CN100516018C - 双酯 - Google Patents
双酯 Download PDFInfo
- Publication number
- CN100516018C CN100516018C CNB028232739A CN02823273A CN100516018C CN 100516018 C CN100516018 C CN 100516018C CN B028232739 A CNB028232739 A CN B028232739A CN 02823273 A CN02823273 A CN 02823273A CN 100516018 C CN100516018 C CN 100516018C
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- China
- Prior art keywords
- group
- ester
- methyl
- compound
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000002148 esters Chemical class 0.000 title claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 22
- -1 acetate ethylidene ester Chemical class 0.000 claims description 108
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 77
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 57
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 39
- 229940067597 azelate Drugs 0.000 claims description 34
- 239000001301 oxygen Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 239000001361 adipic acid Substances 0.000 claims description 21
- 235000011037 adipic acid Nutrition 0.000 claims description 21
- WNLRTRBMVRJNCN-UHFFFAOYSA-N hexanedioic acid Natural products OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 21
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 18
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 12
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 206010000496 acne Diseases 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
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- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000029663 wound healing Effects 0.000 claims description 3
- 206010061217 Infestation Diseases 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000002831 pharmacologic agent Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 3
- 229920002554 vinyl polymer Polymers 0.000 claims 3
- 230000001035 methylating effect Effects 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 206010039796 Seborrhoeic keratosis Diseases 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
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- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 125000005042 acyloxymethyl group Chemical group 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 61
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- 239000002253 acid Substances 0.000 description 30
- TVIDDXQYHWJXFK-UHFFFAOYSA-N n-Dodecanedioic acid Natural products OC(=O)CCCCCCCCCCC(O)=O TVIDDXQYHWJXFK-UHFFFAOYSA-N 0.000 description 26
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 26
- 238000007738 vacuum evaporation Methods 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 17
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
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- 238000003756 stirring Methods 0.000 description 11
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- 239000000047 product Substances 0.000 description 10
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 description 9
- 229930040373 Paraformaldehyde Natural products 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 229920002866 paraformaldehyde Polymers 0.000 description 9
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- SNOFKGQEUYMNCE-UHFFFAOYSA-N 2,2,2-trifluoro-1-$l^{1}-oxidanylethanone Chemical compound [O]C(=O)C(F)(F)F SNOFKGQEUYMNCE-UHFFFAOYSA-N 0.000 description 7
- JHZWMBRFGLKQSH-UHFFFAOYSA-N methyl $l^{1}-oxidanylformate Chemical compound COC([O])=O JHZWMBRFGLKQSH-UHFFFAOYSA-N 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- XTBFPVLHGVYOQH-UHFFFAOYSA-N methyl phenyl carbonate Chemical compound COC(=O)OC1=CC=CC=C1 XTBFPVLHGVYOQH-UHFFFAOYSA-N 0.000 description 7
