CN1022630C - (环烷基胺基)亚甲基双(膦酸)化合物的制备方法 - Google Patents
(环烷基胺基)亚甲基双(膦酸)化合物的制备方法 Download PDFInfo
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- CN1022630C CN1022630C CN89101539A CN89101539A CN1022630C CN 1022630 C CN1022630 C CN 1022630C CN 89101539 A CN89101539 A CN 89101539A CN 89101539 A CN89101539 A CN 89101539A CN 1022630 C CN1022630 C CN 1022630C
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- methylene
- amido
- bis
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- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 title claims description 18
- 239000004480 active ingredient Substances 0.000 title abstract description 6
- 125000006310 cycloalkyl amino group Chemical group 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 title description 10
- 229940079593 drug Drugs 0.000 title description 5
- 239000002253 acid Substances 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 16
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims description 43
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- 238000000034 method Methods 0.000 claims description 14
- -1 Cycloalkyl amine Chemical class 0.000 claims description 10
- 125000005907 alkyl ester group Chemical group 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
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- 229940078581 Bone resorption inhibitor Drugs 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
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- 239000003435 antirheumatic agent Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- 229910052791 calcium Inorganic materials 0.000 description 9
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical class OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 8
- 108090000445 Parathyroid hormone Proteins 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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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 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000002456 anti-arthritic effect Effects 0.000 description 2
