CN1652758A - 使用文拉法辛和衍生物治疗胃肠和泌尿生殖疼痛症的方法 - Google Patents
使用文拉法辛和衍生物治疗胃肠和泌尿生殖疼痛症的方法 Download PDFInfo
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- CN1652758A CN1652758A CNA038112612A CN03811261A CN1652758A CN 1652758 A CN1652758 A CN 1652758A CN A038112612 A CNA038112612 A CN A038112612A CN 03811261 A CN03811261 A CN 03811261A CN 1652758 A CN1652758 A CN 1652758A
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- carbon atom
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- functional gastrointestinal
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Abstract
本发明提供了治疗哺乳动物中功能性胃肠和泌尿生殖病症的方法,包括给所述哺乳动物施用有效量的式(I)所示羟基环烷苯乙胺化合物或其可药用盐,其中A是式(II)所示部分,其中虚线代表任选的不饱和;R1是氢或烷基;R2是烷基;R4是氢、烷基、甲酰基或烷酰基(alkanol);R5和R6独立地为氢、羟基、烷基、烷氧基、烷酰氧基、氰基、硝基、烷基巯基、氨基、烷基氨基、二烷基氨基、链烷酰氨基、卤素、三氟甲基,或者二者一起是亚甲二氧基;R7是氢或烷基;且n是0、1、2、3或4。
Description
发明背景
(1-[2-(二甲基氨基)-1-(4-甲氧基苯基)乙基]环己醇)或其可治疗用盐—通常称为文拉法辛及其类似物公开在U.S.专利4,535,186(Husbands等人.)中。据以前报道,这些化合物可用作抗抑郁剂。U.S.专利4,535,186公开了文拉法辛及其类似物的制备,该文献引入本文以供参考。
据表明,文拉法辛及其活性代谢物O-去甲基文拉法辛是有效的单胺神经递质摄取抑制剂,这种抑制作用是与临床上抗抑郁活性有关的机制。由于其新的结构,文拉法辛具有与其它可使用的抗抑郁剂例如三环类抗抑郁剂地昔帕明、去甲替林(nostriptyline)、普罗替林、丙米嗪、阿米替林、曲米帕明和多塞平无关的作用机制。
据信,文拉法辛的作用机制与对单胺神经递质血清素和去甲肾上腺素摄取的有效抑制有关。在较小程度上,文拉法辛还抑制多巴胺重摄取,但是其对单胺氧化酶没有任何抑制活性。O-去甲基文拉法辛-文拉法辛在人体内的主要代谢物表现出类似的药理性质。已经根据文拉法辛抑制去甲肾上腺素和血清素(5-HT)摄取的能力预测到其具有与三环类抗抑郁剂相当或超过三环类抗抑郁剂的效力(Stuart A.Montgomery,M.D.,J.Clin.Psychiatry,54:3,March 1993)。
与传统的三环类抗抑郁药物不同,文拉法辛在体外对毒蕈碱性、组胺能或肾上腺素能受体实质性没有亲和力。在这些受体上的药理活性与使用三环类抗抑郁药物所观察到的各种抗胆碱能、镇静和心血管作用有关。
功能性胃肠和泌尿生殖病症包括过敏性肠综合征、症状性GERD、食管过敏、非溃疡性消化不良、非心脏性胸疼、胆囊运动障碍、奥狄括约肌功能障碍、间质性膀胱炎(膀胱过敏)和慢性骨盆疼痛(包括但不限于外阴痛、前列腺痛和肛部痛)。
功能性胃肠和泌尿生殖病症是慢性病症,对于它们没有发现任何具体的结构、生化或感染病因。
过敏性肠综合征也称为“痉挛性结肠”,是常见的结肠和小肠病症,特征为腹痛和肠习惯改变症状。IBS患者一般经受交替发生的腹泻和便秘,而某些患者主要经受腹泻或便秘。与其它胃肠病症相比,更常见于IBS中的其它症状包括腹部膨胀,伴有肠运动的疼痛缓减,伴有疼痛发作的排便频繁,伴有疼痛发作的排便松弛,排出粘液,以及排便不完全感。
非溃疡性消化不良是胃十二指肠的功能性障碍,其特征是持续或反复感觉到上腹部不适或疼痛,该不适或疼痛与腹泻或便秘无关。不适是消极感觉,特征为一种或多种症状,包括较早的饱感、饭后发胀或肿胀。
非心脏性胸疼患者经常经受其疼痛的再现,伴有体积小于在无症状个人中产生疼痛所需体积的食管囊膨胀。内脏过敏可能是患者疼痛的原因。
胆囊运动障碍患者经受右上象限疼痛或上腹部疼痛,这种疼痛可以是伤残性的,并持续数分钟到数小时。这种疼痛可以是连续的,伴有间歇性的加剧。疼痛可传播到背部或肩部,并且可伴有恶心和呕吐。
IBS患者占就诊初级保健医师的患者的12%,占就诊胃肠病医师的患者的25-50%。虽然据信IBS是良性的,但它是慢性复发性病症,显著影响生命质量,并且带来高的直接成本,包括就诊、研究、药物和损失工作时间。
已经证实了三环类抗抑郁剂例如阿米替林、多塞平和丙米嗪对于治疗过敏性肠综合征有效。然而,TCA的应用受到副作用例如镇静作用和便秘以及在安全性方面的考虑的限制。
还已经报道了用SSRI治疗IBS。然而,SSRI似乎不影响健康个体或IBS患者中的整个肠传输时间,而TCA例如丙米嗪延长口盲肠传输时间。
发明描述
本发明提供了治疗、预防或控制哺乳动物,优选人中的功能性胃肠病症,包括过敏性肠综合征、慢性腹部疼痛和非溃疡性消化不良以及伴随症状的方法。
本发明方法包括对有此需要的哺乳动物施用有效量的一种或多种选自取代的苯乙胺的化合物。本发明化合物具有以下结构式:
