CN101888991A - 类视色素前体药物化合物 - Google Patents
类视色素前体药物化合物 Download PDFInfo
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- CN101888991A CN101888991A CN200780101344XA CN200780101344A CN101888991A CN 101888991 A CN101888991 A CN 101888991A CN 200780101344X A CN200780101344X A CN 200780101344XA CN 200780101344 A CN200780101344 A CN 200780101344A CN 101888991 A CN101888991 A CN 101888991A
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the nitrogen atom of at least one of the carboxamide groups further acylated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/88—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having the nitrogen atom of at least one of the carboxamide groups further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/30—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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Abstract
本发明提供具有吸收至生物体内后转换为类视色素的性质的下述通式(I)所表示的化合物或其盐、或其酯:,R1~R5表示氢原子、烷基或者三烷基甲硅烷基,X表示-NH-CO-、-CO-NH-、-N(COR6)-CO-、-CO-N(COR7)-(R6及R7表示低级烷氧基或者羧基取代的苯基)等;Z表示-Y-CH(R12)-COOH、-CHO、-CH=CH-COOH或者-COOR13(Y表示单键、-CH2-、-CH(OH)-、-CO-、-CO-NH-或者-CO-NH-CH2-CO-NH-,R12表示氢原子或者低级烷基,R13表示氢原子、-CH(R14)-COOH(R14表示氢原子、低级烷基或者羟基)、-[CH2CH2-O]n-CH2-CH2-OH、-CH2-O-[CH2CH2-O]m-CH2-OH 或者-[CH(CH3)-CO-O]p-CH(CH3)-COOH(n、m或p表示1至100的整数)。
Description
技术领域
本发明涉及生物体内与视黄酸等类视色素发挥同样生理活性的类视色素前体药物化合物。
背景技术
视黄酸(维生素A酸)是维生素A的活性代谢产物,具有使处于产生过程中的未成熟细胞向具有特定功能的成熟细胞分化的作用、细胞的增殖促进作用、或生命维持作用等极其重要的生理作用。已知目前为止所合成的各种维生素A衍生物,例如日本特开昭61-22047号公报或日本特开昭61-76440号公报记载的苯甲酸衍生物、以及ジヤ一ナル·オブ·メデイシナル·ケミストリ一(Journal of Medicinal Chemistry,1988,Vol.31,No.11,p.2182)中记载的化合物等,也具有同样的生理作用。将具有视黄酸及视黄酸样生物活性的上述化合物统称为“类视色素”。
已知例如,全反式(all-trans)视黄酸作为配体与属于细胞核内存在的核内受体超家族(receptor superfamily)(Evans,R.M.,Science,240,p.889,1988)的视黄酸受体(RAR)结合,控制动物细胞的增殖、分化或者细胞死亡等(Petkovich,M.,et al.,Nature,330,pp.444-450,1987)。并且,对于视黄酸生理活性的表达,已证明了类视色素X受体(将RXR,9-cis-视黄酸作为配体)的存在。已知类视色素X受体与视黄酸受体(RAR)形成二聚体,引起或抑制基因转录,并调节视黄酸生理活性的表达(Mangelsdorf,D.J.et al.,Nature,345,pp.224-229)。
有文献指出具有视黄酸样生物活性的上述化合物(例如,4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]苯甲酸:Am80等),也与视黄酸同样地与RAR结合并发挥生理活性(参照Hashimoto,Y.,Cell struct.Funct.,16,pp.113-123,1991;Hashimoto,Y.,et al.,Biochem.Biophys.Res.Commun.,166,pp.1300-1307,1990)。这些化合物在临床上被有效用于维生素A缺乏症、上皮组织的角化病、风湿症、迟发性过敏、骨疾病以及白血病或某种癌症的治疗或预防。例如,Am80在临床上被用作复发性白血病的治疗剂,在美国将4-[3,5-双(三甲基甲硅烷基)苯甲酰胺]苯甲酸(Am555S、日本特开平2-247185号公报等)作为能够口服给药的抗肿瘤剂正在临床开发中。
由此,类视色素被用作癌症治疗药、皮肤科用药等,并且作为除此之外的各种难治性疾病的治疗药的可能性较大。但是,现在所使用的类视色素从副作用等观点来看还不能满足上述要求,因此需要在以下方面进行改良:除了要增强对靶向器官的选择性、减少酸性基团引起的器官损害之外,特别是要减轻口服给药中对消化道的直接作用等。通过提供具有吸收至生物体内后转换为类视色素的性质的类视色素前体药物化合物,有可能解决后者的问题,现有技术中几乎没有从这个观点出发提出的化合物。
[专利文献1]日本特开昭61-22047号公报
[专利文献2]日本特开昭61-76440号公报
[专利文献3]日本特开平2-247185号公报
[非专利文献1]Journal of Medicinal Chemistry,31,No.11,p.2182,1988
[非专利文献2]Cell struct.Funct.,16,pp.113-123,1991
[非专利文献3]Biochem.Biophys.Res.Commun.,166,pp.1300-1307,1990
发明内容
发明要解决的问题
本发明的课题在于提供具有吸收至生物体内后转换为类视色素的性质的类视色素前体药物化合物。更具体而言,本发明的课题是提供类视色素前体药物化合物,该化合物是其本身不具有类视色素的生理作用、或者具有较弱的类视色素作用的化合物,是吸收至生物体内后受到酶的化学变化而转换为强效的类视色素的类视色素前体药物化合物。
本发明人为了解决上述课题进行了努力研究,结果发现,将下述通式所表示的化合物作为类视色素前体药物化合物极其有效,从而完成了本发明。
