CN1269785A - 用作fp激活剂的芳香族c16-c20-取代四氢***素 - Google Patents
用作fp激活剂的芳香族c16-c20-取代四氢***素 Download PDFInfo
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- CN1269785A CN1269785A CN98808989A CN98808989A CN1269785A CN 1269785 A CN1269785 A CN 1269785A CN 98808989 A CN98808989 A CN 98808989A CN 98808989 A CN98808989 A CN 98808989A CN 1269785 A CN1269785 A CN 1269785A
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- Prior art keywords
- phenyl
- alkyl
- aromatic ring
- prostaglandin
- aliphatic
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- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000001931 aliphatic group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 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 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- 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
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一种新的PGF类似物。具体地是,本发明涉及具有通式(Ⅰ)结构的化合物,其中R1,R2,R3,R4,X,Y和Z的定义见后文。本发明还涉及所述化合物的光学异构体,非对映体和对映体,及其药学上认可的盐,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,例如骨病和青光眼。因此,本发明还提供含所述化合物的药物组合物。本发明还提供用本发明化合物或含化合物的组合物治疗骨病和青光眼的方法。
Description
发明领域
本发明涉及天然***素新的类似物。具体地说,本发明涉及新的***素F类似物。本发明还涉及新的***素F类似物的用途。较好的用途包括治疗骨病和青光眼。
发明背景
天然***素(PGA,PGB,PGE,PGF和PGI)是C-20不饱和脂肪酸。PGF2α,是天然人***素F,其特征在于脂环C9和C11位的羟基,C5和C6之间的顺式双键,以及C13和C14之间的反式双键。PGF2α的结构如以下通式:
本领域已公开了一些天然***素F的类似物。例如,1977年5月17日授于Bindra和Johnson的美国专利4,024,179;1976年7月1日公开的Beck,Lerch,Seeger和Teufel的德国专利DT-002,460,990;1978年12月5日授于Hayashi,Kori和Miyake的美国专利4,128,720;1977年3月8日授于Hess,Johnson,Bindra和Schaaf的美国专利4,011,262;1973年12月4日授于Bergstrom和Sjovall的美国专利3,776,938;P.W.Collins和S.W.Djuric,“治疗用***素和前列环素类似物的合成”,
Chem.Rev.Vol.93(1993),pp.1533-1546;G.L.Bundy和F.H.Lincoln,“17-苯基-18,19,20-三去甲***素的合成:1.PG1系列”
prostaglandin,Vol.9,No.1(1975),pp.1-4;W.Bartman,G.Beck,U.Lerch,H.Teufel和B.Scholkens,“溶黄体性***素:合成与生物活性”,
prostaglandin,Vol.17,No.2(1979),pp.301-311;G.Selen,B.Resul,J.Sternschantz和U.Hacksell,“17-苯基-18,19,20-三去甲***素F2α异丙酯衍生物:潜在抗青光眼药”,
Journal of Medicinal Chemistry,Vol.38,No.2(1995),pp.289-304。
已知,天然***素具有广泛的药理活性。例如,已知***素能够:松弛平滑肌使血管和支气管扩张,抑制胃酸分泌,抑制血小板凝聚,降低眼压,以及催产。虽然天然***素是用它们对某一特定***素受体的活性来描述的,但是它们一般不具有对任何一个***素受体的特异性。所以,已知全身性使用天然***素会引起炎症和皮表刺激等副作用。一般认为,天然***素体内释放后被迅速代谢限制了***素的某些局部作用。这严重影响了***素激活整个体内的***素受体和全身性使用天然***素的效果。
