(V)的一种吡啶(或吡啶的同系物)-三氧化硫络合物磺化(其中:m为0、1、2或3),反应将以高产率得到具有如下结构式(III)的化合物,吡啶-三氧化硫络合物优先与羟基反应(正是所希望的):
磺化反应可在有机溶剂中进行,这些溶剂如:吡啶,-、二或三甲基吡啶,氧化烃(如二氯甲烷、1,2-二氯乙烷)、乙腈、二甲基甲酰胺和二噁烷。反应最佳温度约为0~100℃。
以碱为媒介,可将通式III的化合物环化生成相应的中间体,其结构式如下:碱最好是无机碱,例如碱金属碳酸盐(象碳酸钠或碳酸钾)并应过量(约为通式III反应物的2~10倍),反应最好在一种水合有机溶剂的混合物中进行,有机组分可为乙酸乙酯、乙腈、丙酮、甲基乙基甲酮、甲基丙基甲酮、甲基丁基甲酮、甲基异丁基甲酮、1,2-二氯乙烷、吡啶或-、二或三甲基吡啶、
一种通式IV的中间体可用来制备一种抗菌剂、该药是具有如下结构式,的化合物的盐,如美国专利4,337,197中所述,通式IV中间体上的保护基“R3”可首先被置换,生成相应的氧肟酸,其结构式如下:置换各种“R3”基团的反应,在工艺方面已众所周知,当然,这将取决于“R3”基团本身的特点。
通式VII的化合物经磺化,可生成具有如下结构式的相应的化合物:或它们的硷式盐,以上过程可由通式VII化合物与一种三氧化硫-吡啶(或二甲基甲酰胺、2,6-二甲基吡啶)络合物反应而完成。
就制备所需的通式I产物而言,将通式IX中R1和R2均为甲基)的一种化合物,即:与一种羧酸化合物酰化,羧酸化合物结构式如下:其中,R是一个羧酸保护基,随后即用常法移去。上述酰化作用是常见的,用卤代羧酸、羧酸酐或活性酯等羧酸便可完成。
下面举例进一步说明本发明的方法,该方法用于制备〔3S、(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸,作为一种原料和一种外消旋混合物的组分。
实例1
〔3±(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸二钠盐。
A)N-(特丁氧羰基)-N2-(苯甲氧基)-D,L1-3-羟基缬氨酰胺
将24.84克(106.6毫摩尔)N-特丁氧羰基-D,L-3-羟基缬氨酸和16.33克(106.6毫摩尔)羟基苯并三唑-水合物溶500毫升无水四氢呋喃,冷至-10℃,加入22克(106.6毫摩尔)二环己基碳化二亚胺。混合物在氮保护下于0℃搅拌1小时。接着,在15分钟内,将溶于250毫升无水四氢呋喃中的13.13克(106.6毫摩尔)O-苄基胲溶液,加入上述已被活化的酯类混合物中。将生成的混合物在氮保护下,于0℃搅拌1小时。滤除不溶性物质,将滤液在真空中汽提为泡沫状,泡沫用乙酸乙酯萃取,再滤除难溶的物质,滤液用5%的碳酸氢钠溶液洗涤两次。有机相经干燥(用硫酸钠)、蒸发成奖状,再用130毫升异丙醚将其结晶,得到24.7克标题化合物,熔点:76-78℃。母液蒸发成奖状(10克),再将其用一根内含300克硅胶制剂CC-4的柱子进行色谱分离(该固定相装填在三氯甲烷中),首先用1升三氯甲烷洗脱该柱,然后用2升含2%的甲醇的三氯甲烷洗脱。后一种溶剂洗脱附加产物(蒋层色谱Rf:0.9,三氯甲烷/甲醇,3∶1)和移至溶剂前沿的杂质。收集的馏分在真空中蒸发成奖状物(8克),用25毫升异丙醚将其结晶后得到5克另一种标题化合物,熔点:76-78℃。
B)N-(特丁氧羰基)-N2-(苯甲氧基)-D,L-3-(磺氧基)缬氨酰胺吡啶鎓盐。
将无水吡啶(8.08毫升、0.10毫摩尔)装在-500毫升的圆底烧瓶内,并在氮保护下冷至-10℃,再滴加(在强烈电磁搅拌中)氯磺酸三甲基甲硅酯(156毫升、0.10毫摩尔),加完之后,将很稠的反应物(由于产物沉淀)于0℃搅拌半小时,在真空中抽除三甲基氯硅烷,得到15克吡啶-三氧化硫络合物。
将N-(特丁氧羰基)-N2-(苯甲氧基)-D,L-3-羟基缬氨酰胺(16.92克,50毫摩尔)溶于200毫升无水吡啶中,再加入9.87克(62.5毫摩尔)吡啶-三氧化硫络合物。混合物在氮保护下,于55℃搅拌2小时,再加入另一部分(790毫克,5毫摩尔)吡啶-三氧化硫络合物,继续搅拌1小时。薄层色谱(正丁醇/乙酸/水(3∶1∶1)显示产物仅有一种,Rf:0.77(原料已移至溶剂前沿)。反应混合物在真空中汽提,得一种油,该油在真空中用乙腈汽提三次,得粗制的泡沫状的标题化合物,产量被认为是定量性的。
C)(3±)-3-〔(特丁氧羰基)氨基〕-4,4-二甲基-1-(苯甲氧基)-2-氮杂环丁酮。
