CN102271667A - 用于治疗椎管狭窄的5-ht2a和5-ht2b受体拮抗剂 - Google Patents
用于治疗椎管狭窄的5-ht2a和5-ht2b受体拮抗剂 Download PDFInfo
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Images
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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Abstract
本发明涉及一种使用5-HT2A和5-HT2B受体拮抗剂对椎管狭窄患者以及由此在这些患者中引起的症状进行治疗和预防性处理的新方法。
Description
本发明涉及一种对椎管狭窄患者以及由此在这些患者中引起的症状进行治疗和预防处理的化合物的新用途。
椎管狭窄指的是脊柱的脊柱管变窄,大多数是由退行性磨损而引起的椎关节、韧带和椎间盘的改变。其特征是脊柱管变窄,其对其中包含的脊髓和神经根产生压力。目前脊柱的这些变窄属于诊断和手术最多的脊柱疾病。
如果变窄处在颈椎高度,则称作颈椎管狭窄;将胸椎变窄称作胸椎管狭窄;如果涉及腰椎,则称作腰椎管狭窄。
有许多解剖学原因可能会引起椎管变窄。在罕见的先天性病例中,会出现先天狭窄(例如发育不良、畸形、半脱位、脊柱裂、脊膜膨出)。颈椎的获得性改变比较常见,其成因可能是外伤、不稳定性、炎症或肿瘤,或者术后改变(例如伤疤)。但从临床角度来看,脊柱椎管狭窄的最大原因仍然是退行性疾病,即继退行性紊乱之后附带出现的生理性磨损症状。
构成椎管壁的不同解剖学结构均参与了椎管狭窄的形成,包括椎间盘、椎间关节以及黄韧带(这是一种纵向延伸的强劲韧带)。如果受损的椎间盘向后膨出或者脱出,就会形成直接的缩窄。而椎间关节关节病则会导致形成骨质突出(骨赘(Spondylophyte)),这不仅会使得椎管变窄,而且也会使得椎间孔变窄,从而间接影响椎管的宽度。另一个原因是黄韧带增厚,向后封闭椎管。
退行性改变可能会发生在椎管的不同部位上,因此可能会导致缩窄、刺激脊髓和/或神经根。如果形成椎体后缘骨质增生,就会引起多数向中间发生的退行性脊柱病。若为起始于钩突的退行性引起的骨质增生,则侧向缩窄的占位性病变就会引起钩骨病。椎管以及椎间孔侧向缩窄同样也会引起锥关节病意义上的椎间关节病。此外所有形式的椎间盘脱出或者膨出也可能会引起狭窄。亚洲人群中经常出现的症状是后纵韧带钙化或者骨化,简称为OPLL(ossificationof the posterior longitudinal ligament)。上述改变会从腹侧或者侧面使得椎管变窄,因此从前端或者侧面挤压脊髓,而背侧占位性病变的原因也比较罕见。其原因是黄韧带肥厚,也就是椎弓间韧带增厚,或者钙化或骨化。
根据流行病学研究结果,估测发病率为2~8%,在五十岁或六十岁年显示出典型症状,没有性别优势。对于60岁以上的患者,椎管狭窄甚至是脊柱手术的主要原因。在挥鞭伤患者、竞技运动员或飞行员所属的高危人群中,据描述年轻人的发病率也很高。
腰椎最常发生椎管狭窄。作为腰椎管狭窄的主要病痛,会在腿部出现沉重感、疼痛并且乏力,尤其在行走和站立时更是如此;大约90%的患者会在臀部和/或腿部出现麻木感。85%以上的患者有背痛。90%的患者中会出现神经源性间歇性跛行(90%),也就是行走短距离之后出现疼痛状况。保持直立姿势时会增强病痛,反之弯身姿势则可改善症状。其它症状是肌肉痉挛、运动协调障碍(共济失调)以及膀胱/直肠疾病,即排便和排尿问题。最常见的检查结果是脊柱弯曲受限(40%)、后仰时疼痛(79%)、拉赛格征(12%)、感觉异常(32%)、轻瘫(27%)、反射缺乏(64%)以及膀胱功能障碍(6%)。
与此不同的是,颈椎范围内的椎管狭窄(颈椎管狭窄)临床表现非常不同。手臂和/或腿部可能存在无特征的弥漫性疼痛或者失去感觉,同样也可能存在颈痛(颈部疼痛)或者臂痛(手臂疼痛)。患者经常诉说手臂和/或腿部渐渐变得乏力,多数是单侧乏力。比较典型的是行走不稳与痉挛步态,此外还可能有排尿障碍。
与腰椎管狭窄和颈椎管狭窄相比,胸椎管狭窄极为罕见。
椎管狭窄的诊断:
在检查过程中可以确定远端轻瘫和感觉障碍。经常可在脊柱的相关部分下方检测到反射亢进。步态共济失调(痉挛性,两腿分得很开,步覆蹒跚)同样也是疾病症状。很罕见并且仅限于颈椎管狭窄患者的是阳性锥体束征(巴宾斯基征)或者阳性莱尔米特征,可在颈椎弯曲时沿着脊柱引起触电感。
然而,若要详细搞清楚椎管狭窄引起的疼痛或者神经性异常,应采用成像方法进行检查。在常规的X光照片中无法直接识别椎管狭窄,为此需要采用断面成像方法,如CT(计算机断层扫描)和MRT(磁共振成像技术),其横断面走向可以表现椎管的宽度。最有价值的是MRT,不仅对骨结构的成像效果明显好于CT,而且也能表现相关脊柱区域内的软组织结构。
除了临床检查和成像诊断之外,电生理性检查也有助于判断、评估椎管狭窄的严重程度。尤其可以利用肌电图(EMG)、神经传导速度(NLG)和体感诱发电位(SSEP)来评估脊柱功能障碍的范围和严重程度以及预后。
椎管狭窄的自然过程在患者之间很不一样。患病初期几乎没有感觉,随着时间的推移,就会显现出反复无常的症状进展状态。很少会出现呈直线变化的恶化趋势。在不同那个的疾病阶段可能会出现停滞。随着退行性改变逐渐严重,就会出现椎管进行性变窄,最终挤压脊髓。可能会出现难以忍受的疼痛,最终出现麻痹症状。
常规治疗:
如果存在根据既往病历、医院、成像方法和/或电生理学检查作出的可靠诊断,并且尤其存在痉挛症状与运动障碍(局部轻瘫)和高度感觉障碍时,则为需进行手术的临床适应症。手术目的是消除狭窄,从而减轻脊髓的压力。可根据成像检查结果(X光检查、CT、MRT、脊髓造影)采用不同的手术方法。最常见的方法是腹侧减压与融合术、通过椎体置换与融合扩大腹侧减压的全脊柱切除术、采用或不采用硬膜开口和扩充的背侧减压术以及椎板成形术。实施矫形手术消除腰椎管狭窄、尤其是在颈椎范围内实施神经外科手术消除颈椎管狭窄的此类手术方法通常有比较大的风险,因此多数仅用于进行性病程,尤其当存在麻痹危险时,以及经过医生进行全面的风险评估之后,才会使用这些手术方法。除此之外,在实施这些手术方法时,也要考虑到轻微事故导致不可修复性脊髓损伤的风险。
如果仅存在轻度感觉障碍和/或运动障碍,或者有手术禁忌,则多数对椎管狭窄进行保守治疗。一方面可利用外固定器(颈托)将颈椎固定,如果是腰椎管狭窄,则佩戴束带或者围腰进行固定。
另一方面可进行康复训练治疗来稳定肌肉组织、消除脊柱前弯。
通过给予缓解疼痛的药物如止疼药(例如扑热息痛,N-乙酰水杨酸)、阿片类药物、止痛贴、植入式镇痛泵,或者通过神经阻滞剂渗透疗法、根周疗法、激痛点渗透疗法或者经皮神经电刺激(TENS)疗法,对大多数情况下存在的主要疼痛症状进行对症治疗。在肌肉痉挛的情况下,使用药物如巴氯芬或者四氢西泮。同样也可以使用非甾体抗炎药或者硬膜外给药的皮质类固醇。
尽管上述药物可以缓解疼痛,但是疼痛缓解作用时间通常有限,几乎无法干预疾病的其它影响,如肌肉强直、无痛运动自由度受限、影响劳动力。
病理学与分子靶:
除了对症治疗疼痛或者使用炎症抑制药物进行治疗之外,迄今描述的药物只有少数几种能够偶尔通过根本上干预病理生理过程全面明显改善椎管狭窄的临床症状。
实验证明,有各种不同的病理机制与炎症过程联合参与了多种多样的椎管狭窄症状。
