CN1336367A - 巯基酮和巯基醇以及它们的制备方法 - Google Patents
巯基酮和巯基醇以及它们的制备方法 Download PDFInfo
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- CN1336367A CN1336367A CN01117103A CN01117103A CN1336367A CN 1336367 A CN1336367 A CN 1336367A CN 01117103 A CN01117103 A CN 01117103A CN 01117103 A CN01117103 A CN 01117103A CN 1336367 A CN1336367 A CN 1336367A
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- aryl
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- hydroxyl
- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 57
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- 150000001875 compounds Chemical class 0.000 claims abstract description 55
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 46
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical group 0.000 claims abstract description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 12
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 11
- 150000002825 nitriles Chemical group 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 9
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- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 32
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- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims 1
- JWIPGAFCGUDKEY-UHFFFAOYSA-L O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Cl)(=O)=O.C1=CC=NC=C1 JWIPGAFCGUDKEY-UHFFFAOYSA-L 0.000 claims 1
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
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- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (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)
- General Health & Medical Sciences (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
- Fats And Perfumes (AREA)
- Steroid Compounds (AREA)
- Furan Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明涉及右式的基质金属蛋白酶(MMP)抑制剂化合物,其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代,C1-C6烷基硫代、芳基、-O芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基。R2是α-OH或β-OH,R6为H或R2和R6一起形成羰基;化学中间体;以及制备这些化合物和其中间体的方法。在具有羟基的碳为S构型的巯基醇已被发现在体外和体内抑制MMP酶方面比类似物(R)-醇至少有效4倍。
Description
本申请是申请号为97117406.7的专利申请的分案申请。
发明领域
本发明涉及可用作基质金属蛋白酶抑制剂的式I巯基酮和非对映巯基醇衍生物以及每种非对映体立体有择合成的方法。出人意料地发现带羟基的C为S-构型的巯基乙醇体外体内药效都比类似物(R)-醇强至少4倍。
发明背景
基质金属蛋白酶(MMP)是一类含锌的钙依赖性蛋白酶,包括基质溶素,胶原酶,和明胶酶。这些MMP酶能降解结缔组织的蛋白成分,且看来参入组织重塑,即伤口愈合和结缔组织更新。已鉴定了大约13种MMP。胶原酶裂解原纤维胶原。基质溶素除降解胶原外还降解纤连蛋白,层粘连蛋白和粘蛋白。明胶酶可以降解变性胶原(明胶)和基底膜主要成份IV型胶原。
高水平的胶原酶和基质溶素与骨一和类风湿关节炎有关,在滑膜和软骨中已发现它们的量与疾病的严重程度呈正比。明胶酶被认为在肿瘤转移中起关键作用,因为它们降解肿瘤细胞为了从原发肿瘤病灶转移所必须经过的基底膜,从而促进从原发病的移转。明胶酶也与实体肿瘤生长所必需的血管生成过程有关。除了与骨-和类风湿关节炎及肿瘤转移相关外,MMP与角膜溃疡,龈炎,多发性硬化和其它神经病学疾病和气肿有关(Beeley等,Curr.Opin.Ther Patents4(1),7-16(1994))。
结合酶活性位点的锌的化合物阻止MMP的催化活性。已在一些肽基异羟肟酸,肽基烷基羧酸,肽基次膦酸和膦酸中发现了MMP抑制剂活性。而且结合一个与硫羟基团间隔两个原子的羰基的肽基硫醇已显示出是有效的MMP抑制剂。例如《药物化学》(Jourmal of Medicinal Chemistry)36,4030-4039(1993)中公开的下面的化合物中,SSR异构体是有效的(IC50=2nM)人胶原酶抑制剂(JR.Morphy等《药物化学动态》(Current Medicinal Chemistry)2,743-762(1995)。Merck在PCT申请WO9407481中公开了下面的化合物作为MMP基质溶素的适中的抑制剂。下式化合物公开于PCT申请WO9513289。下面的巯基硫化物MMP抑制剂化合物公开于PCT申请WO9509833。下式的MMP抑制化合物其中P是H,甲基或苯基,公开于Donald等的美国专利4595700。其中P是2-氧代丙基的化合物的效价比其中P是甲基的化合物有效约20倍,而后者的效价又比其中P是氢原子的化合物有效约20倍(EP0322184A2)。在所有上面提到的例子中巯基部分与酰胺羰基间隔两个碳原子。
发明概述