将盛有粗N-(特丁氧羰基)-N2-(苯甲氧基)-D,L-3-(磺氧基)-缬氨酰胺、吡啶鎓盐(约50毫摩尔)的烧瓶放入冰浴并加入400毫升乙酸乙酯,用强烈搅拌再加入90毫升碳酸钾水溶液(含42.8克,0.31摩尔碳酸钾)。生成的混合物在氮保护下,经强烈搅拌回流(油浴,温度95℃)2小时。反应混合物冷至室温并进行相分离,水相用2×200毫升乙酸乙酯萃取,所有的有机相归在一起,干燥(用硫酸钠)并在真空中蒸发。该油倒入125毫升40%乙酸乙酯/正乙烷混合溶剂中,并用3~4升40%乙酸乙酯/正乙烷溶剂使上述溶液迅速通过-350毫升硅胶制剂CC-7的滤层(10厘米厚)过滤。滤液在真空中蒸发,得到一种固体(12.2克),将它在50毫升异丙醚中结晶,得到7.15克标题化合物,其熔点为110℃。母液蒸发得4.75克胶质固体,约含15%付产物(根据′H核磁共振谱)。
D)(3±)-3-〔(特丁氧羰基)氨基〕-1-羟基-4,4-二甲基-2-氮杂环丁酮
在常压与室温下,将(3±)-3-〔(特丁氧羰基)氨基〕-4,4-二甲基-1-(苯甲氧基)-2-氮杂环丁酮(8.07克,25毫摩尔)放入40毫升甲醇中,以0.6克、负载在活性炭上的10%钯为催化剂,加氢2小时。反应混合物通过次乙酰塑料滤层过滤,滤液在真空中浓缩。加入乙腈到上述浓缩物中再蒸发,重复两次。得到5.78克固体泡沫状标题化合物。
E)(3±)-3-〔(特丁氧羰基)氨基〕-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸,钾盐
在氩的保护和0℃下,将吡啶-三氧化硫络合物(8.02克、50毫摩尔)分批加入下述溶液中,该溶液由(3±)-3-〔(特丁氧羰基)氨基〕-1-羟基-4,4-二甲基-2-氮杂环丁酮(5.78克、25毫摩尔)溶于无水吡啶(120毫升)制成。反应混合物在室温下搅拌2.5小时并在真空中浓缩,将残留物溶于32毫升由10%丙酮:0.5M磷酸二氢钾组成的水性缓冲(PH7)溶液中,用1N的氢氧化钾将PH值调至5.2,该物料用270毫升DoWe×-50(K+)树脂由10%丙酮水溶液淋洗,进行色谱分离。合并适合的馏分并在真空中浓缩,得到13.6克粗产品。将其用色谱法进一步精制,操作过程是:将粗产品通过680毫升HP-20树脂,先用200毫升水淋洗,再用10%丙酮水溶液淋洗,汇集适合的馏分,冻干(在真空中冷冻脱水),得到7.13克混合化合物,其熔点为163~170℃dec
F) (3±)-3-氨基-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸盐
在氩的保护和-10℃下、将(3±)-3-〔(特丁氧羰基)氨基〕-4,4-二甲基-1-氮杂环丁基硫酸钾盐(5.48克、15毫摩尔)于-10℃下悬浮在20毫升无水二氯甲烷中。加入苯甲醚(6毫升),随即用2分多钟加入26毫升三氟乙酸。反应混合物于-10℃下搅拌20分钟,然后在真空中浓缩,残留物用乙醚(三次)研细,在真空中干燥,得到粗制的白色固体标题化合物。
G)〔3±(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二苯基甲酯、钠盐
将(Z)-(2-氨基-4-噻唑基)〔〔(2-二苯基甲氧基)-2-氧代乙氧基〕亚胺基〕乙酸(6.52克、16毫摩尔)和三乙胺(2.5毫升、18毫摩尔)在-30℃、氢保护下,同溶于60毫升二甲基甲酰胺中。滴加氯磷酸二苯酯(3.5毫升、17毫摩尔),反应混合物在-30℃下搅拌1.5小时。
将以上制备的粗的(3±)-3-氨基-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸盐于0℃溶于10毫升二甲基甲酰胺中,并加入6.6毫升三乙胺。在-30℃下将该溶液滴加在上面的混合酐中。反应混合物在-30~-20℃下搅拌3.5小时,再升至室温。将不溶物滤除,滤液在真空中浓缩。将残留物溶于60毫升,由20%丙酮:0.5M磷酸二氢钠组成的缓冲液(PH7)中,再用2N的氢氧化钠溶液将PH调至6.0。用300毫升DoWex-50(Na+)树脂为固定相,20%丙酮水溶液为流动相将该溶液色谱分离精制。汇集适合的馏分,冻干。将粗产物溶于200毫升含水乙腈中,滤除不溶的无机盐。滤液在真空中浓缩,得到19.32克标题化合物(含有原料酸杂质)。
H)〔3±(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕-氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二钠盐。