椎管狭窄患者身体姿态引起的硬膜外压力与脊髓和神经节供血血管直径的生理变化已经得到了临床证明,并且与神经源性间歇性跛行的形成有关。就此而言,将讨论局部血管的内皮细胞功能障碍和改变的反应以及体内的信使物质。将要讨论的另一种病理机制是脊髓和背侧与腹侧神经节中神经递质受体的上调,这些受体会导致神经冲动过程发生变化,并且使得脊髓过度敏感和兴奋。
这些病理机制构成使用降钙素(Calcif Tissue Int 1992 May;50(5);400-3)治疗椎管狭窄、以及使用沙格雷酯之类的血清素拮抗剂治疗腰椎区域椎间盘脱出症状的理论根据。尤其描述施用沙格雷酯作为5-HT2A受体拮抗剂来治疗腰椎管狭窄症神经源性间歇性跛行患者。假设作用机制是改善因狭窄症而慢性变窄的神经末梢中的供血(J Peripher Nerv Syst.2004 Dec;9(4):263-9)。EP 1609480 A1公开了一种用来治疗椎管狭窄的药物,包括一种EP2激动剂和一种EP3激动剂的组合物。在日本允许使用利马前列素阿法环糊精(一种前列腺素E1衍生物,商品名为Opalmon)来治疗与腰椎管狭窄有关的症状(Spine 2008 June;33(13):1465-9)。此外US 20060058310 A1还描述了使用醛糖还原酶抑制剂来治疗椎管狭窄,DE 69919191 T2公开了使用一种哒嗪酮化合物来治疗椎管狭窄。
麦角菌可产生引起麦角中毒(圣安东尼之火)的生物碱,这种疾病的症状有肠道痉挛、手指和脚趾因为供血障碍而坏死以及出现幻觉。麦角林构成麦角碱的基本骨架。
麦角林包含与不同神经递质及其受体相互作用的基本结构要素。主体仿效神经递质多巴胺、血清素、去甲肾上腺素和组胺的结构。通过化学修饰对麦角林的主体进行修饰,就能产生作为激动剂或者作为拮抗剂作用于上述一种或多种神经递质受体的化合物。由于其药理学作用,在医疗领域主要将某些麦角碱用来治疗偏头痛、周围循环障碍、帕金森病以及多动腿综合征,或者将其作为产妇产后恢复和辅助治疗产后大出血的药物,以及作为抗高血压药物。
例如有人描述了使用麦角林衍生物,并且联合运用行为疗法和物理疗法,对腰椎管狭窄进行治疗的方法(Reumalologia 2004,T.42(1),59-63)。推测所使用的药物起到改善神经末梢中的微循环的作用。然而这里所述的结果是并未经过进一步验证的观测结果,既没有证明所用化合物的推测作用,也没有公开所用不同类别物质的具体特性。
众所周知,尼麦角林是一种肾上腺素能拮抗剂,并用作血管活性药物,用于改善供血以及用于血管疾病和痴呆疾病。尼麦角林在治疗相关剂量范围内不作用于多血清素系统如巴胺激动剂,如沙格雷酯或者麦角林衍生物特麦角脲。
麦角碱的作用多种多样。其可以刺激多巴胺受体,并且可抑制分泌催乳素和生长激素。可以将麦角乙脲的8-(R)-非对映异构体看成是目前最为强效的人H1受体激动剂(Bakker et al.,Mol Pharmacol 65:538-549,2004)。最近的研究(Dissertation FU Berlin,2008)结果表明,有一些麦角林衍生物对α2-肾上腺素受体的亲和性很高,并且是5-HT2A-、5-HT2B-和5-HT7-受体拮抗剂。
由WO 07/1 10047 A2已知,使用麦角林衍生物特麦角脲和丙麦角脲来治疗慢性疼痛,主要用来治疗纤维肌痛的慢性疼痛症状。鉴于特麦角脲对疼痛过程的多巴胺作用,给予特麦角脲对于纤维肌痛有一定疗效。纤维肌痛的主要症状均为非区域性、非特异性慢性疼痛以及压痛点压力较高,怀疑其原因是中枢神经系统(ZNS)的功能失调。根据对大批纤维肌痛患者进行调查的结果,大约80%患者声称颈椎区域有疼痛,仅仅大约20%患者还有颈椎管狭窄。
Holman和Myers(ARTHRITIS & RHEUMATISM,Vol.52,No.8,August 2005,pp 2495-2505)使用普拉克索(一种多巴胺激动剂)在纤维肌痛患者人群中进行了双盲研究,颈脊髓病患者均被排除在外。Holman新近的论文中详细阐述了相关结果,患有颈椎管狭窄的纤维肌痛患者对多巴胺激动剂的反应差,因此要给予其它的治疗选项,如普瑞巴林(J Pain 2008 Jul;9(7):613-22)。
除此之外,上述专利WO 07/110047还在实施例8中描述了同时施用特麦角脲和羟可酮镇痛药对下腰区椎间盘脱出的慢性疼痛患者进行治疗,没有描述使用特麦角脲治疗椎管狭窄尤其是颈椎管狭窄。椎间盘脱出通常是一种暂时性事件。椎间盘脱出多数涉及腰椎区域,很少涉及颈椎区域。使用特麦角脲治疗腰椎间盘脱出引起的慢性疼痛。已知特麦角脲具有多巴胺作用,因此预期对疼痛过程有疗效。
椎间盘脱出不仅其症状有别,而且椎管狭窄症原因也有差异。椎间盘脱出也可能伴随出现间歇性椎管变窄以及由此引起痛感,或者椎间盘脱出可能与椎管狭窄同时出现,这里涉及的是椎体的一种机械锁定,因此产生压力作用于脊髓而出现痛感。在各种不同的论文中均已指出,椎管狭窄包括对于椎间盘脱出而言的非典型的症状,如手臂、腿部和颈部运动功能和感觉有一定的限制,这些均与典型的行走障碍有关联,尤其是神经源性间歇性跛行(Clin.Biomech.1992(7),3-17)。此外还可表明,单纯椎管变窄并非一定会引起椎管狭窄,据此可以得出反推结论,椎管变窄并非椎管狭窄的单纯原因,而是其它特定原因也起到作用,在治疗过程中必须对此加以考虑(Clin.Biomech.1992(7),3-17)。而椎管狭窄的特征始终是椎体增生或者骨化,因此这是一种涉及脊柱的退行性疾病。椎体的这种退行性改变并非源自于椎间盘脱出,与此相反,正如以上所述,椎间盘脱出的特征在于机械锁定或损害以及所谓的“滑脱作用”。从“颈椎病与颈痛”(BMJ 2007(334),527-531)一文可知,疼痛性脊柱改变可能有极其不同的症状。
因此不可认为椎间盘脱出的治疗方法也能成功应用于治疗椎管狭窄,因为原则上必须研究不同的作用原理。
与本专利申请相关进行的临床研究的设计目的首先是为了试验特麦角脲作为典型的多巴胺激动剂对纤维肌痛患者的疗效。Holman的上述论文中还对患者的颈椎管狭窄以及慢性颈痛病史进行了研究。其工作假设是颈椎管狭窄或者慢性颈痛患者对特麦角脲疗法没有反应-与没有颈椎管狭窄的原发性纤维肌痛患者不同。对于另一种多巴胺激动剂罗匹尼罗,目前已在临床研究中证明,用这种多巴胺激动剂治疗对于纤维肌痛患者没有确凿的疗效(http://ctr.gsk.co.uk/summary/ropinirole/ll_rof102100.pdf)。与此一致的是,特麦角脲与安慰剂相比对于原发性纤维肌痛患者也没有确凿的明显疗效。
但尽管如此,本发明的发明人仍然指出了令人惊奇的结论,特麦角脲在椎管狭窄患者中能够选择性缓解椎管狭窄在这些患者中引起的症状,而在没有椎管狭窄的颈痛患者中则没有取得显著疗效。存在于特麦角脲中的5-HT2A和5-HT2B受体拮抗剂组合物能够在有疗效的剂量范围内同时显著抑制两种受体亚型,这就是能够取得显著疗效的原因。同时还描述了对于治疗应用的独特作用原理。
本发明因此提供一种使用5-HT2A和5-HT2B受体拮抗剂化合物对椎管狭窄尤其是颈椎管狭窄患者以及由此在这些患者中引起的症状进行治疗或预防的新方法。本发明尤其提供这种使用方法在疾病早期阶段对椎管狭窄进行预防性处理和介入治疗。在已经出现麻痹症并且出现截瘫危险的晚期阶段,则不可避免要进行手术治疗。在这种晚期阶段,本发明所述的应用在某些情况下还是一种伴随疗法。
在先技术迄今为止还没有描述使用5-HT2A以及5-HT2B受体拮抗剂化合物治疗椎管狭窄尤其是颈椎管狭窄患者。优选的化合物还有5-HT7受体拮抗剂和/或α2肾上腺素受体拮抗剂,还特别适宜选用另外的α2-肾上腺素受体拮抗剂,尤其是α2C肾上腺素受体拮抗剂。