即,本发明提供下述通式(I)表示的化合物或其盐:
[化1]
[式中,R1、R2、R3、R4及R5分别独立地表示氢原子、低级烷基、或者三低级烷基甲硅烷基(tri(lower alkyl)silyl group),它们当中相邻的2个低级烷基可以结合到一起,与它们所结合的苯环上的碳原子共同形成具有1个或者2个以上烷基的5元环或者6元环;X表示-NH-CO-、-CO-NH-、-N(COR6)-CO-、-CO-N(COR7)-、-CO-N[CON(R8)(R9)]-或者-N[CON(R10)(R11)](R6及R7表示低级烷氧基(该烷氧基可具有取代基)或者苯基(该苯基具有至少1个烷氧基羰基或者羧基作为取代基,也可具有其它取代基),R8、R9、R10及R11分别独立地表示氢原子或者低级烷基);Z表示-Y-CH(R12)-COOH、-CHO、-CH=CH-COOH或者-COOR13(Y表示单键、-CH2-、-CH(OH)-、-CO-、-CO-NH-或者-CO-NH-CH2-CO-NH-,R12表示氢原子或者低级烷基,R13表示氢原子、-CH(R14)-COOH(R14表示氢原子、低级烷基或者羟基)、-[CH2CH2-O]n-CH2-CH2-OH(n表示1至100的整数)、-CH2-O-[CH2CH2-O]m-CH2-OH(m表示1至100的整数)、或者-[CH(CH3)-CO-O]p-CH(CH3)-COOH(p表示1至100的整数),X为-NH-CO-或者-CO-NH-时,R13表示氢原子以外的基团]。
根据上述发明优选的实施方式,本发明提供:X与Z为对位的上述化合物或其盐;R1、R4及R5为氢原子、R2及R3为低级烷基的上述化合物或其盐;R1、R4及R5为氢原子、R2及R3相互结合形成6元环的上述化合物或其盐;R1、R4及R5为氢原子、R2及R3相互结合形成5,5,8,8-四甲基-5,6,7,8-四氢萘环的上述化合物或其盐;R1、R3及R5为氢原子、R2及R4为三甲基甲硅烷基的上述化合物或其盐。
此外,根据更优选的实施方式,本发明提供:X为-N(COR6)-CO-或者-CO-N(COR7)-(R6或者R7为甲氧基或者乙氧基、或者经羧基取代的苯基)、Z为-COOR13(R13为氢原子)的上述化合物或其盐;X为-NH-CO-(该酰胺基的碳原子与Z取代的苯环结合)、Z为-Y-CH(R12)-COOH(Y为-CH2-、-CH(OH)-或者-CO-)或者-COOR13的上述化合物或其盐。
从其它观点来看,本发明提供含有上述通式所表示的化合物及生理学上接受的它们的盐作为有效成分的药物。该药物作为类视色素样作用剂有用。本发明进一步提供用于制造上述药物的上述化合物或其盐的用途。
具体实施方式
上述通式(I)中,R1、R2、R3、R4及R5分别独立地表示氢原子、低级烷基或者三低级烷基甲硅烷基。作为低级烷基可以使用碳原子数为1至6个左右、优选碳原子数为1至4个的直链或者支链烷基。例如可以使用甲基、乙基、正丙基、异丙基、正丁基、仲丁基、或者叔丁基等。对本说明书中提到的其它低级烷基也同样,对于具有烷基部分的取代基(例如烷氧基)的烷基部分也同样。作为三低级烷基甲硅烷基例如优选三甲基甲硅烷基。例如优选R1、R4及R5为氢原子、R2及R3为低级烷基。此外,优选R1、R3及R5为氢原子、R2及R4为三低级烷基甲硅烷基,更优选R1、R3及R5为氢原子、R2及R4为三甲基甲硅烷基。
选自R1、R2、R3、R4及R5中相邻的2个低级烷基可以结合到一起,与它们所结合的苯环上的碳原子共同形成具有1个或者2个以上烷基的1个或者2个5元环或者6元环,优选为1个。作为环上可取代的烷基,可以使用碳原子数为1至6个左右、优选碳原子数为1至4个的直链或者支链烷基。例如可以使用甲基、乙基等,优选2~4个甲基、进一步优选4个甲基取代。例如,优选通过R2及R3取代的苯环和R2及R3,形成5,6,7,8-四氢萘环、5,5,8,8-四甲基-5,6,7,8-四氢萘环等。
X表示-NH-CO-、-CO-NH-、-N(COR6)-CO-、-CO-N(COR7)-、-CO-N[CON(R8)(R9)]-或者-N[CON(R10)(R11)],R6及R7表示可具有取代基的低级烷氧基、或表示苯基(该苯基具有至少1个烷氧基羰基或者羧基作为取代基,也可具有其它取代基),R8、R9、R10及R11分别独立地表示氢原子或者低级烷基。优选X与Z在它们所结合的苯环上为对位。作为X优选-NH-CO-(该酰胺基的碳原子与Z取代的苯环结合)。当X表示-N(COR6)-CO-、-CO-N(COR7)-、-CO-N[CON(R8)(R9)]-或者-N[CON(R10)(R11)]时,优选Z为-COOH。当X为-NH-CO-(该酰胺基的碳原子与Z取代的苯环结合)时,优选Z为-Y-CH(R12)-COOH(优选Y为-CH2-、-CH(OH)-或者-CO-,更优选Y为-CH2-)或者-COOR13(R13为氢原子以外的基团)。m、n和p分别表示1~100的整数,但可以分别是5~50左右、更优选5~30左右的范围。
上述化合物有时形成碱加成盐,例如有时作为钠盐、钾盐、镁盐、或者钙盐等金属盐,铵盐或者三乙胺盐或者乙醇胺盐等有机胺盐等而存在,这些盐中,可以使用生理学上接受的盐作为本发明药物的有效成分。此外,上述化合物中,存在于Z部位的羧基可形成酯。本说明书中称作“化合物或其盐、或其酯”时的酯是指存在于Z部位的羧基形成酯的情形。
作为上述酯优选生理学上接受的酯。作为理想的酯残基的具体例,例如可列举:甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苄基、乙酰氧基甲基、1-(乙酰氧基)乙基、丙酰氧基甲基、1-(丙酰氧基)乙基、丁酰氧基甲基、1-(丁酰氧基)乙基、异丁酰氧基甲基、1-(异丁酰氧基)乙基、戊酰氧基甲基、1-(戊酰氧基)乙基、异戊酰氧基甲基、1-(异戊酰氧基)乙基、新戊酰氧基甲基、1-(新戊酰氧基)乙基、甲氧基羰基氧基甲基、1-(甲氧基羰基氧基)乙基、乙氧基羰基氧基甲基、1-(乙氧基羰基氧基)乙基、丙氧基羰基氧基甲基、1-(丙氧基羰基氧基)乙基、异丙氧基羰基氧基甲基、1-(异丙氧基羰基氧基)乙基、丁氧基羰基氧基甲基、1-(丁氧基羰基氧基)乙基、异丁氧基羰基氧基甲基、1-(异丁氧基羰基氧基)乙基、叔丁氧基羰基氧基甲基、1-(叔丁氧基羰基氧基)乙基、环戊烷羰基氧基甲基、1-(环戊烷羰基氧基)乙基、环己烷羰基氧基甲基、1-(环己烷羰基氧基)乙基、环戊氧基羰基氧基甲基、1-(环戊氧基羰基氧基)乙基、环己氧基羰基氧基甲基、1-(环己氧基羰基氧基)乙基、苯甲酰氧基甲基、1-(苯甲酰氧基)乙基、苯氧基羰基氧基甲基、1-(苯氧基羰基氧基)乙基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基或者2-三甲基甲硅烷基乙基等,但不限于这些基团。
本发明的化合物根据取代基的种类有时具有1个或2个以上的不对称碳原子,但基于这些不对称碳原子的任意光学异构体、光学异构体的任意混合物、外消旋体、基于2个以上不对称碳原子的非对映异构体、非对映异构体的任意混合物等,均包含在本发明的范围内。并且,游离化合物或者盐形态的化合物的任意水合物或者溶剂合物也包含在本发明的范围内。
