CN1108255A - 抑制经期前综合征/晚黄体期焦虑疾病的症状的方法 - Google Patents
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Abstract
本发明提供了抑制一种或多种经期前综合征/
晚黄体期焦虑疾病的症状的方法,该方法包含给需要
治疗的妇女施用有效量的式I化合物或其可药用盐或溶剂化物,其中R1和R3独立地为氢、-CH3、-CO-(C1-C6烷基)或-CO-Ar,其中Ar是任意取代的苯基;R2选自吡咯烷子基、六亚甲基亚氨基和吡啶子基。
Description
每个月,在月经来潮前几天,上百万其他方面健康的妇女出现情绪失调以及与季节易感性疾病(SAD)、嗜碳水化合物性肥胖或者各种非厌食型食欲过盛患者所述的惊人相似的食欲等症状。1931年这种综合征被R.T.Frank首先称为“经期前紧张”,而且这是非常普遍的现象。根据Guy Abraham of UCLA,每10位走入妇科学家办公室的患者中,有3或4位患有经期前紧张,而且其中一些患者的症状甚至严重到包括企图自杀(Current Progress in Obstetrics and Gynecology,3:5-39(1980))。
最初对经期前综合征(PMS)的描述集中于它与神经紧张、头痛和体重增加的关系上。所发现的实际上在一些PMS患者中出现的体重增加最初归因于盐和水的过量潴留。但是,很快即表明它也是患有PMS患者嗜好和过量消耗碳水化合物,特别是有甜味的食物的普遍趋势的结果。PMS目前还称作晚黄体期综合征(或者晚黄体期焦虑疾病)(D.N.S.Ⅲ,Revised,American Psychiatric Association(1987))。
已经提出了许多有关PMS病因学的建议。例如,有些人假设这是由子宫毒素引起的。其他人认为其原因在于过量消耗甜食,推测这随后伴随有胰岛素分泌过量、低血糖以及脑葡萄糖不足,并且导致经常出现抑郁和焦虑。还有人假设这种行为症状是由经常出现的组织水肿造成的,而且这种心理变化是由因月经不适产生的失落感或社会复杂性而造成的。
但是这些理论均未得到证实:子宫切除后可持续PMS,因此子宫毒素不会是其诱因;PMS的胰岛素分泌过多与低血糖含量无关,并且可能是行为失常(即经期前妇女选择高碳水化合物饮食的趋势,这增强了胰岛素分泌)的结果而不是诱因;PMS的情绪和食欲变化与组织水肿关系不大;并且被假设为没有人生中精神动力学或社会复杂性的次人类灵长目也具有经期前的特征行为变化。
已经提出了多种克服或减轻PMS症状的治疗方法。这些方法包括无碳水化合物饮食、补充维生素、卵巢激素、解毒剂、卵巢和垂体照射法以及使用利尿药。但是所有这些方法只取得了有限的成功。
晚黄体期焦虑疾病(LLPDD)是与经期前综合征(PMS)有关的流行术语。许多妇女自述了各种与月经周期特殊阶段有关的身体和情绪变化。对于这些女性中的多数人,这些变化并不严重,几乎不造成痛苦,并且对社会或工作没有影响。相反,LLPDD的基本特征是临床上显著的情绪和行为症状,这些症状于黄体期的最后一周出现并在卵泡期出现后的几天内缓解。在多数女性中,这些症状于月经来潮前一周出现,并在月经来潮后几天内缓解。
只有当所述症状严重到足以对社会或工作造成明显损害,并且在过去的一年中大多数月经周期中都出现时,才确诊为LLPDD。
最常体验到的症状是明显的感情不稳定性(例如突然流泪,悲伤或易怒)、持续的易怒感觉、愤怒或紧张、压抑感以及自我非难思维。还常见的还有对通常的活动降低兴趣、容易疲劳和丧失活力、主观感觉难以集中、食欲变化,嗜好特殊食物(特别是碳水化合物)以及睡眠失调。还可存在其他身体症状,如乳房触痛或肿胀、头痛、关节或肌肉痛、肿胀感以及体重增加。
一般来说,给LLPDD患者施用非甾族抗炎药物,但是这些药物只对某些身体症状有效。如果这些PMS身体症状严重,可以根据症状进行治疗。通过饮食或利尿药疗法可以减轻水潴留,但是水潴留的严重程度未必与心理症状有关。近来的研究已表明安体舒通(spironolacture)(Aldactone,Searle)也可以有效地缓解抑郁和哭喊发作。
尝试使用过其他药物,包括孕酮、碳酸锂、thiazide、利尿药、抗抑郁药和bromocyptone(Parlodel
,Sandoz),未获得确定的成功。
由于现存治疗PMS/LLPDD方法的缺点和不适当,需要寻找新的治疗方法。因此,本发明提供了有效减轻PMS/LLPDD症状的方法。
本发明提供了抑制一种或多种经期前综合征/晚黄体期焦虑疾病的症状的方法,该方法包含给需要治疗的妇女施用有效量的式Ⅰ化合物及其可药用盐和溶剂化物,
其中R1和R3独立地为氢、-CH3、-CO-(C1-C5烷基)或-CO-Ar,其中Ar是任意取代的苯基;R2选自吡咯烷子基(pyrrolidino)、六亚甲基亚氨基和哌啶子基。
本发明涉及发现选自2-苯基-3-芳酰基苯并噻吩类化合物(各种苯并噻吩),即式Ⅰ化合物,可用于抑制经期前综合征/晚黄体期焦虑疾病(PMS/LLPDD)的症状。因此本发明提供了抑制一种或多种经期前综合征/晚黄体期焦虑疾病的症状的方法,该方法包含给需要治疗的妇女施用有效量的式Ⅰ化合物或其可药用盐或溶剂化物。
术语“抑制”定义为包括其通常可接受的含义,它包括例如对易患PMS/LLPDD症状的妇女进行预防性治疗、控制每一症状和/或治疗已存在的症状。就其本身而言,本发明方法包括医疗和/或(如果需要)预防性治疗。
雷洛昔芬,即其中R1和R3各自为氢,且R2为1-哌啶基的式Ⅰ化合物的盐酸盐,是核调节分子。雷洛昔芬已表明可与雌激素受体结合,并且最初被认为是具有抗雌激素活性,因为它阻断了雌激素激活子宫组织和雌激素依赖型乳腺癌的能力。实际上,在某些细胞中雷洛昔芬的确阻断了雌激素的作用;然而在其他各类细胞中,雷洛昔芬激活了与雌激素激活的基因相同的基因并显示出同样的药理学例如骨质疏松、高脂血,结果雷洛昔芬被称作具有激动剂-拮抗剂混合性质的抗雌激素。
