CN100366241C - Ibat抑制剂在治疗或预防便秘中的应用 - Google Patents
Ibat抑制剂在治疗或预防便秘中的应用 Download PDFInfo
- Publication number
- CN100366241C CN100366241C CNB200480009415XA CN200480009415A CN100366241C CN 100366241 C CN100366241 C CN 100366241C CN B200480009415X A CNB200480009415X A CN B200480009415XA CN 200480009415 A CN200480009415 A CN 200480009415A CN 100366241 C CN100366241 C CN 100366241C
- Authority
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- China
- Prior art keywords
- carbamoyl
- phenyl
- alkyl
- dioxo
- tetrahydrochysene
- 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.)
- Expired - Lifetime
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Abstract
本发明公开了IBAT抑制剂在治疗和/或预防温血动物如人的便秘中的应用。
Description
发明领域
本发明涉及功能性便秘和便秘为主要特征的肠易激综合征(C-IBS)的新的治疗和/或预防。更具体来说,本发明涉及回肠胆汁酸(IBAT)抑制剂在治疗和/或预防这些病症中的应用,以及用于治疗和/或预防这些病症的包含所述IBAT抑制剂的药物组合物。
在西方国家,便秘和/或其相关症状影响很多人,并且在儿童和老年人中最常见。根据人口统计学因素、抽样以及所用的定义,便秘可占人口的最高达20%。在5个不同欧洲国家对大约2000个人进行的研究中(Gastroenterology 118:A720,2000),有6%-23%的受试者说在过去的12个月期间他们经受了便秘,有大约20%的受试者在该期间内服用了通泻剂,至少10%的受试者经受了每月至少一次的大便困难。在1991年的National Health Interview Survey中,在美国约有四百五十万人说他们在大部分或所有时间内发生便秘。这些报道的便秘最经常见于妇女、儿童和年龄在65岁及以上的成年人。怀孕的妇女也抱怨便秘,并且这是分娩或手术后的常见问题。在大多数研究中,妇女是便秘患者当中最大的一个群体,并且问题随着年龄的增长而日益严重。
对西方国家人口的调查揭示,在15-20%的青少年和成人中发生IBS,在妇女中的流行率更高(流行率在其他人口群体中有所不同)。30-35%的IBS患者的主要症状是便秘,并伴有腹部疼痛和/或不适(C-IBS)。
便秘的原因是不同的,并且包括常见因素例如性别、年龄、民族、饮食和锻炼;结肠解剖学和机能例如腔内容物、水和钠的吸收、结肠的直径和长度以及结肠运动机能;排便机能例如正常机能消失、肛门括约肌复合体松弛不能、用力无效、直肠感觉以及粪的尺寸和稠度的降低;直肠肛门和骨盆底病症;和心理以及行为因素。某些病症可引起或导致便秘,例如神经病症如多发性硬化、帕金森病;慢性特发性肠假梗阻;中风和脊髓损伤;代谢和内分泌病症例如糖尿病、甲状腺活动不足或活动过度和尿毒症;和全身病症例如淀粉样变性、狼疮和硬皮病。某些药物治疗也可能引起便秘,包括镇痛药例如阿片类药物,抗胆碱能药物例如解痉药,三环类抗抑郁剂、吩噻唑啉类药物和抗毒蕈碱药物;分泌素受体拮抗剂;和含有钙/铝的抗酸剂。
功能性便秘包括一组机能障碍,这些障碍呈现为持续的排便困难、稀少或似乎不完全。其在妇女中更常见,并且发现通常随着年龄的增长而增多。
IBS包括一组肠障碍,其中排便伴有腹部不适或疼痛,或者肠习惯发生改变,并且特征是排便障碍。IBS具有慢性复发病程,并且与其它功能性胃肠障碍重叠。其带来了高的直接医疗费用和间接的成本损失,包括误工。
与便秘有关的症状包括粪便稀少、没有排便的强烈要求、粪便难以通过、用力无效、需要指状、排便不完全感、肛门或会阴疼痛、在肛门脱出以及弄脏衣服。肿胀(膨胀)、不适和疼痛也是便秘症状。当疼痛是便秘症状时,其可以由多种因素,包括肠道的强收缩和肿胀而引起。在便秘患者中,高幅度蔓延性收缩与疼痛之间似乎有联系(Dig DisSci 36,827-862,1991)。有时使用解痉药来缓解该疼痛,因为据信解痉药能够减少与疼痛有关的强收缩(Pharmacol.Ther.,80,49-98,1998)。已发现抗毒蕈碱化合物阿托品(Digestive Diseases&Sciences 40(6):1381-7,1995)和zamifenacin(Aliment.Pharmacol.Ther.,11,561-8,1997)能够减轻便秘疼痛。
对于便秘自身,目前的治疗包括:(i)纤维性饮食;(ii)其它散装通泻剂例如欧车前、甲基纤维素和聚卡波非钙;(iii)聚乙二醇溶液(PEG);(iv)兴奋性通泻剂例如双醋苯啶、匹可硫酸钠或蕃泻苷类;(v)5-羟色胺4(5-HT4)激动剂例如普卡必利;(vi)灌肠剂和栓剂;和(vii)手术;但是这些治疗的治疗结果通常令人失望,并且它们可导致不适的副作用。例如,纤维性饮食的增加经常不缓解便秘,并且在某些情况下实际上加重了该症状,例如加重膨胀感觉(Gut 27:41,1986)。其它散装通泻剂经常出于相同原因而没有疗效,并且散装通泻剂一般仅适于长期使用,它们不适于迅速缓解临时便秘。使用PEG溶液可能是有效的,但是通常需要饮用大体积的液体(大约每天一升,最长达3天),这同样令人不舒服,对于难以饮用这么大量的患者例如儿童明显不适合。兴奋性通泻剂治疗具有很多报道的副作用,并且可导致通泻剂依赖和滥用。在结肠中也具有所需作用的5-HT4激动剂可影响胃排空和小肠(Clinical Pharmacology&Therapeutics,67:2(PII-33),2000),导致腹泻。灌肠剂和栓剂可导致直肠粘膜的严重破坏,此外,如果在灌肠剂中使用大体积,则如果保持灌肠剂就有可能发生严重的水中毒。手术例如结肠切除术可能是有效的,但是已有报道会带来令人不满意的结果,例如可能需要进一步手术,便秘可能持续,或者有可能发展成具有失禁的腹泻。
