CN1269786A - 用作fp激活剂的芳香族c16-c20-取代四氢前列腺素 - Google Patents
用作fp激活剂的芳香族c16-c20-取代四氢前列腺素 Download PDFInfo
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- CN1269786A CN1269786A CN98808990A CN98808990A CN1269786A CN 1269786 A CN1269786 A CN 1269786A CN 98808990 A CN98808990 A CN 98808990A CN 98808990 A CN98808990 A CN 98808990A CN 1269786 A CN1269786 A CN 1269786A
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- Prior art keywords
- alkyl
- prostaglandin
- aromatic ring
- compound
- dihydro
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- 125000003118 aryl group Chemical group 0.000 title claims description 24
- 150000003180 prostaglandins Chemical class 0.000 title description 24
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 12
- 239000000556 agonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 208000020084 Bone disease Diseases 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 10
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- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- 150000003949 imides Chemical class 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000001931 aliphatic group Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 31
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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 abstract 1
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
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- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
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- 238000012360 testing method Methods 0.000 description 8
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- FAHUKNBUIVOJJR-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine Chemical compound C1=CC(F)=CC=C1C1C2=CC=CN2CCN1 FAHUKNBUIVOJJR-UHFFFAOYSA-N 0.000 description 7
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
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- 239000004593 Epoxy Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 229960001866 silicon dioxide Drugs 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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- 238000002425 crystallisation Methods 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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- 239000002243 precursor Substances 0.000 description 4
