CN1578782A - 硅化合物 - Google Patents
硅化合物 Download PDFInfo
- Publication number
- CN1578782A CN1578782A CNA028217349A CN02821734A CN1578782A CN 1578782 A CN1578782 A CN 1578782A CN A028217349 A CNA028217349 A CN A028217349A CN 02821734 A CN02821734 A CN 02821734A CN 1578782 A CN1578782 A CN 1578782A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- hydrogen
- methoxy
- phenyl
- 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.)
- Pending
Links
- 150000003377 silicon compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- -1 alkanamido Chemical class 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 229940002612 prodrug Drugs 0.000 claims abstract description 5
- 239000000651 prodrug Substances 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
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- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
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- 229910052757 nitrogen Inorganic materials 0.000 abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 4
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 2
- 125000004663 dialkyl amino group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
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- 238000000034 method Methods 0.000 description 27
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 15
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
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- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
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- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 6
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 6
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 5
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- 238000006243 chemical reaction Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000002858 neurotransmitter agent Substances 0.000 description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 5
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
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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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Abstract
式(I)化合物,其中R1和R2独立地是氢或烷基,或一起与氮原子形成杂环基;R3和R4独立地是氢、羟基、烷基、烷氧基、烷酰氧基、氰基、硝基、烷基硫基、氨基、烷基氨基、二烷基氨基、烷酰胺基、卤素或三氟甲基;R5是氢或烷基;n是0、1、2、3或4;或其可药用盐或可水解为上述定义化合物的前体药物形式。
Description
发明领域
本发明涉及化合物以及它们的治疗应用。
发明背景
去甲肾上腺素、5-羟基色胺(5-HT,5-羟色胺)和多巴胺是哺乳动物的一元胺神经递质。
去甲肾上腺素(降肾上腺素)在交感神经系统中担当神经递质,并作为激素贯穿全身。其神经递质的作用包括调节情绪,同时,其激素的功效包括控制血压、心率、呼吸以及肠胃道的收缩。