本发明的化合物中,作为优选的化合物可列举以下化合物,但本发明的化合物、或者能够用于本发明药物的有效成分的化合物并不限于下述化合物。例示的化合物中,Me表示甲基、Et表示乙基、n表示例如12左右的整数(使用分子量600的PEG时n为约12.2)。
[化2]
[化3]
关于上述通式(I)所表示的化合物的制造方法、上述化合物中的代表化合物的合成例,本说明书的实施例中会进行具体且详细地说明。此外,关于R1、R2、R3、R4及R5取代的苯环的修饰,可参考例如记载了Am80、Am555S的制造方法的公知文献。因此,通过参照它们的实施例、公知文献,并且通过根据需要对这些方法加以适当改变、修饰,本领域技术人员可容易地制造上述通式(I)所包含的任意化合物。
上述通式(I)所表示的化合物,是其本身不具有类视色素生理作用、或者具有较弱类视色素作用的化合物,吸收至生物体内后受到酶的化学变化而转换为强效的类视色素,与类视色素受体结合发挥类视色素样的作用。本说明书中所用的术语“类视色素受体”包含视黄酸受体RAR和RXR,是指1种或者2种以上能与视黄酸等类视色素相互作用的受体。上述化合物作为类视色素的前体药物有用,含有上述化合物为有效成分的药物作为类视色素作用剂有用。不受任何特定理论的限制,但本发明的通式(I)所表示的化合物为了发挥类视色素样作用,必须代谢为上述通式(I)中Z为羧基的化合物,该具有羧基的化合物形成活性代谢产物从而发挥类视色素样的作用。具有类视色素样作用的上述活性代谢产物,例如具有细胞分化作用、细胞增殖促进作用以及生命维持作用等,对维生素A缺乏症、上皮组织的角化病、干癣、过敏症、风湿等免疫性疾病、骨疾病、白血病、或者癌症起到预防和/或治疗作用。
含有将上述通式(I)所表示的化合物作为类视色素前体药物化合物的药物,含有选自上述通式(I)所表示的化合物及其盐、以及它们的水合物及溶剂合物中的1种或2种以上物质作为有效成分。作为本发明的药物可以给予上述物质本身,优选可按照本领域技术人员公知的方法给予可以制造的口服用或者非口服用的药物组合物。作为适合口服给药的药物组合物,例如可列举:片剂、胶囊剂、散剂、细粒剂、颗粒剂、液剂及糖浆剂等,作为适合非口服给药的药物组合物,例如可列举注射剂、栓剂、吸入剂、滴眼剂、滴鼻剂等。
上述药物组合物可以加入药理学、药剂学上可接受的添加物来制造。作为药理学、药剂学上可接受的添加物的例子,例如可列举赋形剂、崩解剂或崩解助剂、粘合剂、润滑剂、包衣剂、色素、稀释剂、基质、溶解剂或溶解助剂、等渗剂、pH调节剂、稳定剂、抛射剂以及胶粘剂等。
本发明药物的给药量没有特殊限定,可根据其作用的种类、作用的强弱等进行适当选择,还可根据患者的体重或年龄、疾病的种类或症状、给药途径等通常应该考虑的各种因素,进行适当增减。一般可按照将视黄酸等用作药物时的给药量,考察前体药物的吸收效率、代谢效率再进行适当选择。例如,口服给药时成人可以按照每日0.01~1,000mg左右的范围使用。
实施例
以下,通过实施例对本发明进行更具体地说明,但本发明的范围不限于下述实施例的范围。
例1:2-[2-(2-羟基)乙氧基]乙基4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]苯甲酸酯
[化4]
向冰浴冷却的Am-80(1,40mg,0.114mmol)和三乙胺(48μl,0.345mmol)的二氯甲烷(2.5ml)溶液中添加氯甲酸异丁酯(16μl,0.123mmol),搅拌1小时。在该反应液中加入三甘醇(152μl,1.14mmol),再于室温下搅拌16小时。加入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂,用硅胶柱色谱(以7-10%甲醇-氯仿洗脱)对残渣进行纯化,得到标记化合物244mg(80%)。
无色微细针状结晶、熔点123.5-124.5℃(二氯甲烷-己烷)
MS(m/z):483(M+,15),468(21),378(4),318(13),291(7),149(15),104(16),89(9),75(8),58(8),45(100),31(14)
IR(KBr)cm-1:1711,1646
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.69(4H,s),2.48(1H,br s,OH),3.58-3.64(2H,m),3.66-3.75(6H,m),3.84-3.89(2H,m),4.50-4.55(2H,m),7.31(1H,d,J=8.5Hz),7.45(1H,dd,J=8.5,2.5Hz),7.55(1H,d,J=2.5Hz),7.92(2H,A 2B2,J=8Hz),7.94(1H,br s,CONH),8.15(2H,A2 B 2,J=8Hz).
例2:Am-80的六甘醇酯
[化5]
采用与上述完全相同的方法由Am-80(1,40mg,0.114mmol)和六甘醇(322mg,1.14mmol)得到标记化合物3(49mg,70%)。
无色玻璃状物质
MS(m/z):615(M+,5),600(2),378(3),362(3),334(3),318(3),291(4),193(3),149(4),133(4),104(7),89(21),45(100)
IR(CHCl3)cm-1:1713,1669
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.69(4H,s),2.28(1H,br s,OH),3.55-3.74(20H,m),3.82-3.88(2H,m),4.47-4.53(2H,m),7.30(1H,d,J=8.5Hz),7.46(1H,dd,J=8.5,2.5Hz),7.57(1H,d,J=2.5Hz),7.94(2H,A 2B2,J=8Hz),8.14(2H,A2B2,J=8Hz),8.20(1H,br s,CONH).
例3:Am-80的聚乙二醇(平均分子量600)酯
[化6]
采用与上述完全相同的方法由Am-80(1,60mg,0.171mmol)和聚乙二醇(1.026g,约1.71mmol)得到标记化合物4(132mg,约83%)。
无色饴状物质
MS(m/z):703(对应于八亚乙基衍生物,0.3),672(0.3),615(0.3),351(24),336(100),149(68),121(23),104(21),65(28),45(33)
IR(CHCl3)cm-1:1713,1668
1H-NMR(CDCl3)δ:1.27(6H,s),1.28(6H,s),1.68(4H,s),3.00(1H,br s,OH),3.55-3.73(ca.45H,m),3.81-3.87(2H,m),4.46-4.52(2H,m),7.28(1H,d,J=8.5Hz),7.51(1H,dd,J=8.5,2Hz),7.62(1H,d,J=2Hz),8.01(2H,A 2B2,J=8Hz),8.10(2H,A2 B 2,J=8Hz),8.74(1H,br s,CONH).