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 238000000935 solvent evaporation Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
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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
-
- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种新的PGF类似物。具体地说,本发明涉及具有通式(A)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
本发明涉及天然前列腺素新的类似物。具体地说,本发明涉及新的前列腺素F类似物。本发明还涉及新的前列腺素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
天然前列腺素(PGA,PGB,PGE,PGF和PGI)是C-20不饱和脂肪酸。PGF2α,是天然人前列腺素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前列腺素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,“治疗用前列腺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-18,19,20-三去甲前列腺素的合成:1.PG1系列”
prostaglandin,Vol.9,No.1(1975),pp.1-4;W.Bartman,G.Beck,U.Lerch,H.Teufel和B.Scholkens,“溶黄体性前列腺素: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-18,19,20-三去甲前列腺素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,天然前列腺素具有广泛的药理活性。例如,已知前列腺素能够: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。虽然天然前列腺素是用它们对某一特定前列腺素受体的活性来描述的,但是它们一般不具有对任何一个前列腺素受体的特异性。所以,已知全身性使用天然前列腺素会引起炎症和皮表刺激等副作用。一般认为,天然前列腺素体内释放后被迅速代谢限制了前列腺素的某些局部作用。这严重影响了前列腺素激活整个体内的前列腺素受体和全身性使用天然前列腺素的效果。
已知,前列腺素,特别是E系列前列腺素(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。
考虑到天然前列腺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前列腺素的类似物。本领域已经公开了许多此类类似物。虽然已经公开了大量前列腺素类似物,但人们仍然需要强效选择性前列腺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卤素,羟基,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),杂环和杂芳基。
“芳环”是芳烃环系统。芳环是单环或稠二环系统。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,螺环或桥环双环系统。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:卤素,羟基,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,杂芳环。例如,杂烃基是被以下取代基取代的烃基: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),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系统。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个杂原子的芳环系统。杂芳环是单环或稠二环系统。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
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,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或S(O)2R9;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。