5-HT是广泛分布于全身,包括血小板、肠壁和中枢神经系统(CNS)。5-HT在炎症反应中起到类似于组胺的作用。在中枢神经系统中,它也作为神经递质在控制情绪方面起作用。多巴胺是一种儿茶酚胺,贯穿全身对多巴胺和肾上腺素能受体起作用。同时,它也刺激神经末端释放去甲肾上腺素。多巴胺影响控制运动、情绪反应和经历快乐与痛苦的能力的脑过程。多巴胺相当程度地牵涉到帕金森病中并在成瘾中起作用。
选择性地调节这些神经递质活性的化合物,单独地或以任意组合,可以充当有效的治疗剂治疗许多种不同的中枢神经系统或外周神经系统疾病。比如,关于慢性疼痛综合征如神经病性疼痛的发生机理还并不很清楚,但是调节从外周神经到中枢神经系统的伤害性传导的脊椎上(supraspinal)和脊柱事件能够由5-HT和去甲肾上腺素途径介导。5-HT途径也被认为在调节内啡肽效应中具有作用。因此,这些一元胺可以在慢性疼痛信号的传递中起重要的作用。
文拉法辛,即,1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]环己烷-1-醇是一种抗抑郁药物,其制备法公开在US 4535186中。在Montgomery,J.Clin.Psychiatry,
54,119-126(1993)中包含有关其药理学以及临床效力的综述。文拉法辛是一种5-羟色胺/去甲肾上腺素的重摄取抑制剂。然而,与其作为一种药物使用相关联,具有包括,恶心、失眠症、头痛、眩晕、出汗以及偶发性惊厥在内的副作用。
药物的硅杂-取代(C/Si-交换)是日前为寻找具有有利生物学特性的有机硅化合物的方法。这一方法包括用硅取代化合物中特定的碳原子,并监测所述化合物的生物学特性如何变化。该方法的综述提供在Tacke和Zilch,Endeavour,New Series,
10,191-197(1986)中。
发明概要
本发明提供包含硅原子并具有所希望特性的化合物。
本发明的化合物具有式1:
其中R1和R2独立地是氢或烷基,或一起与氮原子形成杂环;
R3和R4独立地是氢、羟基、C1-6烷基、烷氧基、烷酰氧基、氰基、硝基、烷基硫基、氨基、烷基氨基、二烷基氨基、烷酰氨基、卤素或三氟甲基;
R5是氢或烷基;和
n是0、1、2、3或4;
或其可药用盐或是可代谢为上述定义化合物的前体药物形式。
本发明化合物与母体化合物比较,可以具有改良的药理学特征。例如,所述化合物可以更好地被患者耐受,或具有改良的药物代谢动力学特征。
发明内容
用于此处的术语“烷基”指具有1-6个碳原子的直链或支链烷基部分,包括例如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基以及类似的。“C1-6烷基”具有同样的含义。
用于此处的术语“烷氧基”指包含1-6个碳原子的直链或支链烷氧基基团,包括例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基以及类似的。“C1-6烷氧基”具有同样的含义。
用于此处的术语“卤素”指F、Cl、Br或I。
用于此处的术语“杂环基”指具有4-7个碳原子和1个或更多个选自N、O、S、P和Si的杂原子的饱和或不饱和的杂环部分,包括,例如哌啶基、吡咯烷基、吗啉基等。
用在此处的术语“烷酰氧基”指具有1-6个碳原子的直链或支链烷酰氧基部分。
用在此处的术语“烷基硫基(alkylmercapto)”指包含1-6个碳原子的直链或支链烷基硫基部分,包括例如甲基硫基。
术语“烷基氨基”指包含1-6个碳原子的直链或支链烷基氨基部分,包括例如甲基氨基。
术语“二烷基氨基”指二烷基氨基部分,其中每一个烷基基团如上定义。这一术语包含例如二甲基氨基。
术语“烷酰氨基(alkanamido)”指包含有2-6个碳原子的直链或支链烷酰氨基部分,包括例如甲酰氨基。
关于通式I,R1优选是氢或C1-3烷基,更优选甲基。R2优选是C1-3烷基,更优选甲基。R1和R2也可以形成杂环,例如NR1R2可以形成吗啉基基团或哌啶基基团。R3和R4优选是氢和烷氧基。更优选R3是氢以及R4是甲氧基。R5优选是氢。也优选n是0、1或2。更优选n为2。
本发明优选的化合物包括:
1-[2-二甲氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇;
1-[2-二甲氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环丁烷-1-醇;和
1-[2-二甲氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环戊烷-1-醇。
本发明的化合物是手性的。它们可以是单个对映体或非对映体、或外消旋物的形式。
本发明的化合物可以以外消旋形式制备,或通过本领域理解的特定合成或拆分以单个对映体形式来制备。例如,化合物可以用标准技术拆分成其对映体,例如经与光学活性酸形成盐而形成非对映体对,然后分级结晶和再生游离碱。作为选择方案,本发明新化合物的对映体可以用手性柱通过HPLC分离。
本发明的化合物可以是一种被保护的氨基形式。用在此处的术语“被保护的氨基”指用本领域技术人员熟悉的方法保护的氨基基团。例如,氨基基团可以被苄氧羰基、叔丁氧羰基、乙酰基或类似的基团保护,或可以是苯二(甲)酰亚氨基或类似的基团形式。
该通式的有些化合物可以以溶剂化物例如水合物的形式存在,它们也是在本发明范围之内。
本发明化合物可以以前体药物的形式存在。在这一方面,与硅原子连接的羟基(OH)基团可以包含在合适的条件下被修饰或移去从而提供活性形式化合物的基团。合适的基团对于技术人员来说是显而易见的,包括替代硅原子上的OH基团并能够被水解形成OH基团的基团。比如,适宜的替代基团包括H、OR6、N(R6)2、或NHR6,其中R6是烷基,优选甲基。可水解的包含磷或包含硫的基团也可以用于前体药物形式中。
