CN1144783C - 前列腺素衍生物 - Google Patents
前列腺素衍生物 Download PDFInfo
- Publication number
- CN1144783C CN1144783C CNB998066095A CN99806609A CN1144783C CN 1144783 C CN1144783 C CN 1144783C CN B998066095 A CNB998066095 A CN B998066095A CN 99806609 A CN99806609 A CN 99806609A CN 1144783 C CN1144783 C CN 1144783C
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- Prior art keywords
- compound
- cyclohexyl
- methyl
- group
- dehydrogenations
- Prior art date
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- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 230000001939 inductive effect Effects 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 8
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 7
- 239000000470 constituent Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 125000000304 alkynyl group Chemical group 0.000 abstract description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 abstract 1
- -1 suberyl Chemical group 0.000 description 55
- 150000001875 compounds Chemical class 0.000 description 53
- 125000001309 chloro group Chemical group Cl* 0.000 description 41
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 150000004702 methyl esters Chemical class 0.000 description 28
- 239000001257 hydrogen Substances 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- 238000006243 chemical reaction Methods 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 241000282693 Cercopithecidae Species 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 244000005700 microbiome Species 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 238000010898 silica gel chromatography Methods 0.000 description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- NSULUCGIYKEPPA-UHFFFAOYSA-M C(C)(C)(C)OC(=O)C#CCCC[Zn+].I(=O)(=O)[O-] Chemical compound C(C)(C)(C)OC(=O)C#CCCC[Zn+].I(=O)(=O)[O-] NSULUCGIYKEPPA-UHFFFAOYSA-M 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 241000190932 Rhodopseudomonas Species 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ISFPWNFOLCXMKV-UHFFFAOYSA-M COC(=O)C#CCCC[Zn+].I(=O)(=O)[O-] Chemical compound COC(=O)C#CCCC[Zn+].I(=O)(=O)[O-] ISFPWNFOLCXMKV-UHFFFAOYSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 241000282894 Sus scrofa domesticus Species 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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Abstract
式(I)表示的前列腺素衍生物或其可药用盐。(式中,X表示卤素原子,n表示1~5的整数,R1表示C3-10的环烷基,C1-4的烷基取代的C3-10的环烷基、C4-13的环烷基烷基、C5-10的烷基、C5-10的烯基、C5-10的炔基或桥环烃基,R2表示氢原子、C1-10的烷基或C3-10的环烷基。)
Description
技术领域
本发明涉及新型前列腺素衍生物。
背景技术
微量的前列腺素(以下称为PG)就可以发挥主要的生理作用,因此为了应用到医药上,对天然PG的衍生物的合成以及生物活性进行了探讨,在许多的文献中均有报道。
其中,在报道了PG的各种中枢作用的同时,也逐步明确了其在脑中的含量、生物合成、代谢途径以及它们在脑内的存在或发达、随年龄增加发生的变化,并对PG与睡眠、觉醒等的联系产生了兴趣。其中已知PGD2是脑中的液态因子,可以调节睡眠的出现与维持,并且已经明确猴子身上PGD2诱发的睡眠在脑电波和行为上与自发性的自然睡眠没有区别(美国国家科学院院报Proc.Natl.Acad.Sci.USA,第85卷,第4028~4086页(1988年)),期待它可以作为新的具有睡眠诱发作用的化合物。