本发明所述的拮抗剂一般是能够结合在上述受体(5-HT2A、5-HT2B和5-HT7受体以及α2肾上腺素受体,尤其是α2C肾上腺素受体)上的化合物,这些化合物可以减小或消除体内信使物质血清素和去甲肾上腺素的作用,或者可以减小或消除激动作用物质的作用。
通常以pA2值来表征某一种化合物的拮抗作用。
pA2值是一种拮抗剂物质的量浓度的负常用对数,需要将激动剂例如血清素浓度加倍,以在没有拮抗剂存在的情况下达到原有效果。因此pA2值是某一种拮抗剂与受体之间亲和性的衡量尺度,与拮抗剂如何起作用无关。优选按照Arunlakshana和Schild所述的方法(Arunlakshana O,Schild HO,《Somequantitative uses of drug antagonists》,Br J Pharmacol 14:48-58(1959))来测定pA2值。
尤其可以在一定的试验条件下,通过对猪冠状动脉的收缩作用特性来鉴别5-HT2A受体拮抗剂(s.a.Cushing DJ,Cohen ML(1993),J Pharmacol ExpTher 264;1 93-200)。
尤其可以在一定的试验条件下,通过对猪肺动脉的舒张作用特性来鉴别适合的5-HT2B受体拮抗剂(s.a.Glusa E,Pertz HH(2000)Br J Pharmacol 130:692-698)。
尤其可以在一定的试验条件下,通过对断奶仔猪肺动脉的舒张作用特性来鉴别适合的5-HT7受体拮抗剂(s.a.et al.(2005)Nauyn-Schmiedebergs Arch Pharmacol 371:89-98)。
尤其可以在精选的试验条件下,通过对屠宰猪肺动脉的收缩作用特性来鉴别适合的α2肾上腺素受体拮抗剂,尤其是α2C肾上腺素受体拮抗剂(s.a.et al.Br J Pharmacol 2007 May;151(2):186-94)。由于含有α2A和α2C受体的活性物质通常存在重叠的相互作用,因此以下将α2C受体的抑制常数定义为某一物质的α2抗肾上腺素作用的衡量尺度。
优选的本发明化合物对5-HT2A、5-HT2B、5-HT7受体和α2肾上腺素受体优选α2C肾上腺素受体具有以下pA2值:
本发明的化合物优选是pA2值≥7.5的5-HT2A受体拮抗剂。
本发明的化合物优选是pA2值≥7.5的5-HT2B受体拮抗剂。
本发明的化合物优选对5-HT2A受体以及5-HT2B受体的pA2值≥7.5,还优选pA2值≥8。
在特别优选的实施方式中,本发明的化合物对5-HT2A受体以及5-HT2B受体的pA2值>7.5,还优选pA2值≥8。
此外,本发明所述的首选化合物还有5-HT7受体拮抗剂,尤其是pA2值≥7.5的受体拮抗剂。
此外并特别优选的是本发明的化合物除了其作为5-HT2A和5-HT2B受体拮抗剂的特性之外,还特别优选α2肾上腺素受体拮抗剂,优选α2C肾上腺素拮抗剂,优选pA2值≥7.5的。
此外本发明的化合物尤其优选那些对于5-HT2A受体的pA2值与对于5-HT2B的化合物的pA2值差异最多为±1单位的化合物。也就是说,本发明特别优选这样的化合物,即其中
|pA2(5-HT2A)-pA2(5-HT2B)|≤1。
这样就能保证在相同剂量范围内使用代表性活性物质进行治疗的情况下显著抑制那些通过这所述一种或所述另一种受体运作的病理生理过程,从而可以实现增强疗效,且不同病史椎管狭窄患者的反应更宽。
下表所示为5-HT2A和5-HT2B受体拮抗剂化合物及其pA2值示例。
表-精选化合物的5-HT2A和5-HT2B受体拮抗特性
化合物 | pA2(5-HT2B受体) | pA2(5-HT2A受体) |
赛庚啶 | 9.2 | 8.9 |
米安色林 | 7.8 | 8.0 |
利坦色林 | 9.4 | 9.4 |
甲替平 | 8.3 | 8.5 |
酮色林 | 7.2 | 9.3 |
美西麦角* | 8.9 | 8.4 |
甲麦角林* | 7.6 | 8.6 |
麦角乙脲* | 10.3 | 9.4 |
特麦角脲* | 8.9 | 9.1 |
溴隐亭* | 9.4 | 6.9 |
曲唑酮 | 7.9 | 6.9 |
苯噻啶 | 8.5 | 8.9 |
美舒麦角* | 9.1 | 7.7 |
尼麦角林* | 7.8 | 7.5 |
沙格雷酯 | 6.6 | 8.5 |
*麦角林
如表所示,按照本发明特别优选的是赛庚啶、米安色林、利坦色林、甲替平、美西麦角、甲麦角林、麦角乙脲、特麦角脲、曲唑酮、苯噻啶和尼麦角林,因为这些化合物对5-HT2A和5-HT2B受体的pA2值均≥7.5,而且相互间的差异小于一个单位(绝对值)。按照本发明所述,还特别优选赛庚啶、利坦色林、甲替平、美西麦角、麦角乙脲、特麦角脲和苯噻啶,因为这些化合物对5-HT2A-和5-HT2B受体的pA2值均≥8,而且相互间的差异小于一个单位(绝对值)。这些化合物中还特别优选的是特麦角脲和麦角乙脲。
本发明所使用的化合物可用于治疗椎管狭窄患者以及因此在这些患者中引起的症状。本发明所使用的化合物特别优选用来治疗颈椎管狭窄患者以及由此出现的症状。与引言中已经详细说明的一样,椎管狭窄这个概念表示椎管缩窄,尤其是椎管的退行性改变或者缩窄。若为按照本发明优选对其进行治疗的颈椎管狭窄,则该狭窄处在颈椎区域之中,因此会在脊髓与变得比较小的椎管之间出现尺寸差异。后果就是压迫脊髓和/或神经根。根据放射学标准,如果颈椎的矢状径缩窄到10-12(13/14)mm,则称作相对狭窄;如果低于10mm,则称作绝对狭窄。颈脊髓病的临床表现可能极为不同。手臂和/或腿部可能存在无特征的弥漫性疼痛或者失去感觉,同样也可能存在颈痛(颈部疼痛)或者臂痛(手臂疼痛)。患者经常诉说手臂和/或腿部渐渐变得乏力,多数是单侧乏力。比较典型的是行走不稳与痉挛步态,此外还可能有排尿障碍。
与此相反,如前所述,椎间盘脱出的特征在于椎体的机械移位或者所谓的椎间盘滑脱,从而对脊髓造成疼痛性压迫。这种症状明显有别于椎体的退行性改变,椎管狭窄的特征就是退行性改变。与椎管狭窄的不同之处在于,椎间盘脱出很少涉及所谓的马尾(causa equina)。椎管狭窄的临床症状并非直接由狭窄本身引起,而是由椎体的另外的退行性变形引起的,这些退行性变形在没有无症状的椎管狭窄情况下可能保持不变(Clin.Biomech.1992(7),3-17)。
等级0 | 根性症状,没有脊髓参与的征兆 |
等级I | 脊髓参与的征兆,无行走障碍 |
等级II | 轻微行走障碍,有完全的劳动力 |
等级III | 中度行走障碍,无助行器行走,劳动/活动受限 |
等级IV | 仅可使用支撑工具行走 |
等级V | 卧床,需要轮椅 |
胸椎管狭窄:
由于胸椎与肋骨之间的解剖学关系,因此胸椎结合成比较坚固的支撑结构,因此纵向与横向的运动自由度小于颈椎和腰椎,因此磨损和骨重建的危险/可能性比较小。胸椎管狭窄很少发生,诊断和治疗方法与其它椎管狭窄的诊断和治疗方法相同。
腰椎管狭窄:
典型病痛:经常“仅仅”沿着特定的腰神经根的皮节有疼痛(多数L3~L5)。经常伴发髋曲肌麻痹,股前肌群麻痹,抬脚麻痹比较罕见,落脚麻痹非常罕见。典型特征为“间歇性跛行”(神经源性跛行),也就是患者必须在短时间后坐下,然后疼痛减轻,然后可以重新行走几米,然后又要重新坐下,以此类推。
上述所有椎管狭窄的诊断方法包括专家(神经病学家)详细的临麻神经病学研究(任选地也包括诱发电位)、详细的既往病历、进一步的专门研究(EMG,测量神经传导速度、上述诱发电位等等),尤其包括成像方法(MRT、CT、可能的脊髓造影),其中MRT是最为优选的诊断方法,用它来测定椎管的矢状径缩窄,并且可以明确搞清楚是否存在椎管狭窄。