尽管通常雷洛昔芬和雌激素利用并竞争同样的受体,但是施用这两种药剂的药理学结果是难以预见的并且彼此不同。
通常可以将本发明化合物与普通的赋形剂、稀释剂或载体一起配制,并压成便于口服的片剂、或者配制成便于口服的酏剂或溶液剂;或者通过肌内或静脉途径给药。所述化合物可以经皮给药,并且可以配制成缓释剂型等。
本发明方法中所使用的化合物可以按既定的方法,例如US4,133,814、4,418,068和4,380,635中所详述的方法(这些专利均引入本文作为参考)制备。术语“取代的苯基”是指具有一个或两个选自C1-C4烷基、C1-C5烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基的取代基的苯基分子。术语“C1-C4烷基”和“C1-C5烷氧基”具有上面所引用的美国专利中所述的定义。
用于本发明方法的化合物可以与各种有机和无机酸和碱反应生成可药用的酸和碱加成盐,可药用的酸和碱加成盐包括通常用于制药化学的生理上适用的盐。所述的盐也是本发明的一部分。用于生成所述盐的常用无机酸包括氢氯酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可应用由有机酸得到的盐,可以应用的有机酸有例如脂肪族一和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸、芳香族酸、脂肪族和芳香族磺酸。因此所述可药用的盐包括乙酸盐、苯乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻-乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯丁酸盐、β-羟基丁酸盐、丁炔-1,4-二酸盐、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、羟基乙酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯丙酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选的盐是盐酸盐。
可药用的酸加成盐通常由式Ⅰ化合物与等摩尔或过量的酸反应而制得。通常使反应物于互溶剂如乙醚或苯中进行化合。盐通常约在1小时至10天内从溶液中析出,可经过滤分离,或可按常规方法除去溶剂。
通常用于形成所述盐的碱包括氢氧化铵,碱金属和碱土金属氢氧化物、碳酸盐,以及脂肪族的伯、仲和叔胺、脂肪族二胺。在制备加成盐中尤其适用的碱包括氢氧化铵、碳酸钾、甲胺、二乙胺、1,2-乙二胺和环己胺。
与衍生它们的化合物比较,可药用的盐和溶剂化物通常具有提高的溶解性能,因此常常更适用于配制成液体剂或乳剂。
药用制剂可用本领域已知的方法制备。例如,可将所述化合物与普通的赋形剂、稀释剂或载体进行配制,并制成片剂、胶囊、悬浮液、粉剂等。适用于上述制剂的赋形剂、稀释剂和载体的实例包括如下:填充剂和增量剂如淀粉、糖类、甘露糖醇和硅衍生物;粘合剂如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如碳酸钙和碳酸氢钠;阻滞溶解剂如石蜡;吸收促进剂如季铵化合物;表面活性剂如鲸蜡醇、单硬脂酸甘油酯;吸附载体如高岭土和膨润土;润滑剂如滑石、硬脂酸钙和硬脂酸镁,以及固态聚乙二醇类。
所述化合物也可配制成便于口服的酏剂或溶液剂,或适于非肠道给药的溶液剂,例如经肌内、皮下或静脉内途径给药。此外,所述化合物也非常适合配制成缓释剂型等。该制剂也可这样构成,使他们仅仅或最好在特定的生理学部位,可能在一定的时间内释放活性成分。包衣、包膜和保护基质可以由例如聚合物质或蜡制成。
根据本发明,抑制PMS/LLPDD症状所需要的式I化合物的具体剂量取决于病症的严重程度、给药途径和有关因素,这些将由主治医生确定,一般来讲,每天可接受的和有效的剂量为约0.1mg~约1000mg/天,更通常为约50mg~约600mg/天。对需治疗的患者施用的上述剂量可为每天1次~约3次,或按需要更经常地施用以有效地治疗一种或多种上述症状。
正如施用带有碱基(如哌啶子基环)的药物所常用的那样,通常最好施用酸加成盐形式的式I化合物。口服本发明化合物也是有利的。
下列制剂实施例仅用于说明本发明,而非以任何方式限制本发明范围。
制剂
在以下制剂中,“活性成分”是指式I化合物。
制剂1:明胶胶囊
用下列成分制备硬明胶胶囊:
成分 用量(mg/胶囊)
活性成分 0.1~1000
淀粉,NF 0~650
可流动的淀粉粉末 0~650
硅氧烷流体(350厘沲) 0~15
将各成分混合,通过美国45号筛,装填入硬明胶胶囊。
已制备的雷洛昔芬的具体胶囊制剂的实例包括如下所示那些:
制剂2:雷洛昔芬胶囊
成分 用量(mg/胶囊)
雷洛昔芬盐酸盐 1
淀粉,NF 112
可流动的淀粉粉末 225.3
硅氧烷流体(350厘沲) 1.7
制剂3:雷洛昔芬胶囊
成分 用量(mg/胶囊)
雷洛昔芬盐酸盐 5
淀粉,NF 108
可流动的淀粉粉末 225.3
硅氧烷流体(350厘沲) 1.7
制剂4:雷洛昔芬胶囊
成分 用量(mg/胶囊)
雷洛昔芬盐酸盐 10
淀粉,NF 103
可流动的淀粉粉末 225.3
硅氧烷流体(350厘沲) 1.7
制剂5:雷洛昔芬胶囊
成分 用量(mg/胶囊)
雷洛昔芬盐酸盐 50
淀粉,NF 150
可流动的淀粉粉末 397