例4:(S)-1-(苄氧基羰基)乙基4-[[3,5-二(三甲基甲硅烷基)苯基]氨基甲酰基]苯甲酸酯
[化7]
向Am-55S(3,60mg,0.156mmol)和L-乳酸苄酯(31mg,0.172mmol)的二氯甲烷(3ml)溶液中添加二环己基碳二亚胺(39mg,0.189mmol)和4-二甲氨基吡啶(2mg,16.4μmol),室温下搅拌5小时。加入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱(以氯仿洗脱)对残渣进行纯化,得到标记化合物456mg(66%)。
无色饴状物
MS(m/z):547(M+,18),368(4),311(5),104(6),91(100),73(11).IR(CHCl3)cm-1:1721,1671
1H-NMR(CDCl3)δ:0.29(18H,s),1.65(3H,d,J=7Hz),5.17(1H,d,J=12.5Hz),5.23(1H,d,J=12.5Hz),7.30-7.37(5H,m),7.46(1H,t,J=0.5Hz),7.80(2H,br s),7.93(2H,A 2B2,J=8.5Hz),8.13(2H,A2 B 2,J=8.5Hz),8.13(1H,br s,CONH).
例5:(S)-1-(羧基)乙基4-[[3,5-二(三甲基甲硅烷基)苯基]氨基甲酰基]苯甲酸酯
[化8]
在大气压的氢气环境下,对上述得到的化合物6(54mg,98.7μmol)和钯-碳(10%,6mg)的甲醇(4ml)悬浮液进行30分钟催化还原。对反应液进行硅藻土过滤,再用10%甲醇-氯仿洗涤硅藻土。对馏去溶剂后得到的结晶进行重结晶,由此得到标记化合物7(38mg,84%)。
无色鳞片状晶体,熔点198-200℃(二氯甲烷-己烷)
MS(m/z):457(M+,89),370(93),221(33),176(39),149(60),129(29),104(35),75(29),73(100)
IR(CHCl3)cm-1:1720,1709,1644,1626
1H-NMR(CDCl3)δ:0.30(18H,s),1.72(3H,d,J=7Hz),5.42(1H,q,J=7Hz),7.46(1H,br s),7.77(2H,br s),7.80(1H,br s,CONH),7.97(2H,A 2B2,J=8.5Hz),8.21(2H,A2 B 2,J=8.5Hz).
例6:(S)-O-叔丁基乳酸苄酯
[化9]
向(S)-乳酸苄酯(18.0g,0.100mol)和二碳酸二叔丁酯(54.5g,0.250mol)的二氯甲烷(100ml)溶液中加入高氯酸镁(2.23g,10mmol),加热回流24小时。冷却后,将反应液注入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱[以己烷-乙酸乙酯(19∶1)洗脱]对残渣进行纯化,回收原料(3.11g,17%)的同时作为无色油状物得到标记化合物8(18.4g,78%)。
IR(无水)cm-1:1747
1H-NMR(CDCl3)δ:1.18(9H,s),1.35(3H,d,J=7Hz),4.16(1H,q,J=7Hz),5.13(1H,d,J=12.5Hz),5.19(1H,d,J=12.5Hz),7.29-7.42(5H,m).
例7:O-叔丁基乳酸二聚体苄酯的制备
[化10]
在大气压的氢气环境下,对上述得到的化合物8(660mg,2.80mmol)和钯-碳(10%,42mg)的甲醇(12ml)悬浮液进行1小时催化还原。对反应液进行硅藻土过滤,用10%甲醇-氯仿洗涤硅藻土。馏去溶剂后得到382mg的残渣。向该残渣和乳酸苄酯(471mg,2.62mmol)的二氯甲烷(8ml)溶液中添加二环己基碳二亚胺(DCC,664mg,3.22mmol)和4-二甲氨基吡啶(15mg,0.123mmol),室温下搅拌27小时。冰浴下冷却反应液后,添加乙醇(0.45ml,7.72mmol)和乙酸(0.12ml,2.10mmol),搅拌使过量的DCC分解。加入饱和碳酸氢钠溶液,用硅藻土过滤,再用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂,用硅胶柱色谱[以己烷-乙酸乙酯(6∶1)洗脱]对残渣进行纯化,作为无色粘稠性油状物得到标记化合物9(688mg,80%)。
IR(无水)cm-1:1747
1H-NMR(CDCl3)δ:1.19(9H,s),1.35(3H,d,J=7Hz),1.52(3H,d,J=7Hz),4.18(1H,q,J=7Hz),5.16(2H,s),5.19(1H,q,J=7Hz),7.30-7.40(5H,m).
例8:O-叔丁基乳酸四聚体苄酯的制备
[化11]
冰冷上述得到的化合物9(80mg,0.260mmol)的二氯甲烷(0.8ml)溶液,添加三氟乙酸(0.20ml)搅拌30分钟,再于室温下搅拌30分钟。加入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。在无水硫酸钠上干燥后,馏去溶剂,得到67mg的残渣-1。另一方面,在大气压的氢气环境下,对9(80mg,0.260mmol)和钯-碳(10%,5mg)的甲醇(3ml)悬浮液进行1小时催化还原。按照常规方法进行处理得到60mg的残渣-2。合并残渣-1和残渣-2并溶解于二氯甲烷(2.5ml)中,添加二环己基碳二亚胺(60mg,0.291mmol)和4-二甲氨基吡啶(3mg,24.6μmol),室温下搅拌18小时。按照常规方法进行处理后,用硅胶柱色谱[以己烷-乙酸乙酯(5∶1)洗脱]进行纯化,作为无色粘稠油状物得到标记化合物10(99mg,84%)。
IR(无水)cm-1:1748,1670
1H-NMR(CDCl3)δ:1.21(9H,s),1.39(3H,d,J=7Hz),1.517(3H,d,J=7Hz),1.520(3H,d,J=7Hz),1.57(3H,d,J=7Hz),4.20(1H,q,J=7Hz),5.10-5.23(5H,m),7.28-7.40(5H,m).