但是,包括PGD2的PGD2衍生物由于其效果或药剂的稳定性等问题,尚不能实际应用。
发明公开
本发明人进行了悉心的研究,结果发现13、14位具有三键的下式(I)所示前列腺素衍生物的特征是具有睡眠诱发作用,从而完成了本发明。
也就是说,本发明涉及式(I)表示的前列腺素衍生物或其可药用盐。
(式中,X表示卤素原子,n表示1~5的整数,R1表示C3-10的环烷基,C1-4的烷基取代的C3-10的环烷基、C4-13的环烷基烷基、C5-10的烷基、C5-10的烯基、C5-10的炔基或桥环烃基,R2表示氢原子、C1-10的烷基或C3-10的环烷基)
进一步,本发明涉及式(I)中R1为C3-10的环烷基、C1-4的烷基取代的C3-10环烷基、C4-13的环烷基烷基的前列腺素衍生物或其可药用盐(X、n、R2与上述含义相同)。
而且,本发明还涉及含有上述前列腺素或其可药用盐作为有效成分的药物组合物。
而且,本发明还涉及含有上述前列腺素或其可药用盐作为有效成分的睡眠诱发剂。
而且,本发明还涉及睡眠诱发方法,其特征在于将药理学有效量的上述前列腺素衍生物或其可药用盐投给人。
本发明中,卤素原子是指氟原子、氯原子、溴原子或碘原子。
C3-10的环烷基例如环丙基、环丁基、环戊基、环己基、环庚基等。
C1-4的烷基取代的C3-10的环烷基例如甲基环丙基、甲基环己基、乙基环己基等。
C4-13的环烷基烷基例如环丙基甲基、环丁基甲基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、环庚基甲基等。
C5-10的烷基表示直链状或支链状的烷基,例如戊基、己基、庚基、辛基、1-甲基戊基、2-甲基戊基、1-甲基己基、2-甲基己基、2,4-二甲基戊基、2-乙基戊基、2-甲基庚基、2-乙基己基、2-丙基戊基、2-丙基己基、2,6-二甲基庚基等。
C5-10的烯基表示直链状或支链状的烯基,例如3-戊烯基、4-己烯基、5-庚烯基、4-甲基-3-戊烯基、2,4-二甲基戊烯基、6-甲基-5-庚烯基、2,6-二甲基-5-庚烯基等。
C5-10的炔基表示直链状或支链状的炔基,例如3-戊炔基、3-己炔基、4-己炔基、1-甲基戊-3-炔基、2-甲基戊-3-炔基、1-甲基己-3-炔基、2-甲基己-3-炔基等。
桥环烃基例如冰片基、降冰片基、全刚烷基、蒎烷基、2-金钟柏烷基(thujyl)、蒈烷基(caryl)、莰基等。
R2的C1-10的烷基表示直链状或支链状的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、2-乙基丙基、己基、异己基、1-乙基丁基、庚基、异庚基、辛基、壬基、癸基等。
可药用盐例如与钠、钾等碱金属形成的盐,与钙、镁等的碱土金属形成的盐,与氨、甲胺、二甲胺、环戊胺、苯甲胺、哌啶、单乙醇胺、二乙醇胺、单甲基单乙醇胺、氨基丁三醇、赖氨酸、四烷基铵、三(羟甲基)氨基甲烷等形成的盐。
式(I)的化合物可以按照下述反应式概括的方法制备。
(反应式中,R3表示C1-10的烷基或C3-10的环烷基,X、R1、n与上述含义相同。)
其次,说明上述反应,
(1)首先,按照佐藤等的方法〔有机化学杂志(J.Org.Chem.),第53卷,第5590页(1988年)〕使公知的式(II)的化合物与式(III)所示的有机铝化合物0.8~2.0当量在-10~30℃,优选0~10℃下,在惰性溶剂(例如苯、甲苯、四氢呋喃、二乙醚、二氯甲烷、正己烷)中反应立体异构性的得到式(IV)的化合物。
(2)使式(IV)的化合物与式(V)所示有机铜化合物0.5~4当量、三甲基氯甲硅烷0.5~4.0当量在惰性溶剂(例如苯、甲苯、四氢呋喃、二乙醚、二氯甲烷、正己烷、正戊烷等)中,在-78~40℃下反应,再使用无机酸(例如盐酸、硫酸、硝酸等)或有机酸(例如醋酸、对甲苯磺酸等)或其胺盐(例如对甲苯磺酸吡啶盐等),在有机溶剂(例如丙酮、甲醇、乙醇、异丙醇、二乙醚或其混合溶剂)中,在0~40℃下进行水解,立体选择性的得到式(VI)的化合物。
(3)使式(VI)的化合物与硼氢化钾、硼氢化钠、氰基硼氢化钠、三叔丁基硼氢化锂等还原剂0.5~5当量在有机溶剂(例如四氢呋喃、二乙醚、乙醇、甲醇等)中,在-78~40℃下反应,得到式(VII)与式(VII’)的化合物。可以采用柱层析等常规分离法精制这些式(VII)以及式(VII’)的化合物。
(4)使式(VII)(或式(VII’))的化合物与甲磺酰氯或对甲苯磺酰氯1~6当量在吡啶等适当溶剂中(必要时,在0.8~6当量的4-二甲氨基吡啶存在下),在-20~40℃下甲磺酰化或甲苯磺酰化后,用氯化四正丁基铵1~16当量氯化,得到式(VIII)(或式(VIII’))的化合物(X为氯原子)。
这里,也可以按照常规的方法进行溴化、氟化。例如溴化可以通过使用1~10当量的四溴化碳,在三苯基膦1~10当量以及吡啶1~10当量的存在下,在乙腈中反应得到。氟化可以通过在二氯甲烷中使之与二乙氨基磺胺三氟化物(DAST)5~20当量反应得到。
(5)使用氢氟酸、聚(氟化氢)吡啶鎓盐、盐酸等,在常规的条件下,在甲醇、乙醇、乙腈或其混合溶剂或它们与水的混合溶剂中,使式(VIII)(或式(VIII’))的化合物脱掉羟基保护基叔丁基二甲基甲硅烷基,得到式(Ia)(或式(Ia’))的PG衍生物。
(6)使用1~6当量的碱,在通常水解时使用的溶剂中,使式(Ia)(或式(Ia’))的化合物水解,得到本发明涉及的PG衍生物式(Ib)(或式(Ib’))。这里所使用的碱例如氢氧化锂、碳酸钾等,溶剂例如乙腈、丙酮、甲醇、乙醇、水或其混合溶剂等。
另外,在磷酸缓冲液、Tris-盐酸缓冲液等缓冲液中,必要时使用有机溶剂(丙酮、甲醇、乙醇等与水的混合物),使式(Ia)(或式(Ia’))的化合物与酶反应进行水解,也可以得到本发明涉及的PD衍生物式(Ib)(或式(Ib’))。这里使用的酶是微生物产生的酶(例如属于念珠菌属(Candida)、假单胞菌属(Pseudomonas)的微生物产生的酶)、由动物脏器制得的酶(例如猪肝脏或猪胰脏制得的酶)等,市售的酶例如脂肪酶VII(Sigma公司,来源于念珠菌属的微生物)、脂肪酶AY(天野制药,来源于念珠菌属的微生物)、脂肪酶AY(天野制药,来源于假单胞菌属的微生物)、脂肪酶PS(天野制药,来源于假单胞菌属的微生物)、脂肪酶MF(天野制药,来源于假单胞菌属的微生物)、PLE(Sigma公司,由猪肝脏制得)、脂肪酶II(Sigma公司,由猪胰脏制得)、脂蛋白脂肪酶(东京化成工业社,由猪胰脏制得)等。
