CN1636559A - 甲基文拉法辛的醚 - Google Patents
甲基文拉法辛的醚 Download PDFInfo
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- CN1636559A CN1636559A CNA2004100882450A CN200410088245A CN1636559A CN 1636559 A CN1636559 A CN 1636559A CN A2004100882450 A CNA2004100882450 A CN A2004100882450A CN 200410088245 A CN200410088245 A CN 200410088245A CN 1636559 A CN1636559 A CN 1636559A
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- Prior art keywords
- alkyl
- application
- nervous system
- central nervous
- ethyl
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- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 title description 11
- 150000002170 ethers Chemical class 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 -OH Chemical group 0.000 claims abstract description 8
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 8
- 150000004677 hydrates Chemical class 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 230000001149 cognitive effect Effects 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 2
- 206010003805 Autism Diseases 0.000 claims description 2
- 208000020706 Autistic disease Diseases 0.000 claims description 2
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 2
- 208000022497 Cocaine-Related disease Diseases 0.000 claims description 2
- 206010013954 Dysphoria Diseases 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 201000006145 cocaine dependence Diseases 0.000 claims description 2
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- 206010013663 drug dependence Diseases 0.000 claims description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 11
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical class C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 abstract description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 1
- 125000005309 thioalkoxy group Chemical group 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 229960004688 venlafaxine Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 3
- 239000000391 magnesium silicate Substances 0.000 description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 description 3