例9:Am-55s(5)的乳酸四聚体酯(苄酯)
[化12]
冰冷上述得到的化合物10(84mg,0.186mmol)的二氯甲烷(0.8ml)溶液,添加三氟乙酸(0.20ml)搅拌15分钟,再于室温下搅拌45分钟。加入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。在无水硫酸钠上干燥后,馏去溶剂,得到74mg的残渣-1。向该残渣和5(72mg,0.187mmol)的二氯甲烷(4ml)溶液中添加二环己基碳二亚胺(46mg,0.223mmol)和4-二甲氨基吡啶(2mg,16.4μmol),室温下搅拌4小时。按照常规方法进行处理后,用硅胶柱色谱[以苯-乙酸乙酯(14∶1)洗脱]进行纯化,作为无色粘稠油状物得到标记化合物11(105mg,74%)。
MS(m/z):763(M+,12),512(2),440(2),368(17),176(9),104(9),91(100),73(15),56(11)
IR(CHCl3)cm-1:1748,1672
1H-NMR(CDCl3)δ:0.29(18H,s),1.50(3H,d,J=7.5Hz),1.51(3H,d,J=7Hz),1.59(3H,d,J=7.5Hz),1.72(3H,d,J=7Hz),5.08-5.24(5H,m),5.37(1H,q,J=7Hz),7.28-7.39(5H,m),7.45(1H,dif t,J=1Hz),7.80(2H,br s),7.92(2H,A 2B2,J=8.5Hz),8.12(2H,A2 B 2,J=8.5Hz),8.22(1H,br s,CONH).
例10:Am-55s(5)的乳酸四聚体酯(羧酸)
[化13]
在大气压的氢气环境下,对上述得到的化合物11(102mg,0.134mmol)钯-碳(10%,10mg)的甲醇(5ml)悬浮液进行30分钟催化还原。按照常规方法进行处理后,用硅胶柱色谱[以氯仿~甲醇-氯仿(19∶1)洗脱]对残渣进行纯化,作为无色泡状物得到标记化合物12(89mg,99%)。
MS(m/z):673(M+,69),601(42),370(79),368(71),296(45),176(88),149(62),104(65),73(100),55(58),45(49)
IR(KBr)cm-1:1753,1726,1652
1H-NMR(CDCl3)δ:0.31(18H,s),1.56(3H,d,J=7Hz),1.57(3H,d,J=7.5Hz),1.62(3H,d,J=7Hz),1.73(3H,d,J=7.5Hz),5.12-5.28(3H,m),5.40(1H,q,J=7Hz),7.46(1H,br s),7.76(2H,br s),7.87(1H,br s,CONH),7.95(2H,A 2B2,J=8Hz),8.19(2H,A2 B 2,J=8Hz).
例11:Am-81(13)的N-乙氧基羰基体(14)
[化14]
冰冷Am-81(13,110mg,0.301mmol)的DMF(3ml)溶液,添加氢化钠(60%,30mg,0.750mmol)搅拌10分钟。添加氯甲酸乙酯(72μl,0.753mmol),再于冰冷下搅拌2小时。加入饱和氯化铵水溶液,用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱[以苯-乙酸乙酯(119∶1)洗脱]对残渣进行纯化,再进行重结晶,回收13(23mg,21%)的同时得到标记化合物14(96mg,73%)。
14:无色微细针状结晶、熔点131-132℃(二氯甲烷-己烷)。
MS(m/z):437(M+,17),422(10),350(7),229(10),214(72),163(100),135(19),103(13),43(11),29(16)
IR(KBr)cm-1:1736,1722,1687
1H-NMR(CDCl3)δ:1.04(3H,t,J=7Hz),1.23(6H,s),1.28(6H,s),1.68(4H,s),3.94(3H,s),4.12(2H,q,J=7Hz),6.98(1H,dd,J=8,2.5Hz),7.09(1H,d,J=2.5Hz),7.33(1H,d,J=8Hz),7.72(2H,A 2B2,J=8Hz),8.08(2H,A2 B 2,J=8Hz).
例12:Am-580乙酯(15)的N-乙氧基羰基体(16)
[化15]
采用与制备上述14时同样的方法,由15(120mg,0.317mmol)得到169mg的反应混合物。将其溶解于乙醇(3ml)中,50℃下过热搅拌1.5小时后,馏去溶剂。用硅胶柱色谱[以苯-乙酸乙酯(79∶1)洗脱]对残渣进行纯化,再进行重结晶,回收15(12mg,10%)的同时得到标记化合物16(120mg,84%)。
16:无色棱晶、熔点125-126℃(二氯甲烷-己烷)
MS(m/z):451(M+,1),406(1),215(100),172(4),157(5),43(4)
IR(KBr)cm-1:1737,1708,1688
1H-NMR(CDCl3)δ:1.02(3H,t,J=7Hz),1.25(6H,s),1.28(6H,s),1.38(3H,t,J=7Hz),1.68(4H,s),4.13(2H,q,J=7Hz),4.37(2H,q,J=7Hz),7.31(2H,A 2B2,J=8Hz),7.35(1H,d,J=8Hz),7.49(1H,dd,J=8,2Hz),7.67(1H,d,J=2Hz),8.08(2H,A2 B 2,J=8Hz).
实施例13:Am-580的丙酸酯类似物(18)
[化16]
向化合物17(39mg,0.168mmol)的苯(2.5ml)溶液中,加入亚硫酰氯(122μl,1.67mmol)和DMF(1滴),加热回流1小时。馏去挥发性物质后,添加苯(3ml),再次馏去并对残渣进行减压干燥。对该残渣的二氯甲烷(1ml)溶液进行冰冷,向其中添加3-(4-氨基苯基)丙酸甲酯(36mg,0.201mmol)和三乙胺(117μl,0.841mmol)的二氯甲烷(2ml)溶液,在0℃下搅拌30分钟,再于室温下搅拌16小时。加入饱和碳酸氢钠溶液并用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱(以氯仿洗脱)对残渣进行纯化,再进行重结晶,回收17(6mg,15%)的同时得到标记化合物18(55mg,83%)。
18:无色针状结晶、熔点118.5-119.5℃(二氯甲烷-己烷)
MS(m/z):393(M+,15),249(4),215(100),172(5),157(10),91(6),43(9)
IR(KBr)cm-1:1731,1638
1H-NMR(CDCl3)δ:1.29(6H,s),1.30(6H,s),1.70(4H,s),2.61(2H,t,J=8Hz),2.92(2H,t,J=8Hz),3.66(3H,s),7.17(2H,A 2B2,J=8.5Hz),7.36(1H,d,J=8Hz),7.55(1H,dd,J=8,2Hz),7.56(2H,A2 B 2,J=8.5Hz),7.86(1H,d,J=2Hz),7.99(1H,br s,CONH).
例14:Am-580的丙酸类似物(19)
[化17]
将上述得到的化合物18(30mg,76.3mol)溶解于甲醇-1,2-二甲氧基乙烷-水(3∶2∶1,3ml)中,加入氢氧化锂一水合物(6.5mg,0.155mmol),加热回流1小时。冰冷反应溶液后,加入盐酸溶液(1N,155μl,0.155mmol)并用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。对残渣进行重结晶,得到标记化合物19(28mg,97%)。
无色棱晶、熔点172.5-174℃(二氯甲烷-己烷)
MS(m/z):379(M+,15),215(100),157(12),131(5),128(6),91(5),43(12)
IR(KBr)cm-1:1704,1638
1H-NMR(CDCl3)δ:1.30(6H,s),1.32(6H,s),1.71(4H,s),2.68(2H,t,J=8Hz),2.96(2H,t,J=8Hz),7.22(2H,A 2B2,J=8.5Hz),7.39(1H,d,J=8Hz),7.54(1H,dd,J=8,2Hz),7.57(2H,A2 B 2,J=8.5Hz),7.75(1H,br s,CONH),7.85(1H,d,J=2Hz).