- 239000002674 ointment Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- TYFQFVWCELRYAO-UHFFFAOYSA-N Suberic acid Natural products OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 4
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 4
- 229940087004 mustargen Drugs 0.000 description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 description 2
- MTRYLAXNDGUFAK-UHFFFAOYSA-N 9-ethoxy-9-oxononanoic acid Chemical compound CCOC(=O)CCCCCCCC(O)=O MTRYLAXNDGUFAK-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明关于C6-14烷烃-二羧酸的酰氧甲基酯,或其生理学上允许的盐或酯,作为治疗或预防制剂用于药物中。
Description
本发明是关于某种双酯化合物,它们的制备和它们的应用,尤其是作为抗生素,通过局部、口服的或非肠胃的给药,或者在治疗癌症中的应用。
已知各种烷烃-二羧酸具有用于治疗和预防疾病中的生物特性。已知这种二羧酸的一个实例是直链烷烃-α,ω-二羧酸,如杜鹃花酸(C9H16O4-壬二酸或庚-1,7-二羧酸)。壬二酸的主要医学应用是治疗癌症,以20%霜剂形式局部施用(例如,从德国、柏林、Schering AG可获得)。
壬二酸的局部施用有助于使角质化正常,并降低丙酸杆菌痤疮的增生,即,呈现出抗炎和抗菌两种特性。然而,不像许多抗生素那样,它不诱发抗菌。
临床研究指出壬二酸具有其他的有利治疗效果。例如,在治疗丘疹浓疱(papulopustular rocasea)中,在治疗高色素沉着中,作为对表皮葡萄球菌和金黄色葡萄球菌的抗菌素,作为对白色念珠菌、光滑念珠菌(candida glabrata)、卵状糠疹癣菌和对发癣菌属的抗菌剂,和作为抗肿瘤剂或作为其他抗癌剂的细胞毒性增强剂,在治疗男性脱发中,等等,它是相当有效的。
然而,壬二酸在局部治疗痤疮中,其功效是相当低的(其理由是在商业中获得的霜剂,是以20%的很高浓度存在,而多数皮肤病霜剂含有不到5%的其活性成分),并有局部付作用,例如,灼烧感觉,也是常见的。
而且,壬二酸的生物吸收和生物排泄特性相当差。因此,局部给药只有剂量的约3.6%被吸收。而口服给药也只有约60%被吸收。而且所吸收的60%壬二酸也在12小时内随尿排出。
因此,对当前的壬二酸需要一种改进方式,尤其是这种方式能够降低所需要的剂量和/或治疗时间。
现已提出对于壬二酸和其他二羧酸药物化合物以酯类方式给药,然而,还没有报导这些酯类已证明具有有效特性,实际上,Wilkerson等人在Arch.Dermatol.126:252-253(1990)中,报导了壬二酸酯并不能对荷兰猪皮肤脱色。
我们惊奇地发现,相对于烷烃-二羧酸本身,烷烃-二羧酸双酯具有改进的特性。
双酯是用于含有酰氧甲氧羰基基团的化合物术语,并且这种化合物也称为缩醛酯。
从文献中已知壬二酸的一种双酯,在脱色组合物中作为对过氧化氢的活化剂-即二(1-(乙酰氧)乙基)-壬二酸酯(参看EP-A-125781和EP-A-122763)。然而,这种双酯并不描述为具有药物用途。
因此,本发明的一个方面是提供一种C6-14烷烃-二羧酸的酰氧甲基酯,或其生物学上允许的盐或酯,并在药物中用作治疗或预防制剂。
本发明的再一个方面是提供一种C6-14烷烃-二羧酸的酰氧甲基酯,而不是二(1-(乙酰氧)乙基)壬二酸酯,和其生物学上允许的盐和酯。
本文所用的酰基术语,是指通过氧-取代原子,优选是碳原子连接的基团,例如,羰基-连接基团。对羰基基团的原子α优选是碳,也可以是氧;即,“酰氧甲基”术语可包括烷氧羰基氧甲基。本发明的化合物中,酰基基团优选含有2~16个碳原子。
本发明所使用的烷烃-二羧酸是C6~C14的二羧酸,特别是C8~C10的二羧酸,尤其是C9的二羧酸。链接羰基基团的分子主键可以是直链的、支链的或环状的,或者它们的混合物,然而,特别优选的是n-烷烃-α-ω-二酸的酸,即,在直链(CH2)n基团的任何一端具有羧基基团。
因此,在优选实施方案中,本发明化合物是式I的化合物。
(式中,n是4~12,优选6,7或8,最优选是7的整数,
R1是氢,一个任意取代的,任意不饱和的C1-15烷基基团,或者,优选是-CHR3-O-CO-R2基团,
各个R2,单独地是一个任意取代的,任意不饱和的C1-15烷基或烷氧基基团,或者,与R3一起对其γ是2~5个主键原子的桥连基团,
和各个R3,单独地是氢,一个任意取代的,任意不饱和的C1-15烷基基团,一个R2-CO-O-基团,或与R2一起形成桥连基团,如上所定义的),和它们在生理学上允许的盐。
式I的化合物中,R2也可表示含有至多16个碳的芳香基、芳烷基、烷芳基、芳氧基、芳烷氧基或烷芳氧基(优选是芳基或芳烷基基团),例如,一个苯基、苄基,等基团。
式I化合物中的烷基基团,优选是C1-7,更好是C1-6的支链、直链、或环状的烷基基团,并可以任意取代的,例如,用1个或多个羟基基团,氧代基团、卤原子(例如,F或C1)、烷氧基团(例如,C1-6烷氧基团)、酰氧基(例如,C1-6烷酰氧基)基团、硫醇基团、氨基基团、芳香基团(例如,C9-10芳香基团)、烷基硫代(例如,C1-6烷基硫代)基团、烷氨基(例如,Cl-6烷氨基或N-(C1-6烷基)-C1-6-烷氨基)基团等进行取代。
R3基团的优选实例包括氢、甲基、乙基、丙基和桥连基团,尤其是氢和甲基。R2基团的优选实例包括甲基、乙基、丙基、丁基(例如,n-丁基或t-丁基)、戊基、苄基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、苄氧基、苯基和庚基。R1基团的优选实例包括C1-10烷基(尤其是甲基和乙基)和-CHR3-O-CO-R2基团,尤其是后者。
式I化合物中尤其好的为:n为7,8,9或10;R2为C2-6烷基或烷氧基或苯基;R3是H或甲基;和R1是CH3或CHR3OCOR2。
式I化合物的最佳实施例包括如下:
双[(乙酰氧基)甲基]己二酸酯
双[(三氟乙酰氧基)甲基]己二酸酯
双[(丙酰氧基)甲基]己二酸酯
双[(丁酰氧基)甲基]己二酸酯
双[(2,2-二甲基丙酰氧基)甲基]己二酸酯
双[(苯基乙酰氧基)甲基]己二酸酯
双[(硬脂酰氧基)甲基]己二酸酯
双[(甲氧羰氧基)甲基]己二酸酯
双[(乙氧羰氧基)甲基]己二酸酯
双[(苯基甲氧羰氧基)甲基]己二酸酯
双[1-(乙酰氧基)乙基]己二酸酯
双[1-(三氟乙酰氧基)乙基]己二酸酯
双[1-(丙酰氧基)乙基]己二酸酯
双[1-(丁酰氧基)乙基]己二酸酯
双[(2,2-二甲基丙酰氧基)乙基]己二酸酯
双[1-(苯基乙酰氧基)乙基]己二酸酯
双[1-(硬脂酰氧基)乙基]己二酸酯
双[1-(甲氧羰氧基)乙基]己二酸酯
双[1-(乙氧羰基)乙基]己二酸酯
双[苯甲酰氧基甲基]己二酸酯
双[己酰氧基甲基]己二酸酯
双[辛酰氧基甲基]己二酸酯
己二酸2,2-二甲基丙酰氧基甲基酯甲基酯
己二酸1-乙氧羰氧基-乙基酯甲基酯
双[(乙酰氧基)甲基]庚二酸酯
双[(三氟乙酰氧基)甲基]庚二酸酯
双[(丙酰氧基)甲基]庚二酸酯
双[(丁酰氧基)甲基]庚二酸酯
双[(2,2-二甲基丙酰氧基)甲基]庚二酸酯
双[(苯基乙酰氧基)甲基]庚二酸酯
双[(硬脂酰氧基)甲基]庚二酸酯
双[(甲氧羰氧基)甲基]庚二酸酯
双[(乙氧羰氧基)甲基]庚二酸酯
双[(苯基甲氧羰氧基)甲基]庚二酸酯
双[1-(乙酰氧基)乙基]庚二酸酯