本发明化合物可以是可药用盐,比如,无机或有机酸的加成盐的形式。这样的无机酸加成盐包括,例如氢溴酸、氢氯酸、硝酸、磷酸、和硫酸的盐。有机酸加成盐包括,如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、2-(4-氯苯氧基)-2-甲基丙酸、1,2-乙二磺酸、乙磺酸、乙二胺四乙酸(EDTA)、富马酸、葡庚糖酸、葡糖酸、谷氨酸、N-乙醇酰阿散酸、4-己基间苯二酚、苯甲酰氨基乙酸(hippuric acid)、2-(4-羟苯甲酰基)苯甲酸、1-羟基-2-萘甲酸、3-羟基-2-萘甲酸、2-羟乙磺酸、乳糖酸、正十二烷基硫酸、马来酸、苹果酸、扁桃酸、甲磺酸、甲基硫酸(methyl sulphate)、粘酸、2-萘磺酸、pamoic acid、泛酸、phosphanilic acid((4-氨基苯基)膦酸)、苦味酸、水杨酸、硬脂酸、琥珀酸、单宁酸、酒石酸、对苯二酸、对甲苯磺酸、10-十一碳烯酸的盐以及类似物。
盐也可以是与无机碱形成的。这样的无机碱盐包括,如铝、铋、钙、锂、镁、钾、钠、锌以及类似物的盐。
将会理解,只要它们是药学可接受的,这些盐可以用于治疗之中。这些盐可以通过将化合物以常规方法与合适的酸或碱反应来制备得到。
本发明化合物可以用本领域已知的任何合适方法和/或用下述显示在方案1和2中的方法进行制备。
方案1
方案2
可以理解,上述详细描述的方法仅仅为了举例说明本发明,而不应被理解为限制性的。利用本领域技术人员已知的相似或类似的试剂和/或条件的方法也可以用于得到本发明化合物。尤其是,包含方案1和2中所举例说明的基团R1到R5的替代方案的本发明化合物可以通过类似的方法来合成,所述替代基团在通式I的范围内。
得到的最终产物或中间体的任何混合物可以用公知的方法,在组成成分理化特性不同的基础上分离成纯的最终产物或中间体,例如,在这种情况下,如果合适或可能,可以通过层析、蒸馏、分级结晶、或形成盐来分离。
化合物活性以及选择性可以用本领域已知的任何合适的方法进行测定。
用于此处的术语“活性化合物”表示通式I化合物,包括其可药用盐。
本发明化合物可以用于治疗众多失调、状况和疾病,包括,但不限于,成瘾、焦虑、抑郁、性功能障碍、高血压、偏头痛、阿尔茨海默病、肥胖症、呕吐、精神病、精神分裂症、帕金森病、多动腿综合征、睡眠障碍、注意缺陷多动症、肠易激惹综合征、早泄、经期焦虑综合征、经前期紧张、尿失禁、包括炎性疼痛、神经病性疼痛、慢性头痛以及慢性疼痛在内的疼痛、Lesche-Nyhane病、威尔逊病以及图雷特综合征。
在治疗应用中,活性化合物可以通过口服、直肠、肠胃外、吸入(肺递送)、局部、眼、鼻部途径给药、或给药至口腔。优选口服给药。这样,本发明治疗组合物可以采用用于这样的给药方法的任何已知药用组合物的形式。该组合物可以用本领域技术人员已知的方法进行配制从而得到本发明化合物的控制释放,如快速释放或持续释放。适合用于这样的组合物可药用载体是本领域熟知的。本发明组合物可以包含0.1-99%重量的活性化合物。一般地,本发明组合物以单位剂量形式制备。优选单位剂量包含活性成分的量为1-500mg。用于制备这些组合物的赋形剂是本领域已知的赋形剂。
投入剂量优选与文拉法辛的剂量相同。比如,初始剂量可以是10-100mg,每天2-3次,或对严重受疾病侵袭的患者可以多达每天150-400mg。
合适的剂量水平可以由本领域技术人员已知的任何适当方法来确定。然而,可以理解,对于任何特定患者来说,特定剂量水平将依赖于各种的因素,包括所用特定化合物的活性、年龄、体重、健康状况、性别、饮食、投药时间、投药途径、排泄率、药物的组合以及所治疗的疾病的严重程度。
用于口服的组合物是本发明任选的组合物,用于这样的投用方式有例如,片剂、胶囊、颗粒、糖浆、水性、或油性悬浮液等的已知药物形式。包含活性成分的药用组合物可以是一种适合于口服的形式,如,片剂、锭剂、糖锭、水性或油性悬浮液、可分散的粉末或颗粒、乳剂、硬或软胶囊、或糖浆剂或酏剂。准备用于口服的组合物可以按照任何本领域生产药用组合物的已知方法进行制备,而且为了提供药学上精致而可口的制备物,这样的组合物可以包含一种或一种以上选自增甜剂、增香剂、着色剂和防腐剂的物质。片剂含有与适合于片剂生产的非毒性可药用赋形剂混合的活性成分。这些赋形剂可以是,例如惰性稀释剂例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒或崩解剂例如玉米淀粉或褐藻酸;粘合剂例如淀粉明胶、阿拉伯树胶、微晶纤维素或聚乙烯吡咯烷酮;以及润滑剂如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的或为了延缓在肠胃道内的崩解以及吸收,可以用已知技术进行包衣,从而提供了较长时期的持续作用。例如,可以用如甘油一硬脂酸酯或甘油二硬脂酸酯等延时材料。
口服用的制剂也可以表现为硬明胶胶囊,其中活性成分与如碳酸钙、磷酸钙或陶土等惰性固体稀释剂混合,或表现为软明胶胶囊存在,其中活性成分与如花生油、液状石蜡或橄榄油等水或油介质混合。
水性悬浮液含有与适合于水性悬浮液制备的赋形剂混合的活性成分。这样的赋形剂是如羧甲基纤维素钠、甲基纤维素、羧丙基甲基纤维素、褐藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶等悬浮剂;分散剂或湿润剂可以是自然存在的磷脂,如卵磷脂、或一种烯化氧与脂肪酸的缩合产物,如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪族醇的缩合产物,如十七乙烯氧基十六醇,或环氧乙烷与来源于脂肪酸的偏酯的缩合产物,如聚氧乙烯脱水山梨糖醇一油酸酯。水性悬浮液也可以包含一种或一种以上防腐剂,如对羟基苯甲酸乙基或正丙基酯,一种或一种以上着色剂,一种或一种以上调味剂,以及一种或一种以上增甜剂,如蔗糖或糖精。
油性悬浮液可以通过将活性成分悬浮在植物油,如落花生油、橄榄油、芝麻油或椰子油、或在矿物油如液体石蜡中来配制。油性悬浮液可以包含增稠剂,如蜂蜡、硬石蜡或十六(烷)醇。可以加入增甜剂例如上述那些和调味剂,以提供可口的口服制备物。这些组合物可以由加入如抗坏血酸等抗氧化剂来保存。
适合于通过加水进行水性悬浮液制备的可分散粉末和颗粒提供了活性成分和分散或湿润剂、悬浮剂和一种或一种以上防腐剂混合物。适合的增甜剂、增香剂和着色剂也可以存在。
