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Publication numberCN1144091 A
Publication typeApplication
Application numberCN 93108417
Publication date5 Mar 1997
Filing date11 Jun 1993
Priority date11 Jun 1992
Also published asCA2137819A1, EP0649409A1, US5324840, US5475113, US6624188, WO1993025530A2, WO1993025530A3
Publication number93108417.2, CN 1144091 A, CN 1144091A, CN 93108417, CN-A-1144091, CN1144091 A, CN1144091A, CN93108417, CN93108417.2
InventorsRA钱德拉拉纳
Applicant阿勒根公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Compounds having retinoid-like activity
CN 1144091 A
Abstract  translated from Chinese
本发明公开了治疗若干种用视网膜样化合物可治疗的疾病和症状的药物组合物和方法,其中用于治疗的化合物基本上无致畸作用,对皮肤没有刺激。 The present invention discloses a method of treating retinal-like compounds with several diseases and conditions treatable by pharmaceutical compositions and methods, wherein the compound for the treatment of substantially no teratogenic effect, on the skin without irritation. 该方法适用于治疗怀孕或育龄期的雌性哺乳动物,包括人类在内。 This method is suitable for the treatment of pregnant or of childbearing age in female mammals, including humans.
Claims(62)  translated from Chinese
1.一种给予包括人类在内的哺乳动物一种药物组合物的方法,所说的药物组合物含有一种有效剂量的式(i)或式(ii)化合物 A given mammal, including a human a pharmaceutical composition of the method, said pharmaceutical composition comprising an effective amount of a compound of formula (i) or formula (ii) 其中的符号定义如下:R1为低级烷基、Cl、Br、或I;R2为H、低级烷基、Cl、Br、和I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基,或者R5和R6可以不存在;A为(CH2)n,其中的n为0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷基,含2-6个碳并有1或2个双键的烯基,含2-6个碳并有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR6、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中的R7含1-5个碳的烷基、环烷基或烯基,R6为含1-10个碳的烷基或含5-10个碳的环烷基,或者R6为苯基或低级烷基苯基,R9和R10分别为H、含1-10个碳的烷基,或5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基,苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;X1为CR5或N,当X1为N时,其可位于6元芳环的任何未取代的位置上;Y为苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、咪唑基和噁唑基;Z分别为H、或者是一或二个取代基,所说的取代基是低级烷基、低级烷氧基、低级硫代烷氧基、含1个或多个双键的低级烯基、含1或多个双键的低级烯氧基,或含1个或多个双键的低级硫代烯氧基,或Z为-(CR14)4-,或Z为-(CR14)=(CR14)-C(R14)2-,或Z为-(CR14)3-N-,或Z为-(CR14)=(CR14)-X2-,或Z为-C(R14)2-C(R14)2-X2-,或Z为-C(R14)2-CR14=CR14-X2-,或Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或Z为-C(R14)2-C(R14)2-C(R14)2-X2-,其中R14分别为H、低级烷基、低级烷氧基、低级硫代烷氧基、Cl、Br或I,X2为O、S或NR15,R15为H或低级烷基;式(ii)中5元环内的虚线环表示该5元环内有两个双键,X3为O、S、NH或N-低级烷基,X3基团可以在5元环的任何未取代的位置上,所说的化合物基本上无致畸作用,给予所说的组合物以治疗和预防下列一种或多种疾病和症状:皮肤病,恶性细胞过度增殖性疾病,由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖性疾病,自身免疫疾病,免疫学疾病,慢性炎症,与脂质代谢和转移有关的疾病如脂质代谢障碍;干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the symbols are defined as follows: R1 is a lower alkyl group, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, and I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2, NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H, lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or lower thioalkoxy, or R5 and R6 may be absent; A is (CH2) n, where n is 0-5, 3-6 carbon lower branched chain alkyl groups, cycloalkyl having 3 to 6 carbon alkyl group containing 2-6 carbon and one or two double bonds alkenyl containing 2-6 carbon and one or two triple bonds alkynyl; B is H, COOH or a pharmaceutically acceptable salts, COOR6, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 contains 1-5 carbons, alkyl, cycloalkyl group or alkenyl group, R6 is an alkyl group having 1 to 10 carbon containing 5-10 carbons or a cycloalkyl group, or R6 is phenyl or lower alkylphenyl, R9 and R10 are H, containing 1- 10 carbons, or 5 to 10 carbon cycloalkyl group, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, R13 containing 2-5 carbon divalent alkyl group; X1 is CR5 or N, when X1 is N, which may be located at any unsubstituted position on the six-membered aryl ring; Y is phenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl; Z are H, or one or two substituents, said substituent is lower alkyl, lower alkoxy, lower thioalkoxy, containing one or more double bonds lower alkenyl group, containing one or more double bonds a lower alkenyl group, or an one or more double bonds thio lower alkenyl group, or Z is - (CR14) 4-, or Z is - (CR14) = (CR14) -C (R14) 2-, or Z is - (CR14 ) 3-N-, or Z is - (CR14) = (CR14) -X2-, or Z is -C (R14) 2-C (R14) 2-X2-, or Z is -C (R14) 2- CR14 = CR14-X2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-X2-, wherein each R14 is H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl, Br or I, X2 is O, S or NR15, R15 is H or a lower alkyl group; the formula (ii) 5-membered ring in the dotted circle within the representation within the five-membered ring has two double bonds, X3 is O, S, NH, or N- lower alkyl, X3 groups may be 5 yuan any non-substituted positions on the ring, said compound is substantially no teratogenic effect, administering the compositions to treat and prevent disease and one or more of the following symptoms: skin diseases, malignant hyperproliferative cell disease, atherosclerosis, neointimal hyperplasia caused by the sclerosis and restenosis, non-malignant cells hyperproliferative diseases, autoimmune diseases, immunological diseases, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism barriers; dry eye; promote wound healing; change and prevent sun damage in the skin.
2.按权利要求1的方法,其中化合物为式(i)定义的化合物。 2. A method according to claim 1, wherein the compound is a compound of formula (i) defined.
3.按权利要求1的方法,其中化合物为式(ii)定义的化合物。 3. The method according to claim 1, wherein the compound is a compound of formula (ii) definition.
4.按权利要求2的方法,其中化合物为式(i)中Y为苯基,X1CH,Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-的化合物。 4. The method according to claim 2, wherein the compound is of formula (i) in which Y is phenyl, X1CH, Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2 compounds -.
5.按权利要求4的方法,其中Z为-C(CH3)2-C(CH2)2-C(CH2)2-C(CH3)2-。 5. The method according to claim 4, wherein Z is -C (CH3) 2-C (CH2) 2-C (CH2) 2-C (CH3) 2-.
6.按权利要求5的方法,其中R1为甲基。 6. The method according to claim 5, wherein R1 is methyl.
7.按权利要求6的方法,其中R3选自甲基、乙基、异丙基、氯代和溴代。 7. A method according to claim 6, wherein R3 is selected from methyl, ethyl, isopropyl, chloro and bromo.
8.按权利要求7的方法,其中AB为COOR8基团。 8. The method according to claim 7, wherein AB is COOR8 group.
9.按权利要求2的方法,其中R8为H或乙基。 9. The method according to claim 2, wherein R8 is H or ethyl.
10.按权利要求2的方法,其中Y为噻吩基或呋喃基,X1为CH,Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-。 10. The method according to claim 2, wherein Y is thienyl or furyl, X1 is CH, Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-.
11.按权利要求10的方法,其中Z为-C(CH3)2-CH2-CH2--C(CH3)2-。 11. The method according to claim 10, wherein Z is -C (CH3) 2-CH2-CH2 - C (CH3) 2-.
12.按权利要求11的方法,其中R1为甲基。 12. The method according to claim 11, wherein R1 is methyl.
13.按权利要求11的方法,其中R3选自甲基、乙基、异丙基、氯代和溴代。 13. The method according to claim 11, wherein R3 is selected from methyl, ethyl, isopropyl, chloro and bromo.
14.按权利要求13的方法,其中AB为COOR8基团。 14. The method according to claim 13, wherein AB is COOR8 group.
15.按权利要求14的方法,其中R8为H或乙基。 15. The method according to claim 14, wherein R8 is H or ethyl.
16.按权利要求1的方法,其中X1为CH,Z为-C(R14)2-C(R14)2-C(R14)2-X2-,而X2为O或S。 16. The method according to claim 1, wherein X1 is CH, Z is -C (R14) 2-C (R14) 2-C (R14) 2-X2-, and X2 is O or S.
17.一种给予育龄期或怀孕雌性哺乳动物包括人类女性在内以一种实质上无致畸作用的药物组合物的方法,所说的组合物含有一种有效剂量的式(i)或式(ii)化合物 17. A grant of childbearing age or pregnant women, including female mammals, including humans, to pharmaceutical compositions of a substantially non-teratogenic effects, said composition comprising an effective amount of formula (i) or formula (ii) Compound 其中的符号定义如下:R1为低级烷基、Cl、Br、或I;R2为H、低级烷基、Cl、Br、和I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基,或者R5和R6可以不存在;A为(CH2)n,其中n等于0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R8为含1-10个碳的烷基或含5-10个碳的环烷基,或者R8为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基或5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基,苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;X1为CR5或N,当X1为N时,其可位于6元芳环的任何未取代的位置上;Y为苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、咪唑基和噁唑基;Z为H、或者一或二个取代基,该取代基为低级烷基、低级烷氧基、低级硫代烷氧基、具有一个或多个双键的低级烯基、具有一个或多个双键的烯氧基,具有一个或多个双键的硫代烯氧基,或Z为-(CR14)4-,或Z为-(CR14)=(CR14)-C(R14)2-,或Z为-(CR14)3-N-,或Z为-(CR14)=(CR14)-X2-,或Z为-C(R14)2-C(R14)2-X2-,或Z为-C(R14)2-CR14=CR14-X2-,或Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或Z为-C(R14)2-C(R14)2-C(R14)2-X2-,其中R14分别为H、低级烷基、低级烷氧基、低级硫代烷氧基、Cl、Br或I,X2为O、S或NR15,R15为H或低级烷基;式(ii)中5元环内的虚线环表示在5元环内有两个双键,X3为O、S、NH或N-低级烷基,X3基团可位于5元芳环的任何未取代的位置上,给予所说的组合物以便治疗和预防下列一种或多种疾病和症状:皮肤病,恶性细胞过度增殖疾病,由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖疾病,自身免疫疾病,免疫学疾病,慢性炎症,与脂质代谢和转移有关的疾病如脂质代谢障碍;干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the symbols are defined as follows: R1 is a lower alkyl group, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, and I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2, NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H, lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or lower thioalkoxy, or R5 and R6 may be absent; A is (CH2) n, where n is equal to 0-5, 3-6 carbon lower branched chain alkyl group containing 3-6 carbon cycloalkyl group, containing 2-6 carbons and 1 or 2 double bonds, alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, a cycloalkyl group or alkenyl group, R8 is an alkyl group having 1 to 10 carbon containing 5-10 carbons or a cycloalkyl group, or R8 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 months carbon alkyl group or a 5 to 10 carbon cycloalkyl group, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is a lower alkoxy group, R13 containing 2-5 carbon divalent alkyl group; X1 is CR5 or N, when X1 is N, which may be located at any unsubstituted position on the six-membered aryl ring; Y is phenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl; Z is H, or one or two substituents, the substituent is a lower alkyl, lower alkoxy, lower thioalkoxy, lower alkenyl group having one or more double bonds, having one or more double bonds of an alkenyl group having one or more double bonds thio-ene group, or Z is - (CR14) 4-, or Z is - (CR14) = (CR14) -C (R14) 2-, or Z is - (CR14) 3-N-, or Z is - (CR14 ) = (CR14) -X2-, or Z is -C (R14) 2-C (R14) 2-X2-, or Z is -C (R14) 2-CR14 = CR14-X2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-X2-, wherein R14 are H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl, Br or I, X2 is O, S or NR15, R15 is H or lower alkyl; formula (ii) the 5 membered the dotted line represents the inner ring in the five-membered ring has two double bonds, X3 is O, S, NH, or N- lower alkyl, X3 group may be located at any position not substituted on the aromatic 5-membered ring, to give the said composition for the treatment and prevention of disease and one or more of the following symptoms: skin diseases, malignant cell proliferation disorders, atherosclerosis and heart valves caused by neointimal hyperplasia restenosis, non-malignant cell proliferation disease, autoimmune disease, immunological diseases, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism disorders; dry eye; promote wound healing; changes and prevent sun injury to the skin.
18.按权利要求17的方法,其中化合物为式(i)定义的化合物。 18. The method according to claim 17, wherein the compound is a compound of formula (i) defined.
19.按权利要求18的方法,其中化合物为Y为苯基,X1为CH,Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-的式(i)化合物。 19. A method according to claim 18 of the formula 2-, wherein the compound Y is phenyl, X1 is CH, Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) (i) compounds.
20.按权利要求17的方法,其中X1为CH,Z为-C(R14)2-C(R14)2-C(R14)2-X2-,而X2为O或S。 20. The method according to claim 17, wherein X1 is CH, Z is -C (R14) 2-C (R14) 2-C (R14) 2-X2-, and X2 is O or S.
21.一种下式的化合物 21. A compound of the formula 其中R1为低级烷基、Cl、Br、或I;R2为H、低级烷基、Cl、Br、和I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H1低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基;A为(CH2)n,其中n等于0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R8为含1-10个碳的烷基或含5-10个碳的环烷基,或者R8为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基、5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基、苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;R20分别为H或低级烷基,Y1为噻吩基、呋喃基或吡啶基。 Wherein R1 is a lower alkyl group, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, and I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2 , NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H1 lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or lower thioalkoxy; A is (CH2) n, where n is equal to 0-5, 3-6 carbon lower branched chain alkyl group containing 3-6 carbon cycloalkyl group, containing 2-6 carbons and 1 or 2 double bond of an alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, cycloalkyl or alkenyl group, R8 is an alkyl group having 1 to 10 carbon containing 5-10 carbon atoms or a cycloalkyl group, or R8 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 carbon alkyl, 5-10 carbon cycloalkyl, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, R13 is a divalent alkyl group containing 2-5 carbon group; R20 are independently H or lower alkyl, Y1 is thienyl, furyl or pyridyl.
22.按权利要求21的化合物,其中R20为甲基。 22. A compound according to claim 21, wherein R20 is methyl.
23.按权利要求21的化合物,其中R2、R5和R6为H。 23. A compound according to claim 21, wherein R2, R5 and R6 are H.
24.按权利要求21的化合物,其中R1为甲基。 24. The compound according to claim 21, wherein R1 is methyl.
25.按权利要求21的化合物,其中R3为甲基、Cl或Br。 25. The compound according to claim 21, wherein R3 is methyl, Cl or Br.
26.按权利要求21的化合物,其中相联的AB为COOR6基团。 26. A compound according to claim 21, wherein the associated AB is COOR6 group.
27.按权利要求26的化合物,其中Y1为噻吩基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 27. A compound according to claim 26, wherein Y1 is a thienyl group, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
28.按权利要求26的化合物,其中Y1为呋喃基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 28. The compound according to claim 26, wherein Y1 is furanyl, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
29.按权利要求26的化合物,其中Y1为吡啶基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 29. The compound according to claim 26, wherein Y1 is a pyridyl group, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
30.一种下式的化合物 30. A compound of the formula 其中R1为低级烷基、Cl、Br、或I;R2为H、低级烷基、Cl、Br、或I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基;A为(CH2)n,其中n等于0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷氧基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R6为含1-10个碳的烷基,或5-10个碳的环烷基,或R8为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基、或5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基、苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;R20分别为H或低级烷基,Y2为苯基、呋喃基或吡啶基,X4为S、O或N-低级烷基。 Wherein R1 is a lower alkyl group, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, or I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2 , NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H, lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or lower thioalkoxy ; A is (CH2) n, where n is equal to 0-5, 3-6 carbon lower branched chain alkyl groups, cycloalkyl having 3 to 6 carbon alkoxy group containing 2-6 carbons and 1 or two double bonds, an alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11 , CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, cycloalkyl or alkenyl group, R6 is 1 to 10 carbon alkyl group, or 5 to 10 carbon cycloalkyl group, or R8 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 carbons, or 5-10 carbons cycloalkyl, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, R13 containing 2-5 carbon atoms a divalent alkyl group; R20 is H or a lower alkyl group, respectively, Y2 is phenyl, furyl or pyridyl, X4 is S, O, or N- lower alkyl.
31.按权利要求30的化合物,其中R20为甲基。 31. A compound according to claim 30, wherein R20 is methyl.
32.按权利要求30的化合物,其中R2、R5和R6为H。 32. A compound according to claim 30, wherein R2, R5 and R6 are H.
33.按权利要求30的化合物,其中R1为甲基。 33. A compound according to claim 30, wherein R1 is methyl.
34.按权利要求30的化合物,其中R3为甲基、Cl或Br。 34. A compound according to claim 30, wherein R3 is methyl, Cl or Br.
35.按权利要求30的化合物,其中相连的AB为COOR8基团,X4为O或S。 35. The compound according to claim 30, wherein AB is connected to a group COOR8, X4 is O or S.
36.按权利要求35的化合物,其中X4为O,Y2为噻吩基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 36. A compound according to claim 35, wherein X4 is O, Y2 is thienyl, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
37.按权利要求35的化合物,其中X4为O,Y2为呋喃基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 37. A compound according to claim 35, wherein X4 is O, Y2 is furanyl, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
38.按权利要求35的化合物,其中X4为O,Y2为吡啶基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 38. A compound according to claim 35, wherein X4 is O, Y2 is a pyridyl group, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
39.按权利要求35的化合物,其中X4为O,Y2为苯基,R1、R3和R20为甲基,R2、R5和R6为H,R8为H或乙基。 39. The compound according to claim 35, wherein X4 is O, Y2 is a phenyl group, R1, R3 and R20 are methyl, R2, R5 and R6 is H, R8 is H or ethyl.
40.一种下式的化合物 40. A compound of the formula 其中R1为低级烷基、Cl、Br、或I;R2为H、低级烷基、Cl、Br、和I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;A为(CH2)n,n等于0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR6、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R6为含1-10个碳的烷基,或5-10个碳的环烷基,或R6为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基、或5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基、苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;Y2为苯基、噻吩基、呋喃基或吡啶基;R21和R22为H或低级烷基,且二者不能同时为H。 Wherein R1 is a lower alkyl group, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, and I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2 , NHR11, N (R11) 2, NHCOR11, or NR11-COR11; A is (CH2) n, n is equal to 0-5, 3-6 carbon lower branched chain alkyl group containing 3-6 carbon cycloalkyl group, containing 2-6 carbons and 1 or 2 double bonds, alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt, COOR6, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, a cycloalkyl group or alkenyl group, R6 is an alkyl group having 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or R6 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 months carbon alkyl group, or 5 to 10 carbon cycloalkyl group, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is a lower alkyl, R13 containing 2-5 carbon divalent alkyl group; Y2 is phenyl, thienyl, furyl or pyridyl; R21 and R22 are H or lower alkyl, and the two can not simultaneously H .
41.按权利要求40的化合物,其中R21为叔丁基,R22为H。 41. A compound according to claim 40, wherein R21 is tert-butyl, R22 is H.
42.按权利要求40的化合物,其中R1为甲基。 42. The compound according to claim 40, wherein R1 is methyl.
43.按权利要求40的化合物,其中R3为甲基、Cl或Br。 43. The compound according to claim 40, wherein R3 is methyl, Cl or Br.
44.按权利要求40的化合物,其中相连的AB为COOR8基团。 44. The compound according to claim 40, wherein AB is connected to a group COOR8.
45.按权利要求44的化合物,其中Y2为噻吩基,R1和R3为甲基,R21为叔丁基,R2和R22为H,R8为H或乙基,相对于R3基团而言,R21基团处于1,3位或1,4位。 45. A compound according to claim 44, wherein Y2 is a thienyl group, R1 and R3 is methyl, R21 is tert-butyl, R2 and R22 is H, R8 is H or ethyl, relative to the R3 group, R21 groups in the 1,3-position or 1,4-position.
46.按权利要求44的化合物,其中Y2为呋喃基,R1和R3为甲基、R21为叔丁基,R2和R22为H,R8为H或乙基,相对于R3基团而言,R22基团处于1,3位或1,4位。 46. The compound according to claim 44, wherein Y2 is a furyl group, R1 and R3 is methyl, R21 is tert-butyl, R2 and R22 is H, R8 is H or ethyl, relative to the R3 group, R22 groups in the 1,3-position or 1,4-position.
47.按权利要求44的化合物,其中Y2为吡啶基,R1和R3为甲基,R22为叔丁基,R2和R22为H,R8为H或乙基,并且相对于R3基团而言,R21基团处于1,3位或1,4位。 47. The compound according to claim 44, wherein Y2 is a pyridyl group, R1 and R3 is methyl, R22 is tert-butyl, R2 and R22 is H, R8 is H or ethyl, and relative to the R3 group, R21 groups in the 1,3-position or 1,4-position.
48.按权利要求44的化合物,其中Y2为苯基,R2和R3为甲基,R22为叔丁基,R2和R22为H,R8为H或乙基,并且相对于R3基团而言,R21基团处于1,3位或1,4位。 48. The compound according to claim 44, wherein Y2 is a phenyl group, R2 and R3 is methyl, R22 is tert-butyl, R2 and R22 is H, R8 is H or ethyl, and relative to the R3 group, R21 groups in the 1,3-position or 1,4-position.
49.一种给予包括人类在内的哺乳动物以一种药物组合物的方法,所说的组合物含有一种有效剂量的下式化合物 49. A administered to a mammal including a human, method of a pharmaceutical composition, said composition comprising an effective amount of a compound of formula of 其中部分示出的环代表选自下组的一个芳环;5元碳环、5元杂芳环、6元碳环和6元杂芳环,其中每一个环可以与也可以不与另一个环缩合;R1为低级烷基、Cl、Br、或IR2为H、低级烷基、Cl、Br、和IR3为低级烷基、Cl、Br、I、或为低级烷氧基、低级硫代烷氧基、COO-低级烷基、COS-低级烷基、NH-低级烷基或N-(低级烷基)2基团,所说的化合物具有视网膜样生物活性,并且实质上无致畸作用,给予所说的组合物以治疗和预防下列一种或多种疾病和症状:皮肤病,恶性细胞过度增殖性疾病,由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖性疾病,自身免疫疾病,免疫学疾病,慢性炎症,与脂质代谢和转移有关的疾病如脂质代谢障碍,干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the cycloalkyl portion is shown a representative selected from the group consisting of an aromatic ring; 5 yuan carbocyclic ring, 5-membered heteroaryl ring, 6-membered carbon ring and a 6-membered heteroaromatic ring, wherein each ring may or may not be another cyclocondensation; R1 is a lower alkyl group, Cl, Br, or IR2 is H, lower alkyl, Cl, Br, and IR3 is a lower alkyl group, Cl, Br, I, or lower alkoxy, lower thioalkoxy, group, COO- lower alkyl, COS- lower alkyl, NH- lower alkyl or N- (lower alkyl) 2 group, said compound having a retina-like biological activity and substantially no teratogenic effect, administering the compositions for the treatment and prevention of disease and one or more of the following symptoms: skin diseases, malignant cells hyperproliferative diseases, atherosclerosis and heart valves caused by neointimal hyperplasia in restenosis, non-malignant cell hyperproliferative diseases, autoimmune diseases, immunological diseases, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism disorders, dry eye; promote wound healing; changes and prevent sun injury to the skin.
50.按权利要求49的方法,其中的化合物具有如下生物学特性,即在用ICR小鼠做测试致畸性的给药试验中,在健康ICR鼠怀孕的第11天,按一次剂量至少为1mg化合物/Kg受试动物体重的量给予所说的鼠以该化合物时,该化合物不会引起胎儿吸除(resorption),不会给受试动物的胚胎造成可检测出的致畸效应。 50. The method according to claim 49, wherein the compound has the following biological characteristics, i.e. by doing tests ICR mice Teratogenicity administration test in healthy ICR mice at day 11 of pregnancy, according to a dose of at least compound 1mg / Kg of the test volume of said animal body weight given to rats when the compound that does not cause fetal gettering (resorption), not to the subject animal embryos resulting teratogenic effect detectable.
51.按权利要求50的方法,其中化合物具有如下的生物学特性,即在无毛雌性小鼠上多处局部涂抹给药两周急性皮肤毒性试验中,其中,在两周试验内的第1、2、3、4、5、8、9、10和11天在无毛鼠背的皮肤上局部涂抹给予日剂量的化合物,按日观察该化合物的局部给药效果,把皮肤鳞片和鳞屑划为0-+5级,皮肤擦伤亦划为0-+5级,0分别表示无鳞片、鳞屑或擦伤,+5分别表示出现严重鳞片、鳞屑或擦伤,该化合物的日剂量为100nmol时不会造成受试动物死亡,鳞屑-鳞片严重程度不超过+2,或小于之,擦伤程度不超过+1,或小于之。 51. The method according to claim 50, wherein the compound has the following biological characteristics, i.e. on hairless female mice were administered for two weeks in various topical acute dermal toxicity test, wherein, in the first two weeks of the test , 2,3,4,5,8,9,10 and 11 days in the hairless mouse dorsal skin topical administration of a compound daily dose, daily topical administration of the compounds observed effect, the skin scales and scales draw 0 to + 5, skin abrasions are also classified as 0- + 5, 0, respectively, no scales, scales or abrasions, + 5 denote severe scales, scales or abrasions, the daily dose of the compound is 100nmol When not cause the death of the animals tested, scales - scales the extent of not more than +2 or less than, the scratch with less than +1, or less than it.
52.一种给予育龄或怀孕雌性哺乳动物包括人类女性在内以一种基本上无致畸作用的药物组合物的方法,所说的组合物包含一种有效剂量的下式化合物 52. A given childbearing age or pregnant female mammals, including the human female, including a pharmaceutical composition in a substantially non-teratogenic effects, said composition comprising an effective amount of a compound of formula 其中部分示出的环代表一选自下组的芳环:5元碳环,5元杂芳环,6元碳环,6元杂芳环,每一环可以与也可以不与另一环缩合;R1为低级烷基、Cl、Br、或IR2为H、低级烷基、Cl、Br、或IR3为低级烷基、Cl、Br、I、或低级烷氧基、低级硫代烷氧基、COO-低级烷基、COS-低级烷基、NH-低级烷基或N-(低级烷基)2基团;所说的组合物具有视网膜样生物活性,给予该组合物能治疗和预防下列一种或多种疾病和症状:皮肤病、恶性细胞过度增殖性疾病、由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖性疾病、自身免疫疾病、免疫学疾病、慢性炎症、与脂质代谢和转移有关的疾病如脂质代谢障碍,干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the partially shown represents a ring selected from the group of aromatic rings: 5-membered carbocyclic ring, a 5-membered heteroaryl ring, 6-membered carbon ring, 6-membered heteroaromatic ring, each ring may or may not be with another ring condensation; R1 is a lower alkyl group, Cl, Br, or IR2 is H, lower alkyl, Cl, Br, or IR3 is a lower alkyl group, Cl, Br, I, or lower alkoxy, lower thioalkoxy , COO- lower alkyl, COS- lower alkyl, NH- lower alkyl or N- (lower alkyl) 2 group; said composition having a retina-like biological activity, the composition is administered to treat and prevent the following one or more diseases and symptoms: skin diseases, malignant cells hyperproliferative disease, atherosclerosis and heart valves caused by neointimal hyperplasia restenosis, non-malignant cell hyperproliferative diseases, autoimmune diseases, the immune learning disorders, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism disorders, dry eye; promote wound healing; changes and prevent sun injury to the skin.
53.按权利要求52的方法,其中化合物具有如下生物学特性,即在用ICR小鼠做测试致畸性的给药试验中,当在健康ICR鼠怀孕的第11天,按至少为1mg化合物/Kg受试动物体重的一次剂量给予所说的鼠以该化合物时,该化合物不会引起胎儿吸除(resorption),不会给受试动物的胚胎造成可检测出的致畸效应。 53. The method according to claim 52, wherein the compound has the following biological characteristics, i.e., for testing using ICR mice administered teratogenicity test, when healthy ICR mice at day 11 of pregnancy, the compound according to at least 1mg / Kg body weight of test animals administered a single dose of said mouse with the compound when the compound does not cause fetal gettering (resorption), not to the subject animal embryos resulting teratogenic effect detectable.
54.按权利要求53的方法,其中化合物具有如下的生物学活性,即在无毛雌性小鼠上多处局部涂敷给药两周急性皮肤毒性试验中,其中,在两周试验内的第1、2、3、4、5、8、9、10和11天在无毛鼠背的皮肤上局部涂敷给予日剂量的化合物,按日观察该化合物的局部给药效果,把皮肤鳞片和鳞屑划为0-+5级,皮肤擦伤亦划为0-+5级,0分别表示无鳞片、鳞屑或擦伤,+5分别表示出现严重鳞片、鳞屑或擦伤,该化合物的日剂量为100nmol时不会造成受试动物死亡,鳞屑-鳞片严重程度不超过+2,或小于之,擦伤程度不超过+1,或小于之。 54. The method according to claim 53, wherein the compound has the following biological activity, i.e., in the hairless female mice were administered two weeks topical application in various acute dermal toxicity test, wherein, in the first two weeks of the test 1,2,3,4,5,8,9,10 and 11 days in the hairless mouse dorsal skin topically applying a daily dose of the compound administered, the daily observation of the effect of local administration of the compound, the skin scaly and scaly zoned 0- + 5, skin abrasions are also classified as 0- + 5, 0 denote no scales, scales or abrasions, + 5 denote severe scales, scales or abrasions, the daily dose of the compound when 100nmol not cause the death of the animals tested, scales - scales the extent of not more than +2 or less than, the scratch with less than +1, or less than it.
55.一种给予包括人类在内的哺乳动物以一种药物组合物的方法,所说的组合物包含一种有效剂量的式(i)或式(ii)化合物 55. A administered to a mammal including a human, method of a pharmaceutical composition, said composition comprising an effective amount of a compound of formula (i) or formula (ii) 其中的符号定义如下:R1为低级烷基、Cl、Br或I;R2为H、低级烷基、Cl、Br或IR3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基,或者R5和R6可以不存在;A为(CH2)n,其中n等于0-5,含3-6个碳的支链烷基,含3-6个碳的环烷基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R8为含1-10个碳的烷基,或5-10个碳的环烷基,或R8为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基,5-10个碳的环烷基,或苯基或低级烷基苯基,R11为含1-10个碳的烷基,苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;X1为CR5或N,当X1为N时,其可位于6元芳环的任何未取代的位置上;Y为苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、咪唑基和噁唑基;Z分别为H、或者为一或二个取代基,所说的取代基是低级烷基、低级烷氧基、低级硫代烷氧基,含1个或多个双键的低级烯基、含1个或多个双键的烯氧基,或含1个或多个双键的硫代烯氧基,或Z为-(CR14)4-,或Z为-(CR14)=(CR14)-C(R14)2-,或Z为-(CR14)3-N-,或Z为-(CR14)=(CR14)-X2-,或Z为-C(R14)2-C(R14)2-X2-,或Z为-C(R14)2-CR14=CR14-X2-,或Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或Z为-C(R14)2-C(R14)2-C(R14)2-X2-,其中R14分别为H、低级烷基、低级烷氧基、低级硫代烷氧基、Cl、Br或I,X2为O、S或NR15,R15为H或低级烷基;式(ii)中5元环内的虚线环表示在5元环内存在有两个双键,X3为O、S、NH或N-低级烷基,X3基团可位于5元芳环的任何未取代的位置上,所说的组合物给药时能治疗和预防下列一种或多种疾病和症状:皮肤病,恶性细胞过度增殖性疾病,由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖性疾病,自身免疫疾病,免疫学疾病,慢性炎症,与脂质代谢和转移有关的疾病如脂质代谢障碍;干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the symbols are defined as follows: R1 is a lower alkyl group, Cl, Br or I; R2 is H, lower alkyl, Cl, Br, or IR3 is a lower alkyl group, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2, NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H, lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or thio-lower alkoxy group, or R5 and R6 may be absent; A is (CH2) n, where n is equal to 0-5, containing 3-6 carbon branched chain alkyl group containing 3-6 carbon cycloalkyl group, containing 2- 6 carbons and 1 or 2 double bonds in the alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10 , -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, cycloalkyl or alkenyl group, R8 is an alkyl group having 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 carbons, 5 to 10 carbon cycloalkyl group, or phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, R13 containing 2-5 carbon divalent alkyl group; X1 is CR5 or N, when X1 is N, which may be located at any unsubstituted position on the six-membered aryl ring; Y is phenyl, thienyl, furyl , pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl; Z are H, or is one or two substituents, said substituent is a lower alkyl group, a lower alkoxy, lower thioalkoxy, containing one or more double bonds lower alkenyl group, containing one or more double bonds in the alkenyl group, containing one or more double bonds or thio alkenyl group, or Z is - (CR14) 4-, or Z is - (CR14) = (CR14) -C (R14) 2-, or Z is - (CR14) 3-N-, or Z is - (CR14) = (CR14) -X2-, or Z is -C (R14) 2-C (R14) 2-X2-, or Z is -C (R14) 2-CR14 = CR14-X2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-X2 -, respectively, wherein R14 is H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl, Br or I, X2 is O, S or NR15, R15 is H or lower alkyl; formula (ii) the dotted circle within the 5 membered ring in the five-membered ring represents two double bonds in the memory, X3 is O, S, NH, or N- lower alkyl, any position not substituted group may be positioned X3 aromatic 5-membered ring, the said composition is administered to treat and prevent disease and one or more of the following symptoms: skin diseases, malignant cells hyperproliferative diseases caused by neointimal hyperplasia of atherosclerosis and heart valves again narrow, non-malignant cell hyperproliferative diseases, autoimmune diseases, immunological diseases, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism disorders; dry eye; promote wound healing; sun changes and prevent skin injury. 所说的化合物具有视网膜样生物活性,并还具有下述生物特性:基本上无致畸性,即在用ICR小鼠做测试致畸性的给药试验中,当在健康ICR鼠怀孕的第11天,按至少为1mg化合物/Kg受试动物体重的一次剂量给予所说的鼠以该化合物时,该化合物不会引起胎儿吸除,不会使受试动物的胚胎造成可检测出的致畸效应;基本无皮肤毒性,即在无毛雌性小鼠上多处局部涂敷给药两周急性皮肤毒性试验中,其中,在两周试验内的第1、2、3、4、5、8、9、10和11天在无毛鼠背的皮肤上局部涂敷给予日剂量的化合物,按日观察该化合物的局部给药效果,把皮肤鳞片和鳞屑划为0-+5级,皮肤擦伤亦划为0-+5级,0分别表示无鳞片、鳞屑或擦伤,+5分别表示出现严重鳞片、鳞屑或擦伤,该化合物的日剂量为100nmol时不会造成受试动物死亡,鳞屑-鳞片严重程度不超过+2,或小于之,擦伤程度不超过+1,或小于之。 Said compound having a retina-like biological activity, and further having the following biological properties: substantially non-teratogenic, i.e., in ICR mice for testing with teratogenicity test administration, the health of pregnant ICR mice when 11 days, a compound according to at least 1mg / single dose when administered to the mice of said compound, the compound does not cause fetal gettering, does not make the subject animal embryos cause detectable induced Kg body weight of test animal abnormal effect; substantially non-toxic skin, i.e. on hairless female mice were administered two weeks topical application in various acute dermal toxicity test, wherein, in the first two weeks of the test 1,2,3,4,5, compounds 8,9,10 and 11 days in the hairless mouse dorsal skin topically applying a daily dose administered, the daily observation of the effect of local administration of the compound, the skin scales and scales classified as 0- + 5, the skin abrasions also classified as 0- + 5, 0, respectively, no scales, scales or abrasions, + 5 denote severe scales, scales or abrasions, the daily dose of the compound is not cause the death of the test animals when 100nmol , scales - scales the extent of not more than +2 or less than, the scratch with less than +1, or less than it.
56.按权利要求55的方法,其中在测定致畸性的给药试验中,一次剂量至少为10mg化合物/Kg体重受试动物,该化合物不会引起胎儿吸除,不会使受试动物的胚胎造成可检测出的致畸效应。 56. The method according to claim 55 wherein the measurement administration teratogenicity test, a dose of at least 10mg compound / Kg body weight of the test animal, the compound does not cause fetal gettering, does not make the animals tested Embryonic cause teratogenic effects detectable.
57.按权利要求56的方法,其中化合物为式(i)定义的化合物。 57. The method according to claim 56, wherein the compound is a compound of formula (i) defined.
58.按权利要求55的方法,其中化合物为式(i)定义的化合物。 58. The method according to claim 55, wherein the compound is a compound of formula (i) defined.
59.一种给予育龄或怀孕雌性哺乳动物包括人类女性在内以一种药物组合物的方法,所说的组合物包含一种有效剂量的式(i)或式(ii)化合物 59. A given childbearing age or pregnant female mammals, including the human female, including the manner of a pharmaceutical composition, said composition comprising an effective amount of a compound of formula (i) or formula (ii) 其中的符号定义如下:R1为低级烷基、Cl、Br或I;R2为H、低级烷基、Cl、Br或I;R3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、含1-6个碳的低级烷氧基或低级硫代烷氧基,或R5和R6可以不存在;A为(CH2)n,其中n等于0-5,含3-6个碳的低级支链烷基,含3-6个碳的环烷基,含2-6个碳且有1或2个双键的烯基,含2-6个碳且有1或2个三键的炔基;B为H、COOH或其药物中可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳的烷基、环烷基或烯基,R8为含1-10个碳的烷基,或含5-10个碳的环烷基,或R8为苯基或低级烷基苯基,R9和R10分别为H、1-10个碳的烷基,或5-10个碳的环烷基,或苯基或低级烷基苯基,R11为1-10个碳的烷基、苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳的二价烷基基团;X1为CR5或N,当X1为N时,其可位于6元芳环的任何未取代的位置上;Y为苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、咪唑基和噁唑基;Z分别为H、或者为一或二个取代基,该取代基为低级烷基,低级烷氧基,低级硫代烷氧基,具有1个或多个双键的低级烯基、具有1个或多个双键的低级烯氧基,或具有1个或多个双键的低级硫代烯氧基,或Z为-(CR14)4-,或Z为-(CR14)=(CR14)-C(R14)2-,或Z为-(CR14)3-N-,或Z为-(CR14)=(CR14)-X2-,或Z为-C(R14)2-C(R14)2-X2-,或Z为-C(R14)2-CR14=CR14-X2-,或Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或Z为-C(R14)2-C(R14)2-C(R14)2-X2-,其中R14分别为H、低级烷基、低级烷氧基、低级硫代烷氧基、Cl、Br或I,X2为O、S或NR15,R15为H或低级烷基;式(ii)的5元环内的虚线环表示该5元环内存在两个双键,X3为O、S、NH或N-低级烷基,X3基可位于5元芳环的任何未取代的位置上,以所说的组合物给药来治疗和预防下列一种或多种疾病和症状:皮肤病,恶性细胞过度增殖性疾病,由新内膜过度增生引起的动脉粥样硬化和心瓣再狭窄,非恶性细胞过度增殖性疾病,自身免疫疾病,免疫学疾病,慢性炎症,与脂质代谢和转移有关的疾病如脂质代谢障碍;干眼病;促进伤口愈合;改变和防止太阳对皮肤的损伤作用。 Wherein the symbols are defined as follows: R1 is a lower alkyl group, Cl, Br or I; R2 is H, lower alkyl, Cl, Br or I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2, NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each H, lower alkyl, Cl, Br, I, 1-6 carbon lower alkoxy or lower thio alkoxy, or R5 and R6 may be absent; A is (CH2) n, where n is equal to 0-5, 3-6 carbon lower branched chain alkyl group containing 3-6 carbon cycloalkyl, containing 2-6 carbons and 1 or 2 double bonds, alkenyl group containing 2-6 carbons and one or two triple bond alkynyl group; B is H, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is an alkyl group containing 1-5 carbons, cycloalkyl or alkenyl group, R8 is an alkyl group having 1 to 10 carbons, or a cycloalkyl containing 5 to 10 carbon alkyl group, or R8 is phenyl or lower alkylphenyl, R9 and R10 are H, 1-10 carbons alkyl group, or 5 to 10 carbon cycloalkyl group, or phenyl or lower alkylphenyl, R11 is an alkyl group of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl , R13 containing 2-5 carbon divalent alkyl group; X1 is CR5 or N, when X1 is N, which may be located at any unsubstituted position on the six-membered aryl ring; Y is phenyl, thienyl , furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl; Z are H, or is one or two substituents, and the substituent is lower alkyl, lower alkoxy, lower thioalkoxy, lower alkenyl having one or more double bonds group having 1 or more double bonds a lower alkenyl group, or with one or more double bond, thio lower alkenyl group, or Z is - (CR14) 4-, or Z is - (CR14) = (CR14) -C (R14) 2-, or Z is - (CR14) 3-N- or Z is - (CR14) = (CR14) -X2-, or Z is -C (R14) 2-C (R14) 2-X2-, or Z is -C (R14) 2-CR14 = CR14-X2 -, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or Z is -C (R14) 2-C (R14) 2-C (R14 ) 2-X2-, wherein each R14 is H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl, Br or I, X2 is O, S or NR15, R15 is H or lower alkyl; the dotted circle of formula (ii) 5-membered ring indicates that the 5-membered ring memory in two double bonds, X3 is O, S, NH, or N- lower alkyl, X3 group may be located at any unsubstituted aromatic 5-membered ring, position, with said composition is administered to treat and prevent disease and one or more of the following symptoms: skin diseases, malignant cells hyperproliferative diseases caused by neointimal hyperplasia of atherosclerosis and heart valve restenosis, non-malignant cells hyperproliferative diseases, autoimmune diseases, immunological diseases, chronic inflammation, and lipid metabolism and metastasis-related diseases such as lipid metabolism disorders; dry eye; promote wound healing; change of the sun and prevent injury to the skin. 所说的化合物具有视网膜样生物活性,并还具有下述生物特性:基本无致畸性,即在用ICR小鼠做测试致畸性的给药试验中,在健康ICR鼠怀孕的第11天,按至少为1mg化合物/Kg受试动物体重的一次剂量给予所说的鼠以该化合物时,该化合物不会引起胎儿吸除,不会使受试动物的胚胎造成可检测出的致畸效应,基本无皮肤毒性,即在无毛雌性小鼠上多处局部涂敷给药两周急性皮肤毒性试验中,其中,在两周试验内的第1、2、3、4、5、8、9、10和11天在无毛鼠背的皮肤上局部涂敷给予日剂量的化合物,按日观察该化合物的局部给药效果,把皮肤鳞片和鳞屑划为0-+5级,皮肤擦伤亦划为0-+5级,0分别表示无鳞片、鳞屑或擦伤,+5分别表示出现严重鳞片、鳞屑或擦伤,该化合物的日剂量为100nmol时不会造成受试动物死亡,鳞屑-鳞片严重程度不超过+2,或小于之,擦伤程度不超过+1,或小于之。 Said compound having the retina-like biological activity, and also has the following biological characteristics: Basic non-teratogenic, that doing the test teratogenicity test administered by ICR mice in healthy ICR mice on day 11 of pregnancy , a compound according to at least 1mg / Kg body weight of test animals administered a single dose of said mouse with the compound when the compound does not cause fetal gettering, does not make the subject animal embryos cause teratogenic effects detectable , almost no skin toxicity, i.e. on hairless female mice were administered two weeks topical application in various acute dermal toxicity test, wherein, in the first two weeks of the test 1,2,3,4,5,8, daily dose of the compounds 9, 10 and 11 days for topical application on the skin of hairless mice to give back, to observe the effect of daily topical administration of the compound, the skin scales and scales classified as 0- + 5, skin abrasions also classified as 0- + 5, 0, respectively, no scales, scales or abrasions, + 5 denote severe scales, scales or abrasions, the daily dose of the compound is not cause the death of the test animals when 100nmol, scaly - not more than +2 severity scales, or less than, the abrasion degree is not more than +1 or less than it.
60.按权利要求59的方法,其中在测定致畸性的给药试验中,一次剂量至少为10mg化合物/Kg体重受试动物,该化合物不会引起胎儿吸除,不会使受试动物的胚胎造成可检测出的致畸效应。 60. The method according to claim 59, wherein the measurement administration teratogenicity test, a dose of at least 10mg compound / Kg body weight of the test animal, the compound does not cause fetal gettering, does not make the animals tested Embryonic cause teratogenic effects detectable.
61.按权利要求60的方法,其中化合物为式(i)定义的化合物。 61. The method according to claim 60, wherein the compound is a compound of formula (i) defined.
62.按权利要求59的方法,其中化合物为式(i)定义的化合物。 62. The method according to claim 59, wherein the compound is a compound of formula (i) defined.
Description  translated from Chinese
具有视网膜样活性的化合物 A compound having a retina-like activity