双[1-(三氟乙酰氧基)乙基]庚二酸酯
双[1-(丙酰氧基)乙基]庚二酸酯
双[1-(丁酰氧基)乙基]庚二酸酯
双[(2,2-二甲基丙酰氧基)乙基]庚二酸酯
双[1-(苯基乙酰氧基)乙基]庚二酸酯
双[1-(硬脂酰氧基)乙基]庚二酸酯
双[1-(甲氧羰氧基)乙基]庚二酸酯
双[1-(乙氧羰氧基)乙基]庚二酸酯
双[1-(苯基甲氧羰氧基)乙基]庚二酸酯
双[苯酰氧基甲基]庚二酸酯
双[己酰氧基甲基]庚二酸酯
双[辛酰氧基甲基]庚二酸酯
庚二酸2,2-二甲基丙酰氧基甲基酯甲基酯
庚二酸1-乙氧羰氧基-乙基酯甲酯
双[(乙酰氧基)甲基]辛二酸酯
双[(三氟乙酰氧基)甲基]辛二酸酯
双[(丙酰氧基)甲基]辛二酸酯
双[(丁酰氧基)甲基]辛二酸酯
双[(2,2-二甲基丙酰氧基)甲基]辛二酸酯
双[(苯基乙酰氧基)甲基]辛二酸酯
双[(硬脂酰氧基)甲基]辛二酸酯
双[(甲氧羰氧基)甲基]辛二酸酯
双[(乙氧羰氧基)甲基]辛二酸酯
双[(苯基甲氧羰氧基)甲基]辛二酸酯
双[1-(乙酰氧基)乙基]辛二酸酯
双[1-(三氟乙酰氧基)乙基]辛二酸酯
双[1-(丙酰氧基)乙基]辛二酸酯
双[1-(丁酰氧基)乙基]辛二酸酯
双[(2,2-二甲基丙酰氧基)乙基]辛二酸酯
双[1-(苯基乙酰氧基)乙基]辛二酸酯
双[1-(硬脂酰氧基)乙基]辛二酸酯
双[1-(甲氧羰氧基)乙基]辛二酸酯
双[1-(乙氧羰氧基)乙基]辛二酸酯
双[1-(苯基甲氧羰氧基)乙基]辛二酸酯
双[苯甲酰氧基甲基]辛二酸酯
双[己酰氧基甲基]辛二酸酯
双[辛酰氧基甲基]辛二酸酯
辛二酸2,2-二甲基丙酰氧基甲基酯甲基酯
辛二酸1-乙氧羰氧基-乙基酯甲基酯
双[(乙酰氧基)甲基]壬二酸酯
双[(三氟乙酰氧基)甲基]壬二酸酯
双[(丙酰氧基)甲基]壬二酸酯
双[(丁酰氧基)甲基]壬二酸酯
双[(2,2-二甲基丙酰氧基)甲基]壬二酸酯
双[(苯基乙酰氧基)甲基]壬二酸酯
双[(硬脂酰氧基)甲基]壬二酸酯
双[(甲氧羰氧基)甲基]壬二酸酯
双[(乙氧羰氧基)甲基]壬二酸酯
双[(苯基甲氧羰氧基)甲基]壬二酸酯
双[1-(乙酰氧基)乙基]壬二酸酯
双[1-(三氟乙酰氧基)乙基]壬二酸酯
双[1-(丙酰氧基)乙基]壬二酸酯
双[1-(丁酰氧基)乙基]壬二酸酯
双[(2,2-二甲基丙酰氧基)乙基]壬二酸酯
双[1-(苯基乙酰氧基)乙基]壬二酸酯
双[1-(硬脂酰氧基)乙基]壬二酸酯
双[1-(甲氧羰氧基)乙基]壬二酸酯
双[1-(乙氧羰氧基)乙基]壬二酸酯
双[1-(苯基甲氧羰氧基)乙基]壬二酸酯
双[苯甲酰氧基甲基]壬二酸酯
双[己酰氧基甲基]壬二酸酯
双[辛酰氧基甲基]壬二酸酯
壬二酸2,2-二甲基丙酰氧基甲基酯甲基酯
壬二酸1-乙氧羰氧基-乙基酯甲基酯
双[(乙酰氧基)甲基]癸二酸酯
双[(三氟乙酰氧基)甲基]癸二酸酯
双[(丙酰氧基)甲基]癸二酸酯
双[(丁酰氧基)甲基]癸二酸酯
双[(2,2-二甲基丙酰氧基)甲基]癸二酸酯
双[(苯基乙酰氧基)甲基]癸二酸酯
双[(硬脂酰氧基)甲基]癸二酸酯
双[(甲氧羰氧基)甲基]癸二酸酯
双[(乙氧羰氧基)甲基]癸二酸酯
双[(苯基甲氧羰氧基)甲基]癸二酸酯
双[1-(乙酰氧基)乙基]癸二酸酯
双[1-(三氟乙酰氧基)乙基]癸二酸酯
双[1-(丙酰氧基)乙基]癸二酸酯
双[1-(丁酰氧基)乙基]癸二酸酯
双[(2,2-二甲基丙酰氧基)乙基]癸二酸酯
双[1-(苯基乙酰氧基)乙基]癸二酸酯
双[1-(硬脂酰氧基)乙基]癸二酸酯
双[1-(甲氧羰氧基)乙基]癸二酸酯
双[1-(乙氧羰氧基)乙基]癸二酸酯
双[1-(苯基甲氧羰氧基)乙基]癸二酸酯
双[苯甲酰氧基甲基]癸二酸酯
双[己酰氧基甲基]癸二酸酯
双[辛酰氧基甲基]癸二酸酯
癸二酸2,2-二甲基丙酰氧基甲基酯甲基酯
癸二酸1-乙氧羰氧基-乙基酯甲基酯
双[(乙酰氧基)甲基]十一烷二酸酯
双[(三氟乙酰氧基)甲基]十一烷二酸酯
双[(丙酰氧基)甲基]十一烷二酸酯
双[(丁酰氧基)甲基]十一烷二酸酯
双[(2,2-二甲基丙酰氧基)甲基]十一烷二酸酯
双[(苯基乙酰氧基)甲基]十一烷二酸酯
双[(硬脂酰氧基)甲基]十一烷二酸酯
双[(甲氧羰氧基)甲基]十一烷二酸酯
双[(乙酰羰氧基)甲基]十一烷二酸酯
双[(苯基甲氧羰氧基)甲基]十一烷二酸酯
双[1-(乙酰氧基)乙基]十一烷二酸酯
双[1-(三氟乙酰氧基)乙基]十一烷二酸酯
双[1-(丙酰氧基)乙基]十一烷二酸酯
双[1-(丁酰氧基)乙基]十一烷二酸酯
双[(2,2-二甲基丙酰氧基)乙基]十一烷二酸酯
双[1-(苯基乙酰氧基)乙基]十一烷二酸酯
双[1-(硬脂酰氧基)乙基]十一烷二酸酯
双[1-(甲氧羰氧基)乙基]十一烷二酸酯
双[1-(乙氧羰氧基)乙基]十一烷二酸酯
双[1-(苯基甲氧羰氧基)乙基]十一烷二酸酯
双[苯甲酰氧基甲基]十一烷二酸酯
双[己酰氧基甲基]十一烷二酸酯
双[辛酰氧基甲基]十一烷二酸酯
十一烷二酸2,2-二甲基丙酰氧基甲基酯甲基酯
十一烷二酸1-乙氧羰氧基-乙基酯甲酯
双[(乙酰氧基)甲基]十二烷二酸酯
双[(三氟乙酰氧基)甲基]十二烷二酸酯
双[(丙酰氧基)甲基]十二烷二酸酯
双[(丁酰氧基)甲基]十二烷二酸酯
双[(2,2-二甲基丙酰氧基)甲基]十二烷二酸酯
双[(苯基乙酰氧基)甲基]十二烷二酸酯
双[(硬脂酰氧基)甲基]十二烷二酸酯
双[(甲氧羰氧基)甲基]十二烷二酸酯
双[(乙氧羰氧基)甲基]十二烷二酸酯
双[(苯基甲氧羰氧基)甲基]十二烷二酸酯
双[1-(乙酰氧基)乙基]十二烷二酸酯
双[1-(三氟乙酰氧基)乙基]十二烷二酸酯
双[1-(丙酰氧基)乙基]十二烷二酸酯
双[1-(丁酰氧基)乙基]十二烷二酸酯
双[(2,2-二甲基丙酰氧基)乙基]十二烷二酸酯
双[1-(苯基乙酰氧基)乙基]十二烷二酸酯
双[1-(硬脂酰氧基)乙基]十二烷二酸酯
双[1-(甲氧羰氧基)乙基]十二烷二酸酯
双[1-(乙氧羰氧基)乙基]十二烷二酸酯
双[1-(苯基甲氧羰氧基)乙基]十二烷二酸酯
双[苯甲酰氧基甲基]十二烷二酸酯
双[己酰氧基甲基]十二烷二酸酯
双[辛酰氧基甲基]十二烷二酸酯
十二烷二酸2,2-二甲基丙酰氧基甲基酯甲基酯,和
十二烷二酸1-乙氧羰氧基-乙基酯甲基酯。
本发明的化合物或本发明中使用的化合物,可利用现有技术中公知的标准方法和工艺进行制备,以衍生多功能的化合物,最好是酯化,更好是形成酰氧甲基酯。
正如文献中所知的,化合物的酯化需要涉及到适当基团的保护和脱保护,如,使用McOmie在Plenum 1973“Protective Groups in Organic Chemistry”中,和T.W.Greene在Wiley-Inter science 1981“Protective Groups in OrganicChemistry”中所描述的技术。根据本发明制备二羰酸双酯的原料通常是相应的二羰酸或它们的衍生物。现有技术中已知的二羰酸或其衍生物的一些实例和适用于作为合成本发明双酯的原料包括:
己二酸
庚二酸
辛二酸
壬二酸
癸二酸
十一烷二酸
十二烷二酸
1,11-十一烷二羧酸,和
1,12-十二烷二羧酸,所有这些都可从商业上通过Sigma-Aldrich获得。
在合成本发明的二羧酸中用作中间物的某些二羧酸衍生物,包括:
己二酸单甲酯
己二酸单乙酯
辛二酸单甲酯
壬二酸单甲酯,和
癸二酸单甲酯(所有这些都可通过Sigma-Aldrich获得),
壬二酸二铯盐(参看Cimecioglu等人,Makromol.Chem.Rapid Commun.10:319-324(1989)),和
壬二酸单乙酯
本发明的再一方面是提供一种制备本发明化合物的方法,所述方法包括:使C4-12烷烃-二羧酸,或其盐,或其酯,与酰氧甲基化剂进行反应。
酰氧甲基化剂的实例包括式II化合物
R2-CO-O-CHR3-X (II)
式中R2和R3定义如上,X是离去基团,例如,卤原子、羟基基团、磺酸酯基团,等。
式II的化合物优选与二羧酸的盐反应,例如,铯盐与其中一个羧基基团处于保护形式(例如,被酯化)的二羧酸反应,或者,与其中一个或两个羧基基团处于被活化形式(例如,酰基卤形式)的二羧酸反应。
因此,例如,式II化合物可与式III化合物反应
(式中,R1和n定义如上,R4是羟基或卤基团),或与其盐反应。