- 235000019792 magnesium silicate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 description 3
- 229960002416 venlafaxine hydrochloride Drugs 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 239000000460 chlorine Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
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- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
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Abstract
本发明提供了式(I)所示的文拉法辛代谢物4－[2－(二甲基氨基)－1－(1－羟基环己基)乙基]苯酚的O－α－酰氧基烷基醚或其可药用盐或水合物、其R、S或RS形式；其中，手性中心(*)的构型可以是R、S或RS(外消旋体)；R1选自C1－C6烷基、C1－C6烷氧基、C3－C6环烷基或基团(a)；R2选自H或C1－C6烷基；或者R1和R2可以连接在一起从而(i)形成式(b)的基团；R3选自H或C1－C6烷基；R4和R5彼此独立地选自H、C1－C6烷基、C3－C6环烷基、C1－C6烷氧基、C1－C6硫代烷氧基、－CN、－OH、－CF3、－OCF3、卤素、－NH2、－NO2或单或二烷基氨基(其中的各烷基含有1至6个碳原子)；以及药物组合物和治疗中枢神经系统疾病的方法。
Description
本申请是基于申请日为2000年11月21日申请号为00816149.6的申请所提交的分案申请。
技术领域
本发明涉及O-去甲基文拉法辛的醚，更具体地讲，本发明涉及4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]-苯酚的O-α-酰氧基烷基醚、其制备方法及其药物组合物和用途。
背景技术
有许多专利和文献描述了文拉法辛及其盐和类似物的生物学活性。文拉法辛盐酸盐的片剂由Wyeth-Ayerst实验室以EFFEXOR的名称上市销售。
经氢溴酸盐的单晶X射线分析和反常色散技术证实，文拉法辛的(+)对映体的绝对构型为S(Yardley等，J.Med.Chem.，1990，33，2899)。
美国专利号4,535,186(Husbands等)中公开了并要求保护(R/S)-1-[2-(二甲基氨基)-1-(4-甲氧基苯基)乙基]环己醇及其代谢物1-[2-(二甲基氨基)-1-(4-羟基苯基)乙基]环己醇和1-[1-(4-甲氧基苯基)-2-(甲基氨基)乙基]环己醇。美国专利号5,530,013(Husbands等)要求保护文拉法辛在诱导认知力增强中的用途。美国专利号5,506,270(Upton等)要求保护文拉法辛用于在非抑郁性的妇女中治疗下丘脑性经闭的用途。
美国专利号5,788,986(Dodman)和5,554,383(Dodman)教导了并要求保护血清素重吸收抑制剂在改变狗的行为中的应用。
发明内容
本发明提供了结构式I的具有药物活性的文拉法辛代谢物4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酚(“O-去甲基文拉法辛”或“ODV”)的O-α-酰氧基烷基醚
其中
手性中心(*)的构型可以是R、S或RS(外消旋体)；
R1选自C1-C6烷基、C1-C6烷氧基、C3-C6环烷基或基团(a)：
R2选自H或C1-C6烷基；或者
R1和R2可以连接在一起从而
形成式(b)的基团：
R3选自H或C1-C6烷基；
R4和R5彼此独立地选自H、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6硫代烷氧基、-CN、-OH、-CF3、-OCF3、卤素、-NH2、-NO2或-N(CH3)2，
或其可药用盐或水合物。
具体实施方式
在本发明的一些优选的实施方案中，R1是叔丁基、甲氧基或异苯并呋喃酮。
在本发明的其它优选实施方案中，R2是C1-C3烷基，在本发明更优选的优选的实施方案中，R2是甲基。
式I化合物的具体例子包括：
新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯；
丙酸1-{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}乙酯；和