已知,***素,特别是E系列***素(PGE),是骨吸收的强刺激剂。PGF2α也是骨吸收的刺激剂,但强度不如PGE2。而且,已知PGF2α对骨形成几乎没有作用。有人提出,PGF2α对骨吸收,骨形成和细胞复制的某些作用可能是由内源性PGE2产生增加介导的。
考虑到天然***素广泛的药理活性及其全身性使用时的多种副作用,人们一直在试图制备出对某一或某些特定受体具有选择性的天然***素的类似物。本领域已经公开了许多此类类似物。虽然已经公开了大量***素类似物,但人们仍然需要强效选择性***素类似物来治疗多种疾病。
本发明概述
本发明提供了新的PGF类似物。具体地说,本发明涉及结构式如以下通式的化合物:其中R1,R2,R3,R4,X,Y和Z的定义见后文。
本发明还包括以上通式的光学异构体,非对映体和对映体,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,例如骨病和青光眼。所以,本发明还提供了包含上述化合物的药物组合物。本发明还提供了用本发明化合物或包含它们的组合物治疗骨病和青光眼的方法。
本发明详细说明术语和定义
“酰基”是适合将氮原子酰化成酰胺或氨基甲酸盐(酯)的基团或是将氧原子酰化成酯基的基团。较好的酰基包括苯甲酰基,乙酰基,叔丁基乙酰基,乙酰基,对苯基苯甲酰基和三氟乙酰基。更好的是乙酰基和苯甲酰基。最好是乙酰基。
“烃基”是饱和或不饱和的具有1至18个碳原子的烃链,以1至12个碳原子为宜,1至6个更好,1至4个则还要好。烃基链可以是直链或支链。较好的支链烃基具有1至2个分支,以1个分支为佳。较好的是饱和烃基。不饱和烃基具有一个或多个双键或一个或多个三键。较好的是具有1个或2个双键或具有1个三键的不饱和烃基,具有一个双键的更好。烃链可以是非取代的,或者被1至4个取代基取代。较好的是非取代烃基。较好的取代烃基是一取代,二取代或三取代的。较好的烃基取代基包括甲基,乙基,丙基和丁基,卤素,羟基,烷氧基(例如甲氧基,乙氧基,丙氧基,丁氧基和戊氧基),芳氧基(例如苯氧基,氯苯氧基,甲苯氧基,甲氧基苯氧基,苄氧基,烷氧基羰基苯氧基,酰氧基苯氧基),酰氧基(例如丙酰氧基,苯甲酰氧基,乙酰氧基),氨基甲酰氧基,羧基,巯基,烷基硫基,酰基硫基,芳基硫基(例如苯基硫基,氯苯基硫基,烃基苯基硫基,烷氧基苯基硫基,苄基硫基,烷氧基羰基苯基硫基),芳基(例如苯基,甲苯基,烷氧基苯基,烷氧基羰基苯基,卤代苯基),杂环基,杂芳基,氨基(例如,氨基,一和二C1-C3烷基氨基,甲基苯基氨基,甲基苄基氨基,C1-C3烷基酰胺基,氨基甲酰胺基(carbamamido),脲基,胍基)。
“芳环”是芳烃环***。芳环是单环或稠二环***。单芳环的环内含约5至10个碳原子,以5至7个为佳,5至6个最好。二环芳环含8至12个环碳原子,以9或10个为佳。芳环可以是非取代的,或者在环上被1至4个取代基取代。较好的芳环取代基包括:卤素,氰基,烃基,杂烃基,卤代烃基,苯基,苯氧基或以上不只一个。更好的是卤素和卤代烃基。较好的芳环包括萘基和苯基。最好的是苯基。
“脂族碳环”是饱和或不饱和的环烃。脂族碳环是非芳香性的。脂族碳环是单环,稠环,螺环或桥环双环***。单环脂族碳环具有约4至10个环碳原子,以4至7个为佳,5至6个最好。双环脂族碳环具有8至12个环碳原子,以9至10个为佳。脂族碳环可以是非取代的,也可以在环上被1至4个取代基所取代。较好的脂族碳环取代基包括:卤素,氰基,烃基,杂烃基,卤代烃基,苯基,苯氧基或以上不只一个。更好的取代基包括卤素和卤代烃基。较好的脂族碳环包括:环戊基,环己基,环己烯基,环庚基和环辛基。更好的是环己基,环庚基和环辛基。最好的是环庚基。
“卤素”是氟,氯,溴或碘。较好的是氟,氯和溴;更好的氟和氯,尤其是氟。
“卤代烃基”是具有一个或多个卤素取代基的直链,支链或环烃。较好的是C1-C12卤代烃基;C1-C6的更好;C1-C3的还要好。较好的卤素取代基是氟和氯。最好的卤代烃基是三氟甲基。
“杂烃基”是含有碳原子和至少一个杂原子,而且任意两个杂原子不相邻的饱和或不饱和链。杂烃链的链内含1至18个原子(包括碳原子和杂原子),以1至12个为佳,1至6个更好,1至4个则还要好。杂烃链可以是直链或支链。较好的支链杂烃链具有1个或2个支链,以1个支链为佳。较好的杂烃基是饱和的。不饱和杂烃链含有一个或多个双键和/或一个或多个三键。较好的不饱和杂烃链含1个或2个双键,或含1个三键,更好的是含1个双键的。杂烃链可以是非取代的,也可以被1至4个取代基所取代。较好的是非取代杂烃基。较好的杂烃基取代基包括甲基,乙基,丙基和丁基,卤素,羟基,烷氧基(例如甲氧基,乙氧基,丙氧基,丁氧基和戊氧基),芳氧基(例如苯氧基,氯苯氧基,甲苯氧基,甲氧基苯氧基,苄氧基,烷氧基羰基苯氧基,酰氧基苯氧基),酰氧基(例如丙酰氧基,苯甲酰氧基,乙酰氧基),氨基甲酰氧基,羧基,巯基,烷基硫基,酰基硫基,芳基硫基(例如苯基硫基,氯苯基硫基,烃基苯基硫基,烷氧基苯基硫基,苄基硫基,烷氧基羰基苯基硫基),芳基(例如苯基,甲苯基,烷氧基苯基,烷氧基羰基苯基,卤代苯基),杂环基,杂芳基,氨基(例如,氨基,一和二C1-C3烷基氨基,甲基苯基氨基,甲基苄基氨基,C1-C3烷基酰胺基,氨基甲酰胺基(carbamamido),脲基,胍基)。
“杂原子”是氮,硫或氧原子。含一个以上杂原子的基团可含不同的杂原子。