以上结构中,R3和R4各自选自H,CH3和C2H5。较好的R3和R4是H。
以上结构中,Y是NR10,S,S(O)或S(O)2;R10是H,酰基,烃基,杂烃基,脂族碳环,脂族杂环,芳环和杂芳环。较好的R10是H和CH3。较好的Y是NH和S。
以上结构中,Z是脂族碳环,脂族杂环,芳环和杂芳环。较好的Z是单环脂族碳环,单环脂族杂环,单环芳环和单环杂芳环。更好的Z是单环芳环或单环杂芳环。最好的Z是噻吩基或苯基。
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-18,19,20-三去甲前列腺素F2α异丙酯衍生物:潜在抗青光眼药”,
Jorunal 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7-[3-(R)-羟基-5-氧-1-环戊-1-基]庚酸甲酯(S1a)是市售商品(例如SumitomoChemical或Cayman Chemical的产品)。
以上方案1中,7[3-(R)-羟基-5-氧-1-环戊-1-基]庚酸甲酯(S1a)在允许甲硅烷基化进行的溶剂中与甲硅烷基化剂和碱反应。较好的甲硅烷基化剂包括叔丁基二甲基甲硅烷基氯和叔丁基二甲基甲硅烷基三氟甲基磺酸酯。最好的甲硅烷基化剂是叔丁基二甲基甲硅烷基三氟甲基磺酸酯。较好的碱包括三乙胺,三甲胺和2,6-二甲基吡啶。更好的碱是三乙胺和2,6-二甲基吡啶。碱最好是2,6-二甲基吡啶。较好的溶剂包括卤烃溶剂,其中最好的是二氯甲烷。反应宜在-100℃-100℃之间的温度进行,-80℃-80℃更好,最好是-70℃-23℃。
所得的甲硅烷基化化合物用本领域一般技术人员已知的方法来分离。此类方法包括但不限于:萃取,溶剂蒸发,蒸馏和结晶。较好的是在真空蒸馏分离后进行甲硅烷基醚的纯化。
然后,甲硅烷基化化合物与铜酸盐反应,该铜酸盐是通过合适的溴烯烃形成Grignard试剂而产生的,参见例如:H.O.House等,“碳负离子化学:用于生成有机铜酸锂的方便前体”,
J.Org.Chem.Vol.40(1975),pp.1460-69;和P.Knochel等,“作为有效和选择性a’/d’多重偶合剂的锌和铜的卡宾体”,
J.Amer.Chem. Soc.,Vol.111(1989),p.6474-76。较好的溴烯烃包括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。较好的溶剂包括醚类溶剂,其中以二乙醚和四氢呋喃为佳。溶剂最好是四氢呋喃。Grignard试剂可在100℃至23℃之间的某温度形成,85℃至30℃之间更好,最好是75℃至65℃之间。反应时间以1小时至6小时为佳,2小时至5小时更好,最好的是3小时和4小时。
Grignard试剂一旦形成,则由烯烃镁生成铜酸盐。形成铜酸盐的温度范围在-100℃至0℃之间。较好的温度范围是-80℃至-20℃。更好的是-75℃至-50℃。反应时间以30分钟至6小时为宜。更好的是45分钟至3小时。最好的是1小时至1.5小时。
S1b化合物用本领域已知技术来分离。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,用10%EtOAc/己烷作为洗脱剂进行快速硅胶(Merck,230-400目)层析来纯化S1b。
然后,S1b与氢化物还原剂和极性质子溶剂反应形成C9醇。较好的还原剂包括氢化铝锂,硼氢化钠和L-selectride。更好的还原剂是硼氢化钠和L-selectride。最好是硼氢化钠。较好的溶剂包括甲醇,乙醇和丁醇。最好是甲醇。还原反应在-100℃至23℃进行。-60℃至0℃更好。最好的温度范围是-45℃至-20℃。
所得的S1b的醇用本领域一般技术人员已知的方法来分离。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,用20%EtOAc/己烷作为洗脱剂进行快速硅胶(Merck,230-400目)层析来纯化醇。
可如前文所述对醇加以保护。然后,加或不加保护的醇在卤烃溶剂中与间-氯过苯甲酸反应,生成新的环氧中间体S1c。较好的卤烃溶剂有二氯甲烷,二氯乙烷和氯仿。较好的是二氯甲烷和二氯乙烷。最好的是二氯甲烷。
用本领域一般技术人员已知的方法分离化合物S1c。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,用20%EtOAc/己烷作为洗脱剂进行快速硅胶(Merck,230-400目)层析来纯化S1c。
环氧中间体S1c可与含有氧,硫和氮的多种亲核试剂反应,参见例如J.G.Smith,“用于合成的环氧试剂”,
Synthesis,(1984),p.629-656,得到通式I即C11被保护的13,14-二氢-15-取代-16-四去甲前列腺素F1α衍生物。
就含硫亲核试剂而言,反应宜在150℃至0℃之间进行,120℃至20℃之间更好,最好是80℃至50℃之间。反应用较好的碱有三乙胺,N,N-二异丙基乙胺和三甲胺。碱最好是三乙胺。反应用较好的溶剂是芳烃溶剂,较好的包括二甲苯,甲苯和苯。最好的溶剂是苯。就氮和氧亲核试剂而言,较好的溶剂包括醚类溶剂和极性质子溶剂。更好的醚类溶剂包括二乙醚,二丁基醚和四氢呋喃。最好的醚类溶剂是四氢呋喃。更好的极性质子溶剂包括乙醇,甲醇和叔丁醇。最好的极性质子溶剂是乙醇。