硅氧烷流体(350厘沲) 3.0
可以对上述具体的制剂进行合理的改变。
用下列成分制备片剂:
制剂6:片剂
成分 用量(mg/片)
活性成分 2.5~1000
微晶纤维素 200~650
煅制二氧化硅 10~650
硬脂酸 5~15
将各成分混合,压成片剂。
另外,每片含0.1~1000mg活性成分的片剂按以下方法制备:
制剂7:片剂
成分 用量(mg/片)
活性成分 25~1000
淀粉 45
微晶纤维素 35
聚乙烯吡咯烷酮(10%水溶液) 4
羧甲基纤维素钠 4.5
硬脂酸镁 0.5
滑石 1
将活性成分、淀粉和纤维素通过美国45号筛并充分混合。聚乙烯吡咯烷酮溶液与所得的粉末混合,然后通过美国14号筛。将制备的颗粒于50°-60℃干燥,并通过美国18号筛。然后将预先通过美国60号筛的羧甲基纤维素钠、硬脂酸镁和滑石加入此颗粒中,混合后将颗粒在压片机上压片,得到片剂:
每5ml剂量含0.1-1000mg药物的悬浮液按下法制备:
制剂8:悬浮液
成分 用量(mg/5ml)
活性成分 0.1~1000mg
羧甲基纤维素钠 50mg
糖浆 1.25mg
苯甲酸溶液 0.10ml
调味剂 适量
着色剂 适量
纯化水 至 5ml
将药物通过美国45号筛,并与羧甲基纤维素钠和糖浆混合制成调匀的糊状物。苯甲酸溶液、调味剂和着色剂用一部分水稀释,并在搅拌下加入糊状物中。然后加入足够的水到所需体积。
试验方法
选择3-50名妇女进行临床研究。这些妇女月经规律,总的来说健康,并患有一种或多种上述PMS/LLPDD症状。由于这些症状有几分特应性和主观性,因此该研究设安慰剂对照组,即将这些妇女分为两组,一组接受本发明的活性药剂,另一组接受安慰剂。试验组的妇女每天通过口服途径接受10-600mg药物,使其连续治疗1-3个月。准确记录各组中这些症状的数目及严重程度,并在研究结束时对这些结果进行比较。在每组各受试者之间进行结果比较,并且还将每位患者的结果与研究开始前每位患者自述的症状进行比较。
当用于上述研究时,本发明化合物对一种或多种所述症状所具有的阳性效果说明了本发明化合物的效用。
Claims (4)
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Application Number | Priority Date | Filing Date | Title |
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US171,148 | 1993-12-21 | ||
US08/171,148 US5389670A (en) | 1993-12-21 | 1993-12-21 | Methods of inhibiting the symptoms of premenstrual syndrome/late luteal phase dysphoric disorder |
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CN1108255A true CN1108255A (zh) | 1995-09-13 |
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CN94119273A Pending CN1108255A (zh) | 1993-12-21 | 1994-12-19 | 抑制经期前综合征/晚黄体期焦虑疾病的症状的方法 |
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US (2) | US5389670A (zh) |
EP (1) | EP0659412B1 (zh) |
JP (1) | JPH07196503A (zh) |
KR (1) | KR950016737A (zh) |
CN (1) | CN1108255A (zh) |
AT (1) | ATE214927T1 (zh) |
AU (1) | AU8155994A (zh) |
CA (1) | CA2138505A1 (zh) |
CZ (1) | CZ321894A3 (zh) |
DE (1) | DE69430232T2 (zh) |
DK (1) | DK0659412T3 (zh) |
ES (1) | ES2170767T3 (zh) |
HU (1) | HUT71338A (zh) |
IL (1) | IL112054A0 (zh) |
NO (1) | NO944921L (zh) |
PT (1) | PT659412E (zh) |
RU (1) | RU94044488A (zh) |
ZA (1) | ZA9410077B (zh) |
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CN114555070A (zh) * | 2019-08-26 | 2022-05-27 | 经期药丸私人有限责任公司 | 月经周期诱发的症状治疗 |
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US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
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US20030083733A1 (en) * | 1997-10-10 | 2003-05-01 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5514704A (en) * | 1995-03-13 | 1996-05-07 | Eli Lilly And Company | Benzothiophenes to inhibit leukotrienes |