“脂族杂环”是环内含碳原子和1至4个杂原子的饱和或不饱和环,环内任意两个杂原子不相邻,与杂原子连接的碳原子都不再连有羟基,氨基或巯基。脂族杂环是非芳香性的。脂族杂环可以是单环,或稠合或桥连的二环***。单环脂族杂环含约4至10个成环原子(碳原子和杂原子),以4至7个为佳,5至6个最好。二环脂族杂环含8至12个成环原子,以9或10个为佳。脂族杂环可以是非取代的,也可以在环上被1至4个取代基取代。较好的脂族杂环取代基包括:卤素,氰基,烃基,杂烃基,卤代烃基,苯基,苯氧基或以上不只一个。较好的取代基是卤素和卤代烃基。较好的脂族杂环包括哌嗪基(piperzyl),吗啉基,四氢呋喃基,四氢吡喃基和哌啶基(piperdyl)。
“杂芳环”是环内含碳原子和约1至4个杂原子的芳环***。杂芳环是单环或稠二环***。单环杂芳环含约5至10个成环原子(碳原子和杂原子),以5至7个为佳,5至6个最好。双环杂芳环含8至12个成环原子,以9或10个为佳。杂芳环可以是非取代的,也可以在环上被1至4个取代基取代。较好的杂芳环取代基包括:卤素,氰基,烃基,杂烃基,卤代烃基,苯基,苯氧基或以上不只一个。更好的取代基包括卤素,卤代烃基和苯基。较好的杂芳环包括噻吩基,噻唑基,嘌呤基,嘧啶基,吡啶基和呋喃基。更好的杂芳环包括噻吩基,呋喃基和嘧啶基。最好的是噻吩基。
“低级烃基”是由1至6个碳原子构成的烃链,1至4个碳原子的更好。
“苯基”是非取代或被1至4个取代基取代的单芳环。取代基可在苯环上的邻位,间位或对位取代,或以上不只一处。较好的苯基取代基包括:卤素,氰基,烃基,杂烃基,卤代烃基,苯基,苯氧基或以上不只一个。苯环上更好的取代基是卤素和卤代烃基。最好的是卤素。苯环上较好的取代方式是邻位或间位。最好的是邻位取代。化合物
以上结构中,R1是CO2H,C(O)NHOH,CO2R5,CH2OH,S(O)2R5,C(O)NHR5,C(O)NHS(O)2R5,或四唑;R5是烃基,杂烃基,脂族碳环,脂族杂环,芳环或杂芳环。较好的R5是CH3,C2H5,C3H7。较好的R1是CO2H,C(O)NHOH,CO2CH3,CO2C2H5,CO2C3H7,CO2C4H9,CO2C3H7O2和C(O)NHS(O)2R5。更好的R1是CO2H,C(O)NHOH,CO2CH3和CO2C3H5。最好的R1是CO2H和CO2CH3。
以上结构中,R2是H或低级烃基。较好的R2是H和CH3。最好的R2是H。
以上结构中,X是NR6R7,OR8,SR9,S(O)R9,S(O)2R9或F;R6,R7和R8各自选自H,酰基,烃基,杂烃基,脂族碳环,脂族杂环,芳环和杂芳环;R9是烃基,杂烃基,脂族碳环,脂族杂环,芳环和杂芳环。较好的R6,R7是H,CH3和C2H5。较好的R8是H,CH3,C2H5和C3H7。较好的R9是CH3和C2H5。较好的X是NR6R7和OR8。X最好是OH。
上述结构中,R3和R4各自选自H,CH3,C2H5,OR10,SR10或OH,R3和R4不能都是OH;R10是烃基,杂烃基,脂族碳环,脂族杂环,芳环或杂芳环,R10具有1至8个成环原子;较好的R3和R4是H。
上述结构中,Y是(CH2)n;n是0至3的整数;以n为0,1和2为佳。最好n是1。
上述结构中,当n是0,2或3时,Z是脂族碳环,脂族杂环,单杂芳环或取代的苯基;当n是1时,Z是脂族碳环,脂族杂环或取代的苯基。Z以单环为佳。更好的Z是取代的苯基和单环杂芳环。最好的Z是取代的苯基和取代或非取代噻吩基。
本发明还包括以上结构的光学异构体,非对映体和对映体。所以,在所有立体化学不确定的立构中心(C11,C12,C15和C16),两种差向异构体都包括。本发明化合物内所有上述立构中心较好的立体化学都与天然PGF2α的相似。
已发现,本发明的新PGF类似物可治疗骨病,尤其是需要显著增加骨量,骨容量或骨强度的那些。出人意料的是,与已知骨病治疗方法相比,本发明化合物具有以下优点:(1)通过形成新的骨小梁增加骨小梁数量;(2)增加骨量和骨容量的同时维持骨转化率正常;和(3)增加骨内膜表面的骨形成,但不增加皮层孔隙。
为了测定和评价药理活性,用各种本领域技术人员熟知的方法在动物体内对本发明化合物进行了测试。例如,本发明化合物的骨活性可方便地用测试本发明化合物提高骨量,骨容量或骨密度的能力的试验来证明。此类试验实例之一是去卵巢大鼠试验。
在去卵巢大鼠试验中,6月龄的大鼠被切去卵巢,再生长2个月,然后每天皮下给予测试化合物一次。研究结束时,双能X光吸收法(DXA)或外周定量计算机体层摄影术(pQCT)或微观计算机体层摄影术(mCT)测定骨容量或骨形成的增加。或者,可用静态或动态组织形态学测算来测定骨容量或骨形成的增加。
对青光眼的药理活性可用测定本发明化合物降低眼压的能力的试验来证明。此类试验的实例可参见以下文献:C.Liljebris,G.Selen,B.Resul,J.Sternschantz和U.Hacksell,“17-苯基-18,19,20-三去甲***素F2α异丙酯衍生物:潜在抗青光眼药”,
Journal of Medicinal Chemistry,Vol.38,No.2(1995),pp.289-304。
方案1中,R1,R2,R3,R4,X,Y和Z的定义见前文。方案1中作为起始物的Corey内酯(S1a)是市售商品(例如Sumitomo Chemical或Cayman Chemical的产品)。