优选使用所述的化合物来治疗颈椎管狭窄和/或腰椎管狭窄,优选用来治疗颈椎管狭窄。
本发明所述的应用包括治疗所有随颈椎管狭窄任选伴随出现的症状。
除了上述已经提及的症状之外,还包括可通过给予本发明所述化合物加以缓解或者改善的症状,如轻瘫、感觉减退、失去感觉、疼痛和/或感觉障碍诸如麻木感。
本发明所述的应用还可用来改善身体损害,尤其可改善相关脊柱段受限的活动性。本发明所述的应用还实现了改善肌力下降、改善行走障碍、改善蚁走感和/或改善共济失调。尤其可以在治疗椎管狭窄中使用本发明的化合物,实现改善受限的无痛运动机能、减轻头部位置。这类疼痛引起的头部位置不正通常会导致活动性恶化,并且会因为另外肌肉僵硬和受力不当引起的肌肉僵直而导致痛感增加。此外如果小便失禁和/或大便失禁的原因在于椎管狭窄,则本发明所述的应用可以改善症状。
在特别优选的本发明的应用中,可对挥鞭伤、其它创伤性改变或者椎间盘脱出的慢性作用引起的椎管狭窄进行治疗。
在特别优选的本发明的另一种应用中,可对挥鞭伤患者进行预防性处理,以防止由此引起椎管狭窄的慢性后果。
在特别优选的本发明的另一种应用中,可对椎管狭窄患者以及由此在这些患者中引起的症状进行预防性处理,以防止综合症状变为慢性。
本发明还涉及麦角林衍生物,尤其是以上所述的化合物,例如以上已经详细描述过的5-HT2A和5-HT2B受体拮抗剂,可将其用来治疗或者预防性处理椎管狭窄患者,尤其优选用来治疗以上已经详细描述过的颈椎管狭窄患者以及由此在这些患者中引起的症状。本发明所述的麦角林衍生物均为从麦角林:
衍生而来的化合物,任选地也可以具有形式上脱氢形式的4,6,6α,7,8,9,10,10α-八氢-吲哚并[4,3-fg]喹啉骨架。属于脱氢形式的尤其是基于麦角乙脲的骨架:
这是一种4,6,6α,7,8,9-六氢-吲哚并[4,3-fg]喹啉骨架。本发明所述的麦角林衍生物是形式上通过取代麦角林或脱氢麦角林中的至少一个氢原子而产生的所有衍生物。
优选的麦角林衍生物是具有以下通式的化合物
其中
R1和R4相互独立地表示:氢、烷酰基(优选-CHO、-COCH3、-COC2H5、-COC3H7、-CO-环-C3H5、-COCH(CH3)2、-COC(CH3)3)、羧基(-COOH)、烷氧羰基(优选-COOCH3、-COOC2H5、-COOC3H7、-COO-环-C3H5、-COOCH(CH3)2、-COOC(CH3)3)、烷氧基硫羰基、烷硫基硫羰基、氨甲酰基(-CONH2)、单烷基氨基羰基或二烷基氨基羰基(优选-CONHCH3、-CONHC2H5、-CONHC3H7、-CONH-环-C3H5、-CONH[CH(CH3)2]、-CONH[C(CH3)3]、-CON(CH3)2、-CON(C2H5)2、-CON(C3H7)2、-CON(环-C3H5)2、-CON[CH(CH3)2]2、-CON[C(CH3)3]2)、氨基(-NH2)、单烷基氨基或二烷基氨基(优选-NHCH3、-NHC2H5、-NHC3H7、-NH-环-C3H5、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N(环-C3H5)2、-N[CH(CH3)2]2、-N[C(CH3)3]2)、烷基亚硫酰基(优选-SOCH3、-SOC2H5、-SOC3H7、-SO-环-C3H5、-SOCH(CH3)2、-SOC(CH3)3)、烷基磺酰基(优选-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-环-C3H5、-SO2CH(CH3)2、-SO2C(CH3)3)、磺基(-SO3H3)、烷基磺酸酯(优选-SO3CH3、-SO3C2H5、-SO3C3H7、-SO3-环-C3H5、-SO3CH(CH3)2、-SO3C(CH3)3)、卤代烷基(优选-CH2F、-CHF2、-CF3、-CH2Cl、-CH2Br、-CH2I、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、-CH2-CH2Cl、-CH2-CH2Br、-CH2-CH2I)、烷基(优选-CH3、-C2H5、-C3H7、-CH(CH3)2、-C(CH3)3、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C5H11、-C6H13、-C7H15、-C8H17、-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11)、芳基(优选苯基)、芳基烷基(优选-CH2-Ph、-CPh3)、烯基(优选-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C2H4-CH=CH2、-CH=C(CH3)2)、炔基(优选-C≡CH、-C≡C-CH3、-CH2-C≡CH);
R2和R3独立表示:
氢,
任选取代的直链、支化或环状、饱和或不饱和烃残基;例如
-任选取代的烷基,
-任选取代的烯基,
-任选取代的芳基,
-任选取代的烷基芳基,
优选如以下所定义。
本发明所述与其余取代基团有关的任选取代烷基优选包括:
具有1~8个碳原子、优选具有1~6个碳原子的直链或者支化烷基;具有3~8个碳原子、优选具有5或6个碳原子的环烷基;或者具有1~4个碳原子且用环烷基取代的烷基,可任选分别带有优选1~3个取代基,所述取代基优选选自:羟基、卤素和氰基。这里以及本发明所述的卤素包括氟、氯、溴和碘,优选氟或氯。此外还可以将一个或多个、优选将1~3个碳原子替换成杂原子基团,所述杂原子包含氮、氧或硫。这意味着例如可以将烷基残基中的一个或多个亚甲基基团替换成NH、O或S。
例如具有1~8个碳原子的烷基残基包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、叔戊基、2-甲基丁基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基3-乙基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1-乙基-1-甲基丙基、正庚基、1-甲基己基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、1-乙基戊基、2-乙基戊基、3-乙基戊基、4-乙基戊基、1,1-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、4,4-二甲基戊基、1-丙基丁基、正辛基、1-甲基庚基、2-甲基庚基、3-甲基庚基、4-甲基庚基、5-甲基庚基、6-甲基庚基、1-乙基己基、2-乙基己基、3-乙基己基、4-乙基己基、5-乙基己基、1,1-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、5,5-二甲基己基、1-丙基戊基、2-丙基戊基等等。优选具有1~6个碳原子的烷基残基,尤其是甲基、乙基和正丙基。最优选甲基。
使用一个或多个杂原子基团(如-O-、-S-或-NH-)替代后产生的烷基例如优选在其中将一个或多个甲基替换成-O-生成醚基的烷基,例如甲氧基甲基、乙氧基甲基、2-甲氧基亚乙基等等。按照本发明所述,也包括烷基定义的聚醚基团。
具有3~8个碳原子的环烷基残基优选包括:环丙基、环丁基、环戊基、环己基、环庚基、环辛基等等。优选环丙基、环丁基、环戊基和环己基。由环烷基将亚甲基替换成杂原子基团而形成的杂环烷基残基例如可以是5元或6元杂环残基,四氢呋喃基、吡咯烷基、哌啶基或者四氢吡喃基等等,它们任选可以与芳环缩合。