其中A是下式所示部分
其中虚线代表任选的不饱和;
R1是氢或具有1-6个碳原子的烷基;
R2是具有1-6个碳原子的烷基;
R4是氢、具有1-6个碳原子的烷基、甲酰基或具有2-7个碳原子的烷酰基(alkanol);
R5和R6独立地为氢、羟基、具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、具有2-7个碳原子的烷酰氧基、氰基、硝基、具有1-6个碳原子的烷基巯基、氨基、具有1-6个碳原子的烷基氨基、其中每个烷基具有1-6个碳原子的二烷基氨基、具有2-7个碳原子的链烷酰氨基、卤素、三氟甲基,或者二者一起是亚甲二氧基;
R7是氢或具有1-6个碳原子的烷基;且
n是一个整数0、1、2、3或4,
或其可药用盐。
可用于本发明方法中的更优选的化合物是下式所示化合物或其可药用盐
其中
A如上所定义;
R1是氢或具有1-3个碳原子的烷基;
R2是具有1-3个碳原子的烷基;
R5是氢、羟基、具有1-3个碳原子的烷氧基、氯、溴、三氟甲基或具有1-3个碳原子的烷基;
R6是具有1-3个碳原子的烷基、具有1-3个碳原子的烷氧基、氯、溴、三氟甲基或具有2-3个碳原子的烷酰氧基;
R7是氢或具有1-3个碳原子的烷基;
可用于本发明方法中的最优选的化合物是定义如下的那些:其中R5和R6都在间位,或者R5和R6中有一个在对位,且n是2。
值得特别关注的化合物是1-[(2-二甲基氨基)-1-(4-甲氧基苯基)乙基]环己醇和1-[(2-二甲基氨基)-1-(4-羟基苯基)乙基]环己醇及其对映体和可药用盐。
已经发现,其中R4是甲酰基或具有2-7个碳原子的烷酰基的化合物不如携带相应游离羟基的衍生物有效。然而,在长期治疗中,酰氧基衍生物将起前药的作用,因为酰基在体内通过在胃中酸解或通过酶的作用而被除去。
本发明碱性化合物的可药用酸加成盐是通过将游离碱与等当量的用于形成无毒盐的任何酸反应而以常规方法形成的。酸的实例有无机酸或有机酸,包括盐酸、氢溴酸、富马酸、马来酸、琥珀酸、硫酸、磷酸、酒石酸、乙酸、柠檬酸、草酸和类似的酸。对于胃肠外给药,使用水溶性盐是优选的,但是可药用盐的游离碱形式也适用于本发明抗抑郁剂的口服或胃肠外给药。代表R5或R6的卤素取代基包括氯、溴、碘或氟取代基。
依据本发明,可将含有本发明化合物的药物组合物施用给个体。可将活性组分制成任何常规口服剂型,包括片剂、胶囊剂和液体制剂例如酏剂和悬浮液,这些剂型含有各种着色剂、调味剂、稳定剂和味道掩蔽剂。为了制备口服剂型,可将活性组分与用以辅助制片或胶囊化过程的各种常规制片材料例如淀粉、碳酸钙、乳糖、蔗糖和磷酸二钙混和。在需要时,提供作为添加剂的硬脂酸镁以行使润滑剂功能。
可将活性组分溶解或悬浮在可药用无菌液体载体例如无菌水、无菌有机溶剂或无菌水与无菌有机溶剂的混合物中。液体载体优选为适于胃肠外注射的液体载体。当活性组分足以溶解时,其可以溶解在作为载体的标准盐水中,如果其太难溶,则通常将其溶解在合适的有机溶剂例如丙二醇或聚乙二醇水溶液中。含有10-75%重量的丙二醇的丙二醇水溶液通常是合适的。在其它情况下,其它组合物可通过将细碎的活性组分分散在淀粉或羧甲基纤维素水溶液或合适的油例如花生油中来制得。是无菌溶液或悬浮液的液体药物组合物可通过肌内、腹膜内或皮下注射来使用。
药物组合物优选呈单位剂型,例如片剂或胶囊。在这样的形式中,将组合物细分成含有适当量活性组分的单位剂量;单位剂型可以是包装的组合物,例如成袋的粉剂或小瓶或安瓿。单位剂型可以是胶囊剂、扁囊剂或片剂自身,或者其可以是适当数目的包装形式的任何这些剂型。单位剂量的组合物中的活性组分的量可以从2mg或更小改变或调节至50mg或更多,这根据特定需求以及活性组分的活性而定。对于人,文拉法辛的常用口服推荐剂量为约75-约200mg/天,该剂量可以分成2或3份剂量施用,如果口服给药的话,优选与食物一起服用。对于人,最大推荐日剂量为约375mg,但是本领域技术人员应当理解,在本发明中,剂量将由每一个例的具体情况来决定。
本领域技术人员还应当意识到,本发明化合物的给药途径可显著不同。除了其它口服给药剂型以外,还可以采用缓释组合物。其它可接受的途径可包括但不限于静脉内、肌内和腹膜内注射,皮下植入以及颊、舌下、经皮、局部、直肠、阴道和鼻内给药。也可以使用生物可侵蚀、非生物可侵蚀、生物可降解和非生物可降解给药系统。
还应当理解,本发明涉及用于治疗哺乳动物,优选人中的过敏性肠综合征的症状的所有方法和原理。对于本发明目的,治疗过敏性肠综合征应理解为包括在接受本发明化合物的哺乳动物中产生所需效果的,用文拉法辛进行的所有预防、治疗、进展抑制、医治、维持、治愈或其它治疗、治疗方案或给药。
Claims (20)
1.治疗哺乳动物中功能性胃肠或泌尿生殖病症的方法,包括给所述哺乳动物施用有效量的下式所示化合物或其可药用盐:
其中A是下式所示部分
其中虚线代表任选的不饱和;
R1是氢或具有1-6个碳原子的烷基;
R2是具有1-6个碳原子的烷基;
R4是氢、具有1-6个碳原子的烷基、甲酰基或具有2-7个碳原子的烷酰基(alkanol);
R5和R6独立地为氢、羟基、具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、具有2-7个碳原子的烷酰氧基、氰基、硝基、具有1-6个碳原子的烷基巯基、氨基、具有1-6个碳原子的烷基氨基、其中每个烷基具有1-6个碳原子的二烷基氨基、具有2-7个碳原子的链烷酰氨基、卤素、三氟甲基,或者二者一起是亚甲二氧基;
R7是氢或具有1-6个碳原子的烷基;且