酶的用量可以根据酶的效价以及底物〔式(Ia)的化合物〕的量适当选择,通常是底物的0.1~20倍重量份。反应温度为25~50℃,优选30~40℃。
本发明涉及的式(I)的化合物可以列举出如下。
表1
X n R1 R2 8位 15位
化合物1 β-Cl 1 环戊基 甲基 α α
化合物2 β-Cl 2 环戊基 甲基 α α
化合物3 β-Cl 2 环戊基 氢 α α
化合物4 β-Cl 3 环戊基 甲基 α α
化合物5 β-Cl 3 环戊基 氢 α α
化合物6 β-Cl 4 环戊基 甲基 α α
化合物7 β-Cl 4 环戊基 氢 α α
化合物8 β-Cl 3 环己基 叔丁基 α α
化合物9 β-Cl 3 环己基 甲基 β α
化合物10 β-Cl 3 环己基 氢 β α
化合物11 β-Cl 2 环己基 甲基 α α
化合物12 β-Cl 2 环己基 氢 α α
化合物13 β-Cl 3 环己基 甲基 α α
化合物14 β-Cl 3 环己基 氢 α α
化合物15 β-Br 3 环己基 甲基 α α
表1(续)
X n R1 R2 8位 15位
化合物16 β-Br 3 环己基 氢 α α
化合物17 F 3 环己基 甲基 α α
化合物18 F 3 环己基 氢 α α
化合物19 β-Cl 4 环己基 甲基 α α
化合物20 β-Cl 4 环己基 氢 α α
化合物21 β-Cl 3 环己基 甲基 α β
化合物22 β-Cl 3 环己基 氢 α β
化合物23 β-Cl 4 环己基 甲基 α β
化合物24 β-Cl 4 环己基 氢 α β
化合物25 α-Cl 3 环己基 甲基 α α
化合物26 α-Cl 3 环己基 氢 α α
化合物27 β-Cl 3 环庚基 甲基 α α
化合物28 β-Cl 3 环庚基 氢 α α
化合物29 β-Cl 2 环戊基甲基 甲基 α α
化合物30 β-Cl 2 环戊基甲基 氢 α α
化合物31 β-Cl 3 环戊基甲基 环己基 α α
化合物32 β-Cl 3 环戊基甲基 甲基 α α
化合物33 β-Cl 3 环戊基甲基 氢 α α
化合物34 β-Br 3 环戊基甲基 甲基 α α
化合物35 β-Br 3 环戊基甲基 氢 α α
化合物36 β-Cl 4 环戊基甲基 甲基 α α
化合物37 β-Cl 4 环戊基甲基 氢 α α
化合物38 β-Cl 3 环己基甲基 甲基 α α
化合物39 β-Cl 3 环己基甲基 氢 α α
化合物40 β-Cl 3 2-甲基-1-己基 甲基 α α
表1(续)
X n R1 R2 8位 15位
化合物41 β-Cl 3 2-甲基-1-己基 氢 α α
化合物42 β-Cl 3 2,6-二甲基-5-庚烯基 甲基 α α
化合物43 β-Cl 3 2,6-二甲基-5-庚烯基 氢 α α
化合物44 β-Cl 3 1-甲基-3-己烯基 甲基 α α
化合物45 β-Cl 3 1-甲基-3-己烯基 氢 α α
本发明涉及的化合物可以口服给药,或采用静脉内、经鼻给药等形式非口服给药。这些化合物可以按照常规的方法制成片剂、粉剂、颗粒剂、散剂、胶囊剂、液体制剂、乳剂、悬浊剂等形式口服给药。作为静脉给药的制剂可以使用水性或非水性溶液剂、乳剂、悬浊剂、使用之前溶解于注射用溶剂的固体制剂等。经鼻给药一般是以含有药物的溶液以及粉末(硬胶囊)形式,使用专用的滴鼻器或喷雾器定量地喷(喷雾)到鼻腔内。另外,本发明的化合物也可以与α、β或γ-环糊精或甲基化环糊精等形成包合化合物制成制剂。给药量根据年龄、体重等有所不同,对于成人为1ng~1mg/日。
工业实用性
本发明的化合物具有充分的睡眠诱发作用,而且稳定性优良,作为睡眠诱发剂是有用的。
发明的最佳实施方式
以下,结合实施例和实验例更详细地说明本发明。另外,化合物的命名中,例如“16,17,18,19,20-五降”中的“降”是指在这一位置没有碳链(所举的例子表示16~20位没有碳链)。另外,“1a-高”中的“高”是指这一位置碳链多(所举的例子表示1位和2位之间具有1a的碳链)。
实施例1
9-去氧-9β-氯-16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α叔丁酯的制备(化合物8)
(1)在氩气流下,将(3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基丙-1-炔(3.61g)溶解于甲苯(28.8ml),在0℃下加入正丁基锂(1.95M,己烷溶液,6.4ml),在相同温度下搅拌30分钟。在0℃下,向该溶液中加入氯化二乙基铝(0.97M,己烷溶液,14.8ml),在室温下搅拌30分钟。在室温下向该溶液中加入(4R)-2-(N,N-二乙氨基)甲基-4-(叔丁基二甲基甲硅烷氧基)环戊-2-烯-1-酮(0.25M,甲苯溶液,14.8ml),搅拌15分钟。在搅拌下将反应液注入到己烷(100ml)-饱和氯化铵水溶液(100ml)-盐酸水溶液(3N,30ml)的混合液中。然后分离有机层,用饱和碳酸氢钠水溶液(50ml)洗涤。用无水硫酸镁干燥得到的有机层,过滤后浓缩,将得到的残渣用硅胶柱层析(洗脱溶剂,己烷∶乙酸乙酯=10∶1)精制,得到(3R,4R)-2-亚甲基-3-〔(3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基丙-1-炔基〕-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮(3.69g)。
1H-NMR(CDCl3,200MHz)δppm;0.07,0.08and 0.12(3s,12H),0.88(s,18H),0.92-1.92(m,11H),2.32(dd,J=17.8,7.4Hz,1H).2.71(dd,J=17.8,6.5Hz,1H),3.48-3.58(m,1H),4.11(dd,J=6.2,1.4Hz,1H),4.20-4.32(m.1H),5.55(d,J=2.6Hz,1H),6.13(d.J=3.0Hz,1H)
IR(neat);2930,2850,1375,1640,1470,1380,1255,830,770cm-1