具有1~8个碳原子的卤素取代的直链或支化烷基残基例如包括:氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、三溴甲基、1-氟乙基、1-氯乙基、1-溴乙基、2-氟乙基、2-氯乙基、2-溴乙基、1,2-二氟乙基、1,2-二氯乙基、1,2-二溴甲基、2,2,2-三氟乙基、七氟乙基、1-氟丙基、1-氯丙基、1-溴丙基、2-氟丙基、2-氯丙基、2-溴丙基、3-氟丙基、3-氯丙基、3-溴丙基、1,2-二氟丙基、1,2-二氯丙基、1,2-二溴丙基、2,3-二氟丙基、2,3-二氯丙基、2,3-二溴丙基、3,3,3-三氟丙基、2,2,3,3,3-五氟丙基、2-氟丁基、2-氯丁基、2-溴丁基、4-氟丁基、4-氯丁基、4-溴丁基、4,4,4-三氟丁基、2,2,3,3,4,4,4-七氟丁基、全氟丁基、2-氟戊基、2-氯戊基、2-溴戊基、5-氟戊基、5-氯戊基、5-溴戊基、全氟戊基、2-氟己基、2-氯己基、2-溴己基、6-氟己基、6-氯己基、6-溴己基、全氟己基、2-氟庚基、2-氯庚基、2-溴庚基、7-氟庚基、7-氯庚基、7-溴庚基、全氟庚基等等。
羟基取代的烷基残基例如包括上述具有1~3个羟基残基的烷基残基,例如羟甲基、2-羟乙基、3-羟丙基等等。
在本发明的整个范围内,任选取代的烯基优选包括:
具有2~8个碳原子的直链或支链烯基,以及具有3~8个碳原子的环烯基,其任选地可通过1~3个取代基例如羟基、卤素或者烷氧基取代。例如包括:乙烯基、1-甲基乙烯基、烯丙基、1-丁烯基、异丙烯基、环丙烯基、环丁烯基、环戊烯基、环己烯基。优选乙烯基或者烯丙基。
在本发明的整个范围内,任选取代的芳基优选包括:
具有6~14个碳原子的芳烃残基(不包括取代基的碳原子)以及具有直至3个选自S、O、N系列的杂原子的5~10元芳杂环残基,所述芳杂环可以是单环或双环,并且可以通过选自羟基、卤素、氰基、烷基、酰基和烷氧基的1~3个取代基取代。关于烷基和卤素的定义,可参阅上述定义或者示例。
这里和以下所述作为芳基取代基的烷氧基例如包括:通过氧原子结合在芳基上的一种上述烷基残基,如具有直至6个碳原子的直链或支化烷氧基残基,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、仲戊氧基、叔戊氧基、2-甲基丁氧基、正己氧基、异己氧基、叔己氧基、仲己氧基、2-甲基戊氧基、3-甲基戊氧基、1-乙基丁氧基、2-乙基丁氧基、1,1-二甲基丁氧基、2,2-二甲基丁氧基、3,3-二甲基丁氧基、1-乙基-1-甲基丙氧基等等。优选甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等等。这里和以下所述作为芳基取代基的酰基包括:脂族酰基、芳族酰基,如C1~C6烷酰基,如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基等等,以及C6~C10芳酰基,如苯甲酰基、甲苯甲酰基、二甲苯酰基等等。
具有6~14个碳原子的芳烃残基例如包括:任选地可以取代的苯基、萘基、菲基和蒽基,它们可以任选被取代。优选苯基。
杂芳基残基例如包括:吡啶基、吡啶基-N-氧化物、嘧啶基、哒嗪基、吡嗪基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基或异噁唑基、吲嗪基、吲哚基、苯并[b]噻吩基、苯并[b]呋喃基、吲唑基、醌醇基、异醌醇基、萘啶基、喹唑啉基、5元或6元芳杂环,例如优选吡啶基、吡啶基-N-氧化物、嘧啶基、哒嗪基、呋喃基和噻吩基。
在本发明的整个范围内,任选取代的烷基芳基优选包括:
如上所述具有1~8个碳原子、优选具有1~4个碳原子、并且如上所述使用芳基取代的直链或支化烷基。优选芳基烷基是苄基。
-CO-R8,其中R8表示可以是以上所述的一种任选取代的直链、支化或环状、饱和或不饱和烃残基;
-NH-CO-R9,其中R9表示可以是以上所述的一种任选取代的直链、支化或环状、饱和或不饱和烃残基;
-NH-CO-NR11R12,其中R11和R12各自独主表示氢和/或可以是以上所述的一种任选取代的直链、支化或环状、饱和或不饱和烃残基,或者R11和R12与它们所结合的氮原子一起构成一个任选地可包含另外1个或2个杂原子的5元或6元任选取代的环,例如哌啶-1-基、吗啉-4-基、硫代吗啉-4-基、吡咯烷-1-基、噁唑烷-3-基、噻唑烷-3-基、2-羧基-吡咯烷-1-基(脯氨酰基)、3-或4-羟基-羧基-吡咯烷-1-基(3-或4-羟基-脯氨酰基)等等。
-R13-O-CO-R14、其中R13表示一个二价的任选取代的直链、支化或环状、饱和或不饱和烃残基,例如任选取代的烷二基或者任选取代烯二基,其中,任选取代的烷二基优选包括:一个二价的直链或支化烷二基残基,该残基优选具有1~7个碳原子,优选具有1~6个碳原子,更优选具有1~4个碳原子,且任选地可以带有1~3个选自羟基、卤素和氰基的取代基;示例并优选提及:亚甲基、1,2-乙烷二基、乙烷-1,1-二基、1,3-亚丙基、丙烷-1,1-二基、丙烷-1,2-二基、丙烷-2,2-二基、1,4-亚丁基、丁烷-1,2-二基、丁烷-1,3-二基、丁烷-2,3-二基、戊烷-1,5-二基、戊烷-2,4-二基、3-甲基戊烷-2,4-二基和己烷-1,6-二基;优选的取代的烷二基残基是羟基取代的烷二基残基。任选取代的烯二基优选具有2~7个碳原子、更优选具有2~6个碳原子、更优选具有2~4个碳原子的二价直链或支化烯二基残基,该残基任选地可以有1~3个选自羟基、卤素和氰基的取代基。示例并优选提及:乙烯-1,1-二基、乙烯-1,2-二基、丙烯-1,1-二基、丙烯-1,2-二基、丙烯-1,3-二基、丁-1-烯-1,4-二基、丁-1-烯-1,3-二基、丁-2-烯-1,4-二基、丁-1,3-二烯-1,4-二基、戊-2-烯-1,5-二基、己-3-烯-1,6-二基和己-2,4-二烯-1,6-二基。R13在本发明的范围中尤其优选烷二基,更优选具有1~3个碳原子的烷二基,更优选1,2-乙烷二基(-CH2CH2-)或者1,3-丙烷二基(-CH2CH2CH2-),
并且R14表示一个任选取代的直链、支化或环状、饱和或不饱和烃残基,如前述定义,该烃残基可以任选具有一个或多个杂原子;以及
-CO-NR15R16,其中R15和R16各自相互独立地表示氢和/或如前述定义的任选取代的直链、支化或环状、饱和或不饱和烃残基,或者R15和R16与它们所连接的氮原子一起形成任选地可以包含1个或2个另外的杂原子的5元或6元任选取代的环,同样如前述已经定义的那样;
R5表示氢、卤素、氰基或硝基;
R6和R7相互独立地表示氢或者烷氧基,关于其中的烷基部分,可以参考之前所述的烷基定义,或者共同表示在碳原子之间形成双键的一个键(即具有以下结构:
以及其盐类,
用于治疗或者预防性处理椎管狭窄尤其是颈椎管狭窄患者以及因此在这些患者中引起的症状。
在存在不对称的碳原子的情况下,如在麦角林衍生物的情况下那样,本发明所使用的化合物包括立体异构形式(消旋体,对映异构体,非对映异构体)。因此本发明包括使用所有的立体异构形式,如对映异构体、非对映异构体及其相应的混合物,如消旋体。纯净的对映异构体形式任选地可以通过常规的光学拆分法,如非对映异构体的分级结晶,通过与光活性化合物进行反应而获得。如果本发明的化合物能够以互变异构体形式出现,则本发明包括使用所有的互变异构体形式。