例15:Am-80的丙酸酯类似物(21)
[化18]
将4-[2-(甲氧基羰基)乙基]苯甲酸(77mg,0.370mmol)和亚硫酰氯(135μl,1.85mmol)的苯溶液(3ml)加热回流1小时。进行与实施例13相同的处理得到酰基氯。将其溶解于二氯甲烷(1ml),冰冷下向该溶液中滴加20(50mg,0.246mmol)和三乙胺(171μl,1.23mmol)的二氯甲烷(1ml)溶液并搅拌10分钟后,再于室温下搅拌4小时。加入饱和碳酸氢钠溶液并用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱[以苯-乙酸乙酯(8∶1)洗脱]对残渣进行纯化,再进行重结晶,得到标记化合物21(94mg,97%)。
21:无色棱晶、熔点135-136℃(二氯甲烷-己烷)
MS(m/z):393(M+,35),378(100),362(5),191(76),131(35),103(18),91(10),59(7),43(10)
IR(KBr)cm-1:1707,1659
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.69(4H,s),2.67(2H,t,J=7.5Hz),3.02(2H,t,J=7.5Hz),3.68(3H,s),7.30(1H,d,J=8.5Hz),7.32(2H,A 2B2,J=8Hz),7.41(1H,dd,J=8.5,2.5Hz),7.53(1H,d,J=2.5Hz),7.69(1H,br s,CONH),7.80(2H,A2 B 2,J=8Hz).
例16:Am-80的丙酸类似物(22)
[化19]
采用与例14同样的方法,用氢氧化锂水解21(50mg,0.127mmol),进行后处理后,对残渣进行重结晶,得到标记化合物22(45mg,93%)。
无色针状结晶、熔点229-230℃(甲醇-二氯甲烷)
MS(m/z):379(M+,33),364(100),177(92),131(14),107(22),103(20),77(16)
IR(KBr)cm-1:1711,1616
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.69(4H,s),2.72(2H,t,J=7.5Hz),3.04(2H,t,J=7.5Hz),7.30(1H,d,J=8.5Hz),7.33(2H,A 2B2,J=8.5Hz),7.41(1H,dd,J=8.5,2Hz),7.53(1H,d,J=2Hz),7.73(1H,br s,CONH),7.80(2H,A2 B 2,J=8.5Hz).
例17:Am-80与丙氨酸甲酯的缩合
[化20]
向冰冷的Am-80(1,60mg,0.171mmol)和三乙胺(95μl,0.683mmol)的二氯甲烷(3ml)溶液中添加氯甲酸异丁酯(24μl,0.185mmol),搅拌1小时。在该反应液中加入L-丙氨酸甲酯盐酸盐(29mg,0.208mmol),再于室温下搅拌16小时。加入饱和碳酸氢钠溶液,用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。用硅胶柱色谱(以5-10%甲醇-氯仿洗脱)对残渣进行纯化,回收1(6.5mg,11%)的同时得到标记化合物23(64mg,86%)。
23:无色饴状物质
MS(m/z):436(M+,58),421(84),334(17),318(100),234(26),174(23),104(62),76(25),43(34)
IR(CHCl3)cm-1:1733,1657
1H-NMR(CDCl3)δ:1.27(12H,s),1.50(3H,d,J=7Hz),1.68(4H,s),3.75(3H,s),4.74(1H,dq,J=7.5,7Hz),7.22(1H,br d,J=7.5Hz,NH),7.27(1H,d,J=8.5Hz),7.51(1H,dd,J=8.5,2Hz),7.65(2H,A 2B2,J=8.5Hz),ca.7.64-7.67(1H,m),7.73(2H,A2 B 2,J=8.5Hz),8.69(1H,br s,CONH).
例18:Am-80与丙氨酸甲酯缩合物的水解
[化21]
采用与例14同样的方法,将上述得到的化合物23(61mg,0.140mmol)溶解于甲醇-1,2-二甲氧基乙烷-水(3∶2∶1,3ml)中,加入氢氧化锂一水合物(7mg,0.167mmol)加热回流1小时。将反应溶液冰冷后,加入盐酸溶液(1N,167μl,0.167mmol)并用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂。对残渣进行重结晶,得到标记化合物24(51mg,86%)。
无色棱晶、熔点197-198℃(二氯甲烷-乙酸乙酯)
MS(m/z):422(M+,57),407(89),318(100),220(34),174(30),104(73),76(36),43(45)
IR(KBr)cm-1:1720,1660,1624
1H-NMR(DMSO-d6)δ:1.23(6H,s),1.24(6H,s),1.41(3H,d,J=7Hz),1.64(4H,s),4.43(1H,dq,J=7,7Hz),7.28(1H,d,J=8.5Hz),7.57(1H,dd,J=8.5,2Hz),7.67(1H,d,J=2Hz),7.99(2H,A 2B2,J=8.5Hz),8.04(2H,A2 B 2,J=8.5Hz),8.81(1H,d,J=7Hz,NH),10.19(1H,br s,CONH).
例19:Am-80与缩水甘油基甘氨酸甲酯的缩合
[化22]
采用与例17同样的方法,使Am-80(1,60mg,0.171mmol)与缩水甘油基甘氨酸甲酯盐酸盐(38mg,0.208mmol)缩合。进行后处理后,用硅胶柱色谱(以5-10%甲醇-氯仿洗脱)对残渣进行纯化,回收1(9mg,15%)的同时得到标记化合物25(58mg,71%)。
25:无色针状结晶、熔点240-242℃(甲醇-二氯甲烷)
MS(m/z):479(M+,92),464(48),375(56),334(30),318(100),291(26),160(67),104(89),88(42)
IR(KBr)cm-1:1745,1655,1637
1H-NMR(DMSO-d6)δ:1.23(6H,s),1.24(6H,s),1.64(4H,s),3.62(3H,s),3.87(2H,d,J=6Hz),3.94(2H,d,J=6Hz),7.28(1H,d,J=8.5Hz),7.57(1H,dd,J=8.5,2Hz),7.67(1H,d,J=2Hz),8.00(2H,A 2B2,J=9Hz),8.04(2H,A2 B 2,J=9Hz),8.38(1H,t,J=6Hz,NH),8.95(1H,t,J=6Hz,NH),10.19(1H,br s,CONH).