本发明涉及的是给予包括人类在内的哺乳动物以具有视网膜样(retinoid)活性且基本上无致畸活性并能明显降低皮肤毒性的化合物的方法。 The present invention relates to a given mammal, including humans, having a retina-like (retinoid) activity and substantially no teratogenic activity and methods can significantly reduce the dermal toxicity of the compound. 本发明还涉及适合于给予所说的具有视网膜样活性、能降低皮肤毒性且基本上无致畸活性的化合物的药物组合物。 The present invention also relates to compounds having adapted retina-like activity, can reduce skin toxicity and substantially no teratogenic activity of administering the pharmaceutical composition. 另外,本发明同时还涉及具有所说视网膜样活性、能降低皮肤毒性且无致畸活性的新的化合物。 Further, the present invention also relates to said retina-like activity, can reduce skin toxicity and no teratogenic activity of the new compounds.

具有视网膜样活性的化合物是现有技术所熟知的,并且在大量的美国和其它国家专利文献以及科学出版物上有描述说明。 The compound has a retina-like activity is well known in the prior art, and in a large number of US and other national patent documents and scientific publications described instructions. 视网膜样活性能治愈或缓解包括人类在内的哺乳动物物种的许多疾病症状和病情,这点是本领域普遍公知和接受的。 Retina-like activity can cure or alleviate the mammalian species, including humans, the symptoms of many diseases and conditions, this point is generally known in the art and accepted. 换言之,本领域通常认为,含有一种或若干种视网膜样化合物活性成份的药物组合物可用作细胞增殖及分化的调节剂,尤其是作为制剂,可用于治疗皮肤病,如痤疮、毛囊角化病、牛皮癣、鱼鳞癣、湿疹和特应性皮炎;治疗和防止恶性细胞过度增殖性疾病如上皮癌、乳腺癌、前列腺癌、头颈癌和髓细胞样白血病;改变和防止新内膜增生所致的动脉粥样硬化及心瓣再狭窄;治疗和防止其它非恶性细胞过度增殖性疾病如子宫内膜增生、良性前列腺肥大、增生性玻璃状视网膜病及发育不良;治疗自身免疫疾病和免疫学病变(如盘状红斑狼疮);治疗慢性炎症如肺纤维化;治疗和防止与脂质代谢和转移有关的疾病如脂质代谢障碍;促进伤口愈合;治疗干眼病以及转变和防止太阳对皮肤的损伤效应。 In other words, the art generally believe that the pharmaceutical compositions containing one or several active ingredients retinal-like compounds may be used as the proliferation and differentiation modulators, especially as agents for the treatment of skin diseases, such as acne, Darier's disease, psoriasis, ichthyosis, eczema and atopic dermatitis; the treatment and prevention of malignant cells hyperproliferative diseases such as epithelial cancer, breast cancer, prostate cancer, head and neck cancer and myeloid leukemia; changes and prevent neointimal hyperplasia of atherosclerosis and restenosis; treating and preventing other non-malignant cells hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative retinopathy and glassy dysplasia; treatment of autoimmune diseases and immunological diseases (such as discoid lupus erythematosus); treatment of chronic inflammatory diseases such as pulmonary fibrosis; the treatment and prevention of lipid metabolism and metastasis-related diseases such as lipid metabolism disorders; promoting wound healing; treatment and prevention of dry eye as well as changes in sun-damaged skin effects.

然而,现有技术所开发研制的具有视网膜样特性的化合物均有缺点。 However, the compound having a retina-like properties of the prior art have developed disadvantages. 现有技术的一些化合物当涂抹用于皮肤(治疗皮肤病的一种重要应用方式)时能产生严重的刺激,并且口服给药时也会引起皮肤毒性。 Can produce severe irritation of some compounds of the prior art when applied to the skin (the treatment of skin diseases is an important application mode), and can also cause skin toxicity when administered orally. 具有视网膜样活性的现有技术的许多化合物是致畸的。 Many compounds have the art retina-like activity is teratogenic. 致畸性或致畸活性可定义为,一种药剂对发育中的胎儿所产生的不良影响。 Teratogenicity or teratogenic activity is defined as the adverse effects of a drug on the developing fetus produced. 本领域一般认为,孕妇,甚至于虽未妊娠但处于育龄期的妇女应避免致畸药物。 This field is generally believed that pregnant women, even though not pregnant, but in women of childbearing age should avoid teratogenic drugs.

由于如前所述的原因,现有技术十分需要能有效地治疗以往靠视网膜样化合物治疗的那些疾病、并且降低了或无致畸活性、同时对皮肤无明显刺激的新的化学物质、药物组合物及治疗方法。 Due to reasons described above, the prior art requires very effective in treating those diseases by the conventional treatment of retinal-like compounds, and reducing or non-teratogenic activity, while no significant stimulation of new skin chemicals, pharmaceutical compositions thereof and methods of treatment.

关于具有视网膜样或其它生物学活性的具体化合物或化合物种类,请参见下列实例。 On the particular compound or class of compounds having a retina-like or other biological activity, see the following examples.

DE3316-932A公开了1-苯基-2-苯并二氢吡喃基-丙烯衍生物及硫和氨类似物。 DE3316-932A discloses 1-phenyl-2-chromanyl - propylene derivatives and analogs of sulfur and ammonia. 该说明书中的具体实施例是对-[(E)-2-(4,4-二甲基-6-苯并二氢吡喃基,二氢苯并噻喃基或1,2,3,4-四氢-6-喹啉基)丙烯基]-1-苯甲酸乙酯。 The specification of specific embodiments is - [(E) -2- (4,4- dimethyl-6-chromanyl, thiochroman-yl or 1,2,3, 4-tetrahydro-6-quinolyl) propenyl] -1-benzoate.

US4,826,984公开了苯并吡喃基(苯并二氢吡喃基)和苯并吡喃基-丙烯基苯甲酸及其酯,其中一个实施例是对-(2-(4,4-二甲基苯并二氢吡喃-6-基)-丙烯基苯甲酸乙酯。 US4,826,984 discloses benzopyranyl (chromanyl) and benzopyranyl - propenyl benzoic acid and its esters, wherein an embodiment is - (2- (4,4- methyl-chroman-6-yl) - propenyl benzoate.

EP130795A公开了4,4-二甲基-6-苯并二氢吡喃基链烯基苯甲酸衍生物、二氢苯并噻喃基和四氢喹啉基类似物。 EP130795A discloses the 4,4-dimethyl-6-chromanyl alkenyl acid derivative, thiochroman group and tetrahydroquinolyl like. 这些化合物中的苯并二氢吡喃、二氢苯并噻喃和四氢喹啉环上的第2和第7位是未取代的。 These compounds are chroman, bits 2 and 7 of thiochroman and tetrahydroquinoline ring is unsubstituted.

WO8500-806A公开了4,4-二甲基-苯并二氢吡喃-6-基、4,4-二甲基-二氢苯并噻喃-6-基-乙烯基和4,4-二甲基-苯并二氢吡喃-6-基和4,4,-二甲基-二氢苯并噻喃-6-基-丙烯基苯甲酸,它们的酯,以及相应的噻吩羧酸和其它杂环酸类似物。 WO8500-806A discloses 4,4-dimethyl - chroman-6-yl, 4,4-dimethyl - thiochroman-6-yl - vinyl and 4,4- dimethyl - chroman-6-yl and 4,4 - dimethyl - thiochroman-6-yl - propenyl benzoic acid, esters thereof, and the corresponding thiophene carboxylic acid and other heterocyclic acid analogs. 苯并二氢吡喃或二氢苯并噻喃环上的第2位是未取代的。 Chroman or the two thiochroman ring is unsubstituted.

EP350846A公开了对-(2-(3,4-二氢-4,4-二甲基-二氢苯并二氢吡喃-7-基)-丙烯基)苯甲酸乙酯及相关化合物。 EP350846A discloses a - (2- (3,4-dihydro-4,4 - dihydro-chroman-7-yl) - propenyl) benzoate and related compounds.

WO8504652A公开了某些二芳基取代的丙烯基化合物,其中的一个实施例是(E)-4-[2-(4-异丙苯基)-丙烯基苯甲酸乙酯。 WO8504652A discloses certain diaryl-substituted propenyl compound, which is one embodiment of (E) -4- [2- (4- isopropylphenyl) - propenyl benzoate.

EP206751A公开了作为白三烯(leukotriene)合成抑制剂的2-取代的苯基-链烯基-喹啉衍生物。 EP206751A discloses as leukotrienes (leukotriene) synthesis inhibitor 2- substituted phenyl - alkenyl - quinoline derivatives. 该参考文献中的-个化合物实例是(E)-4-(3-(2-(喹啉-2-基)-1-甲基乙烯基苯氧基)丁酸。 The references of - a compound of Example is (E) -4- (3- (2- (quinolin-2-yl) -1-methyl-vinyl-phenoxy) butyric acid.

EP0098591A1公开了灭鼠用的(rodenticidal)二取代的丙烯基化合物,其中的一个实例是对-[2-(4,5,6,7-四氢-4,4,7,7-四甲基苯并[b]噻吩-2-基)丙烯基苯甲酸乙酯,另一个实例是6-[(E)-2-(4,5,6,7-四氢-4,4,7,7-四甲基苯并[b]噻吩-2-基)丙烯基]烟酸乙酯。 EP0098591A1 discloses (rodenticidal) disubstituted propenyl compound rodent used, an example of which is - [2- (4,5,6,7-tetrahydro--4,4,7,7- tetramethyl- benzo [b] thiophen-2-yl) propenyl benzoate, another example is 6 - [(E) -2- (4,5,6,7- tetrahydro -4,4,7,7 - tetramethyl-benzo [b] thiophen-2-yl) propenyl] nicotinic acid ethyl ester.

GB专利2190-378公开了四甲基-四氢萘丙烯基苯酚化合物,其中的实例有邻、间、或对(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)丙烯基)苯酚。 GB Patent No. 2190-378 discloses a tetramethyl - tetrahydro-naphthalen-allyl phenol compound, which is exemplified o-, m-, or p (E) -2- (5,6,7,8- tetrahydro-5,5 , 8,8-tetramethyl-2-naphthyl) propenyl) phenol.

DE3602-473A公开了芳烯基-苯酚衍生物,其中的实例是(E)-1-(4-羟苯基)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)丙烯和(E)-1-(4-甲氧苯基)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)丙烯。 DE3602-473A discloses arylalkenyl - phenol derivative, which is an instance of (E) -1- (4- hydroxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8 , 8-tetramethyl-2-naphthyl) acrylamide and (E) -1- (4- methoxyphenyl) -2- (5,6,7,8-tetrahydro -5,5,8,8 - tetramethyl-2-naphthyl) acrylamide.

EP176033A公开了异噁唑基-乙烯基1,2-二氢化茚和四氢萘衍生物,其中的一个实例是(E)-5-[2-(3-氟-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-1-丙烯基]异噁唑-3-羧酸。 EP176033A discloses isoxazolyl - vinyl indan and tetrahydronaphthalene derivatives, an example of which is (E) -5- [2- (3- fluoro -5,5,8,8 - tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl) -1-propenyl] isoxazole-3-carboxylic acid.

EP公开号303915公开了以2,3-二氢化茚基及四氢萘基和取代的苯基丙烯作为视网膜样物质,其中苯基上的取代基是硫取代基。 EP Publication No. 303,915 discloses a 2,3-indanyl and tetrahydro naphthyl and substituted phenyl propylene as a retina-like substance, wherein the substituents on the phenyl substituent is sulfur. 所公开的化合物中的一个实例是甲基4-(2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基(丙烯基)苯砜。 The compounds disclosed in one example is methyl 4- (2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl group (propenyl) phenyl sulfone .

EP176032A公开了6-苯乙烯基-四氢-萘衍生物,其中的实例有(E)-4-[2-(5,6,7,8-四氢-5,5,8,8-四甲基-7-羟基-2-萘基)-1-丙烯基]苄醇,和E-4-[2-(5,8-二氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸。 EP176032A discloses 6- styryl - tetrahydro - naphthalene derivative, which is exemplified by (E) -4- [2- (5,6,7,8- tetrahydro-5,5,8,8-tetramethyl methyl-7-hydroxy-2-naphthyl) -1-propenyl] benzyl alcohol, and E-4- [2- (5,8- dihydro-5,5,8,8-tetramethyl -2 - naphthyl) -1-propenyl] benzoic acid.

EP专利315071公开了1-苯并环庚烯基-2-羰基-苯乙烯衍生物,其中的一个实例是对-(E)-2-(6,7,8,9-四氢-7,7-二甲基-5H-苯并环庚烯-2-基)丙烯基苯甲酸乙酯。 EP Patent No. 315,071 discloses 1-benzocyclohepten-2-carbonyl group - a styrene derivative, an example of which is - (E) -2- (6,7,8,9- tetrahydro -7, 7- dimethyl -5H- benzocyclohepten-2-yl) propenyl benzoate.

DE3524-199-A公开了茋-4-羧酸衍生物,其中的实例有[E-2-(3,4-二异丙苯基)丙烯基]苯甲酸、[E-2-(3-叔丁苯基)丙烯基]苯甲酸。 DE3524-199-A discloses a stilbene-4-carboxylic acid derivative, which is exemplified by [E-2- (3,4- dicumyl yl) propenyl] benzoic acid, [E-2- (3- t-butylphenyl) propenyl] benzoic acid.

EP专利245825公开了杂环基-链烯基苯衍生物,其中的实例有3-(β-(4′-羟基-3′-甲氧苯基)乙烯基)-5-甲基吡唑和5-(β-4′-羟基-3′,5′-双-(1,1-二甲基乙基)苯基)-乙烯基)-5-甲基吡唑。 EP Patent 245,825 discloses a heterocyclyl - alkenylbenzene derivative, which is exemplified by 3- (β- (4'- hydroxy-3'-methoxyphenyl) vinyl) -5-methyl-pyrazole and 5- (β-4'- hydroxy-3 ', 5'-bis - (1,1-dimethylethyl) phenyl) - vinyl) -5-methyl-pyrazole.

