CN1382121A - C16不饱和的fp选择性前列腺素类似物 - Google Patents
C16不饱和的fp选择性前列腺素类似物 Download PDFInfo
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- CN1382121A CN1382121A CN00807178A CN00807178A CN1382121A CN 1382121 A CN1382121 A CN 1382121A CN 00807178 A CN00807178 A CN 00807178A CN 00807178 A CN00807178 A CN 00807178A CN 1382121 A CN1382121 A CN 1382121A
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- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 19
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
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- 230000003287 optical effect Effects 0.000 claims abstract description 3
- -1 hydrocarbon radical Chemical class 0.000 claims description 46
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- 208000035475 disorder Diseases 0.000 claims description 4
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- 125000004404 heteroalkyl group Chemical group 0.000 claims description 3
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- 239000000243 solution Substances 0.000 description 36
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- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
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- 239000012044 organic layer Substances 0.000 description 18
- 125000001183 hydrocarbyl group Chemical group 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 210000000988 bone and bone Anatomy 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
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- 238000004809 thin layer chromatography Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 11
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
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- 238000012986 modification Methods 0.000 description 9
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- 229920006395 saturated elastomer Polymers 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
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- 239000003921 oil Substances 0.000 description 7
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
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- 239000011734 sodium Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
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- 125000001544 thienyl group Chemical group 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
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- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
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- 125000004429 atom Chemical group 0.000 description 4
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- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- 239000003795 chemical substances by application Substances 0.000 description 3
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 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 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
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Abstract
本发明提供新的PGF类似物。具体地说,本发明是关于结构为通式I的化合物,其中,R1、X和Z如后文所述。本发明还包括该通式的光学异构体、非对映异构体和对映异构体,以及它们的药学上认可的盐,可生物水解的酰胺,酯和酰亚胺。本发明的化合物可用于治疗多种疾病,例如骨科疾病。于是,本发明还提供了包含这些化合物的药物组合物。本发明还提供用本发明化合物或组合物治疗骨科疾病的方法。
Description
发明领域
本发明涉及天然前列腺素的新的类似物。具体地说，本发明涉及新的前列腺素F类似物。本发明还涉及所述新前列腺素F类似物的使用方法。优选用途包括用于治疗骨科疾病和青光眼。
发明背景
天然前列腺素(PGA，PGB，PGE，PGF和PGI)属于C-20不饱和脂肪酸。PGF2α，即天然人前列腺素F，其特征在于碳脂环的C9和C11上是羟基，C5和C6之间是顺式双键，C13和C14之间是反式双键。因此，PGF2α的通式为：