例20:Am-80与缩水甘油基甘氨酸甲酯缩合物的水解
[化23]
采用与例18同样的方法,在加热回流下用氢氧化锂一水合物(6mg,0.143mmol)水解上述得到的化合物25(50mg,0.104mmol)。按照常规方法进行处理后,对残渣进行重结晶,得到标记化合物26(44mg,91%)。
无色棱晶、熔点228-229℃(甲醇-乙酸乙酯)
MS(m/z):465(M+,15),432(18),408(47),393(83),375(83),347(34),336(63),318(90),206(44),160(100),149(49),104(100),76(51),43(47)
IR(KBr)cm-1:1715,1664,1634
1H-NMR(DMSO-d6)δ:1.23(6H,s),1.24(6H,s),1.64(4H,s),3.76(2H,d,J=6Hz),3.94(2H,d,J=6Hz),7.28(1H,d,J=8.5Hz),7.57(1H,dd,J=8.5,2Hz),7.67(1H,d,J=2Hz),8.00(2H,A 2B2,J=8.5Hz),8.04(2H,A2 B 2,J=8.5Hz),8.23(1H,t,J=6Hz,NH),8.93(1H,t,J=6Hz,NH),10.19(1H,br s,CONH).
例21:Am-81(13)的N-(4-甲氧基羰基)-苯甲酰(27)
[化24]
采用与例11同样的方法,在DMF(3ml)中冰冷下用氢化钠(60%,22mg,0.550mmol)和氯化对苯二甲酸单甲基酯(Terephthalic acidmonomethyl ester chloride)(71mg,0.358mmol)处理Am-81(13,100mg,0.274mmol)。用硅胶柱色谱[以己烷-乙酸乙酯(6∶1)洗脱]对反应产物进行纯化,回收13(22mg,22%)的同时得到标记化合物27(71mg,49%)。
MS(m/z):527(M+,13),512(4),163(100),135(14),103(10),77(5)
IR(KBr)cm-1:1720,1696,1668
1H-NMR(CDCl3)δ:1.05(6H,s),1.23(6H,s),1.61(4H,s),3.92(6H,s),6.91(1H,d,J=2Hz),6.96(1H,dd,J=8.5,2Hz),7.29(1H,d,J=8.5Hz),7.75(4H,A 2B2,J=8Hz),8.01(4H,A2 B 2,J=8Hz).
例22:4-(3,5-双三甲基硅烷基(シラニル)苯甲酰氨基)苯丙酸
[化25]
冰冷3,5-双(三甲基甲硅烷基)苯甲酸(120mg,0.451mmol)和氰尿酰氯(125mg,0.678mmol)的丙酮(4ml)溶液,添加三乙胺(251μl,1.80mmol),搅拌5分钟。再于室温下搅拌3.5小时后,添加3-(4-氨基苯基)丙酸甲酯(121mg,0.676mmol)并进一步搅拌16小时。加入饱和碳酸氢钠溶液并用乙酸乙酯萃取,按照常规方法进行处理后,用残硅胶色谱[以苯-乙酸乙酯(14∶1)洗脱]分离残渣,然后进行重结晶,作为无色鳞片状结晶得到4-(3,5-双三甲基硅烷基苯甲酰氨基)苯丙酸甲酯(169mg,88%)。
Mp:119-120.5℃和136-137℃(二氯甲烷-己烷)
MS(m/z):427(M+,25),249(100),221(9),73(64)
IR(KBr)cm-1:1733,1643,1600
1H-NMR(CDCl3)δ:0.32(18H,s),2.64(2H,t,J=8Hz),2.95(2H,t,J=8Hz),3.68(3H,s),7.22(2H,A2B2,J=8.5Hz),7.58(2H,A2B2,J=8.5Hz),7.72(1H,br s,NH),7.82(1H,dd,J=1,1Hz),7.93(2H,d,J=1Hz).
将上述甲酯(556mg,1.30mmol)溶解于甲醇-DME-水(3∶2∶1,9ml)中,添加氢氧化锂一水盐(LiOH·H2O,82mg,1.95mmol),加热回流2小时。冰冷后,加入盐酸溶液(1N,2.00ml,2.00mmol),用乙酸乙酯进行萃取。水洗有机层,在无水硫酸钠上干燥后,馏去溶剂对残渣进行重结晶,作为无色棱晶得到标记化合物(522mg,97%)。
Mp:151-152℃(二氯甲烷-己烷)
MS(m/z):413(M+,22),398(3),249(100),221(9),133(7),83(9),73(71)
IR(KBr)cm-1:1706,1639
1H-NMR(CDCl3)δ:0.31(18H,s),2.69(2H,t,J=7.5Hz),2.97(2H,t,J=7.5Hz),7.23(2H,A 2B2,J=8.5Hz),7.59(2H,A2 B 2,J=8.5Hz),7.78(1H,br s,NH),7.81(1H,dd,J=1,1Hz),7.93(2H,d,J=1Hz).
例23:4-甲酰基-N-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)苯甲酰胺
[化26]
将Am-80(320mg,0.912mmol)和三乙胺(152μl,1.09mmol)的四氢呋喃(5ml)溶液冷却至-20℃,对其滴加氯甲酸甲酯(82μl,1.06mmol)的四氢呋喃溶液,搅拌1小时。对反应液进行硅藻土过滤后,用四氢呋喃(3ml)洗涤。冰冷滤液,添加NaBH4(208mg,5.47mmol)后,一边剧烈搅拌一边缓慢滴加水(4ml),再继续搅拌18小时至26℃。加入饱和氯化铵溶液并用乙酸乙酯萃取,按照常规方法进行处理。用硅胶色谱[以己烷-乙酸乙酯(2∶1)洗脱]分离残渣,再进行重结晶,作为无色棱晶得到4-羟甲基-N-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)苯甲酰胺(290mg,94%)。
Mp:161-162.5℃(二氯甲烷-己烷)
MS(m/z):337(M+,27),322(87),135(100),107(18),89(34),77(28)
IR(KBr)cm-1:1634
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.69(4H,s),1.93(1H,t,J=4.5Hz,OH),4.78(2H,d,J=4.5Hz),7.30(1H,d,J=8.5Hz),7.43(1H,dd,J=8.5,2.5Hz),7.47(2H,A 2B2,J=8Hz),7.54(1H,d,J=2.5Hz),7.76(1H,br s,NH),7.85(2H,A2 B 2,J=8Hz).