可用Lewis酸来催化氮和氧亲核试剂的开环反应。较好的Lewis酸包括高氯酸镁,三甲基甲硅烷基三氟甲烷磺酸酯和三甲基铝。其中最好的是高氯酸镁。反应在150℃和23℃之间的温度进行,125℃和40℃之间的更好,100℃和75℃之间的还要好。
可分离所得的化合物,但通常用本领域一般技术人员已知的方法去保护,然后分离得到最后的13,14-二氢-15-取代-16-四去甲前列腺素F1α衍生物。实施例2-28例举了由通式I表示的化合物。
由通式I表示的化合物,用本领域一般技术人员已知的方法,可直接制得通式II表示的化合物。例如,通式I的甲酯与胺或羟胺缩合得到通式II化合物。实施例29-32例举了由通式II表示的化合物。
由通式I表示的化合物,用本领域一般技术人员已知的方法,可直接制得通式III表示的化合物。按照以下文献中的方法,适当保护的通式I衍生物被氧化成酮:A.McKillop和D.W.Young,“使用支持剂的有机合成-第一部分”,Synthesis(1979),p.401-22;G.Piancatelli等,“氯铬酸吡啶鎓:多能氧化有机合成”,Synthesis(1982),p.245-58;E.J.Corey和J.W.Suggs,“氯铬酸吡啶鎓:将伯醇和仲醇氧化成羰基化合物的有效试剂”,
Tetrahedron Lett.,Vol.31(1975),p.2647-50。酮然后与N-甲胺缩合得到亚胺。加入甲基铈亲核试剂(约1.5当量)(参见T.Imamoto等,“用金属铈或有机铈(III)试剂的碳-碳键形成反应”,
J.Org.Chem.,Vol.49(1984),p.3904-12;T.Imamoto等,“羰基化合物与Grignard反应试剂在氯化铈存在下的反应”,
J.Am.Chem.Soc.,Vol.111(1989),p.4392-98)得到通式III的氨基甲基衍生物。实施例39-42例举了通式III表示的化合物。
通过活化,然后亲核取代适当官能化的羟基,可由通式I化合物制得通式IV和V化合物。此类转化参见:E.J.Corey等,“形成9-表-前列腺素F2α的简单的立体特异性途径”,
J.C.S.Chem.Comm.(1975),p.658-9;E.J.Corey等,“用于合成的氧亲核试剂的超氧化物离子”
Tetrahedron Lett.,(1975),p.3183-6;E.J.Corey等,“5-脱氧白三烯D的总合成方法。4-甲酰-反,反-1,3-丁二烯阴离子的新且有用的对等物”,
Tetrahedron Lett.,Vol.23(1982),p.3463-66。实施例33-36例举了通式V表示的化合物。
通过以下文献中的选择性氧化可由通式V化合物(X是SR9)制得通式VI表示的化合物:E.J.Corey等,“白三烯S肽单位的迁移和降解路径”,
Tetrahedron Lett.,Vol.23(1982),p.3467-70;
Prostaglandins Vol.24(1982),p.801;Y.Girad等,“白三烯C4,D4和E4的砜的合成”,
Tetrahedron Lett.,Vol.23(1982),p.1023-26。实施例37-38例举了通式VI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溶液或溶于10%H2SO4水溶液的钼酸铵/硫酸高铈(cerric)显色。
实施例1
13,14-二氢-16-(3-氟苯基硫)四去甲前列腺素F1α(1i)和13,14-二氢-15-甲基-16-(3-氟苯基硫)四去甲前列腺素F1α(1j)的制备:a.7-(2-氧-4-(1,1,2,2-四甲基-1-硅丙氧基)环戊-1-烯基)庚酸甲酯:在-78℃的7-[3-(R)-羟基-5-氧-1-环戊烯-1-基)庚酸甲酯(1a)(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)。将溶液保持在-78℃,用15分钟滴加TBDMS三氟甲基磺酸酯(1.2当量)的CH2Cl2溶液。将反应缓慢温热至室温,室温下搅拌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),浓缩。真空(10mmHg)蒸馏残留物,得到甲硅烷基醚1b黄色液体。b.7-(5-丁-3-烯基-2-羟基-4-(1,1,2,2-四甲基-1-硅丙氧基)环戊基)庚酸甲酯1c,1d:室温下在MgO粉(2当量)THF浆中加入1颗I2晶体,并用10分钟滴加1-溴丁烯(2当量)。反应随滴加而放热。滴加完毕后,反应回流3小时,然后冷却至室温。用THF稀释Grignard试剂,在-78℃通过套管加入配有机械搅拌并装有CuBr.DMS(2当量)的THF/DMS1∶1溶液的三颈烧瓶。加完Grignard试剂(约20分钟)后,反应在-78℃搅拌1小时。此时,反应的颜色是深红色。然后用25分钟滴加酮1b(1当量)的THF溶液。反应在-78℃搅拌15分钟,2小时后缓慢升温至室温。用NH4Cl水溶液终止反应,任过量DMS蒸发通宵。将反应分配在盐水/CH2Cl2之间,分层。水层用CH2Cl2反萃取,合并并干燥(Na2SO4)有机层。真空去除溶剂,残留物经SiO2层析(10%己烷/EtOAc)生成1c的酮前体,呈澄清的油状。以同样方法制备1d的酮前体。