(2)在氩气流下,在-70℃下,向碘化5-叔丁氧基羰基-4-戊炔基锌(II)(0.81N,四氢呋喃溶液,40.69m1)中加入氰化铜(I)·2氯化锂(1.0M,四氢呋喃溶液,41.21ml),在相同温度下搅拌20分钟。在-70℃下,向该溶液中加入上述(1)得到的化合物(7.86g)的二乙醚(66.0ml)溶液和氯代三甲基甲硅烷(3.77ml),搅拌下用约1小时升温至0℃。向反应液中加入饱和氯化铵水溶液(250ml),用己烷萃取。用饱和食盐水洗涤有机层后,干燥、浓缩,将得到的残渣溶解于二乙醚(16.5ml)-异丙醇(66.0ml),加入对甲苯磺酸吡啶鎓盐(208mg),在室温下搅拌12小时。向反应液中加入己烷(200ml),用饱和碳酸氢钠水溶液和饱和食盐水洗涤后,干燥、浓缩,将得到的残渣用硅胶柱层析(展开溶剂,己烷∶乙酸乙酯=15∶1)精制,得到16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGE1叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)(5.73g)
1H-NMR(CDCl3,200MHz)δppm;0.08(s,3H),0.09(s,3H).0.10(s,3H),0.13(s,3H).0.89(s,9H),0.90(s,9H),0.96-1.96(m,19H),1.49(s,9H),1.97-2.35(m,2H),2.56-2.75(m,2H),4.03-4.19(m,1H),4.22-4.35(m,1H)
IR(neat);2932,2857,2238,1747,1708,1452,1393,1370,1278,1258,1162,1078,840,779,755,670cm-1
(3)将(2)得到的化合物(5.73g)的甲醇(94.7ml)溶液冷却至0℃,加入硼氢化钾(1.02g),搅拌15分钟。加入水,用乙醚(200ml)萃取,用饱和氯化铵水溶液、饱和食盐水洗涤后,用无水硫酸镁干燥,浓缩。将残渣用硅胶柱层析(展开溶剂,己烷∶乙酸乙酯=5∶1)精制,得到16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)(2.17g)以及16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1β叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)(2.75g).
16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.09(s,3H),0.10(s,3H),0.11(s,3H),0.12(s,3H),0.90(s,9H),0.91(s,9H),0.94-2.07(m,21H),1.50(s,9H),2.26-2.38(m,1H),2.42-2.51(m,1H),2.55(d,J=9.5Hz,1H),4.02-4.20(m,1H),4.09(dd,J=6.4,1.7Hz,1H),4.24-4.33(m,1H)
IR(neat);3468,2930,2856,2236,1709,1473,1463,1392,1370,1277,1257,1162,1104,1075,1006,939,899,838,778,756,668cm-116,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1β叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.07(s,3H),0.08(s,6H),0.11(s,3H),0.88(s,9H),0.90(s,9H),0.92-1.93(m,21H),1.49(s,9H),2.22(ddd,J=9.4,6.4,1.7Hz,1H),2.24-2.37(m,1H),3.91-4.28(m,3H)
IR(neat);3435,2930,2857,2237,1710,1473,1463,1392,1370,1277,1257,1162,1073,898,838,778,756,670cm-1
(4)在0℃下,向上述(3)得到的16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)(641mg)的吡啶(4.95ml)溶液中加入甲磺酰氯(0.153ml),在室温下搅拌2小时。将其加入到氯化四正丁基铵(4.40g)的甲苯(4.95ml)悬浊液中,在40℃下搅拌过夜。加入饱和食盐水(50ml)和乙酸乙酯(50ml)后,分离有机层,用乙酸乙酯(20ml)萃取水层。将得到的有机层合并,用饱和食盐水洗涤后,用无水硫酸镁干燥,过滤。减压条件下浓缩滤液,将粗产物用硅胶柱层析(展开溶剂,己烷∶乙酸乙酯=25∶1~10∶1)精制,得到9-去氧-9β-氯-16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α叔丁酯11,15-二(叔丁基二甲基甲硅烷基醚)(624mg)。
1H-NMR(CDCl3,200MHz)δppm;0.07(s,3H),0.08(s,6H),0.11(s,3H),0.88(s,9H),0.90(s,9H),0.93-1.92(m,19H),1.49(s,9H),1.94-2.19(m,1H),2.14(dd,J=7.8,5.4Hz,1H),2.23-2.37(m,2H),3.87-4.03(m,1H),4.08(dd,J=6.2,1.7Hz,1H),4.18-4.29(m,1H)
IR(neat);2930,2856,2237,1709,1473,1463,1392,1369,1276,1257,1163,1102,1077,1006,899,838,778,755,670cm-1
(5)在0℃下,向上述(4)得到的化合物(604mg)的乙腈(30.2ml)溶液中加入氢氟酸水溶液(46%,8.80ml),在相同温度下搅拌2小时。搅拌下将反应液注入到乙酸乙酯(100m1)和饱和碳酸氢钠水溶液(155ml)的混合液中后,分离有机层,用乙酸乙酯(20ml)萃取水层。合并得到的有机层,用饱和食盐水洗涤后,用无水硫酸镁干燥,过滤。在减压条件下浓缩滤液,将得到的粗产物用硅胶柱层析(展开溶剂,己烷∶乙酸乙酯=1∶1)精制,得到标题化合物(295mg)。
1H-NMR(CDCl2,300MHz)δppm;0.95-1.34(m,6H),1.45-1.89(m,11H),1.49(s,9H),2.03-2.38(m,8H),3.89-4.00(m,1H),4.16(dd,J=6.1,1.9Hz,1H),4.32-4.41(m,1H)
IR(neat);3391,2980,2930,2855,2237,1707,1478,1452,1395,1370,1278,1161,1081,1032,894,845,756,692cm-1
实施例2