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- 229940098773 bovine serum albumin Drugs 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
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- ZMIRFCWMDNOYEN-UHFFFAOYSA-N 1-phosphorosooxyethane Chemical compound CCOP=O ZMIRFCWMDNOYEN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
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- 206010031243 Osteogenesis imperfecta Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 208000032183 Scleromalacia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KTLIMPGQZDZPSB-UHFFFAOYSA-M diethylphosphinate Chemical compound CCP([O-])(=O)CC KTLIMPGQZDZPSB-UHFFFAOYSA-M 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- JROGBPMEKVAPEH-GXGBFOEMSA-N emetine dihydrochloride Chemical compound Cl.Cl.N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC JROGBPMEKVAPEH-GXGBFOEMSA-N 0.000 description 1
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- 230000000148 hypercalcaemia Effects 0.000 description 1
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- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- IDIOJRGTRFRIJL-UHFFFAOYSA-N iodosilane Chemical compound I[SiH3] IDIOJRGTRFRIJL-UHFFFAOYSA-N 0.000 description 1
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- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- YZHUMGUJCQRKBT-UHFFFAOYSA-M sodium chlorate Chemical compound [Na+].[O-]Cl(=O)=O YZHUMGUJCQRKBT-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
-
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Abstract
公开了以下列通式表示的(环烷基胺基)亚甲基双(膦酸)、以及它的低级烷基酯或其药用的盐:
其中R,R1,R2,R3和R4代表一个氢原子或一个低级烷基,n代表3到10间的整数。以及含有该成份的骨吸收抑制剂和抗关节炎药。
Description
本发明涉及到(环烷基胺基)亚甲基双(膦酸)、它的低级烷基酯或其医药用的盐。这些化合物具有抑制骨吸收、抗炎、抗风湿的作用。本发明还涉及以此化合物作活性成份的医药品。
(环烷基胺基)亚甲基双(膦酸)的许多衍生物是已知的。日本专利公告No37,829/79公开了一类化合物,它们含有一个未取代的环戊基或环己基基团。日本专利公开No12,319/80相应地公开了一种化合物,该化合物含有一个环己基作为环烷基基团。这些日本专利公报指出,这些化合物可以用作农药,尤其是可作为除莠剂,还可用在防止水及水溶液的沉淀的方法中,但是用此化合物作为药品未曾提及。
本发明目的是提供(环烷基胺基)亚甲基双(膦酸)的一类衍生物,它们含有碳原子数为3-10的未取代或取代的环烷基,可以用作骨吸收抑制剂和抗关节炎药。
本发明提供了一种含有如下通式所代表的(环烷基胺基)亚甲基双(膦酸)、它的低级烷基酯或其医药用的盐作为活性成份的药物组合物。