EP210929A公开了一些用于皮肤病和眼科药物的2-芳基-萘衍生物。 EP210929A discloses certain 2-aryl-for dermatological and ophthalmic drugs - naphthalene derivatives. 用于合成这些化合物的中间体包括某些芳乙烯基苯衍生物。 Intermediate for the synthesis of these compounds include certain aromatic vinyl benzene derivatives.

DE3531722A公开了某些具有维生素A样活性的苯并降冰片烯衍生物。 DE3531722A discloses certain benzo-like activity with vitamin A norbornene derivative.

GB2164-938A公开了某些具有视网膜样活性的2-苯乙烯基-萘衍生物。 GB2164-938A discloses certain 2-styryl has a retina-like activity - naphthalene derivatives. 这些化合物的一个实例是2-(4-甲基-β-甲基-苯乙烯基)萘。 An example of these compounds is 2- (4-methyl -β- methyl - styryl) naphthalene.

US4,326,055公开了带有一个取代的苯环和一个取代的1,2-二氢化茚或四氢萘基团的乙烯衍生物。 US4,326,055 discloses ethylene derivatives having a substituted benzene ring and a substituted indane or tetrahydronaphthalene group. 这些化合物被认为是肿瘤抑制剂,可用于治疗皮肤病和风湿病。 These compounds are considered to be a tumor suppressor, useful in the treatment of skin diseases and rheumatism.

US4,723,028公开了具有视网膜样活性的1,2-二苯乙烯(茋)衍生物。 US4,723,028 discloses a retina-like activity of stilbene (stilbene) derivatives.

US4,740,51 9公开了具有视网膜样活性的某些芳族杂环衍生物。 US4,740,51 9 discloses certain aromatic heterocyclic derivatives have retina-like activity.

已公开的欧洲专利申请0130795公开了一些乙烯衍生物,其中乙烯部分被一个取代的苯基和一个取代的苯并二氢吡喃、二氢苯并噻喃或喹啉基团所取代。 European Patent Application 0130795 discloses a number of published ethylene derivatives, wherein the ethylene moiety is substituted with a substituted phenyl and a substituted chroman, thiochroman or quinoline group. 这些化合物可用于抑制哺乳动物体内软骨的降解。 These compounds are useful for inhibiting cartilage degradation in vivo in mammals.

本发明人的一些尚未结案的申请和最近授权的专利受让予了本申请的同一受让人,它们涉及到了具有视网膜样活性的其它一些化合物。 Some applications have not yet concluded the present inventors and patent recently authorized transferee to the same assignee of the present application, they relate to the retina-like activity have some other compounds.

按照本发明,现已发现,下式1所示的局部结构或部分能使具有视网膜样或有关生物活性的二取代乙烯一类化合物显著降低致畸活性,同时降低皮肤毒性。 According to the present invention, it has now been found, as shown in the following formula 1 or a partial structure having a retina-like portion to make or related biological activity of a di-substituted vinyl compounds significantly reduced teratogenic activity, while reducing skin toxicity. 在式1中,局部给出的环代表一芳香环,该芳香环可以是碳环或杂芳香环的6元或5元环,并且可以与特别是如下所述的另一环缩合。 In Formula 1, represents a partial ring is given an aromatic ring, the aromatic ring may be a carbon ring or a 6-membered heteroaromatic ring or 5-membered ring, and may be as follows with particular said another ring condensed. R1为低级烷基、Cl、Br、或I,R2为H、低级烷基、Cl、Br、或I,R3为低级烷基、Cl、Br、或I、或者为醚、硫醚、酯、硫酯、胺或取代的胺基团。 R1 is a lower alkyl group, Cl, Br, or I, R2 is H, lower alkyl, Cl, Br, or I, R3 is lower alkyl, Cl, Br, or I, or an ether, thioether, ester, thioester, amine or substituted amine groups. 本发明的一个重要特征是乙烯部分(双键)连接在芳香环上,即其中,芳香环中与直接连接双键的碳所相邻的碳上(也就是说邻位上的碳)有一个带位阻基团(不是氢)的取代基(R3),并且,与邻位取代的芳香环相连的烯烃双键上的碳亦被一取代基(R1)(非氢)所取代。 An important feature of the present invention is an ethylene moiety (double bond) is connected to the aromatic ring, i.e. wherein the aromatic ring and the double bond is directly connected to the carbon adjacent to the carbon (carbon that is ortho-position) has a with a steric hindrance group (other than hydrogen) substituent (R3), and carbon olefinic double bond and ortho-substituted on the aromatic ring was also attached to a substituent (R1) (non-hydrogen) replaced.

如前所述,本发明包括用一种非致畸药物组合物治疗包括人类、尤其是育龄妇女和孕妇在内的哺乳动物的方法,所说的组合物含一种或一种以上式2或式3化合物作为活性成份,能用于治疗以往靠视网膜样化合物治疗的疾病,也就是说可作为细胞增殖或分化的调节剂,尤其是作为制剂用于治疗皮肤病如痤疮、毛囊角化病、牛皮癣、鱼鳞癣、湿疹和特应性皮炎;治疗和预防恶性细胞增多病患如上皮癌、乳腺癌、前列腺癌、头颈癌和髓细胞性白血病;改变和防止由于新内膜增生所致的动脉粥样硬化及心瓣再狭窄;治疗和防止其它非恶性细胞增多疾病如子宫内膜增生、良性前列腺肥大、增生性玻璃状视网膜病及发育异常;治疗自身免疫疾病和免疫学病变(如盘状红斑狼疮);治疗慢性炎症如肺纤维化;治疗和预防与脂质代谢和转移有关的疾病如脂质代谢障碍;促进伤口愈合;治疗干眼病;以及转变和防止太阳对皮肤的损伤效应。 As described above, the present invention comprises a non-teratogenic pharmaceutical composition for the treatment, including a human, especially pregnant women and women of childbearing age, including mammal, said composition comprising one or more Formula 2 or as an active ingredient a compound of formula 3, can be used to treat retinal-like compounds by the conventional treatment of the disease, that is can be used as cell proliferation or differentiation modulators, particularly as a preparation for the treatment of skin diseases such as acne, Darier's disease, psoriasis, ichthyosis, eczema and atopic dermatitis; the treatment and prevention of malignant cells increased in patients with epithelial cancers such as breast cancer, prostate cancer, head and neck cancer and myeloid leukemia; changes and prevent the artery due to neointimal hyperplasia of atherosclerosis and restenosis; the treatment and prevention of other diseases such as non-malignant cells increased endometrial hyperplasia, benign prostatic hypertrophy, proliferative retinopathy and vitreous abnormalities; treatment of autoimmune diseases and immunological diseases (such as a disk erythematosus); treatment of chronic inflammatory diseases such as pulmonary fibrosis; treatment and prevention of lipid metabolism and transfer-related diseases such as lipid metabolism disorders; promote wound healing; treatment of dry eye; and transition effects and prevent sun damage to the skin.

本发明还涉及用于上述治疗方法的药物组合物。 The present invention also relates to pharmaceutical compositions for the above-described methods of treatment. 本发明特别包括用视网膜样化合物治疗有效但因其人所共知的皮肤毒性问题而使用受限的那些疾病的治疗方法。 The present invention particularly comprises a therapeutically effective retinal-like compounds, but because of its treatment of the well-known problems of skin toxicity and limited use of those diseases. 式2中的有关符号定义如下:R1为低级烷基、Cl、Br、或IR2为H、低级烷基、Cl、Br、或IR3为低级烷基、Cl、Br、I、OR11、SR11、OCOR11、SCOR11、NH2、NHR11、N(R11)2、NHCOR11或NR11-COR11;R5和R6分别为H、低级烷基、Cl、Br、I、1-6个碳原子的低级烷氧基或低级硫代烷氧基,或者R6不存在;A为n等于0-5的(CH2)n、含3-6个碳原子的低级支链烷基、含3-6个碳原子的环烷基、含2-6个碳原子且1或2个双键的链烯基,含2-6个碳原子且1或2个三键的炔基;B为氢、COOH或其药物中可接受的盐、COOR8、CONR9R10、-CH2OH、CH2OR11、CH2OCOR11、CHO、CH(OR12)2、CHOR13O、-COR7、CR7(OR12)2或CR7OR13O,其中R7为含1-5个碳原子的烷基,环烷基或链烯基,R8为含1-10个碳原子的烷基,或含5-10个碳原子的环烷基,或者为苯基或低级烷基苯基,R9和R10分别为氢、含1-10个碳原子的烷基、或含5-10个碳原子的环烷基、或者为苯基或低级烷基苯基,R11为含1-10个碳原子的烷基、苯基或低级烷基苯基,R12为低级烷基,R13为含2-5个碳原子的二价烷基;X1为CR5或N,当X1为N时,其可处于6元芳香环上任一未取代的位置上;Y为苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、咪唑基和噁唑基;Z分别为H、或者为一或二个取代基,该取代基是低级烷基、低级烷氧基、低级硫代烷氧基、含1或1个以上双键的低级链烯基、含1或1个以上双键的低级烯氧基,或含1或1个以上双键的低级硫代烯氧基,或Z为-(CR14)4-,或Z为-(CR14)=(CR14)-C(R14)2-,或Z为-(CR14)3-N-,或Z为-(CR14)=(CR14)-X2-,或Z为-C(R14)2-C(R14)2-X2-,或Z为-C(R14)2-CR14=CR14-X2-,或Z为-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或Z为-C(R14)2-C(R14)2-C(R14)2-X2-,其中R14分别为H、低级烷基、低级烷氧基、低级硫代烷氧基、Cl、Br或I,X2为O、S或NR15,R15为H或低级烷基。 Formula 2 relevant symbols are defined as follows: R1 is a lower alkyl group, Cl, Br, or IR2 is H, lower alkyl, Cl, Br, or IR3 is a lower alkyl group, Cl, Br, I, OR11, SR11, OCOR11 , SCOR11, NH2, NHR11, N (R11) 2, NHCOR11, or NR11-COR11; R5 and R6 are each a lower alkoxy group H, lower alkyl, Cl, Br, I, 1-6 carbon atoms or a lower sulfur alkoxy group, or R6 does not exist; A is n is 0-5 (CH2) n, containing 3-6 carbon atoms, lower branched chain alkyl group containing 3-6 carbon atoms, a cycloalkyl group, containing 2-6 carbon atoms and 1 or 2 double bonds alkenyl group containing 2-6 carbon atoms and 1 or 2 triple bonds, alkynyl group; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, or CR7OR13O, where R7 is 1 to 5 carbon atoms, a cycloalkyl group or alkenyl group, R8 is 1 to 10 carbon atoms, containing 5 to 10 carbon atoms, or cycloalkyl, or is phenyl or lower alkylphenyl, R9 and R10 are independently hydrogen, containing 1 alkyl group to 10 carbon atoms, containing 5 to 10 carbon atoms, or cycloalkyl, or is phenyl or lower alkylphenyl, R11 is an alkyl group having 1 to 10 carbon atoms, a phenyl group or a lower alkylphenyl, R12 is lower alkyl, R13 containing 2-5 carbon atoms, divalent alkyl group; X1 is CR5 or N, when X1 is N, which may be in took a 6-membered aromatic ring unsubstituted position; Y is phenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl; Z are H, or is one or two substituents, the substituent is lower alkyl, lower alkoxy, lower thioalkoxy, containing 1 or more double bonds or a lower alkenyl group, containing 1 or more double bonds or a lower alkenyl group, containing 1 or more double bonds or a thio lower alkylene group, or Z is - (CR14) 4-, or Z is - (CR14) = (CR14) -C (R14) 2-, or Z is - (CR14) 3-N-, or Z is - (CR14) = (CR14) -X2-, or Z is -C (R14) 2-C (R14) 2-X2-, or Z is -C (R14) 2-CR14 = CR14-X2-, or Z is -C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or Z is -C (R14) 2 -C (R14) 2-C (R14) 2-X2-, wherein each R14 is H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl, Br or I, X2 is O, S or NR15, R15 is H or lower alkyl.

式3中的符号R1、R2、R3、R5、Y、A、B和Z与式2的有关定义相同,或者R5可以不存在;5元环中的虚线圈表示该环中有两个双键,并且X3为O、S、NH或N-低级烷基,X3可以在5元芳香环上任一未取代的位置上。 Formula 3 symbols R1, R2, R3, the same as R5, Y, A, B and Z and the definition of Formula 2, or R5 may be absent; five-membered ring in the dashed circle indicates that the ring has two double bonds and X3 is O, S, NH, or N- lower alkyl, X3 can be anywhere on the unsubstituted 5-membered aromatic ring position.

本发明的新化合物由下式4、5和6表征: The new compounds of the present invention are represented by the following formulas 4, 5 and 6 Characterization: 式4中R1、R2、R3、R5、R6、A和B与式2有关定义相同。 Wherein R1, the same R2, R3, R5, R6, A and B of the definition of formula 2 4.

R20分别为H或低级烷基,Y1为噻吩基、呋喃基或吡啶基。 R20 are independently H or lower alkyl, Y1 is thienyl, furyl or pyridyl. 式5中R1、R2、R3、R5、R6、A和B与式2有关定义相同;R20同式4定义;Y2为苯基、噻吩基、呋喃基或吡啶基,X4为S、O、NH或N-低级烷基。 Formula 5 wherein R1, R2, R3, R5, R6, A and B of the definition of Formula 2; R20 is defined in formula 4; Y2 is a phenyl, thienyl, furyl or pyridyl, X4 is S, O, NH or N- lower alkyl. 式6中R1、R2、R3、A和B与式2有关定义相同;Y2为苯基、噻吩基、呋喃基或吡啶基R21和R22为H或低级烷基,但其中的两个取代基不能同时为H。 6, wherein R1, R2, the same as R3, A and B and the definition of Formula 2; Y2 is phenyl, thienyl, furyl or pyridyl group R21 and R22 is H or lower alkyl, but in which the two substituents can not Meanwhile is H.

图1给出了口插管法给予一次剂量化合物10mg/Kg后,不同时间上,小鼠血浆和胚胎中化合物AGN191701的浓度(ng/ml或ng/g,如图所示)曲线。 Figure 1 shows the time after oral intubation dose of compound administered 10mg / Kg, at different times, (ng / ml or ng / g, as shown) and the embryonic mouse plasma concentration curve of the compound of AGN191701.

图2给出了呈比较标准百分率的3H-胸苷的结合量(DNA合成的度量)与试验化合物和对照化合物的浓度函数关系曲线。 Figure 2 shows the comparison of the standard form of the percentage of the combined amount of 3H- thymidine (DNA synthesis metric) concentration as a function of the curve with the test compound and control compound. X轴上的刻度为视网膜样化合物的对数摩尔浓度。 Scale on the X axis is the logarithm of the molar concentration of the retinal-like compounds.

图3给出了对化合物AGN191440(化合物11)所做的HL60细胞NBT还原(细胞分化)分析结果曲线。 Figure 3 shows the compound AGN191440 (Compound 11) made of HL60 cells NBT reduction (cell differentiation) curve analysis.

图4给出了对化合物AGN191701(化合物19)所做的HL60细胞NBT还原(细胞分化)分析结果曲线。 Figure 4 shows the compound AGN191701 (Compound 19) made of HL60 cells NBT reduction (cell differentiation) curve analysis.

图5给出对化合物AGN191768(化合物15)所做的HL60细胞NBT还原(细胞分化)分析结果曲线。 Figure 5 shows the compound AGN191768 (Compound 15) made HL60 cells NBT reduction (cell differentiation) curve analysis.

图6给出了对现有技术化合物AGN191183和AGN191440(化合物11)所做的HL60细胞转谷氨酰胺酶分析结果曲线。 Figure 6 shows the prior art compounds AGN191183 and AGN191440 (Compound 11) made of HL60 cells transglutaminase analysis curve.

图7给出了对AGN191642(化合物13)所做的HL60细胞转谷氨酰胺酶分析结果曲线。 Figure 7 shows the right AGN191642 (Compound 13) made of HL60 cells transglutaminase analysis curve.

图8给出了对AGN191701(化合物19)所做的HL60细胞转谷氨酰胺酶分析结果曲线。 Figure 8 shows the right AGN191701 (Compound 19) made of HL60 cells transglutaminase analysis curve.

图9给出了对AGN191659(化合物21)所做的HL60细胞转谷氨酰胺酶分析结果曲线。 Figure 9 shows on AGN191659 (Compound 21) made of HL60 cells transglutaminase analysis curve.

一般实施方式定义烷基一词指且包括被称为直链烷基、支链烷基和环烷基的任何和全部基团。 Definitions The term alkyl means a general embodiment and includes a known linear alkyl, branched alkyl and cycloalkyl of any and all groups. 烯基一词指且包括具有一个或一个以上不饱和位点的直链烯基、支链烯基和环烯基。 The term alkenyl refers to and includes one having one or more sites of unsaturation of the straight chain alkenyl, branched alkenyl and cycloalkenyl. 低级烷基是指上面限定的宽范围定义中含1-6个碳原子的烷基基团,如果适用的话,包括含3-6个碳原子的支链和环烷基基团。 Lower alkyl group means an alkyl group as defined above in the definition of a wide range of 1 to 6 carbon atoms, if applicable, including branched and cyclic alkyl groups of 3-6 carbon atoms. 同样地,低级烯基定义为含2-6个碳原子的直链烯基和3-6个碳原子的支链和环烯基。 Similarly, lower alkenyl defined as containing 2-6 carbon atoms, straight-chain and branched alkenyl groups and cyclic alkenyl groups of 3-6 carbon atoms.

本文所用的“酯”一词指且包括有机化学经典定义范围内的任何化合物。 As used herein, the term "ester" refers to and includes any compounds within the scope of the definition of classic organic chemistry. 当B(式2、3、4、5和6中的)为-COOH时,该词义包括用醇,特别是用有1-6个碳原子的脂族醇处理该官能团后所得的产物。 When B (formula 2,3,4,5 and 6) is -COOH, this meaning includes alcohols, particularly aliphatic alcohols with 1 to 6 carbon atoms in the product obtained after the functional group. 当酯是由B为-CH2H的化合物衍生而来时,该词义包括式-CH2OOCR11的化合物,其中R11为任何取代或未取代的脂族、芳香族或脂族芳香族基团,脂族部分有1-6个碳原子的是优选的。 When the ester is a compound -CH2H B is derived from, this meaning -CH2OOCR11 comprising a compound of formula, wherein R11 is any substituted or unsubstituted aliphatic, aromatic or aliphatic aromatic group, an aliphatic portion has 1 to 6 carbon atoms are preferred.

优选的酯衍生于有10个或低于10个碳原子的饱和脂族醇或酸,或者是衍生于有5至10个碳原子的环醇或饱和脂环醇和酸。 Preferred esters derived from less than 10 or 10 carbon atoms, saturated aliphatic alcohols or acids, or is derived from, or have a cyclic alcohol saturated alicyclic alcohols and acids of 5 to 10 carbon atoms. 特别优选的脂族酯是由低级烷基酸或醇而衍生的那些酯。 Particularly preferred aliphatic esters are those esters derived from lower alkyl acids or alcohols derived. 苯基酯或低级烷基苯基酯亦是优选的。 Phenyl ester or lower alkylphenyl esters are also preferred.

酰胺的定义与有机化学对此的经典定义相同。 Amide define this classic definition of the same organic chemistry. 在本发明中,其包括未取代的酰胺和全部脂族和芳香族单和双取代的酰胺。 In the present invention, which include unsubstituted amides and all aliphatic and aromatic mono- and di-substituted amides. 优选的酰胺是衍生自含10或低于10个碳原子的饱和脂族基团或含5-10个碳原子的环基或饱和脂族环基的单和双取代的酰胺。 Preferred amides are derived from or containing less than 10 mono- and di-substituted amides of saturated aliphatic groups 10 carbon atoms containing 5 to 10 carbon atoms or a cycloalkyl group or a saturated aliphatic cyclic group. 特别优选的酰胺是衍生自低级烷基胺的那些酰胺。 Particularly preferred amides are those amides derived from lower alkyl amines. 由苯基胺或低级烷基苯基胺所衍生的那些单和双取代的酰胺亦是优选的。 Mono- and di-substituted amides those by phenyl or lower alkylphenyl amines derived amines also are preferred. 未取代的酰胺也是优选的。 Unsubstituted amides are also preferred.

缩醛和缩酮包括式-CK的基团,其中K为(-OR)2。 Acetals and ketals include a group of the formula -CK where K is (-OR) 2. 在此R为低级烷基。 Here R is lower alkyl. K也可以是-OR1O-,其中R1为2-5碳原子的直链或支链低级烷基。 K may also be -OR1O-, wherein R1 is a straight-chain or branched lower alkyl group of 2-5 carbon atoms.

对于用于本发明治疗方法的任一化合物来说,如果化合物具有能够生成盐的官能团,如酸或胺官能团,则可以制成药物中可接受的盐。 For any compound used in the treatment method of the present invention, if a compound having a functional group capable of salt formation, such as an acid or amine functional groups can be made into a pharmaceutical acceptable salt thereof. 药物中可接受的盐可以是任何保留了母体化合物活性且对受药者及本文所涉及的受药者无任何损害和不良影响的盐。 Pharmaceutical acceptable salt thereof may be any retained activity of the parent compound without any damage and adverse effects on those affected by the drug and drug are referred to herein salts.

上述盐可以由任何有机或无机酸或碱得到,该盐可以是一价或多价离子盐。 Such salts can be obtained from any organic or inorganic acid or base, the salt may be a monovalent or multivalent ion salts. 其中与酸官能团相关特别优选的是无机离子、钠、钾、钙和镁。 Wherein associated with the acid functionality is particularly preferred that the inorganic ions, sodium, potassium, calcium and magnesium. 有机胺的盐可用胺制得,尤其是铵盐如一、二和三烷基胺或醇胺。 Amine salts of organic amines are available in the system, especially ammonium mono-, di- and tri-alkyl amines or alcohol amines. 所说的盐也还可以由咖啡因、氨基丁三醇及类似分子制得。 Said salt can also be made of caffeine, tromethamine and similar molecules prepared. 如果有能够形成酸加成盐(acid addition salts)的碱性足够强的氨存在的话,可以用任何无机或有机酸或烷基化剂如甲基碘制成所说的盐。 If there are capable of forming acid addition salts (acid addition salts) are sufficiently basic ammonia present, may be any salt-forming inorganic or organic acid or an alkylating agent such as methyl iodide complete said. 优选的盐是由无机酸如盐酸、硫酸或磷酸生成的那些盐。 Preferred salts are those derived from inorganic acids such as hydrochloric, sulfuric or phosphoric acid generated. 很多简单的有机酸如一元、二元或三元酸亦可采用。 Many simple organic acids such as a mono-, di- or tri-acid may also be used.

按照本发明治疗方法采用的化合物以及包含新的组成部分的本发明的化合物均包括至少一个双键,因此可以存在有反式和顺式(E和Z)异构体。 Compound and a compound containing new components according to the present invention is a method of treatment employed in this invention includes at least one double bond, and therefore may exist trans and cis (E and Z) isomers. 另外,用于本发明治疗方法的一些化合物可以包含一个或一个以上手性中心,因此存在有对映形和非对映形。 In addition, some of the compounds used in the treatment methods of the invention may contain one or more chiral centers, therefore there is shaped enantiomers and diastereomers shape. 本发明的范围包括所有这些异构体本身以及顺反异构体混合物,还包括非对映体混合物和对映体的外消旋混合物(旋光异构体)。 Per se scope of the present invention includes a mixture of cis and trans isomers and all such isomers, including diastereomeric mixtures and enantiomers of the racemic mixture of the outer (optical isomers).

给药方法用于本发明治疗方法的化合物可以采用内吸收或局部给药的方式,这取决于对欲治疗病情、具体治疗部位的需要,所给药剂的数量等之类的考虑。 Compounds for the treatment methods of the invention the method of administration may be employed for the absorption or topical administration, depending on the disease to be treated, need for specific treatment site, consider the number of other agents and the like are given.

具体说治疗皮肤病时,可以采用局部给药的方式,但在某些情况下,如治疗严重的膀胱痤疮(Cystic acne),可以优选口服给药的方式。 Specifically, the treatment of skin diseases, topical administration may be used, but in some cases, such as treatment of severe acne bladder (Cystic acne), oral administration may be preferred manner. 可以使用任何通用的局部用配制剂如溶液、悬浮液、凝胶、软膏或油膏等。 May be used any conventional topical formulations such as solutions, suspensions, gels, ointments or salves and the like. 所说的局部用配制剂的制备例如在Remington′sPharmaceutical Science(第17版,Nack出版公司,Easton,Pennsylvania)所列举的药物配制剂技术中有充分的描述。 The preparation of said topical formulation of pharmaceutical formulation technique such as in Remington'sPharmaceutical Science (17th Edition, Nack Publishing Company, Easton, Pennsylvania) as exemplified for the full description. 对于局部使用来说,这些化合物也可以以粉末或喷雾剂,尤其是气溶胶的形式给药。 For topical use, these compounds can also be in a powder or spray, particularly in the form of aerosol administration.

如果药剂为内吸收给药,可以将其制成粉剂、丸剂、片剂等,或制成糖浆或酏剂,以便用于口服给药。 If the absorbing agent is administered, may be made into powder, pill, tablet or the like, or made into syrups or elixirs, for oral administration in order. 对于静脉内或腹膜内给药,可将化合物制成能够注射给药的溶液或悬浮液。 For intravenous or intraperitoneal administration, the compound can be administered by injection into a solution or suspension. 在某些情况下,可以将这些化合物配制成栓剂或作为埋于皮下的缓释配制剂,或配制成肌内注射剂。 In some cases, these compounds can be formulated as a suppository or as a sustained release formulation under the skin, or formulated as intramuscular injection.

可将其它药物加到局部用配制剂中以达到治疗皮肤干燥、避免光照之第二目的;治疗皮肤病、防止感染、减少刺激和炎症等的药物亦可加入。 Other drugs can be added to topical formulations to achieve therapeutic skin dry, avoid light of the second object; treatment of skin diseases and prevent infection, reduce irritation and inflammation of the drug may be added.

通过给予治疗有效量的一种或一种以上本发明的化合物能够达到治疗皮肤病或其它任何已知或发现能用视网膜样化合物治疗的病症之目的。 Compound by administering a therapeutically effective amount of one or more of the present invention can achieve the purpose of skin disease or any other known or can be found in the retina-like compounds to treat disorders of the treatment. 治疗用浓度系为达到减轻特定病情或阻滞其扩大之目的的浓度。 System in order to achieve therapeutic concentrations mitigate concentration of specific illness or retardation enlarged purposes. 在某些情况下,可以预防性地使用药剂以防止一特定病症的突发。 In some cases, agents may be used prophylactically to prevent a burst of a particular condition. 具体的治疗浓度随着病情的不同而改变,在某些情况下,可以随着治疗病症的严重程度和病人对治疗的敏感程度而改变。 Specific therapeutic concentrations with different conditions is changed, in some cases, may vary with the severity of the condition being treated and the patient's sensitivity to treatment is changed. 因此,一具体治疗浓度最好当时当地通过例行试验来确定。 Therefore, the concentration of a specific treatment is best determined by prevailing local routine tests. 但是,可以预知,例如治疗痤疮或其它此类皮肤病时,含0.001-5%(wt),最好约0.01-1%(wt)的配制剂通常为治疗有效浓度。 However, can be predicted, for example, the treatment of acne, or other such dermatoses, containing 0.001-5% (wt), preferably from about 0.01-1% (wt) of the formulation is generally a therapeutically effective concentration. 如果采用内吸收给药,多数情况下,0.01-100mg/Kg体重/天,最好约0.1-10mg/Kg即能达到治疗效果。 If the absorption of administration, in most cases, 0.01-100mg / Kg body weight / day, preferably from about 0.1-10mg / Kg that is able to achieve a therapeutic effect.

生物学活性用于本发明治疗方法的化合物无致畸活性,或者显著低于现有技术化合物的致畸性。 The method of the present invention is treated with the compounds for biological activity of non-teratogenic activity, or significantly lower than the prior art compounds teratogenicity. 本发明化合物无致畸性由ICR孕鼠的体内畸形学研究而得到证实。 No teratogenic compounds of the invention in vivo study by malformations pregnant ICR mice and confirmed. 研究方法说明如下:动物采用ICR小鼠(Ace动物,Boyertown,PA)。 Methods are described as follows: animal using ICR mice (Ace Animals, Boyertown, PA). 将成龄雄性和未交配过的雌性ICR小鼠饲养在受控环境室内,在使用两周前,使之适应12小时光照/黑暗周期(光照周期上午6时至下午6时)。 Become old male and virgin female ICR mice were housed in a controlled environment chamber, using two weeks ago, to adapt a 12 hour light / dark cycle (light period 6:00 to 18:00). 所有的鼠均按Purina Lab Chow饲养,并随意供给自来水。 All rats reared according to Purina Lab Chow and water ad libitum. 3-4只雌鼠为一组与一只经证实有生育力的雄鼠同关一笼4小时。 3-4 females as a group and have a proven fertility of male mice with a cage four hours off. 阴道栓物一经存在后即刻作为交配成功的证据,该天称为受孕的第0天。 After a vaginal suppository thing exists immediately mating success as evidence that the day is called day 0 of pregnancy.