9-去氧-9β-氯-16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯(化合物13)的制备
(1)用碘化5-甲氧羰基-4-戊炔基锌(II)代替实施例1(2)的5-叔丁氧基羰基-4-戊炔基锌(II)碘化物,得到16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGE1甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm;0.07(s,3H),0.09(s,3H),0.10(s,3H),0.12(s,3H),0.82-1.92(m,17H),0.89(s,9H),0.90(s,9H),2.14-2.28(m,1H),2.17(dd,J=18.3,7.1Hz,1H),2.28-2.40(m,2H),2.68(ddd,J=18.3,6.8,1.3Hz,1H),2.69(ddd,J=9.5,6.8,1.6Hz,1H),3.75(s,3H),4.09(dd,J=6.2,1.6Hz,1H),4.29(q,J=6.8Hz,1H)
IR(neat);2930,2857,2236,1748,1718,1472,1463,1452,1435,1407,1374,1362,1337,1256,1102,1078,1007,940,898,839,779,753,670cm-1
(2)使用上述(1)得到的化合物,与实施例1(3)相同,得到16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)以及16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚),
16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl2,200MHz)δppm;0.08(s,3H),0.09(s,3H),0.10(s,3H),0.11(s,3H),0.82-2.07(m,20H),0.88(s,9H),0.90(s,9H),2.35-2.50(m,1H),2.35(t,J=6.7Hz,2H),3.75(s,3H),4.02-4.17(m,1H),4.07(dd,J=6.2,1.9Hz,1H),4.24-4.32(m,1H)
IR(neat);3468,2930,2856,2238,1719,1472,1463,1435,1386,1362,1337,1255,1104,1077,1006,963,927,898,838,778,754,668cm-1
16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl2,200MHz)δppm;0.07(s,3H),0.08(s,6H),0.11(s,3H),0.82-1.95(m,20H),0.88(s,9H),0.90(s,9H),2.25(ddd,J=9.3,6.2,1.6Hz,1H),2.35(t,J=6.6Hz,2H),3.75(s,3H),3.91-4.04(m,1H),4.08(dd,J=6.2,1.6Hz,1H),4.15-4.30(m,1H)
IR(neat);3441,2929,2856,2239,1719,1472,1463,1436,1388,1361,1337,1103,1074,1006,962,899,838,778,754,670cm-1
(3)使用上述(2)得到的16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚),与实施例1(4)相同,得到9-去氧-9β-氯-16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm;0.07(s,3H),0.08(s,6H),0.11(s,3H),0.50-1.92(m,17H),0.88(s,9H),0.90(s,9H),1.95-2.20(m,1H),2.14(dd,J=7.7,5.5Hz,1H),2.23-2.42(m,4H),3.76(s,3H),3.95(α,J=7.7Hz,1H),4.08(dd,J=6.2,1.7Hz,1H),4.25-4.30(m,1H)
IR(neat);2930,2856,2239,1719,1472,1463,1435,1362,1338,1255,1102,1078,1006,963,899,838,778,753,670cm-1
(4)使用上述(3)得到的化合物,与实施例1(5)相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;0.96-1.35(m,6H),1.47-1.91(m,11H),2.09-2.41(m,6H),3.76(s,3H),3.95(q,J=7.4Hz,1H),4.16(dd,J=6.1,1.9Hz,1H),4.37(q,J=6.3Hz,1H)
IR(neat);3392,2928,2855,2238,1715,1436,1384,1260,1156,1080,1012,955,894,822,754,692cm-1
实施例3
9-去氧-9β-氯-16,17,18,19,20-五降-15-环己基-2,2,3,3,13,14-六去氢-PGF1α(化合物14)的制备
将实施例2得到的化合物(410mg)溶解于丙酮(22.4ml),加入脂肪酶PS(11.7g)悬浊于水(66ml)所得混合物,再加入pH7.0的磷酸缓冲液(11.3ml)和水(161ml),在38℃下搅拌12小时。过滤反应液后,用乙酸乙酯萃取。用饱和食盐水洗涤有机层,用无水硫酸镁干燥,继续过滤。减压条件下浓缩滤液,将得到的粗产物用硅胶柱层析(展开溶剂,乙酸乙酯)精制,得到标题化合物(400mg)。
1H-NMR(CDCl3,300MHz)δppm;0.76-2.44(m,14H),2.34(ddd,J=9.5,6.2,1.9Hz,1H),2.41(t,J=6.3Hz,1H),3.89-3.99(m,1H),4.18(dd,J=6.1,1.9Hz,1H),4.32-4.41(m,1H)
IR(neat);3368,2928,2854,2237,1694,1451,1385,1262,1082,1007,893,758,595cm-1
实施例4
9-去氧-9β-氯-17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGFtα甲酯(化合物32)的制备