其中R、R1、R2、R3和R4代表一个氢原子或一个低级烷基。n代表3-10的整数。
本发明还提供了一种骨吸收抑制剂和一种抗关节炎药,其活性成份含有分子通式为(Ⅰ)的化合物、它的低级烷基酯及其医药用的盐。
本发明还提供了一种以分子通式(Ⅰ)表示的新化合物、它的低级烷基酯和医药用的盐。式中R、R1、R2、R3、R4代表一个氢原子或一个低级烷基。n代表3-10的整数,但当n是5或6时,R代表一个低级烷基酯。
分子通式Ⅰ中的低级烷基酯是具有1-5个碳原子的直链或支链的烃基团。典型的低级烷基是甲基、乙基、丙基或异丙基。
化学结构为
的基团在分子通式(Ⅰ)中代表一个环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或
环癸基,它们是被一个低级烷基取代或不被取代的。
化合物Ⅰ的盐是医药上可接受的盐类。作为比较理想的盐,它可以是带有无机碱基的盐、如钠盐、钾盐或者类似的盐,也可以是带有有机碱基的盐如:胺盐、三乙胺盐及类似盐。
本发明的化合物的制备按照下列反应式进行:
在此反应中,将环烷基胺(Ⅱ)、低级烷基正甲酸盐(Ⅲ)、磷酸或其低级烷基酯(Ⅳ)按照各自相应的反应量进行混合并加热,反应不必在溶解条件下进行,但此反应一般是在100-200℃下进行的,最好是在大约150℃下,反应10-60分钟,
对如此得到的反应产物须进行分离和纯化,例如,将反应混合物装入二氧化硅凝胶柱中,并且用甲醇-氯仿混合液洗脱,以上述反应的形式,还可以从磷酸或其酯(Ⅳ)分别获得相应的双膦酸或双膦酸盐。
通过水解,双膦酸盐可被转化成相应的双膦酸,该水解反应可通过在浓盐酸中回流加热双膦酸盐进行。此外,还可用强酸或三甲硅烷基卤化物在无水溶剂中处理双膦酸盐,在此方法中,一般可以直接或以恰当的稀溶液形式使用商售的在乙酸中的脱水氢溴酸,或用三甲硅烷基碘化物溶解在一种溶剂中的溶液,这些溶剂如四氯化碳、二甲基甲酰胺、氯仿、甲苯等。至于反应温度,该水解反应在低温或加热条件下都可进行。例如当该酯用三甲硅烷基卤化物在低温-10℃甚至更低的温度下水解时可以得到一个部份水解的产物。
如果要使双膦酸转化成盐,则以通常方式用碱如氢氧化钠、氢氧化钾、氨或有机胺等进行处理。
本发明提供的化合物(Ⅰ)及其盐具有骨吸收抑制作用,而且还对因骨吸收导致的高血钙症有抑制作用,另外已经确认它有明显的抗炎、解热、镇痛作用。
为证实本发明提供的化合物(Ⅰ)及其盐对高血钙的抑制作用,下面介绍一些实验测试方法及测试结果。
(1)对鼠高血钙症的抑制作用
用甲状旁腺激素诱导出鼠的高血钙症。并测定施用本化合物后鼠血清含钙量的减少值。测定方法:
把溶于0.1%的牛血清白蛋白生理盐水溶液中的人1-34甲状旁腺激素(PTH,Peptide药厂生产)(PTH的含量是6μg/ml),给禁食20小时的5周雄性Wistar大鼠按照30μg/Kg(相当于该溶液5ml/Kg)的量静脉注射。并以同样方式给正常对照组白鼠只注射0.1%的牛血清白蛋白生理盐水溶液。注射甲状旁腺激素45分钟后,用乙醚将白鼠麻醉并且剖腹,用真空采血管从腹腔静脉收集血液。将采集的血液立即在4℃,3000rpm条件下离心10分钟,分离血清,并用Ca++检测器(Sera250,Horiba制造公司生产)立即测定血清中的钙离子(Ca++)浓度。
用氢氧化钠和盐酸将本发明所提供的化合物溶解在生理盐水中(pH7.4),按照2ml/kg的剂量皮下给药。在注射甲状旁腺激素前72小时注射本发明化合物。以同样方式给正常对照组和对照组注射生理盐水或蒸馏水。作为参照化合物本测定方法中使用了鲑降钙素(SCT,Armour公司生产),在甲状旁腺激素注射前30分钟按照2ml/kg的剂量给大鼠皮下注射该除钙素。
各组结果以平均值±标准误差的形式表示,采用方差的单方向分析法将各组进行比较。显著性水平取5%。
结果:表1表示了皮下用药后得到的数据(表1见文后)
(2)甲状旁腺激素诱导大鼠高血钙症
方法
状甲状旁腺激素(人PTH1-34,30μg/kg)给大鼠(Wistar种,雄性,约3周令)静脉注射,注射45分钟后采血,用Ca++检测器测定血清钙离子(Ca++)的浓度。
在注射甲状旁腺激素3天前将试验化合物皮下和经口给药,测定结晶以平均值±标准误差表示,
用单方向ANOVA法分析这些值的统计学意义。(*:P<0.05,**:P<0.01)结果
甲状旁腺激素可能是通过刺激骨骼释放钙的升高血清Ca++的水平。双膦酸盐,制备例5的化合物(以下用YM-21175-1表示)和APD*在注射甲状旁腺激素3天前给大鼠皮下注射或口服时可抑制血清钙的含量的增加,抑制与施用剂量有关。不论是皮下注射还是口服,YM-21175-1都比APD的药效强10倍。(表2见文后)
(3)通过切除大鼠神经诱导骨骼废用性萎缩
方法