化合物S1f可由化合物S1e经标准还原反应得到。通式1化合物可由化合物S1f经同时饱和其中的双键得到。实施例2,4,5,7,9,11,13,16,18,20,22,24,26和28例举了通式I表示的化合物。只需将通式I化合物去酯即可得到通式II化合物。实施例1,3,6,8,10,12,14,15,17,19,21,23,25,27和29例举了通式II化合物。S1e与碳亲核试剂加成,然后饱和并皂化,得到通式III表示的化合物。实施例43和44例举了通式III表示的化合物。先形成亚胺,然后还原亚胺,N烷基化,氢化,皂化,即得到通式IV化合物。如前所述先形成亚胺,然后亲核加成,饱和双键并皂化,可得到其它通式IV化合物。实施例48,49和50例举了通式IV表示的化合物。
对S1e化合物进行双羟基保护,然后进行标准酮亲核还原,可得到通式V和通式VII表示的化合物。可将所得的游离醇活化,用亲核试剂(例如但不限于氟化物,醇盐或硫化物)取代,得到通式V和通式VII表示的化合物。实施例36,37和38例举了通式V表示的化合物。实施例39,40,41,42和45例举了通式VII表示的化合物。在X必须为硫的条件下选择性氧化通式VII化合物,制得通式VIII化合物。实施例46和47例举了通式VIII表示的化合物。由通式I或II化合物(通式II化合物可能需要经羧酸酯活化)都可以经与活化羧酸酯的亲核加成生成酰胺或新的酯键以得到异羟肟酸、磺酰胺或酯,由此制得通式VI表示的化合物。实施例30-35例举了同时VI表示的化合物。
以下非限定性实施例说明了本发明的化合物,组合物和用途。
实施例
适当地用1H和13C NMR,元素分析,质谱,高分辨质谱和/或IR波谱来分析化合物。
通常,使用惰性溶剂,以干燥的为佳。例如,由钠和二苯甲酮蒸馏四氢呋喃(THF),由氢化钙蒸馏二异丙基胺,其他溶剂都是购得的适当级别的商品。在硅胶(70-230目;Aldrich)或(230-400目;Merck)上适当进行层析。在玻璃支持的硅胶板上(200-300目;Baker)进行薄层层析,用UV,5%磷钼酸EtOH溶液,高锰酸钾水溶液,碘,茴香醛乙醇溶液或溶于10%H2SO4水溶液的钼酸铵/硫酸高铈(cerric)显色。
实施例113,14-二氢-17-(3-氟苯基)-17-三去甲***素F1α(1n)的制备:a.7-苯甲酰氧-6-(2,5-二氧环戊基)-2-氧杂二环[3.3.0]辛-3-酮(1b):1,2-二(三甲基甲硅烷氧基)乙烷(1.3当量)-78℃溶于含三甲基甲硅烷基三氟甲烷磺酸酯的二氯甲烷(1ml),将其加入配有磁力搅拌棒的圆底烧瓶。20分钟内向其中加入1a(1当量)的CH2Cl2溶液。反应在-78℃搅拌1小时,1小时后缓慢升温至25℃。在0℃用水终止反应,用CH2Cl2萃取,MgSO4干燥,真空浓缩,得到粗制的1b。b.6-(2,5-二氧环戊基)-7-羟基-2-氧杂二环[3.3-0]辛-3-酮(1c):在0℃充分搅拌粗制1b(1当量)的甲醇溶液,向其中加入甲醇钠(1.2当量)的MeOH悬浮液。反应在0℃搅拌1小时,1小时后缓慢升温至25℃。用酸性离子交换树脂中和反应,用MeOH充分洗涤树脂。真空浓缩滤液得到浆状物,经硅胶柱快速层析(以4∶1己烷∶乙酸乙酯和2%MeOH的CH2Cl2溶液洗脱)得到黄色浆状1c。c.6-(2,5-二氧环戊基)-2-氧杂-7-(1,1,2,2-四甲基-1-硅丙氧基)二环[3.3.0]辛-3-酮(1d):在配有磁力搅拌棒的圆底烧瓶中搅拌1c(1当量)的CH2Cl2溶液。在-78℃向此溶液中滴加2,6-二甲基吡啶(1.9当量),然后滴加TBDMSOTf(1.8当量)。反应在-78℃搅拌30分钟,然后过夜升温至25℃。用水终止反应。有机层用水洗涤,MgSO4干燥,真空浓缩,得到黄色油状物,进行硅胶柱快速层析(先后用己烷和1%MeOH的CH2Cl2溶液洗脱)。然后用1N HCl,0.1N HCl,水和盐水洗涤产物,得到1d。d.6-(2,5-二氧环戊基)-2-氧杂-7-(1,1,2,2-四甲基-1-硅丙氧基)二环[3.3.0]辛-3-醇(1e):在配有磁力搅拌棒的圆底烧瓶中搅拌1d(1当量)的无水甲苯溶液。在-78℃向此溶液中缓慢加入DIBAL(1.24当量)。反应混合物搅拌2小时,然后升温至0℃。在反应混合物中加入饱和NH4Cl,然后缓慢升温至25℃。用水稀释,抽滤去除不溶的沉淀,用乙酸乙酯洗涤沉淀。用乙酸乙酯萃取液相,合并有机相,MgSO4干燥,真空浓缩,得到黄色浆状物。产物1e必须立即使用或于-70℃保存一夜。e.7-(5-(2,5-二氧环戊基)-2-羟基-4-(1,1,2,2-四甲基-(1-硅丙氧基)环戊基)庚-5-烯酸甲酯(1f):0℃,N2下,向溴化(4-羧基丁基)三苯基磷鎓(2.2当量)的THF悬浮液中滴加KHMDS(4.4当量)溶液。所得的深橙色反应混合物在25℃搅拌1小时。在-78℃,向反应混合物中加入1e(1当量)的THF溶液。任反应混合物在一通宵后升温至25℃。在0℃用水终止反应,用1N HCl调节pH至3.5-4.0。用乙酸乙酯萃取水相,合并有机相,MgSO4干燥,真空浓缩,得到含粗制酸的棕红色浆状物。在0℃充分搅拌粗制酸在***和MeOH中所成的溶液,加入TMS-重氮甲烷,直至得到稳定的黄色。