本领域已经有了天然前列腺素F的类似物。例如，1977年5月17日Bindra和Johnson的美国专利4,024,179，公开于1976年7月1日Beck，Lerch，Seeger和Teufel的德国专利DT-002,460,990；1978年12月5日Hayyashi，kori和Miyake的美国专利4,128,720；1977年3月8日Hess，Johnson，Bindra和Schaaf的美国专利4,011,262；1973年12月4日Bergstrom和Sjovall的美国专利3,776,938；P.W.Collins和S.W.Djuric，“治疗用前列腺素和前列环素类似物的合成”，化学评论，第93卷(1993)，pp.1533-1564；G.L.Bundy和F.H.Lincoln，“17-苯基-18，19，20-三去甲前列腺素：I。PG1系列”，前列腺素，第9卷，第1期(1975)，pp.1-4；W.Bartman，G.Beck和U.Lerch，H.Teufel和B.Scholkens，“黄体溶解性前列腺素：合成方法与生物活性”，前列腺素，第17卷，第2期(1979)，pp.301-311；C.Liljebris，G.Selen，B.Resul，J.Sternschantz和U.Hacksell，“17-苯基-18，19，20-三去甲前列腺素F2α异丙酯的衍生物：潜在的抗青光眼药物”，药物化学杂志，第38卷，第2期(1995)，pp.289-304。
已知天然前列腺素有多种药学特性。例如：前列腺素能松弛平滑肌，引起血管舒张和支气管舒张，能抑制胃酸分泌，抑制血小板凝结，降低眼内压，引产。虽然天然前列腺素是根据其对特定前列腺素受体的活性进行表征，但它们对任何一种特定前列腺素受体一般都没有特异性。所以，天然前列腺素在全身性使用时会引起例如炎症和表面刺激等副作用。普遍认为，天然前列腺素在体内释放后被迅速代谢，使它们的作用局限于一个区域。这能避免前列腺素激活全身前列腺素受体而象全身性给予天然前列腺素时那样引起副作用。
已知前列腺素，尤其是E类前列腺素(PGE)是骨吸收的强刺激剂。PGF2α也是骨吸收的刺激剂，但效力不及PGE2。此外，已知与PGE2相比，PGF2α对骨形成几乎没有作用。曾认为，PGF2α对骨吸收、骨形成和骨细胞复制的作用是内源性PGE2生成增强介导的。
由于天然前列腺素具有广泛的药学特性，但全身性给药时有副作用，所以一直希望能制备出对一个或数个受体具有特异性的天然前列腺素的类似物。本领域已经开发出许多此类类似物。虽然已有许多前列腺素类似物，但仍需要效力和选择性更高的前列腺素类似物用于治疗多种疾病。
发明概述
本发明提供新的PGF类似物。具体地说，本发明涉及具有以下结构通式的化合物：
其中的R1，X和Z如后文所述。
本发明还包括以上通式的光学异构体，非对映异构体和对映异构体，以及它们的药学上认可的盐，可生物水解的酰胺、酯和酰亚胺。
本发明化合物可用于治疗多种疾病，例如骨科疾病和青光眼。于是，本发明还提供包含以上化合物的药物组合物。本发明还提供用本发明化合物或组合物治疗骨科疾病和青光眼的方法。
本发明的详细描述术语和定义
“烃基”表示具有1-18个碳原子的饱和或不饱和烃链，以1-12个碳原子为佳，1-6个更好，1-4个最好。烃链可以是直链或支链。较好的支链烃基具有1到2个分支，以1个为佳。较好的是饱和烃链。不饱和烃基含有一个或多个双键和/或一个或多个三键。优选的不饱和烃基含一个或多个双键或一个三键，更好的是含一个双键。烃链可以是非取代的，或被1-4个取代基取代。优选的是单取代、二取代或三取代的烃基。取代基可以是低级烃基，卤素，羟基，芳氧基(例如苯氧基)，酰氧基(例如乙酰氧基)，羧基，单芳环(例如苯基)，单杂芳环，单脂肪环，单杂脂肪环，和氨基。
“低级烃基”指含1-6个碳原子的烃链，以1-3个为佳。
“芳环”即芳性烃环。芳环包括单环和稠双环系统。单芳环的环内含约5-10个碳原子，以5-7个为佳，5-6个最好。双芳环的环系统内含约8-12个碳原子，以9-10个为佳。双芳环包括其中之一为芳环的系统。优选的是两环都为芳性的环系统。芳环可以是非取代，或被1-4个取代基环上取代。取代基可以是卤素，氰基，烃基，杂烃基，卤烃基，苯基，苯氧基，或以上所述的组合。优选的取代基包括卤素和卤烃基。优选的芳环包括萘基和苯基。最好是苯基。
“碳脂环”指饱和或不饱和烃环。碳脂环不是芳性的。碳脂环是单环。碳脂环的环内含约4-10个碳原子，以4-7个为佳，5-6个最好。碳脂环可以是非取代的，也可被1-4个取代基环上取代。取代基可以是卤素，氰基，烃基，杂烃基，卤烃基，苯基，苯氧基，或以上所述的组合。优选的取代基包括卤素和卤烃基。优选的碳脂环包括环戊基，环己基，环己烯基，环庚基和环辛基。更好的碳脂环包括环己基，环庚基和环辛基。
“卤素”指氟、氯、溴、碘。以氟、氯和溴为佳，氯和氟更好，尤其是氟。
“卤烃基”指被一个或多个卤素取代基取代的直链，支链或环烃基。所述卤烃基以C1-12为佳，C1-6更好，尤其是C1-3。优选的卤素取代基是氟和氯。最好的卤烃基是三氟甲基。
“杂烃基”指含碳原子和至少一个杂原子的饱和或不饱和链，其中，任两杂原子不毗邻。杂烃链的链内含1-18个原子(包括碳原子和杂原子)，以1-12个为佳，1-6个更好，1-4还要好。杂烃链可以是支链或直链。优选的分支杂烃链有1到2个分支，以1个为佳。优选的杂烃基是饱和的。不饱和杂烃基含一个或多个双键和/或一个或多个三键。优选的不饱和杂烃基含1到2个双键或1个三键，只含1个双键更好。杂烃链可以是非取代的，或被1-4个取代基取代。优选的取代杂烃基是单取代、二取代或三取代的。取代基可以是低级烃基，卤素，羟基芳氧基(例如苯氧基)，酰氧基(例如乙酰氧基)，羧基，单芳环(例如苯基)，单杂芳环，单碳脂环，单杂脂环，和氨基。
“低级杂烃基”指含有1-6个原子的烃链，以1-3个为佳。
“杂芳环”指环内含碳原子和1-4个杂原子的芳环。杂环包括单环和稠双环系统。单杂芳环的环内含5-10个原子(包括碳原子和杂原子)，以5-7个为佳，5-6个最好。双杂芳环包括仅其中一环为芳性的系统。优选的是两环都为芳性的双杂芳环系统。双杂芳环含8-12个环内原子，最好是9或10个。杂芳环可以是非取代的，或被1-4个取代基环上取代。取代基可以是卤素、氰基、羟基、杂烃基、卤烃基和苯基、苯氧基，或以上取代基的组合。其中优选的是卤素、卤代烃基和苯基。优选的单杂芳环包括噻吩基，噻唑基，嘌呤基，嘧啶基，吡啶基，和呋喃基。更好的包括噻吩基，呋喃基和吡啶基。最好的是噻吩基。优选的双杂芳环包括苯并[β]噻唑基，苯并[β]噻吩基，喹啉基，喹喔啉基，苯并[β]呋喃基，苯并咪唑基，苯并噁唑基，吲哚基和苯邻甲内酰胺基(anthranilyl)。更好的双杂芳环包括苯并[β]噻唑基，苯并[β]噻吩基和苯并噁唑基。
“杂原子”指氮、硫或氧原子。含多个杂原子的基团所含的杂原子可以不同。
“杂脂环”指环内含碳原子和1-4个杂原子的饱和或不饱和环，其中环内任2个杂原子不相邻，连接杂原子的环内碳原子不再连有羟基、氨基或巯基。杂脂环不是芳性的。杂脂环是单环。杂脂环含约4-10个环原子(包括碳原子和杂原子)，以4-7个为佳，5-6个最好。杂脂环可以是非取代的，或被1-4个取代基环上取代。取代基可以是卤素、氰基、烃基、杂烃基、卤烃基、苯基、苯氧基或以上所述的组合。优选的取代基包括卤素和卤烃基。优选的杂脂环包括piperzyl，吗啉基，四氢呋喃基，四氢吡喃基和哌啶基。
“苯基”指非取代或被1-4个取代基取代的单芳环。取代基可以稠合，但不可以桥连，并可取代在苯环的邻位、间位或对位，或以上所述的组合物。取代基可以是卤素、酰基、氰基、烃基、杂烃基、卤烃基、苯基、苯氧基或以上所述的组合。苯环上优选的取代基包括卤素和卤烃基，最好的是卤素。苯环上优选的取代方式是邻位或间位取代，最好是间位取代。化合物
本发明包括具有以下结构的化合物：
以上结构中，R1是CO2H，C(O)NHOH，CO2R2，CH2OH，S(O)2R2，C(O)NHR2，C(O)NHS(O)2R2，或四唑；其中R2是烃基，杂烃基，碳脂环，杂脂环，单芳环或单杂芳环，R3是低级烃基，低级杂烃基或卤烃基。优选的R2是甲基，乙基和异丙基。优选的R1是CO2H，C(O)NHOH，CO2R2，C(O)NHS(O)2R2或四唑；最好是CO2H和CO2R2。
以上结构中，X是CH＝C＝CH，CH＝CH，CH＝N，C(O)或C(O)Y；其中，Y是O，S或NH。优选的X是CH＝C＝CH，CH＝N，C(O)或C(O)Y。X不能是芳环或杂芳环系统的一部分。
以上结构中，Z是芳环或杂芳环，条件是：当Z是杂芳环时，Z通过一个环碳原子连接。优选的Z是单芳环，更好的是呋喃基，噻吩基和苯基。
本发明还包括以上结构的异构体，非对映异构体和对映异构体。因此，在没有指明立构中心的立体化学时，两种差向异构体都包含在内。本发明化合物中此类立构中心的立体化学以类似于天然PGF2α的为佳。
已发现，本发明的新PGF类似物能治疗骨科疾病，尤其是需要显著增加骨质量、骨体积和骨强度的那些。出人意料的是，本发明化合物与已知骨病疗法相比，具有以下优点：1)通过形成新的小梁增加小梁数；2)增加骨质量和体积的同时保持更接近正常的骨更新速度；和/或3)增强骨内膜表面处的骨形成，但不增加皮质空隙度。