将大鼠(Wistar,雄性,6周令)的臂丛神经切断导致左前臂废用。两周后取下其左肱骨,去净骨骼周围的软组织,将骨骼用酒精和丙酮相继进行脱水、脱脂。并称取骨骼的干重量。
化合物经口施药每天一次持续二周。结果以平均值±标准误差表示,用单方向ANOVA准则分析这些数值的统计学意义(*:P<0.05,**P<0.01)结果:
切除神经的肱骨干重与假切除者比较明显地减轻,口服双膦酸盐、YM-21175-1和APD,表现出抑制切除神经肱骨干重的减少,抑制与剂量有关,YM-21175-1的药效比APD强30倍。(表3见文后)
(4)辅助剂诱发大鼠关节炎
方法
将灭活芽胞杆菌的油悬浮液注射于大鼠(Lewis,雄性,5周令)的左后爪真皮下。从注射之日起开始将化合物给大鼠每日口服,持续5周。测量左后爪的厚度,并于最后一剂药的下一天取下大鼠的左股骨。将骨骼脱水,脱脂。并称取其干重。然后在骨骼燃烧成灰后称取骨灰的重量。
以骨灰与骨干重的比计算其骨骼无机物的含量,数据以平均值±标准误差(N=6)表示,用单向ANOVA准则分析其统计学意义。(**:P<0.01)
结果:
辅助剂诱发的关节炎是一种常用的人体类风湿性关节炎的模型。注射辅助剂诱导关节炎的大鼠不仅表现为足关节肿胀,而且还有骨骼无机物含量的减少。这被认为是因骨吸收增加和/或后肢废用而引起的。
1mg/kg的消炎痛明显地抑制后肢的肿胀,由于抑制了关节炎的发展,也就抑制了骨骼无机物含量的减少。YM-21175-1仅在大剂量时才抑制肿胀,而在1mg/kg时即可抑制骨骼无机物含量的减少,因此,消炎痛与YM-21175-1在抗炎消肿方面可能存在着差异。YM-21175-1比APD的药效更强。(表4见文后)
将YM-21175-1对骨损失的抑制作用与APD的加以比较,作为三种试验的结果,YM-21175-1被认为可用于治疗骨硬化病、类风湿性关节炎及其他骨吸收增强的疾病。另外还证实YM-21175-1比APD的药效更强。
试验结果证明本发明所提供的化合物具有明显地降低血清钙浓度的作用。因此,进一步肯定了本发明的化合物具有骨吸收抑制作用。有些疾病是因过份的骨吸收而致,在此可提及的有佩吉特病(变形性骨炎)、高血钙症、转移性骨肿瘤和骨脆症。再者,如炎症性关节炎如慢性类风湿关节炎之后的较强的骨吸收,从临床观点看是一个非常重要的问题。本发明所提供的化合物可以用作为该病的治疗药物,用以抑制骨吸收和防止骨损失,或防止因较强的骨吸收而导致的血清钙值上升,或降低血钙值。
本发明所提供的化合物(Ⅰ)及其盐可以与其他任何药用载体、赋形剂、稀释剂等混合形成组成物,如片剂、胶囊、粉剂、颗粒剂、丸剂等、用于口服的针剂、糖浆;栓剂、膏剂等其他非口服用药的剂形。尽管根据用药途径、病人症状等不同,本发明所提供的化合物用量也有变化。但一般情况下,口服给药成人用量是1mg/天至1g/天,非口服用量是0.1-10mg/天。
本发明的化合物作为药物的配方举例如下:
(1)片剂
制备例8的化合物 5gm
乳糖 119mg
玉米淀粉 67mg
羟基丙基纤维素 4mg
羧甲基纤维素钙 4mg
硬脂酸镁 1mg
总计 200mg
将5克制备例8的化合物,119克乳糖和67克玉米淀粉均匀混合,加入40ml10%(w/w)的
羟基丙基纤维素水溶液,将上述混合物制成湿颗粒然后将所得到的颗粒和4克羧甲基纤维素钙和1克硬脂酸镁混合,将该混合物加工成片剂,每片重量200mg。
(2)胶囊
制备例8的化合物 5mg
结晶纤维素 50mg
结晶乳糖 144mg
硬脂酸镁 1mg
总计 200mg
将上述成份按照上述量1000倍的量混合,并装入明胶胶囊,每颗胶囊含有上述混合物200mg。
在下列制备例中将对本发明化合物的制造方法作介绍:
制备例1
将4.0克环庚基胺,6.27克乙基原甲酸酯,和19.5克二乙基亚膦酸酯的混合物在150℃下搅拌加热1.5小时。冷却后,在减压条件下将反应液浓缩,以排除未反应的乙基亚膦酸盐和乙基原甲酸酯。然后将剩余物用硅胶柱层析法进行纯化。(甲醇/氯仿=1/49),得到9.0克呈浅黄色油样的(环庚基胺基)亚甲基双膦酸四乙基酯。
该产物的物理化学性质如下:
(ⅰ)质谱(FAB Mass)400(M++1)
(ⅱ)核磁共振谱(δ值,在CDCl3中)
1.32(12H,OCH2CH3×4)
1.20-2.08(12H,环庚基中的亚甲基H)
2.96(1H,
)
3.36(1H,-NHCH-)
4.00-4.40(8H,-OCH2CH3×4)
以与制备例同样的方法,可以制备下列化合物。
制备例2
(环丙基胺基)亚甲基双膦酸四乙基酯黄色的油
(ⅰ)质谱(FAB Mass)344(M++1)
(ⅱ)核磁共振谱
1.35(12H,OCH2CH3×4)
1.94(1H,-NH-)
2.65(1H,N-
)
3.40(1H,-NCH-)
3.96-4.40(8H,-OCH2CH3×4)
制备例3
(环辛基胺基)亚甲基双膦酸四乙基酯