本发明所使用的化合物可以作为盐存在,并且本发明包括所有这些盐。所述化合物可以其药学可接受的盐形式使用。包含碱性基团的化合物尤其可以作为药学可接受的酸的盐使用,例如与无机酸、羧酸和磺酸,例如与盐酸、氢溴酸、氢碘酸、硫酸、磷酸、酒石酸、甲磺酸、羟乙基磺酸、醋尿酸(乙酰甘氨酸)、马来酸、丙酸、富马酸、甲苯磺酸、苯磺酸、三氟醋酸、萘二磺酸-1,5、水杨酸、苯甲酸、乳酸、苹果酸、3-羟基-2-萘甲酸-2、柠檬酸或者醋酸等等反应生成的盐。本发明所使用的含有酸性基团的化合物可以与药学可接受的碱的药学可接受的盐形式使用,例如与碱金属氢氧化物(钠盐等等),碱土金属氢氧化物(钙盐,镁盐等等),胺等等。
例如WO_9220339_A1、WO_08061805_A1、WO_08043601_A2、WO_07110047_A2、WO_07065713_A2、WO_05025546_A1、WO_03076439_A2、WO_0215890_A1、WO_0215889_A1和其中引用的文献中就描述了麦角林衍生物。就此而言,上述文献中的全部内容均应作为本发明的公开内容。
优选以下通式的化合物:
其中
R1和R4相互独立地表示:氢、烷基、烯基,
R2和R3表示:
氢,
-NH-CO-NR11R12,其中R11和R12各自相互独立地表示氢和/或烷基,或者R11和R12与它们所结合的氮原子一起构成5元或6元任选取代的环,其任选地可以包含另外1个杂原子;和/或
-CO-NR15R16,其中R15和R16各自相互独立地表示氢和/或任选取代的直链、支化或环状、饱和或不饱和烃残基,或者R15和R16与它们所结合的氮原子一起构成5元或6元任选取代的环,其任选地可以包含另外1个或2个杂原子;
R5表示氢;
R6和R7相互独立地表示氢,或者共同表示在碳原子之间形成双键的一个键,
其中优选的取代基如上所述。
尤其优选的是使用根据下式的化合物:
这些化合物优选选自:
其中8β-衍生物各自表示8α-衍生物的差向异构体,如8α-麦角乙脲或者8α-特麦角脲。
特别优选使用这些化合物中的8α-麦角乙脲或者8α-特麦角脲,最优选使用特麦角脲或者8α-特麦角脲。
本发明还提供将上述化合物与一种或多种另外的活性物质联合使用的用途。优选这类其它活性物质尤其包括已知可用来治疗椎管狭窄的其它活性物质,尤其是US-20060058310_A1已知的醛糖还原酶抑制剂,由DE 69919191 T2已知的哒嗪酮化合物,尤其是EP 1609480 A1所公开的EP2-激动剂和EP3-激动剂或者其组合,如注册商品名称为Opalmon的前列腺素E1衍生物。
可以与本发明所用化合物联合使用的其它活性物质例如包括:前列腺素,前列腺素衍生物,即所谓的“非甾体抗炎药”(NSAID),维生素,肌肉松弛剂,抗抑郁剂,聚ADP核糖聚合酶(PARP)抑制剂,兴奋性氨基酸受体拮抗剂(如NMDA受体拮抗剂和AMPA受体拮抗剂),自由基清除剂,星形胶质细胞调节剂,IL-8-受体拮抗剂,免疫抑制剂(如环孢菌素和FK506)以及糖醛还原酶抑制剂。前列腺素(简称为PG)的实例包括PG-受体激动剂、PG-受体拮抗剂等等。PG-受体的实例包括PGE-受体(EP1,EP2,EP3和EP4)、PGD-受体(DP,CRTH2)、PGF-受体(FP)、PGI-受体(IP)、TX-受体(TP)等等。前列腺素衍生物的实例还包括利马前列素、伊洛前列素和贝前列素。
NSAID例如包括:双水杨酸酯,水杨酸钠,阿司匹林,阿司匹林-二铝酸盐,二氟尼柳,吲哚美辛,舒洛芬,乌芬那酯,二甲基异丙基甘菊环,丁苯羟酸,联苯乙酸,双氯芬酸,托美丁钠,舒林酸,芬布芬,萘丁美酮,丙谷美辛,吲哚美辛法尼酯,阿西美辛,丙谷美辛马来酸酯,氨芬酸钠,莫苯唑酸,依托度酸,布洛芬,布洛芬吡啶甲醇,萘普生,氟比洛芬,氟比洛芬酯,酮洛芬,非诺洛芬钙,噻洛芬酸,奥沙普秦,普拉洛芬,洛索洛芬钠,阿明洛芬,扎托洛芬,甲芬那酸,甲芬那酸铝,托芬那酸,夫洛非宁,酮保泰松,羟保泰松,吡罗昔康,替诺昔康,安吡昔康,联苯乙酸,依匹唑,盐酸噻拉米特,盐酸替诺立定,依莫法宗,安乃近,米格来宁,散利痛,Sedes G,氨丙吡酮-N,溴己新(Solvon),醋氨酚,非那西丁,甲磺酸二甲替嗪等等。肌肉松弛剂的实例包括:盐酸托哌酮,氯唑沙宗,氯美扎酮,美索巴莫,苯丙氨酯,甲磺酸普立地诺,氯苯甘油氨酯,巴氯芬,盐酸乙哌立松,氟喹酮,盐酸替扎尼定,阿库氯铵,氯琥珀胆碱,氯筒箭毒碱,丹曲林钠,泮库溴铵,维库溴铵等等。抗抑郁药的实例包括三环抗抑郁药,如盐酸丙咪嗪,盐酸去甲丙咪嗪,盐酸氯米帕明,马来酸三甲丙咪嗪,盐酸阿米替林,盐酸去甲替林,盐酸洛非帕明,阿莫沙平,盐酸度硫平等等。四环抗抑郁药的实例包括马普替林、米安色林等等。
上述组合物包括不同的施用方式,如同时或者依次施用分开的活性物质,或者同时施用一种活性物质组合制剂。上述组合物也包括任意排列组合的相关介绍,例如可作为“Kit-of-Parts”。
本发明还涉及5-HT2A和5-HT2B受体拮抗剂化合物(所述化合物对5-HT2A和5-HT2B受体的pA2值≥7.5)用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
本发明还涉及麦角林衍生物用于治疗或者预防性处理椎管狭窄尤其是颈椎管狭窄患者以及由此在这些患者中引起的症状,其中所述麦角林衍生物如前所述。
本发明还涉及具有以下通式的化合物
如前述,以及这些化合物的盐用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
本发明还涉及并优选8α-麦角乙脲或8α-特麦角脲,更优选8α-特麦角脲用来治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
本发明尤其涉及特别优选的8α-特麦角脲用于治疗或预防性处理颈椎管狭窄患者或者由此在这些患者中引起的症状。
本发明还涉及包含上述权利要求中任一项所述的一种或者多种化合物以及一种或多种另外的活性成分的组合制剂,用来治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
在本发明中,优选以药物组合物形式将上述化合物与一种或多种常规药物助剂同时给予。因此本发明还涉及包含上述化合物以及一种或者多种常规药物助剂的药物组合物用来治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
所述药物组合物例如适合于吸入给药或者静脉给药,腹膜内给药,肌内给药,阴道内给药,口腔内给药,经皮给药,皮下给药,粘膜给药,口服给药,直肠给药,透皮给药,局部给药,真皮内给药,胃内给药或者皮内给药,并例如以如下形式提供:丸剂、片剂、肠溶片剂、包衣片剂、多层片剂,用于口服给药的缓释制剂、皮下或皮肤给药的缓释制剂(尤其作为贴剂),长效制剂,锭剂,药塞,凝胶剂,软膏,糖浆,吸入粉剂,颗粒,栓剂,乳液,分散液,微胶囊,微米制剂,纳米制剂,脂质体制剂,胶囊,肠溶胶囊,粉剂,吸入粉剂,微晶制剂,吸入喷雾剂,散剂,滴剂,鼻滴剂,鼻喷剂,气雾剂,安瓿剂,溶液,浓汁(),悬浮液,乳液,输注液或注射液等等。优选口服与皮肤、透皮给药形式。