为了测定和评价药学活性，用多种本领域已知的动物试验对本发明化合物进行了检测。例如，可以按照专用于检测化合物增加骨体积、质量或密度的试验来检验本发明化合物的骨活性。此类试验的例子之一是摘除卵巢的大鼠试验。
在摘除卵巢大鼠试验中，摘除6月龄大鼠的卵巢，2个月后，每日皮下给予一次待测化合物。研究结束时，用双能X光吸光测定法(DXA)或外周定量计算机化断层X射线照相(pQCT)或显微计算机化断层X射线照相(mCT)测定骨质量和/或密度。或者，可用静态和动态组织形态测定法来测定骨体积和骨形成的增加。
可用专用于测定被测化合物降低眼内压能力的试验来验证对青光眼的药学活性。此类试验的例子参见：C.Liljebres，G.Selen，B.Resul，J.Sternschantz和U.Hacksell，“17-苯基-18，19，20-三去甲前列腺素F2α异丙酯的衍生物：潜在的抗青光眼药物”，药物化学杂志，第38卷，第2期(1995)，pp.289-304。
可通过常规有机合成方法来制造本发明化合物。特别优选的是按照以下总反应方案I，II和III进行的合成方法。方案I描述用于制造X为CH＝CH(式I)或CH＝C＝CH(式II)的本发明化合物。方案II用于制造X为C(O)(式III)或C(O)Y(式IV)的本发明化合物。方案III用于制造X为CH＝N(式V)的本发明化合物。方案I
其中，R1和Z如前所述。作为方案I起始物的7[3-(R)-羟基-5-氧-1-环戊烯-1-基]庚酸甲酯(S1a)是购买的(例如可购自Sumitomo Chemical或CaymanChemical)。
其中，7[3-(R)-羟基-5-氧-1-环戊烯-1-基]庚酸甲酯(S1a)在硅烷化溶剂中与硅烷化试剂和碱反应。优选的硅烷化试剂包括叔丁基二甲基氯甲硅烷和三氟甲烷磺酸叔丁基二甲基甲硅烷酯，最好是三氟甲烷磺酸叔丁基二甲基甲硅烷酯。优选的碱包括三乙基胺，三甲基胺和2，6-二甲基吡啶，更好的是三乙基胺和2，6-二甲基吡啶，最好是2，6-二甲基吡啶。优选的溶剂包括卤代烃溶剂，最好是二氯甲烷。反应宜在-100℃至100℃之间进行，以-80℃至80℃为佳，-70℃至23℃最好。
用常规方法分离生成的硅烷化化合物。此类方法包括但不限于萃取，溶剂蒸发，蒸馏和结晶。较好的是，分离后真空蒸馏纯化所述的硅烷醚。
然后该硅烷化化合物与铜酸盐反应，铜酸盐由合适的溴烯烃通过Grignard反应而成，参见H.O.House等，“碳负离子化学：生成锂有机铜酸盐的方便前体”，有机化学杂志Vol.40(1975)，pp.1460-69；和P.Knochel等，“锌和铜卡宾体是有效的选择性a′/d′多偶联试剂”，美国化学协会杂志111(1989)p.6474-76。优选的溴烯烃包括4-溴-1-丁烯、4-溴-1-丁炔，4-溴-2-甲基-1-丁烯和4-溴-2-乙基-1-丁烯。溴烯烃最好是4-溴-1-丁烯。优选的溶剂包括醚类，其中优选乙醚和四氢呋喃，最好是四氢呋喃。可在100℃至23℃形成Grignard试剂，以85℃至30℃为佳，最好是75℃至65℃。反应时间以1-6小时为佳，2-5小时更好，3-4小时最好。
一旦Grignard试剂形成后，即由烯基镁形成铜酸盐。形成铜酸盐的温度为-100℃至0℃，以-80℃至-20℃为佳，更好的是-75℃至-50℃。优选的反应时间为30分钟至6小时，以45分钟至3小时为佳，最好是1小时至1.5小时。
由此形成的烯烃用常规技术来分离。这些方法包括但不限于萃取，溶剂蒸发，蒸馏和结晶。较好的是，在硅胶柱(Merck，230-400目)上，以10％EtOAc/己烷为洗脱剂，进行快速层析来纯化该烯烃。然后，该烯烃与氢化物还原剂和极性质子溶剂反应，生成C-9醇。优选的还原剂包括氢化锂铝，硼氢化钠和L-selectride，更好的是硼氢化钠和L-selectride，最好是硼氢化钠。优选溶剂包括甲醇，乙醇和丁醇，最好是甲醇。还原反应在-100℃至23℃之间进行，以-60℃至0℃为佳，最好是-45℃至-20℃。
用常规方法分离出所得的醇。此类方法包括但不限于萃取、溶剂蒸发、蒸馏和重结晶。优选在硅胶(Merck，230-400目)上，以20％EtOAc/己烷为洗脱液，通过快速层析来纯化醇。
可如前所述对所得的醇进行保护。此处优选的硅烷化试剂仍是叔丁基二甲基氯甲硅烷和三氟甲磺酸叔丁基二甲基甲硅烷酯。最好是三氟甲磺酸叔丁基二甲基甲硅烷酯。优选的碱包括三乙基胺，三甲基胺和2，6-二甲基吡啶。更好的是三乙基胺和2，6-二甲基吡啶。最好是2，6-二甲基吡啶。优选的溶剂包括卤代烃溶剂，最好是二氯甲烷。反应可在-100-100℃进行，以-80-80℃为佳，最好是-70-23℃。
用常规方法分离生成的甲硅烷化化合物S1b。此类方法包括但不限于萃取、溶剂蒸发、蒸馏或重结晶。较好的是，在真空蒸馏分离后对甲硅烷基醚进行纯化，得化合物S1b。
然后，用某种形式的锇和高碘酸钠，在能够溶解这两者的溶剂中处理被保护的醇。优选的锇形式包括四氧化锇和锇酸钾。优选的溶剂系统包括乙酸与水的1∶1混合物，以及水、乙酸与THF的1∶1∶2混合物。处理的结果得到醛S1c。
用常规方法分离化合物S1c。这些方法包括但不限于萃取、溶剂蒸发、蒸馏和重结晶。优选在硅胶(Merck，230-400目)上，以20％EtOAc/己烷为洗脱液，通过快速层析来纯化S1c。
重要中间产物醛S1c可与多种不饱和链烯基阴离子亲核体反应生成C-9和C-11被保护的13，14-二氢前列腺素F1α衍生物。
可分离出所得的化合物，但一般用常规方法对其进行去保护，而且还可以在C-1位进行反应以在R1处生成所需的酸衍生物。例如，甲酯与胺或羟基胺缩合反应可分别生成酰胺或异羟肟酸化合物。在C-1位进行反应后，分离得到的是最终产物13，14-二氢-15-取代-15-五去甲前列腺素F1α衍生物，通式I。通式I所示的化合物可参见实施例1-12，18和20。
代之以合适的丙二烯阴离子，参照通式I化合物的方法，可由中间体S1c直接制得通式II化合物。与丙二烯亲核试剂的反应宜在-80-0℃间进行，-80--20℃更好，-80--40℃最好。该反应的优选碱包括正丁基锂、仲丁基锂和叔丁基锂。最好是正丁基锂。该反应的优选溶剂是醚类溶剂，包括乙醚和四氢呋喃，最好是四氢呋喃。对于杂环亲核试剂来说，优选的溶剂是醚类溶剂，优选的是乙醚、丁醚和四氢呋喃，最好的是四氢呋喃。分离后，可用常规方法进行C-1位的反应和/或去保护。通式II所示的化合物参见实施例13-17和19。方案II
在方案2中，R1、Y和Z如前所述。被保护醇S1b(方案I所得)与硼氢化试剂在醚溶剂中反应，然后氧化去除硼试剂，得到S2a型化合物。优选的硼氢化试剂包括-氯甲硼烷-二甲基硫醚、乙硼烷、甲硼烷-四氢呋喃和甲硼烷-二甲基硫醚，最好是甲硼烷-二甲基硫醚。优选的醚类溶剂包括THF和乙醚，最好是THF。反应在-20-30℃进行约1-24小时。优选温度范围是0-20℃。然后，可用碱性过氧化氢将该反应的硼氢化产物氧化成醇(参见硼在有机化学中，H.C.Brown，Crnell University Press，Ithaca，NY 1972，pp.321-325)，然后可常规方法将该醇氧化成醛(W＝H)或酸(W＝OH)。或者，也可用铬酸或铬(Cr(VI))盐直接将硼氢化物氧化成醛或酸。参见Brown，H.C.；Kulkarni，Rao和Patill，Tetrahedron，1986，，45515。优选的方法在二氯甲烷中，在室温下，以PCC处理硼氢化产物。以上反应的产物是S2a型化合物。
用常规方法分离S2a化合物。这些方法包括但不限于萃取、溶剂蒸发、蒸馏和重结晶。较好的是，在硅胶(Merck，230-400目)上，以20％EtOAc/己烷为洗脱液，通过快速层析来纯化S2a，如果W＝OH，则在洗脱液中加入0.1％乙酸。
重要的中间体S2a醛可与多种不饱和碳亲核试剂反应生成，如通式III所示，C-9和C-11被保护的13，14-二氢-16-四去甲前列腺素F1α衍生物。
与芳族或杂芳族亲核试剂的反应宜在-80-0℃间进行，以-80--20℃为佳，-80--40℃更好。该反应的优选碱包括正丁基锂、仲丁基锂、二异丙基氨化锂和叔丁基锂，最好的是正丁基锂。该反应的优选溶剂是醚溶剂，包括乙醚和四氢呋喃，以四氢呋喃最佳。对杂环亲核试剂来说，优选的溶剂是醚，以乙醚、丁醚和四氢呋喃为佳，以四氢呋喃为最佳。