本发明药用组合物也可以是水包油乳状液形式。油相可以是如橄榄油或落花生油等植物油,或如液体石蜡等矿物油,或这些的混合物。合适的乳化剂可以是自然存在的橡胶如阿拉伯树胶或黄蓍胶,自然存在的磷酯如大豆、卵磷脂、和来自脂肪酸和己糖醇酐的酯或偏酯,如脱水山梨糖醇一油酸酯和所述偏酯与环氧乙烷的缩合产物如聚氧乙烯脱水山梨糖醇一油酸。乳状液也可以包含增甜剂和增香剂。
糖浆剂和酏剂可以与增甜剂,如丙三醇、丙二醇、山梨(糖)醇或蔗糖一起配制。这样的配制物也可以包含一种缓和剂(润滑剂)、防腐剂以及增香和着色剂。药用组合物可以是一种无菌可注射水性或油质悬浮液形式。该悬浮液可以按照本领域已知的方法使用那些上述提及的合适的分散或湿润剂和悬浮剂来配制。无菌可注射制备物也可以是一种存在于无毒性可肠胃外用稀释液或溶剂中的无菌注射液体或悬浮液,如一种溶于1,3-丁二醇中的溶液。在可接受的载体和溶剂中可以使用,水、林各溶液(Ginger’s solution)和等压氯化钠溶液。另外,无菌的不挥发油常规地是作为溶剂或悬浮介质使用。为了该目的,可以用任何刺激性小的不挥发油,包括合成的甘油单酯或甘油二酯。另外,如油酸这样的脂肪酸可用在注射剂制备中。
通式I的化合物也可以以用于药物直肠投入的栓剂形式给药。这些组合物能够通过混合药物与合适的非刺激性赋形剂而配制成,该赋形剂在常温下是固体而在肠温下成为液体,从而在直肠中融合而释放药物。这样的物质有可可油(cocoa butter)和聚乙二醇。
局部给药的组合物也适合于本发明。药物活性化合物可以分散在可药用的乳膏、油膏或凝胶中。适合的乳膏可以通过将活性化合物掺入在如轻液体石蜡等局部用载体中、用表面活性剂分散在水性介质中进行制备。油膏可以通过将活性化合物与例如矿物油或蜡等局部用载体混合进行制备。凝胶可以通过将活性化合物与包含有成凝胶剂的局部用载体混合进行制备。可局部投药的组合物也可以包含这样一种基质,其中本发明的药物活性化合物被分散在基质中,使得化合物与皮肤保持接触,以经皮投用化合物。
以下实施例用来举例说明本发明。除了9→10和15→16的转化外,所有合成是在干燥氮气条件下进行。四氢呋喃、二乙醚、甲醇、三乙胺和正己烷按照标准程序进行干燥和纯化,在氮气下贮存。
附注数字的化合物是显示在上述方案1和2中的那些化合物。四氯硅烷(1)和四甲氧硅烷(4)是市售可得到的。关于中间体2、3、11和12的制备,类似的方法公开于R.West,J.Am.Chem.Soc.1954,76,6012-6014。
中间体2:1,1-二氯-1-硅杂环己烷(2)
将溶于二乙醚(300mL)的50ml的1,5-二溴戊烷(161g,700mmol)溶液加入到二乙醚(400mL)中的镁屑的搅拌悬浮液(37.4g,1.54mol)中,通过温和加热开始反应。随后,在2小时内加入剩余的1,5-二溴戊烷溶液,在回流下引起反应混合液沸腾。加样完成以后,混合液在回流下再加热90分钟,然后冷却至20℃。得到的二相格氏试剂(Grignard reagent)(通过倾析从残剩镁屑中分离出,然后经二乙醚(2×50mL)洗脱镁)在2小时以内逐滴地加入到溶于二乙醚(300mL)的1(131g,771mmol)的溶液中,回流下使混合液沸腾。在加样过程中,用机械搅拌器剧烈搅拌混合液(镁盐沉淀)。混合液在20℃下搅拌16小时,沉淀物通过过滤去除,并用二乙醚(2×200mL)进行冲洗。将过滤液和洗液合并在一起,在大气压下通过蒸馏除去溶剂,从而引起镁盐的继沉淀。通过倾析去除沉淀物,用正戊烷(2×50mL)洗涤,然后合并有机溶液。如上所述去除溶剂,粗产物通过蒸馏分离,bp166-178℃/980mbar。减压下的再蒸馏(Vigreux柱,30cm)提供了一种作为无色液体(72.9g,431mmol)的产量在62%(相对于1,5-二溴戊烷)的2,bp 70-71℃/37mbar。
中间体3:1,1-二甲氧基-1-硅杂环己烷(3)
方法A:将甲醇(34.8g,1.09mol)在10分钟内逐滴加到搅拌的溶于正己烷(500mL)中的2(83.2g,492mmol)和三乙胺(110g,1.09mol)的溶液中,回流下引起反应混合液沸腾(形成沉淀物)。当加样完成以后,在回流下将混合液再加热2小时,然后冷却到20℃,在这一温度下,保持静止16小时。用布氏漏斗通过吸滤(700-750mbar)去除沉淀物,用正己烷(1.5L)彻底洗涤。将过滤液和洗涤溶液合并,在大气压下(Vigreux柱,20cm)通过蒸馏将溶剂除去,然后,真空下将残余物蒸馏(Vigreux柱,20cm)得到包含有少量固体物质的粗产物3(69g,bp 70-75℃/30mbar)。馏出液用正戊烷(150mL)稀释,将混合液在4℃下静止保持16小时,通过过滤除去形成的沉淀物。滤饼用正戊烷(20mL)洗涤,滤液和洗涤液合并。在大气压下(Vigreux柱,30cm)通过蒸馏除去溶剂,真空下(Vigreux柱,30cm)将残余物蒸馏得到产量为80%的为无色液体的3(62.8g,392mmol);bp 62℃/20mbar。
方法B.类似于方法A(参考上面),从镁屑(22.0g,905mmol)、1,5-二溴戊烷(46.0g,200mmol)和二乙醚(200mL)制备1,5-二(溴镁)戊烷(1,5-bis(bromomagnesio)pentane)。在1小时时间内0℃环境下将双相格氏试剂加入溶于二乙醚(500mL)的4(45.7g,300mmol)的剧烈搅拌的溶液中(形成沉淀物)。加样完成以后,混合物在回流下加热16小时,然后冷却到20℃。通过过滤移去沉淀物,并用二乙醚(3×50mL)洗涤,滤液和洗涤液合并在一起,减压下去除溶剂,残余物在真空下蒸馏2次,得到产量为43%(相对于1,5-二溴戊烷)的为无色液体的3(13.9g,86.7mmol);bp 75℃/36mbar。
中间体5:4-甲氧基苯乙酮2,4,6-三异丙基苯磺酰腙(5)
按照描述在Chamberlin等,J.Org.Chem.1978,43,147-154(那里称作方法A)的一般方法合成该化合物;也参照Yu等,Chem.Eur.J.1997,3,417-423.