将1c的酮前体(1当量)溶于MeOH,冷却至-40℃。在10分钟内分批加入硼氢化钠(0.9当量)。加完后,反应在-40℃搅拌13小时,然后在-78℃搅拌12小时。用水终止反应,分配在盐水/CH2Cl2之间,分离各层。水层用CH2Cl2反萃取,合并并干燥(Na2SO4)有机层。真空去除溶剂,残留物经SiO2层析(30%EtOAc/己烷)生成醇1c,呈无色油状。以同样方法制备醇1d。c.7-(2-羟基-5-(2-(2-环氧乙基)乙基-4-(1,1,2,2-四甲基-1-硅丙氧基)环戊基)庚酸甲酯1e,1f:将醇1c(1当量)溶于CH2Cl2并冷却至0℃。加入碳酸氢钠,然后15分钟内分批加入m-CPBA(57%-85%纯)(3当量)。加完后,反应在室温下搅拌20小时。将反应倒入水中,分配在盐水/CH2Cl2之间,分离各层。水层用CH2Cl2反萃取,合并并干燥(Na2SO4)有机层。真空去除溶剂,残留物经SiO2层析(20%EtOAc/己烷)生成环氧非对映体1e,呈无色油状。以同样方法合成化合物1f。d.13,14-二氢-16-(3-氟苯基硫)四去甲前列腺素F1α甲酯(1g)和13,14-二氢-15-甲基-16-(3-氟苯基硫)四去甲前列腺素F1α甲酯(1h):在5ml圆底烧瓶中加入环氧化物1e(1当量)和100μl无水苯。将烧瓶冷却至0℃,然后与60μl3-氟苯硫酚(1.2当量)和78μl三乙胺(1.2当量)反应,参见J.G.Smith,“用于合成的环氧试剂”,Synthesis,(1984),p.629-656。去除冰浴,反应在室温下氮气氛下搅拌通宵。用TLC跟踪反应。如有必要可加入过量的苯硫酚。用盐水终止反应,用二氯甲烷萃取。有机层用1N HCl,盐水洗涤3次,用硫酸钠干燥,浓缩。不对该粗反应混合物进一步纯化,加入3ml CH3CN和0.1ml HF/吡啶(0.1mmol),同时将烧瓶保持在0℃。0℃反应3小时后,用饱和NaCl终止反应。水层以CH2Cl2萃取3次。合并有机层,用1N HCl,盐水洗涤3次,干燥(Na2SO4)。柱层析(7∶3己烷∶乙酸乙酯)后得到1g澄清的油。以相同的方法制备酯1h。e.13,14-二氢-16-(3-氟苯基硫)四去甲前列腺素F1α(1i)和13,14-二氢-15-甲基-16-(3-氟苯基硫)四去甲前列腺素F1α(1j):在5ml圆底烧瓶中加入50mg(0.12mmol)13,14-二氢-16-(3-氟苯基硫)四去甲前列腺素F1α甲酯(1g)和4mlTHF水溶液(3∶1,THF/水),将烧瓶冷却至0℃。加入过量(2.5当量)氢氧化锂,去除冰浴,反应在室温下搅拌通宵。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,层析(二氯甲烷,甲醇,乙酸,9.6,0.4,0.015)残留物,得到30mg澄清的油1i。以相同方法制备酸1j。
使用实施例1的方法(并使用相应的苯硫酚),得到以下实施例2-23的化合物。
实施例2
实施例3
13,14-二氢-16-(3-甲基苯基硫)四去甲前列腺素F1α甲酯:
实施例4
13,14-二氢-16-(3-三氟甲基苯基硫)四去甲前列腺素F1α甲酯:
实施例513,14-二氢-16-(2,3,5,6-四氟苯基硫)四去甲前列腺素F1α甲酯:
实施例813,14-二氢-16-(2-氟苯基硫)四去甲前列腺素F1α甲酯:
实施例1113,14-二氢-16-(2-噻吩基硫)四去甲前列腺素F1α甲酯:
实施例1213,14-二氢-16-(苯基硫)四去甲前列腺素F1α:
实施例1313,14-二氢-16-(3-甲基苯基硫)四去甲前列腺素F1α:
实施例1613,14-二氢-15-甲基-16-(2-甲基苯基硫)四去甲前列腺素F1α:
实施例1713,14-二氢-16-(4-甲基苯基硫)四去甲前列腺素F1α:
实施例1813,14-二氢-16-(1-萘基硫)四去甲前列腺素F1α:
实施例21
实施例22
实施例23
13,14-二氢-16-(3-氟苯基磺酰基)四去甲前列腺素F1α:
在13,14-二氢-16-(3-氟苯基硫)四去甲前列腺素F1α(1当量)的CH3Cl溶液中-78℃滴加过乙酸(2当量)。溶液在-78℃保持1小时,然后任其升温至0℃,并在0℃保持1小时。加入饱和NaCl,分离各层。用CH2Cl2萃取水层,合并有机层。有机层用盐水洗涤,干燥(Na2SO4)和浓缩。残留物经SiO2层析(96CH2Cl2,4MeOH,0.1乙酸)得到13,14-二氢-16-(3-氟苯基磺酰基)四去甲前列腺素F1α,呈澄清的油状。
实施例24
在10ml圆底烧瓶中加入环氧化物1e(1.26mmol),间甲苯胺(1.5当量),10mg高氯酸镁和2ml THF,反应在氮气下回流通宵。将烧瓶冷却至室温,真空去除溶剂。不再纯化,在此粗反应混合物中加入3ml CH3CN和0.5ml HF/吡啶(0.5mmol,0.6当量),同时保持烧瓶为0℃。0℃保持5小时后,用饱和NaCl终止反应。水层用CH2Cl2萃取3次。合并有机层,用饱和NaHCO3,盐水洗涤3次,干燥(Na2SO4)。柱层析(95%CH2Cl2,5%MeOH)后,得到澄清油状13,14-二氢-16-(3-甲基苯基氨基)四去甲前列腺素F1α甲酯。