(ⅰ)质谱(FAB Mass)414(M++1)
(ⅱ)核磁共振谱(δ值,在CDCl3中)
1.34(12H,-OCH2CH3×4)
1.20-2.40(14H,环辛基中的亚甲基H)
3.36(1H,-NHCH-)
4.00-4.48(8H,-OCH2CH3×4)
制备例4
[(3-甲基环己基)胺基]亚甲基双四乙基酯。
(ⅰ)质谱(FAB Mass)400(M++1)
(ⅱ)核磁共振谱
0.92(3H,
),
1.34(12H,-OCH2CH3×4)
2.80(1H,-N
),
3.44(1H,-NCH-)
4.00-4.42(8H,-OCH2CH3×4)
制备例5
将4.0g(环庚基胺基)亚甲基双膦酸四乙基酯溶解于40ml浓盐酸中,回流加热2.5小时,冷却后,在减压条件下浓缩反应液去除盐酸。然后向剩余物中加30ml纯水。再将此混合液在减压条件下浓缩,对此法得到的油样产物用甲醇和丙酮将其固态化,并过滤。最后用丙酮洗涤剩余物,得到2.5g(环庚基胺基)亚甲基双(膦酸)白色固体。
该物质具有以下物理化学性质
(ⅰ)质谱(FAB Mass)288(M++1)
(ⅱ)元素分析(C8H19NO6P2)
计算值(%):C,33.46;H,6.67;N,4.87;P21.57
测定值(%):C,33.27;H,6.40;N,4.88;P21.54
(ⅲ)熔点:232-233℃(从MeoH-H2O中重结晶)
用与制备例5同样的方法,还可制备下列化合物。
制备例6
(环辛基胺基)亚甲基双(膦酸)
(ⅰ)质谱(FAB Mass)302(M++1)
(ⅱ)元素分析(C9H21NO6P2)
计算值(%):C,35.89;H,7.03;N,4.65;P,20.57
测定值(%):C,35.87;H,6.82;N,4.69;P,20.49
(ⅲ)熔点(℃)228-229(未纯化的)制备例7
(环丁基胺基)亚甲基双(膦酸)
(ⅰ)元素分析(C5H13NO6P2)
计算值(%):C,24.50;H,5.35;N,5.71
测定值(%):C,24.41;H,5.23;N,5.66
(ⅱ)熔点(℃):256-258(用甲醇再结晶)
制备例8
[(3-甲基环己基)胺基]亚甲基双(膦酸)
(ⅰ)质谱(FAB Mass)288(M++1)
(ⅱ)元素分析(C8H19NO6P2·0.2H2O)
计算值(%):C,33.04;H,6.72;N,4.81;P,21.30
测定值(%):C,32.88;H,6.47;N,4.77;P,21.32
(ⅲ)熔点(℃):220-221(未纯化的)
制备例9
[(2-甲基环己基)胺基]亚甲基双(膦酸)
(ⅰ)元素分析(C8H19NO6P2)
计算值(%):C,33.46;H,6.67;N,4.88
测定值(%):C,33.07;H,6.39;N,4.86
(ⅱ)熔点(℃):238-240(用甲醇-丙酮再结晶)
制备例10
[(4-甲基环己基)胺基]亚甲基双(膦酸)
(ⅰ)元素分析(C8H19NO6P2)
计算值(%):C,33.46;H,6.67;N,4.88
测定值(%):C,33.13;H,6,41;N,4.75
(ⅱ)熔点(℃):255-258(用甲醇-水重结晶)
制备例11
将1.28克(环丙基胺基)亚甲基双膦酸四乙基酯13ml25%的溴化氢乙酸溶液中,将上述混合液在45℃下搅拌2小时,在减压下将反应液浓缩,并加入20ml净化水。然后再在减压下对该混合物再次浓缩。用甲醇和丙酮将这样获得的油样产物固态化并过滤。用丙酮洗涤结晶体,得到0.42克(环丙基胺基)亚甲基双(膦酸)白色固体。
此产物的物理化学性质如下:
(ⅰ)质谱(FAB Mass)232(M++1)
(ⅱ)元素分析(C4H11NO6P2·0.2H2O)
计算值(%):C,20.47;H,4.89;N,5.96;P26.39
测定值(%):C,20.45;H,4.73;N,5.83;P26.33
(ⅲ)熔点(℃):214-216(未纯化的)
制备例12
将3.0克环戊基胺,6.2克乙基正甲酸盐和19.4克二乙基亚膦酸盐在150℃下搅拌加热1.5小时,冷却后,在减压下将反应液浓缩去除未发生反应的乙基正甲酸盐和二乙基亚膦酸盐。然后用硅胶柱层析法(甲醇/氯仿=1/49)将剩余物纯化,得到10.7克浅黄色油样的(环戊基胺基)亚甲基双膦酸四乙酯。
此物质的物理化学性质如下:
(ⅰ)质谱(FAB Mass):372(M++1)
(ⅱ)核磁共振谱(δ值,在CDCl3中)
1.34(12H,OCH2CH3×4)
1.42-2.00(8H,环戊基中的亚甲基H)
3.30(1H,-NHCH-)
3.48(1H,
)
4.00-4.36(8H,-OCH2CH3×4)
以与制备例12同样的方式还可制备下列化合物。
制备例13
(环己基胺基)亚甲基双膦酸四乙基酯
(ⅰ)质谱(FAB Mass)386(M++1)
(ⅱ)核磁共振谱(δ值,在CDCl3)