(1)用碘化5-甲氧羰基-4-戊炔基锌(II)代替实施例1(2)的碘化5-叔丁氧基羰基-4-戊炔基锌(II),用(3R,4R)-2-亚甲基-3-〔(3S)-3-(叔丁基二甲基甲硅烷氧基)-4-环戊基丁-1-炔基〕-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮代替(3R,4R)-2-亚甲基-3-〔(3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基丙-1-炔基〕-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮,得到17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGE1甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm;0.10(s,6H),0.11(s,3H),0.13(s,3H),0.89(s,9H),0.90(s,9H),0.96-2.40(m,20H),2.17(dd,J=18.2,7.0Hz,1H),2.60-2.76(m,2H),3.76(s,3H),4.22-4.43(m,1H),4.37(dt,J=1.7,6.8Hz,1H)
IR(neat);2952,2930,2858,2237,1749,1718,1472,1463,1435,1361,1256,1078,1005,939,838,778,753,670,562cm-1
(2)使用上述(1)得到的化合物,与实施例1(3)相同,得到17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)以及17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.09(s,3H),0.10(s,6H),0.11(s,3H),0.88(s,9H),0.90(s,9H),1.38-2.06(m,20H),2.29-2.49,(m,1H),2.36(t,J=6.7Hz,2H),2.53(d,J=9.4Hz,1H),3.76(s,3H),4.05-4.18(m,1H),4.23-4.40(m,1H),4.35(dt,J=1.9,7.0Hz,1H)
IR(neat);3467,2951,2930,2857,2237,1718,1472,1463,1435,1388,1361,1336,1255,1077,1005,939,869,837,777,753,667cm-1
17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.07(s,3H),0.09(s,3H),0.10(s,3H),0.12(s,3H),0.88(s,9H),0.90(s,9H),0.98-2.07(m,21H),2.22(ddd,J=9.2,6.3,1.7Hz,1H),2.35(t,J=6.8Hz,2H),3.76(s,3H),3.90-4.06(m,1H),4.16-4.29(m,1H),4.36(dt,J=1.6,6.8Hz,1H)
IR(neat);3435,2951,2930,2857,2237,1718,1472,1463,
1435,1387,1361,1335,1255,1075,1005,939,836,777,753,669cm-1
(3)使用上述(2)得到的17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚),与实施例1(4)相同,得到9-去氧-9β-氯-17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm:0.07(s,3H),0.08(s,3H),0.10(s,3H),0.12(s,3H),0.88(s,9H),0.90(s,9H),1.00-2.41(m,23H),3.76(s,3H),3.87-4.03(m,1H),4.19-4.30(m,1H),4.35(dt,J=1.6,6.8Hz,1H)
IR(neat);2951,2930,2857,2238,1718,1472,1463,1434,1387,1361,1252,1077,1005,939,904,836,777,752,669cm-1
(4)使用上述(3)得到的化合物,与实施例1(5)相同,得到标题化合物。
1H-NMR(CDCl2,200MHz)δppm;1.02-1.31(m,4H),1.44-2.46(m,19H),1.92(d,J=5.9Hz,1H),2.04(d,J=4.4Hz,1H),3.77(s,3H),3.88-4.03(m,1H),4.29-4.46(m,2H)
IR(neat);3368,2945,2863,2236,1715,1435,1257,1161,1078,1045,820,753cm-1
实施例5
9-去氧-9β-氯-17,18,19,20-四降-16-环戊基-2,2,3,3,13,14-六去氢-PGF1α(化合物33)的制备
使用实施例4得到的化合物,与实施例3实质上相同,得到标题化合物,
1H-NMR(CDCl3,200MHz)δppm;1.03-2.48(m,23H),2.74-3.20(br,3H),3.87-4.03(m,1H),4.29-4.47(m,2H)
IR(neat);3367,2944,2863,2623,2236,1695,1450,1262,1167,1077,1042,990,872,757,594cm-1
实施例6
9-去氧-9β-氯-17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯(化合物38)的制备
(1)用碘化5-甲氧羰基-4-戊炔基锌(II)代替实施例1(2)的碘化5-叔丁氧基羰基-4-戊炔基锌(II),用(3R,4R)-2-亚甲基-3-〔(3S)-3-(叔丁基二甲基甲硅烷氧基)-4-环己基丁-1-炔基〕-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮代替(3R,4R)-2-亚甲基-3-〔(3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基丙-1-炔基〕-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮,得到17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGE1甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm:0.10(s,6H),0.11(s,3H),0.13(s,3H),0.90(s,18H),1.10-1.80(m,19H),2.14-2.27(m,1H),2.17(dd,J=18.2,7.0Hz,1H),2.34(t J=6.6Hz,2H),2.60-2.75(m,2H),3.76(s,3H),4.23-4.35(m,1H),4.45(dt,J=1.4Hz,7.9Hz,1H)