3-{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}-2-苯并呋喃-1(3H)-酮。
具体地讲，本发明提供了式I的O-α-酰氧基烷基R-醚和式I的O-α-酰氧基烷基S-醚(二者均基本不含对方)化合物和/或其组合物。此外，本发明还提供了式I的4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]-苯酚的O-α-酰氧基烷基RS-醚。
本文中所用的“基本不含”是指化合物或组合物中所需异构体的比例明显大于其光学对映体。在本发明的一个优选的实施方案中，“基本不含”是指化合物或组合物由至少约90％的所需异构体和约10％或更少的光学对映体组成。在本发明更优选的实施方案中，化合物或组合物由至少约95％的所需异构体和约5％或更少的光学对映体组成。在本发明的另一个实施方案中，化合物或组合物由至少约99％的所需异构体和约1％或更少的光学对映体组成。优选经鉴定或分离的对映体可以显示出完全鉴定的化合物的物理性质，即均匀的熔点以及在旋光计中平面偏振光的均匀旋转。更优选对映体可以重结晶成分析纯的。
本文中、例如在R1的定义中所用的C1-C6烷基包括在指定碳原子范围内的直链或支链的烷基基团，例如甲基、乙基、丙基、正丁基或叔丁基。
本文所用的卤素是指氯、溴、碘和氟。
可药用盐是指从可药用的酸、包括无机酸和有机酸，例如，但不仅限于，乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等制备的盐。
本发明的化合物很容易通过本领域已知的方法制备，例如，按照Bodor等，J.Org.Chem.(48)5280-5284(1983)描述的方法制备。如需要，可将任何活泼的取代基或原子在反应前进行保护并在反应后脱保护。
因此，本发明提供了制备本文中所定义的式(I)化合物或其可药用盐或水合物的方法，该方法包括如下方法之一：
(i)将下式的R-、S-或(R/S)-4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酚：
或其盐，与式(V)的化合物反应
R1-CO-CHR2-X (V)
其中R1和R2如上所定义，条件是，连接在一起的R1和R2基团上的活泼取代基例如-OH或-NH2取代基可以通过保护基进行保护，然后除去该保护基，X是离去基，例如卤原子如氯、溴或更优选的碘；或者
(ii)将式(IV)化合物或其可药用盐或盐的水合物进行还原
其中：手性中心(*)的构型可以是R、S或RS(外消旋体)，R4和R5彼此独立地选自H、C1-C6烷基、C1-C6烷氧基、C1-C6硫代烷氧基、-CN、-OH、-CF3、-OCF3、卤素、-NH2、-NO2或-N(CH3)2，条件是R4和R5中至少有一个是-NO2，或生成式(IV)化合物或所述化合物的可药用盐或盐的水合物，其中R4和R5如上所定义，条件是R4和R5中至少有一个是-NH2；或者
(iii)将其中R1和R2如式(I)中所定义的对映体混合物形式的式(I)化合物进行分离从而分离出特定的对映体形式；或者
(iv)通过与酸加成将其中R1和R2如式(I)中所定义的式(I)化合物转化成其可药用盐或盐的水合物。
关于上述方法(i)，按照反应方案Ia和Ib将适宜的R-、S-或(R/S)-4-[2-(二甲基氨基)-1-(1-羟基-环己基)乙基]苯酚与适宜的O-α-酰氧基烷基卤化物(例如：新戊酰氧基甲基氯、3-溴-苯并[c]呋喃-2-酮、碘代新戊酸甲酯)(反应方案Ia)或(酰氧基)苄基α-卤化物(反应方案Ib)在惰性溶剂(乙腈、四氢呋喃、二甲基甲酰胺)中、在碱金属碳酸盐(碳酸钠或碳酸钾)或过渡金属碳酸盐(碳酸银)的存在下反应。
反应方案Ia
反应方案Ib
其中R1选自C1-C6烷基、C1-C6烷氧基、C3-C6环烷基或基团(a)：
R2选自H或C1-C6烷基；
或者R2和R3连接在一起形成式(b)的基团；
R3选自H或C1-C6烷基；
R4和R5彼此独立地选自H、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6硫代烷氧基、-CN、-OH、-CF3、-OCF3、卤素、-NH2、-NO2或单或二烷基氨基，其中的各烷基含有1至6个碳原子。
在本发明的某些优选的实施方案中，可以通过将适宜的R-、S-或(R/S)-4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酚与适宜的O-α-酰氧基烷基碘化物在惰性溶剂(乙腈、四氢呋喃、二甲基甲酰胺)中、在碱金属碳酸盐例如碳酸钾或过渡金属碳酸盐例如碳酸银的存在下反应来提高收率。特别优选在碳酸银的存在下、在约0-5℃的低温下使用O-α-酰氧基烷基碘化物。
在略微改变的形式中，其中R1和R2连接在一起形成
并且R4和R5之一或二者均是NH2的式I化合物可以通过催化还原(例如用钯催化剂)从其中R4或R5是NO2的相应类似物制得。