中间体6和7:1-(4-甲氧基苯基)乙烯基锂(6)和1-甲氧基-1-[1-(4-甲氧基苯基)乙烯基]-1-硅杂环己烷(7)。
将溶于正庚烷(70mL,189mmol的n-BuLi)中的2.7M的正丁基锂溶液在-78℃在50分钟内逐滴加入由5(40.0g,92.9mmol)、N,N,N’,N’-四甲基乙二胺(40mL)和正己烷(360mL)组成的搅拌混合物中。形成的黄色混合物在-78℃下搅拌2小时,然后让其温度上升至0℃(放出氮;颜色变为桔黄;形成1-(4-甲氧基苯基)乙烯基锂(6))。氮的放出完成后,将混合物在20℃下进一步搅拌10分钟,然后在0℃在30分钟内逐滴加入到正己烷(100mL)中的3(15.0g,93.6mmol)的溶液中。使形成的混合物温度上升至20℃(在大约12小时内颜色由桔黄变成黄色),搅拌3天。形成的清澈黄色溶液在冰浴中冷却,并加入碘代甲烷(125g,881mmol)(形成沉淀物)。2小时以后,移去冰浴,在20℃下继续搅拌1天。用过滤移去沉淀物,并用正己烷(4×250mL)进行洗涤,将过滤液和洗涤液合并。在减压下(300mbar,40℃;旋转蒸发器)将溶剂去除,残余物在真空下蒸馏(Kugelrohr装置;第一级分:≤90℃/0.001mbar,丢弃;第二级分:90-145℃/0.001mbar,粗产物)。将三轮同样的该制备的粗产物合并(→43.0g),并在真空下蒸馏(Vigreux柱,15cm),得到产量为45%(相对于3)的为无色油状液体的7(33.2g,127mmol);bp 105℃/0.001mbar。
中间体8:1-[1-(4-甲氧基苯基)乙烯基]-1-硅杂环己烷(8)。
在20℃10分钟内,将二乙醚(50mL)中的7(32.0g,122mmol)的溶液加入到溶于二乙醚(200mL)的氢化锂铝(2.48g,65.3mmol)的悬浮搅拌液中。混合液在回流下加热2小时后,让其冷却至20℃,然后在0℃缓慢地加到4M盐酸(210mL)和二乙醚(100mL)的搅拌混合液中。有机相被分离,水层用二乙醚(3×100mL)萃取。合并的有机溶液,在冰浴上用无水硫酸镁干燥,之后使用密实充填了无水硫酸镁的层析柱(柱直径,3.5cm;柱长度,15cm)进行额外的彻底动态干燥。最后用二乙醚(500mL)洗脱硫酸镁,合并有机溶液。溶剂在800-900mbar(旋转蒸发器)被移去,真空下蒸馏残余物(Vigreux柱,15cm),得到一种产量为82%的无色油性液体的8(23.3g,100mmol);bp 91-92℃/0.001mbar。
中间体9:1-二甲基氨基-1-[2-二甲基氨基-1-(4-甲氧苯基)乙基]-1-硅杂环己烷(9)
在-50℃5分钟内将1.6M的溶于正己烷的正丁基锂溶液(9.5mL,15.2mmol n-BuLi)逐滴加到溶于四氢呋喃(150mL)的二甲胺(5.51g,122mmol)搅拌溶液中,使形成的混合液在4小时内温度上升到-15℃,然后冷却至-35℃,接着在10分钟内逐滴加入8(3.20g,13.8mmol)(放出氢;温度从-35℃上升到-30℃)。形成的黄色溶液在-30℃下搅拌3小时,然后在-26℃下保持静止16小时。随后,将溶液放置在冰浴上再次搅拌然后将氯三甲基硅烷(1.72g,15.8mmol)一次性加入(颜色从黄色变为无色)。0℃下混合液搅拌30分钟,真空下在水浴中(5-15℃)完全除去溶剂,然后加入正己烷(40mL)。将混合液在20℃下搅拌30分钟,通过过滤除去形成的沉淀物,并用正己烷(20mL)洗涤过滤饼。合并过滤液以及洗涤液,在真空水浴中(5-15℃)完全去除溶剂,残余物真空下(Vigreux柱,5cm)蒸馏,得到一种产率为76%的无色油性液体的9(3.37g,10.5mmol);bp 115-118℃/0.003mbar。
中间体11:1,1-二氯-1-硅杂环戊烷(11)。
该化合物由类似于2的合成(1,4-二溴丁烷(151g,699mmol)、镁屑(37.4g,1.54mol)、1(131g,771mmol))来制备。在大气压下蒸馏后(Vigreux柱,15cm;71g的粗产物;bp 141-145℃),真空下再蒸馏(Vigreux柱,30cm),以产率61%(相对于1,4-二溴丁烷)的无色液体分离出化合物11(66.2g,427mmol);bp 71-73℃/100mbar。
中间体12:1,1-二甲氧基-1-硅杂环戊烷(12)
该化合物由类似3的合成方法A(11(66.2g,427mmol)、甲醇(30.4g,949mmol)、三乙胺(96.1g,950mmol))来制备。在大气压下蒸馏以后(Vigreux柱,15cm;53g的粗产物;bp 136-144℃),真空下再蒸馏,分离出产量为74%的无色液体的化合物12(46.2g,316mmol);bp 73℃/mbar。