反应通常是在溶剂或溶剂混合物中进行,溶剂例如,丙酮、二乙醚、二甲基甲酰胺、二甲基亚砜等。在混合物沸点的温度下,优选在室温下进行。酯化反应的条件取决于所用的试剂,选择的条件要使双酯获得最大产额。
正如早期提到的,本发明的化合物,或根据本发明化合物的应用,优选以医学上可接受的盐形式。如果本发明的化合物具有一个或多个碱性基团,这种盐可以是具有生理学上可接受的有机酸或无机酸的酸加成盐。或者可以是具有生理学上可接受的有机碱或无机碱的碱加成盐。通常适宜酸包括氢氯酸、氢溴酸、乳酸、柠檬酸、甲烷磺酸、马来酸、富马酸、和硬酯酸。通常适宜的碱包括氢氧化钠、氢氧化钾、氢氧化钙,和葡甲胺。
在科技文献和专利文献中,已详尽描述了盐的形成工艺。
正如上所述,本发明的化合物和根据本发明的应用,它们的盐类具有有价值的药理特性。该化合物可用于治疗痤疮、rocasea(红斑痤疮)、高度色素沉着、伤口愈合、光化性角化病、基细胞癌和其他皮肤疾病。尤其是该化合物在光动力治疗后,可用于延缓或预防基细胞癌的复发。该化合物也可用于治疗细菌、病毒和真菌的感染,并还可以用于治疗或预防癌症。
因此本发明的再一方面是提供一种对使用C6-14烷烃-二羧酸药物治疗易于具有敏感症状的人类或非人类动物(例如,哺乳类动物)的治疗方法,其改进包括对所述主体以一种酰氧甲基酯形式的有效量的所述药物进行给药。
本发明的再一方面是提供一种C6-14烷烃-二羧酸药物的酰氧甲基酯,或其盐或其酯的应用,它用于制造药剂以用于对使用所述二羧酸药物,具有易于敏感症状的人类或非人类动物(例如哺乳类动物)的治疗方法中。
根据现有技术中的已知技术,本发明的组合物,可以通常的方式,用一种或多种生理学上可接受的载体或赋形剂进行配制。因此本发明的又一方面是提供一种药物组合物,该组合物包括C6-14烷烃-二羧酸的酰氧甲基酯或一种生理学上允许的盐或酯,与至少一种药物学的载体或赋形剂一起配制。
适宜时,本发明的组合物在与载体或赋形剂配合之前或之后可进行灭菌,例如利用γ辐射,强行过滤(strike filtration)、高压釜蒸或加热灭菌。
本发明的化合物还可与其他的药物活性的物质一起配制。这种物质的选择取决于组合物的适应症。治疗痤疮的组合物,可以将一种或多种本发明的化合物与以下物质一起配制,即,例如,过氧化苯甲酰、氯洁霉素、维A酸、红霉素、四环素、阿达帕林、他佐罗汀、亚磺酰胺(sulfectamide)或其他抗痤疮试剂。用于治疗红斑痤疮的组合物,可以将一种或多种本发明的化合物与其他对治疗红斑痤疮的有效化合物一起配制,例如,四环素或甲硝唑。用于治疗高度色素沉着的组合物,可将一种或多种本发明的化合物的混合物与乙醇酸、氢醌,或其他对皮肤高度色素沉着有效试剂一起进行配制。
治疗感染(例如,细菌、真菌和病毒感染)的组合物,除了一种或多种本发明的化合物外,可含有其他的药物活性的抗感染制剂,例如,用于治疗细菌感染的组合物可含有青霉素、头孢菌素、肽抗菌素、大环内酯抗菌素、抗细菌磺酰胺、万古霉素或其他抗细菌制剂,例如以下文献中描述的化合物:Norrby,R.的Expert Opin.Pharmacother.2001,2,293-302;Wada,K,等人的Nippon Rinsho 2001,59,790-94;Grandi,G,的Trends Biotechnol,2001,19,181-88;Guay,D.R.的Drugs 2001,61,353-64;Kopp-Hoolihan.L.的J.AmDiet.Assoc.2001,101,229-38和239-41;Robert.P.Y.等人的Prugs 2001,61,175-85;Fulton,B.等人的Paediatr.Drugs 2001,3,137-58;Bhanot,S.K.等人的Curr.Pharm.Des.2001,7,311-35;Krasemann,C,等人的Clin,Infect Dis.2001,32增补版S51-63;Bush,K等人的Curr.Opin.Investig.Drugs 2000,1,22-30;Bubin.B.K等人的Curr.Opin Investig,Drug 20001,169-72;Leung.W.K.等人的Expert Opin.Pharmacother.2001,1,507-14;Periti,P.的Expert.Opin.Pharmacother.2000,1,1203-17;Anonymus的Nat.Biotechnol,2000,18增补版,IT24-6;Dbaibo,G.S.的J.Med.Liban,2000,48,177-81;Muller,M等人的Cell.Mol.Life Sci.1999,56,280-5;Gray,C.P.等人的Cell Mol.Life Sci.1999,56,779-87;Bax,R等人的Int.J.Antimicrob.Agents 2000,16,51-9和Bush.K.等人的Curr.Opin.Chem.Biol.2000,4,433-9或其中的参考文献。
用于治疗真菌感染的本发明组合物可以含有以下物质,例如,制霉素、amphothericin、灰黄霉素、咪唑衍生物和三唑衍生物、如氯三氨唑、微那唑(micronazole)、益康唑、酮康唑、和联苯苄唑,和其他试剂,例如以下文献中所描述的抗真菌制剂:Espinel-Ingroff,A.等人的Mycopathologica 2001,150,101-15;Yang,Y.L.等人的J.Microbiol.Immunol.Infect.2001,34,79-86;Willems,L.等人的J.Clin.Pharm.Ther.2001,26,159-69;Worthen,D.R.等人的Drug De v.Ind.Pharm.2001,27,277-86;Dupont,B.的Rev.Prat.2001,51,752-7;Kauffman,C.A.的AIDS Patient Care STDS II增补版1,S18-21中;Rex,J.H.等人的Clin.Infect.Dis.2001,32,1191-2000中;Hann,I.M.等人的Int.J.Antimicrob.Agents 2001,17,161-9中;Arikan,S.等人的Curr.Pharm.Des.2001,7,393-415中;Kroting,H.C.等人的Hautarzi 2001,52,91-7;Fringuelli,R.等人的J.Chemothe r.2001,13,9-14;Anonymous的Nat.Biotechnol.2000,18,Suppl.IT 24-6;Ellepola,A.N.等人的Dent.Update 2000,27,165-70和172-4;Ellepola,A.N.等人的Dent.Update 2000,27,111-2和114-6;Neely,M.N.等人的Eur.J.Microbiol.Infect.Dis.2000,19,897-914;Walsh,T.J.等人的Med.Mycol.2000,38,Suppl.1,335-47;Graybill,J.R.等人的Med.Mycol.2000,38,Suppl.1,323-33和Fingquelievich,J.L.等人的Med.Mycol.2000,38 Suppl.1,317-22或其中的文献。
用于治疗病毒感染的本发明组合物,例如可含有治疗DNA病毒或RNA病毒的制剂。可含于本发明组合物中的通常化合物可以是无环鸟苷、丙氧鸟苷、伐昔洛韦、三唑核苷、磷卡萘、蛋白酶抑制剂,如塞喹努佛、吲哚那韦、利托那韦和奈非那韦、逆向转录酶抑制剂,如叠氮胸苷、双脱氧腺苷、助昔他平(zulcitabine)、司他夫定、拉米夫定(lamivudine)、阿巴加韦(abakavir)、奈韦拉平和埃他维来兹(etavirenze)和神经酰胺酶抑制剂,如札那米韦或其他抗病毒制剂,例如以下文献中描述的制剂:Delaney,W.E.等人的Antivir.Chem.Chemother,2001,12,1-35;Nuss,N.等人的Antivir.Ther.2001,6,1-7;Roberts,N.A.等人的Prog.Drug Res.2001,56,195-237;Field,H.J.的J.Clin.Virol.2001,21,261-9;Bowers,M.的BETA 1996,Jun 19-22;Mediratta,P.K.等人的Indian J.Med.Sci.2000,54,485-90;Fleming,D.M.的Int.J.Clin.Pract.2001,55,189-35;Mahalingam,S.等人的Bioessays 2001,23,428-35;Nabel.G.J.的Nature2001,410(6831),1002-7;Lever,A.M.的Sex Transm.Infect.2001,77,93-6;McClellan等人的Drugs 2001,61,263-843和Brown,T.J.等人的Dermatol.Clin.2001,19,23-34和其中的文献。