胆汁酸的通泻作用已有报道(Br J Surg 1979;66;776-9;Gut 1975,16,894-902;和Gut1973,14,348-353),并且虽然其易于口服给药来治疗便秘(Myo Clinic Proceedings,1973,48,356),但是当它们提高能动性时它们对小肠有不利作用,有可能导致副作用例如减少营养物质的吸收。
很明显需要确定另外的便秘疗法,并且优选更有效的疗法或具有减轻的副作用的疗法。
文献中已经公开了很多IBAT抑制剂(见下文),并且经确定它们可用于治疗异常脂血症和障碍,例如高脂血症,以及可用于治疗和预防不同的心血管临床病症,例如动脉粥样硬化。用IBAT抑制剂治疗乙醇脂血症的基本原理是其提高胆汁酸和胆固醇分泌,应当实现有利的负胆固醇平衡以及改善动脉粥样硬化形成性脂蛋白状况。
文献中没有提出或涉及使用IBAT抑制剂来治疗胃肠(GI)病症。实际上,某些报道提出使用IBAT抑制剂治疗异常脂血症可能会引起GI问题,例如Glaxo SmithKline出版的临床研究(abstract,DALMSeptember 2001)表明在人中抑制IBAT期间发生的GI副作用(腹泻和腹部痉挛)。
本发明涉及使用IBAT抑制剂来治疗和/或预防便秘的新疗法。该治疗和/或预防使得将胆汁酸递送到结肠内,胆汁酸在结肠中其内源性通泻剂的作用。局部递送给结肠避免了口服递送胆汁酸的副作用(上述),因为它们通常不影响结肠之间的GI道。预计通过施用IBAT抑制剂来避免影响结肠以上的GI道还给出了优于现有药物例如5-HT4激动剂治疗的优点。此外,某些IBAT抑制剂具有非常低的生物利用度(<2%),在这种情况下,全身暴露很低,从而降低了副作用危险性。此外,IBAT抑制剂可通过类似于抗毒蕈碱药物的继发机制来缓解疼痛。之所以缓解疼痛是因为IBAT抑制剂将提高水在底部肠中的能动性和含量。这又使得较软内容物更易于移动,并且不积聚,因此肠壁的肿胀程度较低,而众所周知肠道肿胀会产生疼痛。此外,当肠的内容物变软时,需要较少的高幅度散播性收缩来移动肠的内容物,这样疼痛又得到减轻。
因此,本发明包括IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药在治疗和/或预防便秘中的应用。
应当理解,除非另有说明,当在本文中使用术语“便秘”时,该术语是指功能性便秘和C-IBS。在本发明的一个方面,“便秘”是指功能性便秘。在本发明的另一个方面,“便秘”是指C-IBS。
本发明的一个方面涉及治疗便秘。本发明的另一个方面涉及预防便秘。本发明的第三个方面涉及治疗和预防便秘。
在本发明的一个方面,当提及治疗便秘并且便秘涉及C-IBS时,应当理解,这包括交替的(便秘-腹泻)肠易激综合征。
在本文中,当使用术语“功能性便秘”和“C-IBS”时,应当理解,它们是根据“Rome 2 Criteria”(Gut 45(Suppl2):43,1999,II43-II47)定义的。
在文献中IBAT抑制剂经常有不同的名字。可以理解的是,本文中所指的“IBAT抑制剂”,该术语同样包括在文献中所知的如下化合物:
i)回肠顶端钠协同-依赖性胆汁酸转运器(ASBT)抑制剂;
ii)胆汁酸转运器(BAT)抑制剂;
iii)回肠钠/胆汁酸协同转运器系统抑制剂;
iv)顶端钠-胆汁酸协同转运器抑制剂;
v)回肠钠-依赖性胆汁酸转运器抑制剂;
vi)胆汁酸重吸收(BARI′s)抑制剂;和
vii)钠胆汁酸转运器(SBAT)抑制剂;
其中它们通过IBAT抑制剂进行作用。
已经描述了具有IBAT抑制活性的合适的化合物,参见例如在以下专利中描述的化合物:WO 93/16055、WO 94/18183、WO 94/18184、WO 94/24087、WO 96/05188、WO 96/08484、WO 96/16051、WO97/33882、WO 98/07749、WO 98/38182、WO 98/40375、WO 98/56757、WO 99/32478、WO 99/35135、WO 99/64409、WO 99/64410、WO00/01687、WO 00/20392、WO 00/20393、WO00/20410、WO 00/20437、WO 01/34570、WO 00/35889、WO 00/47568、WO 00/61568、WO01/68637、WO 01/68096、WO 02/08211、WO 00/38725、WO 00/38726、WO 00/38727、WO 00/38728、WO 00/38729、DE 19825804、JP10072371、US 5070103、EP 251315、EP 417725、EP 489423、EP 549967、EP 573848、EP 624593、EP 624594、EP 624595、EP 869121、EP 864582和EP 1070703,这些专利申请的内容,特别是在权利要求1中描述的化合物以及命名实施例在此处引用作为参考。
适用于本发明的IBAT抑制剂类别是苯并硫杂类。其它合适的IBAT抑制剂类别是1,2-苯并硫氮杂类、1,4-苯并硫氮杂类和1,5-苯并硫氮杂类。另外适合的IBAT抑制剂类别是1,2,5-苯并硫二氮杂类。
一种具有IBAT抑制活性的特别适合的化合物是(3R,5R)-3-丁基-3-乙基-1,1-二氧化-5-苯基-2,3,4,5-四氢-1,4-苯并硫氮杂-8-基-β-D-吡喃葡萄糖艾杜糖醛酸(EP 864582)。
具有IBAT抑制活性的另一适合的化合物是S-8921(EP 597107)。
另一合适的IBAT抑制剂是下式化合物:
WO 01/66533公开了其他适合的IBAT抑制剂。本发明的特别的化合物选自WO 01/66533的实施例1-39的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或其前药,本文引用实施例1-39的化合物作为参考。本文同样引用WO 01/66533的权利要求1-6作为参考。