可分离生成的醇，但一般以粗分离产物的形式进行氧化。将苄型醇氧化成苄型酮的该反应是众所周知的。进行该反应的优选试剂包括KMnO4、MnO2、铬酸、Jones′s试剂、Collins′试剂和PCC。最好的方法是在室温下，在二氯甲烷中，用PCC氧化4小时。以20％己烷/乙酸乙酯为洗脱液的柱层析分离该酮。然后用标准条件去除酯。参见Greene和Wuts，“有机合成中的保护基”，Wiley Interscience，NY pp.224-276。然后，游离酸与2.1当量含氮强碱反应，去除酸和苄型酮相邻碳上的保护基。此类碱包括LDA。该烯醇化物与过氧化剂反应，被氧化成α-羟基酮。此类氧化剂包括间-氯过氧苯甲酸、二甲基氧杂环丙烷、Davis′s试剂和过乙酸。可分离出该粗产物，或去除其余保护基。此时可进行C-1位的反应。例如，用常规方法重新酯化，形成酰胺、异羟肟酸或磺酰胺，从而得到通式III所示的化合物。通式III所示的化合物参见实施例21-30。
通式IV所示的化合物可由中间体S2b制得。此时，可用多种醇和胺与游离酸缩合，这可以通过使用诸如DCC的偶合剂，或用例如草酰氯活化酸来实现。然后，可选择性地去除甲酯，参见Greene和Wuts，“有机合成中的保护基”，Wiley Interscience，NY pp.224-276，并用前文就酮中间体所述相同的方法进行该烯醇化酯(ester enolate)的氧化。如前所述，去除其余保护基，按需要进行C-1位的反应，得到化合物IV。通式IV化合物参见实施例31-40。方案III
在方案3中，R1和Z如前所述。烯烃S1b(方案1所得)与锇盐反应，并可以与催化性再氧化试剂(reoxidant)(以N-氧化N-甲基吗啉为佳)反应，得二元醇。萃取分离该二元醇，硅胶层析纯化。然后，选择性氧化该二元醇，得到α-羟基醛。这一氧化有多种方法。例如，可用选择性氧化剂，如DMSO-草酰氯。或者，可先选择性保护伯醇，再保护仲醇，然后去除伯醇上的保护，如方案II所述进行伯醇的氧化。然而，优选方法是加入邻溴苄基溴保护基，它可以在与氢化三丁基锡等试剂发生氧化反应的同时被去除。该方法得到S3a型化合物，其中P＝H。这一步后是醛与胺的缩合，生成S3b型亚胺。如方案I和II所述，适当去除保护基，并在C-1位反应，得到通式V化合物。通式V化合物参见实施例41-48。
以下非限定性实施例说明本发明的化合物、组合物和用途。
实施例
用1H和13C NMR、元素分析、质谱、高分辨率质谱和/或IR光谱分析化合物。
通常，使用惰性溶剂(以无水的为佳)，例如，钠和二苯甲酮蒸馏得到四氢呋喃(THF)，氢化钙蒸馏得到二异丙基胺，其它溶剂都是购买的适当级别的商品。层析在适当的硅胶(70-230目；Aldrich)或(230-400目；Merck)上进行。在玻载硅胶板(200-300目；J.T.Baker)上进行薄层层析，并用5％磷钼酸的EtOH溶液，或用钼酸铵/硫酸高铈在10％H2SO4水溶液中所成的溶液，UV光下显示。
实施例1
13，14-二氢-16-17-Z-二脱氢-17-(2-氟苯基)前列腺素F1α的制备a.7-(2-氧-4-(1，1，2，2-四甲基-1-硅杂丙氧基)环戊-1-烯基)庚酸甲酯(E1b)：
在-78℃，向7-[3-(R)-羟基-5-氧-1-环戊-1-烯基]庚酸甲酯S1a(1当量)的CH2Cl2溶液中用15分钟滴加2，6-二甲基吡啶(1.3当量)。将溶液保温在-78℃。用15分钟滴加TBDMS三氟甲磺酸酯(Triflate)(1.2当量)的CH2Cl2溶液。将反应逐渐升至室温，并室温搅拌15小时。加入10％HCl水溶液，分层。用CH2Cl2萃取水层，合并有机层。有机层用盐水洗涤，干燥(Na2SO4)，并浓缩。残留物经真空(10mmHg)蒸馏，得甲硅烷基醚E1b。b.7-(5-丁-3-烯基-2-羟基-4-(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E1c)：
室温下，向Mg粉末(2当量)的THF浆中加入晶体碘(催化剂I2)，并用10分钟滴加1-溴丁烯(2当量)。反应在加入过程中不断放热。加完后，回流3小时，冷却至室温。用THF稀释该Grignard试剂，在-78℃，通过套管加到配有机械搅拌的三颈烧瓶中，其中已加有溶于THF/DMS 1∶1溶液的CuBr.DMS(2当量)。加入Grignard试剂(约20分钟)后，-78℃搅拌反应1小时。反应此时呈暗红色。然后用25分钟滴加酮E1b(1当量)的THF溶液。-78℃搅拌反应15分钟，然后经2小时缓慢升至室温。用NH4Cl水溶液终止反应，通宵蒸发过量的DMS。将反应液在盐水/CH2Cl2之间分配，分层。用CH2Cl2反萃水层，合并有机层，干燥(Na2SO4)。真空去除溶剂，残留物经SiO2(10％己烷/EtAOc)层析得E1c的酮前体。
将该E1c的酮前体(1当量)溶于MeOH，冷却至-40℃。用10分钟分批加入硼氢化钠(0.9当量)。加完后，-40℃搅拌反应13小时，然后在-78℃反应12小时。用水终止反应，在盐水/CH2Cl2之间分配，分层。用CH2Cl2反萃水层，合并有机层，干燥(Na2SO4)。真空去除溶剂，残留物经SiO2(30％EtAOc/己烷)层析得醇E1c。c.7-(5-丁-3-烯基-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E1d)：
将醇E1c(1当量)溶于CH2Cl2，冷却至0℃，用15分钟滴加2，6-二甲基吡啶(1.3当量)。溶液保温在-78℃，用15分钟滴加TBDMS三氟甲磺酸酯(1.2当量)的CH2Cl2溶液。将反应逐渐升至室温，并搅拌15小时。加入10％HCl水溶液，分层。用CH2Cl2萃取水层，合并有机层。有机层用盐水洗涤，干燥(Na2SO4)，并浓缩。残留物经层析(10％EtOAc/己烷)得甲硅烷基醚E1d。d.7-(5-3-氧丙烷基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E1e)：
在50ml的园底烧瓶中加入过碘酸钠(2当量)和10ml水。搅拌至过碘酸盐完全溶解。然后加入等量冰醋酸，接着加入2份四氢呋喃。最后加入几摩尔百分比的锇酸钾，接着加入烯E1d(1当量)。在室温氮气氛下搅拌反应，用TLC监测反应。当TLC显示不再有起始物时，用盐水终止反应，并用4∶1的乙酸乙酯/己烷萃取。有机相用盐水洗至中性，硫酸钠干燥，并浓缩。经柱层析(7∶3己烷∶乙酸乙酯)后得E1e。e.9，11-(1，1，2，2-四甲基-1-硅杂丙氧基)-13，14-二氢-16-17-二脱氢-17-(邻氟苯基)前列腺素F1α，E1f)：
在园底烧瓶中加入氯化铬(II)(2当量)和氯化镍(II)(0.02当量)。加入DMF，搅拌溶液。向其中加入α-溴-(邻氟)苯乙烯(2当量)和该醛(1当量)。用TLC监测反应，当起始物消失后用氯化铵终止反应。用乙醚萃取混合物，用盐水洗涤至中性，用硫酸镁干燥，并浓缩。经柱层析(7∶3的己烷∶乙酸乙酯)得E1f。f.13，14-二氢-16-17-Z-二脱氢-17-(2-氟苯基)前列腺素F1α(E1g)：
在一园底小烧瓶中加入甲酯E1f和3ml CH3CN。然后加入0.1ml HF/吡啶(0.1mmol，1当量)，同时将烧瓶由0℃升至室温。21℃反应3小时后，用饱和NaCl水溶液终止反应。用CH2Cl2萃取水层3次。合并有机层，用1N HCl洗涤三次，用盐水洗涤，干燥(Na2SO4)。柱层析(7∶3的己烷∶乙酸乙酯)得澄清油状物。将该油状物加入数毫升3∶1的THF∶水溶液中，将烧瓶冷却至0℃。加入过量(2.5当量)氢氧化锂，移走冰浴，室温下搅拌反应过夜。在反应混合物中加入二氯甲烷和饱和柠檬酸，水层用二氯甲烷洗涤3次，合并有机层，用盐水洗涤，干燥(Na2SO4)，真空浓缩，残留物经层析(二氯甲烷/甲醇/乙酸：9.6/0.4/0.015)，得E1g。
实施例2-17
代之以合适的起始物，参照实施例1来制备实施例2-17。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例2
13，14-二氢-16-17-E-二脱氢-17-(2-氟苯基)-17-三去甲前列腺素F1α
实施例313，14-二氢-E-16-17-二脱氢-17-苯基-17-三去甲前列腺素F1α
实施例413，14-二氢-E-16-17-二脱氢-17-(2，4-二氯苯基)-17-三去甲前列腺素F1α
实施例513，14-二氢-E-16-17-二脱氢-17-(2-氟-4-甲基苯基)-17-三去甲前列腺素F1α
实施例613，14-二氢-E-16-17-二脱氢-17-(2-氟-5-氯苯基)-17-三去甲前列腺素F1α
实施例713，14-二氢-E-16-17-二脱氢-17-(2，5-二氟苯基)-17-三去甲前列腺素F1α
实施例813，14-二氢-E-16-17-二脱氢-17-(2-氟-3-氯苯基)-17-三去甲前列腺素F1α