外消旋的1-[2-(二甲基氨基)-1-(4-羟基苯基)乙基]环己醇可以按照美国专利号4,535,186(Husbands等)的实施例26中描述的方法制备，该专利引入本文作为参考。可以理解，可以通过本领域已知的常规拆分技术将对映体相互分离。
或者，这些R和S对映体可以通过将分离的文拉法辛对映体用三溴化硼或乙硫醇阴离子进行O-去甲基化制得。
式I的O-α-酰氧基烷基醚及其可药用盐和水合物可用于本领域已知的文拉法辛及其盐的生物学和药理学活性。这些O-α-酰氧基烷基醚可用于治疗或抑制中枢神经系统疾病，包括抑郁(包括但不仅限于大抑郁、双相性精神障碍和心境恶劣)、纤维肌痛、焦虑、恐慌症、广场恐怖症、创伤后精神紧张性障碍、月经前的烦燥不安(也称为经前期综合征)、注意力缺乏障碍(有或没有多动症)、强迫症(包括拔毛发癖)、社交焦虑症、广泛焦虑症、孤独症、精神分裂症、肥胖、神经性食欲缺乏、神经性食欲过盛、Gilles de la Tourette综合征、血管舒缩性潮红、可卡因和酒精成瘾、性功能障碍(包括早泄)、边缘人格病、慢性疲劳综合征、尿失禁、疼痛(包括但不仅限于偏头痛、慢性背部疼痛、幻肢疼痛、中枢疼痛、神经病性疼痛例如糖尿病性神经病和带状疱疹后神经病)、雷诺氏综合征等。这些化合物还可用于诱导认知力的提高以及用于停止吸烟和使用其它烟草。
本发明还包括在哺乳动物、优选人中治疗、预防、抑制或减轻以上所列疾病的方法，该方法包括，向需要所述治疗的哺乳动物提供药物有效量的本发明化合物。
本文中关于提供本发明的化合物或物质时所用的“提供”是指直接施用所述化合物或物质或者施用可以在体内形成等量化合物或物质的前药、衍生物或类似物。
药物有效剂量包括可以对所述疾病提供缓解或预防作用的剂量。本发明的化合物可以以本领域已知的用于文拉法辛盐酸盐的剂量和药物制剂(例如已知的由Wyeth-Ayerst实验室以Effexor商标名上市销售文拉法辛盐酸盐产品的剂量)提供。应当理解，起始剂量、在此基础上增加的剂量以及最终的每日给药量应由医学专业人员根据各用药者的需要和病症来确定。例如，对于成年人的每日剂量可以从约75mg至约450mg/天，优选约75至约225mg/天。可以施用75mg/天的起始剂量，并按照医学专业人员所确定的逐渐增加剂量。
本发明还包括含有药物有效量的本发明化合物和一种或多种可药用载体或赋形剂的药物组合物。优选的给药方法包括将本发明的化合物用于公开的PCT申请WO99/22724(Sherman等)中所描述的缓释制剂中，该专利申请引入本文作为参考。
通过以下具体实施例对本发明进行描述，但本发明并不受这些实施例的限制。
实施例1
新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯
将4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酚(1g，3.79mmol)、新戊酸氯甲酯(0.75g，5mmol)、无水K2CO3(0.7g，5mmol)和KI(75mg，0.5mmol)在乙腈(50mL)中搅拌并回流过夜。蒸除溶剂并将残余物在乙酸乙酯和水之间进行分配。将乙酸乙酯层干燥(MgSO4)然后蒸发得到作为次要成分的标题化合物。IR(KBr)1758cm-1。MS(+)FAB[M+H]+378.3 C22H35NO4的计算值377。
实施例2
新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯
0℃下，用4小时的时间向ODV(2.0g，7.6mmol)和碳酸银(8.4g，30.4mmol)的乙腈(60mL)溶液中滴加新戊酸碘代甲酯(按照Bodor等，J.Org.Chem.1983，48，5280-5284中的描述制备)(3.4g，14.0mmol)的乙腈(100mL)溶液。将反应混合物用硅藻土(CELITE，Celite Corporation，Lompoc，CA)过滤，然后吸附在活性硅酸镁(60-100目)(FLORISIL，U.S.Silica Company)上并通过柱色谱(FLORISIL，乙酸乙酯∶乙腈9∶1)纯化得到黄色半固体状的标题化合物(0.87g，45％，以68％的转化率计算)：1H NMR(CD3CN)δ0.78-1.0(m，2H)，1.19(s，9H)，1.15-1.35(m，4H)，1.4-1.7(m，4H)，2.2(s，6H)，2.25(dd，J＝11.2，4.5Hz，1H)，2.94(dd，J＝11.2，4.5Hz，1H)，3.22(t，J＝11.2Hz，1H)，5.7(s，2H)，6.95(d，J＝8.7Hz，1H)，7.13(d，J＝8.7Hz，1H)；13C-NMR(CD3CN)δ22.22，22.44，26.91，27.10(t)，32.83，38.78(t)，39.55(s)，45.71(q)，52.58，61.74，74.45(d)，86.78(t)，116.54，131.48(d)，136.68，156.44，178.05(s)；MS(ESI)m/z 378(M+H)+；进一步以马来酸盐的形式进行鉴定。分析(C26H39NO8-0.25H2O)计算值：C：62.69，H：7.99，N：2.81，实测值：C：62.68，H：7.68，N：2.65。