用于治疗和预防有关癌症疾病的组合物,例如可将一种或多种本发明的化合物与用于治疗或预防癌症的其他制剂一起配制。用于治疗癌症的典型物质。例如可以是烷基化剂,例如环磷酰胺、苯丁酸氮芥、萃丙氨酸氮芥、异环磷酰胺、苏消安、替旦帕(tiotepa)、卡氮芥、约氮芥、福泰氮芥、替莫唑胺,抗代射物,例如甲氨蝶呤、雷替曲塞、巯嘌呤、克劳里平(clodribine)、氟达那苷、阿糖胞苷、氟尿嘧啶、双氟去氧胞苷、植物生物碱和其他天然制品,如长春碱、长春新碱、长春烯碱、鬼臼乙叉甙、帕克里他赛(paclitaxel)、多西他赛、细胞毒性抗菌素,如达克汀诺霉素(daktinomycine)、阿霉素、柔红霉素、表阿霉素、去甲柔毛霉素、米托蒽醌、博来霉素、普卡霉素、丝裂霉素和其他细胞毒性试剂,例如顺铂、碳铂、胺苄吖啶、六甲嘧胺、磷次氮芥、拓朴替康、伊立替康、佛坦波芬(verteporfine)、激素、类激素物质和以下文献中描述的其他物质:Stachel,S.J.等人的Curr.Pharm.Des.2001,7,1277-90;Guertitte,F.的Curr.Pharm.Des.2001,7,1229-1249;de Groot,F.M.等人的Curr.Med.Chem.2001,8,1093-1122;Sebti,S.M.等人的Oncogene 2000,19,6584-93;Ramirez De Molina,A.等人的Int.J.Oncol.2001,19,5-17;Crul,M.等人的Anticancer Drugs 2001,12,163-84;Chamberlain,R.S.等人的ExpertOpin.Pharmacother.2000,1,603-14;Rowley,P.T.等人的Anticancer Res.2000,20,4419-29;Schirner,M.的Cancer Metastasis Rev.2000,19,67-73;Hofman,J.的Rev Physiol.Biochem.Pharmacol.2001,142,1-96;Goss,P.E.等人的J.Clin.Oncol.2001,19,881-94;Hadi,S.M.等人的IUBMB Life 2000,50,167-71;Perry,P.J.等人的Expert Opin.Investig.Drugs 1999,8,1981-2008;Koki,A.T.等人的Expert Opin,Investig.Drugs 1999,8,1623-1638和Kushner,D.M.等人的Curr.Oncol.Rep.2000,2,23-30以及其中的参考文献。
可以包含在本发明组合物中的用于预防癌症的代表性物质,例如可以是维生素E,及其它具有抗氧化特性的制剂以及COX-2抑制剂。
本发明的组合物,可根据症状以及所择的一种或多种物质,而局部、口服、肠胃或全身地给药。
组合物可采用以肠胃或非肠胃给药的形式提供,例如,以肠胃给药的组合物可以是活性成分任选地和一种或多种惰性通用载体一起形成的平片或包衣片,持续释放片、软胶囊、硬胶囊、栓剂、悬浮剂和溶液。
用非肠胃给药的组合物,例如可以配制成皮内、皮下、腹腔和静脉注射或输液剂。其他的非肠胃组合物包括用于局部给药的组合物,包括用于既可对皮肤又可对粘膜给药的组合物以及对头发给药的组合物。这种局部给药的组合物包括凝胶、霜剂、油膏、洗发剂、肥皂、喷液、洗液、软膏、气溶胶和其他用于局部的药物制剂。
所有的组合物可任选地与一种或多种惰性载体和/或稀释剂一起配制,例如,水、水/乙醇、乙醇、水/甘油、聚乙二醇、氯化钠、葡萄糖、蔗糖、乳糖、玉米淀粉、微晶纤维素、山梨糖醇、硬脂酸镁、醇类、聚乙烯吡咯烷酮、脂肪酸、脂肪、脂肪蜡、EDTA和氯化钙。
此外组合物还可添加包括润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、甜味剂、调味剂和吸收增强剂。
组合物可以是以微乳剂、纳米颗粒、微球、尼奥体(niosomes)或脂质体的形式。
组合物最好是使其中的药物处于非水性环境中(例如,油膏)。
如上所述,组合物中的活性化合物浓度,取决于以下几种因素,即,给药方式,化合物的化学性质,临床状况和病人的状况。因此,浓度可在很大的范围内变化。然而,一般适宜的活性剂浓度范围为0.005~100%,例如0.01~70%,商业上为0.05~50%,但优选是0.1~20%(w/w)。根据本发明,具有高浓度二羧酸双酯(>10%)的代表性组合物包括口服制剂,如胶囊或片剂,而其他形式的组合物通常的活性化合物的浓度较低(<10%)。
根据本发明的组合物优选是一种易于使用的形式,然而,也可以使用浓缩物和套合。这种套合可包括2个或多个容器,例如,
a)第一个容器含有二羧酸双酯或其药物学上允许的盐,和
b)第二个容器含有在使用前用于溶解或分散第一容器中所含物的溶剂。
这种套合制剂一般可用于当组合物中的二羧酸双酯或其他药物学活性物质在准备使用的制剂中是不稳定时(例如,贮存期限小于6个月,或优选小于12个月)。
可以认为,以酰氧甲基酯形式存在,是有利于其他二羧酸药剂物质,尤其是具有经皮肤摄取差或随尿快速排泄的那些二羧酸药剂物质。并认为本发明可以扩展到其他的二羧酸药剂物质,特别是烷烃、氮杂烷烃、硫杂烷烃和氧杂烷烃的二羧酸。
按以下非限定性实施例,更详细地描述本发明。
氯甲酯原料的合成
新戊酸氯甲基酯和1-氯乙基乙基新戊酸酯可从市场上购得。其他的氯甲基酯,可通过仲甲醛与酰基氯反应而进行合成。
实施例A
苯甲酸氯甲基酯的合成
在120℃下,加热苄基氯(14.05g,0.10mol)和仲甲醛(3.6g,0.12mol),直到仲甲醛消失为止(约2小时)。将反应混合物真空蒸馏,得到无色油状的苯甲酸氯甲基酯(b.p.116℃,10mbar)。1H-NMR(CDCl3)δ8.18-7.46(m,5H),6.00(s,2H)。13C-NMR(CDCl3)δ133.89,131.36,130.01,128.91,128.54,69.21。
实施例B
丁酸氯甲基酯的合成
在120℃下,加热丁酰氯(10.65g,0.10mol)和仲甲醛(3.60g,0.12mol),直到仲甲醛消失为止(约2小时)。将反应混合物真空蒸馏,得到无色油状的氯甲基丁酸酯(b.p.90℃,25mbar)。1H-NMR(CDCl3)δ5.67(s,2H),2.37-2.29(m,2H),1.64-1.58(m,2H),1.26(s,8H)。
实施例C
己酸氯甲基酯的合成
将亚硫酰氯(14.27g,0.12mmol)滴加到己酸(11.61g,0.10mmol)中,70℃下加热反应混合物24小时。含有己酰氯的反应混合物不必再净化,加入仲甲醛(3.60g,0.12mol),并在120℃下加热该反应混合物,直到仲甲醛消失(约2小时)。真空蒸馏该反应混合物,得无色油状的己酸氯甲基酯(b.p.118℃,25mbar)。1H-NMR(CDCl3)δ5.67(s,2H),2.37-2.29(m,2H),1.65-1.58(m,2H),1.31-1.26(m,4H),0.88(t,3H)。13C-NMR(CDCl3)δ179.89,171.77,68.53,33.95,31.18,24.34,22.26,13.83。
实施例D
辛酸氯甲基酯的合成
将辛酰氯(16.26g,0.10mol)和仲甲醛(3.6g,0.12mol),120℃下,加热到仲甲醛消失为止(约2小时),真空蒸馏该反应混合物,得到无色油状辛酸氯甲基酯(b.p.140℃,25mbar)。1H-NMR(CDCl3)δ5.67(s,2H),2.37-2.29(m,2H),1.64-1.58(m,2H),1.26(s,2H),0.84(t,3H)。13C-NMR(CDCl3)δ171.75,162.30,68.51,33.94,31.55,28.97,28.85,28.80,24.64,24.50,22.52,13.98。