实施例913，14-二氢-E-16-17-二脱氢-17-(2-氟-3-甲氧基苯基)-17-三去甲前列腺素F1α
实施例1013，14-二氢-16-17-二脱氢-17-(3-氟苯基)-17-三去甲前列腺素F1α
实施例1113，14-二氢-16-17-二脱氢-17-(4-氟苯基)-17-三去甲前列腺素F1α
实施例1213，14-二氢-E-16-17-二脱氢-17-(3-三氟甲基苯基)-17-三去甲前列腺素F1α
实施例1313，14-二氢-16-17-二烯-18-(苯基)-18-二去甲前列腺素F1α
实施例1413，14-二氢-16-17-二烯-18-(2-氟苯基)-18-二去甲前列腺素F1α
实施例1513，14-二氢-16-17-二烯-18-(2，4-二氟苯基)-18-二去甲前列腺素F1α
实施例1613，14-二氢-16-17-二烯-18-(3-三氟甲基苯基)-18-二去甲前列腺素F1α
实施例1713，14-二氢-16-17-二烯-18-(4-甲氧基苯基)-18-二去甲前列腺素F1α
实施例1813，14-二氢-16-17-链烯基-17-(2-氟苯基)-17-三去甲前列腺素
F1α1-异羟肟酸的制备
在火焰干燥的配有磁力搅拌棒的园底烧瓶中加入3，14-二氢-16，17-链烯基-17-(2-氟苯基)三去甲前列腺素F1α甲酯(实施例1)(1.0当量)的甲醇溶液。在该溶液中加入羟胺的甲醇(1.25当量)溶液。将该溶液搅拌数分钟。然后用1N盐酸处理该溶液，并用乙酸乙酯萃取。有机层用盐水洗涤，无水硫酸镁干燥，过滤，减压浓缩。残留物经层析纯化得13，14-二氢-16-17-链烯基-17-(2-氟苯基)-17-三去甲前列腺素F1α1-异羟肟酸。
实施例19-20
代之以合适的起始物，按照实施例18制备实施例19-20。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例19
13，14-二氢-15，16-二烯-17-苯基-17-三去甲前列腺素F1α1-异羟肟酸
实施例2013，14-二氢-16，17-链烯基-17-(3-氟苯基)-17-三去甲前列腺素F1α1-N-甲磺酰胺
实施例2113，14-二氢-16-酮-17-苯基-17-三去甲前列腺素F1α
a.7-(5-(4-氧丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E21a)：
在50ml的园底烧瓶中加入硼烷-二甲基硫醚加合物(2当量)和10ml乙醚，搅拌，直至硼烷完全溶解。将烧瓶冷却至0℃，分批加入烯烃。当TLC显示反应完全后，将混合物倒入充分混合的氯铬酸吡啶鎓(PCC)二氯甲烷溶液中。氮气氛中，室温下反应，以TLC监测反应。当TLC显示无起始物时，用饱和氯化铵水溶液终止反应，用4∶1的乙酸乙酯∶己烷萃取。有机层用盐水洗涤至pH中性，以硫酸钠干燥，浓缩。柱层析(1∶1.5的己烷∶乙酸乙酯)得E21a。b.7-(5-(4-羟基-4-苯基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E21b)：
在50ml的园底烧瓶中加入苯基锂(1当量)的THF溶液，冷却至-78℃。然后加入E21a的THF溶液，搅拌30分钟。以TLC监测反应，当起始物消失后用氯化铵终止反应。用乙醚萃取该混合物，并用盐水洗涤至pH中性，以硫酸镁干燥，浓缩。柱层析(7∶3的己烷∶乙酸乙酯)得E21b。c.7-(5-(4-氧-4-苯基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E21c)：
在园底小烧瓶中加入甲酯E21b和一份二氯甲烷。缓慢加入PCC和活化分子筛。室温下搅拌溶液，并以TLC监测反应，直至氧化完全。此时，用Fluorosil过滤粗产物，浓缩，并用层析将酮与残留的醇分离。柱层析(7∶3的己烷∶乙酸乙酯)得E21c。d.7-(5-(3-羟基-4-氧-4-苯基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸(E21d)：
将油状物E21c加入数毫升3∶1的THF∶水溶液中，将烧瓶冷却至0℃。加入过量氢氧化锂(2.5当量)，移走冰浴，室温下搅拌反应过夜。向反应混合物中加入二氯甲烷和饱和柠檬酸，水层用二氯甲烷洗涤3次，合并有机层，用盐水洗涤，用硫酸钠干燥，真空浓缩，残留物经层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得游离酸，然后将该游离酸溶于THF，冷却至-78℃。加入含2.1当量LDA的THF溶液，然后加入2.2当量TMSCl。再然后加入1.1当量mCPBA，将整个反应系升至室温。接着逐渐调至酸性，用3∶1的乙酸乙酯/己烷混合物萃取，得到羟基酮E21d。e.13，14-二氢-16-酮-17-苯基-17-三去甲前列腺素F1α(E21e)：
在一园底小烧瓶中加入酸E21d和一份CH3CN和HF/吡啶(0.1mmol，1当量)，同时将烧瓶缓慢地由0℃升至室温。21℃反应3小时后，用饱和NaCl水溶液终止反应。水层用CH2Cl2萃取3次。合并有机层，用0.1N HCl和盐水洗涤3次，干燥(硫酸钠)，残留物经层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得所述最终产物。
实施例22-27
代之以合适的起始物，基本上按照实施例21所述制备实施例22-27。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例2213，14-二氢-16-酮-16-(3，5-二氟苯基)-16-四去甲前列腺素F1α
实施例2313，14-二氢-16-氧-16-(2-呋喃基)-16-四去甲前列腺素F1α
实施例2413，14-二氢-16-氧，16-(3-氯-5-甲基苯基)-16-四去甲前列腺素F1α
实施例2513，14-二氢-16-氧-16-(4-氟苯并[b]呋喃-2-基)-16-四去甲前列腺素F1α
实施例2613，14-二氢-16-氧-16-(2-硫茚基)-16-四去甲前列腺素F1α
实施例2713，14-二氢-16-氧-17-(2-苯并噻唑基)-16-四去甲前列腺素F1α
实施例2813，14-二氢-16-氧-16-(2，4-二氟苯基)-16-四去甲前列腺素F1α1-异羟肟酸
的制备
火焰干燥一配有磁力搅拌棒的25ml园底烧瓶，在其中加入13，14-二氢-16-酮-16-(3，5-二氟苯基)-16-四去甲前列腺素F1α甲酯(实施例22)(1.0当量)的甲醇溶液。向该溶液中加入羟基胺的甲醇溶液(1.25当量)，搅拌数分钟，然后用1.0N的盐酸(HCl)处理，用乙酸乙酯萃取两次。有机层用盐水洗涤，硫酸镁干燥，过滤，减压浓缩。残留物经层析得13，14-二氢-16-氧-16-(2，4-二氟苯基)-16-四去甲前列腺素F1α1-异羟肟酸。
实施例29-30
代之以合适的起始物，基本上按照实施例18制备实施例29-30。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例29
13，14-二氢-16-氧-16-(4-甲基苯基)-16-四去甲前列腺素F1α1-异羟肟酸
实施例3013，14-二氢-16-氧，16-(2-硫茚基)-16-四去甲前列腺素F1α1-甲磺酰胺
实施例3113，14-二氢-15-(N-苯基氨基甲酰基)-15-五去甲前列腺素F1αa.7-(5-(4-羧基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E31a)：
在一50ml园底烧瓶中加入化合物E21a。然后用中性高锰酸钾(KMnO4)溶液滴定。当TLC显示反应完全，用饱和柠檬酸钠洗涤混合物，并用二氯甲烷萃取3次。分离出有机层，以硫酸钠干燥，并浓缩。经柱层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得E31a。b.7-(5-(3-N-苯基氨基甲酰基-丙基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E31b)：
在一50ml园底烧瓶中加入苯胺(1当量)的THF溶液，然后加入过量二环己基碳二亚胺(DDC)，然后加入E31a的THF溶液，搅拌30分钟。用TLC监测反应，可按需要略加热，当显示无起始物后，用氯化铵终止反应。用乙醚萃取反应混合物，用盐水洗至pH中性，硫酸镁干燥，浓缩。经柱层析(1∶1的己烷/乙酸乙酯)得E31b。d.7-(5-(3-羟基-4-氧-4-苯基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸(E31c)：