将硅藻土滤饼加入盐水中并用乙酸乙酯萃取。蒸除溶剂得到0.65g(33％)回收的ODV。
实施例3
新戊酸4-[(1R)-2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酯
0℃下，向ODV(3.0g，11.4mmol)和碳酸银(12.6g，45.6mmol)的乙腈(300mL)溶液中于16小时内分8等份加入新戊酸碘代甲酯(按照Bodor等，J.Org.Chem.1983，48，5280-5284中的描述制备)(6.9g，28.5mmol)的乙腈(40mL)溶液。将反应混合物用硅藻土(CELITE，Celite Corporation，Lompoc，CA)过滤，然后吸附在活性硅酸镁(60-100目)(FLORISIL，U.S.Silica Company)上并通过柱色谱(FLORISIL，乙酸乙酯∶乙腈9∶1)纯化得到白色泡沫状标题化合物(1.15g，39％，以60％的转化率计算)：1H NMR(CD3CN)δ0.78-1.0(m，2H)，1.19(s，9H)，1.15-1.35(m，4H)，1.4-1.7(m，4H)，2.2(s，6H)，2.25(dd，J＝11.2，4.5Hz，1H)，2.94(dd，J＝11.2，4.5Hz，1H)，3.22(t，J＝11.2Hz，1H)，5.7(s，2H)，6.95(d，J＝8.7Hz，1H)，7.13(d，J＝8.7Hz，1H)；13C-NMR(CD3CN)δ22.22，22.44，26.91，27.10(t)，32.83，38.78(t)，39.55(s)，45.71(q)，52.58，61.74，74.45(d)，86.78(t)，116.54，131.48(d)，136.68，156.44，178.05(s)；[α]20 D-5.95°(c1.00，MeOH)；MS(ESI)m/z378(M+H)+。
将硅藻土滤饼加入盐水中并用乙酸乙酯萃取。蒸除溶剂得到1.2g(40％)回收的ODV。
实施例4
新戊酸4-[(1S)-2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯酯
0℃下，向ODV(4.0g，15.2mmol)和碳酸银(16.8g，60.8mmol)的乙腈(400mL)溶液中于9小时内加入新戊酸碘代甲酯(按照Bodor等，J.Org.Chem.1983，48，5280-5284中的描述制备)(8.3g，34.3mmol)的乙腈(150mL)溶液。将反应混合物用硅藻土(CELITE，Celite Corporation，Lompoc，CA)过滤，然后吸附在活性硅酸镁(60-100目)(FLORISIL，U.S.Silica Company)上并通过柱色谱(FLORISIL，乙酸乙酯∶乙腈9∶1)纯化得到澄清的粘稠油状标题化合物(1.58g，48％，以57％的转化率计算)：1H NMR(CD3CN)δ0.78-1.0(m，2H)，1.19(s，9H)，1.15-1.35(m，4H)，1.4-1.7(m，4H)，2.2(s，6H)，2.25(dd，J＝11.2，4.5Hz，1H)，2.94(dd，J＝11.2，4.5Hz，1H)，3.22(t，J＝11.2Hz，1H)，5.7(s，2H)，6.95(d，J＝8.7Hz，1H)，7.13(d，J＝8.7Hz，1H)；13C-NMR(CD3CN)δ22.22，22.44，26.91，27.10(t)，32.83，38.78(t)，39.55(s)，45.71(q)，52.58，61.74，74.45(d)，86.78(t)，116.54，131.48(d)，136.68，156.44，178.05(s)；[α]20 D+7.23°(c1.00，MeOH)；MS(ESI)m/z378(M+H)+。
将硅藻土滤饼加入盐水中并用乙酸乙酯萃取。蒸除溶剂得到1.7g(43％)回收的ODV。
实施例5
新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯
马来酸盐