1.32(12H,-OCH2CH3×4)
1.2-2.0(10H,环己基中的亚甲基H)
3.44(1H,NHCH)
4.00-4.40(8H,-OCH2CH3×4)
制备例14
将8.0克(环戊基胺基)亚甲基双膦酸四乙基酯溶于80ml浓盐酸中,回流加热2.5小时,冷却后,在减压下将反应液浓缩除去盐酸,剩余物中加入70ml纯水,再在减压下将上述混合液浓缩。把得到的油样产物用丙酮和乙腈将其固态化并过滤。然后再在甲醇水溶液中重结晶,产生3.6克的(环戊基胺基)亚甲基双(膦酸)白色晶体。
此物质的物理化学性质如下:
(ⅰ)质谱(FAB Mass)260(M++1)
(ⅱ)元素分析(C6H15NO6P2·0.1H2O)
计算值(%):C,27.62;H,5.87;N,5.37;P,23.74
测定值(%):C,27.62;H,5.67;N,5.48;P,23.66
(ⅲ)熔点(℃)228-229℃
以制备例14同样的方式还可以生产下列化合物。
制备例15
(环己基胺基)亚甲基双(膦酸)
(ⅰ)质谱(FAB Mass)274(M++1)
(ⅱ)元素分析(C7H17NO6P2)
计算值(%):C,30.78;H,6.27;N,5.13;P,22.68
测定值(%):C,30.48;H,6.11;N,5.16;P,22.17
(ⅲ)熔点(℃)267-269℃(未纯化的)
表1 皮下用药测试结果
剂量 血清Ca++
被试化合物 N
(mg/kg) (mmole/l)
正常对照组 - 5 1.42±0.02
对照组 - 5 1.48±0.03
制备例8的化合物 0.3 5 1.25±0.02**
制备例8的化合物 1.5 5 1.12±0.02**
正常对照组 - 5 1.41±0.02**
对照组 - 5 1.46±0.02
制备例15的化合物 0.03 5 1.37±0.02**
制备例15的化合物 0.1 5 1.20±0.02**
正常对照组 - 5 1.34±0.02**
对照组 - 5 1.43±0.01
制备例14的化合物 0.1 5 1.34±0.02**
制备例14的化合物 0.3 5 1.21±0.01**
制备例5的化合物 0.1 5 1.12±0.01**
制备例5的化合物 0.3 5 0.97±0.02**
正常对照组 - 5 1.36±0.01**
对照组 - 5 1.45±0.02
制备例9的化合物 0.1 5 1.31±0.01**
制备例9的化合物 0.3 5 1.19±0.01**
制备例10的化合物 0.1 5 1.35±0.01**
制备例10的化合物 0.3 5 1.22±0.01**
正常对照组 - 5 1.35±0.02**
对照组 - 5 1.44±0.01
制备例11的化合物 1.0 5 1.35±0.02**
正常对照组 - 5 1.38±0.01**
对照组 - 5 1.48±0.02
制备例7的化合物 0.1 5 1.40±0.02**
制备例7的化合物 0.3 5 1.29±0.01**
制备例6的化合物 0.1 5 1.33±0.03**
制备例6的化合物 0.3 5 1.12±0.03**
正常对照组 - 5 1.38±0.01**
对照组 - 5 1.49±0.00
降钙素 0.3IU 5 1.07±0.02**
注意:平均值±标准误差*:P<0.05,**:P<0.01
表2
YM-21175-1和APD对甲状旁腺激素诱导的大鼠高血钙症的影响
剂量(mg/kg) N 血清钙(mmole/l)
正常组(-PTH) - 5 1.42±0.02
对照组(+PTH) - 5 1.49±0.02
APD 0.03皮下 5 1.49±0.02
0.1皮下 5 1.46±0.01
0.3皮下 5 1.41±0.02*
APD 30经口 5 1.50±0.02
100经口 5 1.42±0.02
300经口 5 1.22±0.02**
YM-21175-1 0.01皮下 5 1.44±0.02
0.03皮下 5 1.36±0.02**
0.01皮下 5 1.15±0.01**
正常组(-PTH) - 5 1.35±0.02
对照组(+PTH) - 5 1.45±0.02
YM-21175-1 10经口 5 1.37±0.02
30经口 5 1.23±0.05**
100经口 5 1.05±0.04**
(一种市售的用于治疗变形性骨炎的药物)
表3 YM-21175-1和APD对大鼠中切除神经诱导的废用性骨萎缩的影响
剂量
N 骨干重(mg)
(mg/kg)
假切除神经 - 6 154±3**
对照组 - 6 113±2
APD 10 5 126±3
30 5 128±4*
100 6 135±2**
YM-21175-1 0.3 6 126±2
1 6 132±6**
3 6 135±3**
10 6 150±4**