将E31b加入数毫升3∶1的THF∶水溶液中，将该烧瓶冷却至0℃。加入过量氢氧化锂(2.5当量)，移走冰浴，室温下搅拌反应过夜。在反应混合物中加入二氯甲烷和饱和柠檬酸，水层用二氯甲烷洗涤3次，合并有机层，用盐水洗涤，硫酸钠干燥，真空浓缩，残留物经层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得游离酸。将该酸溶于THF并冷却至-78℃。加入含2.1当量LDA的THF溶液，然后加入2.2当量TMSCl。再然后加入1.1当量mCPBA，让整个反应系升至室温。调至酸性后用3∶1的乙酸乙酯/己烷混合物萃取，得到羟基酰胺E31c。e.13，14-二氢-15-(N-苯基氨基甲酰基)-15-五去甲前列腺素F1α(E31d)：
在一园底小烧瓶中加入酸E31c和一份CH3CN和HF/吡啶(0.1mmol，1当量)，同时让该烧瓶由0℃缓慢升至室温。21℃保温3小时，然后用饱和NaCl水溶液终止反应。水层用CH2Cl2萃取3次，合并有机层，用0.1N HCl和盐水洗涤3次，硫酸钠干燥，残留物经层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得最终产物。
实施例32-37
代之以合适的起始物，基本上按照实施例31所述制备实施例32-37。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例32
13，14-二氢-15-(N-3，4-二氟苯基氨基甲酰基)-15-五去甲前列腺素F1α
实施例3313，14-二氢-15-(N-2-呋喃基氨基甲酰基)-15-五去甲前列腺素F1α
实施例3413，14-二氢-15-(N-2-氟苯基氨基甲酰基)-15-五去甲前列腺素F1α
实施例3513，14-二氢-15-(苯氧基羰基)-15-五去甲前列腺素F1α
实施例3613，14-二氢-15-(2-氟苯氧基羰基)-15-五去甲前列腺素F1α
实施例3713，14-二氢-15-(3-三氟甲基硫杂苯氧基羰基)-15-五去甲前列腺素F1α
实施例38-40
代之以合适的起始物，基本上按照实施例28所述制备实施例38-40。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例38
13，14-二氢-15-(N-3，4-二氟苯基氨基甲酰基)-15-五去甲
PGF1α1-异羟肟酸的制备
实施例3913，14-二氢-15-(N-3-氯苯基氨基甲酰基)-15-五去甲PGF1α1-异羟肟酸
的制备
实施例4013，14-二氢-15-(N-苯基氨基甲酰基)-15-五去甲PGF1α1-N甲磺酰胺
的制备
实施例4113，14-二氢-17-氮杂-16-烯基-17-苯基-17-三去甲PGF1α的制备a.7-(5-(3-羟基-4-氧丁基丁基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E41a)：
在一50ml园底烧瓶中加入化合物E21a，然后加入一份二氯甲烷(CH2Cl2)。然后加入略微摩尔量过量的间氯过氧苯甲酸(m-CPBA)(Aldrich)。当TLC显示反应完全，用亚硫酸钠溶液洗涤反应混合物，分离有机层，用硫酸钠干燥，并浓缩，经柱层析(20％的EtOAc己烷溶液)得澄清油状环氧化物。将该油状物溶于DMSO，加入1当量邻溴苄醇。加热，进行醇对环氧化物的亲核开环反应。将反应物加入盐水中，用3∶1的乙酸乙酯∶己烷混合物彻底萃取。萃得物经层析(10％EtOAc的己烷溶液)得油状苄醚。然后将该苄醚溶于苯，缓慢加入氢化三正丁基锡的稀溶液，升温至回流温度。为确保反应完全可继续加入该氢化物。回收所得的醛E41a，小心地在硅胶上层析(20％EtOAc己烷溶液)。b.7-(5-(5-氮杂-3-羟基戊-4-烯基)-2，4-二(1，1，2，2-四甲基-1-硅杂丙氧基)环戊基)庚酸甲酯(E41b)：
在一50ml园底烧瓶中加入苯胺(1当量)的C6H6溶液，然后加入E41a。然后加热该混合物，通过用Dean-Stark捕获器进行的共沸蒸馏去除生成的水。用TLC监测反应。真空去除苯，从而分离得到产物，经柱层析(1∶1的己烷∶乙酸乙酯)得E41b。c.13，14-二氢-17-氮杂-16-烯基-17-苯基-17-三去甲PGF1α(E41c)：
在一园底小烧瓶中加入甲酯E41b和CH3CN与HF/吡啶(0.1mmol，1当量)，同时让该烧瓶由0℃缓慢升至室温。21℃保温3小时，然后将反应混合物加到硅胶层析柱上，经5％甲醇的CH2Cl2溶液层析，得到二羟基酯。将该酯滴溶于甲醇，然后滴加到猪肝酯酶(Sigma)的pH7水溶液中进行皂化。必须注意保持MeOH的总浓度低于10％(v/v)。当TLC显示反应完全后，用柠檬酸酸化，用CH2Cl2萃取3次，合并有机层，用盐水洗涤，硫酸钠干燥，残留物经层析(二氯甲烷/甲醇/乙酸9.6/0.4/0.015)得最终产物。
实施例42-45
代之以合适的起始物，基本上按照实施例41所述制备实施例42-45。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例42
13，14-二氢-17-氮杂-16-烯基-17-(2-氟苯基)-17-三去甲PGF1α
实施例4313，14-二氢-17-氮杂-16-烯基-17-(2-呋喃基)-17-三去甲前列腺素F1α
实施例4413，14-二氢-17-氮杂-16-烯基-17-(4-苯基苯基)-17-三去甲前列腺素F1α
实施例4513，14-二氢-17-氮杂-16-烯基-17-(3-氟苯基)-17-三去甲前列腺素F1α
实施例46-48
代之以合适的起始物，基本上按照实施例28所述制备实施例46-48。本领域技术人员能够适当改变反应的温度、压力、气氛、溶剂或顺序。此外，本领域技术人员可适当用保护基阻断副反应或提高得率。有机化学技术人员均可方便的实施所有以上修改，因此，这些都属于本发明范围之内。
实施例4613，14-二氢-17-氮杂-16-烯基-17-(2-呋喃基)-17-三去甲前列腺素F1α1-异羟肟酸
的制备
实施例4713，14-二氢-17-氮杂-16-烯基-17-(3-氯苯基)-17-三去甲前列腺素F1α1-异羟肟酸
的制备
实施例4813，14-二氢-17-氮杂-16-烯基-17-(2-噻吩基)-17-三去甲前列腺素F1α1-异羟肟酸
的制备组合物
本发明组合物包含安全有效量的标题化合物和药学上认可的载体。本发明中，“安全有效量”表示化合物的量在经可靠医学判断认可的范围内，就显著改善所治病情而言足够高，但就避免严重副作用而言足够低(具有合理的效/险比)。化合物的安全有效量取决于具体的待治疾病，患者的年龄和身体状况，疾病的严重程度，疗程长短，当前疗法的特性，具体所用的药学上认可的载体等因素，这些都是医护人员所熟知的。
除所述化合物之外，本发明组合物还包含“药学上认可的载体”。“药学上认可的载体”指适合给予患者的一种或多种相容性固体或液体充填性稀释剂或包胶物质。“相容性”在此表示所述组合物的组分能够与所述化合物混合，并能够彼此混合，其间没有会在一般使用条件下严重降低组合物药效的相互反应。当然，药学上认可的载体必须具有足够高的纯度和足够低的毒性，从而适合给予接受治疗的患者。
所述药学上认可的的载体或组分有例如：乳糖、葡萄糖和蔗糖等糖类；玉米淀粉和马铃薯淀粉等淀粉；羧甲基纤维素钠、乙基纤维素、纤维素乙酸酯等纤维素及其衍生物；粉状黄著胶；麦芽糖；明胶；滑石粉、硬脂酸、硬脂酸镁等固体润滑剂；硫酸钙；花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油等植物油；丙二醇、甘油、山梨醇、甘露醇和聚乙二醇等多元醇；藻酸；Tween等乳化剂；十二烷基硫酸钠等润湿剂；色素；赋味剂；赋形剂；成片剂；稳定剂；抗氧化剂；防腐剂；无热原水；等渗盐水和磷酸盐缓冲液。
选择何种药学上认可的载体与某化合物联用主要取决于该化合物的给药途径。本发明化合物可以全身性给予。给药途径包括透皮、口服、皮下或静脉注射等非肠胃途径、局部、和/或鼻内。
化合物的用量可用动物模型进行常规试验来确定。此类模型包括但不限于健全和摘除了卵巢的大鼠模型，也可使用白鼬、狗和非人类灵长动物以及废模型。
优选的注射用单位剂型包括化合物的无菌水溶液，生理盐水溶液，或两者混合配制的溶液。所述溶液的pH应调节至7.4。适用于注射和手术移植的载体包括水凝胶、控释或缓释装置、聚乳酸和胶原基质。