向按照实施例1中的描述制备的新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}-甲酯(0.032g，0.085mmol)的THF(1.0mL)溶液中于室温下加入马来酸(0.007g，0.06mmol)的THF(1.0mL)溶液。将混合物升温并用己烷稀释。将溶液冷却，滤出形成的结晶得到白色固体状的所需马来酸盐：mp 112-113℃，1H NMR(DMSO-d6)δ0.9-1.6(m，10H)，1.13(s，9H)，2.7(br.s，6H)，2.97(m，1H)，3.55(m，2H)，4.59(br.s，1H)，5.78(s，2H)，6.02(s，2H)，7.03(d，J＝8.6Hz，1H)，7.33(d，J＝8.6Hz，1H)，8.4(br.s，1H)；MS(ESI)m/z 378(M+H)+；(C26H39NO8-0.25H2O)计算值：C：62.69，H：7.99，N：2.81，实测值：C：62.68，H：7.68，N：2.65。
Claims (11)
1.式(I)化合物或其可药用盐或水合物在制备用于治疗哺乳动物中枢神经系统疾病的药物中的应用：
其中
手性中心(*)的构型是R、S或RS外消旋体；
R1选自C1-C6烷基；
R2选自H或C1-C6烷基。
2.权利要求1的应用，其中R2是C1-C6烷基。
3.权利要求1的应用，所述化合物是新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯或其可药用盐或水合物。
4.权利要求1至3中任意一项所述的应用，其中的中枢神经系统疾病选自如下的一种或多种：抑郁；广泛焦虑症；恐慌症；创伤后精神紧张性障碍；注意力缺乏障碍，伴有或不伴有多动症；焦虑；精神分裂症；可卡因成瘾；酒精成瘾；月经前的烦燥不安和孤独症。
5.权利要求1至3中任意一项所述的应用，其中的中枢神经系统疾病是神经性食欲缺乏、神经性食欲过盛、血管舒缩性潮红和慢性疲劳综合征。
6.权利要求1至3中任意一项所述的应用，其中的中枢神经系统疾病是尿失禁。
7.权利要求1至3中任意一项所述的应用，其中的中枢神经系统疾病是疼痛。
8.权利要求1至3中任意一项所述的应用，其中的中枢神经系统疾病是性功能障碍。
9.式(I)化合物或其可药用盐或水合物在制备用于提高哺乳动物认知力的药物中的应用：
其中
手性中心(*)的构型是R、S或RS外消旋体；
R1选自C1-C6烷基；
R2选自H或C1-C6烷基。
10.权利要求9的应用，其中R2是C1-C6烷基。
11.权利要求9的应用，所述化合物是新戊酸{4-[2-(二甲基氨基)-1-(1-羟基环己基)乙基]苯氧基}甲酯或其可药用盐或水合物。
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| KR20030058931A (ko) | 2003-07-07 |
| EP1232141B1 (en) | 2004-10-06 |
| SI1232141T1 (en) | 2004-12-31 |
| CZ20021816A3 (cs) | 2002-08-14 |
| HK1045835A1 (zh) | 2002-12-13 |
| IL149531A0 (en) | 2002-11-10 |
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| PL355171A1 (en) | 2004-04-05 |
| KR100843991B1 (ko) | 2008-07-07 |
| PT1232141E (pt) | 2004-12-31 |
| ATE278659T1 (de) | 2004-10-15 |
| CN1198793C (zh) | 2005-04-27 |
| DE60014693T2 (de) | 2005-03-10 |
| DK1232141T3 (da) | 2004-11-29 |
| AR024498A1 (es) | 2002-10-02 |
| IL149531A (en) | 2008-12-29 |
| ZA200204986B (en) | 2003-09-27 |
| MXPA02005174A (es) | 2002-11-07 |
| CA2391288A1 (en) | 2001-05-31 |
| WO2001038293A1 (en) | 2001-05-31 |
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| AU767835B2 (en) | 2003-11-27 |
| EP1232141A1 (en) | 2002-08-21 |
| HUP0203594A2 (en) | 2003-02-28 |
| JP2003514889A (ja) | 2003-04-22 |
| AU1783301A (en) | 2001-06-04 |
| BR0015795A (pt) | 2002-07-23 |
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