实施例E
2-氯乙酸己基酯的合成
将在CH2Cl2(10ml)中的氯乙酰氯(2.48g,22.00mmol)滴加到己-1-醇(2.04g,20.00mmol)和三乙胺(2.22g,22.00mmol)的CH2Cl2(25ml)的溶液中,室温下搅拌反应混合物3小时,真空蒸发,然后用二乙醚(25ml)稀释。用饱和NaHCO3(3×10ml)洗涤有机层,用MgSO4干燥,并过滤。真空蒸发,得到红色油状产物。1H-NMR(CDCl3)δ4.01(s,2H),1.63-1.53(m,2H),1.28-1.13(m,8H),0.85(t,3H)。13C-NMR(CDCl3)δ167.36,66.36,40.86,31.28,28.36,25.36,22.43,13.88。
用于合成链烷双酸酯的一般工艺
将Cs2CO3·NaI(作为催化剂)和链烷双酸的THF的不均匀溶液,在60℃下搅拌半小时。再将氯代烷酯的THF溶液滴加到溶液中,并在60℃下搅拌48小时。将反应混合物冷却到室温下,真空蒸发并向残留物中加入二乙醚。用饱和NaHCO3洗涤有机层,过滤,并用MgSO4干燥。真空蒸发得到所要的产物。
实施例1
双[[(2,2-二甲基丙酰基)氧]甲基]壬二酸酯(化合物I)
将碳酸铯(32.6g,0.120mol)添加到壬二酸(9.4g,50.0mmol),新戊酸氯甲基酯(15.1g,0.10mmol),和NaI(0.5g,3.3mmol)的无水N,N-二甲基甲酰胺(50ml)的搅拌溶液中。在氩气环境中,约40℃(浴温)下,将混合物搅拌2天。并在约35℃(浴温)和5-1mmHg下蒸发掉过量的溶剂,将残留物溶解在水(50ml)和二乙醚(25ml)中,用乙醚(1×15ml)萃取水相部分,用饱和的NaCl溶液(1×10ml)洗涤合并的乙醚溶液,并干燥(Na2SO4)。在抽成0.2mmHg真空后,过滤并蒸发留下12.34g(59%)。1H-NMR(200MHz,CDCl3):δ1.20(20H,s),1.32(4H,s),1.63(4H,m),2.35(4H,t,J=7.4Hz),5.76(4H,d,J=2.8Hz)。13C-NMR(50MHz,CDCl3):δ24.58,26.84,28.80,29.01,33.92,38.73,79.22,164.87,172.29,MS(ES):439.3[M+Na]+。
实施例2
含化合物I的霜剂
实施例3
由实施例2的霜剂进行临床试验
症状:红斑痤疮
一个47岁的男性病人,在面部(位于眼下和鼻子周围的大于20cm2面积)具有20年的红斑痤疮历史,每天二次(早和晚)给药10%霜剂(实施例2)。2-3天后,症状减轻,经1个星期的治疗,病人完全消失了视觉症状。病人继续使用2%霜剂每2-3周一次,9个月后,就完全消除症状。病人以前使用口服土霉素胶囊和1%甲硝痤软膏,没有主要的临床效果。
实施例4
由实例2霜剂的临床试验
症状:伤口愈合
一个77岁的男性老病人,在前额和头发处具有几处伤痕和极干的皮肤,试用不同的润肤霜,没有任何痊愈迹象。每天用2%霜剂(实施例2)治疗,一星期后,观察病人,皮肤已正常化,只留下2处伤痕,观察病人在治疗区域出现了新生长的头发。
实施例5
含化合物I的油膏
使用研钵和研杵,通过混合化合物I和无水油膏基剂,制备含有10%wt实施例1的化合物I的油膏。
实施例6
双[[2,2-二甲基丙酰基]氧甲基]十二烷二酸酯的合成
在60℃下,将Cs2CO3(13.03g,40mmol)、NaI(200mg,1.3mmol)和十二烷二酸(4.60g,20mmol)的THF(40ml)不均匀溶液搅拌半小时。向该溶液中滴加新戊酸氯甲基酯(6.02g,40mmol)的THF溶液(10ml),60℃下搅拌48小时。将反应混合物冷却到室温,并真空蒸发。加入二乙醚(50ml),用饱和的NaHCO3(3×25ml)洗涤残留物,用MgSO4干燥,并过滤。真空蒸发,得到无色油状产物(5.13g,56.0%)。MS(ES):481.4[M+Na]+。1H-NMR(CDCl3)δ5.95(s,4H),2.51-2.47(m,4H),1.58-1.52(m,4H),1.21-1.15(m,30H)。13C-NMR δ176.30,172.50,79.13,38.69,33.91,29.26,28.87,26.76,25.54,24.61。
实施例7
双[1-[乙氧羰氧基]-乙基]壬二酸酯的合成
60℃下,将Cs2CO3(13.03g,40mmol)、NaI(200mg,1.3mmol)和壬二酸(3.76g,20mmol)在THF(40ml)中的不均匀溶液,搅拌半小时。向该溶液中滴加氯乙基乙基碳酸酯(6.10g,40mmol)的THF(10ml)溶液,60℃下搅拌48小时。将反应混合物冷却到室温,并真空蒸发,加入二乙醚(50ml),用饱和的NaHCO3(3×25ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发,得到黄色油状产物(3.83g,45.6%)。1H-NMR(CDCl3)δ6.39(q,2H),4.26-4.16(m,4H),2.31-2.25(m,4H),1.55-1.58(m,4H),1.46(d,2H),1.32-1.18(m,12H),13C-NMR(CDCl3)δ178.35,171.63,152.97,91.08,64.89,33.91,28.75,24.53,19.49,14.04。
实施例8
双-[[1-乙氧基羰氧基]乙基]十二烷二酸酯的合成
在60℃下,将Cs2CO3(13.03g,40mmol)、NaI(200mg,1.3mmol)和十二烷二酸(4.60g,20mmol)在THF(40ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加1-氯乙基乙基碳酸酯(6.10g,40mmol)的THF(10ml)溶液,60℃下搅拌48小时。使反应混合物冷却到室温,并真空蒸发,加入二乙醚(50ml),用饱和的NaHCO3(3×25ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发,得到黄色油状产物(4.25g,47.5%)。1H-NMR(CDCl3)δ8.39(q,2H),6.27-6.10(m,4H),4.35-4.24(m,4H),3.60-3.57(4H),3.46-3.43(d,6H),3.32-3.22(m,18H)。
实施例9
壬二酸2,2-二甲基-丙酰氧甲基酯甲酯的合成
60℃下,将Cs2CO3(1.30g,40mmol)、NaI(30mg,0.20mmol)和壬二酸单甲酯的在THF(15ml)中的不均匀溶液搅拌半小时。并向该溶液滴加新戊酸氯甲基酯(0.60g,4.0mmol)的THF(5ml)溶液,60℃下搅拌48小时。使反应混合物冷却到室温,真空蒸发,加入二乙醚(25ml),用饱和的NaHCO3(3×15ml)洗涤残留物,并用MgSO4干燥并过滤。真空蒸发得到无色油状产物(0.85g,67.5%)。1H-NMR(CDCl3)δ5.74(s,2H),3.66(s,3H),2.38-2.26(m,4H),1.63-1,56(m,4H),1.31(s,6H),1.21(s,9H)。13C-NMR(CDCl3)δ177.05,174.06,172.23,79.19,51.33,38.63,33.90,33.82,28.78,28.72,28.64,26.74,24.73,24.47。
实施例10
壬二酸1-(乙氧羰氧基)-乙基酯甲酯的合成