n是0、1、2、3或4。
3.权利要求1或2的方法,其中R5和R6都在间位,或者R5和R6中有一个在对位,且n是2。
4.权利要求2的方法,其中所述化合物是1-[(2-二甲基氨基)-1-(4-甲氧基苯基)乙基]环己醇或其可药用盐。
5.权利要求2的方法,其中所述化合物是1-[2-(二甲基氨基)-1-(4-羟基苯基)乙基]环己醇或其可药用盐。
6.权利要求1-5任一项的方法,其中所述有效量包括35mg/天-约75mg/天的日剂量。
7.权利要求1-5任一项的方法,其中所述有效量包括约50mg/天-约375mg/天的日剂量。
8.权利要求1-5任一项的方法,其中所述有效量包括约75mg/天-约200mg/天的日剂量。
9.权利要求1-8任一项的方法,其中所述个体是人。
10.权利要求1-9任一项的方法,其中所述功能性胃肠病症是过敏性肠综合征。
11.权利要求1-9任一项的方法,其中所述功能性胃肠病症是症状性GERD。
12.权利要求1-9任一项的方法,其中所述功能性胃肠病症是食管过敏。
13.权利要求1-9任一项的方法,其中所述功能性胃肠病症是非溃疡性消化不良。
14.权利要求1-9任一项的方法,其中所述功能性胃肠病症是非心脏性胸疼。
15.权利要求1-9任一项的方法,其中所述功能性胃肠病症是胆囊运动障碍。
16.权利要求1-9任一项的方法,其中所述功能性胃肠病症是奥狄括约肌功能障碍。
17.权利要求1-9任一项的方法,其中所述功能性泌尿生殖病症是慢性骨盆疼痛。
18.权利要求1-9任一项的方法,其中所述功能性泌尿生殖病症是间质性膀胱炎。
19.如权利要求1-5任一项中所定义的化合物在制备用于治疗哺乳动物中功能性胃肠或泌尿生殖病症的药物中的应用。
20.权利要求19的应用,其中所述病症是如在权利要求10-18任一项中所定义的病症。
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7531543B2 (en) * | 2003-10-14 | 2009-05-12 | Wyeth | Phenylpiperazine cycloalkanol derivatives and methods of their use |
US7365076B2 (en) * | 2003-10-14 | 2008-04-29 | Wyeth | Substituted aryl cycloalkanol derivatives and methods of their use |
US7491723B2 (en) * | 2003-10-14 | 2009-02-17 | Wyeth | Alkanol and cycloalkanol-amine derivatives and methods of their use |
US7550485B2 (en) * | 2003-10-14 | 2009-06-23 | Wyeth | Substituted N-heterocycle derivatives and methods of their use |
US7402698B2 (en) * | 2003-10-14 | 2008-07-22 | Wyeth | Secondary amino-and cycloamino-cycloalkanol derivatives and methods of their use |
US7419980B2 (en) * | 2003-10-14 | 2008-09-02 | Wyeth | Fused-aryl and heteroaryl derivatives and methods of their use |
US7524846B2 (en) * | 2003-10-14 | 2009-04-28 | Wyeth | Arylalkyl- and cycloalkylalkyl-piperazine derivatives and methods of their use |
US20070142367A1 (en) * | 2003-11-10 | 2007-06-21 | Lundeen James E | Method and medicine for treating gastrointestinal disorder including fecal incontinence |
US20050113365A1 (en) * | 2003-11-10 | 2005-05-26 | Sir Isaac Newton Enterprises Llc | Method and medicine for treating gastrointestinal disorder including irritable bowel syndrome |
US20060148782A1 (en) * | 2003-11-10 | 2006-07-06 | Lundeen James E | Method and medicine for treating a mammal presenting urinary incontinence, urinary urgency, or both |
US20060148783A1 (en) * | 2003-11-10 | 2006-07-06 | Lundeen James E | Method and medicine for treating gastrointestinal disorder including fecal incontinence |