IR(neat);2928,2856,2238,1748,1718,1472,1463,1435,1362,1256,1077cm-1
(2)使用上述(1)得到的化合物,与实施例1(3)相同,得到17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)以及17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.09(s,6H),0.11(s,6H),0.78-2.06(m,22H),0.88(s,9H),0.90(s,9H),2.29-2.49(m,1H),2.36(t,J=6.7Hz,2H),2.54(d,J=9.7Hz,1H),3.76(s,3H),4.06-4.20(m,1H),4.22-4.33(m,1H),4.37-4.49(m,1H)
IR(neat);3435,2928,2855,2237,1718,1472,1463,1448,1435,1388,1361,1252,1074,1003,938,837,777,753,667cm-1
17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.08(s,3H),0.09(s,3H),0.10(s,3H),0.11(s,3H),0.77-1.94(m,23H),0.88(s,9H),0.90(s,9H),2.22(ddd,J=9.3,6.3,1.9Hz,1H),2.35(t,J=6.9Hz,2H),3.76(s,3H),3.91-4.06(m,1H),4.16-4.29(m,1H),4.38-4.49(m,1H)
IR(neat);3436,2928,2855,2237,1718,1472,1463,1448,1435,1388,1361,1255,1074,1004,938,889,836,777,753,669,568cm-1
(3)使用上述(2)得到的17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚),与实施例1(4)相同,得到9-去氧-9β-氯-17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;0.07(s,3H),0.09(s,3H),0.10(s,3H),0.11(s,3H),0.78-1.78(m,19H),0.88(s,9H),0.90(s,9H),1.99-2.41(m,6H),3.76(s,3H),3.8 7-4.03(m,1H),4.19-4.30(m,1H),4.37-4.49(m,1H)
IR(neat);2928,2855,2238,1719,1472,1463,1448,1434,1388,1361,1252,1075,1004,938,909,891,836,777,752,668cm-1
(4)使用上述(3)得到的化合物,与实施例1(5)相同,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;0.82-1.84(m,19H),1.90(d,J=5.9Hz,1H),2.00-2.44(m,6H),2.04(d,J=3.5Hz,1H),3.77(s,3H),3.88-4.03(m,1H),4.29-4.54(m,2H)
IR(neat);3400,2924,2851,2237,1716,1435,1256,1156,1078,1044,981,821,753cm-1
实施例7
9-去氧-9β-氯-17,18,19,20-四降-16-环己基-2,2,3,3,13,14-六去氢-PGF1α(化合物39)的制备
使用实施例6得到的化合物,与实施例3实质上相同,得到标题化合物。
1H-NMR(CDCl2,200MHz)δppm;0.82-1.84(m,19H),2.02-2.72(m,9H),3.88-4.02(m,1H),4.29-4.54(m,2H)
IR(neat);3350,2924,2852,2625,2236,1691,1448,1267,1061,1042,980,894,757,594cm-1.
实施例8
9-去氧-9β-氯-1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α甲酯(化合物19)的制备
(1)用碘化6-甲氧羰基-5-己炔基锌(II)代替实施例1(2)的碘化5-叔丁氧基羰基-4-戊炔基锌(II),得到1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGE1甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm;0.08(s,3H),0.09(s,3H),0.10(s,3H),0.13(s,3H),0.78-1.94(m,19H),0.89(s,9H),0.90(s,9H),2.09-2.27(n,1H),2.17(dd,J=18.2,7.1Hz,1H),2.33(t,J=6.9Hz,2H),2.59-2.76(m,1H),2.68(ddd,J=18.2,6.7,1.2Hz,1H),3.76(s,3H),4.09(dd,J=6.2,1.5Hz,1H),4.22-4.36(m,1H)
IR(neat);2929,2856,2238,1748,1718,1472,1463,1451,1435,1406,1374,1361,1337,1255,1100,1077,1006,939,898,881,837,778,753,669,587cm-1
(2)使用上述(1)得到的化合物,与实施例1(3)相同,得到1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)以及1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚).