本发明基质金属蛋白酶抑制剂化合物以式I表示其中R1是C1-C12烷基,其是直链或支链,且任选地被卤原子,羟基,C1-C6烷氧基,氨基,羧基,C1-C6烷氧羰基,甲酰氨,腈,一或二(C1-C6)烷基氨基,硫代,C1-C6烷硫基,芳基,-O芳基或-OCH2芳基取代,其中芳基可任选地被C1-C6烷基,C1-C6烷氧基,羧基,卤素,氰基,硝基,甲酰氨,或羟基取代;和C1-C6链烷磺酰氧。R2是α-OH或β-OH且R6是H或R2和R6一起形成羰基。在上述定义中,芳基是5元至10元碳环或杂环的单环或双环芳基,如苯,呋喃,噻吩,咪唑,萘,喹啉,吲哚,苯并噻吩,苯并咪唑,吡啶,嘧啶或苯并呋喃。本发明也涉及合成式I化合物所需要的所有化学中间体。
已发现式I非对映化合物在体外和体内抑制基质金属蛋白酶胶原酶,基质溶素,和明胶酶。因此被期望可用于治疗关节炎,角膜溃疡,龈炎,多发性硬化,气肿,抑制实体肿瘤生长,防止肿瘤转移。因为在体外和体内发现(S)-构型(式I,R2是β-OH)的醇的效价比相应的(R)-构型非对映体至少高4倍,因此希望立体有择合成巯基醇。这里所公开的是式I化合物两种非对映体中的一种(R2是α-OH或β-OH)通过内酯非对映体而被合成的方法。也公开了非对映和对映体纯中间体及其制备方法。发明的详细说明
每一种式I非对映醇和酮的立体有择合成的方法在图示I,II和III中给出。图示II和III提出非对映呋喃酮中间体另外的合成的要点。化合物名称后面的罗马数字指图示I,II和III中所示的结构。化学合成领域技术人员应该理解除图示I所示的(S)-(-)-4-苄基-2-噁唑烷酮(A)外的立体化学定向基团,包括但不限于另外被取代的噁唑烷酮,麻黄碱衍生物和手性2,10-樟脑磺内酰胺,可以用来获得相同的结果。也可以使用除下面具体实施例中所使用的之外的羟基和硫醇保护基。可以使用的硫羟基保护基,W,包括苯基,-C(O)芳基,其中芳基如上定义且如上可任意地被取代,-C(O)C1-C12烷基,-CR3R4R5,其中R3,R4和R5各自独立地是H,甲基,-OC1-C12烷基,O-四氢吡喃基,-S-苄基,和可任选地被甲氧基,羟基,硝基,或甲基取代的苯基;二硫化物或任何其它适于保护硫原子的基团。硫羟基保护基Z是H,苯基,-CR3R4R5,其中R3,R4和R5独立地为H,甲基,-OC1-C12烷基,O-四氢吡喃,-S-苄基,和可任选地被甲氧基,羟基,硝基,或甲基取代的苯基;二硫化物或任何其它适于保护硫原子的基团。羟基保护基Y,包括三甲基甲硅烷基,叔丁基二甲基甲硅烷基,三乙基甲硅烷基,异丙基二甲基甲硅烷基,三苯代甲基二甲基甲硅烷基,叔丁基二苯基甲硅烷基,甲基二异丙基甲硅烷基,甲基二叔丁基甲硅烷基,三异丙基甲硅烷基,三苯基甲硅烷基,苯甲基,可任选地被甲氧基,硝基,卤原子,氰基取代的苯甲基;和取代的甲基和乙基醚,包括三苯甲基,甲氧基甲基,甲氧基乙氧基甲基,四氢吡喃和烯丙基。也可以使用其它合适的氧原子和硫原子保护基,如《有机合成中的保护基团》(第二版,T.W.Greene和P.G.M.Wuts,John Wiley和Sons,纽约,NY,1991)中所描述的。除图示I,II,III中使用的外,去除各种手性辅助剂和巯基与羟基保护基可能需要的方法对于有机合成领域中的技术人员来说是显而易见的。本领域技术人员明白分子中存在的各种官能团一定要与建议的化学转化相一致。这经常需要判断合成步骤的顺序,保护基团和去保护条件。
根据图示I,II和III指明的步骤并根据实施例中给出的方法,用合适的式R1CH2COOH取代的羧酸或其酸的卤化物或酸酐可以制备R1可任选地被取代的本发明化合物和中间体,这些酸可以商购或根据标准的文献所公开的方法制备。显而易见地,根据取代基的官能可能需要标准保护基团化学。
其中R2是α-OH(R构型)或β-OH(S构型)的本发明式I化合物各自根据如图示I指明的本文所公开的方法,从一般的手性酸式i的2(R)-2-R1-戊-4-烯酸开始而制备。这些2-取代的戊-4-烯酸根据文献方法制备,或根据图示I和下面的实施例1-6中所示的反应顺序制备。
在图示I中给出了制备起始酸(i)的合成示意图。(4S)-4-苄基-3-((2R)-2-R1-戊-4-烯酰基)噁唑烷-2-酮,B,是通过用其中R1是如上所定义的C1-C12烷基的式R1CH2C(O)-卤素的链烷酸卤化物或其酸酐酰化(S)-(-)-4-苯甲基-2-噁唑烷酮,A,而制备的。各种N-酰基噁唑烷酮A文献中己被公开,包括已用于合成MMP抑制剂的烷基-O-CH2芳基和烷基-芳基衍生物(Tomczuk,B.E.等,Bioorg & Med.Chem.Lett.5,343,1995;Chapman,K.T.,等,Bioorg.&Med.Chem.Lett.6,803,1996)。然后酰基链用烯丙基化试剂如烯丙基卤化物或三氟甲磺酸酯,优选烯丙基溴立体有择地对羰基α烷基化,得到的(4S)-4-苄基-3-((2R)-2-R1-戊-4-烯酰基)噁唑烷-2-酮用氢过氧化锂或其它合适的碱水溶液水解,得到(2R)-2-R1-戊-4-酸(1)。
酸(i)与碘反应主要生成式iib的四氢呋喃酮,而酸i的二甲酰胺与碘反应主要生成式iia二氢呋喃酮。如果合适,碘代甲基二氢呋喃酮iia或iib之一通过与HSW阴离子反应,其中W如上定义,优选与硫羚乙酸的钠盐,锂盐或钾盐反应,而转化为保护的硫醇(iia或iib)。然后水解S-酰基硫甲基二氢呋喃酮iiia或iiib(W=Ac),被保护的硝醇作为可裂解的硫醚-SZ,得到iva或ivb,其中Z定义为H,苯基,-CR3R4R5,其中R3,R4和R5独立地为H,甲基,-OC1-C12烷基,O-四氢吡喃基,-S-苄基,和可任选地被甲氧基,羟甲,硝基,或甲基取代的苯基;二硫化物,或任何其它适于保护硫原子的基团。iva和ivb优选的保护基Z是三苯甲基,其容易在三氟乙酸中由硫醇和三苯甲基氯生成,且不参与下面反应步骤中的化学反应。
水解二氢呋喃酮iva或ivb分别产生S保护的4-羟基-5-巯基戊酸va或vb。戊酸va或vb中的羟基通过基团Y通过生成醚而被保护,其中Y定义为H,三甲基甲硅烷基,叔丁基二甲基甲硅烷基,三乙基甲硅烷基,异丙基二甲基甲硅烷基,三苯甲基二甲基甲硅烷基,叔丁基二苯基甲硅烷基,甲基二异丙基甲硅烷基,甲基二叔丁基甲硅烷基,三异丙基甲硅烷基,三苯基甲硅烷基,苯甲基,可任选地被甲氧基,硝基,卤原子或氰基,三苯甲基,甲氧基甲基,甲氧乙氧甲基,四氢吡喃和烯丙基取代的苯甲基。优选的保护基Y是叔丁基二甲基甲硅烷基。
使用标准酰胺偶联技术使O,S-保护酸via或vib与2(S)-叔丁基-N-甲基甘氨酸偶联,得到各自保护的式I化合物viia或viib。去除羟基保护基(Y)分别得到S-保护的式I化合物viiia或viiib。然后从viiia或viiib上去除硫保护基(Z),分别得到其中R2是β-OH(S构型)或α-OH(R构型)的式I化合物。两者之一的其中R2是OH且R6是H,Z是一保护基团的式I化合物可以在去除保护基后被氧化,得到其中R2和R6一起形成羰基的式I化合物。