向上述醇(1.891g,5.61mmol)的二氯甲烷(35ml)溶液中添加二氧化锰(3.905g,44.9mmol),一边搅拌一边加热回流2小时。将反应液在减压下进行硅藻土过滤,用氯仿洗涤硅藻土。馏去溶剂后,对残渣进行重结晶,作为无色棱晶得到标记化合物(1.802g,96%)。
Mp:185.5-186.5℃(二氯甲烷-己烷)
MS(m/z):335(M+,32),320(100),133(68),105(28),77(24),51(9)
IR(KBr)cm-1:1690,1662
1H-NMR(CDCl3)δ:1.29(6H,s),1.30(6H,s),1.70(4H,s),7.33(1H,d,J=8.5Hz),7.44(1H,dd,J=8.5,2Hz),7.53(1H,d,J=2Hz),7.79(1H,br s,NH),7.99(2H,A 2B2,J=8.5Hz),8.03(2H,A2 B 2,J=8.5Hz).
例24:4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]肉桂酸
[化27]
4-甲酰基-N-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)苯甲酰胺(1.765g,5.27mmol)和膦酰基乙酸三乙酯(1.523g,6.80mmol)的乙醇(40ml)溶液中加入碳酸钾(910mg,6.59mmol),在62-64℃下搅拌3小时。冰冷反应液后,加入饱和氯化铵溶液并用乙酸乙酯萃取。按照常规方法处理后,用硅胶色谱[以苯-乙酸乙酯(39∶1~14∶1)洗脱]分离残渣,进行重结晶,作为无色针状结晶得到4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]肉桂酸乙基(2.076g,97%)。
Mp:166-166.5℃(二氯甲烷-己烷)
MS(m/z):405(M+,31),390(100),203(60),175(22),102(29),91(20)
IR(KBr)cm-1:1697,1663,1644
1H-NMR(CDCl3)δ:1.28(6H,s),1.30(6H,s),1.35(3H,t,J=7Hz),1.70(4H,s),4.29(2H,q,J=7Hz),6.52(1H,d,J=16Hz),7.31(1H,d,J=8.5Hz),7.43(1H,dd,J=8.5,2.5Hz),7.53(1H,d,J=2.5Hz),7.63(2H,A 2B2,J=8Hz),7.71(1H,d,J=16Hz),7.74(1H,br s,NH),7.89(2H,A2 B 2,J=8Hz)
将上述酯(109mg,0.269mmol)溶解于甲醇-DME-水(3∶2∶1,4.2ml)中,添加氢氧化锂一水盐(LiOH·H2O,15mg,0.357mmol)加热回流1小时。冰浴冷却后,加入盐酸溶液(1N,0.36ml,0.36mmol)并用乙酸乙酯进行萃取。水洗有机层,用无水硫酸钠干燥后,馏去溶剂。对残渣进行重结晶,作为无色棱晶得到标记化合物(96mg,95%)。
Mp:226-227℃(二氯甲烷)
MS(m/z):377(M+,29),362(100),175(96),147(18),102(17),91(41),44(32)
IR(KBr)cm-1:1682,1646,1625
1H-NMR(CDCl3)δ:1.29(6H,s),1.31(6H,s),1.70(4H,s),6.54(1H,d,J=16Hz),7.32(1H,d,J=8.5Hz),7.43(1H,dd,J=8.5,2.5Hz),7.53(1H,d,J=2.5Hz),7.66(2H,A 2B2,J=8Hz),7.74(1H,br s,NH),7.81(1H,d,J=16Hz),7.91(2H,A2 B 2,J=8Hz).
产业适用性
由于本发明的化合物具有吸收至生物体内后转换为类视色素的性质,因此作为类视色素前体药物化合物有用。
Claims (6)
1.下述通式(I)所表示的化合物或其盐、或其酯:
[化1]
[式中,R1、R2、R3、R4及R5分别独立地表示氢原子、低级烷基、或者三低级烷基甲硅烷基,它们当中相邻的2个低级烷基可以结合到一起,与它们所结合的苯环上的碳原子共同形成具有1个或者2个以上烷基的5元环或者6元环;X表示-NH-CO-、-CO-NH-、-N(COR6)-CO-、-CO-N(COR7)-、-CO-N[CON(R8)(R9)]-或者-N[CON(R10)(R11)](R6及R7表示低级烷氧基(该烷氧基可具有取代基)或者苯基(该苯基具有至少1个烷氧基羰基或者羧基作为取代基,也可具有其它取代基),R8、R9、R10及R11分别独立地表示氢原子或者低级烷基);Z表示-Y-CH(R12)-COOH、-CHO、-CH=CH-COOH或者-COOR13(Y表示单键、-CH2-、-CH(OH)-、-CO-、-CO-NH-或者-CO-NH-CH2-CO-NH-,R12表示氢原子或者低级烷基,R13表示氢原子、-CH(R14)-COOH(R14表示氢原子、低级烷基或者羟基)、-[CH2CH2-O]n-CH2-CH2-OH(n表示1至100的整数)、-CH2-O-[CH2CH2-O]m-CH2-OH(m表示1至100的整数)、或者-[CH(CH3)-CO-O]p-CH(CH3)-COOH(p表示1至100的整数),X为-NH-CO-或者-CO-NH-时,R13表示氢原子以外的基团]。
2.权利要求1所述的化合物或其盐、或其酯,其中X与Z在它们所结合的苯环上为对位。
3.权利要求1所述的化合物或其盐、或其酯,其中R1、R4及R5为氢原子,R2及R3相互结合并与它们所结合的苯环共同形成5,5,8,8-四甲基-5,6,7,8-四氢萘环。
4.权利要求1所述的化合物或其盐、或其酯,其中R1、R3及R5为氢原子,R2及R4为三甲基甲硅烷基。
5.权利要求1所述的化合物或其盐、或其酯,其中X为-N(COR6)-CO-或者-CO-N(COR7)-(R6或者R7为甲氧基或者乙氧基),Z为-COOR13(R13为氢原子)。
6.权利要求1所述的化合物或其盐、或其酯,其中X为-NH-CO-(该酰胺基的碳原子与Z取代的苯环结合),Z为-Y-CH(R12)-COOH(Y为-CH2-、-CH(OH)-或者-CO-)或者-COOR13。
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US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
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US20140121407A1 (en) * | 2011-07-05 | 2014-05-01 | Research Foundation Itsuu Laboratory | Deuterated phenylpropionic acid derivative |
US20220259157A1 (en) * | 2019-06-28 | 2022-08-18 | Carl Wagner | Compositions Comprising a Retinoid X Receptor (RXR) Agonist, a Retinoic Acid Receptor (RAR) Agonist, or a Dual RXR/RAR Agonist |
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JPS6122047A (ja) | 1984-07-07 | 1986-01-30 | Koichi Shiyudo | 安息香酸誘導体 |
JPS6176440A (ja) | 1984-09-19 | 1986-04-18 | Koichi Shiyudo | 安息香酸誘導体 |
JP2761023B2 (ja) | 1989-03-20 | 1998-06-04 | 大鵬薬品工業株式会社 | 新規安息香酸誘導体及びその製造方法 |
US5675024A (en) | 1995-11-22 | 1997-10-07 | Allergan | Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity |
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US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
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