60℃下,将Cs2CO3(1.30g,4.0mmol)、NaI(30mg,0.20mmol)和壬二酸单甲酯(0.95g,4.0mmol)在THF(15ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加1-氯乙基乙基碳酸酯(0.61g,4.0mmol)的THF(5ml)溶液,60℃下搅拌48小时,使反应混合物冷却到室温,真空蒸发。加入二乙醚(25ml),用饱和的NaHCO3(3×25ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发得到无色油状产物(0.96g,75.1%)。1H-NMR(CDCl3)δ6.74(q,1H),4.19(q,2H),3.64(s,3H),2.34-2.24(m,4H),1.63-1.53(m,4H),1.49(d,2H),1.33-1.24(m,9H),13C-NMR(CDCl3)δ174.55,172.04,162.92,153.39,91.48,64.75,51.79,36.85,34.37,31.78,29.24,25.19,24.82,19.09,14.48。
实施例11
双(苯甲酰基氧甲基)壬二酸酯的合成
60℃下,将Cs2CO3(3.25g,10.00mmol)、NaI(50mg,0.33mmol)和壬二酸(0.94g,5.00mmol)在THF(20ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加氯甲基苯甲酸酯(1.70g,10mmol)的THF(10ml)溶液,60℃下搅拌48小时,使反应混合物冷却到室温并真空蒸发。加入二乙醚(25ml),用饱和的NaHCO3(3×15ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发得到白色固体产物(1.76g,77.2%)。1H-NMP(CDCl3)δ8.09-7.39(m,10H),5.97(s,4H),2.37-2.29(m,4H),1.61-1.56(m,4H),1.28-1.25(m,6H),13C-NMR(CDCl3)δ172.65,165.20,133.63,130.01,128.92,128.44,79.71,33.84,28.70,28.65,24.42。
实施例12
双(丁酰基氧甲基)壬二酸酯的合成
60℃下,将Cs2CO3(2.60g,8.00mmol)、NaI(30mg,0.20mmol)和壬二酸(0.94g,4.00mmol)在THF(15ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加氯甲基丁酸酯(1.09g,8.00mmol)的THF(5ml)溶液,60℃下搅拌48小时,使反应混合物冷却到室温并真空蒸发。加入二乙醚(25ml),用饱和的NaHCO3(3×0.5ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发得到无色油状产物(0.76g,49.0%)。1H-NMR(CDCl3)δ5.70(s,4H),2.29(t,8H),1.65-1.55(m,8H),1.27(s,6H),0.90(t,6H)。13C-NMR(CDCl3)δ172.31,162.50,78.97,35.73,33.81,28.67,24.41,18.05,13.43。
实施例13
双(己酰基氧甲基)壬二酸酯的合成
60℃下,将Cs2CO3(1.30g,4.00mmol)、NaI(20mg,0.13mmol)和壬二酸(037g,2.00mmol)在THF(15ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加己酸氯甲基酯(0.65g,4.00mmol)的THF(5ml)溶液,60℃下搅拌48小时,使反应混合物冷却到室温并真空蒸发。加入二乙醚(20ml),并用饱和的NaHCO3(3×10ml)洗涤残留物,用MgSO4干燥并过滤。真空蒸发得到无色油状产物(0.91g,51.9%)。1H-NMR(CDCl3)δ5.72(s,4H),2.43-2.32(m,8H),1.75-1.64(m,8H),1.36-1.33(m,14H),0.91(t,6H)。13C-NMR(CDCl3)δ172.80,162.72,79.40,34.49,34.30,34.25,31.51,29.19,29.12,24.85,24.66,22.62,14.22。
实施例14
双(辛酰氧甲基)壬二酸酯的合成
60℃下,将Cs2CO3(2.60g,4.00mmol)、NaI(30mg,0.20mmol)和壬二酸(0.75g,4.00mmol)在THF(20ml)中的不均匀溶液搅拌半小时,并向该溶液中滴加辛酸氯甲基酯(1.53g,8.00mmol)的THF(5ml)溶液,60℃下搅拌48小时,使反应混合物冷却到室温并真空蒸发。加入二乙醚(20ml),并用饱和的NaHCO3(3×15ml)洗涤残留物,并用MgSO4干燥并过滤。真空蒸发得到无色油状产物(0.95g,47.9%)。1H-NMR(CDCl3)δ5.76(s,4H),2.37(t,8H),1.65(t,8H),1.30(s br,22H),90(t,6H)。13C-NMR(CDCl3)δ172.89,62.32,79.44,34.35,34.26,31.99,29.32,29.23,29.14,24.99,24.86,22.94,14.41。
实施例15
壬二酸和壬二酸衍生物的抗菌活性
在琼脂凝胶上试验壬二酸和实施例7、12和13的壬二酸衍生物对金黄色葡萄球菌的抗菌效果。所有的衍生物都呈现出很大的抑制区,而同量的壬二酸(10mg)却不呈现抑制效果。
衍生物对粪肠球菌、酿脓链球菌和表皮葡萄球菌也呈现出很高的活性。
实施例16
实施例2霜剂的临床试验
症状:皮肤癌
一个面部(鼻子上方一处病变)患有皮肤癌的76岁老妇人,用光动力疗法治疗(5-ALA甲基酯,由Norway,Oslo,ASA,Photocure购得)。治疗效果非常好。约1年后,她又观察到在同一区域的新的病变。现在她正以每周使用5%的霜剂(实施例2),约1.5年,以使疾病发展处于控制之下。
实施例17
实施例2霜剂的临床试验
安全性
用实施例2的霜剂对各种皮肤疾病治疗约2年(参看上述实例)。没有观察到面部或全身性副效应。对实施例3的病人,以每天用霜剂(2-10%)治疗几个星期,没有观察到任何中毒迹象。
Claims (11)
1.一种式I的化合物或其生理学上允许的盐,
其中,n是4-12的整数,
R1是氢,任意取代的、任意不饱和的C1-15烷基基团,或者-CHR3-O-CO-R2基团,
各个R2独立地是任意取代的、任意不饱和的C1-15烷基或烷氧基基团,具有至多16个碳的芳基、烷芳基、芳烷基、芳氧基、烷芳氧基或芳烷氧基基团,或者与对其是γ位的R3一起是2~5主链原子桥连基团,和
各个R3独立地是氢,任意取代的、任意不饱和的C1-15烷基基团,R2-CO-O-基团或与R2一起形成桥连基团,如上所述,
其中所述C1-15烷基基团,当被取代时,其被一个或多个下列基团取代:羟基、氧代基团、卤原子、烷氧基团、酰氧基基团、硫醇基团、氨基基团、芳香基团、烷硫基或烷氨基,
对于所述式(I)化合物,下述化合物除外:
双(1-(乙酰氧基)乙基)壬二酸酯,
双(乙酸亚乙基酯)己二酸酯,
乙烯基(乙酸亚乙基酯)己二酸酯。
2.根据权利要求1的化合物或其生理学上允许的盐,其中在式I中,n是6、7或8。
3.根据权利要求1的化合物或其生理学上允许的盐,其中式I中,n是6、7或8,R1是C1-10烷基基团或式-CHR3-O-CO-R2基团,R3是氢或C1-3烷基基团,各个R2是甲基、乙基、丙基、丁基、戊基、苄基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或苄氧基基团。
4.根据权利要求1的化合物或其生理学上允许的盐,其中式I中,n是7、8、9或10,R2是C2-6烷基或烷氧基或苯基、R3是H或甲基、R1是CH3或CHR3OCOR2。
5.权利要求1-4中任一项化合物或其生理学上允许的盐的制造方法,所述方法包括使C4-12烷烃-二羧酸或其盐或酯,与酰氧甲基化试剂反应。
6.根据权利要求5的方法,所述方法包括使式III的化合物或其盐与式II的酰氧甲基化试剂反应,
式III中,R1和n是如权利要求1~4任一项所定义,R4是羟基或卤素基团,
R2-CO-O-CHR3-X (II)
式II中R2和R3的定义是如权利要求1、3或4任一项所定义,X是离去基团。
7.根据权利要求6的方法,其中所述离去基团是卤素原子、羟基基团,或磺酸酯基团。
8.一种药物组合物,包括式I化合物或其生理学上允许的盐,