如图示II所示,硫代乙酸酯iiia或iiib(W=Ac)也可以通过商购的(R)-(-)-或(S)-(+)-二氢-5-(羟基甲基)-2(3H)-呋喃酮而获得。因此作为叔丁基二甲基甲硅烷基醚或任何合适的大的保护基团如三苯代甲基的(S)-(+)对映体的羟基的保护作用之后是所得内酯的去质子化作用和用R1X的阴离子的烷基化作用,其中R1如上文所定义,X是合适的离去基团如卤原子或三氟甲磺酸酯(triflate),得到内酯X。内酯X也可以通过适当被取代的假麻黄碱酰胺的烷基化作用,或者通过用对映体纯环氧化物将非手性酰胺烯醇酯烷基化,接着酸诱导的水解/平衡,而获得(Myers,A.G.等,《有机化学》61,2428,1996)。接着进行醇的去保护,得到2(R)-2-R1-5(S)-5-羟基甲基二氢呋喃-2-酮(xia)(Lewis.C.N.等,JCS Chem.Commun.1786,1987)。该醇可以通过Mitsun obu类型反应而转化为硫代乙酸内酯iiia(Volante,R.P.TetrahedronLefters,22,3119,1981),或者通过将醇转化为合适的离去基团如卤化物,三氟甲磺酸酯(triflate),甲磺酰酯或甲苯磺酸酯,然后用硫代乙酸或其它合适的被保护硫醇等价物和碱取代而转化为硫代乙酸内酯iiia。使用相同的方法,(R)-(-)-二氢-5-(羟基甲基)-2(3H)-呋喃酮可以通过羟基内酯中间体xib转化为硫代乙酸内酯iiib(图示II)。
两种非对映体内酯iiia和iiib也可以如图示III所示由戊烯酸i合成。使用Sharpless方法(Sharpless,K.B.等,Chem.Rev.94,2483,1994)将酸进行不对称二羟基化得到二醇xii,其然后经过酸催化内酯化得到内酯-醇xia或xib。该内酯然后通过上述图示II中iia转化为iiia的相同方法被转化为相应的硫代乙酸内酯,iiia或iiib。
反应流程式I续
反应流程式II.另一种制备内酯iiib的方法
下面的实施例详细说明上述方法,只是为详细说明的目的,在任何方面不应理解为对本发明的限制。这些方法中所使用的化学品和试剂或者是商购的或者是合成有机化学领域技术人员根据文献方法容易制备的。
实施例1(S)-3-(1-氧代壬基)-4-(苯基甲基)-2-噁唑烷酮
在0℃,向15.80g(0.10mol)壬酸的150mL二氯甲烷溶液中加入0.1mL N,N-二甲基甲酰胺和9.59mL(0.11mol)草酰氯。反应混合物升至室温并搅拌过夜。然后将反应混合物真空浓缩,用己烷稀释且过滤。真空浓缩滤液得到17.67g(100%)壬酰氯,其不用进一步纯化而用于下面步骤中。
向冷却到-78℃的25.2g(0.142mol)(S)-(-)-4-苄基-2-噁唑烷酮(Aldich化学公司)的300mL THF溶液中加入97.0mL(0.155mol)1.6M正丁基锂。反应混合物在-78℃搅拌1小时,然后加入溶解于75mL THF中的壬酰氯(17.4g,0.129mol)。所得混合物在-78℃搅拌3小时,然后用5%Hcl溶液骤冷。用乙醚萃取反应混合物,合并的有机相用水,饱和碳酸氢钠和盐水洗涤。然后用MgSO4干燥有机相,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得到24.75g(78%)所需产物的白色固体。
实施例2
(S)-3-(4-甲基-1-氧代戊基)4-(苯基甲基)-2-噁唑烷酮
根据上面的方法,用15.0g(0.129mol)4-甲基戊酸代替壬酸,得到23.69g(66%)标题化合物。
实施例3(4S)4-苄基-3-((2R)-2-庚基-戊-4-烯酰基)噁唑烷-2-酮
向冷却至-78℃的5.50g(0.017mol)噁唑烷酮的40mL THF溶液中加入17.3mL(0.035mol)二异丙酰胺的庚烷/THF/苯中的2.0M溶液。反应混合物在-78℃搅拌1小时后向反应混合物中加入纯烯丙基溴(7.5mL,0.087mol)。反应物升至0℃(冰浴)并再搅拌3小时后用5%HCl溶液中止。用乙醚萃取所得混合物,合并的有机层用水,盐水洗涤,用MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得到5.0g(81%)无色油状物所需烯丙基化的产物。电子喷射质谱:358.2(M+H)+。
实施例4(4S)-4-苄基-3-((2R)-2-异丁基-戊-4-烯酰基)噁唑烷-2-酮
用实施例3描述的相同方法进行异丁基取代的噁唑烷酮的烯丙基化作用,产率85%,得到无色油状产物,CI质谱:316.3(M+H)。
实施例5(2R)-2-庚基-戊-4-烯酸
向冷却至0℃的8.69g(0.024mol)由实施例3得到的产物的425mL THF/H2O(3∶1)的溶液中加入10.8mL(0.097mol)30%过氧化氢溶液,接着加入2.03g(0.049mol)LiOH/H2O。所得溶液在0℃搅拌1.5小时后用15.4g亚硫酸钠的100mL水溶液中止。反应混合物用盐酸水溶液酸化至pH3,并用乙酸乙酯萃取。合并的有机层用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得4.33g(90%)无色油状所需产物。CI质谱:199(M+H)。
实施例6(R)-2-异丁基-戊-4-烯酸
用实施例5描述的相同的方法进行实施例4的产物的水解,产率92%,得到无色油状产物。CI质谱:157.2(M+H)。
实施例7(R)-2-庚基-戊-4-烯酸二甲酰胺
在0℃向于5.00g(0.025mol)实施例5的产物和2.27g(0.028mol)二甲胺盐酸盐的DMF混合物中加入4.21mL(0.028mol)氰膦酸二乙酯,接着加入7.38mL(0.053mol)三乙胺。反应混合物在0℃搅拌1小时后在室温下搅拌3小时。所得浅黄色悬浮液用750mL乙酸乙酯/己烷(2∶1)稀释,然后用5%HCl水溶液,水,饱和碳酸氢钠和盐水洗涤该溶液。有机层用硫酸镁干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶4)洗脱,得到5.68g(100%)无色油状标题化合物。CI质谱:226.3(M+H)。
实施例8(R)-2-异丁基-戊-4-烯酸二甲酰胺
用实施例7描述的相同的方法,用实施例6的产物,以88%的产率得到相应的无色油状N,N-二甲酰胺。CI质谱:184.2(M+H)。
实施例9(3R,5S)-3-庚基-5-碘甲基-二氢呋喃-2-酮
室温下向5.68g(0.025mol)实施例7的产物的90mL DME/H2O(1∶1)的混合物中加入7.69g(0.030mol)碘。所符溶液在室温下搅拌60小时后用乙醚稀释并连续用饱和Na2S2O3水溶液,饱和碳酸氢钠溶液和盐水洗涤。有机层用硫酸镁干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得5.11g(63%)白色固体标题化合物和0.788g(10%)无色油状碘代-顺内酯,CI质谱:325.3(M+H)。
实施例10(3R,5S)-5-碘代甲基-3-异丁基-二氢呋喃-2-酮
用实施例9描述的相同方法,由4.14g(0.023mol)实施例8的产物,得到4.539g(71%)无色油状标题化合物,以及0.691g(11%)相应的碘代-顺内酯,CI质谱:283.2(M+H)。
实施例11(3R,5R)-3-庚基-5-碘代甲基-二氢呋喃-2-酮
向冷却至0℃的7.14g(0.036mol)实施例5的产物的750mL THF/H2O(2∶1)的溶液中加入7.22g(0.072mol)KHCO3,接着加入11.97g(0.072mol)KI,然后加入18.30g(0.072mol)碘。反应物升至室温并搅拌18小时。所得混合物用乙醚稀释,有机层用亚硫酸氢钠水溶液,H2O和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得8.30g(71%)标题化合物和3.36g(29%)相应的碘代-反内酯白色固体。CI质谱:325.3(M+H)。
实施例12(3R,5R)-5-碘代甲基-3-异丁基-二氢呋喃-2-酮