加入1滴冰醋酸,薄层层析证实反应已完全。真空浓缩反应液,硅胶柱快速层析(用30%乙酸乙酯的己烷溶液洗脱)纯化,得1f。f.7-(2,4-二羟基-5-甲酰基-环戊基)庚-5-烯酸甲酯(1g):在配有磁力搅拌棒的圆底烧瓶中加入一定量的酮缩醇1f。向其中加入足量由2份丙酮对1份1N HCl组成的混合物,使得酮缩醇完全溶解。搅拌,直至TLC证明起始物已耗尽,通常为一通宵。用***萃取含产物1g的粗制混合物,***萃取物原位与TMS-重氮甲烷再酯化。在0℃低压浓缩有机萃取液,不加纯化立即使用。g.3-(2-氟苯基)丙酸甲酯(1i):2-氟肉桂酸(1h)(1.0当量)和钯碳加入1/1甲醇/乙酸乙酯溶液,将其加入Parr容器。将此不均匀的溶液置于Parr振荡仪上,加氢(50psi)直到吸收停止。用硅藻土过滤混合物,低压浓缩。用二***吸收残留物,与重氮甲烷反应,至黄色稳定。低压浓缩溶液得到粗制甲酯。硅胶柱层析(己烷/乙酸乙酯5/1)纯化得到一定得率的3-(2-氟苯基)丙酸甲酯(1i)。h.4-(2-氟苯基)-2-氧-丁基膦酸二甲酯(1j):在经火焰干燥的配有搅拌棒和温度计的圆底烧瓶内加入甲基膦酸二甲酯(1.0当量)的无水THF溶液。将溶液冷却至-78℃,与正丁基锂(1.05当量)反应。反应混合物搅拌15分钟。向此溶液中加入3-(2-氟苯基)丙酸甲酯(1.1当量)的无水THF溶液。此后6小时,混合物缓慢升温至室温。用饱和氯化铵溶液处理混合物,并用CH2Cl2萃取。有机层先用水再用盐水洗涤。合并水相,用CH2Cl2反萃取,合并有机层,用无水MgSO4干燥,过滤,低压浓缩。硅胶柱层析(己烷/乙酸乙酯/2-丙醇45/50/5至己烷/乙酸乙酯/2-丙醇40/50/10)纯化,得到1.34g(70%)油状4-(2-氟苯基)-2-氧-丁基膦酸二甲酯(1j)。i.17-(2-氟苯基)-17-三去甲-15-氧-***素F2α甲酯(1k):在火焰干燥的配有磁力搅拌棒的圆底烧瓶内加入4-(2-氟苯基)-2-氧-丁基膦酸二甲酯(1j)(1.43当量)的DME溶液与水。在溶液中加入溴化锂(1.65当量),三乙胺(1.65当量)和7-(2-甲酰基-3,5-二羟基环戊基)庚-5-烯酸甲酯(1g)(1.0当量)。溶液在室温下搅拌48小时。此时,再次加入三乙胺和水,再搅拌1小时。将溶液倒入盐水,用乙酸乙酯萃取3次。合并有机层,无水MgSO4干燥,过滤,低压浓缩。硅胶柱层析(二氯甲烷/甲醇19/1)纯化,得到油状17-(2-氟苯基)-17-三去甲-15-氧-***素F2α甲酯(1k)。j.15-(R,S)-17-(2-氟苯基)-17-三去甲-***素F2α甲酯(1l):在火焰干燥的配有磁力搅拌棒的圆底烧瓶内加入17-(2-氟苯基)-17-三去甲-15-氧-***素F2α甲酯(1k)(1.0当量),三氯化铈(1.05当量)的甲醇溶液。溶液在室温下搅拌5分钟。将溶液冷却至-10℃,加入硼氢化钠(1.02当量)的甲醇溶液。溶液在-10℃搅拌3小时。混合物中加水,用1N盐酸将pH调节至6-7。混合物用乙酸乙酯萃取2次,合并有机层,无水MgSO4干燥,过滤,低压浓缩。硅胶柱层析(3%甲醇的二氯甲烷溶液至5%甲醇的二氯甲烷溶液)纯化,得到(43%)15(R)异构体和(19.6%)15(S)异构体,均为澄清的油状物。k.13,14-二氢-17-(2-氟苯基)-17-三去甲-***素F1α甲酯(1m):在火焰干燥的配有磁力搅拌棒的圆底烧瓶内加入17-(2-氟苯基)-17-三去甲-***素F2α甲酯(11)(1.0当量)和钯碳的乙酸乙酯悬浮液(3ml)。用气球向不均匀的溶液中加氢18小时。用硅藻土过滤混合物,低压浓缩,得到一定量的13,14-二氢-17-(2-氟苯基)-17-三去甲-***素F1α甲酯(1m)。1.13,14-二氢-17-(2-氟苯基)-17-三去甲-***素F1α甲酯(1n):在火焰干燥的配有磁力搅拌棒的圆底烧瓶内加入13,14-二氢-17-(2-氟苯基)-17-三去甲-***素F1α甲酯(1m)(1.0当量)和一水合氢氧化锂(1.8当量)的50/50THF/水溶液。混合物在室温下搅拌6小时,然后用水稀释,用1N HCl酸化至pH2-3。水相用乙酸乙酯萃取3次,合并有机相。合并后的有机相用无水MgSO4干燥,过滤,低压浓缩,得到粗制酸。HPLC纯化得到(41%)分析样品。用实施例1的方法(并使用合适的起始物)得到实施例2-29的化合物。
实施例213,14-二氢-17-(2,4-二氟苯基)-17-三去甲***素F1α甲酯
实施例413,14-二氢-17-(2-氟苯基)-17-三去甲***素F1α甲酯
实施例613,14-二氢-17-(3-氟苯基)-17-三去甲***素F1α
实施例813,14-二氢-17-(4-氟苯基)-17-三去甲***素F1α
实施例1513,14-二氢-17-(3,5-二氟苯基)-17-三去甲***素F1α
实施例1713,14-二氢-18-(2-噻吩基)-18-二去甲***素F1α
实施例2013,14-二氢-17-((3-三氟甲基)苯基)-17-三去甲***素F1α甲酯
实施例2113,14-二氢-17-((3-三氟甲基)苯基)-17-三去甲***素F1α
实施例2213,14-二氢-17-((4-三氟甲基)苯基)-17-三去甲***素F1α甲酯