其中,n是4-12的整数,
R1是氢,任意取代的、任意不饱和的C1-15烷基基团,或者-CHR3-O-CO-R2基团,
各个R2独立地是任意取代的、任意不饱和的C1-15烷基或烷氧基基团,具有至多16个碳的芳基、烷芳基、芳烷基、芳氧基、烷芳氧基或芳烷氧基基团,或者与对其是γ位的R3一起是2~5主链原子桥连基团,和
各个R3独立地是氢,任意取代的、任意不饱和的C1-15烷基基团,R2-CO-O-基团或与R2一起形成桥连基团,如上所述,
其中所述C1-15烷基基团,当被取代时,其被一个或多个下列基团取代:羟基、氧代基团、卤原子、烷氧基团、酰氧基基团、硫醇基团、氨基基团、芳香基团、烷硫基或烷氨基,
对于所述式(I)化合物,下述化合物除外:
双(1-(乙酰氧基)乙基)壬二酸酯,
双(乙酸亚乙基酯)己二酸酯,
乙烯基(乙酸亚乙基酯)己二酸酯,
与至少一种医药载体或赋形剂一起。
9.式I化合物或其生理学上允许的盐的用途,
其中,n是4-12的整数,
R1是氢,任意取代的、任意不饱和的C1-15烷基基团,或者-CHR3-O-CO-R2基团,
各个R2独立地是任意取代的、任意不饱和的C1-15烷基或烷氧基基团,具有至多16个碳的芳基、烷芳基、芳烷基、芳氧基、烷芳氧基或芳烷氧基基团,或者与对其是γ位的R3一起是2~5主链原子桥连基团,和
各个R3独立地是氢,任意取代的、任意不饱和的C1-15烷基基团,R2-CO-O-基团或与R2一起形成桥连基团,如上所述,
其中所述C1-15烷基基团,当被取代时,其被一个或多个下列基团取代:羟基、氧代基团、卤原子、烷氧基团、酰氧基基团、硫醇基团、氨基基团、芳香基团、烷硫基或烷氨基,
对于所述式(I)化合物,下述化合物除外:
双(1-(乙酰氧基)乙基)壬二酸酯,
双(乙酸亚乙基酯)己二酸酯,
乙烯基(乙酸亚乙基酯)己二酸酯,
它是以n-烷烃-α,ω-二羧酸的酰氧甲基酯的药物物质或其盐形式,用于制造药物,该药物用于对使用所述二羧酸药物治疗具有易于敏感症状的人类或非人类动物的治疗方法中。
10.权利要求9的用途,其中所述药物用于治疗痤疮、红斑痤疮、高度色素沉着、伤口愈合、光化性角化症、或细菌、病毒或真菌感染,或用于治疗或预防癌症的方法中。
11.权利要求10的用途,其中所述癌症为基质细胞癌。
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LU86918A1 (fr) * | 1987-06-12 | 1989-03-08 | Oreal | Nouveaux diesters de l'acide azelaique,leur procede de preparation,les compositions topiques les contenant et leur utilisation dans le traitement de l'acne |
AU663866B2 (en) | 1991-03-28 | 1995-10-26 | Nycomed Imaging As | Cross-linking agent |
DE69326447T2 (de) | 1992-03-06 | 2000-05-18 | Nycomed Imaging As, Oslo | Verbesserungen in bezug auf kontrastmittel |
JP4029440B2 (ja) | 1997-07-09 | 2008-01-09 | 大日本インキ化学工業株式会社 | 側鎖型ラジカル重合性化合物及びそれを用いた液晶デバイス |
-
2001
- 2001-11-22 GB GBGB0128052.8A patent/GB0128052D0/en not_active Ceased
-
2002
- 2002-11-22 WO PCT/GB2002/005305 patent/WO2003045893A1/en active Application Filing
- 2002-11-22 US US10/496,328 patent/US7629383B2/en not_active Expired - Fee Related
- 2002-11-22 HU HU0402122A patent/HUP0402122A2/hu unknown
- 2002-11-22 CN CNB028232739A patent/CN100516018C/zh not_active Expired - Fee Related
- 2002-11-22 JP JP2003547347A patent/JP4426298B2/ja not_active Expired - Fee Related
- 2002-11-22 DE DE60233819T patent/DE60233819D1/de not_active Expired - Lifetime
- 2002-11-22 RU RU2004118713/04A patent/RU2350599C2/ru not_active IP Right Cessation
- 2002-11-22 AT AT02779748T patent/ATE443695T1/de not_active IP Right Cessation
- 2002-11-22 CA CA2467773A patent/CA2467773C/en not_active Expired - Fee Related
- 2002-11-22 MX MXPA04004763A patent/MXPA04004763A/es unknown
- 2002-11-22 KR KR10-2004-7007220A patent/KR20040071138A/ko not_active Application Discontinuation
- 2002-11-22 AU AU2002343086A patent/AU2002343086C1/en not_active Ceased
- 2002-11-22 EP EP02779748A patent/EP1448508B1/en not_active Expired - Lifetime
-
2004
- 2004-06-21 NO NO20042603A patent/NO20042603L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
NO20042603L (no) | 2004-06-21 |
MXPA04004763A (es) | 2004-07-30 |
AU2002343086A1 (en) | 2003-06-10 |
EP1448508B1 (en) | 2009-09-23 |
ATE443695T1 (de) | 2009-10-15 |
EP1448508A1 (en) | 2004-08-25 |
JP4426298B2 (ja) | 2010-03-03 |
AU2002343086C1 (en) | 2008-06-26 |
RU2350599C2 (ru) | 2009-03-27 |
WO2003045893A1 (en) | 2003-06-05 |
HUP0402122A2 (hu) | 2005-02-28 |
CN1589254A (zh) | 2005-03-02 |
AU2002343086B2 (en) | 2008-01-03 |
US7629383B2 (en) | 2009-12-08 |
KR20040071138A (ko) | 2004-08-11 |
RU2004118713A (ru) | 2005-03-27 |
GB0128052D0 (en) | 2002-01-16 |
DE60233819D1 (de) | 2009-11-05 |
CA2467773A1 (en) | 2003-06-05 |
US20050203181A1 (en) | 2005-09-15 |
CA2467773C (en) | 2011-08-16 |
JP2005510556A (ja) | 2005-04-21 |
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