畸形学在受孕的第11天上午(上午10点)给予一次口服剂量(0.1,1.0,10或100mg/Kg)的试验用药剂。 Teratology in the first 11 days of pregnancy morning (10:00) to give an oral doses (0.1, 1.0 or 100mg / Kg) of the test drug. 在受孕的第17天,在轻度醚麻醉状态下,通过宫颈脱位而将全部动物致死。 In the first 17 days of pregnancy, under mild ether anesthesia by cervical dislocation and the whole animal to death. 剖腹取胎检查外形畸形状况并称量;然后将每胎之胎鼠的一半在95%乙醇中固定并采用快速茜素红-S染色法将骨骼染色。 Caesarean births take shape deformity status checks and weighed; then half of pups per litter and the use of fixed quickly -S Alizarin Red staining of the bone staining in 95% ethanol. 将上述制备物在解剖显微镜下扫描检查中轴骨骼和附属骨骼的畸形状况。 The above preparation was checked under a dissecting microscope to scan the axial skeleton and skeletal deformities subsidiary condition. 每胎胎鼠的另一半在布安液中固定,并通过手动切片刀系列切片(freehand razorserial sectioning)扫描检查大脑、脸及腭的异常情况。 Pups per litter and the other half was fixed in Bouin and scan abnormalities of the brain, face and palate knife series by manually slice (freehand razorserial sectioning).

通过计算出受害孕体占全部植入部位的百分率,分析剂量与畸形和吸除(resorption)发生率相关性的差异。 By calculating the victim conceptus percentage of total implant site, analyze dose and deformity and suction (resorption) differences in the incidence of correlation. 在统计学意义上比较各组情况,方法即以学生的拱形t-试验为基础,将百分率转变为平方根。 Compare groups on statistical significance, the method that is arched student t- test is based on the percentage change of the square root. 在0.05可能性水平上的值被认为是显著的。 Likelihood value at the 0.05 level were considered significant. 由剂量响应数据的拟合对数曲线计算出中值有效剂量。 From the dose response data are fit logarithmic curve calculated median effective dose.

表1致畸效应# # % % %化合物 剂量 处理的胎鼠 正常胎鼠 再吸收的 颚裂 肢体缺陷(mg/kg) (Resorbed)AGN191440 1 7 5 19 13 17(化合物11) 10 8 1 2 88 75100 3 0 100 -- --AGN191183 0.01 5 2 3 29 20(现有技术) 0.1 4 0 30 100 1001 2 0 100 -- --10 2 0 100 -- -- Table 1 teratogenic effects ##%%% normal fetal rat fetal resorption compound dose treatment of limb defects of cleft palate (mg / kg) (Resorbed) AGN191440 1 7 5 19 13 17 (Compound 11) 1081288 75100 3 0 100 - --AGN191183 0.01 5 2 3 29 20 (prior art) 0.1 4,030,100,100,120,100 - --10 2 0 100 - -

表1(续)致畸效应# # % % %化合物 剂量 处理的胎鼠 正常胎鼠 再吸收的 颚裂 肢体缺陷(mg/kg) (Resorbed)AGN191701 1 1 1 18 0 0(化合物19) 10 3 3 14 0 0100 3 2 2 19 22 Table 1 (continued) cleft palate limb defects (mg / kg) (Resorbed) normal fetal rat fetal teratogenic effects ##%%% compound dose treatment resorption AGN191701 1 1 1 18 0 0 (Compound 19) 103 314,001,003,221,922

研究结果示于表1。 The results are shown in Table 1. 从表1可以看出,化合物AGN191183是具有式7所示结构的现有技术化合物。 As can be seen from Table 1, the prior art compound AGN191183 is a compound having the structure shown in formula 7. 式7的化合物缺少按本发明所要求且如式1所示的降低致畸性(或无致畸性)所必需的结构部分。 The compounds of formula 7 according to the present invention, lack the desired and as shown in formula 1 is reduced Teratogenicity (or non-teratogenic) moiety necessary. 有关该化合物的数据表明其具有明显的致畸性,因为当以一次剂量0.1mg/Kg给予该化合物时,全部胎鼠(100%)均出现畸形效应。 Data on this compound showed it to have a significant teratogenic, because when one dose to 0.1mg / Kg given to the compound, all fetuses (100%) were deformity effects. 与此相反,本发明的两个举例性化合物(在本申请中,化合物AGN191440亦称化合物11,AGN191701亦称化合物19)致畸性均显著降低。 In contrast, two exemplary compounds of the present invention (in the present application, the compound AGN191440 known compound 11, AGN191701 also known as Compound 19) were significantly reduced teratogenic. 化合物AGN191440的致畸作用比AGN191183约低100倍(例如1mg/Kg的AGN191440所产生的致畸作用比AGN191183在0.01mg/Kg时的还要低),AGN191701的致畸作用比AGN191183的约低104倍(如,100mg/Kg的AGN191701产生的致畸作用低于0.01mg/Kg的AGN191183所产生的致畸作用)。 Teratogenicity compound AGN191440 of about 100-fold lower than AGN191183 (e.g. teratogenic effects produced 1mg / Kg of AGN191440 at 0.01mg / Kg when lower than AGN191183), AGN191701 teratogenic effect than low AGN191183 about 104 times (e.g., teratogenicity 100mg / Kg of AGN191701 teratogenic effect produced below 0.01mg / Kg of AGN191183 generated). 采用试管生物分析法测定鸡胚细胞中软骨形成(骨形成)的抑制作用,该方法为畸形的经典测定法,所得结果示于表2。 Inhibition of cartilage formation in chicken embryo cells (bone formation) was measured by tube bioassay, the classical method for deformity assay results are shown in Table 2. 分析方法描述如下:按照一种生物分析法,采用肢芽间质细胞的高密度“斑点”培养物来比较受试药剂的不同浓度抑制软骨形成分化的能力。 Analysis methods are described as follows: According to a bio-assay, using inter-limb bud mesenchymal cells in high-density "spot" culture to compare the ability of different concentrations of the test agents inhibit the differentiation of cartilage formation. 将孕期第12天的鼠胎的前肢芽(542体节)在胰蛋白酶-EDTA溶液中解离出来,并将所得单细胞悬浮液涂覆在塑料培养皿上呈20μl斑点(200,000细胞/斑点)铺板。 The first trimester fetal mice 12 days of forelimb buds (54 2 somites) -EDTA in trypsin solution dissociate, and the resulting single cell suspension was coated on a plastic dish was 20μl spots (200,000 cells / spots) plank. 在初始铺板后24小时将浓度为0.3ng/ml-3μg/ml(1nM-10μM)的视网膜样化合物加到培养基(Eagle′s MEM+10%胎牛血清,GIBGO)中。 In 24 hours after the initial plated at a concentration of 0.3ng / ml-3μg / ml (1nM-10μM) was added to the culture medium of the retina-like compound (Eagle's MEM + 10% fetal bovine serum, GIBGO) in. 对照培养物仅接受载体(乙醇,浓度≤1%(V));在另一系列培养物中将视黄酸用作阳性对照。 Control cultures received only vehicle (ethanol, concentration ≤1% (V)); In another series of retinoic acid in the culture was used as positive control.

在铺板后96小时终止培养,此时,除掉培养基,将细胞在含0.5%氯化十六烷基吡啶嗡的10%福尔马林中固定1小时。 In the 96 hours after plating termination of culture, this time, to get rid of the medium, the cells containing 0.5% cetylpyridinium chloride in 10% formalin fixed for 1 hour. 培养物在乙酸中洗涤,并在PH 1.0的0.5%Alcian兰溶液中染色1小时,再于3%的乙酸中分化,然后用乙醇脱水,最后在显微镜下记录形成的软骨。 Culture was washed in acetic acid, in PH 1.0 and the 0.5% Alcian blue staining solution for one hour at 3% regenerated acetic acid, and then dehydrated with ethanol, and finally record chondrogenesis under the microscope. 与对照培养物相比,染色的培养物中如无软骨结节或数目减少即为软骨形成受阻的度量。 Compared to control cultures, cultures stained cartilage nodules in the absence or reduction is the number of chondrogenic metric blocked. 对每一处理的四个相同培养物计算整个斑点内染上色的软骨结节数,平均结节数和标准偏差。 Four identical cultures were calculated for each treatment throughout the infected spot color cartilage nodules, the number of nodules and the average standard deviation. 按照剂量响应数据的拟合对数曲线计算出与对照比较而言的引起50%软骨形成抑制的中值浓度(IC50)。 Caused 50% compared with control values in cartilage formation concentration (IC50) inhibition dose-response data in accordance with a logarithmic curve fitting calculated in terms.

由表2可以看出,现有技术的化合物AGN191183其IC50浓度(抑制50%软骨形成的浓度)比本发明化合物AGN191440的IC50低近1000倍,比本发明化合物AGN191701的IC50低大约6000倍。 As can be seen from Table 2, the compounds of the prior art AGN191183 its IC50 concentration (concentration of 50% inhibition of cartilage formation) than the compounds of the present invention AGN191440 IC50 nearly 1000 times than the compounds of the present invention AGN191701 about 6,000-fold lower IC50. 由此证明现有技术的化合物比本发明的化合物致畸潜力大得多。 Thus proving that the compound than the prior art compounds of the present invention is much greater teratogenic potential.

表2化合物 IC50(μg/ml)AGN191183(现有技术) 0.003AGN191440(化合物11) 2.5AGN191701(化合物19) 19.0药物动力学研究包括经口插管法给予小鼠10mg/Kg剂量的本发明化合物AGN191701,随后测定母体血浆和胚胎中的药物浓度,如图1所示,该研究表明化合物AGN191701(化合物19)确以一定的浓度(substantial concentration)存在于母体血浆和胚胎中。 Table 2 Compound IC50 (μg / ml) AGN191183 (prior art) 0.003AGN191440 (Compound 11) 2.5AGN191701 (Compound 19) 19.0 Kinetics of drug administered include oral intubation mice 10mg / Kg dose of the compound of the invention AGN191701 , followed by determination of drug concentration in maternal plasma and embryos, as shown in FIG. 1, this study indicates that the compounds AGN191701 (Compound 19) determined to a certain concentration (substantial concentration) is present in maternal plasma and embryos. 而且,正如表1的数据表明的那样,该化合物致畸作用极小。 And, as the data in Table 1 shows, the teratogenic effect of the compound is minimal. 相反,现有技术的化合物AGN191183的致畸性是很高的,以至于在不可能检测出药物这样低的浓度下即已经引起异常胚胎。 In contrast, the prior art compound AGN191183 teratogenicity is very high, so that can not be detected in such a low concentration of the drug that is already cause abnormal embryos.

通过若干种分析方法可以证实用于本发明治疗方法的化合物及本发明新化合物具有视网膜样活性。 By several analytical methods can demonstrate that the compounds of the present invention, methods of treatment and novel compounds of the present invention having a retina-like activity is used. 一种包括对人体sebocyte培养物所进行的分析,能够测出3H-胸苷进入细胞受阻,因此测出DNA合成受到抑制,并确定对sebocyte的抗增生作用(即sebostaic作用)。 Comprising human sebocyte cultures analysis conducted, that can detect a blocked 3H- thymidine into the cells, and therefore the measured DNA synthesis was inhibited, and determines on sebocyte antiproliferative effect (i.e. sebostaic effect). 该试验分析也被认为是一种化合物作为抗痤疮药的有效性的一种专门分析方法。 This test analysis is also considered a special analytical method effectiveness of a compound as an anti-acne drug. 试验过程如下。 Test procedure is as follows. 皮肤来源:将由美容手术得到的整容或去额皱的皮肤用作人体皮脂腺细胞(sebocytes)的来源。 Skin Source: Plastic or cosmetic surgery would amount to get wrinkled skin used as a source of human sebaceous gland cells (sebocytes) of. sebocytes的分离: sebocytes of separation:

将分离出的sebocytes在1型有胶原涂层的培养皿中铺板,其中的DMEM/F12(1∶1)培养基中添加有8%胎牛血清、2%人体血清、10ng/ml表皮生长素、1nM霍乱毒素(choleratoxin)、1μM氢化可的松及青霉素/链霉素/两性霉素B。 The separated sebocytes in type 1 collagen coated Petri dish were plated, wherein the DMEM / F12 (1:1) medium supplemented with 8% fetal calf serum, 2% human serum, 10ng / ml epidermal growth hormone , 1nM cholera toxin (choleratoxin), 1μM hydrocortisone and penicillin / streptomycin / amphotericin B. 通过将Dispase解离的细胞在有胶原涂层的24孔(24-well)板上铺板制备第二培养物。 By Dispase dissociated cells in collagen-coated 24-well (24-well) were plated cultures were prepared in a second plate. 增生研究(3H-胸苷的结合)在上述培养基中(其总血清浓度降至2%,并且不包含氢化可的松)用试验化合物或乙醇载体在8天的期间内每2-3天处理一次几近汇合(sub-confluent)的第二培养物。 Hyperplasia Research (3H- thymidine binding) in the above medium (total serum concentration to 2%, and does not contain hydrocortisone) or ethanol vehicle with the test compound over a period of eight days every 2-3 days near the confluence of the processing time (sub-confluent) second culture. 在处理期间的最后6小时,用2μCi/ml3H-胸苷标记培养物。 During the last 6 hours of treatment, with 2μCi / ml3H- thymidine labeled cultures. 用thichoroacetic acid和高氯酸提取出细胞中的DNA,并通过闪烁计数法检定放射性,通过二苯胺比色法分析DNA含量。 With thichoroacetic acid and perchloric acid to extract the cells DNA, and verification radioactivity by scintillation counting method, by diphenylamine colorimetric analysis of DNA content. 结果以CPM/μg DNA表达,或以结合有约1,000-1,500cpm/μg DNA的载体对照的百分数表达。 Results in CPM / μg DNA expression, or to bind about 1,000-1,500cpm / μg DNA expressed as a percentage of vehicle control.

将化合物AGN191701(化合物19)、AGN191659(化合物21)和现有技术化合物AGN191183的试验结果绘成曲线,正如图2曲线所示,在该试验分析中,现有技术的化合物是无效的,而本发明的两个实例化合物是有效的。 Compound AGN191701 (Compound 19), AGN191659 (Compound 21) and the test results of the prior art compounds AGN191183 plotted, as shown in the graph in Figure 2, in the experimental analysis, the compound of the prior art are ineffective, and this Two examples of the compound of the invention is effective.

能够证明本发明所用化合物具有视网膜样活性的其它分析方法是HL-60转谷氨酰胺酶诱导法和HL-60分化法,步骤如下所述。 Can prove that the compounds used in this invention have other analytical methods retina-like activity is transglutaminase HL-60 and HL-60 was induced differentiation method described below. 分化:HL-60细胞氮兰四唑还原分析(NBT还原分析)使HL-60细胞作为一种悬浮培养物在T-162CM2烧瓶中无血清RPMI1640培养基中生长,该培养基中添加有胰岛素(5μg/m1)、转铁蛋白(5μg/m1)和硒(3nM)。 Differentiation: HL-60 cells were analyzed tetrazolium reduction (NBT reduction analysis) enables HL-60 cells were grown as a suspension culture in T-162CM2 flasks in serum-free RPMI1640 medium, and the medium supplemented with insulin ( 5μg / m1), transferrin (5μg / m1) and selenium (3nM). 在上述RPMI1640培养基中,用试验化合物的系列稀释物处理上述细胞(在24孔盘中,1105/孔),所说的培养基中还加有0.2mM的二丁酰环腺苷-磷酸,该成份对细胞的有效分化是必要的。 In the above-mentioned RPMI1640 medium, using serial dilutions of the test compound treated above cells (in 24-well plates, 1 105 / well), said medium further added 0.2mM of dibutyryl cyclic adenosine - phosphate, The component is necessary for effective cell differentiation. 乙醇用于载体对照培养物中。 Ethanol for vehicle control cultures. 在含5%CO2的恒温箱中,37℃下培养3天后,将氮兰四唑(NBT)和四十四酰佛波醇乙酸酯(TAP)与细胞混合,并使NBT和TAP最终浓度分别达到0.1%和100ng/ml,然后再于室温下培养15-30分钟。 In an incubator containing 5% CO2, the lower 37 ℃ cultured for 3 days, the nitroblue tetrazolium (NBT) and tetrakis tetradecanoyl phorbol acetate (TAP) was mixed with the cells, and the final concentration of NBT and TAP respectively 0.1% and 100ng / ml, then incubated at room temperature for 15-30 minutes. 分化的HL-60细胞由于NBT还原而得到一种紫色甲脂沉淀(NBT阳性细胞)。 Differentiation of HL-60 cells as a result of NBT reduction to give a purple precipitate methyl ester (NBT-positive cells). 然后将细胞在10%的仲甲醛中固定,并通过离心分离而成为球形。 Cells were then in 10% paraformaldehyde fixed and separated by centrifugation and become spherical. 把此细胞球再次悬浮于少量体积的磷酸盐缓冲液中。 The ball of cells was resuspended in this small volume of phosphate buffer. 用血球计数计计算确定每一细胞悬浮液中的细胞总数和NBT阳性的细胞数。 Count calculation to determine the number of cells in each cell suspension and the total number of NBT-positive cells with blood cell count. 四份同样培养物的平均值以NBT阳性细胞的百分数表达。 Four parts of the same average value of cultures to express the percentage of NBT-positive cells.

本领域技术人员很容易理解,该试验分析中的细胞分化是视网膜样活性的标志。 Skilled in the art will readily appreciate that the experimental analysis of cell differentiation is a sign of the retina-like activity. 化合物AGN191440(化合物11)、AGN191701(化合物19)和AGN191768(化合物15)的分析结果分别示于图3-5的曲线上。 Compound AGN191440 (Compound 11), AGN191701 (Compound 19) and AGN191768 (Compound 15) The analysis results are shown in Figure 3-5 on the graph. 用HL-60细胞进行组织转谷氨酰胺酶分析(tTGASE)使HL-60细胞作为一种悬浮培养物在T-162cm2烧瓶内无血清RPMI1640培养基中生长,该培养基中添加有胰岛素(5μg/m1)、转铁蛋白(5μg/m1)和硒(3nM)。 Analysis performed tissue transglutaminase (tTGASE) with HL-60 cells so that HL-60 cells as a suspension culture were grown in serum-free RPMI1640 medium in T-162cm2 flasks, the medium supplemented with insulin (5μg / m1), transferrin (5μg / m1) and selenium (3nM). 在上述RPMI1640培养基中,用试验化合物的系列稀释物处理上述细胞(24孔盘中,1106细胞/孔),所说的培养基中另加有1nN的二丁酰环腺苷-磷酸,该成份对细胞的有效分化是必要的。 In the above-mentioned RPMI1640 medium, serial dilutions of test compounds treated with the above-described cells (24 well plates, 1 106 cells / well), said media plus a 1nN of dibutyryl cyclic adenosine - phosphate, the Ingredients effective differentiation of cells is necessary. 乙醇用于载体对照培养物中。 Ethanol for vehicle control cultures. 在含7.5%CO2的恒温箱中37℃下培养1天后,将细胞收集到一组试管中,并通过离心分离使之成球形,把细胞溶解在含20mM Tris-HCl(PH 7.5)、1mM EDTA和0.5Triton X-100的缓冲液中。 Cultured in an incubator at 37 ℃ containing 7.5% CO2 for 1 days, the cells were collected into a group of test tube, and by centrifugal separation to make it spherical, containing the cells were lysed in 20mM Tris-HCl (PH 7.5), 1mM EDTA and buffers 0.5Triton X-100 in. 取一等分溶胞产物在含20mMTris-HCl(PH7.5)、5mM CaCl2、2mg/ml二甲基干酪素、15mMB-巯基乙醇和50μCi/ml[2,3-3H]腐胺二氢氯化物(putrescine dihydrochloride)的反应混合物中分析tTGASE活性。 Take an aliquot of lysate containing 20mMTris-HCl (PH7.5), 5mM CaCl2,2mg / ml dimethyl casein, 15mMB- mercaptoethanol and 50μCi / ml [2,3-3H] putrescine dihydrochloride compound (putrescine dihydrochloride) of the reaction mixture was analyzed tTGASE activity. 在37℃振动水浴中反应60分钟,然后加入含0.1%腐胺(phtrescein)的10%三氯乙酸终止反应。 Reacted for 60 minutes in a shaking water bath at 37 ℃, then added with 0.1% putrescine (phtrescein) of 10% trichloroacetic acid to terminate the reaction. 取一等分终止后的反应混合物点滴在Whatman 3MM过滤器盘上。 After termination of the reaction mixture drip take an aliquot on Whatman 3MM filter plate. 此过滤器盘和作为对照的空白过滤器盘用含0.1%腐胺(putrescein)的5%三氯乙酸洗涤两次,再用甲醇洗涤两次。 This filter plate and washed twice with 5% trichloroacetic acid as a control blank filter discs containing 0.1% putrescine (putrescein), and then washed twice with methanol. 将过滤器盘在加热灯下干燥后,通过闪烁计数确定过滤器盘内的放射性。 After the filter pan and dried under a heat lamp, radioactivity on the filter disc is determined by scintillation counting within. 再取一等分的溶胞产物采用Bradford法(Bio-Rad)分析其保护性浓度。 Analyze its protective concentration and then take an aliquot of the lysate using the Bradford assay (Bio-Rad). 待空白对照过滤器盘的放射性衰减后,算出数据,并以pmol/min/mg蛋白质表达。 Radioactivity to be blank after attenuating filter disc, data is calculated, and pmol / min / mg protein expression.

正如本领域所知道的那样,上述分析试验中转谷氨酰胺酶活性的诱发是视网膜样活性的早期象征。 As is known in the art, as the above analysis test transit glutaminase activity induced retinal-like activity of the early symbol. 图6中的曲线给出了此试验对化合物AGN191183(式7)和AGN191440(化合物11)的分析结果。 Figure 6 shows a graph of this test compound AGN191183 (Formula 7) and AGN191440 (Compound 11) The results of the analysis. 由该曲线可以看出,在此特定的分析试验中,现有技术的化合物是无活性的,而AGN191440是有活性的。 As can be seen from the curves, in this particular analysis test, the compounds of the prior art is inactive, and AGN191440 is active. 图7-9的曲线表明,在该分析试验中,本发明的其它举例性化合物(AGN191642(化合物13)、AGN191701(化合物19)和AGN191659(化合物21))也是有活性的。 Figures 7-9 show curves, in this assay test, other exemplary compounds of the invention (AGN191642 (Compound 13), AGN191701 (Compound 19) and AGN191659 (Compound 21)) is active.

用于本发明治疗方法的化合物(及本发明的新化合物)的另一优良特征是,这些化合物与缺少本发明结构特征的对比化合物相比,毒性明显降低,对皮肤的刺激显然要小。 Another excellent feature of the compound (and the novel compounds of the present invention) treatment process of the invention is that these compounds compared to the lack of structural features of the present invention, comparative compounds, decreased toxicity, skin irritation is obviously smaller. 用于本发明治疗方法的化合物(以及本发明的新化合物)毒性低这点是非常有意义的,因为有毒性,尤其是对皮肤有刺激性是视网膜样化合物的一个共同缺点。 (As well as new compounds of the present invention) The compound of the present invention is a method for the treatment of low toxicity to this point is very significant, because toxic, especially for skin irritation is a common drawback of the retina-like compound. 因此,式1所示的结构赋予本发明化合物显著降低的毒性及皮肤刺激效应这一点是出乎意料之外的。 Thus, the structure shown in Formula 1 given toxicity and skin irritation effects of the compounds of this invention significantly reduced and this is unexpected.

具体地说,测定皮肤毒性的试验是用本发明的某些例举化合物和缺少式1、2或3中R3取代基的类似化合物进行的。 Specifically, the skin toxicity test was measured using certain exemplified compounds of the present invention similar to the substituent R3 and the lack of a compound of formula 1, 2 or 3 conducted. “无毛雌鼠多点局部用药的两周急性皮肤毒性研究”按如下所述进行:把日剂量(以nmol表示)的“试验化合物”涂抹在无毛鼠背的皮肤上(一般每一化合物以5只鼠为一试验组)。 "Two weeks of acute dermal toxicity study hairless female multi-topical" carried out as follows: The daily dose (expressed in nmol) of the "test compound" smear on hairless mouse dorsal skin (typically each compound In 5 rats for a test group). 连续5天按日剂量涂抹试验化合物,然后停止给药两天,此后再连续给药4天。 Applied daily for 5 consecutive days the dose of test compound, administered in two days and then stopped, after which administered continuously for 4 days. 第14天时,如果试验动物还活着则提供用来进行研究和试验。 14 days, if the test animals are still alive are available for research and testing. 这期间,测试和观察与体重和皮肤状况有关的日基础情况。 During this period, test and observe daily basis the situation with weight and skin-related conditions. 皮肤状况按“鳞片/鳞屑”和“擦伤”各分为0-+5级,各数字的对应关系如下。 Skin condition Press "scales / scales" and "bruises" were divided into 0- + 5, the correspondence between each number below. 皮肤刺激性的基本评分鳞片/鳞屑 级别无鳞片 0非常轻微(有少数鳞片) +1轻微(~25%或小于此值) +2中度(大于~25%,小于~75%) +3中上(大于~50%,小于~75%) +4严重(~75%,或大于此值) +5擦伤 级别无擦伤 0非常轻微(轻微浅粉色的1至2处擦伤) +1轻微(1处或几处擦伤,深粉色) +2中度(大于~25%,浅红色) +3中上(大于~50%,红色) +4严重(大于~75%,深红色) +5上述试验结果汇于表3中,其中日剂量用nmol表达,试验动物的体重下降以14天试验期结束时,或试验动物死亡时的百分率表示,死亡率以每组5只动物中死亡的动物数表示。 Basic skin irritation rating scales / scaly level not scaly 0 very slight (a few flakes) +1 slightly (~ 25% or less than this value) +2 moderate (greater than ~ 25%, less than ~ 75%) and +3 On (greater than ~ 50%, less than ~ 75%) +4 severe (~ 75%, or greater than this value) +5 0 abrasions level no scratches very slight (slight pale pink bruising 1-2) +1 minor (one or several abrasions, deep pink) +2 moderate (greater than ~ 25%, light red) in the +3 (greater than ~ 50%, red) +4 severe (greater than 75%, magenta) +5 above test results are summarized in Table 3, wherein the daily dosage used nmol expression, the percentage weight loss of the test animals at the end of 14-day test period, or death of the test animals shows mortality in groups of five animals died The number of animals, said. 表3化合物 日剂量 %体重变化 死亡总数 鏻片/鳞屑 擦伤AGN191183 7.5 -2.3 0/5 +2 +1AGN191183 25 -13.4 0/5 +4 +1AGN191183 75 -29.8 5/5 +1 +1AGN191183 80 -2.3 5/5 +1 +2AGN191440 75 3.1 0/5 +2 +1AGN191440 124 -2.7 0/5 +2 +1AGN191440 1240 -19.5 3/5 +4 +2AGN191548 300 N/A 2/5 +5 +2AGN191549 300 3.6 0/5 +1 0表3(续)化合物 日剂量 %体重变化 死亡总数 鏻片/鳞屑 擦伤A6N191543 800 N/A 2/5 +3 +1AGN191544 800 3.6 0/5 +1 0AGN190316 55 -2.0 0/5 +3 +2AGN190316 60 -28.9 3/5 +2 +3AGN191422 60 0.64 0/5 +1 +2AGN191422 64 1.5 0/5 +1 +1AGN191183为式7所代表的现有技术化合物,AGN191440是化合物11,其除了在四氢萘核的第3位上有甲基外,结构完全与AGN191183相同,因此,属于本发明的范围。 Table 3% of body weight daily dose of the compounds change the total death phosphonium tablets / scaly skin abrasions AGN191183 7.5 -2.3 0/5 +2 + 1AGN191183 25 -13.4 0/5 +4 + 1AGN191183 75 -29.8 5/5 +1 + 1AGN191183 80 -2.3 5/5 +1 + 2AGN191440 75 3.1 0/5 +2 + 1AGN191440 124 -2.7 0/5 +2 + 1AGN191440 1240 -19.5 3/5 +4 + 2AGN191548 300 N / A 2/5 +5 + 2AGN191549 300 3.6 0 / 5 + 1 0 Table 3 (continued)% change in body weight daily dose of a compound total deaths phosphonium tablets / scaly skin abrasions A6N191543 800 N / A 2/5 +3 + 1AGN191544 800 3.6 0/5 +1 0AGN190316 55 -2.0 0/5 +3 + 2AGN190316 60 -28.9 3/5 +2 + 3AGN191422 60 0.64 0/5 +1 + 2AGN191422 64 1.5 0/5 +1 + 1AGN191183 prior art compounds represented by Formula 7, AGN191440 is compound 11, which, in addition In the first three of the tetrahydronaphthalene nucleus are methyl, the structure is completely the same with AGN191183, therefore, within the scope of the present invention. AGN191549是化合物24。 AGN191549 is compound 24. 化合物AGN191548结构与AGN191549完全相同,只是在苯并二氢吡喃核的第7位上无甲基,因此,不属于本发明的范围。 AGN191548 structure AGN191549 identical compound except that bit 7 of the chroman nucleus methylation-free, therefore, outside the scope of the present invention. AGN191544是化合物26。 AGN191544 is compound 26. AGN191543除了在苯环的双键邻位上无甲基外其它结构完全与AGN191544相同,亦不属本发明的范围。 AGN191543 addition to the double bond in the phenyl ring ortho to the methylation-free outer other structures are completely the same with AGN191544, not part of the present invention. AGN191422是化合物10。 AGN191422 is compound 10. AGN190316与AGN191422结构完全相同,但其四氢萘核的第3位上无甲基,因此不属于本发明的范围。 AGN190316 and AGN191422 identical structure, but without its 3-methyl-tetrahydro-naphthalene nucleus on, therefore outside the scope of the invention. 表3的数据证明,本发明的化合物和结构与其相似但缺少本发明特征结构的化合物相比,致死率明显降低,对皮肤的刺激显著减少。 Data in Table 3 confirmed that the compounds of the present invention and its structure is similar to the structure but lacks the compound of the present invention is characterized as compared mortality rate was significantly reduced, significantly reduces skin irritation.