中间体13:1-甲氧基-1-[1-(4-甲氧基苯基)乙烯基]-1-硅杂环戊烷(13)
在-78℃50分钟内,将溶于正庚烷(70mL,189mmol的n-BuLi)的2.7M正丁基锂逐滴加到由5(40.0g,92.9mmol)、N,N,N’,N’-四甲基乙二胺(40mL)、正己烷(360mL)组成的搅拌混合液中。形成的黄色混合物在-78℃下搅拌2小时,然后使之温度上升至0℃(氮放出;颜色变成桔黄色;形成1-(4-甲氧基苯基)乙烯基锂(6))。氮释放完成后,混合液进一步在20℃下搅拌10分钟,然后在-55±5℃下30分钟内逐滴加到溶于正己烷(200mL)的12(14.3g,97.8mmol)的溶液中。使形成的混合液2小时内上升至-30℃,然后在下一个15小时内使之上升到10℃,最后20℃下搅拌1天。将所形成的清澈黄色溶液在冰浴上冷却,并加入碘代甲烷(125g,881mmol)(形成沉淀物)。2小时以后,移开冰浴,继续在20℃下搅拌1天。通过过滤除去沉淀物,并用正己烷洗涤(4×250mL),合并过滤液和洗脱液。在减压下,除去溶剂(300mbar,40℃;旋转蒸发器),真空下蒸馏残余物(Kugelrohr仪器;第一级分:≤90℃/0.001mbar,丢弃;第二级分:90-140℃/0.001mbar,粗产物;15.8g)。真空下蒸馏(Vigreux柱,15cm)得到产量为45%(相对于12)、为无色油性液体(10.9g,43.9mmol)的13;bp 90℃/0.001mbar。
中间体14:1-[1-(甲氧基苯基)乙烯基]-1-硅杂环戊烷(14)。
该化合物由类似于8的合成(13(10.7g,43.1mmol)、氢化锂铝(820mg,21.6mmol)、二乙醚(100mL))进行制备,并以产率79%作为无色油性液体(7.45g,34.1mmol)被分离;bp 77℃/0.001mbar。
中间体15:1-二甲基氨基-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环戊烷(15)。
该化合物由类似于9的合成(14(2.52g,11.5mmol)、二甲胺(7.07g,157mmol)、溶于正己烷的1.6M正丁基锂溶液(7.9mL,12.6mmol的n-BuLi)、氯三甲基硅烷(1.46g,13.4mmol)、四氢呋喃(45mL))进行制备,以产量60%、作为无色油性液体(2.13g,6.95mmol)而分离;bp 112-113℃/0.001mbar。
实施例1:1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇(硅杂-文拉法辛,10;与(±)-10相同)。
在-50℃10分钟内将溶于正庚烷(35mL,94.5mmol的n-BuLi)的2.7M正丁基锂溶液逐滴加入到溶于四氢呋喃(100mL)的二甲胺(21.6g,479mmol)的搅拌溶液中。形成的混合物在2小时内温热至-10℃,然后冷却至-40℃,然后在15分钟内逐滴加入8(20.2g,86.1mmol)(氢的释放;温度从-40℃上升到-35℃)。在2小时内使形成的搅拌黄色溶液上升至-20℃,然后在-26℃下保持静止16小时。随后,溶液升温至20℃,在真空水浴(5-15℃)中去除溶剂,直到得到50mL的残余物。该溶液用二乙醚(200mL)稀释,然后在0℃将它一次性加到搅拌的二乙醚(50mL)和2M醋酸钾/醋酸缓冲液(pH4.5,300mL)的二相混合物中。10分钟内水相pH变化为7.2,通过加入少量冰醋酸将pH再调节到5.0。0℃下混合物进一步搅拌1小时,在此期间水相pH保持恒定pH5.0。水层被分离,有机相用1M醋酸钾/醋酸缓冲液(pH5.0)萃取,并将水溶液合并。加入二乙醚(150mL),通过加入少量的饱和碳酸钾水溶液将水相pH调节到10.5。有机层被分离,水相用二乙醚(5×100mL)萃取。合并有机萃取液,之后加入正己烷(200mL)。在真空水浴(5-15℃)下将溶剂去除直到得到100mL的残余物,由此残余水从有机相中分离出(形成二相系统)。有机层被分离,用正己烷(2×100mL)萃取水相,合并有机溶液。在真空水浴(5-15℃)中溶剂完全被去除,得到无色的油。用晶种(通过将溶于正戊烷(5mL)的油性10(3.20g)冷却到-26℃得到)在-26℃从正戊烷(400mL)中结晶该油,提供产量为90%、作为无色结晶固体(22.8g,77.7mmol)的10(通过将冷溶剂快速倾析,然后真空下干燥(0.001mbar,20℃,6小时)而分离得到);mp 33℃。
实施例2:(-)-1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇((-)-硅杂-文拉法辛,(-)-10)。