实施例25
13,14-二氢-16-(3-甲基苯基氨基)四去甲前列腺素F1α的制备:
在5ml圆底烧瓶中加入13,14-二氢-16-(3-甲基苯基氨基)四去甲前列腺素F1α甲酯(0.15mmol)和4ml THF水溶液(3∶1的THF∶H2O)。将烧瓶冷却至0℃,加入过量氢氧化锂(2.5当量)。去除冰浴,反应在室温下搅拌通宵。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,盐水洗涤,干燥(Na2SO4),浓缩,层析(二氯甲烷,甲醇,乙酸,9.6,0.4,0.015),得到澄清油状13,14-二氢-16-(3-甲基苯基氨基)四去甲前列腺素F1α。
用相应的苯胺,实施例24和25的方法,得到实施例26-28的化合物。
实施例26
实施例27
实施例28
实施例29
在经火焰干燥的配有磁性搅拌棒的25ml圆底烧瓶中加入13,14-二氢-16-(3-三氟甲基苯基硫)四去甲前列腺素F1α甲酯(实施例4)(1.0当量)的甲醇溶液。在此溶液中加入羟胺的甲醇溶液(1.25当量)。该溶液搅拌18小时。溶液然后与1N盐酸反应,用乙酸乙酯萃取。有机层用盐水洗涤,用无水MgSO4干燥,过滤,低压浓缩。层析纯化残留物,得到13,14-二氢-16-(3-三氟甲基苯基硫)四去甲前列腺素F1α1-异羟肟酸。
用实施例29的方法(使用相应的羟胺或磺酰胺),得到了实施例30-32的化合物。
实施例30
实施例31
实施例32
实施例33
实施例1合成的相应的双甲硅烷基化化合物与甲烷磺酰氯(1.2当量)和碱(1.2当量)反应生成甲磺酸酯中间体(参见:E.J.Corey等,“得到9-表-前列腺素F2α的简便立体特异性路径”,
J.C.S.Chem Comm.(1975),p.658-9;E.J.Corey等,“作为合成用氧亲核试剂的超氧化物离子”,
Tetrahedron Lett.(1975)p.3183-6),该中间体立即与亲核试剂(甲硫醇钠)反应(参见:E.J.Corey等,“5-脱氧白三烯D的全合成。一种新的4-甲酰基-反,反-1,3-丁二烯阴离子的有用的对等物”,Tetrahedron Lett.Vol.23(1982)p.3463-66),如实施例1所述去保护后生成13,14-二氢-15-甲基硫-15-去羟基-16-(N-甲基苯基氨基)四去甲前列腺素F1α。
使用实施例33所述的方法(用合适的通式IV的衍生物)制备实施例34-36化合物。本领域技术人员可适当改变温度,压力,气体氛围,溶剂或反应顺序。此外,技术人员还可以适当使用保护基来抑制副反应和提高得率。所有这些修改对有机化学领域的技术人员来说是很简单的,所以属于本发明范围之内。
实施例34
实施例35
实施例36
实施例37
甲酯与合适的氧化剂反应,参见以下文献:E.J.Corey等,“5-脱氧白三烯D的全合成。一种新的4-甲酰基-反,反-1,3-丁二烯阴离子的有用的对等物”,Tetrahedron Lett.Vol.23(1982)p.3463-66;
Prostaglandins Vol.24(1982)p.801;Y.Girard等,“白三烯C4,D4和E4的砜的合成”,
Tetrahedron Lett.Vol.23(1982)p.1023-26,或者参见实施例23。
用实施例37的方法(用合适的通式V的衍生物)制备实施例38。本领域技术人员可适当改变温度,压力,气体氛围,溶剂或反应顺序。此外,技术人员还可以适当使用保护基来抑制副反应和提高得率。所有这些修改对有机化学领域的技术人员来说是很简单的,所以属于本发明范围之内。
实施例38
实施例39
将适当保护的实施例8的衍生物氧化成酮(参见:A.McKillop和D.W.Young,“使用支持剂的有机合成-第一部分”,
Synthesis(1979),p.401-22;E.J.Corey和J.W.Suggs,“氯铬酸吡啶鎓:将伯醇和仲醇氧化成羰基化合物的有效试剂”,Tetrahedron Lett.,Vol.31(1975),p.2647-50),然后与N-甲胺缩合得到亚胺。加入甲基铈亲核试剂(约1.5当量)(有关氯化铈介导的亲核加成参见:T.Imamoto等,利用金属铈或有机铈(III)试剂的碳-碳键形成反应”,
J.Org.Chem.,Vol.49(1984),p.3904-12;T.Imamoto等,“羰基化合物与Grignard试剂在氯化铈存在下的反应”,J.Am.Chem.Soc.,Vol.111(1989),p.4392-98)得到氨基甲基衍生物,然后该衍生物如实施例1所述转化为13,14-二氢-15-甲基-15-氨基甲基-16-(2-氟苯基硫)四去甲前列腺素F1α。
用实施例39的方法(用合适的通式I的衍生物)制备实施例40-42。本领域技术人员可适当改变温度,压力,气体氛围,溶剂或反应顺序。此外,技术人员还可以适当使用保护基来抑制副反应和提高得率。所有这些修改对有机化学领域的技术人员来说是很简单的,所以属于本发明范围之内。