本发明的化合物可以药物组合物形式给予,所述药物组合物可以包含不同有机或无机载体和/或辅料,如通常出于药用目的使用的特别是用于固体药物制剂的那些,例如赋形剂(如蔗糖、淀粉、甘露醇、山梨醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙、碳酸钙)、粘结剂(如纤维素、甲基纤维素、羟丙基纤维素、聚丙基吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖、淀粉)、崩解剂(如淀粉、水解淀粉、羧甲基纤维素、羧甲基纤维素的钙盐、羟丙基淀粉、乙醇钠淀粉、碳酸氢钙、磷酸钙、柠檬酸钙)、润滑剂(如硬脂酸镁、滑石、月桂基硫酸酯钠)、矫味剂(如柠檬酸、薄荷脑、甘氨酸、橙粉)、防腐剂(如苯甲酸钠、亚硫酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯)、稳定剂(如柠檬酸、柠檬酸钠、醋酸,以及源自Titriplex系列的多元羧酸,例如二亚乙基三胺五乙酸(DTPA)、悬浮剂(如甲基纤维素、聚乙烯基吡咯烷酮、硬脂酸铝)、分散剂、稀释剂(如水、有机溶剂)、蜂蜡、可可脂、聚乙二醇、白凡士林等等。
诸如溶液、悬浮液和凝胶的液态药物制剂通常均含有液态载体,如水和/或药物相容性有机溶剂。此外这类液态制剂也可以含有pH调节剂、乳化剂或分散剂、缓冲剂、防腐剂、润湿剂、胶凝剂(例如甲基纤维素)、着色剂和/或芳香剂。所述组合物可以是等渗的,也就是可以具有与血液相同的渗透压。可以通过使用氯化钠或者其它药物可接受的试剂调节组合物的等渗性,例如可使用葡萄糖、麦芽糖、硼酸、酒石酸钠、丙二醇或者其它无机或有机可溶性物质。可以通过使用药物可接受的增稠剂(甲基纤维素)来调节液态组合物的粘度。其它适合的增稠剂例如包括黄原胶、羧甲基纤维素、羟丙基纤维素、卡波姆等类似物质。增稠剂优选的浓度取决于所选用的试剂。可以使用药物可接受的防腐剂来提高液态组合物的稳定性。可以使用苄醇,同样也可以使用防腐剂例如包括对羟基苯甲酸酯、硫柳汞、氯丁醇或者苯扎氯铵。
例如每天可以给予1~4次活性物质,单位剂量为0.25mg~50mg、优选0.25mg~5.0mg。但也可以根据年龄、患者情况、疾病严重程度或者给药方式提高或降低剂量。
本发明尤其还优选涉及以上所述的化合物和组合物用来治疗或者预防性处理颈椎管狭窄患者以及由此在这些患者中引起的症状。
通过以下实施例详细阐述本发明。该实施例仅为本发明的说明,专业人士可以将该具体实施例延用到其它权利要求所述的化合物。
实施例:
将慢性全身性疼痛症状患者纳入临床研究。这些患者中的一个分组相当于原发性纤维肌痛的定义。另一个患者组的诊断特征是慢性颈痛。(在研究期间使用磁共振成像方法(MRI)作为成像法对大多数参与研究的患者的颈椎进行研究。)选择在不使用造影剂并且头部处在标准平躺位置的情况下,可以在颈椎区域进行椎管断面成像的条件。通过1.5特斯拉磁共振扫描仪进行测量。通过起到鉴定人作用的不知情分析者在所有可分析的照片中测量椎管的直径和神经束(所谓的脊髓)的厚度。此外还根据国际公认的分析目录(NJNR Am J Neuroradiol1998 Oct;19(9):1763-71),对存在颈椎管狭窄的检查结果进行评估。该目录包括一个5级评分尺度。0级表示椎管宽度正常,椎管之内前壁或者后壁蛛网膜下腔没有变窄的征兆;1级表示前壁或后壁蛛网膜下腔或者这两个腔存在局部变窄;2级表示脊髓最终完全填满椎管的蛛网膜下腔;3级表示颈脊髓压迫或者脊髓扭曲;4级表示脊髓的高信号,是脊髓病的指征。在本次研究的所有患者中,经分析观察到大约20%的患者有2~4级改变,这说明该患者组为椎管狭窄患者。
使用特麦角脲(1片=0.5mg)或安慰剂对这些患者进行治疗,特麦角脲是一种麦角林化合物,如前所述,不仅作为局部多巴胺激动剂,而且也作为5-HT2A和5-HT2B受体拮抗剂。经过21天将试验药物从每天半片药逐步增加到最多6片药,然后以不变剂量继续治疗9周。在早晨和晚上服用该药物。借助评分尺度用来确定患者疼痛强度、疲劳、睡眠充足性、肌肉僵硬性、恐惧感、神经质和抑郁、舒适感和劳动力以及一份日常生活的调查问卷,检查3周、7周和12周之后的疗程。如果评分值降低或者分析调查问卷得到的分数较低,则表示改善了相应的症状,因此有疗效。
结果令人惊奇,在慢性全身性疼痛症状患者中,仅颈椎管狭窄(2-4级)患者组经过3个月之后有显著的疗效(附图1)。在所提出的所有问题中(总分),该患者组中的多数人均回答总的健康状况或多或少有所改善。在此尤其突出的是疼痛强度减弱,恐惧感和神经质有所改善,尤其是改善了主观感觉的身体损害和劳动力。与此相比,具有慢性全身性疼痛症状、但在颈椎范围内椎管正常无损伤的患者经过特麦角脲治疗后则没有多大变化(附图2)。仅仅肌肉僵硬性和抑郁行为有改善的趋势,而疼痛行为则没有变化。总而言之,与使用安慰剂治疗的无颈椎管狭窄患者组相比,无法证明在经过特麦角脲治疗的患者中有显著改善。
类似地,对没有颈椎狭窄征兆的慢性颈痛患者组进行分析的结果也显示,使用特麦角脲没有疗效(附图3)。与此相反,患者中的多个治疗效果参数变得更差,尤其是身体损害、舒适感、疼痛感、肌肉僵硬性、以及恐惧感/神经质这些治疗效果参数变差。
总而言之确定的是,特麦角脲仅对颈椎管狭窄患者有疗效。
附图说明:
附图1所示为特麦角脲对所选患者评分尺度以及慢性全身性疼痛与颈椎管狭窄(2~4级)患者总的健康状况调查问卷的影响。
附图2所示为特麦角脲对所选患者评分尺度以及没有颈椎管狭窄(0~1级)的慢性全身性疼痛患者总的健康状况调查问卷的影响。
附图3所示为特麦角脲对所选患者评分尺度以及没有椎管狭窄征兆(0~1级)的慢性全身性疼痛与慢性颈痛患者总的健康状况调查问卷的影响。
Claims (21)
1.5-HT2A和5-HT2B受体拮抗剂化合物用于制备用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状的药物的用途,其中所述化合物对5-HT2A和5-HT2B受体的pA2值≥7.5。
2.根据上述权利要求所述的用途,其中所述化合物对5-HT2A受体的pA2值与对5-HT2B受体的pA2值之间最多相差±1个单位。
3.根据上述权利要求所述的用途,其中所述化合物选自:赛庚啶、米安色林、利坦色林、甲替平、美西麦角、甲麦角林、麦角乙脲、特麦角脲、曲唑酮、苯噻啶和尼麦角林。
4.根据上述权利要求所述的用途,其中所述化合物是特麦角脲和/或麦角乙脲。
5.根据上述权利要求所述的用途,其中所述化合物选自8α麦角乙脲或者8α特麦角脲。
6.根据上述权利要求中任一项所述的用途,所述椎管狭窄是颈椎管狭窄。
7.根据上述权利要求中任一项所述的用途,所述用途可用来减缓轻瘫、感觉减退、失去感觉、疼痛和/或感觉障碍诸如麻木感的症状。
8.根据上述权利要求中任一项所述的用途,可用来改善身体损害,尤其是改善受限的无痛运动机能、减轻头部位置不正以及改善肌力下降、改善行走障碍、改善蚁走感和/或改善共济失调、改善小便失禁和/或大便失禁。
9.根据上述权利要求中任一项所述的用途,所述椎管狭窄是挥鞭伤、其它创伤性改变或者椎间盘脱出的慢性后果。
10.根据上述权利要求中任一项所述的用途,所述用途包括预防性处理椎管狭窄患者以及由此在这些患者中引起的症状,从而防止综合症状变为慢性,以及预防性处理挥鞭伤患者,以防止由此引起椎管狭窄的慢性后果。
11.根据上述权利要求中任一项所述的用途,将所述化合物与一种或多种另外的活性成分联合给予患者。
12.5-HT2A和5-HT2B受体拮抗剂化合物用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状,并且其中所述化合物对5-HT2A和5-HT2B受体的pA2值≥7.5。
13.8α麦角乙脲或者8α特麦角脲用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
14.8α特麦角脲用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
15.8α特麦角脲用于治疗或者预防性处理颈椎管狭窄患者以及由此在这些患者中引起的症状。