现在参见结构通式2-6,就这些结构中的符号A[实际上是苯基或杂环基团(分别用Y、Y1或Y2代表)上的一个侧链]来说,在本发明治疗方法中所用化合物以及本发明的新化合物中,优选其中A为(CH2)n的,n为0的化合物是更优选的。 Referring now to the general structural formula 2-6, these structures symbols A [actually phenyl or heterocyclic group (respectively Y, Y1 or Y2 on behalf of) a side chain], in the treatment of the present invention compounds used in the method and novel compounds of the present invention, preferably wherein A is (CH2) n, n is 0 for the compound are more preferable.

关于式2-6中的符号B,当B为-COOH或其碱金属盐或有机胺盐时,这些化合物是本发明优选的。 About 2-6 symbols in formula B, when B is -COOH or an alkali metal salt or organic amine salts, these compounds are preferably present invention. 另外,以下化合物亦是优选的,即其中的B为COOR8(R8为低级烷基的酯),CONR9R10(酰胺)-CH2OH(醇),CH2OCOR11,CH2OR11(R11为低级烷基,与低级醇生成的低级烷基酯和醚),或者B为-CHO或CH(OR12)2,CHOR13O(缩醛衍生物),其中R12和R13的定义同式2。 Further, the following compounds also are preferred, i.e., in which B is COOR8 (R8 is a lower alkyl ester), CONR9R10 (amide) -CH2OH (alcohol), CH2OCOR11, CH2OR11 (R11 is a lower alkyl group, with a lower alcohol generated lower alkyl esters and ethers), or B is -CHO or CH (OR12) 2, CHOR13O (acetal derivatives), where the definition of R12 and R13 in formula 2.

针对式2和3中的符号Y而育,当Y为苯基、吡啶基、噻吩基或呋喃基时,这些化合物是本发明治疗方法所优选使用的。 Formula 2 and 3 for the symbols Y and fertility, when Y is phenyl, pyridyl, thienyl or furyl, these compounds are treatment methods of the invention are preferably used. 式4是本发明的新化合物,其中Y1为噻吩基的化合物是优选的。 Formula 4 are novel compounds of the present invention, a compound wherein Y1 is a thienyl group are preferred. 式5和6也是本发明的新化合物,其中Y2为苯基、噻吩基或吡啶基的化合物是优选的。 The novel compounds of formula 5 and 6 are also the present invention, wherein Y2 is a phenyl group, a compound thienyl or pyridyl is preferred.

式2-6中的符号R2优选为氢或低级烷基,更优选为氢。 The symbol R2 in Formula 2-6 is preferably hydrogen or lower alkyl, more preferably hydrogen.

如上所述,根据本发明,取代基R1不能为氢。 As described above, according to the present invention, substituents R1 can not be hydrogen. 在式2-6所示的全部结构中,R1优选低级烷基,更优选甲基。 In all structural formulas 2-6, R1 is preferably lower alkyl, more preferably methyl. 同样,按照本发明,R3亦不能为氢,该取代基优选低级烷基或卤素,更优选甲基、氯代或溴代。 Similarly, according to the present invention, R3 can not be hydrogen, the substituent is preferably lower alkyl or halogen, more preferably methyl, chloro or bromo.

在式2-5中,R5和R6取代基(如果有的话)优选为氢或低级烷基,更优选氢,或者R5和R6不存在。 In Formula 2-5, R5 and R6 substituents (if any) is preferably hydrogen or lower alkyl, more preferably hydrogen, or R5 and R6 does not exist.

在本发明的治疗方法中,优选X1为CR5的式2化合物,更优选X1为CH的式2化合物。 In the treatment method of the present invention, preferably X1 is the compound of formula 2 CR5, X1 is more preferably a compound of formula CH 2. 在式3中,X3优选为硫。 In the formula 3, X3 is preferably sulfur.

在式2和3中,尤其是式2中,Z优选为一个氢和一个低级烷基,或两个低级烷基,一个氢和一个低级烷氧基,或两个低级烷氧基,一个氢和一个低级硫代烷氧基,或两个低级硫代烷氧基,或一个氢和一个带一双键的低级硫代烯氧基。 In Formula 2 and 3, in particular type 2, Z is preferably a hydrogen and a lower alkyl group, or two lower alkyl groups, a hydrogen and a lower alkoxy group, a lower alkoxy group, or two, a hydrogen and a lower thioalkoxy, lower thioalkoxy, or two, or one hydrogen and lower alkenyl thio group with a double bond. 另外,Z还优选为-(CR14)4-、-C(R14)2-C(R14)2-C(R14)2-C(R14)2-,或-C(R14)2-C(R14)2-C(R14)2-X2-。 Further, Z is also preferably - (CR14) 4 -, - C (R14) 2-C (R14) 2-C (R14) 2-C (R14) 2-, or -C (R14) 2-C (R14 ) 2-C (R14) 2-X2-. 在这些化合物中,R14是氢或低级烷基,尤其是甲基,且X2优选O或S的那些化合物是优选的。 Among these compounds, R14 is hydrogen or lower alkyl, especially methyl, and those compounds X2 preferably O or S is preferred. 当式2的Z为下列之一时,那些化合物是更为优选的:C(CH3)2-CH2-CH2-C(CH3)2-(3,5,5,8,8-五甲基-四氢萘衍生物);C(CH3)2-CH2-CH2-O-(4,4,7-三甲基-2,3-二氢苯并二氢吡喃衍生物);C(CH3)2-CH2-CH2-S-(4,4,7-三甲基-2,3-二氢二氢苯并噻喃衍生物);C(CH3)2-CH2-C(CH3)2-O-(2,2,4,4,7-五甲基-2,3-二氢苯并二氢吡喃衍生物)和C(CH3)2-CH2-C(CH3)2-S-(2,2,4,4,7-五甲基-2,3-二氢二氢苯并噻喃衍生物)。 When Z is one of the following formula 2, those compounds are more preferred: C (CH3) 2-CH2-CH2-C (CH3) 2- (3,5,5,8,8- pentamethyl - four decalin derivatives); C (CH3) 2-CH2-CH2-O- (4,4,7- trimethyl-2,3-dihydro-chroman derivatives); C (CH3) 2 -CH2-CH2-S- (4,4,7- trimethyl-2,3-dihydro-thiochroman derivatives); C (CH3) 2-CH2-C (CH3) 2-O- (2,2,4,4,7- pentamethyl-2,3-dihydro-chroman derivatives) and C (CH3) 2-CH2-C (CH3) 2-S- (2, 2,4,4,7- pentamethyl-2,3-dihydro-thiochroman derivatives).

在式4和5中,R20优选为低级烷基,更优选甲基。 In Formula 4 and 5, R20 is preferably lower alkyl, more preferably methyl. 在式6中,R21和R22之一最好为支链低级烷基,更优选叔丁基。 In formula 6, R21 and R22 is preferably one branched lower alkyl, more preferably t-butyl.

在本发明治疗方法中,作为实质上无致畸作用、无刺激性的视网膜样治疗剂的最优选化合物是参照如下式8、9、10和11所示的那些化合物: In the treatment method of the present invention, as substantially no teratogenic effect, non-irritating most preferred compounds of the retina-like therapeutic agent is a compound represented by the following formula 9, 10, 11 and those reference: 式8参照式8:化合物# R3X6R810 CH3CH Et11 CH3CH H12 Cl CH Et13 Cl CH H14 Br CH Et15 Br CH H16 CH3N Et17 CH3N H Referring to Equation 8 Equation 8: Compound # R3X6R810 CH3CH Et11 CH3CH H12 Cl CH Et13 Cl CH H14 Br CH Et15 Br CH H16 CH3N Et17 CH3N H 参照式9:化合物# X7R818 S Et(4位上COOR8)19 S H(4位上COOR8)20 S Et(5位上COOR8)21 S H(5位上COOR8)22 0 Et(5位上COOR8)23 0 H(5位上COOR8) Referring to Formula 9: Compound # X7R818 S Et (4-position COOR8) 19 SH (4-position COOR8) 20 S Et (5-position COOR8) 21 SH (5-position COOR8) 22 0 Et (5-position COOR8) 23 0 H (5 position COOR8) 式10参照式10化合物# R824 Et25 H Equation 10 Equation 10 reference compounds # R824 Et25 H 参照式11化合物# R8叔丁基在位置26 Et 3 to乙烯基27 H 3 to乙烯基28 Et 4 to乙烯基29 H 4 to乙烯基本发明所用化合物的合成方法本发明的新化合物以及用于本发明新治疗方法的化合物可以通过多种不同的化学合成途径制得。 Referring to the formula 11 compound # R8 tert-butyl in position 26 Et 3 to vinyl vinyl 27 H 3 to 28 Et 4 to novel compounds of ethylene vinyl 29 H 4 to the basic inventive compounds synthesized by the method of the present invention and used in the present The new compounds of the invention can be prepared by treatment of a number of different synthetic chemical pathways. 为了详细说明本发明,提供如下合成流程。 In order to illustrate the present invention, there is provided the following synthetic scheme. 合成化学家很容易理解,本发明所确定的条件是针对制备本发明新化合物的具体实施例的,但可以总结概括使之适应本说明书中的任何及全部新化合物,而且,还可以归纳概括这些条件以便获得本发明治疗方法所用的作为无致畸药物活性制剂的任何及全部化合物。 Synthetic chemist will readily appreciate that the present invention is determined by the condition that the specific embodiments of the preparation of the novel compounds of the present invention against, but can be summarized to adapt this specification any and all new compounds, moreover, can also generalize these conditions in order to obtain any and all compounds of the present invention are methods of treatment as a non-teratogenic pharmaceutically active formulation. 反应流程1 Reaction Scheme 1

参见反应流程1,图示说明了在本发明方法所用的苯基-丙烯基5,6,7,8-四氢萘化合物的合成。 Referring to Reaction Scheme 1, illustrates a method of the present invention is a phenyl group in used - Synthesis propenyl 5,6,7,8-tetrahydronaphthalene compound. 按照反应流程1,在弗瑞德-克来福特类反应条件下,使带有所要求R3、R5、R6和R20取代基(定义同式4)的5,5,7,8-四氢萘基化合物与一种试剂如R1COCl(R1定义同式4)反应,由此将R1-CO-酮官能团引入萘环的2位上。 According to Reaction Scheme 1, in a Friedel - Crafts type reaction under conditions grams, so that with the desired R3, R5, R6 and R20 are substituent group (as defined for formula 4) of 5,5,7,8- tetrahydronaphthalene compound with a reagent such as R1COCl (R1 as defined in formula 4) reaction, thereby R1-CO- ketone functional group into 2-position of the naphthalene ring. 当R1为甲基时,弗瑞德-克来福特型反应中所用的试剂一般为乙酰氯。 When R1 is methyl, Friedel - Crafts Crafts type reagents used in the reaction is typically acetyl chloride. 然后,使产生的式16的酮与式17的一种磷酸酯试剂进行Wittig Horner型反应。 Then, the resulting ketone of formula 16 Formula 17 is a phosphate reagent Wittig Horner type reaction. 式17的磷酸酯试剂带有一个酯(COOR8)取代基,但应该理解,类似的磷酸酯试剂一般地说可以带有AB官能团,该官能团的定义同式2。 Phosphate ester of formula 17 with a reagent ester (COOR8) substituent, but it should be understood that a similar agent generally may have AB phosphate functional group of the functional group defined in formula 2. 如反应流程所示,WittigHorner型反应是在有强碱如NaCH2SOCH3(dimsyl sidium)存在下,在一种象四氢呋喃(THF)这样的溶剂中进行的。 As shown in Reaction Scheme, WittigHorner type reaction is carried out in a strong base such as NaCH2SOCH3 (dimsyl sidium) in the presence of, in one such as tetrahydrofuran (THF) is carried out in such a solvent. 式18化合物中的乙烯键(双键)在该反应中形成。 The compound of formula 18 ethylene bond (double bond) is formed in this reaction. 如上所述,该双键是本发明所用化合物的一个必要特征。 As described above, the double bond is an essential feature of the present invention, the compound used.

式18的化合物可以进一步转化,尤其是对COOR8基团的合成转化而言。 Compounds of formula 18 can be further transformed, especially for the conversion of synthesis COOR8 group concerned.

关于与式18化合物相似的其它化合物的合成,其中AB基团的官能团不同(如见式2),(原理适用于本发明所用的任何和全部化合物)提出如下众所周知的一般原理和合成方法。 On the synthesis of other compounds with a compound of formula 18 similar, wherein the different AB group is a functional group (e.g., see Formula 2), (principle applicable to any and all of the compounds of this invention are) made the following well-known general principles and synthetic methods.

羧酸的酯化一般是在酸催化剂如盐酸或亚硫酰氯的存在下,使酸在适当的醇溶液中回流而完成的。 Esterified carboxylic acid is generally in the presence of an acid catalyst such as hydrochloric acid or thionyl chloride, and the acid was refluxed in a suitable alcohol solution were completed. 另外,也可以二环己基碳化二亚胺和二甲氨吡啶存在下,使羧酸与适当的醇缩合。 It is also possible dicyclohexyl carbodiimide and dimethylamino pyridine in the presence of a carboxylic acid with an appropriate alcohol condensation. 然后按常规方法回收和提纯酯。 Ester is then recovered and purified by conventional methods. 按照March的“Advanced Organic Chemistry”(第2版,McGraw-Hill Book Company,P810)所公开的方法很容易制备缩醛和缩酮。 The method according to March's "Advanced Organic Chemistry" (2nd edition, McGraw-Hill Book Company, P810) are readily prepared disclosed acetals and ketals. 通过已知方法,如McOmie(Plenum Publishing Press,1973)和Protecting Groups(Ed.Greene,John Wiley&Sons,1981)中公开的那些方法,使醇、醛和酮分别形成醚和酯,缩醛或缩酮,可以将它们保护起来。 By known methods, such as McOmie (Plenum Publishing Press, 1973) and Protecting Groups (Ed.Greene, John Wiley & amp; Sons, 1981) that the method disclosed, the alcohol, aldehyde and ketone, respectively, forming an ether and an ester, acetal, or ketals, they can be protected.

为了在尚未对反应流程1(其中式17对应的化合物是无法商购的)中的Wittig Horner(或类似的)偶合反应产生影响之前即已将n值提高,应将芳族或杂芳强羧酸在Arndt-Eistert条件下进行连续处理或采用其它的同系化方法使之同系化。 In order yet to Reaction Scheme 1 (corresponding to a compound of formula 17 can not be commercially available) in a Wittig Horner (or similar) coupling reaction i.e. the value of n has been improved before the impact, should be an aromatic or heteroaromatic carboxylic strong acid under Arndt-Eistert conditions for continuous treatment or to use other methods to make homologation homologation. 另外,非羧酸衍生物也可以通过适当的方法同系化。 In addition, non-carboxylic acid derivative can also be an appropriate method of homologation. 然后使同系化的酸可按上段所述的一般方法进行酯化。 Then homologated acid according to the general method of the preceding paragraph for esterification.

制备A为(CH2)n(n等于1-5)的化合物的另一方法是,采用上述Arndt-Eistert方法或其它同系化方法,使B为酸或其它官能团的式2(或式18)化合物进行同系化。 Preparation A is (CH2) n (n is equal to 1-5) compounds are another method using the above-described Arndt-Eistert method of homologation, or other methods, so that B is (or Formula 18) or other functional group acid compound of formula 2 conduct homologation.

例如,把必要数目的双键结合入与式16的酮进行偶合的中间体磷酸酯上,可以制得其中A为有一个或多个双键的烯基的式2化合物。 For example, the necessary number of double bonds incorporated with a ketone of formula 16 is coupled on the intermediate phosphoric ester, can be prepared in which A is a compound having one or more double bonds in the alkenyl group of formula 2. 简言之,采用应用有机化学家所熟知的合成流程,如Wittig及类似反应,或通过去掉α-卤代-芳烷基-羧酸酯或类似的羰基醛上的卤素而引入一个双键,可以得到A为不饱和碳链的上述化合物。 In short, the application of an organic chemist using known synthetic processes, such as Wittig reaction and the like, or by removing the α- haloalkyl - aralkyl - halogen carboxylic acid ester or the like on the carbonyl group of an aldehyde which introduces a double bond, A compound as described above can be obtained an unsaturated carbon chain. A基团带一个三键(炔键)的式2化合物可以通过相应的磷酸酯中间体而制成。 The compound of formula 2 A group with a triple bond (acetylene bond) may be prepared by the corresponding phosphates intermediates made. 所说的中间体可由现有技术的已知反应而获得,如使相应的芳甲酮与强碱如二异丙酰胺锂进行反应而获得。 Reaction of said intermediates by known art is obtained, such as the corresponding aryl methyl ketone with a strong base such as lithium diisopropylamide obtained by reacting.

由式2和式18的化合物衍生的酸和盐很容易由相应的酯而获得。 Acids and salts from the compound of Formula 2 and Formula 18 is easily derived from the corresponding ester is obtained. 与一种碱金属的碱进行碱性皂化反应即可得到酸。 With a base of an alkali metal, alkaline saponification to give acid. 例如,可将式2或式18的一种酯优选在惰性气氛中室温下溶解于一种极性溶剂如烷醇中,该溶剂中含过量约3摩尔的一种碱,如氢氧化钾,所得溶液被搅拌15-20小时,然后再冷却、酸化,最后采用常规手段回收水解产物。 For example, the formula is preferably an ester of formula 2 or 18 in an inert atmosphere at room temperature is dissolved in a polar solvent such as alcohol, the solvent contains over about 3 moles of a base, such as potassium hydroxide, The resulting solution was stirred for 15-20 hours, then cooled, acidified, and finally the hydrolyzate recovered by conventional means.

采用现有技术已知的适当的酰胺化方法,可将相应的酯或羧酸转化成酰胺。 Appropriate amidation methods known in the art, can be a corresponding ester or carboxylic acid to an amide. 制备该化合物的一种方法是先把酸转化成酰基氯,然后用氢氧化铵或一种适当的胺处理后者。 A process for the preparation of the compound was first acid is converted to the acid chloride and then with ammonium hydroxide or an appropriate amine treatment of the latter. 例如,用一种醇碱溶液如乙醇KOH(过量约10%mole)在室温下处理酸大约30分钟。 For example, with an alcohol such as ethanol alkaline solution KOH (excess of about 10% mole) treatment of the acid for about 30 minutes at room temperature. 除去溶剂,将残留物溶解于有机溶剂如乙醚中,再用二烷基甲酰胺处理,最后用过量10倍的草酰氯处理。 The solvent was removed, the residue was dissolved in an organic solvent such as diethyl ether and treated with a dialkyl formamide, and finally with 10-fold excess of oxalyl chloride. 上述过程均是在适当的低温-10℃-+10℃范围内进行的。 The above process are in the appropriate low temperature -10 ℃ - within the range of + 10 ℃ conducted. 其后,将最后所述溶液在低湿下搅拌1-4小时,最好2小时。 Thereafter, the last-mentioned solution was stirred at low humidity 1-4 hours, preferably 2 hours. 再除去溶剂,将残留物置于惰性有机溶剂如苯中,冷却至约0℃,再用浓氢氧化铵处理。 And then the solvent was removed, and the residue was taken up in an inert organic solvent such as benzene, cooled to about 0 ℃, treated with concentrated ammonium hydroxide. 将所得混合物在低湿下搅拌1-4小时,通过常规手段回收产物。 The resulting mixture was stirred for 1-4 hours at low humidity, the product is recovered by conventional means.

醇可按下述方法制备:用亚硫酰氯将相应的酸转化成酰基氯或用其它方法转化(J.March,“Advanced Organic Chemistry”,第2版,McGraw-Hill Book Company),然后用硼氢化钠还原酰基氯(March,Ibid,P1124),由此得到相应的醇。 Preparation of an alcohol according to the following method: with thionyl chloride to the corresponding acid is converted to the acid chloride or using other procedures for transformation (J.March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then boron Sodium hydride reduction of the acid chloride (March, Ibid, P1124), to thereby obtain the corresponding alcohol. 另外,酯可以在低温下用氢化铝锂还原。 In addition, the ester can be reduced with lithium aluminum hydride at low temperatures. 将上述醇在Williamson反应条件下用适当的烷基卤酰基化(March,Ibid,P357)得到相应的醚。 The above alcohol under Williamson reaction conditions with the appropriate alkyl halide acylated (March, Ibid, P357) to give the corresponding ether. 上述醇在酸催化剂或二环己基碳二酰胺和二甲氨吡啶参与下与适当的酸反应可以转化成酯。 Said alcohol or acid catalyst dicyclohexylcarbodiimide and dimethylaminopyridine diamide participation reaction with a suitable acid may be converted to an ester.

醛可以如此制备,即令相应的伯醇与温和氧化剂反应,所说的氧化剂如含于二氯甲烷中的重铬酸苯基偶氮二氨基吡啶(pyridiniumdichromate)(Corey,EJ,Schmidt,G.,Tet.Lett.,399,1979)或含于二氯甲烷中的二甲亚砜/草酰氯(Omura,K.,Swern,D.,Tetrahedron,1978,34,1651)。 Aldehydes may thus prepared, and even if the corresponding primary alcohol with a mild oxidizing agent, said oxidizing agent such as dichromate in dichloromethane containing phenylazo-diaminopyridine (pyridiniumdichromate) (Corey, EJ, Schmidt, G., Tet.Lett., 399,1979) or an in dichloromethane dimethyl sulfoxide / oxalyl chloride (Omura, K., Swern, D., Tetrahedron, 1978,34,1651).

通过用烷基格利雅试剂或此类试剂处理醛,随后再氧化之,可由适当的醛制成酮。 By using such an alkyl Grignard reagent or reagent aldehyde, followed by oxidation, the one made by the appropriate aldehyde.

按照Narch,Ibid,第810页公开的方法可将相应的醛或酮制成缩醛或缩酮。 A method according Narch, Ibid, p. 810 disclosed may be made of the corresponding aldehyde or ketone acetals or ketals.

用相应的卤代芳香化合物,其中卤素优选I,可以制成B为H的式2化合物。 With the corresponding halogenated aromatic compound, wherein halogen preferably I, B may be made of a compound of the formula H 2.

反应流程2详细说明了制备本发明所用化合物的另一合成方法实例,尤其适用于式2中Y基团为杂芳基如噻吩基的化合物的合成。 Reaction Scheme 2 details the preparation of another synthetic method of the present invention, examples of the compounds used, the synthesis of particularly suitable compounds of formula 2 wherein Y group is a heteroaryl group such as thienyl group. 按照该反应流程实例,式16酮还原成相应的式19醇(如用硼氢化钠还原)。 According to this reaction scheme instance, a ketone of formula 16 is reduced to the corresponding alcohol of formula 19 (e.g., reduction with sodium borohydride). 式19的醇用适当的试剂,如三溴化磷和三苯膦处理,转化成相应的鏻盐(如溴化三苯鏻)。 Alcohol of formula 19 with a suitable reagent, such as phosphorus tribromide and triphenylphosphine, converted to the corresponding phosphonium salt (e.g. triphenylphosphonium bromide). 式20的鏻盐是一种Wittig试剂,其在Wittig反应条件下(如正丁基锂之类的碱)与式21的溴代噻吩甲醛反应。 Phosphonium salt of formula 20 is a Wittig reagent, which (such as n-butyllithium and the like base) of formula bromothiophene 21 under Wittig reaction conditions of formaldehyde. 该反应结果所生成的式22化合物具有本发明所用化合物的基本结构特征,即,R1取代基连在双键上,R3取代基在芳香环的邻位碳上,同时芳香或杂芳香基团也作为另一取代基团连在双键上。 The compound of formula 22 The reaction results generated having the basic configuration of the present invention features compounds, i.e., R1 substituent attached to the double bond, R3 substituents are in the ortho-position carbon on the aromatic ring, while aromatic or heteroaromatic groups may also As another substituent group attached to the double bond. 式22化合物上噻吩部分的溴代基团与叔丁基锂反应并俘获二氧化碳而转化成一个羧酸基团。 Thiophene moiety of the compound of formula 22 is reacted with bromo group t-butyl lithium and capture of carbon dioxide converted to a carboxylic acid group. 式23的化合物即为本发明的活性剂,而且,如上所述,还可以转化成其它同系物和衍生物。 Agents of the invention is the compound of formula 23, and, as described above, may be converted to other homologues and derivatives.

上述反应流程2方法的一个变换实例是,使式20的三苯鏻盐与4-乙酯苯甲醛在1,2-环氧丁烷中加热而进行反应。 Examples of the above reaction scheme converting a second method is to make the triphenyl phosphonium salt of formula 20 with 4-ethyl benzaldehyde and the reaction was heated in 1,2-butylene oxide. 当式16的R3为氯代时,采用该反应是特别有利的。 When R3 is chloro formula 16, using the reaction is particularly advantageous. 这些Wittig-型反应产物即为本发明治疗方法所采用的化合物;当R20为甲基,R3为Cl时,产物为化合物12。 These Wittig- type reaction product to be treated with the compounds used in the method of the invention; When R20 is methyl, R3 is Cl, the product was compound 12. 反应流程3反应流程3提供了制备本发明所用化合物的又一实例,即利用Wittig Horner型反应,使式24的苯并二氢吡喃衍生物酮与式17的磷酸酯反应。 Reaction Scheme 3 Reaction Scheme 3 provides another example of a compound of the present invention, namely the use of Wittig Horner type reaction, the chroman derivative of a ketone of formula 24 is reacted with a phosphoric acid ester of formula 17. (式24中的R1、R3和R20与式4的定义相同)。 (Formula 24 in the R1, R3 and R20 with the same formula 4). 按照US4,980,369的技术教导,尤其是参照该专利中反应流程2所公开的内容,以及该专利文献所给出的制备2,2,4,4,7-五甲基-6乙酰苯并二氢吡喃的实施例(第20栏58行),可以得到式24的苯并二氢吡喃衍生物。 Accordance with the technical teachings US4,980,369, in particular this patent Reaction Scheme 2 Preparation of disclosure, and given with reference to patent document 2,2,4,4,7- pentamethyl -6-acetyl-benzodioxan tetrahydropyranyl embodiments (column 20, line 58), can be obtained chroman derivative of formula (24). 本发明结合参考US4,980,369的说明书。 The invention combines US4,980,369 reference manual. 在含于四氢呋喃中的双(三甲基甲硅烷基)酰胺钾的参与下,式24的苯并二氢吡喃衍生物与式17的磷酸酯发生偶合反应,由此得到式25的化合物,该化合物即为本发明所用的活性剂。 In tetrahydrofuran at-containing bis (trimethylsilyl) amide participation, chroman derivative of formula 24 with a phosphate coupling reaction 17 occurs, thereby obtaining a compound of formula 25, The compounds of the present invention is the use of the active agent. 式25的一个优选化合物实例是化合物24。 A preferred compound of Example 25 is a compound of formula 24. 如上所述,还可以将式25的化合物衍生或转化成同系物。 As described above, the compound of formula 25 can also be converted to derivatives or homologues. 例如,对化合物24皂化得到化合物25。 For example, saponification of compound 24 to give compound 25. 反应流程4 Reaction Scheme 4

反应流程4详细给出了获得本发明化合物的另一合成路线实例,具体地说,化合物为Z是一个或二个低级烷基且X1是CH,尤其是Z为叔丁基的式2化合物。 Reaction Scheme 4 shows the details of the present invention to obtain a compound of alternative synthesis route instance, specifically, the compound is Z is one or two lower alkyl and X1 is CH, especially t-butyl compound of the formula 2 Z is.

按照反应流程4,式26的带取代基的乙酰基(R1=CH3)或乙酰苯同系物与式17的膦酸盐发生Wittig Horner型反应(如在含于四氢呋喃中的dimsyl Sodium参与下)。 4, belt 26 of the acetyl substituent (R1 = CH3) or acetophenone homologs phosphonate of formula 17 occurs Wittig Horner type reaction (e.g. containing in tetrahydrofuran dimsyl Sodium participation) according to reaction scheme. 按该反应方式所得的式27的化合物即为本发明的活性剂。 The reaction system by a compound of formula 27 is the resultant of the active agents of the invention. 如上所述,式27的化合物也可以衍生和转化成同系物。 As described above the compound of formula 27 may be converted to derivatives and homologues. 按该反应流程所获得的优选化合物的实例是化合物26-29。 Examples of preferred compounds obtained by the reaction scheme is a compound 26-29.