表4 YM-21175-1和APD对辅助剂诱发的大鼠关节炎的影响
剂量 骨灰重/骨干重
N 爪厚(mm)
(mg/kg) (%)
正常组 - 6 6.4±0.0 54.8±0.1**
对照组 - 6 13.5±0.1 49.5±0.4
消炎痛 1 6 7.6±0.1** 52.3±0.2**
APD 1 6 12.1±0.6 50.4±0.3
3 6 11.6±0.7 51.2±0.4**
10 6 10.8±0.6** 52.1±0.5**
30 6 12.1±0.3 53.3±0.3**
100 6 9.3±0.3** 56.6±0.3**
YM-21175-1 0.3 6 12.3±0.6 50.7±0.6
1 6 11.7±0.1 52.1±0.8**
3 6 12.3±0.8 53.1±0.4**
10 6 10.5±0.7** 55.9±0.3**
30 5 9.5±0.2** 57.6±0.3**
Claims (2)
Priority Applications (1)
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CN92114203A CN1046853C (zh) | 1988-01-20 | 1992-12-11 | 制备药用组合物的方法 |
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JP11656/1988 | 1988-01-20 | ||
JP1165688 | 1988-01-20 |
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CN92114203A Division CN1046853C (zh) | 1988-01-20 | 1992-12-11 | 制备药用组合物的方法 |
Publications (2)
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CN1035829A CN1035829A (zh) | 1989-09-27 |
CN1022630C true CN1022630C (zh) | 1993-11-03 |
Family
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CN89101539A Expired - Lifetime CN1022630C (zh) | 1988-01-20 | 1989-01-20 | (环烷基胺基)亚甲基双(膦酸)化合物的制备方法 |
Country Status (14)
Country | Link |
---|---|
US (2) | US4970335A (zh) |
EP (1) | EP0325482B1 (zh) |
KR (1) | KR970005179B1 (zh) |
CN (1) | CN1022630C (zh) |
AT (1) | ATE74361T1 (zh) |
AU (1) | AU615711B2 (zh) |
CA (1) | CA1339805C (zh) |
DE (1) | DE68901097D1 (zh) |
DK (1) | DK174744B1 (zh) |
ES (1) | ES2032105T3 (zh) |
GR (1) | GR3004461T3 (zh) |
HU (1) | HU202243B (zh) |
IE (1) | IE60477B1 (zh) |
PH (1) | PH26819A (zh) |
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DE1958123C3 (de) * | 1969-11-19 | 1978-09-28 | Henkel Kgaa, 4000 Duesseldorf | Verfahren zur Herstellung von 1 -Aminoalkan-1,1 -diphosphonsäuren oder deren Salzen |
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DE2104476C2 (de) * | 1971-02-01 | 1983-12-01 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur Verhinderung von Ausfällungen in Wasser oder wäßrigen Lösungen |