16.包含上述权利要求中任一项所定义的一种或者多种化合物以及一种或多种另外的活性成分的组合制剂,用来治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
17.根据上述权利要求中任一项所述的用途,以药物组合物形式将权利要求中所定义的化合物与一种或多种常规药物助剂一起给予。
18.包含上述权利要求中所定义的化合物以及一种或多种常规的药物助剂的药物组合物,用于治疗或者预防性处理椎管狭窄患者以及由此在这些患者中引起的症状。
19.根据上述权利要求所述的药物组合物,其中所述药物组合物适合于口服给药、舌下给药、非肠道给药、皮肤给药、口腔给药、经皮给药、皮下给药、吸入或者鼻腔给药。
20.根据上述权利要求所述的药物组合物,其中所述药物组合物以片剂、多层片剂、胶囊、口服缓释剂、透皮给药系统、栓剂、微米制剂、纳米制剂、脂质体制剂、滴剂、鼻滴剂、鼻喷剂、气雾剂、安瓿剂、溶液、乳液、分散液、粉剂、吸入粉剂、微晶制剂、吸入喷雾剂、透皮给药系统或者皮下给药制剂形式存在。
21.根据上述权利要求中任一项所述的药物组合物用于治疗或者预防性处理颈椎管狭窄患者以及由此在这些患者中引起的症状。
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EP08172859.4 | 2008-12-23 | ||
EP08172859 | 2008-12-23 | ||
PCT/EP2009/067768 WO2010072774A2 (de) | 2008-12-23 | 2009-12-22 | Mittel zur behandlung der spinalkanalstenose |
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CN102271667A true CN102271667A (zh) | 2011-12-07 |
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CN2009801524590A Pending CN102271667A (zh) | 2008-12-23 | 2009-12-22 | 用于治疗椎管狭窄的5-ht2a和5-ht2b受体拮抗剂 |
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EP (1) | EP2367543A2 (zh) |
JP (1) | JP2012513446A (zh) |
KR (1) | KR20110098965A (zh) |
CN (1) | CN102271667A (zh) |
AU (1) | AU2009331469A1 (zh) |
BR (1) | BRPI0923556A2 (zh) |
CA (1) | CA2748163A1 (zh) |
IL (1) | IL213768A0 (zh) |
MX (1) | MX2011006852A (zh) |
SG (1) | SG172315A1 (zh) |
WO (1) | WO2010072774A2 (zh) |
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CN107428745A (zh) | 2015-01-20 | 2017-12-01 | Xoc制药股份有限公司 | 麦角灵化合物及其用途 |
JP2020522504A (ja) | 2017-06-01 | 2020-07-30 | エックスオーシー ファーマシューティカルズ インコーポレイテッドXoc Pharmaceuticals, Inc | 多環式化合物およびそれらの用途 |
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WO2000012091A1 (en) | 1998-09-01 | 2000-03-09 | Welfide Corporation | Remedies for spinal canal stenosis |
JP4552189B2 (ja) | 2002-11-14 | 2010-09-29 | 小野薬品工業株式会社 | 脊柱管狭窄症治療剤 |
JPWO2004089411A1 (ja) | 2003-04-03 | 2006-07-06 | 小野薬品工業株式会社 | 脊柱管狭窄症治療剤 |
DE102006013307B3 (de) | 2006-03-21 | 2007-10-04 | Ergonex Pharma Gmbh | Tergurid/Protergurid zur Behandlung von chronischen Schmerzen |
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2009
- 2009-12-22 JP JP2011542819A patent/JP2012513446A/ja active Pending
- 2009-12-22 EP EP09795786A patent/EP2367543A2/de not_active Withdrawn
- 2009-12-22 WO PCT/EP2009/067768 patent/WO2010072774A2/de active Application Filing
- 2009-12-22 AU AU2009331469A patent/AU2009331469A1/en not_active Abandoned
- 2009-12-22 KR KR1020117017268A patent/KR20110098965A/ko not_active Application Discontinuation
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- 2009-12-22 BR BRPI0923556A patent/BRPI0923556A2/pt not_active Application Discontinuation
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Publication number | Publication date |
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BRPI0923556A2 (pt) | 2016-01-26 |
KR20110098965A (ko) | 2011-09-02 |
EP2367543A2 (de) | 2011-09-28 |
JP2012513446A (ja) | 2012-06-14 |
CA2748163A1 (en) | 2010-07-01 |
AU2009331469A1 (en) | 2011-07-21 |
IL213768A0 (en) | 2011-07-31 |
SG172315A1 (en) | 2011-07-28 |
WO2010072774A3 (de) | 2010-09-23 |
MX2011006852A (es) | 2011-07-20 |
WO2010072774A2 (de) | 2010-07-01 |
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