实施例2313,14-二氢-17-((4-三氟甲基)苯基)-17-三去甲***素F1α
实施例2413,14-二氢-17-(2-甲基苯基)-17-三去甲***素F1α甲酯
实施例2713,14-二氢-17-(3-甲基苯基)-17-三去甲***素F1α
实施例2913,14-二氢-17-(4-甲基苯基)-17-三去甲***素F1α
实施例3013,14-二氢-17-((3-三氟甲基)苯基)-17-三去甲***素F1α-1-异羟肟酸
在13,14-二氢-17-(3-三氟甲基)-苯基-17-三去甲***素F1α甲酯(实施例20)的甲醇溶液中加入羟胺的碱性甲醇溶液(1.25当量)。溶液在室温下搅拌18小时。溶液与1N盐酸反应,并用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸镁干燥,过滤,低压浓缩。残留物经HPLC纯化得到13,14-二氢-17-((3-三氟甲基)苯基)-17-三去甲***素F1α-1-异羟肟酸。
用实施例30的方法(用合适的酯)制备实施例31和32的化合物。
实施例3113,14-二氢-17-(2-甲氧基苯基)-17-三去甲***素F1α-1-异羟肟酸
将实施例23化合物转化为酸酐,然后与甲烷磺胺反应,参见A.D.Kemp和H.Stephen,
J.Chem.Soc.(1984)p.110。
用实施例33的方法,用合适的酸,制得实施例34和35的化合物。
实施例3613,14-二氢-15-氟-17-(3-甲基苯基)-17-三去甲***素F1α
实施例1中相当于实施例27化合物前体的1k经保护和还原得到9,11-保护的二醚。所得的化合物与三氟二乙基氨基硫(DSAT)反应(参见:
Org.React.Vol.35(1988)p.513;
J.Org.Chem.Vol.40(1975)p.574),在如实施例1所述进行适当转化后得到13,14-二氢-15-氟-17-(3-甲基苯基)-17-三去甲***素F1α。
用实施例36的方法,用与实施例1中1k相当的合适中间体(分别来自实施例5和实施例25),与合适的醇酯化,制得实施例37和38化合物。
实施例3813,14-二氢-15-氟-17-(2-甲基苯基)-17-三去甲***素F1α异丙酯
实施例1中相当于实施例23化合物前体的1k经保护和还原得到9,11-保护的二醚。该化合物与甲烷磺酰氯(1.2当量)和碱(1.2当量)反应(参见:
J.C.S.Chem. Comm.(1975)p.658;
Tetrahedron Lett.(1975)p.3183)得到甲磺酰化中间体,然后立即与亲核试剂(甲硫醇钠)反应(参见
Tetrahedron Lett.Vol.23(1982)p.3463)得到被保护的硫烷基醚。然后如实施例1所述转化得到13,14-二氢-15-甲基硫-17-((4-三氟甲基)苯基)-17-三去甲***素F1α。
以相同于实施例39的方法(用实施例7中相当于1k的前体),并如实施例30所述转化成异羟肟酸,得到实施例40化合物。
用相同于实施例39的方法(由实施例21中相当于1k的前体),然后如实施例33所述转化为磺胺,制得实施例41化合物。
实施例41
实施例4213,14-二氢-15-乙氧基-17-((2-三氟甲基)苯基)-17-三去甲***素F1α
实施例1中相当于实施例19化合物前体的1k经保护和还原后得到9,11-保护的二醚。该化合物与甲烷磺酰氯(1.2当量)和碱(1.2当量)反应(参见:
J.C.S.Chem. Comm.(1975)p.658;
Tetrahedron Lett.(1975)p.3183)得到甲磺酸酯中间体,然后立即与乙醇钠反应得到被保护的烷基醚。然后如实施例1所述转化得到13,14-二氢-15-乙氧基-17-((2-三氟甲基)苯基)-17-三去甲***素F1α。
相当于实施例1中的1k的实施例17的前体经保护和还原得到9,11-保护的二醚。所得的被保护二醇与多种碳亲核试剂反应,例如乙基溴化镁,得到叔醇。去保护,然后如实施例1所述转化,得到13,14-二氢-15-乙基-18-(2-噻吩基)-18-二去甲***素F1α。
用实施例43的方法(用合适的碳亲核试剂),得到实施例44化合物。
实施例4413,14-二氢-15-甲基-17-(3,5-二氟苯基)-17-三去甲***素F1α
用实施例43的方法(用相当于1k的实施例13的前体),然后用各种卤代烃(本实施例是碘甲烷)对所得C15醇盐进行O-烷基化,得到实施例45化合物。然后进行实施例34和实施例1中的去保护,氢化,皂化,得到13,14-二氢-15-乙基-15-甲氧基-17-(4-甲氧基苯基)-17-三去甲***素F1α。
实施例39的硫甲基醚与合适的氧化剂反应(参见:
Tetrahedron Lett.(1982)p.3467;
Prostaglandins Vol.24(1982)p.801;
Tetrahedron Lett.Vol.23(1982)p.1023)。
用实施例46的方法,用合适的硫醚,得到实施例47化合物。
实施例47
实施例48
相当于实施例12的之间体的1k与甲胺反应,然后用氰基硼氢化钠还原,皂化和去保护后得到13,14-二氢-15-N-甲基氨基-17-(3-甲氧基苯基)-17-三去甲***素F1α。