确信,利用以上合成路线及后面提供的具体实施例可以使应用有机化学者获得任何和全部用于发明治疗方法的活性剂化合物。 Sure, use of the specific embodiments above Scheme and provided later enable the application in organic chemistry to gain any and all of the active compound for the treatment method of the invention. 不过下面仍然给出了进一步的说明和实施例。 But still below gives further explanation and examples. 概括地说,本发明的化合物可以按照反应流程5-8所确立的反应而获得。 In summary, the compounds of the present invention may be established according to the reaction of Reaction Scheme 5-8 is obtained. 反应流程5 Reaction Scheme 5 反应流程6 Reaction Scheme 6 反应流程7 Reaction Scheme 7 反应流程8 Reaction Scheme 8

反应流程5所示的反应在本领域通常被称为Wittig Horner反应,有时该反应亦称Horner Emmons反应。 The reaction shown in reaction scheme is commonly referred to in the art Wittig Horner reaction, the reaction is sometimes also known as Horner Emmons reaction. 按照该液程,它包括酮与膦酸酯在碱性条件下反应生成烯烃键,由此得到式2的化合物。 According to the process fluid, comprising a ketone with phosphonate reaction under basic conditions an olefin bond, thereby obtaining a compound of Formula 2. 该反应流程中的反应物为式28的芳香或杂芳香酮和式29的芳香或杂芳香膦酸酯。 The reaction scheme for the reactants of formula 28 aromatic or heteroaromatic ketones of formula 29 aromatic or heteroaromatic phosphonate. 这些结构式中的符号与式2定义相同。 These are the same symbols in the formula 2 is defined. 一般来说,式28的杂芳香酮可以通过已知的及化学文献上公开的方法获得;这些方法通常包括通过弗瑞德-克来福特或类似反应把R1CO基团(R1=CH3时为CH3CO)引入其它适当取代的(除R1CO基团外)芳香或杂芳香化合物中。 In general, the heteroaromatic ketones Equation 28 can be obtained by methods known in the chemical literature and public access to; these methods often include by Friedel - Crafts reaction to Ford or similar to R1CO groups (R1 = CH3 when CH3CO ) introducing other suitable substituted (except R1CO group) an aromatic or heteroaromatic compounds. 制备式29相应的膦酸酯的实例提供如下。 Examples of the preparation of the corresponding phosphonate of formula 29 are provided below. 简言之,使具有R2-CH2Y-AB结构的烷基化芳香或杂芳香族化合物与N-溴代琥珀亚酰胺反应,然后再使所得溴代化合物R2-CHBrY-AB与亚磷酸三乙酯反应,即可获得所说的膦酸酯。 Briefly, alkylated aromatic or heteroaromatic compound with N- bromo-succinimide reaction with R2-CH2Y-AB structure, then the resulting bromo compound R2-CHBrY-AB and triethyl phosphite reaction, can be obtained of said phosphonate. 总体上说,反应流程5所示的Wittig Horner反应是制备式2和式3化合物的优选方法,尤其是AB官能团为一强的吸电子基团(如酯)情况时。 Overall, Wittig Horner reaction shown in Reaction Scheme 5 is preferred method for preparing compounds of formula 2 and formula 3, in particular AB functional group is a strong electron withdrawing group (such as an ester) case.

反应流程6示出了利用Wittig Horner反应的另一条制备式2化合物的路线,并以此类推式3化合物。 Reaction Scheme 6 illustrates a Wittig Horner reaction using another route of preparation of compounds of formula 2, and so the compound of formula 3. 出现的符号同式2的定义。 Symbols appearing in formula 2 is defined. 在该反应流程中,由类似于式28化合物的芳香或杂芳香基部分生成式30的磷酸酯。 In this reaction process, by an aromatic or heteroaromatic compound of formula 28 is similar to the base portion 30 of the generated phosphate. 一般说,把式28的酮还原,再将所得醇转化成卤化物(优选溴化物),最后变成磷酸酯,即可得到式30的磷酸酯。 Generally speaking, the reduction of ketone 28 skill, and the resulting alcohol is converted into a halide (preferably bromide), and finally into phosphate, phosphate type 30 can be obtained. 式31的芳香或杂芳香醛或酮可以通过对应用有机化学者来说简便易行的方法来获得。 Equation 31 aromatic or heteroaromatic aldehydes or ketones can be achieved by the application of organic chemistry are concerned easy way to get.

反应流程7给出了获得式2化合物并类推式3化合物的又一优选方法。 Reaction Scheme 7 shows a further preferred compound of formula 2 and a compound of Formula 3 by analogy. 该反应流程图中出现的符号与式2定义相同。 Is defined the same reference numerals appearing in the reaction scheme 2. 按照该方法,鏻盐,特别是式32的三苯鏻盐如可由式28的酮而来。 According to this method, the phosphonium salt, especially triphenyl phosphonium salt of formula 32 such as a ketone of formula 28 may be formed from a. 式32的鏻盐可以由式28的酮还原成醇,随后再与三溴化亚磷和三苯膦反应而获得,与反应流程2给出的反应类似。 Phosphonium salt of formula 32 may be reduced from the ketone to the alcohol of formula 28, followed by phosphorous tribromide and triphenylphosphine obtained by reacting, analogous reactions of Reaction Scheme 2 given. 此后,式32的鏻盐与式31的芳香或杂芳香醛或酮在Wittig反应中发生反应,该反应包括强碱如正丁基锂的作用。 Thereafter, the phosphonium salt of formula 32 and formula 31 aromatic or heteroaromatic aldehyde or ketone reacts in a Wittig reaction, the reaction including the role of a strong base such as n-butyllithium.

反应流程8给出了获得式2化合物的另一种Wittig反应方法,类推式3化合物。 Reaction Scheme 8 shows an alternative method of the Wittig reaction to obtain the compound of Formula 2, the compound of formula 3 by analogy. 该反应流程图中出现的符号与式2定义相同。 Is defined the same reference numerals appearing in the reaction scheme 2. 按照该方法,式28的芳香或杂芳香酮在强碱存在下与一种鏻盐反应,最好是与式33的溴化三苯鏻反应。 According to this method, the formula 28 aromatic or heteroaromatic ketones in the presence of a strong base is reacted with a phosphonium salt, preferably reacted with a triphenylphosphonium bromide of formula (33). 式33的溴化三苯鏻例如可以通过溴代化合物R2-CHBrY-AB与三苯膦反应而获得。 Triphenylphosphonium bromide of formula 33 by, for example bromo compound R2-CHBrY-AB obtained by reaction with triphenylphosphine.

为了获得用于本发明治疗方法的化合物,现将Wittig Horner或Wittig及类似偶合反应中所用的按式29、31和33的试剂例举如下:[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40);(3-乙酯苄基)膦酸二乙酯;(2-乙酯苄基)膦酸二乙酯;(2-乙酯基-5-噻吩基)甲基膦酸二乙酯(化合物41);2-[5-(二乙氧基氧膦基)甲基]呋喃甲酸乙酯(化合物42);3-[5-[(二乙氧基氧膦基)甲基]]烟酸乙酯(化合物43)。 In order to obtain the compound used in the treatment method of the present invention, will now Wittig Horner or Wittig coupling reaction and the like used in the reagent according to formula 29, 31 and 33 are exemplified as follows: [4- (diethoxy phosphinyl) methyl yl] benzoate (Compound 40); (3-ethyl-benzyl) phosphonic acid diethyl ester; (2-ethyl-benzyl) phosphonic acid diethyl ester; (2-ethyl-5-thienyl ) of diethyl methylphosphonate (Compound 41); 2- [5- (diethoxyphosphinyl) methyl] furan-carboxylic acid ethyl ester (compound 42); 3- [5 - [(diethoxy phosphinyl-yl) methyl]] nicotinate (Compound 43).

为了得到用于本发明治疗方法的化合物,将Wittig Horner或Wittig及类似偶合反应中所用的按式28,30和32的试剂举例如下:甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢萘)-2-基]酮(化合物50);1-(3,5,5,8,8-五甲基-5,6,7,8-四氢萘-2-基)乙烷-1-基-溴化三苯鏻(化合物51);2,2,4,4,7-五甲基-6-乙酰苯并二氢吡喃(化合物52),见US4,980,369;2-甲基-5-叔丁基乙酰苯(化合物53);可按化学文献方法获得,见J.Amer.Chem.Soc.,77,P1695(1955);Chem.Br.,32,P2422(1899);J.Org.Chem.,22,P25-29(1957);甲基[3-氯-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物54);[(5,6,7,8-四氢-3-氯-5,5,8,8-四甲基萘-2-基)乙烷-1-基]溴化三苯鏻(化合物55);2-甲基-4-叔丁基乙酰苯(化合物56);可按化学文献方法获得,见CHem.Br.,31,P1345(1898);J.Org.Chem.,22,P25、26(1957);J Chem.Soc.,1952,P1123;甲基[3-溴-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物57);甲基[3-乙基-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物58);甲基3-异丙基[5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物59);Ethanone,1-(5,6,7,8-四氢-2-甲基-3-喹啉基),可按化学文献的方法获得,见CA79(13):78555K;Chem.Ber.106(6),1736-42(1973); In order to obtain the compound used in the treatment methods of the invention, the Wittig Horner or Wittig reagents and the like used in the coupling reaction according to formula 28, 30 and 32, for example as follows: Methyl [3,5,5,8,8 pentamethoxy group (5,6,7,8-tetrahydro-naphthalen) -2-yl] ketone (Compound 50); 1- (3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-naphthalen-2-yl) ethane-1-yl - triphenylphosphonium bromide (Compound 51); 2,2,4,4,7- pentamethyl-6-acetyl chroman (Compound 52), see US4,980,369; 2- methyl-5-tert-butyl-acetophenone (Compound 53); obtained according to the chemical literature, see J.Amer.Chem.Soc, 77, P1695 (1955);. Chem . .Br, 32, P2422 (1899);. J.Org.Chem, 22, P25-29 (1957); methyl [3-chloro-5,5,8,8-tetramethyl (5,6, 7,8-tetrahydro-naphthalen) -2-yl] ketone (Compound 54); [(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene -2 - yl) ethane-1-yl] triphenylphosphonium bromide (Compound 55); 2-methyl-4-t-butyl-acetophenone (Compound 56); obtained according to the chemical literature, see CHem.Br., 31, P1345 (1898);. J.Org.Chem, 22, P25,26 (1957); J Chem.Soc, 1952, P1123;. methyl [3-bromo-5,5,8,8-tetramethylbutyl group (5,6,7,8-tetrahydro-naphthalen) -2-yl] ketone (Compound 57); Methyl [3-ethyl-5,5,8,8-tetramethyl (5,6,7 , 8- tetrahydro-naphthalen) -2-yl] ketone (Compound 58); Methyl 3-isopropyl [5,5,8,8-tetramethyl (5,6,7,8-tetrahydronaphthalene) 2-yl] ketone (Compound 59); Ethanone, 1- (5,6,7,8- tetrahydro-2-methyl-3-quinolyl), obtained according to the method of chemical literature, see CA79 ( 13): 78555K; Chem.Ber.106 (6), 1736-42 (1973);

Ethanone,1-(2-甲基-3-喹啉基),可按化学文献的方法获得,见CA90(19):152027k,德国专利DE270061,1979,1.18;Ethanone,1-(3-甲基-2-萘基),可按化学文献方法获得,见CA111(19):173803c,JP01047734A2,1989,2,22;Ethanone,1-(2-甲基-1H-茚-3-基],可按化学文献方法获得,见CA95(23):202928f,J.Org.Chem.46(24),5022-5(1981);Ethanone,1-(2-甲基-1H-吲哚-3-基),可按化学文献方法获得,见CA115(15):159291k,Tetrahedron 47(28)5111-18(1991);Ethanone,1-(2-甲基苯并[b]噻吩-3-基),可按化学文献方法获得,见CA85(25):192542c,法国专利申请FR2279395,1976,2,20;酮,甲基4,5,6,7-四氢-2-甲基苯并[b]噻吩-3-基,可按化学文献方法获得,见Bull.Soc.Chim.France 3,359-361(1958);Ethanone,1-(4,5,6,7-四氢-2-甲基-3-苯并呋喃基),可按化学文献方法获得,见CA91(18):148446z,J.Org.Chem.44(20)3519-23(1979);Ethanone,1-(4,5,6,7-四氢-2-甲基-1H-吲哚-3-基),可按化学文献方法获得,见CA82(17):111890c,Ann.Chim.(Rome)63(9-10)601-6(1973);噻吩并[2,3-b]吡啶,7-乙酰-4,5,6,7-四氢-2-甲基,可按化学文献方法获得,见CA110(15):135007t,Tetrahedron 44(15)4777-86(1988);Ethanone,1-[6-甲氧甲基)-5-苯并呋喃基],可按化学文献方法获得,见CA87(1):5839m,J.Chem.Soc.,Perkin Trans.1(4),423(1977);Ethanone,1-(6-氯-3-甲基-5-苯并呋喃基),可按化学文献方法获得,见CA78(17):110781y,IndianJ.Chem.10(11)1065-7(1972)。 Ethanone, 1- (2- methyl-3-quinolyl), obtained according to the method of chemical literature, see CA90 (19): 152027k, German Patent DE270061,1979,1.18; Ethanone, 1- (3- methyl- 2-naphthyl), obtained according to the chemical literature, see CA111 (19): 173803c, JP01047734A2,1989,2,22; Ethanone, 1- (2- methyl--1H- inden-3-yl], may obtained by chemical literature, see CA95 (23): 202928f, J.Org.Chem.46 (24), 5022-5 (1981); Ethanone, 1- (2- methyl -1H- indol-3-yl ), obtained according to the chemical literature, see CA115 (15): 159291k, Tetrahedron 47 (28) 5111-18 (1991); Ethanone, 1- (2- methyl-benzo [b] thiophen-3-yl), obtained according to the chemical literature, see CA85 (25): 192542c, French Patent Application FR2279395,1976,2,20; ketone, methyl 4,5,6,7-tetrahydro-2-methyl-benzo [b] thiophen-3-yl, can be obtained in the chemical literature, see Bull.Soc.Chim.France 3,359-361 (1958); Ethanone, 1- (4,5,6,7- tetrahydro-2-methyl- -3-benzofuranyl), obtained according to the chemical literature, see CA91 (18): 148446z, J.Org.Chem.44 (20) 3519-23 (1979); Ethanone, 1- (4,5, 6,7-tetrahydro-2-methyl -1H- indol-3-yl), obtained according to the chemical literature, see CA82 (17): 111890c, Ann.Chim (Rome) 63 (9-10). 601-6 (1973); thieno [2,3-b] pyridine, 7-acetyl-4,5,6,7-tetrahydro-2-methyl, may be obtained in the chemical literature, see CA110 (15) : 135007t, Tetrahedron 44 (15) 4777-86 (1988); Ethanone, 1- [6- methoxymethyl) -5-benzofuranyl], can be obtained in the chemical literature, see CA87 (1): 5839m , J.Chem.Soc, Perkin Trans.1 (4), 423 (1977);. Ethanone, 1- (6- chloro-3-methyl-5-benzofuranyl), obtained according to the chemical literature, see CA78 (17): 110781y, IndianJ.Chem.10 (11) 1065-7 (1972).

为了获得用于本发明治疗方法的化合物,Wittig Horner或Wittig及类似偶合反应中所用的按式26的其它试剂实例可按已知并已确定的方法而得到,例如,在弗瑞德-克来福特型反应条件下,将其它已知的芳香族或杂芳香族化合物酰化(乙酰化),所说的化合物如6-甲基-苯并呋喃(CA103(9):71182s);6-甲基-1H-吲哚(CA114(23):228730w)和6-甲基-苯并[b]噻吩(CA114(15):143128f)。 In order to obtain the compound used in the treatment methods of the invention, Wittig Horner or Wittig reagents, and other similar examples used in the coupling reaction according to equation 26 and identified according to known methods to give, for example, in Friedel - Crafts to Ford type under the reaction conditions, the other known aromatic or heteroaromatic compound acylated (acetylated), said compound such as 6-methyl - benzofuran (CA103 (9): 71182s); 6- A yl -1H- indole (CA114 (23): 228730w) and 6-methyl - benzo [b] thiophene (CA114 (15): 143128f).

实施例4-乙酯基-苄基溴把于100ml二氯甲烷中的15.4 g(71mmol)4-羰基苄基溴的悬浮液加入到搅拌着的于100ml二氯甲烷中的16.09g(78mmol)1,3-二环己基碳化二亚胺之溶液中,然后加入4.9g(106.5 mmol)无水乙醇和0.81g(7.1mmol)4-二甲氨吡啶。 Example 4 - carbethoxy - benzyl bromide in 100ml of methylene chloride to 15.4 g (71mmol) 4- carbonyl benzyl bromide was added to a stirred suspension in 100ml dichloromethane 16.09g (78mmol) solution of 1,3-dicyclohexyl carbodiimide of then added 4.9g (106.5 mmol) of anhydrous ethanol and 0.81g (7.1mmol) 4- dimethylaminopyridine. 再加入50ml二氯甲烷至反应混合物,在回流下加热混合物2小时。 50ml of dichloromethane was added to the reaction mixture, the mixture was heated under reflux for 2 hours. 然后将混合物冷却至室温,过滤除去形成的白色沉淀。 The mixture was then cooled to room temperature, a white precipitate formed was removed by filtration. 滤液用水洗涤,干燥(MgSO4),然后,真空浓缩得到标题无色油状化合物,该油状物在放置时结晶。 The filtrate was washed with water, dried (MgSO4), then concentrated in vacuo to give the title compound as a colorless oil, the oil crystallized upon standing. PMR(CDCl3):δ1.39(3H,t,J-7.2Hz),4.38(2H,q,J-7.2Hz),4.50(2H,s),7.45(2H,d,J-7.7Hz),8.03(2H,d,J-7.7Hz)。 PMR (CDCl3): δ1.39 (3H, t, J-7.2Hz), 4.38 (2H, q, J-7.2Hz), 4.50 (2H, s), 7.45 (2H, d, J-7.7Hz), 8.03 (2H, d, J-7.7Hz). [4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)将11.8g(48mol)4-乙酯基苄基溴与12.0g(72mmol)新鲜蒸馏的亚磷酸三乙酯的混合物放入一个烧瓶中,该烧瓶设有氩气入口和干冰冷却套。 [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40) 11.8g (48mol) 4- carbethoxy-benzyl bromide and 12.0g (72mmol) of freshly distilled triethyl phosphite ester mixture into a flask, the flask provided with an argon inlet and a dry ice cooling jacket. 使氩气流连续在搅拌着的反应混合物上通过,并且混合物在约120℃下加热3小时,此时不再有溴乙烷生成。 So that a continuous stream of argon in the stirred reaction mixture was passed through, and the mixture was heated at about 120 ℃ 3 hours at which time no dibromoethane generated. 将残留物真空蒸馏提纯,得到无色油状标题化合物(BP=170℃/0.35mm)。 The residue was purified by distillation in vacuo to give the title compound as a colorless oil (BP = 170 ℃ / 0.35mm). PMR(CDCL3):δ1.23(6H,t,J-7.1Hz),1.39(3H,t,J-6.9Hz),3.21(2H,d,J-22.1Hz),4.02(4H,m),4.37(2H,q,J-7.5Hz),7.38(2H,d,J-7.9Hz),8.00(2H,d,J-7.9Hz)。 PMR (CDCL3): δ1.23 (6H, t, J-7.1Hz), 1.39 (3H, t, J-6.9Hz), 3.21 (2H, d, J-22.1Hz), 4.02 (4H, m), 4.37 (2H, q, J-7.5Hz), 7.38 (2H, d, J-7.9Hz), 8.00 (2H, d, J-7.9Hz). 5-甲基-2-噻吩甲酸乙酯将10g(70.3 mmol)5-甲基-2-噻吩甲酸和4.85g(105.5mmol)无水乙醇加入到搅拌着的于40mL二氯甲烷中的15.9g(77.4mmol)1,3-二环己基碳化二亚胺的溶液中,然后再加入0.86g二甲氨吡啶,将此悬浮液在室温下搅拌20小时。 5- methyl-2-thiophene carboxylic acid ethyl ester 10g (70.3 mmol) 5- methyl-2-thiophene-carboxylic acid and 4.85g (105.5mmol) of absolute ethanol was added to a stirred solution in 40mL dichloromethane 15.9g (77.4mmol) 1,3- dicyclohexyl carbodiimide was then added 0.86g dimethylaminopyridine, and the suspension was stirred at room temperature for 20 hours. 过滤除去生成的白色沉淀。 The resulting white precipitate was removed by filtration. 滤液用水洗涤,干燥(MgSO4),过滤,减压浓缩。 The filtrate was washed with water, dried (MgSO4), filtered, and concentrated under reduced pressure. 残留物通过球管对球管蒸馏(bulb-to-bulbdistillation)而提纯,得到的标题化合物为一种澄清浅黄色油状物。 The residue was purified by bulb to bulb distillation (bulb-to-bulbdistillation) and purification, the title compound was obtained as a clear pale yellow oil.

PMR(CDCl3):δ1.36(3H,t,J=7.1Hz),2.52(3H,s),4.32(2H,q,J=7.1Hz),6.76(1H,d,J=3.8Hz),7.61(1H,d,J=3.8Hz).5-溴甲基-2-噻吩甲酸乙酯使N-溴代琥珀酰亚胺(23.5g,132mmol),过氧化苯甲酰(0.26g)和90mL苯在氩气下回流。 PMR (CDCl3): δ1.36 (3H, t, J = 7.1Hz), 2.52 (3H, s), 4.32 (2H, q, J = 7.1Hz), 6.76 (1H, d, J = 3.8Hz), 7.61 (1H, d, J = 3.8Hz) .5- bromo-thiophene-2-carboxylic acid ethyl ester of N- bromosuccinimide (23.5g, 132mmol), benzoyl peroxide (0.26g) and 90mL benzene was refluxed under argon. 然后,通过一个加液漏斗滴加5-甲基-2-噻吩甲酸乙酯(22.5g,132mmol),将所得混合物回流6小时,然后冷却到室温,并搅拌16小时。 Then, through an addition funnel a solution of 5-methyl-2-thiophene carboxylic acid ethyl ester (22.5g, 132mmol), and the resulting mixture was refluxed for 6 hours, then cooled to room temperature, and stirred for 16 hours. 此混合物先用50mL水处理,再用375mL乙醚萃取。 The mixture first with 50mL water, and then extracted 3 75mL ether.

合并乙醚萃取物,用75mL饱和NaCl水溶液洗涤,然后干燥(MgSO4)。 The combined ether extracts were washed with 75mL saturated aqueous NaCl, then dried (MgSO4). 真空脱除溶剂,其残留油状物用快速色谱法(SiO2,99∶1,乙酸乙酯于己烷中)提纯,得到的标题化合物为一种澄清的黄色油。 The solvent was removed in vacuo, the residual oil was purified by flash chromatography (SiO2,99:1, ethyl acetate in hexanes) to give, the title compound was obtained as a clear yellow oil.

PMR(CDCl3):δ1.37(3H,t,J=7.3Hz),4.35(2H,q,J=7.3Hz),4.68(3H,s),7.09(1H,d,J=4.0Hz),7.64(1H,d,J=4.0Hz).5-[(二乙氧基氧膦基)甲基]-2-噻吩甲酸乙酯(化合物41)在氩气下,将4.99g(20.0mmol)5-溴甲基-2-噻吩甲酸乙酯和5.17mL(30.0mmol)亚磷酸三乙酯的混合物加热到120℃6小时,蒸馏除去过量的亚磷酸三乙酯。 PMR (CDCl3): δ1.37 (3H, t, J = 7.3Hz), 4.35 (2H, q, J = 7.3Hz), 4.68 (3H, s), 7.09 (1H, d, J = 4.0Hz), 7.64 (1H, d, J = 4.0Hz) .5 - [(diethoxyphosphinyl) methyl] -2-thiophene-carboxylate (Compound 41) Under an argon gas, to 4.99g (20.0mmol) 5-bromo-2-thiophene carboxylic acid ethyl ester and 5.17mL (30.0mmol) mixture of triethyl phosphite was heated to 120 ℃ 6 hours and distilled to remove the excess triethyl phosphite.

将产物真空蒸馏提纯(bp=175℃,3mmHg),得到澄清浅黄色油状标题化合物。 The product was purified by vacuum distillation (bp = 175 ℃, 3mmHg), the title compound as a pale yellow oil clarification.

PMR(CDCl3):δ1.30(6H,t,J=7.1Hz),1.37(3H,t,J=7.2Hz),3.38(2H,d,J=20.9Hz),4.05-4.15(4H,m),4.33(2H,q,J=7.1Hz),6.99(1H,dd,J=3.6,3.6Hz),7.66(1H,d,J=1.1,3.6Hz).2-(5-溴甲基)呋喃甲酸乙酯将于8mL四氯化碳中的2-(5-甲基)呋喃甲酸乙酯溶液加入到于8mL四氯化碳中的1.32g(7.4mmol)N-溴代琥珀酰亚胺和10.9mg过氧化苯甲酰的悬浮液中,所得混合物在55℃下搅拌8小时,然后过滤、浓缩混合物,残留油用快速色谱法(SiO2,己烷中含5%乙酸乙酯)提纯,得到澄清油状标题化合物。 PMR (CDCl3): δ1.30 (6H, t, J = 7.1Hz), 1.37 (3H, t, J = 7.2Hz), 3.38 (2H, d, J = 20.9Hz), 4.05-4.15 (4H, m ), 4.33 (2H, q, J = 7.1Hz), 6.99 (1H, dd, J = 3.6,3.6Hz), 7.66 (1H, d, J = 1.1,3.6Hz) .2- (5- bromomethyl ) furan-carboxylic acid ethyl ester in carbon tetrachloride will 8mL 2- (5-methyl) furan-carboxylic acid ethyl ester was added to carbon tetrachloride in 8mL of 1.32g (7.4mmol) N- bromosuccinimide amine and 10.9mg of benzoyl peroxide suspension and the resulting mixture was stirred for 8 hours at 55 ℃, then filtered, the mixture was concentrated, and the residual oil was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil. 2-[5-(二乙氧基氧膦基)甲基]呋喃甲酸乙酯(化合物42)在氩气中,125℃下,将1.84g(1.30ml,14.8mmol)亚磷酸三乙酯和0.84g(3.6mmol)2-(5-溴甲基)呋喃甲酸乙酯的溶液加热30小时。 2- [5- (diethoxyphosphinyl) methyl] furan-carboxylic acid ethyl ester (Compound 42) in argon at 125 ℃, the 1.84g (1.30ml, 14.8mmol) and triethyl phosphite 0.84g (3.6mmol) 2- (5- bromomethyl) furan-carboxylic acid ethyl ester was heated for 30 hours. 然后冷却溶液,并用Kuegelrohr蒸馏法(165-180℃,1mmHg)提纯之,得到一种澄清的油状标题化合物。 Then the solution was cooled, and purified purposes Kuegelrohr distillation (165-180 ℃, 1mmHg), to give a clear oil of the title compound. [5-溴甲基]烟酸乙酯把10.9mg过氧化苯甲酰和一勺尖(a tipfull of)N-溴代琥珀酰亚胺加到于10mL四氯化碳中的3-[5-甲基]烟酸乙酯溶液中。 [5-bromo-methyl] nicotinate to 10.9mg of benzoyl peroxide and a spoonful tip (a tipfull of) N- bromosuccinimide was added in 10mL of carbon tetrachloride 3- [5 - methyl] nicotinic acid ethyl ester solution. 该混合物加热到60℃,将剩余的1.19g(总计6.7mmol)N-溴代琥珀酰亚胺溶于20mL四氯化碳中,再加到加热的混合物中。 The mixture was heated to 60 ℃, the remaining 1.19g (total 6.7mmol) N- bromosuccinimide was dissolved in 20mL of carbon tetrachloride, and added to the heated mixture. 所得混合物在60℃下搅拌3小时,再于室温下搅拌12小时。 The resulting mixture was stirred for 3 hours at 60 ℃, and then stirred at room temperature for 12 hours. 然后再另加过氧化苯甲酰(9mg),接着再加热4小时。 Then additional benzoyl peroxide (9mg), followed by heating for 4 hours. 此后,将混合物冷却、过滤、浓缩,残留油用快速色谱法(SiO2,己烷中含10%乙酸乙酯)提纯,得到粉色固体标题化合物。 Thereafter, the mixture was cooled, filtered, concentrated, and the residual oil was purified by flash chromatography (SiO2, 10% ethyl acetate in hexane) to afford the title compound as a pink solid. 3-[5-(二乙氧基氧膦基)甲基]烟酸乙酯(化合物43) 3- [5- (diethoxyphosphinyl) methyl] nicotinate (Compound 43)

将0.99g(0.70ml,7.98mmol)亚磷酸三乙酯与0.21g(8.6mmol)3-[5-溴甲基]烟酸乙酯的溶液在氩气中130℃下加热24小时,再于室温下加热48小时。 The 0.99g (0.70ml, 7.98mmol) and triethyl phosphite 0.21g (8.6mmol) 3- [5- bromo-methyl] nicotinate was heated at 130 ℃ in an argon atmosphere for 24 hours, then at room temperature for 48 hours under heating. 然后把溶液冷却,用Kuegelrohr蒸馏法(155-165℃,1mmHg)提纯,得到黄色油状标题化合物。 The solution was then cooled, Kuegelrohr distillation (155-165 ℃, 1mmHg) to afford the title compound as a yellow oil. 甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢萘)-2-基]酮(化合物50)将于二氯甲烷中的3.95g(3.58mL,50.3mmol)乙酰氯和10.21g(41.9mmol)3,5,5,8,8-五甲基-5,6,7,8-四氢萘的溶液在氩气中0℃下加入到于二氯甲烷中的6.71g(50.3mmol)氯化铝悬浮溶液中。 Methyl [3,5,5,8,8-pentamethyl (5,6,7,8-tetrahydro-naphthalen) -2-yl] ketone (Compound 50) will dichloromethane 3.95g (3.58 mL, 50.3mmol) acetyl chloride and 10.21g (41.9mmol) 3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydronaphthalene solution at 0 ℃ under argon was added to in dichloromethane 6.71g (50.3mmol) of aluminum chloride was suspended in solution. 所得混合物在3小时内边搅拌边使之升温至室温。 The resulting mixture over 3 hours with stirring allowed to warm to room temperature. 然后,此混合物再冷却到0℃,滴加1N HCl。 Then, the mixture was cooled to 0 ℃, was added dropwise 1N HCl. 将此混合物溶于水中,用二氯甲烷萃取三次。 The mixture was dissolved in water, extracted three times with dichloromethane. 有机层用1N HCl、水和盐水洗涤,然后干燥(MgSO4)。 The organic layer was 1N HCl, water and brine, then dried (MgSO4). 真空脱除溶剂,所得残留物用快速色谱法提纯,得到象牙色固体标题化合物。 The solvent was removed in vacuo, the resulting residue was purified by flash chromatography to give the title compound as ivory solid.