适用于局部使用的药学上认可的载体包括擦剂、霜剂和凝胶剂等中适用的那些。如欲口服给予化合物，则优选片剂、胶囊等单位剂型。适合制备口服单位剂型的药学上认可的载体众所周知，其选择取决于口味、成本和保存期等对本发明目的影响不大的次级考虑因素，本领域技术人员不难做出此类选择。使用方法
本发明化合物可用于治疗多种疾病，例如眼病、高血压、生育控制、鼻充血、神经性膀胱疾病、胃肠疾病、皮肤病和骨质疏松。
本发明化合物可通过形成新的梁骨和骨质来增加骨体积和增加梁骨数量，同时保持正常的骨更新速度，并且，所述形成发生于骨内膜表面，不损失已有皮质中的骨质。因此，本发明化合物可用于治疗和预防骨科疾病。
治疗骨病的优选给药途径是透皮和鼻内，还包括直肠、舌下和口服。
全身性给予化合物的剂量范围约为每日每公斤体重0.1-1000μg，以0.1-100μg为佳，1-50μg为最佳。根据药物动力学和透皮制剂方面的已有知识，透皮剂量应能达到达到与以上所述相当的血清和血浆水平。全身性给予的血浆水平应在0.01-100ng/ml之间，以0.05-50ng/ml为佳，0.1-10ng/ml为最佳。虽然以上所述为日用剂量，但也可用周或月剂量来计算临床所需的用药量。
为获得所需的效果，剂量可根据患者、疾病、病情、给药途径等而改变。
本发明化合物还可用于降低眼内压。因此，本发明化合物还可用于治疗青光眼。治疗青光眼的优选给药途径是局部使用。组合物和方法实施例
以下非限定性实施例描述了本发明。以下组合物和方法举例不限定本发明的范围，仅指导技术人员如何制备和运用本发明的化合物、组合物和方法。在各种情况中，都可用本发明的其它化合物来取代所例举的化合物，获得相近的效果。熟练技术人员将看出，以下实施例提供的是引导，可根据具体疾病和患者加以变化。
实施例A用混合后直接压片等常规方法制备片剂型药物组合物，配方如下：
成分 含量(毫克/片)
实施例1化合物 5
微晶纤维素 100
淀粉乙醇酸钠 30
硬脂酸镁 3给一骨质疏松患者每日口服一次，该组合物显著增加了骨体积。
实施例B
用常规方法制备液剂型药物组合物，配方如下：
成分 含量
实施例32化合物 1mg
磷酸盐缓冲的生理盐水 10ml
对羟基苯甲酸甲酯 0.05ml
给一骨质疏松患者每日皮下注射一次1.0ml该组合物，该组合物显著最佳了骨体积。
实施例C
用常规方法制备用于降低眼内压的外用药物组合物，配方如下：
成分 含量(wt％)
实施例1化合物 0.004
葡聚糖70 0.1
羟丙基甲基纤维素 0.3
氯化钠 0.77
氯化钾 0.12
EDTA二钠 0.05
氯化苯甲烃铵 0.01
HCl和/或NaOH pH7.2-7.5
纯水 补足100％
虽然以上具体描述了本发明的实施方式，但本领域技术人员可以看出，在本发明范围内可对所述的组合物进行多种改变。因此，权利要求书意欲使得本发明的范围涵盖所有这些改变。
Claims (10)
1.一种化合物，具有以下结构：其中，
(a)R1选自CO2H，C(O)NHOH，CO2R2，CH2OH，S(O)2R2，C(O)NHR2，C(O)NHS(O)2R2或四唑；其中，R2是烃基，杂烃基，碳脂环，杂脂环，单芳香环或单杂芳香环，R3是低级烃基，低级杂烃基或卤代烃基；R2优选甲基，乙基和异丙基；
(b)X是
(1)CH＝C＝CH；
(2)CH＝CH；
(3)CH＝N；
(4)C(O)；
(5)C(O)Y；其中，Y选自O、S和NH；
(c)Z是芳香环或杂芳环，当Z是杂芳环时，它通过环中的碳原子相连；
(d)上述结构的光学异构体，非对映体和对映体，以及以上所述化合物的药学上认可的盐、可生物水解的酰胺、酯或酰亚胺。
2.根据权利要求1所述的化合物，其中的X是CH＝C＝CH或C(O)Y。
3.根据权利要求2所述的化合物，其中的Z是单环。
4.根据权利要求1所述的化合物，其中的X是CH＝CH，CH＝N或C(O)。
5.根据权利要求4所述的化合物，其中的Z是二环。
6.根据前述权利要求中任一项所述的化合物，其中的R1是CO2H，C(O)NHOH，CO2R2，C(O)NHS(O)2R2或四唑。
7.根据前述权利要求中任一项所述的化合物，其中的Z被单取代，该取代基选自低级烃基，卤素和卤代烃基。
8.前述权利要求中任一项所述化合物的用途，即用于制造治疗骨科疾病的药物。
9.根据权利要求8所述的用途，所述骨科疾病是骨质疏松。
10.权利要求1，2，3，4，5，6或7所述化合物的用途，即用于制造治疗青光眼的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12292999P | 1999-03-05 | 1999-03-05 | |
| PCT/US2000/005299 WO2000051979A1 (en) | 1999-03-05 | 2000-02-29 | C16 unsaturated fp-selective prostaglandins analogs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1382121A true CN1382121A (zh) | 2002-11-27 |
Family
ID=22405703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN00807178A Pending CN1382121A (zh) | 1999-03-05 | 2000-02-29 | C16不饱和的fp选择性前列腺素类似物 |
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| EP (1) | EP1159265B1 (zh) |
| JP (1) | JP2002538138A (zh) |
| KR (1) | KR20010102509A (zh) |
| CN (1) | CN1382121A (zh) |
| AT (1) | ATE283256T1 (zh) |
| AU (1) | AU763715B2 (zh) |
| BR (1) | BR0008778A (zh) |
| CA (1) | CA2364944C (zh) |
| CO (1) | CO5150190A1 (zh) |
| CZ (1) | CZ20013175A3 (zh) |
| DE (1) | DE60016181T2 (zh) |
| ES (1) | ES2233351T3 (zh) |
| HU (1) | HUP0200365A2 (zh) |
| IL (1) | IL145123A0 (zh) |
| MX (1) | MXPA01008956A (zh) |
| NO (1) | NO20014240L (zh) |
| NZ (1) | NZ513826A (zh) |
| PL (1) | PL352551A1 (zh) |
| WO (1) | WO2000051979A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102040618B (zh) * | 2009-04-30 | 2013-09-04 | 上海天伟生物制药有限公司 | 一种PGF2a类似物的制备方法及其相关中间体 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ513825A (en) | 1999-03-05 | 2001-09-28 | Procter & Gamble | C 16 unsaturated FP-selective prostaglandins analogs |
| EP1159265B1 (en) * | 1999-03-05 | 2004-11-24 | Duke University | C-16 unsaturated fp-selective prostaglandins analogs |
| US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
| US20020172693A1 (en) | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
| US20020037914A1 (en) | 2000-03-31 | 2002-03-28 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
| US6586462B2 (en) * | 2000-10-20 | 2003-07-01 | Allergan, Inc. | ω-Cycloalkyl 17-heteroaryl prostaglandin E2 analogs as EP2-receptor agonists |