实施例4913,14-二氢-15-N,N’-二甲基氨基-17-(3-甲氧基苯基)-17-三去甲***素F1α
由实施例48化合物,用碘甲烷烷化,制得实施例49化合物。
实施例5013,14-二氢-15-氨基甲基-15-甲基-17-(3-甲氧基苯基)-17-三去甲***素F1α
实施例48的亚胺中间体与(过量)甲基铈反应(有关铈介导的亲核加成参见:
J. Org.Chem.Vol.49(1984)p.3904;
J.Am.Chem.Soc.Vol.111(1989)p.4392),如实施例1所述氢化和皂化后得到13,14-二氢-15-氨基甲基-15-甲基-17-(3-甲氧基苯基)-17-三去甲***素F1α。组合物
本发明组合物包含安全有效量的本发明化合物和药学上认可的载体。在此,“安全有效量”表示化合物的量在医疗判断认可的范围内,多至足以明显改善待治病情,少至足以避免严重的副作用(合理的效/险比)。化合物的安全有效量因具体疾病,患者年龄及身体情况,病情严重程度,疗程,同期治疗的特点,具体使用的药学上认可的载体等医师熟知的因素而不同。
除化合物之外,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”在此表示一种或多种适合给予患者的相容性固体或液体填充稀释剂或包囊材料。“相容性”在此表示,组合物组分能够与化合物及彼此混合,在常用条件下基本上没有降低组合物效果的相互作用。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,以使它们适合给予患者。
可作为药学上认可的载体或其组分的材料有例如糖,例如乳糖,葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素,乙酸纤维素酯;西黄耆胶粉;麦芽;明胶;滑石粉;固体润滑剂,例如硬脂酸,硬脂酸镁;硫酸钙;植物油,例如花生油,棉籽油,芝麻油,橄榄油,玉米油和可可油;多元醇,例如丙二醇,甘油,山梨醇,甘露醇和聚乙二醇;藻酸;乳化剂,例如Tween;湿润剂,例如十二烷基硫酸钠;着色剂;调味剂;赋形剂;成片剂;稳定剂;抗氧化剂;保存剂;无热原水;等渗盐和磷酸盐缓冲液。
选择与某化合物合用的药学上认可的载体主要取决于化合物的给药方式。本发明化合物可以全身性给予。给药途径包括透皮;口服;肠胃外,包括皮下或静脉注射;局部和/或鼻给药。
化合物的适当使用量由常规动物模型实验确定。此类模型包括但不限于健全或去卵巢大鼠模型,犹獾,狗和非人灵长动物模型,以及废用模型。
注射的优选单位剂型包括与水,生理盐水或其混合物形成的无菌溶液。所述溶液的pH调节至7.4。适合注射或手术植入的载体包括水凝胶,控释或缓释装置,聚乳酸和胶原母质。
适合局部的药学上认可的载体包括适用于液剂,霜剂和凝胶等的那些。如果化合物经口腔给予,适宜的单位剂型是片剂,胶囊等。适合制备口服单位剂型的药学上认可的载体是本领域众所周知的。其选择取决于口味,成本和保存期等对本发明目的来说不重要的次要因素,本领域熟练技术人员不难作出此类决定。使用方法
本发明化合物可用于治疗多种疾病,包括例如眼病,高血压,生育控制,鼻充血,神经性膀胱病,肠胃病,皮肤病和骨质疏松。
本发明化合物能够通过形成新的骨小梁增加骨容量和骨小梁数量,增加骨量的同时维持正常的骨转化率,以及在骨内膜表面形成新骨的同时不减少已有皮层内的骨。所以,这些化合物可用来治疗和防止骨病。
治疗骨病的优选给药途径是透皮和经鼻。其它优选给药途径还包括直肠,舌下和口服。
全身给药的剂量范围是每天约0.01至1000μg/kg体重,以每天约0.1至100μg/kg体重为佳,约每天1至50μg/kg体重为最好。根据药物动力学和透皮制剂领域的已知技术,透皮剂量应达到相近的血清或血浆水平。全身给药的血浆水平希望是0.01至100ng/ml,以0.05至50ng/ml为佳,0.1至10ng/ml最好。虽然以上是日用剂量,但也可用周或月累积剂量来估算临床要求。
为了获得理想的效果,剂量可根据患者,病情,病情严重程度,给药途径等而改变。
本发明化合物还可用于降低眼压。所以,这些化合物可用于治疗青光眼。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是本发明的说明。以下组合物和方法实施例不限定本发明的范围,仅为本领域技术人员制备和使用本发明化合物、组合物和方法提供指导。给药实施例中,实施例例举的化合物都可用本发明的其它化合物代替而获得相同的效果。本领域技术人员将发现,实施例提供的是指导,可根据具体的病情和患者加以改变。
实施例A
用常规方法,例如混合和直接压片,制备片剂形式药物组合物,其配方如下:
成分 量(mg/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
当每日口服一次时,以上组合物明显增加骨质疏松患者的骨容量。
实施例B
用常规方法制备药物组合物液剂,其配方如下:
成分 量
实施例1化合物 5mg
磷酸盐缓冲的生理盐水 10ml
对羟苯甲酸甲酯 0.05ml
当每日皮下给予1.0ml以上组合物一次时,骨质疏松患者的骨容量明显增加。
实施例C
用常规方法制备局部使用的降低眼压的药物组合物,其配方如下:
成分 量(wt%)