(a)(-)-硅杂-文拉法辛·(+)-10-樟脑磺酸((-)-10·(+)-CSA)的晶种
在0℃将溶于丙酮(25mL)的(+)-10-樟脑磺酸((+)-CSA)(792mg,3.41mmol)的溶液加到溶于丙酮(25mL)的(±)-10(1.00g,3.41mmol)的溶液中。简单地摇晃一下混合物,在0℃下保持静止。大约10分钟以后,细针型的结晶沉淀出。立即再加入40mL丙酮,将此混合物再4℃下静止放置2天。通过过滤分离沉淀物,用丙酮(20mL)洗涤,从沸腾的丙酮(45mL)中再结晶2次。(为了留下一些晶种,在2次再结晶步骤中,不让固体物质完全溶解)。通过过滤最后分离产物,用丙酮(3mL)洗涤,在真空中干燥(0.001mbar,20℃,6小时),从而得到629mg无色结晶固体物。该物质(长型,非常细的针状)在下列程序中作为晶种。
(b)(-)-硅杂-文拉法辛·(+)-10-樟脑磺酸((-)-10·(+)-CSA)。
在20℃将溶于丙酮中(120mL)的(+)-CSA(4.55g,19.6mmol)的溶液加到溶于丙酮(375mL)的(±)-10(5.75g,19.6mmol)的溶液中。将混合物简单地摇晃一下后,在4℃保持静止2小时。加入一些晶种(见上)以后,将混合物在4℃下保持静止2天。通过过滤分离所形成的沉淀,用丙酮(2×10mL)洗涤,然后从沸腾的丙酮(280mL;在4℃结晶,2天)中重结晶2次。(为了留下一些晶种,在这些重结晶步骤中不完全溶解固体物质)。产物被分离,用以上描述的方法进行洗涤,最后真空下干燥(0.001mbar,20℃,6小时),得到产量为30%(相对于(±)-10)、作为无色结晶固体的(-)-10·(+)-CSA(3.10g,5.90mmol);mp 164℃。
(c)(-)-硅杂-文拉法辛((-)-10)
在20℃将二乙醚(5mL)加到水(85mL)中的(-)-10·(+)-CSA(3.05g,5.80mmol)的搅拌溶液中,并通过加入饱和碳酸钾水溶液将水相的pH调节到10.5。用二乙醚(4×100mL)萃取形成的混合物,合并有机层,之后加入正己烷(200mL)。在真空下水浴(5-15℃)中除去溶剂,直到得到50mL的残余物体积。然后,将混合物保持在-20℃3小时(残留水的结晶)。通过倾析迅速分离有机上清液,分别保存。使该冰融化,形成的水相与正己烷(60mL)一起振荡,将二相系统再次保持在-20℃下3小时。重复倾析过程,合并有机溶液,在真空下水浴(5-15℃)中除去溶剂。形成的无色油被溶解在正庚烷(35mL)中,将该溶液在-20℃中保持静止。大约2-3小时以后,油分离,一些结晶在油滴中生长。然后允许混合物加温至20℃,由此油迅速溶解,而结晶只缓慢溶解。当大多数晶体被溶解后(除了一些晶种外),混合物再次在-20℃下保持静止3天。用倾析分离形成晶状产物,然后在真空中干燥(0.001mbar,20℃,6小时),得到产率为99%的无色晶状固体的(-)-10(1.68g,5.72mmol;包括通过浓缩到10mL处理母液和使用上述结晶方法);mp 64-65℃。
实施例3:(+)-1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇((+)-硅杂-文拉法辛,(+)-1 0).
将在(-)-10·(+)-CSA制备中得到的合并母液(见上)用于(+)-10的制备。为此,母液在真空中浓缩,并如同制备(-)-10所述的用碳酸钾进行处理,再浓缩,然后油性残余物如上所述用(-)-CSA处理。(a)(+)-10·(-)-CSA.产量为32%(相对于(±)-10)的无色结晶固体(3.29g,6.26mmol);mp 164℃。(b)(+)-10.从(+)-10·(-)-CSA(3.23g,6.14mmol)制备;得到产率为94%的无色结晶固体(1.70g,5.79mmol);mp 64-65℃。
实施例4:氯化[2-(1-羟基-1-硅杂环己烷-1-基)-2-(4-甲氧基苯基)乙基]二甲铵(硅杂-文拉法辛盐酸盐,10-HCl).
在20℃将2M HCl乙醚溶液(23mL,46.0mmol的HCl)一次性加入到溶于二氯甲烷(200mL)的10(12.9g,44.0mmol)的搅拌溶液中。形成的溶液冷却到-11℃,将少量晶种(通过在20℃下溶剂的缓慢蒸发从20μL反应混合物中得到)加入。将混合物在-11℃下保持静止1天,然后在-27℃下进一步放置1天。-27℃下通过过滤分离固体,用冰冷丙酮(20mL)进行洗涤,真空下干燥(0.001mbar,20℃,6小时)得到产量为90%(包括母液加工)的无色晶状固体(13.0g,39.4mmol)的10·HCl;mp 160℃。
实施例5:氯化(-)-[2-(1-羟基-1-硅杂环己烷-1-基)-2-(4-甲氧基苯基)乙基]二甲铵((-)-硅杂-文拉法辛盐酸盐,(-)-10·HCl).