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CA2223595C (en) * | 1995-06-07 | 2008-08-05 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
IL120262A (en) * | 1996-02-28 | 2001-01-28 | Pfizer | Droloxifene and derivatives thereof for use in increasing serum testosterone levels |
TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
US5733937A (en) * | 1996-02-28 | 1998-03-31 | Pfizer Inc. | Methods for alleviating symptoms of premenstrual syndrome and late luteal phase dysphoric disorder |
US5985932A (en) * | 1996-02-28 | 1999-11-16 | Pfizer Inc | Inhibition of autoimmune diseases |
US6110942A (en) * | 1996-06-17 | 2000-08-29 | Eli Lilly And Company | Method for minimizing the uterotrophic effect of droloxifene |
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US6117911A (en) * | 1997-04-11 | 2000-09-12 | Neorx Corporation | Compounds and therapies for the prevention of vascular and non-vascular pathologies |
US6008232A (en) * | 1997-08-20 | 1999-12-28 | Eli Lilly And Company | Methods for preventing headaches |
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AU751158B2 (en) | 1998-06-16 | 2002-08-08 | Eli Lilly And Company | Methods for increasing levels of acetylcholine |
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US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
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- 1994-12-19 KR KR1019940034928A patent/KR950016737A/ko not_active Application Discontinuation
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CZ321894A3 (en) | 1995-09-13 |
PT659412E (pt) | 2002-08-30 |
HU9403671D0 (en) | 1995-02-28 |
AU8155994A (en) | 1995-06-29 |
DK0659412T3 (da) | 2002-06-17 |
HUT71338A (en) | 1995-11-28 |
CA2138505A1 (en) | 1995-06-22 |
RU94044488A (ru) | 1996-10-20 |
DE69430232T2 (de) | 2002-11-14 |
US5550150A (en) | 1996-08-27 |
EP0659412A3 (en) | 1995-09-06 |
US5389670A (en) | 1995-02-14 |
ZA9410077B (en) | 1996-06-19 |
ATE214927T1 (de) | 2002-04-15 |
KR950016737A (ko) | 1995-07-20 |
IL112054A0 (en) | 1995-03-15 |
EP0659412A2 (en) | 1995-06-28 |
ES2170767T3 (es) | 2002-08-16 |
DE69430232D1 (de) | 2002-05-02 |
NO944921D0 (no) | 1994-12-19 |
JPH07196503A (ja) | 1995-08-01 |
NO944921L (no) | 1995-06-22 |
EP0659412B1 (en) | 2002-03-27 |
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