PMR(CDCl3):δ1.28(6H,s),1.30(6H,s),1.69(4H,s),2.49(3H,s),2.57(3H,s),7.15(1H,s),7.67(1H,s).4-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]苯甲酸乙酯(化合物10)在氩气中,0℃下,把含于25ml四氢呋喃中5.0g(21.5mmol)甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢-萘)-2-基]酮(化合物50)和3.39g(11.3mmol)[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)的溶液通过套管加入到于25ml四氢呋喃中的0.52g(21.5mmol)氢化钠悬浮液中。 PMR (CDCl3): δ1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.49 (3H, s), 2.57 (3H, s), 7.15 (1H, s), 7.67 (1H, s) .4 - [(E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1 yl] benzoate (Compound 10) in argon at 0 ℃, put in 25ml of tetrahydrofuran containing 5.0g (21.5mmol) methyl [3,5,5,8,8-pentamethyl (5, 6,7,8-tetrahydro - naphthalen) -2-yl] ketone (Compound 50) and 3.39g (11.3mmol) [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40 ) was added via cannula to a solution in 25ml of tetrahydrofuran 0.52g (21.5mmol) of sodium hydride suspension. 使所得悬浮液升温到室温,并搅拌16小时。 The resulting suspension was warmed to room temperature, and stirred for 16 hours. 将所得淤渣溶于水和1N HCl中,并用乙醚萃取。 The resultant sludge was dissolved in water and 1N HCl, and extracted with ether. 乙醚层用水和盐水洗涤,然后干燥(MgSO4)。 The ether layer was washed with water and brine, then dried (MgSO4). 真空脱除溶剂,残留物用快速色谱法(SiO2,己烷中含1%乙酸乙酯)提纯,得到异构体混合物,再用HPLC(已烷中含0.5%乙酸乙酯)分离得到白色固体标题化合物。 The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, hexane containing 1% ethyl acetate) to give a mixture of isomers, and then HPLC (hexane containing 0.5% ethyl acetate) to give a white solid of the title compound.

PMR(CDCl3):δ1.30(12H,s),1.38(3H,t,J=7.0Hz),1.69(4H,s),2.21(3H,s),2.30(3H,s),4.39(2H,q,J=7.1Hz),6.42(1H,g),7.12(2H,overl.s),7.43(2H,d,J=8.3Hz),8.05(2H,d,J=8.3Hz).4-(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]苯甲酸(化合物11)把氢氧化钾的乙醇溶液加到95mg(0.25mmol)4-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘)-2-基]丙烯-1-基]苯甲酸乙酯(化合物10)中,所得混合物在室温下搅拌。 PMR (CDCl3): δ1.30 (12H, s), 1.38 (3H, t, J = 7.0Hz), 1.69 (4H, s), 2.21 (3H, s), 2.30 (3H, s), 4.39 (2H , q, J = 7.1Hz), 6.42 (1H, g), 7.12 (2H, overl.s), 7.43 (2H, d, J = 8.3Hz), 8.05 (2H, d, J = 8.3Hz) .4 - (E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] benzoic acid (Compound 11) The ethanol solution of potassium hydroxide was added 95mg (0.25mmol) 4 - [(E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthyl) 2-yl] propen-1-yl] benzoate (Compound 10), and the resulting mixture was stirred at room temperature. 真空脱除溶剂,将所得固体溶于水中,用1N HCl酸化,尔后用乙醚萃取三次。 The solvent was removed in vacuo, and the resulting solid was dissolved in water, acidified with 1N HCl and then, extracted three times with ether. 乙醚萃取液用水和盐水洗涤,然后干燥(MgSO4)。 Washed with water and ether extracts were washed with brine, then dried (MgSO4). 真空脱除溶剂,得到橙色固体标题化合物。 The solvent was removed in vacuo to give the title compound as an orange solid.

PMR(d6-DMSO):δ1.23(12H,s),1.62(4H,s),2.15(3H,s),2.23(3H,s),6.37(1H,s),7.08(1H,s),7.13(1H,s),7.51(2H,d,J=8.3Hz),7.94(2H,d,J=8.3Hz).2-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基-2-基)丙烯-1-基]-4-溴噻吩将0.41g(0.61mL,0.98mmol,1.6M于己烷中)正丁基锂滴加到处于氩气中-78℃下的含于11mL四氢呋喃中的0.58g(0.98mmol)1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-萘-2-基)乙烷-1-基三苯鏻溴化物(化合物51)的溶液中。 PMR (d6-DMSO): δ1.23 (12H, s), 1.62 (4H, s), 2.15 (3H, s), 2.23 (3H, s), 6.37 (1H, s), 7.08 (1H, s) , 7.13 (1H, s), 7.51 (2H, d, J = 8.3Hz), 7.94 (2H, d, J = 8.3Hz) .2 - [(E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene-2-yl) propen-1-yl] -4-bromo-thiophene 0.41g (0.61mL, 0.98mmol, 1.6M in hexane) was added dropwise n-butyllithium in 0.58g (0.98mmol) 1- (3,5,5,8,8- pentamethyl--5-containing argon at -78 ℃ in 11mL of tetrahydrofuran , 6,7,8-tetrahydro - naphthalen-2-yl) ethane-l-yl triphenyl phosphonium bromide (compound 51) was. 使此悬浮液升温到室温,然后滴加于2mL四氢呋喃中的0.28g(1.47mmol)4-溴-2-噻吩羧基醛的溶液,所得混合物在室温下搅拌20小时。 Make this suspension was warmed to room temperature, then 2mL of tetrahydrofuran was added dropwise to 0.28g (1.47mmol) 4- bromo-2-thiophene carboxaldehyde is added and the resulting mixture was stirred at room temperature for 20 hours. 真空脱除溶剂,其残留固体溶于水中,用1N HCl酸化,再用乙醚萃取三次。 The solvent was removed in vacuo, the residual solid was dissolved in water, acidified with 1N HCl, and extracted with ether three times. 乙醚萃取液用水和盐水洗涤,然后干燥(MgSO4)。 Washed with water and ether extracts were washed with brine, then dried (MgSO4). 再于真空中除去溶剂,所得残留物用快速色谱法(SiO2,己烷中含0.5%乙酸乙酯)提纯,得到白色固体标题化合物。 And then the solvent was removed in vacuo, the resulting residue was purified by flash chromatography (SiO2, hexane containing 0.5% ethyl acetate) to give the title compound as a white solid.

PMR(CDCl3):δ1.27(6H,s),1.29(6H,s),1.68(4H,s),2.26(6H,m),6.45(1H,s),6.75(1H,s),6.95(1H,s),7.07(1H,s),7.11(1H,s),7.17(1H,s).2-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]噻吩-4-羧酸(化合物19)在氩气中,-100℃下,向于15mL四氢呋喃中的500mg(1.24mmol)2[-2-(E)-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-4-溴噻吩的溶液中边搅拌边加入0.527g(0.775ml,1.24mmol,1.6M在己烷中)正丁基锂。 PMR (CDCl3): δ1.27 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 2.26 (6H, m), 6.45 (1H, s), 6.75 (1H, s), 6.95 (1H, s), 7.07 (1H, s), 7.11 (1H, s), 7.17 (1H, s) .2 - [(E) -2- (5,6,7,8- tetrahydro-3, 5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] thiophene-4-carboxylic acid (Compound 19) in argon at -100 ℃, in 15mL of tetrahydrofuran to 500mg (1.24mmol) 2 [-2- (E) - (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] -4-bromo-thiophene was added with stirring 0.527g (0.775ml, 1.24mmol, 1.6M in hexane) of n-butyllithium. 反应物搅拌2分钟,然后用二氧化碳吹扫20分钟。 The reaction was stirred for 2 minutes, 20 minutes and then purged with carbon dioxide. 然后使此反应混合物升温至室温,酸化,用乙醚萃取。 The reaction mixture was then allowed to warm to room temperature, acidified, and extracted with ether.

乙醚萃取液用水和盐水洗涤,然后干燥(MgSO4)。 Washed with water and ether extracts were washed with brine, then dried (MgSO4). 在真空中除去溶剂,将所得残留物溶于2N氢氧化钠水溶液中,再用乙醚洗涤。 The solvent was removed in vacuo, and the resulting residue was dissolved in 2N aqueous sodium hydroxide solution and washed with ether. 所得含水层用1N HCl酸化,再用乙醚萃取。 The resulting aqueous layer was acidified with 1N HCl, and extracted with ether. 此乙醚层用水和盐水洗涤,然后干燥(MgSO4)。 The ether layer was washed with water and brine, then dried (MgSO4). 在真空中除去溶液,所得产物用快速色谱法(己烷中含10%乙酸乙酯)提纯,得到白色固体标题化合物。 The solution was removed in vacuo, the resulting product was purified by flash chromatography (10% ethyl acetate in hexanes) to afford the title compound as a white solid.

PMR(d6-DMSO):δ1.23(12H,s),1.62(4H,s),2.21(3H,s),2.23(3H,s),6.56(1H,s),7.07(1H,s),7.13(1H,s),7.45(2H,s),8.24(2H,s).()-1-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)-乙醇向0℃的含于甲醇中的4.17g(17.1mmol)甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢萘基-2-基]酮的溶液中分次加入0.77g(20.4mmol)硼氢化钠,所得悬浮液在0℃下搅拌4小时。真空脱除溶剂,将所得固体溶于水中,用1N HCl酸化,然后用乙醚萃取三次。乙醚萃取液用水和盐水洗涤,干燥(MgSO4)。再次真空脱除溶剂,所得残留物用快速色谱法(SiO2,己烷中含10%乙酸乙酯)提纯,得到一种单一异构体:白色固体标题化合物。 PMR (d6-DMSO): δ1.23 (12H, s), 1.62 (4H, s), 2.21 (3H, s), 2.23 (3H, s), 6.56 (1H, s), 7.07 (1H, s) , 7.13 (1H, s), 7.45 (2H, s), 8.24 (2H, s). () -1- (5,6,7,8- tetrahydro-3,5,5,8,8- pentamethyl-naphthalen-2-yl) - ethanol To a solution in methanol 4.17g 0 ℃ of (17.1mmol) methyl [3,5,5,8,8-pentamethyl (5,6,7,8 - tetrahydro-naphthalen-2-yl] ketone was added portionwise added 0.77g (20.4mmol) of sodium borohydride, the resulting suspension was stirred at 0 ℃ 4 小时 solvent was removed in vacuo, and the resulting solid was dissolved in water. acidified with 1N HCl, and then extracted three times with ether. The ether extracts washed with water and brine solution, dried (MgSO4). The solvent was removed again in vacuo, the resulting residue was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) purification, to give a single isomer: the title compound as a white solid.

PMR(CDCl3):δ1.28(12H,m),1.47(3H,d,J=6.5H2),1.67(4H,g),2.49(3H,s),5.08(1H,m),7.10(1H,s),7.45(1H,s).[(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)乙烷-1-基]溴化三苯鏻(化合物51)在氩气中0℃下,把42.4g(14.9mL,157mmol)溴化钾加到于乙醚和己烷中的3.87g(15.7mmol)()-1-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)乙醇的溶液中,所得混合物搅拌2小时。 PMR (CDCl3): δ1.28 (12H, m), 1.47 (3H, d, J = 6.5H2), 1.67 (4H, g), 2.49 (3H, s), 5.08 (1H, m), 7.10 (1H , s), 7.45 (1H, s). [(5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) ethane-1-yl] triphenylphosphonium bromide (compound 51) at 0 ℃ in an argon atmosphere, to 42.4g (14.9mL, 157mmol) was added potassium bromide in diethyl ether and hexane 3.87g (15.7mmol) () -1- ( 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) ethanol, and the resulting mixture was stirred for 2 hours. 然后在30分钟内滴加水,分离开各层相。 Then water was added dropwise over 30 minutes, the layers separated phase. 用乙醚萃取含水层三次,乙醚层用水和盐水洗涤然后干燥(MgSO4)。 The aqueous layer was extracted three times with ether, the ether layer was washed with water and brine and then dried (MgSO4). 真空脱除溶剂,其残留物溶于苯中,再加入三苯膦,将此混合物在室温下搅拌24小时。 The solvent was removed in vacuo, the residue was dissolved in benzene, was added triphenylphosphine, and the mixture was stirred at room temperature for 24 hours. 尔后,真空浓缩混合物,所得固体从乙腈和乙酸乙酯及己烷中重结晶,得到白色固体标题化合物。 Thereafter, the mixture was concentrated in vacuo, the resulting solid was recrystallized from acetonitrile and ethyl acetate and hexane to give the title compound as a white solid.

PMR(CDCl3):δ0.61(3H,s),0.89(3H,s),1.27(6H,s),1.62(4H,m),1.85(6H,d),2.04(3H,dd),5.19(2H,m),6.62(1H,d),7.02(1H,s),7.43(6H,m),7.68(6H,m),7.87(3H,m).2-[(E)-(2)-((5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-5-溴噻吩在氩气中,-78℃下,向于60mL四氢呋喃中的3.00g(5.26mmol)[(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)乙烷-1-基]溴化三苯鏻的溶液中滴加2.24g(3.29mL,5.26mmol,1.6M在己烷中)正丁基锂。使此悬浮液升温至室温,再向其中滴加于10mL四氢呋喃中的1.01g(0.63mL,5.26mmol)5-溴-2-噻吩羧基醛的溶液,此混合物在室温下搅拌20小时,然后回流1小时。混合物用1N HCl酸化,再用乙醚萃取三次。乙醚萃取物用水和盐水洗涤,然后干燥(MgSO4)。真空脱除溶剂,其残留物用快速色谱法(SiO2,己烷中含2%乙酸乙酯)提纯,得到白色固体标题化合物。 PMR (CDCl3): δ0.61 (3H, s), 0.89 (3H, s), 1.27 (6H, s), 1.62 (4H, m), 1.85 (6H, d), 2.04 (3H, dd), 5.19 (2H, m), 6.62 (1H, d), 7.02 (1H, s), 7.43 (6H, m), 7.68 (6H, m), 7.87 (3H, m) .2 - [(E) - (2 ) - ((5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-yl) propen-1-yl] -5-bromothiophene in argon, at -78 ℃, in 60mL of tetrahydrofuran to 3.00g (5.26mmol) [(5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) acetic 1-yl] triphenylphosphonium bromide was added dropwise 2.24g (3.29mL, 5.26mmol, 1.6M in hexane) of n-butyllithium. makes this suspension warmed to room temperature, the dropwise addition of in 10mL of tetrahydrofuran 1.01g (0.63mL, 5.26mmol) 5- bromo-2-thiophene carboxaldehyde was added, the mixture was stirred at room temperature for 20 hours and then refluxed for 1 hour. The mixture was acidified with 1N HCl, and extracted with ether three times with water and ether extracts were washed with brine, then dried (MgSO4). The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 2% ethyl acetate in hexanes) to afford the title compound as a white solid.

PMR(CDCl3):δ1.28(12H,s),1.67(4H,s),2.24(6H,2s),6.45(1H,s),6.75(1H,d,J=3.9Hz),6.99(1H,d,J=3.8Hz),7.07(1H,s),7.09(1H,s).5-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-2-噻吩羧酸(化合物21)在氩气中,-78℃下,向含于乙醚中的0.230g(0.57mmol)2-[(E)-2-((5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-5-溴噻吩溶液中滴加0.67mL(1.14mmol,1.7M在己烷中)叔丁基锂。所得混合物搅拌1.5小时,用二氧化碳吹扫,然后在16小时内使其升温至室温。该混合物用1N HCl酸化,再用乙醚萃取。然后,乙醚层用水和盐水洗涤,干燥(MgSO4)。真空脱除溶剂得到兰色固体,此固体再用含于己烷中的乙醚重结晶,由此得到浅兰色固体标题化合物。 PMR (CDCl3): δ1.28 (12H, s), 1.67 (4H, s), 2.24 (6H, 2 s), 6.45 (1H, s), 6.75 (1H, d, J = 3.9Hz), 6.99 (1H, d, J = 3.8Hz), 7.07 (1H, s), 7.09 (1H, s) .5 - [(E) -2- (5,6,7,8- tetrahydro-3,5, 5,8,8- pentamethyl-naphthalen-2-yl) propen-1-yl] -2-thiophene carboxylic acid (Compound 21) in argon, at -78 ℃, To a solution in diethyl ether 0.230g ( 0.57mmol) 2 - [(E) -2 - ((5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] -5-bromo-thiophene was added dropwise 0.67mL (1.14mmol, 1.7M in hexane) tert-butyllithium. The resulting mixture was stirred for 1.5 hours, purged with carbon dioxide, then in 16 hours allowed to warm to room temperature. The The mixture was acidified with 1N HCl, and extracted with ether. Then, the ether layer was washed with water and brine, dried (MgSO4). The solvent was removed in vacuo to give a blue solid which was contained in the hexane and then recrystallized from diethyl ether, whereby to give the title compound as a pale blue solid.

PMR(d6-DMSO):δ1.21(12H,s),1.60(4H,s),2.19(3H,s),2.24(3H,s),6.45(1H,s),6.61(1H,s),6.99(1H,d,J=3.8Hz),7.06(1H,s),7.12(1H,s),7.18(1H,d,J=3.8Hz),7.67(1H,d,J=3.8Hz).5-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-2-噻吩羧酸乙酯(化合物20)把于EtOH中的0.161g(0.437mmol)5-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-2-噻吩羧酸(化合物21,0.03g,0.655mmol),0.099g(0.48mmol)1,3-二环己基碳化二亚胺和于10mL二氯甲烷中的5.3mg(0.044mmol)4-二甲氨吡啶的悬浮液在室温下搅拌16小时。 PMR (d6-DMSO): δ1.21 (12H, s), 1.60 (4H, s), 2.19 (3H, s), 2.24 (3H, s), 6.45 (1H, s), 6.61 (1H, s) , 6.99 (1H, d, J = 3.8Hz), 7.06 (1H, s), 7.12 (1H, s), 7.18 (1H, d, J = 3.8Hz), 7.67 (1H, d, J = 3.8Hz) .5 - [(E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] -2- thiophene-carboxylate (Compound 20) The 0.161g (0.437mmol) in EtOH of 5 - [(E) -2- (5,6,7,8- tetrahydro -3,5,5,8,8 - pentamethyl-naphthalen-2-yl) propen-1-yl] -2-thiophene carboxylic acid (compound 21,0.03g, 0.655mmol), 0.099g (0.48mmol) 1,3- dicyclohexyl carbodiimide and in 10mL dichloromethane 5.3mg (0.044mmol) 4- dimethylaminopyridine was stirred at room temperature for 16 hours. 过滤此反应混合物,滤液用用水和盐水洗涤。 The mixture was filtered, and the filtrate was washed with water and brine the reaction. 把有机层合并且干燥(MgSO4),真空脱除溶剂,残留物用快速色谱法提纯(SiO2,己烷中含5%乙酸乙酯),得到澄清油状标题化合物。 The organic layers were combined and dried (MgSO4), the solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford the title compound as a clear oil.

PMR(CDCl3):δ1.27(12H,s),1.39(3H,t,J=7.2Hz),1.68(4H,s),2.27(3H,s),2.34(3H,s),4.37(2H,q,J=7.Hz),6.57(1H,s),7.00(1H,d,J=3.8Hz),7.09(1H,s),7.11(1H,s),7.74(1H,d,J=3.8Hz).4-[(E)-2-(2,2,4,4,7-五甲基-苯并二氢吡喃-6-基)-丙烯-1-基]-苯甲酸乙酯(化合物24)在氩气中,室温下,把于四氢呋喃中的2.6g(8.6mmol)[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)与6.0mL(8.6mmol)双(三甲基甲硅烷基)酰胺钾的混合物搅拌30分钟。 PMR (CDCl3): δ1.27 (12H, s), 1.39 (3H, t, J = 7.2Hz), 1.68 (4H, s), 2.27 (3H, s), 2.34 (3H, s), 4.37 (2H , q, J = 7.Hz), 6.57 (1H, s), 7.00 (1H, d, J = 3.8Hz), 7.09 (1H, s), 7.11 (1H, s), 7.74 (1H, d, J = 3.8Hz) .4 - [(E) -2- (2,2,4,4,7- pentamethyl - chroman-6-yl) - propen-1-yl] - benzoic acid ethyl ester (Compound 24) in argon at room temperature, in tetrahydrofuran 2.6g (8.6mmol) [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40) and 6.0 mL (8.6mmol) bis (trimethyl-silyl) amide potassium mixture was stirred for 30 minutes. 然后加入1.0g(4.3mmol)甲基(2,2,4,4,7-五甲基苯并二氢吡喃-6-基)酮(也称为2,2,4,4,7-五甲基-6-乙酰基苯并二氢吡喃(化合物52))在THF中的溶液,所得混合物被搅拌20小时。 Was then added 1.0g (4.3mmol) methyl (2,2,4,4,7- pentamethyl-chroman-6-yl) ketone (also known as 2,2,4,4,7- pentamethyl-6-acetyl-chroman (Compound 52)) in THF was added and the resulting mixture was stirred for 20 hours. 再向其中加入4.3mL(8.6mmol)2M乙醇钠,又搅拌2小时。 Thereto was added 4.3mL (8.6mmol) 2M sodium ethoxide, and stirred for 2 hours. 之后,加入碳酸氢钠,再用乙醚萃取该混合物。 Thereafter, sodium bicarbonate, the mixture was extracted with ether. 乙醚层用盐水洗涤,干燥(MgSO4)。 The ether layer was washed with brine, dried (MgSO4). 真空脱除溶剂,残留物用快速色谱法(SiO2,己烷含2%乙酸乙酯)提纯,由此所得的异构体混合物再用HPLC(己烷中含1%乙酸乙酯)分离开,得到澄清油状标题化合物。 The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, hexane containing 2% ethyl acetate), whereby the resulting mixture of isomers and then HPLC (1% ethyl acetate in hexanes) separated, to give the title compound as a clear oil.

PMR(0.1%在CDCl3中的乙苯溶液):δ1.37(6H,s),1.38(6H,s),1.42(3H,t),1.84(4H,s),2.21(3H,s),2.28(3H,s),4.41(2H,q),6.41(1H,s),6.67(1H,s),7.10(1H,s),7.45(2H,d,J=8.2Hz),8.06(2H,d,J=8.2Hz).4-[(E)-2-(2,2,4,4,7-五甲基苯并二氢吡喃-6-基)丙烯--1-基]苯甲酸(化合物25)把氢氧化钾的乙醇溶液加入到4-[(E)-2-(2,2,4,4,7-五甲基苯并二氢吡喃-6-基)丙烯-1-基]苯甲酸乙酯(化合物24)中,此混合物在室温下搅拌。 PMR (0.1% of ethylbenzene solution in CDCl3): δ1.37 (6H, s), 1.38 (6H, s), 1.42 (3H, t), 1.84 (4H, s), 2.21 (3H, s), 2.28 (3H, s), 4.41 (2H, q), 6.41 (1H, s), 6.67 (1H, s), 7.10 (1H, s), 7.45 (2H, d, J = 8.2Hz), 8.06 (2H , d, J = 8.2Hz) .4 - [(E) -2- (2,2,4,4,7- pentamethyl-chroman-6-yl) propenyl --1- yl] benzoic acid (Compound 25) to an ethanol solution of potassium hydroxide was added to 4 - [(E) -2- (2,2,4,4,7- pentamethyl-chroman-6-yl) acrylamide 1-yl] benzoate (Compound 24), and the mixture was stirred at room temperature. 真空脱除溶剂,将所得固体溶于水中,用1N HCl酸化,再用乙醚萃取三次。 The solvent was removed in vacuo, and the resulting solid was dissolved in water, acidified with 1N HCl, and extracted with ether three times. 乙醚萃取物用水和盐水洗涤、干燥(MgSO4)。 The ether extract was washed with water and brine, dried (MgSO4). 再次真空脱除溶剂,得到浅黄色固体标题化合物。 Again solvent was removed in vacuo to give the title compound as a pale yellow solid.

PMR(d6-DMSO):δ1.38(12H,s),1.87(2H,s),2.23(3H,s),2.29(3H,s),6.44(1H,s),6.68(1H,s),7.10(1H,s),7.50(2H,d,J=8.3Hz),8.14(2H,d,J=8.3Hz).4-[(E)-2-(2-甲基-5-叔丁基苯基)丙烯-1-基]苯甲酸乙酯(化合物26)在氩气中,0℃下,把于30mL四氢呋喃中的7.08g(37mmol)2-甲基-5-叔丁基乙酰苯(化合物53)(由化学文献获得)和10.42g(37mmol)[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)的溶液通过套管加入到于30mL四氢呋喃中的1.5g(37mmol)氢化钠悬浮液中。 PMR (d6-DMSO): δ1.38 (12H, s), 1.87 (2H, s), 2.23 (3H, s), 2.29 (3H, s), 6.44 (1H, s), 6.68 (1H, s) , 7.10 (1H, s), 7.50 (2H, d, J = 8.3Hz), 8.14 (2H, d, J = 8.3Hz) .4 - [(E) -2- (2- methyl-5-tert- butyl-phenyl) propen-1-yl] benzoate (Compound 26) in argon at 0 ℃, put in 30mL of tetrahydrofuran 7.08g (37mmol) 2- methyl-5-tert-butyl-acetyl benzene (Compound 53) (obtained by the chemical literature) and 10.42g (37mmol) [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40) was added via cannula to in 30mL of tetrahydrofuran of 1.5g (37mmol) of sodium hydride suspension. 使所得悬浮液升温到室温,并搅拌72小时。 The resulting suspension was warmed to room temperature, and stirred for 72 hours. 把所得淤渣溶于水和1N HCl中,用乙醚萃取。 The resultant sludge was dissolved in water and 1N HCl, and extracted with ether. 乙醚层用水和盐水洗涤,干燥(MgSO4)。 The ether layer was washed with water and brine, dried (MgSO4). 真空脱除溶剂,残留物用快速色谱法(SiO2,己烷中含1%乙酸乙酯)提纯,将由此所得异构体混合物用HPLC法(己烷中含0.5%乙酸乙酯)分离开,得到白色固体标题化合物。 The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, hexane containing 1% ethyl acetate), the thus obtained mixture of isomers (0.5% ethyl acetate in hexanes) separated by HPLC, to give the title compound as a white solid.

PMR(CDCl3):δ1.34(9H,s),1.41(3H,t,)1.69(4H,s),2.20(3H,s),2.36(3H,s),4.38(2H,q),6.41(1H,s),7.04(1H,m),7.12(1H,m),7.22(1H,m),7.42(2H,d,J=8.3Hz),8.03(2H,d,J=8.3Hz).4-[(E)-2-(2-甲基-5-叔丁基苯基)丙烯-1-基]苯甲酸(化合物27)把氢氧化钾的乙醇溶液加入到41mg(0.12mmol)4-[(E)-2-(2-甲基-5-叔丁基苯基)丙烯-1-基]苯甲酸乙酯(化合物26)中,将所得混合物在室温下搅拌。 PMR (CDCl3): δ1.34 (9H, s), 1.41 (3H, t,) 1.69 (4H, s), 2.20 (3H, s), 2.36 (3H, s), 4.38 (2H, q), 6.41 (1H, s), 7.04 (1H, m), 7.12 (1H, m), 7.22 (1H, m), 7.42 (2H, d, J = 8.3Hz), 8.03 (2H, d, J = 8.3Hz) .4 - [(E) -2- (2- methyl-5-tert-butyl-phenyl) propen-1-yl] benzoic acid (Compound 27) to an ethanol solution of potassium hydroxide was added to 41mg (0.12mmol) 4 - [(E) -2- (2- methyl-5-tert-butyl-phenyl) propen-1-yl] benzoate (Compound 26), and the resulting mixture was stirred at room temperature. 真空脱除溶剂,把所得固体溶于水中,用1N HCl酸化,然后用乙醚萃取。 The solvent was removed in vacuo, the resulting solid was dissolved in water, acidified with 1N HCl, and then extracted with ether. 乙醚萃取物用水和盐水洗涤,干燥(MgSO4)。 The ether extract was washed with water and brine, dried (MgSO4). 再次真空脱除溶剂,得到黄色固体标题化合物。 Again solvent was removed in vacuo to give the title compound as a yellow solid.