在20℃将2M HCl乙醚溶液(1.8mL,3.6mmol的HCl)加入溶于二氯甲烷(19mL)的(-)-10(1.00g,3.41mmol)的溶液中,简单地振荡形成的混合物。在20℃下二乙醚蒸气扩散进入该混合物6天后,通过过滤分离得到的晶状产物,并用二乙醚(40mL)进行洗涤,最后真空下干燥(0.001mbar,20℃,6小时),得到产率为93%、作为无色晶状固体的(-)-10·HCl(1.04g,3.15mmol);mp 174℃。
实施例6:氯化(+)-[2-(1-羟基-1-硅杂环己烷-1-基)-2-(4-甲氧基苯基)乙基]二甲铵((+)-硅杂-文拉法辛盐酸盐,(+)-10·HCl).
用类似于用于制备(-)-10·HCl的方法从(+)-10(1.00g,3.41mmol)制备该化合物,分离为产率为92%的无色结晶固体(1.03g,3.12mmol);mp 174℃。
实施例7:1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环戊烷-1-醇(16)
该化合物的制备类似于10的合成(14(2.54g,11.6mmol)、二甲胺(8.07g,179mmol)、1.6M溶于正己烷的正丁基锂溶液(8.0mL,12.8mmol的n-BuLi)、四氢呋喃(65mL))。从正戊烷(45mL;-11℃(1小时)→-26℃(1天))中结晶油性粗产物,化合物16被分离为产率为54%的无色晶状固体(1.77g,6.33mmol);mp 37℃。
实施例8:氯化[2-(1-羟基-1-硅杂环戊烷-1-基)-2-(4-甲氧基苯基)乙基]-二甲铵(16·HCl)。
在20℃下将2M HCl乙醚溶液(2.0mL,4.0mmol的HCl)一次性加到溶于二氯甲烷(16mL)的16(1.02g,3.65mmol)的搅拌溶液中。在-27℃,将混合物保持静止2小时,加入一些晶种(通过20℃下缓慢蒸发溶剂然后将形成的油冷却到-27℃从20μL反应混合物得到)。形成的混合物在-27℃下保持静止3天,通过-27℃下过滤分离沉淀,并用冰冷丙酮(10mL)洗涤,然后真空下干燥(0.001mbar,20℃,6小时),得到产率为52%的作为无色晶状固体的16·HCl(598mg,1.89mmol);mp 153-154℃。
Claims (13)
2.权利要求1的化合物,其中所述R1和R2独立地是氢或C1-3烷基。
3.权利要求2的化合物,其中所述R1和R2是相同的或不相同的,各自是C1-3烷基。
4.权利要求1-3任一项的化合物,其中所述R3是氢且R4是烷氧基。
5.权利要求4的化合物,其中所述R4是甲氧基。
6.任一前述权利要求的化合物,其中n是0、1或2。
7.权利要求6的化合物,其中n是2。
8.任一前述权利要求的化合物,其中R5是氢。
9.权利要求1的化合物,选自外消旋形式或者对映体形式的
1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇;
1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环丁烷-1-醇;和
1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环戊烷-1-醇。
10.权利要求9的化合物,选自
(-)-1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇;和
(+)-1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]-1-硅杂环己烷-1-醇。
11.任何上述权利要求的化合物,用于治疗用途。
12.用于治疗的药用组合物,其包含权利要求1-10任一项的化合物和可药用载体或稀释剂。
13.权利要求1-10任何一项的化合物用于制备药物的用途,其中所述药物用于治疗或预防成瘾、焦虑、抑郁、性功能障碍、高血压、偏头痛、阿尔茨海默病、肥胖症、呕吐、精神病、精神分裂症、帕金森病、多动腿综合征、睡眠障碍、注意缺陷多动症、肠易激惹综合征、早泄、经期焦虑综合征、经前期紧张、尿失禁、包括炎性疼痛、神经病性疼痛、慢性头痛、慢性疼痛在内的疼痛、Lesche-Nyhane病、威尔逊病或图雷特综合征。
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2001
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2002
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- 2002-10-30 HU HU0401699A patent/HUP0401699A2/hu unknown
- 2002-10-30 JP JP2003540186A patent/JP2005507425A/ja not_active Ceased
- 2002-10-30 WO PCT/GB2002/004900 patent/WO2003037905A1/en not_active Application Discontinuation
- 2002-10-30 KR KR1020047005901A patent/KR20050042000A/ko not_active Application Discontinuation
- 2002-10-30 EP EP02777453A patent/EP1440076A1/en not_active Withdrawn
- 2002-10-30 CN CNA028217349A patent/CN1578782A/zh active Pending
- 2002-10-30 RU RU2004116347/04A patent/RU2004116347A/ru not_active Application Discontinuation
- 2002-10-30 AU AU2002339071A patent/AU2002339071B2/en not_active Expired - Fee Related
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Also Published As
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ZA200403197B (en) | 2005-04-28 |
EP1440076A1 (en) | 2004-07-28 |
MXPA04003968A (es) | 2005-01-25 |
RU2004116347A (ru) | 2005-05-10 |
IL161307A0 (en) | 2004-09-27 |
US20050020541A1 (en) | 2005-01-27 |
JP2005507425A (ja) | 2005-03-17 |
WO2003037905A1 (en) | 2003-05-08 |
BR0213731A (pt) | 2004-10-19 |
KR20050042000A (ko) | 2005-05-04 |
PL370584A1 (en) | 2005-05-30 |
CA2464997A1 (en) | 2003-05-08 |
GB0126036D0 (en) | 2001-12-19 |
AU2002339071B2 (en) | 2005-08-11 |
HUP0401699A2 (hu) | 2004-12-28 |
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