US20060148781A1 (en) * | 2003-11-10 | 2006-07-06 | Lundeen James E | Method and medicine for treating gastrointestinal disorder in a non-human mammal |
US7820690B2 (en) * | 2004-03-19 | 2010-10-26 | Solvay Pharmaceuticals Gmbh | Method of treating or inhibiting a non-digestive tract derived abdominal disorder associated with pain using a 5-HT, receptor antagonist |
US7517899B2 (en) * | 2004-03-30 | 2009-04-14 | Wyeth | Phenylaminopropanol derivatives and methods of their use |
US7414052B2 (en) * | 2004-03-30 | 2008-08-19 | Wyeth | Phenylaminopropanol derivatives and methods of their use |
US20080081067A1 (en) * | 2006-10-03 | 2008-04-03 | Gupta Manishkumar | Sustained release pharmaceutical compositions of venlafaxine and process for preparation thereof |
GB201007032D0 (en) * | 2010-04-27 | 2010-06-09 | Dormer Tools Ltd | Twist drill for advanced materials |
CN102095461B (zh) * | 2011-01-18 | 2012-07-18 | 姚贤卿 | 复合型干度质量流量仪及干度标定测量方法 |
RU2740750C1 (ru) * | 2020-03-27 | 2021-01-20 | Аллан Герович Бениашвили | Средство для лечения функциональных заболеваний желудочно-кишечного тракта |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4535186A (en) * | 1983-04-19 | 1985-08-13 | American Home Products Corporation | 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives |
EP0977558B1 (en) * | 1996-02-15 | 2003-10-01 | Janssen Pharmaceutica N.V. | Use of 5ht4 receptor antagonists for overcoming gastrointestinal effects of serotonin reuptake inhibitors |
US6579899B1 (en) * | 1998-07-16 | 2003-06-17 | Massachusetts Institute Of Technology | Composition for treatment of stress |
US6121259A (en) * | 1998-11-23 | 2000-09-19 | Sepracor Inc. | Olanzapine-N-oxide compositions and methods |
ATE286398T1 (de) * | 1998-11-23 | 2005-01-15 | Sepracor Inc | Desmethylolanzapine enthaltende zusammensetzungen und verfahren |
JP2002530339A (ja) * | 1998-11-23 | 2002-09-17 | セプラコール, インク. | 2−ヒドロキシメチルオランザピン組成物及び方法 |
US6294192B1 (en) * | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
GB2355191A (en) * | 1999-10-12 | 2001-04-18 | Laxdale Ltd | Combination formulations for fatigue, head injury and strokes |
WO2003090743A1 (en) * | 2002-04-24 | 2003-11-06 | Cypress Bioscience, Inc. | Prevention and treatment of functional somatic disorders, including stress-related disorders |
MXPA04012347A (es) * | 2002-06-10 | 2005-02-25 | Wyeth Corp | Nueva sal formiato de o-desmetilvenlafaxina. |