用实施例11说明的相同方法,进行6.29g(0.04mol)实施例4的产物的碘代内酯化,得7.21g(63%)标题化合物和3.77g(33%)相应的碘代-反内酯无色油状物。CI质谱:283.2(M+H)。
实施例13硫代乙酸S-((2R,4R)-4-庚基-5-氧代-四氢呋喃-2-基甲基)酯
向6.49g(0.020mol)实施例11产物的50mL无水甲醇溶液中加入1.19g(0.022mol)甲醇钠,接着加入5.73mL(0.080mol)硫羟乙酸。所得混合物回流加热4.5小时后冷却至室温,并用5%HCl溶液酸化。所得溶液用乙醚萃取,合并的有机层用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得5.08g(93%)无色油状物。CI质谱:273.3(M+H)。
实施例14硫代乙酸S-((2S,4R)-4-庚基-5-氧个代-四氢呋喃-2-基甲基)酯
用实施例13说明的相同的方法,将实施例9的产物转化为相应的硫代乙酸酯,以82%的产率,得到无色油状物。CI质谱:273.3(M+H)。
实施例15硫代乙酸S-((4S,2R)-4-庚基-5-氧代-四氢呋喃-2-基甲基)酯
用实施例13说明的相同方法,将实施例12的产物转化为相应的硫代乙酸酯,以75%的产率得到无色油状物。CI质谱:231.3(M+H)。
实施例16硫代乙酸S-((2S,4R)-4-异丁基-5-氧代-四氢呋喃-2-基甲基)酯
用实施例13说明的相同的方法,将实施例10的产物转化为相应的硫代乙酸酯,以75%的产率得无色油状物。CI质谱:231.3(M+H)。
实施例17(3R,5R)-3-庚基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮
在15分钟内向冷却至0℃的实施例13产物的100mL甲醇溶液中分次加入2.69g(0.071mol)固体硼氢化钠。然后真空浓缩反应物,用10%HCl溶液酸化并用二氯甲烷萃取。合并的有机层用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。所得粗产物硫醇溶解于50mL三氟乙酸中,并加入5.98g(0.023mol)三苯代甲醇。室温搅拌1小时后真空浓缩反应混合物,残余物在硅胶上层析,用乙酸乙酯/己烷(1∶50)洗脱,得5.26g(61%)无色油状所需产物。CI质谱:473.5(M+H)。
实施例18(3R,5S)-3-庚基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮
用实施例17说明的相同方法,将实施例14的产物转化为相应的S-三苯代甲基衍生物,以65%的产率获得无色油状物。CI质谱:473.5(M+H)。
实施例19(3R,5R)-3-异丁基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮
用实施例17说明的相同的方法,将实施例15的产物转化为相应的S-三苯代甲基衍生物,以64%的产率得到无色油状物。CI质谱:431.4(M+H)。
实施例20(3R,5S)-3-异丁基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮
用实施例15说明的相同的方法,将实施例14的产物转化为相应的S-三苯代甲基衍生物,以61%的产率得到无色油状物。CI质谱:431.5(M+H)。
实施例21(2R)-2-((2R)-2-羟基-3-三苯代甲基硫烷基丙基)壬酸
室温下向3.72g(7.88mmol)实施例17的产物的100mL甲醇/THF(1∶1)的溶液中加入16.7mL 1.0N NaOH溶液。反应在室温搅拌1小时后,用100mL H2O稀释,并用5%Hcl溶液小心酸化至pH6。所得混合物用乙酸乙酯(EtoAc)萃取,合并的有机层用水和盐水洗涤,用MgSO4干燥,过滤并真空浓缩,3.72g(100%)残余物粗产物羟基-酸不用进一步纯化而用于下步的反应中(实施例25)。电子喷射质谱:489.4(M-H)~。
实施例22(2R)-2-((2S)-2-羟基-3-三苯代甲基硫烷基丙基)壬酸
用实施例19说明的相同的方法,将实施例16的产物转化为相应的羟基-酸衍生物,以95%的产率得到无色油状物。电子喷射质谱:489.4(M-H)~。
实施例23(2R,4R)-4-羟基-2-异丁基-5-三苯代甲基硫烷基戊酸
用实施例21说明的相同的方法,将实施例19的产物转化为相应的羟基-酸衍生物,以99%的产率得到无色油状物。电子喷射质谱:447.3(M-H)~。
实施例24(2R,4S)-4-羟基-2-异丁基-5-三苯代甲基硫烷基戊酸
用实施例21说明的相同的方法,将实施例20的产物转化为相应的羟基-酸衍生物,以99%的产率得到无色油状物。电子喷射质谱:447.3(M-H)-。
实施例25(2R)-2-[(2R)-2-(叔丁基-二甲基甲硅烷基氧)-3-三苯代甲基硫烷基丙基]壬酸
向3.72g(7.88mmol)实施例21的粗产物溶于10mL DMF中的溶液加入2.68g(0.039mol)咪唑,接着加入2.85g(0.019mol)叔丁基二甲基甲硅烷基氯。反应混合物在室温搅拌2小时后,倒入200mL水中。所得溶液用乙醚萃取,合并的有机层用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物溶解于10mL甲醇/THF(1∶1)并加入5.0mL 1N NaOH溶液。室温搅拌0.75小时后用5%HCl溶液将反应混合物酸化至pH5,然后用乙醚萃取。合并的有机层用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析,用乙酸乙酯/己烷(1∶10)洗脱,得4.76g(100%)无色油状所需产物。电子喷射质谱:603.5(M-H)~。
实施例26(2R)-2-[(2S)-2-(叔丁基二甲基甲硅烷基氧)-3-三苯代甲基硫烷基丙基]壬酸
用实施例25说明的相同方法,将实施例22的产物转化为相应的TBDMS醚-酸衍生物,以83%的产率得无色油状物。电子喷射质谱:603.5(M-H)-。
实施例27(2R,4S)-4-(叔丁基二甲基甲硅烷基氧)-2-异丁基-5-三苯代甲基硫烷基戊酸
用实施例25说明的相同的方法,将实施例24的产物转化为相应的TBDMS醚-酸衍生物,以91%的产率得无色油状物。电子喷射质谱:561.4(M-H)-。
实施例28(2R,4R)-4-(叔丁基二甲基甲硅烷基氧)-2-异丁基-5-三苯代甲基硫烷基戊酸
用实施例25说明的相同的方法,将实施例23的产率转化为相应的TBDMS醚-酸衍生物,以95%的产率得无色油状物。电子喷射质谱:561.4(M-H)~。
实施例29(2R)-2-[(2R)-2-(叔丁基-二甲基甲硅烷基氧)-3-三苯代甲基硫烷基丙基]-壬酸((1S)-2,2-二甲基-1-甲基羰基丙基)酰胺
向4.76g(7.88mmol)实施例25的产物溶于150mL二氯甲烷的溶液中加入1.42g(9.85mmol)叔丁基甘氨酸-N-甲基酰胺,接着加入1.86mL(0.013mmol)三乙胺和1.67mL(0.011mmol)氰膦酸二乙酯。反应混合物在室温下搅拌12小时后真空浓缩。所得残余物用乙醚稀释,有机相用5%HCl溶液,水和盐水洗涤,然后有机层用MgSO4干燥,过滤并真空浓缩,得5.13g(89%)所需油状产物,其足够纯,可用于下步反应。FAB质谱:753.4(M+Na)。