将粗制的〔3±(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-1-氧基-1-(磺氧基)-3-氮杂环丁基〕-氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二苯基甲酯、钠盐(19.3克)在-10℃、氩保护下悬浮在50毫升二氯甲烷和6毫升苯甲醚混合溶剂中,加入三氟乙酸(90毫升),将反应混合物搅拌1小时,在真空中浓缩,用乙醚(三次)研细。将此粗产物溶于40毫升0.5M的磷酸二氢钠缓冲液中(PH为7),再用2N的氢氧化钠溶液将PH调至6.8。该溶液用900毫升HP-20为固定相、水为流动相进行色谱分离。将适用的馏分分为两部分,不太纯的部分再用500毫升HP-20进行色谱分离。汇集两次色谱分离所得的适用馏分,冻干得到3.8克标题化合物,其熔点:为195~210℃。dec
对C12,H1.3 N6 O8 S2 Na2 24H2O分析算出:
C,27.46,H 3.41;N,13.35;
S,12.22
测定:
C,27.46;H 3.48;N,13.06;
S,12.04
实例2
〔3S(Z)〕-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二钠盐
A)N-(特丁氧羰基)-L-3-羟基缬氨酸α-甲苄胺盐
将N-特丁氧羰基-β-羟基缬氨酸(7.02克、30毫摩尔)溶于250毫升乙醚制成的溶液用3.63克(30毫摩尔)S-(-)-a-甲苄胺处理,所得溶液接入预先解析出的极细的盐的晶种,在25℃静置8小时后,将生成的白色固体滤出,用乙醚洗涤,在空气中干燥,得到4.78克粗制的标题化合物,其熔点:为137-140℃。
将8.87克粗品经回流溶于200毫升乙腈中,再冷至25℃进行重结晶,在25℃静置1小时,滤出晶体,用乙腈和乙酸乙酯洗涤后,在空气中干燥,得到6.81克标题化合物,其熔点:为144~146℃。将6.81克试样用150毫升乙腈按前次方法进行第二次重结晶,得到6.02克标题化合物,其熔点:为146~147℃,〔α〕D=-4.5°(C=2.0,甲醇)。
B)N-(特丁氧羰基)-L-3-羟基缬氨酸
N-(特丁氧羰基)-L-3-羟基缬氨酸、α-甲苄胺盐(6.02克、17.0毫摩尔)与250毫升乙酸乙酯和100毫升10%硫酸氢钾溶液的混合液一起振荡并按层分离。有机层用水和盐水洗涤,干燥(用硫酸钠)并蒸发成泡沫状物质,加正乙烷研细,得到一种自由流动的白色粉末状的标题化合物3.79克,其熔点:为116~118℃,〔α〕D=+7.6°(C=2.0乙酸乙酯)。
本标题化合物的样品可用重氮甲烷转变为它的甲酯。5毫克甲酯和10毫克三〔3-(七氟丙羟基亚甲基)-d-樟脑(Cam Phorato)〕铕(II)的混合物,在0℃时的质子核磁共振(400兆赫)显示出,它们对映体的比率是95∶5。将该化合物(用盐酸/乙酸乙酯)去保护后成为它的自由氨基酸盐酸盐。与文献上所显示的旋光度比较:后得出结论;该化合物的立体化学绝对构型属于S构型(见Bull.Chem.SoC、日本,39,2287(1966))。
C)N-(特丁氧羰基)-N2-(苯甲氧基)-L-3-羟基缬氨酰胺
按照实例1A的步骤,而用N-(特丁氧羰基)-L-3-羟基缬氨酸代替N-(特丁氧羰基)-D,L-3-羟基缬氨酸,则生成标题化合物。
D)(3S)-3-〔(特丁氧羰基)氨基〕-4,4-二甲基-1-(苯甲氧基)-2-氮杂环丁酮
按照试例1B和1C的步骤,而用N-(特丁氧羰基)-N2-(苯甲氧基)-L-3-羟基缬氨酰胺代替N-(特丁氧羰基)-N2-(苯甲氧基)-D,L-3-羟基缬氨酰胺,制得标题化合物。将结晶后的母液用LPS-1硅胶制成的快速色谱进行精制(流动相为20%乙酸乙酯/正己烷)。
E)(3S)-3-〔(特丁氧羰基)氨基〕-1-羟基-4,4-二甲基-2-氮杂环丁酮
按照实例1D的步骤,而用(3S)-3-〔(特丁氧羰基)氨基〕-4,-4-二甲基-1-(苯甲氧基)-2-氮杂环丁酮代替(3±)-3-〔(特丁氧羰基)氯基〕-4,4-二甲·基-1-(苯甲氧基)-2-氮杂环丁酮,制得标题化合物。
F)(3S)-3-〔(特丁氧羰基)氨基〕-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸盐钾盐。
按照实例1E的步骤,而用(3S)-3-〔(特丁氧羰基)氨基〕-1-羟基-4,4-二甲基-2-氮杂环丁酮代替(3±)-3-〔(特丁氧羰基)氨基〕-1-羟基-4,4-二甲基-2-氮杂环丁酮,制得标题化合物。除去挥发性物质后,将粗制残留物溶于10%的丙酮/0.5M磷酸二氢钾的缓冲液(PH为7.2)中,用3N氢氧化钾溶液将PH值调至5.0。该溶液用色谱法在DoWex(钾型上进行分离,继而用色谱法在HP-20上精制。