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CA1339805C (en) * | 1988-01-20 | 1998-04-07 | Yasuo Isomura | (cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active |
JPH01231980A (ja) * | 1988-03-10 | 1989-09-18 | Ishikawajima Harima Heavy Ind Co Ltd | 管内作業用ピグ |
-
1989
- 1989-01-16 CA CA000588341A patent/CA1339805C/en not_active Expired - Fee Related
- 1989-01-19 PH PH38068A patent/PH26819A/en unknown
- 1989-01-20 KR KR1019890000568A patent/KR970005179B1/ko not_active IP Right Cessation
- 1989-01-20 DE DE8989300560T patent/DE68901097D1/de not_active Expired - Fee Related
- 1989-01-20 HU HU89230A patent/HU202243B/hu not_active IP Right Cessation
- 1989-01-20 CN CN89101539A patent/CN1022630C/zh not_active Expired - Lifetime
- 1989-01-20 DK DK198900243A patent/DK174744B1/da not_active IP Right Cessation
- 1989-01-20 AT AT89300560T patent/ATE74361T1/de not_active IP Right Cessation
- 1989-01-20 IE IE18389A patent/IE60477B1/en not_active IP Right Cessation
- 1989-01-20 ES ES198989300560T patent/ES2032105T3/es not_active Expired - Lifetime
- 1989-01-20 AU AU28670/89A patent/AU615711B2/en not_active Ceased
- 1989-01-20 EP EP89300560A patent/EP0325482B1/en not_active Expired - Lifetime
- 1989-01-23 US US07/300,350 patent/US4970335A/en not_active Expired - Lifetime
-
1990
- 1990-07-10 US US07/551,434 patent/US5041428A/en not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
---|---|
DK24389A (da) | 1989-07-21 |
AU2867089A (en) | 1989-07-20 |
ATE74361T1 (de) | 1992-04-15 |
IE60477B1 (en) | 1994-07-13 |
CN1035829A (zh) | 1989-09-27 |
AU615711B2 (en) | 1991-10-10 |
KR970005179B1 (ko) | 1997-04-14 |
US4970335A (en) | 1990-11-13 |
ES2032105T3 (es) | 1993-01-01 |
DK24389D0 (da) | 1989-01-20 |
IE890183L (en) | 1989-07-20 |
EP0325482A1 (en) | 1989-07-26 |
US5041428A (en) | 1991-08-20 |
DE68901097D1 (de) | 1992-05-07 |
PH26819A (en) | 1992-11-05 |
HUT50841A (en) | 1990-03-28 |
CA1339805C (en) | 1998-04-07 |
EP0325482B1 (en) | 1992-04-01 |
DK174744B1 (da) | 2003-10-13 |
HU202243B (en) | 1991-02-28 |
KR890011601A (ko) | 1989-08-21 |
GR3004461T3 (zh) | 1993-03-31 |
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