实施例30(2R)-2-[(2S)-2-(叔丁基-二甲基甲硅烷基氧)-3-三苯代甲基硫烷基丙基]-壬酸((1S)-2,2-二甲基-1-甲基羰基丙基)酰胺
使用实施例29说明的相同方法,用6.80g(11.26mmol)实施例26的产物制备出7.71g(94%)无色油状所需产物。FAB质谱:753.4(M+Na)。
实施例31(2R,4R)-4-(叔丁基二甲基甲硅烷基氧)-2-异丁基-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例29说明的相同方法,用5.81g(10.33mmol)实施例28的产物制备出4.62g(65%)无色油状所需产物。1H NMR(300MHz,CDl3)δ7.44(m,5H),7.26(m,10H),6.16(m,1H),5.96(d,J=9Hz,1H),4.19(d,J=9Hz,1H),3.58(m,1H)2.76(d,J=4.7Hz,3H),2.29(dd,J=6.2,12Hz,1H),2.13(dd,J=4.5,12Hz,1H)2.0(m,1H),1.7-1.1(m,3H),0.9(s,9H),0.85(s,9H),0.82(dd,J=6,10Hz),-0.039(s,3H),-0.078(s,3H)。
实施例32(2R,4S)-4-(叔丁基二甲基甲硅烷基氧)-2-异丁基-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例29说明的相同方法,用7.20g(12.81mmol)实施例27的产物制备出5.53g(63%)无色油状所需产物。电子喷射质谱:711.4(M+Na)+。
实施例33(2R)-2-((2R)-2-羟基-3-三苯代甲基硫烷基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
向5.13g(7.027mml)实施例29的产物溶于75mL THF的溶液中加入17.6mL(0.018mmol)1.0M氟化四丁铵的THF溶液。反应混合物在室温搅拌4小时后用乙醚稀释。所得溶液用水和盐水洗涤,MgSO4干燥,过滤并真空浓缩。残余物在硅胶上层析用EtOAc/己烷(梯度:1∶3-1∶1)洗脱,得2.78g(64%)无色油状所需产物。电子喷射质谱:617.5(M+H)+。
实施例34(2R)-2-((2S)-2-羟-基-3-三苯代甲基硫烷基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例33描述的相同的方法,用7.63g(0.126mmol)实施例30的产物制备出4.22g(66%)无色油状所需产物。电子喷射质谱:617.5(M+H)+。
实施例35(2R,4R)-4-羟基-2-异丁基-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
使用实施例33描述的相同的方法,用4.58g(0.126mmol)实施例31的产物制备出3.66g(96%)无色油状所需产物。电子喷射质谱:575.4(M+H)+。
实施例36(2R,4S)-4-羟基-2-异丁基-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例31说明的相同的方法,用5.50g(0.126mmol)实施例30的产物制备出3.87g(84%)无色油状所需产物。电子喷射质谱:575.3(M+H)+。
实施例37(2R)-2-((2R)-2-羟基-3-巯基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
向0.700g(1.136mmol)实施例33的产物和0.363mL(2.273mmol)三乙基甲硅烷溶于10mL二氯甲烷的溶液中滴加10mL三氟乙酸。反应混合物在室温搅拌0.5小时后真空浓缩。残余物在硅胶上层析,用EtOAc/己烷(梯度:1∶3-1∶1)洗脱,得0.263g(62%)无色油状所需产物。电子喷射质谱:375.4(M+H)+。实施例38(2R)-2-((2S)-2-羟基-3-巯基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例37说明的相同方法,用1.0g(1.62mmol)实施例34的产物制备出0.24g(40%)无色油状所需产物。电子喷射质谱:375.4(M+H)+。
实施例39(2R,4R)-4-羟基-2-异丁基-5-巯基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例37相同的方法,由1.50g(2.61mmol)实施例35的产物制备出0.47g(54%)无色油状所需产物。电子喷射质谱:333.3(M+H)+。
实施例40(2R,4S)-4-羟基-2-异丁基-5-巯基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
使用实施例37描述的相同方法,用1.50g(2.61mmol)实施例36的产物制备出0.14g(16%)无色油状所需产物。电子喷射质谱:333.3(M+H)+。
实施例41(2R)-2-(2-氧代-3-三苯代甲基硫烷基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
向0.962g(1.562mmol)实施例33的产物的3mL DMSO溶液中加入0.505mL(6.246mmol)吡啶,接着加入0.120mL(1.562mmol)三氟乙酸和0.898(4.685mmol)1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐。反应混合物在室温下搅拌36小时后用200mL EtOAc稀释。所得溶液用0.1NHCl溶液,水,饱和NaHCO3溶液和盐水洗涤,MgSO4干燥,过滤并真空浓缩。得0.948g(99%)残余物,其不用纯化可用于下步反应。电子喷射质谱:615.4(M+H)+。
实施例42(2R)-2-异丁基-4-氧代-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例41说明的相同方法,用1.25g(2.18mmol)实施例35的产物制备出1.25g(100%)无色油状所需产物。电子喷射质谱:573.4(M+H)+。实施例43(2R)-2-(3-巯基-2-氧代丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
用实施例37说明的相同方法,用1.985g(3.23mmol)实施例41的产物制备出0.506g(42%)无色油状所需产物。电子喷射质谱:373.4(M+H)+。
实施例44(2R)-2-异丁基-5-巯基-4-氧戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺
使用如实施例37描述的相同方法,由2.49g实施例42的产物产生0.462g(32%)所需产物的无色油状物。电子喷射质谱:331.3(M+H)+。药理学
表1总结了从本发明的四种非对映异构的醇和两种巯基酮,其中R为异丁基或庚基而获得的药理学数据。药理学方法在表之后,数据表明在体内和体外,2(S)羟基非对映异构体比2(R)羟基类似物具有更好和出人意料的效果,后者不如酮化合物有效。表1:体外和体内对基质金属蛋白酶的抑制实施例 R’ R 胶原酶IC50 基质溶素 明胶酶 体内胶