G)〔3S(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二苯甲酯、钠盐
将1.152克(2.81毫摩尔)的(Z)-(2-氨基-4-噻唑基)〔〔2-二苯甲氧基-2-氧乙氧基〕亚胺基〕乙酸溶于9.4毫升二甲基甲酰胺中,再将二异丙基甲胺(0.54毫升、3.09毫摩尔)加入。将该混合物冷却到-20℃,再加入氯代磷酸二苯酯(0.59毫升,2.81毫摩尔)。将生成的混合物搅拌1小时,得到一种混合酐。
又将(3S)-3-〔(特丁氧羰基)氨基〕-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸盐、钾盐(0.98克、2.81毫摩尔)悬浮在7.5毫升三氯甲烷中,冷至-10℃加入苯甲醚(2.13毫升),然后再加入9.4毫升三氟乙酸。将该混合物在-10℃下搅拌1小时,加入甲苯(约5毫升),蒸发除去挥发物。残留物用正己烷和无水乙醚研碎经真空干燥得到一种白色粉末状(3S)-氨基-2-氧基-4,4-二甲基-1-氮杂环丁基硫酸盐。
将残留物冷至-20℃,溶于9.4毫升二甲基甲酰胺中,加入二异丙基乙胺(1.47毫升、8.34毫摩尔),然后立即加入混合酐。将反应混合物在-20℃搅拌3小时,在真空中除去易挥发物,所得残留物在0℃下溶于20%丙酮水溶液中,用含水碳酸氢钠将其pH值调至6.5。
最后所得的混合物用柱色谱法精制。先以Dowex50×2-400树脂(钠型)为固定相,20%丙酮水溶液为流动相精制;随之,以HP-20为固定相(流动相为水,5%、10%、20%、30%及40%丙酮水溶液)进行色谱精制,得到标题化合物。
H)〔3S(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2-二甲基-4-氧基-1-(磺氧基)-3-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二钠盐
将〔3S(Z)〕-2-〔〔〔1-(2-氨基-4-噻唑基)-2-〔〔2,2一二甲基-4-氧基-1-(磺氧基)-氮杂环丁基〕氨基〕-2-氧代亚乙基〕氨基〕氧基〕乙酸、二苯甲酯、钠盐悬浮在11.2毫升-10℃的二氯甲烷中,加入苯甲醚(1.12毫升),随后,滴加三氟醋酸18.7毫升,混合物在0℃下搅拌40分钟。加入甲苯、蒸发除去易挥发物,该残留物用无水乙醚研碎,真空干燥后得到一种白色固体。将此残留物溶于水(PH为2.75)中,以HP-20为固定相、用色谱法精制(流动相为水,5%、10%、20%的丙酮水溶液),经冻干得到640毫克标题化合物的两性离子。将两性离子溶于水中,加入其两倍当量的碳酸氢钠(244毫克、2.9毫摩尔),溶液pH5.75。用Hp-20为固定相(水为流动相),将该溶液进行色谱分离,经冻干得到572毫克标题化合物,其熔点为140~145℃
对C12 H13 N5 O9 S2 Nα2·1.56 H2O分析算出:
C,28.31,H,3.10;N,13.64
测定:C,28.31,H,3.19;N,13.76
Claims (9)
2.根据权利要求1中所述的方法,其中,用于磺化反应的络合物是吡啶三氧化硫。
3.根据权利要求1中所述的方法,其中,R1和R2都是甲基。
4.根据权利要求1中所述的方法,其中,R3是苄基。
5.根据权利要求1中所述的方法,其中,A是特丁氧羰基。
6.根据权利要求1中所述的方法,其中,A是特丁氧羰基、R1和R2都是甲基和R3是苄基。
7.根据权利要求1中所述的方法,其中,A是特丁氧羰基;R1和R2都是甲基;R3是苄基;用于磺化反应的络合物R是吡啶·三氧化硫。
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US5143913A (en) * | 1988-04-04 | 1992-09-01 | E. R. Squibb & Sons, Inc. | [3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-(hydroxyamino)-2-oxoethoxy]imino]acetyl]amino]-2,2-dimethyl-4-oxo-1-azetidinyl sulfate |