| KR100437873B1 (ko) * | 2001-05-08 | 2004-06-26 | 연성정밀화학(주) | 프로스타글란딘 유도체의 제조방법 및 그의 입체특이적출발물질 |
| JP2008517941A (ja) * | 2004-10-21 | 2008-05-29 | デューク・ユニバーシティー | 眼科用薬剤 |
| US20070254920A1 (en) * | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
| US8623918B2 (en) | 2008-10-29 | 2014-01-07 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
| US8722739B2 (en) | 2008-10-29 | 2014-05-13 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
| US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
| WO2010108012A1 (en) * | 2009-03-18 | 2010-09-23 | Duke University | Compositions and methods for promoting nasal patency and treating neurogenic bladder using prostaglandins |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1520522A (en) * | 1975-06-16 | 1978-08-09 | Ono Pharmaceutical Co | 16-methyleneprostaglandins |
| DE69311361T2 (de) * | 1992-10-13 | 1998-01-08 | Alcon Lab Inc | Zusammensetzungen zur behandlung von glaukoma die prostaglandine und clonidinderivate enthalten |
| WO1999012551A1 (en) * | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume using non-naturally-occurring fp selective agonists |
| EP1159265B1 (en) * | 1999-03-05 | 2004-11-24 | Duke University | C-16 unsaturated fp-selective prostaglandins analogs |
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2000
- 2000-02-29 EP EP00914785A patent/EP1159265B1/en not_active Expired - Lifetime
- 2000-02-29 CA CA002364944A patent/CA2364944C/en not_active Expired - Lifetime
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- 2000-02-29 IL IL14512300A patent/IL145123A0/xx unknown
- 2000-02-29 NZ NZ513826A patent/NZ513826A/en unknown
- 2000-02-29 PL PL00352551A patent/PL352551A1/xx not_active Application Discontinuation
- 2000-02-29 ES ES00914785T patent/ES2233351T3/es not_active Expired - Lifetime
- 2000-02-29 MX MXPA01008956A patent/MXPA01008956A/es not_active Application Discontinuation
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- 2000-02-29 CN CN00807178A patent/CN1382121A/zh active Pending
- 2000-02-29 KR KR1020017011305A patent/KR20010102509A/ko not_active Application Discontinuation
- 2000-02-29 JP JP2000602207A patent/JP2002538138A/ja not_active Withdrawn
- 2000-02-29 AT AT00914785T patent/ATE283256T1/de not_active IP Right Cessation
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- 2000-02-29 WO PCT/US2000/005299 patent/WO2000051979A1/en not_active Application Discontinuation
- 2000-02-29 DE DE60016181T patent/DE60016181T2/de not_active Expired - Lifetime
- 2000-02-29 CZ CZ20013175A patent/CZ20013175A3/cs unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102040618B (zh) * | 2009-04-30 | 2013-09-04 | 上海天伟生物制药有限公司 | 一种PGF2a类似物的制备方法及其相关中间体 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20014240L (no) | 2001-11-02 |
| CO5150190A1 (es) | 2002-04-29 |
| ATE283256T1 (de) | 2004-12-15 |
| IL145123A0 (en) | 2002-06-30 |
| PL352551A1 (en) | 2003-08-25 |
| AU3613000A (en) | 2000-09-21 |
| CA2364944C (en) | 2009-01-20 |
| BR0008778A (pt) | 2001-12-18 |
| US6451859B1 (en) | 2002-09-17 |
| EP1159265B1 (en) | 2004-11-24 |
| NO20014240D0 (no) | 2001-08-31 |
| AU763715B2 (en) | 2003-07-31 |
| MXPA01008956A (es) | 2002-04-24 |
| CA2364944A1 (en) | 2000-09-08 |
| EP1159265A1 (en) | 2001-12-05 |
| JP2002538138A (ja) | 2002-11-12 |
| HUP0200365A2 (hu) | 2002-07-29 |
| NZ513826A (en) | 2001-09-28 |
| ES2233351T3 (es) | 2005-06-16 |
| DE60016181D1 (de) | 2004-12-30 |
| DE60016181T2 (de) | 2005-04-14 |
| WO2000051979A1 (en) | 2000-09-08 |
| KR20010102509A (ko) | 2001-11-15 |
| CZ20013175A3 (cs) | 2002-02-13 |
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