(nM)或抑制 IC50(nM)% 或IC50(nM) 原酶I
百分数 (抑制) 抑制百
分数43 =O 庚基 30.0 28 0.73/50mpk*44 =O 异丁基 38.0 58%@1μM 4.8/60mpk38 2(S)OH 庚基 30.0 96%@0.1μM 22.2/50mpk40 2(S)OH 异丁基 41.0 51%@1μM 19 84.8/50mpk35 2(R)OH 庚基 72%@1μM 38%@1μM 0.44/50mpk39 2(R)OH 异丁基 228 6%@30nM 106 20.4/50mpk体外基质溶素抑制作用
分析基于用酶基质溶素裂解硫代肽底物((Ac-Pro-Leu-Gly(2-巯基-4-甲基戊酰基)Leu-Gly-OEt),Bachem Bioscience),释放与DTNB((5,5’-二硫代双(2-硝基苯甲酸))形成比色反应的底物产物。硫代肽底物配制成100%DMSO中的20mM贮液,冷冻贮藏,同时将DTNB贮液溶解于100%DMSO中,室温下以100mM贮液贮存。在使用之前,用分析缓冲液(50mMHEPES,pH7.0,5mMCaCl2)将底物和DTNB稀释至1mM。将入重组基质溶素贮液(平截的,Affymax)用分析缓冲液稀释至在反应中的最终浓度为12.5nM。
将酶,DTNB和底物(10μM最终浓度)与/没有抑制剂(总反应体积为200μL)加入到96井平板中,在平板读出器上,在405纳米(nm)处用分光光度监测5分钟颜色的增加。对OD405的增加作图,计算代表反应速率的直线的斜率。
证明了反应速率的线性(r2>0.85)。计算对照组速率的平均值,使用Dunnett’s多重比较试验与药物处理的速率比较统计显著性(p<0.05)。使用多种剂量的药物可产生剂量响应关系,使用线性回归(IPRED,HTB)计算具有95%CI的IC50值(Weingarfen和Feder,脊椎动物胶原酶的分光光度分析,动物生物化学147,437-440(1985))。体外明胶酶抑制作用
分析基于用酶明胶酯裂解硫代肽底物(CAC-Pro-leu-Cly(2-巯基-4-甲基戊酰基)Leu-Gly-OEt),Bachem Bioscience),释放与DTNB((5,5’-二硫代双(2-硝基苯甲酸))形成比色反应的底物产物。硫代肽底物配制成100%DMSO中的20mM新鲜贮液,将DTNB溶解于100%DMSO中,在室温下以100mM贮液贮存于黑暗中。在使用之前,用分析缓冲液(50mM HEPES,pH7.0,5mMCaCl2,0.2%Brij)将底物和DTNB稀释至1mM。用分析缓冲液将人嗜中性明胶酶B稀释至0.15nM的最终浓度。
将分析缓冲液,酶,DTNB和底物(500μM最终浓度)与/没有抑制剂(总反应体积为200μL加入到96井平板中,在平板读出器上,在405纳米(nm)处用分光光度监测5分钟的颜色增加。对OD405的增加作用,计算代表反应速率的直线的斜率。
证明了反应速率的线性(r2>0.85)。计算对照组速率的平均值,使用Dunnett’s多重比较试验与药物处理的速率比较统计显著性(p<0.05)。使用多种剂量的药物可产生剂量响应关系,使用线性回归(IPRED,HTB)计算具有95%CI的CI50值。(Weingarten和Feder,脊柱动物胶原酶的分光度分析,动物生物化学147,437-440(1985))。体外胶原酶的抑制作用
分析基于用胶原酶裂解肽底物((Dnp-Pro-Cha-Gly-Gys(Me)-His-Ala-Lys(NMa)-NH2),(Peptide International,Inc.)而释放在荧光计上被定量的荧光NMa基团。Dnp猝灭完整底物中的NMa荧光。分析在含有人重组成纤维细胞胶原酶(平截,mw18,828,WAR,Radnor)的HCBC分析缓冲液(50mM HEPES,pH7.0,5mMCa+2,0.02%Brij,0.5%半胱氨酸)中进行。将底物溶解于甲醇中,以1mM等分试样冷冻贮藏。胶原酶以25μM等分试样冷冻贮藏在缓冲液中。为了分析,将底物溶解于HCBC缓冲液中至最终浓度为10μM,胶原酶的最终浓度为5nM。将化合物溶解于甲醇、DMSO或HCBC中。将甲醇和DMSO用HCBC稀释至<1%。将化合物加入到含酶的96井平板中,通过加入底物开始反应。
将反应计数10分钟(激发340nm,发射444nm),将这段时间的荧光增加量对时间作图成线性直线。计算直线的斜率,其代表反应速率。
证明了反应速率的线性(r2>0.85)。计算对照组速率的平均值,使用Dunnett’s多重比较试验与药物处理的速率比较统计显著性(p<0.05)。使用多种剂量的药物可产生剂量响应关系,使用线性回归(IPRED,HTB)计算具有95%CI的IC50值。(Bickett,D.M等,间质胶原酶(MMP-1)和明胶酶(MMP-9)的高产率荧光团底物,动物生物化学212,58-64(1993))。体内MMP抑制作用
在麻醉状态下,将含有基质金属蛋白酶(在0.5mL缓冲液中含有基质溶素,胶原酶或明胶酶)的一个2cm的透析管(截留分子量12-14,000,10mm扁平宽度)腹膜内或皮下(ip或sc)(背部)埋入小鼠(Sprague-Dawley,150-200g)或大鼠(CD-1,25-50g)。用套管PO,IP,SC或IV向颈静脉给药。以0.1-0.25mL/动物的剂量体积给药。收集透析管的内含物,分析酶活性。
计算每一透析管的酶反应速率。用来自至少3个不同动物的管来计算平均值±半值。通过方差分析确定用赋形剂处理的动物与用药物处理的动物的统计显著性(p<0.05)(试剂与作用21:331,1987)。药物组合物
本发明化合物可以纯物质或与药物载体一起施用于需要它的病人,药物载体可为固体或液体。
可用的固体载体可包括一种或多种物质,这些物质还可起香味剂,润滑剂,加溶剂,悬浮剂,填料,助流剂,压缩剂,粘合剂或片崩解剂或密封物质的作用。为粉末剂时,载体为与磨得很细的活性成分混合的磨得很细的固体。在为片剂时,活性成分与以适宜比例具有必需的压缩性能的载体混合,并压成所需的形状和大小。粉剂和片剂优选含有高达99%的活性成分。适宜的固体载体包括,例如,磷酸钙,硬脂酸镁,滑石,糖类,乳糖,糊精,淀粉,明胶,纤雏素,甲基纤雏素,羧甲基纤雏素钠,聚乙烯吡咯烷酮,低熔点蜡和离子交换树脂。
液体载体可用于制备溶液剂,悬浮剂,乳剂,糖浆和酏剂。本发明的活性成分可溶解或悬浮于药物上可接受的液体载体中,例如水,有机溶剂,两者的混合剂或药物上可接受的油或脂肪。液体载体可包含其它适宜的药物添加剂,例如加溶剂,乳化剂,缓冲剂,保存剂,甜味剂,香味剂,悬浮剂,增稠剂,色料,粘度调节剂,稳定剂或渗透压调节剂。口服和胃肠外给药的液体载体的适宜的实例包括水(特别含有上面添加剂,例如纤雏素衍生物,优选羧甲基纤雏素钠溶液),醇(包括一元醇和多元醇,例如甘醇)和它们的衍生物,和油(例如分馏的椰子油和花生油)。对于胃肠外给药,载体还可为油状酯,例如油酸乙酯和肉豆蔻酸异丙酯。无菌液体载体用于胃肠外给药的无菌液体形式的组合物中。
可通过例如肌肉内,腹膜内或皮下注射来使用为无菌溶液剂或悬浮剂的液体药物组合物。无菌溶液剂也可静脉注射用药。口服用药可为液体或固体组合物形式。
用来抑制病人基质金属蛋白酶的剂量必须由护理的医生自主确定。涉及的变数包括病人机能障碍的严重程度,体重,年龄和反应类型。治疗通常以比化合物最佳剂量少的小剂量开始。此后增加剂量直至在此情况下的最佳效果。准确的剂量将由给药的医生根据经验以及各治疗个体和标准的医学原则来确定。