PMR(d6-DMSO):δ1.24(12H,s),2.13(3H,s),2.28(3H,s),6.37(1H,s),7.09(1H,d,J=8.0Hz),7.2(2H,m),7.49(2H,d,J=8.3Hz),7.95(2H,d,J=8.3Hz).甲基[3-氯-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基1酮(化合物5 4)在氩气中,0℃下,向于24mL二氯甲烷中的13.6g(102mmol)氯化铝悬浮液中加入于56mL二氯甲烷中的7.98g(7.23mL,102mmol)乙酰氯和18.88g(84.8mmol)3-氯-5,6,7,8-四氢-3,5,5,8,8-五甲基萘的溶液。 PMR (d6-DMSO): δ1.24 (12H, s), 2.13 (3H, s), 2.28 (3H, s), 6.37 (1H, s), 7.09 (1H, d, J = 8.0Hz), 7.2 (2H, m), 7.49 (2H, d, J = 8.3Hz), 7.95 (2H, d, J = 8.3Hz). Methyl [3-chloro-5,5,8,8-tetramethyl (5 , 6,7,8-tetrahydro-naphthalen) -2-yl 1-one (Compound 54) in argon at 0 ℃, To a 24mL dichloromethane 13.6g (102mmol) of aluminum chloride suspension Join in 56mL dichloromethane 7.98g (7.23mL, 102mmol) acetyl chloride and 18.88g (84.8mmol) 3- chloro-5,6,7,8 3,5,5,8,8 solution pentamethyl naphthalene. 在3小时内,在搅拌条件下使上述混合物升温至室温。 Over 3 hours, with stirring The mixture was allowed to warm to room temperature. 然后再冷却至0℃,并向该混合物中滴加1N HCl。 Then recooled to 0 ℃, 1N HCl was added dropwise to the mixture. 将此混合物溶于水中,用二氯甲烷萃取三次。 The mixture was dissolved in water, extracted three times with dichloromethane. 有机层用1N HCl,水和盐水洗涤,干燥(MgSO4)。 The organic layer was washed with 1N HCl, water and brine, dried (MgSO4). 真空脱除溶剂,将所得残留物蒸馏(116℃,3mmHg)提纯,得到原材料与产物的混合物。 The solvent was removed in vacuo, and the resulting residue was distilled (116 ℃, 3mmHg) to afford a mixture of raw materials and products.

PMR(CDCl3):δ1.27(12H,s),1.19(4H,s),2.65(3H,s),7.31(1H,s),7.54(1H,s).()-1-(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘基-2-基)乙醇在0℃下,把1.0g(26.4mmol)硼氢化钠分次加进于甲醇中的5.01g(18.9mmol)甲基[3-氯-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物54)的溶液中,所得悬浮液在0℃下搅拌2小时。 PMR (CDCl3): δ1.27 (12H, s), 1.19 (4H, s), 2.65 (3H, s), 7.31 (1H, s), 7.54 (1H, s) () -1- (3. - chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethanol at 0 ℃, to 1.0g (26.4mmol) of sodium borohydride Graded in methanol was added 5.01g (18.9mmol) methyl [3-chloro-5,5,8,8-tetramethyl (5,6,7,8-tetrahydro-naphthalen) -2-yl] ketone ( compound 54) was added and the resulting suspension was stirred at 0 ℃ 2 hours. 然后,用1N HCl酸化混合物,用乙醚萃取三次。 Then, the mixture was acidified with 1N HCl and extracted with ether three times. 乙醚萃取物用水和盐水洗涤,干燥(MgSO4)。 The ether extract was washed with water and brine, dried (MgSO4). 真空脱除溶液,其残留物用快速色谱法(SiO2,己烷中含5%乙酸乙酯)提纯,得到白色固体标题化合物。 Solution was removed in vacuo, the residue was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford the title compound as a white solid.

PMR(CDCl3):δ1.26(12H,m),1.48(3H,d,J=6.5Hz),1.67(4H,s),1.98(1H,s),5.21(1H,m),7.23(1H,s),7.50(1H,s).[(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)乙烷-1-基]三苯鏻溴化物(化合物55)在氩气中,0℃下,向于乙醚和己烷中的3.15g(11.8mmol)()-1-(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)乙醇的溶液中边搅拌边滴加31.9g(11.2mL,118mmol)三溴化磷,将此混合物搅拌1.5小时,然后小心加入水,再用若干份乙醚萃取混合物。 PMR (CDCl3): δ1.26 (12H, m), 1.48 (3H, d, J = 6.5Hz), 1.67 (4H, s), 1.98 (1H, s), 5.21 (1H, m), 7.23 (1H , s), 7.50 (1H, s). [(3- chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-yl) ethan-1 yl] triphenylphosphonium bromide (Compound 55) in argon at 0 ℃, the diethyl ether and hexane 3.15g (11.8mmol) () -1- (3- chloro-5,6,7,8, 8- tetrahydro-5,5,8,8-tetramethyl-2-yl) ethanol was added dropwise with stirring 31.9g (11.2mL, 118mmol) phosphorus tribromide, and the mixture was stirred for 1.5 hours , then water was added carefully and then the mixture was extracted with ether several parts. 乙醚萃取物用水,碳酸氢钠和盐水洗涤,干燥(MgSO4)。 The ether extract was washed with water, aqueous sodium bicarbonate and brine, dried (MgSO4). 真空脱除溶剂,将其中残留油溶于175mL苯中。 The solvent was removed in vacuo, the residual oil was dissolved in 175mL of which benzene. 向此中加入3.09g(11.8mmol)三苯膦,该溶液在室温下搅拌24小时。 To which was then added 3.09g (11.8mmol) of triphenylphosphine, the solution was stirred at room temperature for 24 hours. 采用快速色谱法(SiO2,己烷中含0.5%乙酸乙酯,二氯甲烷中含5%MeOH)提纯,得到白色泡沫体标题化合物。 Using flash chromatography (SiO2, hexane containing 0.5% ethyl acetate in dichloromethane containing 5% MeOH) to afford the title compound as a white foam.

PMR(CDCl3):δ0.70(3H,s),1.02(3H,s),1.28(12H,d,J=15Hz),1.62(4H,m),2.01(3H,dd,J=15,9Hz),5.19(1H,m),6.79(1H,s),7.4-7.9(16H,m).4-[(E)-2-(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘)-2-基]丙烯-1-基]苯甲酸乙酯(化合物12)在氩气中,把0.91g(1.54mmol)[(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)乙烷-1-基]三苯鏻溴化物(化合物55),0.27g(1.54mmol)新鲜蒸馏的4-乙酯基苯甲醛和5.9g(7.0mL,76.9 mmol)1,2-环氧丁烷的悬浮液混合起来并且回流96小时。 PMR (CDCl3): δ0.70 (3H, s), 1.02 (3H, s), 1.28 (12H, d, J = 15Hz), 1.62 (4H, m), 2.01 (3H, dd, J = 15,9Hz ), 5.19 (1H, m), 6.79 (1H, s), 7.4-7.9 (16H, m) .4 - [(E) -2- (3- chloro-5,6,7,8-tetrahydro - 5,5,8,8-tetramethyl-naphthyl) -2-yl] propen-1-yl] benzoate (Compound 12) In an argon atmosphere, to 0.91g (1.54mmol) [(3- chloro - 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-yl) ethane-1-yl] triphenylphosphonium bromide (compound 55), 0.27g (1.54mmol ) freshly distilled 4-ethyl benzaldehyde and 5.9g (7.0mL, 76.9 mmol) 1,2- butylene oxide suspension mixed and refluxed for 96 hours. 所得深褐色溶液在真空中浓缩,残留物用柱色谱法(SiO2,己烷中含2%乙酸乙酯)提纯,得到异构体混合物。 The resulting dark brown solution was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, 2% ethyl acetate in hexanes) to give a mixture of isomers. 采用HPLC法(乙腈中含10%水)分离异构体,得到白色固体标题化合物。 Using HPLC (acetonitrile containing 10% water) isomers were separated to give the title compound as a white solid.

PMR(CDCl3):δ1.29(12H,s),1.41(3H,t,J=7.3Hz),1.69(4H,s),2.24(3H,s),2.23(3H,8),4.49(2H,q,J=6.8 Hz),6.49(1H,s),7.20(1H,s),7.30(1H,s),7.48(2H,d,J=8.4Hz),8.05(2H,d,J=8.4Hz).4[(E)-2-(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯-1-基]苯甲酸(化合物13)把氢氧化钾的乙醇溶液加入到20mg(0.049mmol)4-[(E)-2-(3-氯-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯-1-基]苯甲酸乙酯(化合物12)中,将此混合物在室温下搅拌24小时。 PMR (CDCl3): δ1.29 (12H, s), 1.41 (3H, t, J = 7.3Hz), 1.69 (4H, s), 2.24 (3H, s), 2.23 (3H, 8), 4.49 (2H , q, J = 6.8 Hz), 6.49 (1H, s), 7.20 (1H, s), 7.30 (1H, s), 7.48 (2H, d, J = 8.4Hz), 8.05 (2H, d, J = 8.4Hz) .4 [(E) -2- (3- chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-yl) propen-1-yl ] benzoic acid (Compound 13) to an ethanol solution of potassium hydroxide was added to 20mg (0.049mmol) 4 - [(E) -2- (3- chloro-5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-yl) propen-1-yl] benzoate (Compound 12), and the mixture was stirred at room temperature for 24 hours. 真空脱除溶剂,将所得固体溶于水中,用1N HCl酸化,用乙醚萃取三次。 The solvent was removed in vacuo, and the resulting solid was dissolved in water, acidified with 1N HCl, and extracted with ether three times. 乙醚萃取物用水和盐水洗涤,干燥(MgSO4)。 The ether extract was washed with water and brine, dried (MgSO4). 再次真空脱除溶剂,用乙腈重结晶,得到白色固体标题化合物。 Again solvent was removed in vacuo, and recrystallized from acetonitrile to give the title compound as a white solid.

PMR(CDCl3):δ1.29(12H,s),1.70(4H,s),2.28(3H,d,J=1.4Hz),6.51(1H,s),7.20(1H,s),7.30(1H,s),7.51(1H,d,J=8.4 Hz),8.12(1H,d,J=8.4Hz).4-[(E)-2-(2-甲基-4-叔丁基苯基)丙烯-1-基]苯甲酸乙酯(化合物28)将3.17g(10.5mmol)[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)与7.6mL(10.64mmol)双(三甲基甲硅烷基)酰胺钾(于THF中1.4M)之混合物搅拌30分钟。 PMR (CDCl3): δ1.29 (12H, s), 1.70 (4H, s), 2.28 (3H, d, J = 1.4Hz), 6.51 (1H, s), 7.20 (1H, s), 7.30 (1H , s), 7.51 (1H, d, J = 8.4 Hz), 8.12 (1H, d, J = 8.4Hz) .4 - [(E) -2- (2- methyl-4-t-butylphenyl ) propen-1-yl] benzoate (Compound 28) 3.17g (10.5mmol) [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40) with 7.6mL (10.64 mmol) bis (trimethyl-silyl) amide mixture of potassium (in THF 1.4M) The mixture was stirred for 30 min. 向其中加入于20ml二甲亚砜中的1.0g(5.3mmol)2-甲基-4-叔丁基乙酰苯(化合物56,按化学文献制得)溶液,所得溶液搅拌20小时。 20ml of dimethyl sulfoxide was added thereto in a 1.0g (5.3mmol) 2- methyl-4-t-butyl-acetophenone (Compound 56, prepared according to the chemical literature) was added, the resulting solution was stirred for 20 hours. 再向其中加入碳酸氢钠,用乙醚萃取此溶液。 Sodium bicarbonate was added thereto, the solution was extracted with diethyl ether. 乙醚萃取物用水和盐水洗涤,干燥(MgSO4)。 The ether extract was washed with water and brine, dried (MgSO4). 浓缩所得溶液,其残留油用柱色谱法(SiO2,己烷中含3%乙酸乙酯)提纯,由此得到异构体混合物。 The resulting solution was concentrated, the residual oil was purified by column chromatography (SiO2, hexane containing 3% ethyl acetate), to thereby obtain a mixture of isomers. 通过致光异构化(1小时,己烷,汞灯)提高反式异构体产率(45∶55,E∶Z)。 By actuating photoisomerization (1 hour, hexane, mercury) to improve the yield of the trans isomer (45:55, E:Z). 用HPLC法(乙腈中含20%水)分离异构体,得到澄清油状标题化合物。 The isomers were separated (acetonitrile containing 20% water) by HPLC to give the title compound as a clear oil. 4-[(E)-2-(2-甲基-4-叔丁苯基)丙烯-1-基]苯甲酸(化合物29)把氢氧化钠、2-甲氧乙醇和乙醚的溶液加入到70mg(0.21mmol)4-[(E)-2-(2-甲基-4-叔丁苯基)丙烯-1-基]苯甲酸乙酯(化合物28)中,将所得混合物在室温下搅拌5小时。 4 - [(E) -2- (2- methyl-4-t-butyl-phenyl) propen-1-yl] benzoic acid (Compound 29) Sodium hydroxide, 2-methoxy ethanol and ether was added to the 70mg (0.21mmol) 4 - [(E) -2- (2- methyl-4-t-butyl-phenyl) propen-1-yl] benzoate (Compound 28), and the resulting mixture was stirred at room temperature 5 hours. 真空脱除溶剂,把所得固体溶于水中,用1N HCl酸化,用乙醚萃取,乙醚萃取物用水和盐水洗涤,干燥(MgSO4)。 The solvent was removed in vacuo, the resulting solid was dissolved in water, acidified with 1N HCl, extracted with ether, washed with water and diethyl ether extract was washed with brine, dried (MgSO4). 再次真空脱除溶剂,得到黄色固体标题化合物。 Again solvent was removed in vacuo to give the title compound as a yellow solid.

PMR(d6-Acetone):δ1.30(9H,s),2.19(3H,d,J=1.5Hz),2.33(3H,s),6.41(1H,s),7.12(1H,d,J=8.0Hz),7.23(2H,m),7.54(1H,d,J=8.4Hz),8.05(1H,d,J=8.4Hz).3-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘在氩气中,0℃下,把11.0g(82.2mmol)氯化铝分次加入到于28.9mL(274mmol)溴苯中的25g(137mmol)1,6-二氯-1,6-二甲基己烷的溶液中,将所得悬浮液在0℃下搅拌5分钟,再使之升温到室温15分钟。 PMR (d6-Acetone): δ1.30 (9H, s), 2.19 (3H, d, J = 1.5Hz), 2.33 (3H, s), 6.41 (1H, s), 7.12 (1H, d, J = 8.0Hz), 7.23 (2H, m), 7.54 (1H, d, J = 8.4Hz), 8.05 (1H, d, J = 8.4Hz) .3--bromo-5,6,7,8-tetrahydro - 5,5,8,8-tetramethyl-naphthalene in argon at 0 ℃, to 11.0g (82.2mmol) was added portionwise to aluminum chloride in 28.9mL (274mmol) of bromobenzene in 25g (137mmol) 1 , a solution 2,6-dichloro-1,6-dimethyl hexane, and the resulting suspension was stirred for 5 minutes at 0 ℃, and allowed to warm to room temperature for 15 minutes. 向其中滴加1N HCl。 Thereto was added dropwise 1N HCl. 把混合物溶于水中,用乙醚萃取三次。 The mixture was dissolved in water and extracted with ether three times. 乙醚层用1N HCl、碳酸氢钠和盐水洗涤,然后干燥(MgSO4)。 The ether layer was 1N HCl, sodium bicarbonate and brine, then dried (MgSO4). 蒸馏(110℃,2mmHg)提纯得到黄色固体标题化合物。 Distillation (110 ℃, 2mmHg) afforded the title compound as a yellow solid.

PMR(CDCl3):δ1.25(6H,s),1.27(6H,s),1.67(4H,s),7.16(1H,d,J=8.5 Hz),7.23(1H,dd,J=2.0,8.5Hz),7.40(1H,d,J=2.1Hz).甲基[3-溴-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物57)在氩气中,0℃下,把于二氯甲烷中的3.29mL(密度=1.104,46.3mmol)乙酰氯和10.3g(38.5mmol)3-溴-5,5,8,8-四甲基-5,6,7,8-四氢萘的溶液加入到于二氯甲烷中的6.16g(46.3mmol)氯化铝的悬浮液中。 PMR (CDCl3): δ1.25 (6H, s), 1.27 (6H, s), 1.67 (4H, s), 7.16 (1H, d, J = 8.5 Hz), 7.23 (1H, dd, J = 2.0, 8.5Hz), 7.40 (1H, d, J = 2.1Hz). Methyl [3-bromo-5,5,8,8-tetramethyl (5,6,7,8-tetrahydronaphthalene) -2- yl] ketone (Compound 57) in argon at 0 ℃, the in dichloromethane 3.29mL (density = 1.104,46.3mmol) acetyl chloride and 10.3g (38.5mmol) 3- bromo -5,5, 8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene was added to in dichloromethane 6.16g (46.3mmol) of aluminum chloride suspension. 将所得混合物搅拌2小时,并于16小时内使之升温至室温。 The resulting mixture was stirred for 2 hours and allowed to warm to room temperature over 16 hours. 再将上述混合物冷却至0℃,滴加1N HCl。 The mixture was then cooled to 0 ℃, was added dropwise 1N HCl. 然后把此混合物溶于水中,用二氯甲烷萃取三次。 The mixture is then dissolved in water and extracted three times with dichloromethane. 有机层用1N HCl、水和盐水洗涤,然后干燥(MgSO4)。 The organic layer was 1N HCl, water and brine, then dried (MgSO4). 真空除去溶剂,其残留物蒸馏提纯(116℃,3mmHg),得到一种原料与产物的混合物。 The solvent was removed in vacuo, the residue was purified by distillation (116 ℃, 3mmHg), to give a mixture of starting material and product.

PMR(CDCl3):δ1.27(12H,s),1.68(4H,s),2.64(3H,s),7.45(1H,s),7.50(1H,s).4-[(E)-2-(3-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯-1-基]苯甲酸乙酯(化合物14)将5.56g(18.7mmol)[4-(二乙氧基氧膦基)甲基]苯甲酸乙酯(化合物40)和74mL(18.7mmol)双(三甲基甲硅烷基)酰胺钾的混合物搅拌38分钟。 PMR (CDCl3): δ1.27 (12H, s), 1.68 (4H, s), 2.64 (3H, s), 7.45 (1H, s), 7.50 (1H, s) .4 - [(E) -2 - (3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-yl) propen-1-yl] benzoate (Compound 14) 5.56 g (18.7mmol) [4- (diethoxyphosphinyl) methyl] benzoate (Compound 40) and (18.7mmol) bis (trimethyl-silyl) amide potassium 74mL mixture was stirred 38 minutes . 向其中加入于30mL二甲亚砜中的2.0g(6.5mmol)甲基[3-溴-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物57)的溶液,所得溶液搅拌64小时。 Thereto was added in 30mL of dimethyl sulfoxide in 2.0g (6.5mmol) methyl [3-bromo-5,5,8,8-tetramethyl (5,6,7,8-tetrahydronaphthalene) -2 - yl] ketone (Compound 57) was added, the resulting solution was stirred for 64 hours. 之后,向溶液中加入碳酸氢钠,并用二氯甲烷萃取,然后干燥(MgSO4)。 Thereafter, to the solution was added sodium bicarbonate and extracted with methylene chloride, and then dried (MgSO4). 真空脱除溶剂,其残留油用快速色谱法(SiO2,己烷中含3%乙酸乙酯)提纯。 The solvent was removed in vacuo, the residual oil was purified by flash chromatography (SiO2, 3% ethyl acetate in hexanes).

PMR(CDCl3):1.27(12H,s),1.41(3H,t),1.68(4H,s),2.24(3H,s),4.38(2H,q),6.45(1H,s),7.18(1H,s),7.47(3H,m),8.04(1H,s),8.08(1H,s).4-[(E)-2-(3-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯-1-基]苯甲酸(化合物15)把氢氧化钠、2-甲氧乙醇和乙醚的溶液加入到50mg(0.11mmol)4-[(E)-2-(3-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯-1-基]苯甲酸乙酯(化合物14)中,将此混合物在室温下搅拌17小时。 PMR (CDCl3): 1.27 (12H, s), 1.41 (3H, t), 1.68 (4H, s), 2.24 (3H, s), 4.38 (2H, q), 6.45 (1H, s), 7.18 (1H , s), 7.47 (3H, m), 8.04 (1H, s), 8.08 (1H, s) .4 - [(E) -2- (3- bromo-5,6,7,8-tetrahydro - 5,5,8,8-tetramethyl-2-yl) propen-1-yl] benzoic acid (Compound 15) Sodium hydroxide, 2-methoxy ethanol and ether was added to 50mg (0.11mmol) 4 - [(E) -2- (3- bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-yl) propen-1-yl] benzoic acid ethyl ester (Compound 14), and the mixture was stirred at room temperature for 17 hours. 真空脱除溶剂,把所得固体溶于水中,用2N HCl酸化,然后用乙醚萃取。 The solvent was removed in vacuo, the resulting solid was dissolved in water, acidified with 2N HCl, and then extracted with ether. 乙醚萃取物用水和盐水洗涤,并干燥之(MgSO4)。 Washed with water and diethyl ether extract was washed with brine, and dried (MgSO4). 再次真空脱除溶剂,得到白色固体标题化合物。 Again solvent was removed in vacuo to give the title compound as a white solid.

PMR(d6-DMSO):δ1.30(12H,s),1.69(4H,s),2.26(3H,d,J=1.3Hz),6.48(1H,s),7.20(1H,s),7.49(1H,s),8.14(2H,d,J=8.3Hz).甲基[3-乙基-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物58) PMR (d6-DMSO): δ1.30 (12H, s), 1.69 (4H, s), 2.26 (3H, d, J = 1.3Hz), 6.48 (1H, s), 7.20 (1H, s), 7.49 (1H, s), 8.14 (2H, d, J = 8.3Hz). Methyl [3-ethyl-5,5,8,8-tetramethyl (5,6,7,8-tetrahydronaphthalene) 2-yl] ketone (Compound 58)

在氩气中,在-5℃下,于1小时内把于10mL二氯甲烷中的2.32g(2.10mL,29.5mmol)乙酰氯和4.95g(23mmol)3-乙基-5,5,8,8-四甲基-5,6,7,8-四氢萘(按US2,897,237获得,在此结合参考其说明书)的溶液加入到于20mL二氯甲烷中的4.59g(34.4mmol)氯化铝的悬浮液中。 In argon at -5 ℃, the period of one hour in 10mL dichloromethane 2.32g (2.10mL, 29.5mmol) of acetyl chloride and 4.95g (23mmol) 3- ethyl-5,5,8,8 , 8-tetramethyl-5,6,7,8-tetrahydronaphthalene (obtained according to US2,897,237, incorporated herein by reference the specification) was added to 20mL of methylene chloride in 4.59g (34.4mmol) chloro aluminum suspension. 此混合物在-10-+5℃下搅拌3小时。 The mixture was stirred at -10- + 5 ℃ 3 hours. 然后把混合物溶于水中,用二氯甲烷萃取三次。 The mixture was then dissolved in water and extracted three times with dichloromethane. 有机层用盐水洗涤并干燥(MgSO4)。 The organic layer was washed with brine and dried (MgSO4). 真空脱除溶剂,其残留物用快速色谱法(SiO2,己烷中含10%乙酸乙酯)提纯,得到白色固体标题化合物。 The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 10% ethyl acetate in hexane) to afford the title compound as a white solid.

PMR(CDCl3):δ1.20(3H,t,J=7.5Hz),1.29(6H,s),1.30(6H,s),1.69(4H,s),2.57(3H,s),2.84(2H,q,J=7.3Hz),7.17(1H,s),7.59(1H,s).甲基[3-异丙基-5,5,8,8-四甲基(5,6,7,8-四氢萘)-2-基]酮(化合物59)在氩气中,-5℃下,于1小时内把在25mL二氯甲烷中的3.20g(2.90mL,41mmol)乙酰氯和6.58g(29mmol)3-异丙基-5,5,8,8-四甲基-5,6,7,8-四氢萘(可按US2,879,237获得,其说明书在此结合参考)的溶液加入到于15mL二氯甲烷中的5.80g(43.5mmol)氯化铝的悬浮液中。 PMR (CDCl3): δ1.20 (3H, t, J = 7.5Hz), 1.29 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.57 (3H, s), 2.84 (2H , q, J = 7.3Hz), 7.17 (1H, s), 7.59 (1H, s). Methyl [3-isopropyl-5,5,8,8-tetramethyl (5,6,7, 8- tetrahydro-naphthalen) -2-yl] ketone (Compound 59) In an argon atmosphere, at -5 ℃, over one hour to 3.20g (2.90mL, 41mmol) of acetyl chloride and 6.58 in 25mL dichloromethane g (29mmol) 3- isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (obtained according to US2,879,237, the specification of which is hereby incorporated by reference) was in 15mL of dichloromethane was added to a 5.80g (43.5mmol) of aluminum chloride suspension. 将此混合物在-5℃下搅拌2.5小时,然后使之冷却到0℃,并溶于水中,用己烷萃取三次。 The mixture was stirred at -5 ℃ 2.5 hours and then allowed to cool to 0 ℃, and dissolved in water, extracted three times with hexane. 有机层用盐水洗涤,干燥(MgSO4)。 The organic layer was washed with brine, dried (MgSO4). 真空脱除溶剂,其残留物用快速色谱法(SiO2,己烷中含5%乙酸乙酯)提纯,得到白色固体标题化合物。 The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford the title compound as a white solid.

PMR(CDCl3):δ1.22(6H,s),1.24(6H,s),1.29(6H,s),1.69(4H,s),2.49(3H,s),2.56(3H,s),3.50(1H,pentet,J=6.8 Hz),7.32(1H,s),7.46(1H,s).5-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-2-呋喃甲酸乙酯(化合物22)将于10mL二甲亚砜中的氢化钠混合物在55℃下加热1小时,然后加入到1.159g(4.00mmol)2-[5-(二乙氧基氧膦基)甲基]呋喃甲酸乙酯(化合物42)中。 PMR (CDCl3): δ1.22 (6H, s), 1.24 (6H, s), 1.29 (6H, s), 1.69 (4H, s), 2.49 (3H, s), 2.56 (3H, s), 3.50 (1H, pentet, J = 6.8 Hz), 7.32 (1H, s), 7.46 (1H, s) .5 - [(E) -2- (5,6,7,8- tetrahydro-3,5, 5,8,8- pentamethyl-naphthalen-2-yl) propen-1-yl] -2-furan-carboxylic acid ethyl ester (Compound 22) will 10mL dimethylsulfoxide sodium hydride was heated at 55 ℃ 1 hours, then added to 1.159g (4.00mmol) 2- [5- (diethoxyphosphinyl) methyl] furan-carboxylic acid ethyl ester (Compound 42). 将所得深红色溶液在室温下搅拌45分钟,然后加入到0.501g(2.05mmol)甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢萘)-2-基]酮(化合物50)的溶液中。 The resulting deep red solution was stirred at room temperature for 45 minutes and then added to 0.501g (2.05mmol) methyl [3,5,5,8,8-pentamethyl (5,6,7,8-tetrahydronaphthalene) 2-yl] ketone (Compound 50) solution. 把所得溶液在室温下搅拌48小时,然后加入碳酸氢钠,再用乙醚萃取溶液,并干燥之(MgSO4)。 The resulting solution was stirred for 48 hours at room temperature, followed by addition of sodium bicarbonate solution was extracted with ether, and dried (MgSO4). 浓缩此溶液,其残留油用柱色谱法(SiO2,己烷中含5%乙酸乙酯)提纯。 The solution was concentrated, the residual oil was purified by column chromatography (SiO2, 5% ethyl acetate in hexanes). 最后用HPLC法分离异构体。 Finally isomers were separated by HPLC. 5-[(E)-2-(5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-基)丙烯-1-基]-3-烟酸乙酯(化合物16)在氩气中,0℃下,将0.90g(1.0ml,1mmol)双(三甲基甲硅烷基)酰胺钠(于四氢呋喃中1M)边搅拌边滴加入0.21g(0.70mmol)35-(二乙氧基氧膦基)甲基]烟酸乙酯(化合物43)中。 5 - [(E) -2- (5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-naphthalen-2-yl) propen-1-yl] -3- smoke acid ethyl ester (Compound 16) in argon at 0 ℃, the 0.90g (1.0ml, 1mmol) bis (trimethylsilyl) amide, sodium (in tetrahydrofuran, 1M) was added dropwise with stirring 0.21g ( 0.70mmol) 35- (diethoxyphosphinyl) methyl] nicotinate (Compound 43). 把所得深红色溶液在室温下搅拌1小时,再加入到0.154g(0.63mmol)甲基[3,5,5,8,8-五甲基(5,6,7,8-四氢萘)-2-基]酮(化合物50)的溶液中,此溶液在室温下搅拌72小时。 The resulting deep red solution was stirred at room temperature for 1 hour and then was added to 0.154g (0.63mmol) methyl [3,5,5,8,8-pentamethyl (5,6,7,8-tetrahydronaphthalene) 2-yl] ketone (Compound 50) was added, the solution was stirred at room temperature for 72 hours. 向其中加入碳酸氢钠,用乙醚萃取该溶液,并干燥之(MgSO4)。 Sodium bicarbonate was added thereto, the solution was extracted with ether, and dried (MgSO4). 浓缩该溶液,其残留油用柱色谱法(SiO2,在己烷中5%乙酸乙酯)提纯。 The solution was concentrated, the residual oil (SiO2, 5% ethyl acetate in hexanes) was purified by column chromatography. 最后用HPLC法分离异构体。 Finally isomers were separated by HPLC.

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