实施例40
实施例41
实施例42
13,14-二氢-15-乙炔基-15-氨基甲基-16-(4-甲基苯基硫)四去甲前列腺素F1α异丙酯组合物
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20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20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42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 (9)
(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或S(O)2R9;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;
(d)R3和R4各自选自H,CH3和C2H5;
(e)Y是NR10,S,S(O)或S(O)2;R10是H,酰基,烃基,杂烃基,脂族碳环,脂族杂环,芳环和杂芳环;
(f)Z是脂族碳环,脂族杂环,芳环和杂芳环。
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CO2C3H7。
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,Y是NH或S。
5.根据权利要求4所述的化合物,其中Z是噻吩基或苯基。
6.根据前述权利要求中任一项所述的化合物,其特征在于Z被取代,所述的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。
7.根据前述权利要求中任一项所述的化合物,其特征在于Z被取代,所述的取代基是卤素或烃基。
8.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。
9.根据权利要求8所述的用途,所述的骨病是骨质疏松症。
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US5741810A (en) * | 1996-02-29 | 1998-04-21 | Allergan | Cyclopentane heptan(ene)oic acid, 2- heteroarylalkenyl derivatives as therapeutic agents |
US6242485B1 (en) * | 1996-06-10 | 2001-06-05 | R-Tech Ueno | Endothelin antagonist |
EP0930296B2 (en) * | 1996-09-17 | 2005-11-02 | Asahi Glass Company Ltd. | Fluorinated prostaglandin derivatives and medicines |
WO1998020880A2 (en) * | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc. | 11-halo prostaglandins for the treatment of glaucoma or ocular hypertension |
US6353014B1 (en) * | 1996-11-12 | 2002-03-05 | Alcon Laboratories, Inc. | 15-ketal postaglandins for the treatment of glaucoma or ocular hypertension |
EP1007028A4 (en) * | 1997-05-09 | 2002-06-05 | TREATING GLAUCOMA WITH 8 ISO PROSTAGLANDINE |
-
1998
- 1998-09-04 DE DE69824966T patent/DE69824966T2/de not_active Expired - Lifetime
- 1998-09-04 CN CN98808990A patent/CN1269786A/zh active Pending
- 1998-09-04 HU HU0100638A patent/HUP0100638A3/hu unknown
- 1998-09-04 AU AU92193/98A patent/AU731153B2/en not_active Expired
- 1998-09-04 TR TR2000/00671T patent/TR200000671T2/xx unknown
- 1998-09-04 CA CA002303764A patent/CA2303764C/en not_active Expired - Lifetime
- 1998-09-04 US US09/148,006 patent/US5977173A/en not_active Expired - Lifetime