另外适合的化合物是在WO02/50051中描述的IBAT抑制剂。本发明的特别的化合物选自WO02/50051的实施例1-120的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或其前药,本文引用实施例1-120的化合物作为参考。本文同样引用WO 02/50051的权利要求1-14作为参考。选自WO 02/50051的本发明的特别的化合物选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-1′-苯基-1′-[N′-(羧基甲基)氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(羧基甲基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-1′-苯基-1′-[N′-(2-磺基乙基)氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-1′-苯基-1′-[N′-(2-磺基乙基)氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-羧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(5-羧基戊基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{α-[N′-(2-磺基乙基)氨基甲酰基]-2-氟苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(R)-(2-羟基-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(R)-(2-羟基-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-{N-[(R]-α-(N′-{(R)-1-[N″-(R)-(2-羟基-1-羧基乙基)氨基甲酰基]-2-羟基乙基}氨基甲酰基)苄基]氨基甲酰基甲氧基}-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{α-[N′-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{α-[N′-((乙氧基)(甲基)磷酰基-甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-{N-[(R)-α-(N′-{2-[(羟基)(甲基)磷酰基]乙基}氨基甲酰基)苄基]氨基甲酰基甲氧基}-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-甲硫基-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-{N-[(R)-α-(N′-{2-[(甲基)(乙基)磷酰基]乙基}氨基甲酰基)-4-羟基苄基]氨基甲酰基甲氧基}-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-{N-[(R)-α-(N′-{2-[(甲基)(羟基)磷酰基]乙基}氨基甲酰基)-4-羟基苄基]氨基甲酰基甲氧基}-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[(R)-N′-(2-甲基亚磺酰基-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
和
1,1-二氧代-3,3-二丁基-5-苯基-7-甲氧基-8-[N-{(R)-α-[N′-(2-磺基乙基)氨基甲酰基]-4羟基苄基}氨基甲酰基甲氧基]-2,3,4,5-四氢-1,5-苯并硫氮杂;
或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
另外适合的化合物是在WO 03/020710中描述的IBAT抑制剂。本发明的特别的化合物选自WO 03/020710的实施例1-44的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或其前药,本文引用实施例1-44的化合物作为参考。本文同样引用WO 03/020710的权利要求1-10作为参考。选自WO 03/020710的本发明的特别的化合物选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-氨基甲酰基-2-羟基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(羟基氨基甲酰基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-((R)-α-{N′-[2-(N′-嘧啶-2-基脲基)乙基]氨基甲酰基}苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-[N-((R)-α-{N′-[2-(N′-吡啶-2-基脲基)乙基]氨基甲酰基}苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(1-叔丁氧基羰基哌啶-4-基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2,3-二羟基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-((R)-α-{N′-[2-(3,4-二羟基苯基)-2-甲氧基乙基]氨基甲酰基}苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-氨基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(哌啶-4-基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;或
1,1-二氧代-3-丁基-3-乙基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-N,N-二甲基氨基氨磺酰基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
或它们的可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