实施例38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(乙二胺四乙酸二钠) 0.05
苯扎氯铵 0.01
HCl和/或NaOH pH7.2-7.5
纯水 加至100%
虽然描述了本发明的特定实施方式,但对本领域熟练技术人员显而易见的是,在本发明精神和范围内可对组合物进行多种改变。所有此类修改都应在后文权利要求所界定的本发明范围之内。
Claims (10)
(a)R1是CO2H,C(O)NHOH,CO2R5,CH2OH,S(O)2R5,C(O)NHR5,C(O)NHS(O)2R5,或四唑;R5是烃基,杂烃基,脂族碳环,脂族杂环,芳环或杂芳环;
(b)R2是H或低级烃基;
(c)X是NR6R7,OR8,SR9,S(O)R9,S(O)2R9或F;R6,R7和R8各自选自H,酰基,烃基,杂烃基,脂族碳环,脂族杂环,芳环和杂芳环;R9是烃基,杂烃基,脂族碳环,脂族杂环,芳环或杂芳环;
(d)R3和R4各自选自H,CH3,C2H5;OR10,SR10或OH,R3和R4不能都是OH;R10是烃基,杂烃基,脂族碳环,脂族杂环,芳环或杂芳环,R10具有1至8个成环原子;
(e)Y是(CH2)n;n是1至3的整数;
(f)当n是0,2或3时,Z是脂族碳环,脂族杂环,单环杂芳环或取代的苯基;当n是1时,Z是脂族碳环,脂族杂环或取代的苯基。
2.根据权利要求1所述的化合物,其中R1选自CO2H,C(O)NHOH,CO2CH3和CO2C3H5。
3.根据权利要求2所述的化合物,其中R2是H或CH3。
4.根据权利要求3所述的化合物,其中X是OH。
5.根据权利要求1,2,3或4所述的化合物,其特征在于n是0,2或3,Z是取代的苯基或杂芳环。
6.根据权利要求5所述的化合物,其特征在于Z是取代的苯基或取代或非取代噻吩基。
7.根据权利要求6所述的化合物,其特征在于n是2。
8.根据权利要求1,2,3或4所述的化合物,其特征在于n是1,Z是取代的苯基,所述取代基各自选自卤素,烃基,卤代烃基,氰基,硝基,烷氧基,苯基和苯氧基。
9.根据前述权利要求中任一项所述的化合物的用途,它被用于制造治疗人或其他哺乳动物骨病的药物。
10.根据权利要求9所述的用途,所述的骨病是骨质疏松症。
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EP (1) | EP1021402B1 (zh) |
JP (1) | JP2001515883A (zh) |
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Cited By (2)
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CN104140410A (zh) * | 2013-05-09 | 2014-11-12 | 江苏豪森药业股份有限公司 | 鲁比前列酮的制备方法 |
CN104140410B (zh) * | 2013-05-09 | 2017-12-15 | 江苏豪森药业集团有限公司 | 鲁比前列酮的制备方法 |
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HUP0004436A2 (hu) | 2001-05-28 |
DE69832513D1 (de) | 2005-12-29 |
AR017077A1 (es) | 2001-08-22 |
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AU741014B2 (en) | 2001-11-22 |
EP1021402B1 (en) | 2005-11-23 |
CA2303763A1 (en) | 1999-03-18 |
NZ503736A (en) | 2002-06-28 |
NO20001142D0 (no) | 2000-03-06 |
JP2001515883A (ja) | 2001-09-25 |
CO4970730A1 (es) | 2000-11-07 |
HUP0004436A3 (en) | 2001-09-28 |
EP1021402A1 (en) | 2000-07-26 |
ZA988231B (en) | 1999-03-09 |
ATE310721T1 (de) | 2005-12-15 |
ES2253826T3 (es) | 2006-06-01 |
NO20001142L (no) | 2000-05-04 |
TR200000670T2 (tr) | 2000-11-21 |
IL134792A0 (en) | 2001-04-30 |
AU9219498A (en) | 1999-03-29 |
US6107338A (en) | 2000-08-22 |
SK3362000A3 (en) | 2000-10-09 |
KR20010023837A (ko) | 2001-03-26 |
PL339213A1 (en) | 2000-12-04 |
WO1999012896A1 (en) | 1999-03-18 |
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