- 1998-09-04 BR BR9811774-2A patent/BR9811774A/pt not_active IP Right Cessation
- 1998-09-04 AT AT98944719T patent/ATE270660T1/de not_active IP Right Cessation
- 1998-09-04 ES ES98944719T patent/ES2223141T3/es not_active Expired - Lifetime
- 1998-09-04 IL IL13483998A patent/IL134839A0/xx unknown
- 1998-09-04 EP EP98944719A patent/EP1012136B1/en not_active Expired - Lifetime
- 1998-09-04 WO PCT/US1998/018339 patent/WO1999012895A1/en not_active Application Discontinuation
- 1998-09-04 NZ NZ503735A patent/NZ503735A/en unknown
- 1998-09-04 ID IDW20000639A patent/ID23971A/id unknown
- 1998-09-04 JP JP2000510707A patent/JP2001515882A/ja not_active Withdrawn
- 1998-09-04 PL PL98339212A patent/PL339212A1/xx unknown
- 1998-09-04 KR KR1020007002515A patent/KR20010023839A/ko not_active Application Discontinuation
- 1998-09-04 SK SK337-2000A patent/SK3372000A3/sk unknown
- 1998-09-08 PE PE1998000843A patent/PE115499A1/es not_active Application Discontinuation
- 1998-09-08 AR ARP980104479A patent/AR013477A1/es unknown
- 1998-09-09 ZA ZA988230A patent/ZA988230B/xx unknown
- 1998-09-09 CO CO98051818A patent/CO4970731A1/es unknown
-
2000
- 2000-03-06 NO NO20001141A patent/NO20001141L/no unknown
Also Published As
Publication number | Publication date |
---|---|
BR9811774A (pt) | 2000-08-29 |
SK3372000A3 (en) | 2000-10-09 |
CO4970731A1 (es) | 2000-11-07 |
NO20001141D0 (no) | 2000-03-06 |
WO1999012895A1 (en) | 1999-03-18 |
DE69824966D1 (de) | 2004-08-12 |
ATE270660T1 (de) | 2004-07-15 |
CA2303764A1 (en) | 1999-03-18 |
AU9219398A (en) | 1999-03-29 |
ES2223141T3 (es) | 2005-02-16 |
IL134839A0 (en) | 2001-05-20 |
HUP0100638A3 (en) | 2002-12-28 |
EP1012136A1 (en) | 2000-06-28 |
AR013477A1 (es) | 2000-12-27 |
ID23971A (id) | 2000-06-14 |
KR20010023839A (ko) | 2001-03-26 |
CA2303764C (en) | 2005-02-15 |
PE115499A1 (es) | 2000-02-03 |
ZA988230B (en) | 1999-03-09 |
NZ503735A (en) | 2001-05-25 |
PL339212A1 (en) | 2000-12-04 |
AU731153B2 (en) | 2001-03-22 |
HUP0100638A2 (hu) | 2001-07-30 |
TR200000671T2 (tr) | 2000-07-21 |
JP2001515882A (ja) | 2001-09-25 |
NO20001141L (no) | 2000-05-04 |
US5977173A (en) | 1999-11-02 |
DE69824966T2 (de) | 2005-04-07 |
EP1012136B1 (en) | 2004-07-07 |
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