另外适合的化合物是在WO 03/022825中描述的IBAT抑制剂。本发明的特别的化合物选自WO 03/022825的实施例1-7的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或其前药,本文引用实施例1-7的化合物作为参考。本文同样引用WO 03/022825的权利要求1-8作为参考。选自WO 03/022825的本发明的特别的化合物选自:
1,1-二氧代-3(R)-3-丁基-3-乙基-5-(R)-5-苯基-8-[N-((R)-α-羧基苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,4-苯并硫氮杂;
1,1-二氧代-3(S)-3-丁基-3-乙基-5-(S)-5-苯基-8-[N-((R)-α-羧基苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,4-苯并硫氮杂;
1,1-二氧代-3(R)-3-丁基-3-乙基-5-(R)-5-苯基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
1,1-二氧代-3(S)-3-丁基-3-乙基-5-(S)-5-苯基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
3,5-反式-1,1-二氧代-3-乙基-3-丁基-5-苯基-7-溴-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
3,5-反式-1,1-二氧代-3-(S)-3-乙基-3-丁基-4-羟基-5-(S)-5-苯基-7-溴-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
3,5-反式-1,1-二氧代-3-(R)-3-乙基-3-丁基-4-羟基-5-(R)-5-苯基-7-溴-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
3,5-反式-1,1-二氧代-3-乙基-3-丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
3,5-反式-1,1-二氧代-3-乙基-3-丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂铵盐;
1,1-二氧代-3-(S)-3-乙基-3-丁基-5-(S)-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂二乙胺盐;和
1,1-二氧代-3-(R)-3-乙基-3-丁基-5-(R)-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂二乙胺盐;
或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
另外适合的化合物是在WO 03/022830中描述的IBAT抑制剂。本发明的特别的化合物选自WO 03/022830的实施例1-4的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或其前药,本文引用实施例1-4的化合物作为参考。本文同样引用WO 03/022830的权利要求1-8作为参考。选自WO 03/022830的本发明的特别的化合物选自:
1,1-二氧代-3-丁基-3-乙基-4-羟基-5-苯基-7-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂;
1,1-二氧代-3-丁基-3-乙基-4-羟基-5-苯基-7-(N-{(R)-α-[N-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂铵盐;
1,1-二氧代-3-丁基-3-乙基-4-羟基-5-苯基-7-{N-[-α-(羧基)-2-氟苄基]氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂;和
1,1-二氧代-3-丁基-3-乙基-4-羟基-5-苯基-7-{N-[1-(羧基)-1-(噻吩-2-基)甲基]氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂
或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
另外适合的化合物是在WO 03/022286中描述的IBAT抑制剂。本发明的特别的化合物选自WO 03/022286的实施例1-39的任一种化合物、或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药,本文引用实施例1-39的化合物作为参考。本文同样引用WO 03/022286的权利要求1-10作为参考。选自WO 03/022286的本发明的特别的化合物选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲硫基-乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲硫基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-羟基-1-羧基乙基)氨基甲酰基]丙基}氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;和
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
选自WO 03/022286的另外的本发明的特别的化合物选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;和
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-[N-((R)-α-羧基-4-羟基苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
另外合适的IBAT抑制剂是具有以下结构的那些或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药:
其中:
Rv选自氢或C1-6烷基;
R1和R2之一选自氢或C1-6烷基,另一个选自C1-6烷基;