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2003
- 2003-05-14 TW TW092113062A patent/TW200402289A/zh unknown
- 2003-05-15 CA CA002485736A patent/CA2485736A1/en not_active Abandoned
- 2003-05-15 CN CNA038112612A patent/CN1652758A/zh active Pending
- 2003-05-15 JP JP2004505028A patent/JP2005530779A/ja active Pending
- 2003-05-15 UA UA20041210379A patent/UA81413C2/xx unknown
- 2003-05-15 IL IL16521603A patent/IL165216A0/xx unknown
- 2003-05-15 US US10/438,572 patent/US20040019101A1/en not_active Abandoned
- 2003-05-15 AU AU2003232137A patent/AU2003232137A1/en not_active Withdrawn
- 2003-05-15 KR KR10-2004-7018585A patent/KR20050003464A/ko not_active IP Right Cessation
- 2003-05-15 WO PCT/US2003/015230 patent/WO2003097029A1/en active Application Filing
- 2003-05-15 EP EP03753036A patent/EP1505960A1/en not_active Withdrawn
- 2003-05-15 SG SG200607202-9A patent/SG165991A1/en unknown
- 2003-05-15 BR BR0310083-9A patent/BR0310083A/pt not_active IP Right Cessation
- 2003-05-15 MX MXPA04011329A patent/MXPA04011329A/es unknown
- 2003-05-15 NZ NZ548950A patent/NZ548950A/en unknown
- 2003-05-15 RU RU2004136999/14A patent/RU2004136999A/ru unknown
- 2003-05-16 AR ARP030101715A patent/AR040033A1/es unknown
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2004
- 2004-11-04 CR CR7568A patent/CR7568A/es not_active Application Discontinuation
- 2004-11-09 NO NO20044868A patent/NO20044868L/no not_active Application Discontinuation
- 2004-11-17 EC EC2004005436A patent/ECSP045436A/es unknown
- 2004-12-15 ZA ZA200410157A patent/ZA200410157B/xx unknown
Also Published As
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TW200402289A (en) | 2004-02-16 |
JP2005530779A (ja) | 2005-10-13 |
EP1505960A1 (en) | 2005-02-16 |
NO20044868L (no) | 2004-12-08 |
WO2003097029A1 (en) | 2003-11-27 |
SG165991A1 (en) | 2010-11-29 |
ECSP045436A (es) | 2005-01-03 |
CA2485736A1 (en) | 2003-11-27 |
AR040033A1 (es) | 2005-03-09 |
IL165216A0 (en) | 2005-12-18 |
MXPA04011329A (es) | 2005-02-14 |
US20040019101A1 (en) | 2004-01-29 |
BR0310083A (pt) | 2005-02-15 |
AU2003232137A1 (en) | 2003-12-02 |
ZA200410157B (en) | 2006-05-31 |
CR7568A (es) | 2005-02-08 |
NZ548950A (en) | 2008-01-31 |
RU2004136999A (ru) | 2006-06-10 |
KR20050003464A (ko) | 2005-01-10 |
UA81413C2 (en) | 2008-01-10 |
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