药物组合物优选为单位剂量形式,例如为片剂或胶囊。为这种形式时,将组合物细分成含有适宜量的活性成分的单位剂量;单位剂量形式可以是被包装的组合物,例如被包装的粉末剂,管瓶剂,安瓿剂,预装填注射剂或含液体的小药囊。单位剂量形式可为,例如胶囊或片剂本身,或可为包装形式的适宜数量的任何这些组合物。
Claims (14)
1、根据下式的非对映体纯的和对映体纯的化合物其中R1为直链或支链且任意被卤素,羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基、芳基为选自苯、呋喃、噻吩、咪唑、萘、喹啉、吲哚、苯并噻吩、苯并咪唑、吡啶、嘧啶或苯并呋喃的5至10元碳环或杂环一环或二环芳香基团;W选自苯基、-C(O)芳基、-C(O)取代的芳基、其中芳基如术语R1中所定义,-C(O)C1-C12烷基、-CR3R4R5,其中R3,R4和R5各自独立地选自H、甲基、-OC1-C12烷基、-O-四氢吡喃基、-S-苄基和任意被甲氧基、羟基、硝基或甲基取代的苯基;R6为α-H或β-H。
2、根据权利求1的其中W为乙酰基的化合物,选自:
硫代乙酸S-((2S,4R)-4-异丁基-5-氧代-四氢呋喃-2-基甲基)酯,
硫代乙酸S-((2S,4R)-4-庚基-5-氧代-四氢呋喃-2-基甲基)酯,
硫代乙酸S-((2R,4R)-4-异丁基-5-氧代-四氢呋喃-2-基甲基)酯,和
硫代乙酸S-((2R,4S)-4-庚基-5-氧代-四氢呋喃-2-基甲基)酯。
3、根据权利要求1的其中W为三苯基甲基的化合物,选自:
(3R,5R)-3-庚基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮,
(3R,5S)-3-异丁基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮,
(3R,5S)-3-庚基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮,和
(3R,5R)-3-异丁基-5-三苯代甲基硫烷基甲基-二氢呋喃-2-酮。
4、根据下式的非对映体纯的和对映体纯的化合物:其中Y为H、三甲基甲硅烷基、叔丁基二甲基甲硅烷基、三乙基甲硅烷基、异丙基二甲基甲硅烷基、三苯代甲基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、甲基二异丙基甲硅烷基、甲基二叔丁基甲硅烷基、三异丙基甲硅烷基、三苯基甲硅烷基、被甲氧基、硝基、卤素或氰基任意取代的苄基;取代的甲基或乙基醚,包括三苯甲基、甲氧基甲基、甲氧基乙氧基甲基、四氢吡喃基,或烯丙基;Z为H、苯基,或-CR3R4R5,其中R3,R4和R5独立地为H、甲基、-O-C1-C12烷基、-O-四氢吡喃基、-S-苄基或被甲氧基、羟基、硝基或甲基任意取代的苯基;R1为直链或支链且任意被卤素,羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代。芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基,芳基为选自苯、呋喃、噻吩、咪唑、萘、喹啉、吲哚、苯并噻吩、苯并咪唑、吡啶、嘧啶或苯并呋喃的5至10元碳环或杂环一环或二环芳香基团;和R6为α-H或β-H。
5、根据权利要求4的其中Y为H,Z为三苯代甲基的化合物选自:
(2R)-2-((2R)-2-羟基-3-三苯代甲基硫烷基丙基)壬酸;
(2R)-2-((2S)-2-羟基-3-三苯代甲基硫烷基丙基)壬酸;
(2R,4S)-4-羟基-2-异丁基-5-三苯代甲基硫烷戊酸,和
(2R,4R)-4-羟基-2-异丁基-5-三苯代甲基硫烷基戊酸。
6、根据权利要求4的Y为叔丁基二甲基甲硅烷基,Z为三苯代甲基的化合物选自:
(2R)-2-[(2R)-2-(叔丁基二甲基硅烷氧基)-3-三苯代甲基硫烷基丙基]壬酸,
(2R)-2-[(2S)-2-(叔丁基二甲基硅烷氧基)-3-三苯代甲基硫烷基丙基)壬酸;
(2R,4S)-4-(叔丁基二甲基硅烷氧基)-2-异丁基-5-三苯代甲基硫烷基戊酸,和
(2R,4R)-4-(叔丁基二甲基硅烷氧基)-2-异丁基-5-三苯代甲基硫烷基戊酸。
8、根据权利要求7的其中Z为三苯代甲基的化合物选自:
(2R)-2-(2-氧代-3-三苯代甲基硫烷基丙基)壬酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺,和
(2R)-2-异丁基-4-氧代-5-三苯代甲基硫烷基戊酸((1S)-2,2-二甲基-1-甲基氨基甲酰基丙基)酰胺。
9、一种制备根据下式的化合物的方法其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基,芳基为选自苯、呋喃、噻吩、咪唑、萘、喹啉、吲哚、苯并噻吩、苯并咪唑、吡啶、嘧啶或苯并呋喃的5至10元碳环或杂环一环或二环芳香基团;R2和R6一起形成羰基,其包括:
(1)氧化下式化合物其中R1,R2和R6如前所定义,Y为氢,Z为苯基,-CR3R4R5,其中R3,R4和R5独立地为H、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基、任意被甲氧基、羟基、硝基或甲基取代的苯基;二硫化物或任何其它适宜于保护硫的基团,和
(2)除去硫羟保护基团,产生其中R2和R6一起形成羰基的化合物。
10、根据权利要求9的制备根据下式的化合物的方法其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基,芳基为选自苯、呋喃、噻吩、咪唑、萘、喹啉、吲哚、苯并噻吩、苯并咪唑、吡啶、嘧啶或苯并呋喃的5至10元碳环或杂环一环或二环芳香基团;R2和R6一起形成羰基,其包括:
(1)用二甲亚砜/吡啶/三氟乙酸/1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺或等当量的活化的二甲亚砜氧化或其它氧化方法,包括Dess-Martin试剂,重铬酸盐吡啶、氯铬酸盐吡啶/乙酸钠、过钌酸盐四丙基铵/NMO氧化下式化合物其中R1,R2和R6如前所定义,Y为氢,Z为三苯基甲基,和
(2)除去三苯基甲基硫羟保护基团,产生其中R2和R6一起形成羰基,Z为H的化合物。
11、一种制备下式中间体的方法其中R1为直链或支链且任意被卤素、羟基C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基;Z为H、苯基或CR3R4R5,其中R3,R4和R5独立地选自H、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基和任意被甲氧基、羟基、硝基或甲基取代的苯基,其包括
(2)将步骤(1)的3(R)-3-R1-5(R)-碘甲基二氢呋喃-2-酮与硫试剂,HSW和碱反应,其中W定义为苯基、-C(O)芳基和-C(O)取代的芳基,其中芳基如上定义;-C(O)-C1-C12烷基、或-CR3R4R5,其中R3,R4和R5独立地为氢、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基、或任意被甲氧基、羟基、硝基或甲基取代的苯基、从而获得式iiib中间体。
(3)在还原条件下将步骤(2)的内酯iiib的硫去保护,酸或碱水解,产生化合物ivb(Z=H),和