1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.08(s,3H),0.09(s,3H),0.10(s,3H),0.11(s,3H),0.82-2.06(m,22H),0.89(s,9H),0.90(s,9H),2.34(t,J=7.0Hz,2H),2.40-2.52(m,1H),2.53(d,J=9.7Hz,1H),3.76(s,3H),4.02-4.18(m,1H),4.07(dd,J=6.3,1.9Hz,1H),4.22-4.35(m,1H)
IR(neat);3436,2929,2855,2238,1718,1472,1463,1451,1435,1386,1361,1336,1255,1103,1074,1005,963,939,898,836,777,753,668cm-1
1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1β甲酯11,15-二(叔丁基二甲基甲硅烷基醚)
1H-NMR(CDCl3,200MHz)δppm;0.07(s,3H),0.08(s,6H),0.11(s,3H),0.76-1.94(m,20H),0.88(s,9H),0.90(s,9H),1.52(d,J=5.1Hz,1H),1.88(t,J=6.4Hz,2H),2.23(ddd,J=9.3,6.3,1.6Hz,1H),2.34(t,J=6.9Hz,2H),3.76(s,3H),3.90-4.04(m,1H),4.08(dd,J=6.3,1.6Hz,1H),4.16-4.30(m,1H)
IR(neat);3426,2929,2855,2238,1718,1472,1463,1451,1435,1388,1361,1337,1255,1188,1073,1006,962,938,927,898,836,777,753,669,583cm-1
(3)使用上述(2)得到的1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚),与实施例1(4)相同,得到9-去氧-9β-氯-1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α甲酯11,15-二(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl2,200MHz)δppm;0.07(s,3H),0.08(2s,6H),0.11(s,3H),0.82-1.91(m,19H),0.88(s,9H),0.90(s,9H),1.96-2.19(m,1H),2.14(dd,J=7.6,5.6Hz,2H),2.28(ddd,J=8.9,5.1,1.6Hz,1H),2.34(t,J=6.9Hz,2H),3.76(s,3H),3.88-4.02(m,1H),4.08(dd,J=6.2,1.6Hz,1H),4.20-4.30(m,1H)
IR(neat);2929,2855,2238,1718,1472,1463,1451,1435,1388,1361,1337,1255,1188,1100,1077,1006,962,939,927,898,836,814,777,752,669,587cm-1
(4)使用上述(3)得到的化合物,与实施例1(5)相同,得到标题化合物。
1H-NMR(CDCl2,300MHz)δppm;0.84-1.90(m,19H),1.85(d,J=5.8Hz,1H),2.06-2.39(m,4H),2.18(d,J=3.6Hz,1H),2.35(t,J=6.9Hz,2H),3.76(s,3H),3.90-4.00(m,1H),4.17(dt,J=1.8,5.8Hz,1H),4.3 2-4.42(m,1H)
IR(neat);3368,2928,2854,2237,1715,1435,1256,1156,1079,1011,893,847,805,753cm-1
实施例9
9-去氧-9β-氯-1a-高-16,17,18,19,20-五降-15-环己基-1a,1a,2,2,13,14-六去氢-PGF1α(化合物20)的制备
使用实施例8得到的化合物,与实施例3实质上相同,得到标题化合物。
1H-NMR(CDCl2,300MHz)δppm;0.85-1.89(m,19H),2.09-2.42(m,4H),2.38(t,J=6.9Hz,2H),2.70-3.40(br,3H),3.91-4.00(m,1H),4.19(dd,J=6.1,1.9Hz,1H),4.32-4.42(m,1H)
IR(neat);3368,2929,2854,2624,2236,1691,1450,1262,1081,1006,893,757,595cm-1
实验例〔采用小脑延髓池给药的睡眠诱发试验〕
方法:
将4只雄性恒河猴(体重2.0kg~3.5kg)每1只装入1个笼子中。从给药前1小时至给药后3小时,用摄像机记录各动物的行动。将化合物14溶解于生理盐水,用微孔过滤器灭菌。通过使猴子吸入异氟烷(isoflurane)麻醉,将药物注入到小脑延髓池中。给药量为1μg和10μg/0.1m1/猴。对照组在小脑延髓池内注入等量溶剂。试验程序按照下述时间表进行。
第1周:溶剂给药组
第2周:化合物14 1μg/猴给药组
第3周:化合物14 10μg/猴给药组
重放记录有睡眠的图像,测定闭上双目、身体松弛的时间(秒),求出每小时的睡眠时间,睡眠的情况如表2所示。
表2
睡眠时间(秒) 睡眠例数
0-1h 1-2h 2-3h
溶剂给药组 0 0 0 0/4
1μg/猴 739 1001 735 3/4
10μg/猴 817 2088 1825 4/4
Claims (4)
1、式(I)表示的前列腺素衍生物或其可药用盐:
式中,X表示卤素原子,n表示1~5的整数,R1表示C3-10的环烷基,C4-10的烷基取代的C3-10的环烷基或C4-12的环烷基烷基,R2表示氢原子、C4-10的烷基或C3-10的环烷基。
2、药物组合物。含有权利要求1所述的前列腺素或其可药用盐作为有效成分。
3、睡眠诱发剂,含有权利要求1或2所述的前列腺素或其可药用盐作为有效成分。
4、权利要求1所述的前列腺素衍生物或其可药用盐在制备诱发睡眠的药物中的用途。
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CN1399551A (zh) | 1999-11-24 | 2003-02-26 | 大正制药株式会社 | 经鼻给药制剂 |
US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
US20020172693A1 (en) | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
MXPA04002006A (es) | 2001-08-31 | 2004-06-07 | Sucampo Ag | Analogos de prostagladina como abridor del canal de cloruro. |
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