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US4973747A (en) * | 1989-08-15 | 1990-11-27 | E. R. Squibb & Sons, Inc. | Process for preparing 3-hydroxy 2-keto acids |
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- 1986-01-27 CH CH305/86A patent/CH667872A5/fr not_active IP Right Cessation
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- 1986-01-28 DD DD86286545A patent/DD241600A5/de not_active IP Right Cessation
- 1986-01-28 AT AT0020386A patent/AT389511B/de not_active IP Right Cessation
- 1986-01-28 DD DD86292943A patent/DD248584A5/de unknown
- 1986-01-28 JP JP61017708A patent/JPH0780840B2/ja not_active Expired - Lifetime
- 1986-01-28 AR AR86302968A patent/AR242024A1/es active
- 1986-01-28 CS CS86625A patent/CS253740B2/cs unknown
- 1986-01-28 DD DD86292942A patent/DD248592A5/de unknown
- 1986-01-28 IT IT19206/86A patent/IT1190604B/it active
- 1986-01-28 GR GR860239A patent/GR860239B/el unknown
- 1986-01-28 PL PL25766886A patent/PL257668A1/xx unknown
- 1986-01-28 PL PL1986262318A patent/PL262318A1/xx unknown
- 1986-01-28 CN CN86100736A patent/CN1014894B/zh not_active Expired
- 1986-01-28 PL PL1986262317A patent/PL149156B1/pl unknown
- 1986-09-09 ES ES557056A patent/ES8800897A1/es not_active Expired
- 1986-09-09 ES ES557057A patent/ES8801917A1/es not_active Expired
-
1987
- 1987-02-18 PH PH34871A patent/PH23084A/en unknown
- 1987-02-18 PH PH34872A patent/PH23093A/en unknown
- 1987-09-08 YU YU01670/87A patent/YU167087A/xx unknown
-
1988
- 1988-01-08 GB GB08800425A patent/GB2198133B/en not_active Expired
-
1989
- 1989-11-24 CA CA000615565A patent/CA1279322C/en not_active Expired - Lifetime
-
1990
- 1990-07-03 SE SE9002337A patent/SE502442C2/sv not_active IP Right Cessation
- 1990-07-03 SE SE9002338A patent/SE468896B/sv not_active IP Right Cessation
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1995
- 1995-02-21 JP JP7032368A patent/JPH0853404A/ja active Pending
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