(4)保护上面步骤(3)的游离硫羟,产生化合物ivb,其中Z定义为H、苯基,-CR3R4R5,其中R3,R4和R5独立地为H、甲基、-O-C1-C12烷基、-O-四氢吡喃基、-S-苄基或任意被甲氧基、羟基、硝基或甲基取代的苯基;二硫化物或任何其它适宜于保护硫的基团。
12、根据叔利要求11制备下式中间体的方法其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基;Z为H、苯基或CR3R4R5,其中R3,R4和R5独立地选自H、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基和任意被甲氧基、羟基、硝基或甲基取代的苯基,其包括:
(3)通过在甲醇或乙醇中与硼氢化钠反应,将步骤(2)的内酯iiib的硫去保护,其中W为乙酰基,产生化合物ivb(Z=H),和
(4)保护上面步骤(3)的游离硫羟,产生其中Z为三苯基甲基的化合物ivb。
13、一种制备下式中间体的方法其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基;Z为H、或CR3R4R5,其中R3,R4和R5独立地选自H、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基和任意被甲氧基、羟基、硝基或甲基取代的苯基,其包括
(2)将步骤(1)的3(R)-3-R1-5(S)-碘甲基二氢呋喃-2-酮与硫试剂,HSW和碱反应,其中W定义为苯基、-C(O)芳基和-C(O)取代的芳基,其中芳基如上定义;-C(O)C1-C12烷基,或-CR3R4R5,其中R3,R4和R5独立地为H、甲基、-O-C1-C12烷基、-O-四氢吡喃基、-S-苄基或任意被甲氧基、羟基、硝基或甲基取代的苯基,从而得到下式iiia的中间体,
(3)在还原条件下将步骤(2)的内酯iiia的硫去保护,酸水解或碱水解,产生化合物iva(Z=H),和
(4)保护上面步骤(3)的游离硫羟,产生化合物iva,其中Z定义为H、苯基、-CR3R4R5,其中R3,R4和R5独立地为H、甲基、-O-C1-C12烷基、-O-四氢吡喃基、-S-苄基或任意被甲氧基、羟基、硝基或甲基取代的苯基;二硫化物或任何其它适宜于保护硫的基团。
14、根据权利要求13的制备下式中间体的方法其中R1为直链或支链且任意被卤素、羟基、C1-C6烷氧基、氨基、羧基、C1-C6烷氧羰基、甲酰氨基、腈、一或二(C1-C6)烷基氨基、硫代、C1-C6烷基硫代,芳基、-O-芳基或-OCH2芳基取代的C1-C12烷基,其中芳基任意被C1-C6烷基、C1-C6烷氧基、羧基、卤素、氰基、硝基、甲酰氨基或羟基取代;和C1-C6链烷磺酰氧基;Z为H、苯基或CR3R4R5,其中R3,R4和R5独立地选自H、甲基、-O-C1-C12烷基、O-四氢吡喃基、-S-苄基和任意被甲氧基、羟基、硝基或甲基取代的苯基,其包括:
(1)将下式化合物与碘反应,主要得到下式的(3R,5S)二氢呋喃酮
(3)通过在甲醇或乙醇中与硼氢化钠反应,将步骤(2)的其中W为乙酰基的内酯iiia的硫去保护,,产生化合物iva(Z=H),和
(4)保护上面步骤(3)的游离硫羟,产生其中Z为三苯基甲基的化合物iva。
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US67799496A | 1996-07-10 | 1996-07-10 | |
US677,994 | 1996-07-10 |
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EP (1) | EP0818443B1 (zh) |
JP (1) | JPH1067737A (zh) |
KR (1) | KR980009233A (zh) |
CN (1) | CN1336367A (zh) |
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AU (1) | AU731155B2 (zh) |
BR (1) | BR9703800A (zh) |
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HK (1) | HK1008215A1 (zh) |
HU (1) | HUP9701127A3 (zh) |
IL (1) | IL121125A0 (zh) |
NO (1) | NO308597B1 (zh) |
NZ (1) | NZ328288A (zh) |
PT (1) | PT818443E (zh) |
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US5831004A (en) * | 1994-10-27 | 1998-11-03 | Affymax Technologies N.V. | Inhibitors of metalloproteases, pharmaceutical compositions comprising same and methods of their use |
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NO973004L (no) | 1998-01-12 |
KR980009233A (ko) | 1998-04-30 |
DK0818443T3 (da) | 2002-04-02 |
EP0818443A2 (en) | 1998-01-14 |
SK88597A3 (en) | 1998-01-14 |
DE69708770D1 (de) | 2002-01-17 |
JPH1067737A (ja) | 1998-03-10 |
AU2857197A (en) | 1998-01-22 |
NO973004D0 (no) | 1997-06-27 |
HUP9701127A2 (hu) | 1999-02-01 |
IL121125A0 (en) | 1997-11-20 |
NO308597B1 (no) | 2000-10-02 |
EP0818443B1 (en) | 2001-12-05 |
HK1008215A1 (en) | 1999-05-07 |
HU9701127D0 (en) | 1997-08-28 |
ES2166048T3 (es) | 2002-04-01 |
DE69708770T2 (de) | 2002-08-08 |
ZA976121B (en) | 1999-01-11 |
EP0818443A3 (en) | 1998-08-19 |
PT818443E (pt) | 2002-05-31 |
HUP9701127A3 (en) | 2000-08-28 |
CA2208676A1 (en) | 1998-01-10 |
CZ202597A3 (cs) | 1998-09-16 |
AU731155B2 (en) | 2001-03-22 |
ATE210113T1 (de) | 2001-12-15 |
BR9703800A (pt) | 1998-08-18 |
TW424083B (en) | 2001-03-01 |
NZ328288A (en) | 1999-01-28 |
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