Rx和Ry独立地选自氢、羟基、氨基、巯基、C1-6烷基、C1-6烷氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷基S(O)a,其中a为0-2;
Rz选自卤素、硝基、氰基、羟基、氨基、羧基、氨基甲酰基、巯基、氨磺酰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷酰基、C1-6烷酰氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷酰基氨基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、其中a为0-2的C1-6烷基S(O)a、C1-6烷氧基羰基、N-(C1-6烷基)氨磺酰基和N,N-(C1-6烷基)2氨磺酰基;
v为0-5;
R4和R5之一是式(IA)所示基团:
R3和R6以及R4和R5中的另一个独立地选自氢、卤素、硝基、氰基、羟基、氨基、羧基、氨基甲酰基、巯基、氨磺酰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷酰基、C1-6烷酰氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷酰基氨基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、其中a为0-2的C1-6烷基S(O)a、C1-6烷氧基羰基、N-(C1-6烷基)氨磺酰基和N,N-(C1-6烷基)2氨磺酰基;其中R3和R6以及R4和R5中的另一个可以任选在碳原子上被一个或多个R17取代;
X是-O-、-N(Ra)-、-S(O)b-或-CH[(Ra)-;其中Ra是氢或C1-6烷基,且b为0-2;
环A是芳基或杂芳基;其中环A任选被一个或多个选自R18的取代基取代;
R7是氢、C1-6烷基、碳环基或杂环基;其中R7任选在碳上被一个或多个选自R19的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R20的基团取代;
R8是氢或C1-6烷基;
R9是氢或C1-6烷基;
R10是氢、卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷酰基、C1-10烷酰氧基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、N,N,N-(C1-10烷基)3铵基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1- 10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、C1-10烷氧基羰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)p-R21-(C1-10亚烷基)q-或杂环基-(C1-10亚烷基)r-R22-(C1-10亚烷基)s-;其中R10任选在碳上被一个或多个选自R23的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R24的基团取代;或者R10是式(IB)所示基团:
其中:
R11是氢或C1-6烷基;
R12和R13独立地选自氢、卤素、氨基甲酰基、氨磺酰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷酰基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、碳环基或杂环基;其中R12和R13可以任选独立地在碳上被一个或多个选自R25的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R26的基团取代;
R14选自氢、卤素、氨基甲酰基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷酰基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)p-R27-(C1-10亚烷基)q-或杂环基-(C1-10亚烷基)r-R28-(C1-10亚烷基)s-;其中R14任选在碳上被一个或多个选自R29的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R30的基团取代;或者R14是式(IC)所示基团:
R15是氢或C1-6烷基;且R16是氢或C1-6烷基;其中R16可任选在碳上被一个或多个选自R31的基团取代;或者R15和R16与它们所连接的氮一起形成杂环基;其中所述杂环基可任选在碳上被一个或多个R37取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R38的基团取代;
n为1-3;其中R7的值可以相同或不同;
R17、R18、R19、R23、R25、R29、R31和R37独立地选自卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷酰基、C1-10烷酰氧基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、N,N,N-(C1-10烷基)3铵基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、C1-10烷氧基羰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)p-R32-(C1-10亚烷基)q-或杂环基-(C1-10亚烷基)r-R33-(C1-10亚烷基)s-;其中R17、R18、R19、R23、R25、R29、R31和R37可以任选独立地在碳原子上被一个或多个R34取代;并且其中如果所述杂环基包含-NH-基团,则氮原子可以任选被选自R35的基团取代;
R21、R22、R27、R28、R32或R33独立地选自-O-、-NR36-、-S(O)x-、-NR36C(O)NR36、-NR36C(S)NR36、-OC(O)N=C-、-NR36C(O)-或-C(O)NR36-;其中R36选自氢或C1-6烷基,x为0-2;
p、q、r和s独立地选自0-2;
R34选自卤素、羟基、氰基、氨基甲酰基、脲基、氨基、硝基、氨基甲酰基、巯基、氨磺酰基、三氟甲基、三氟甲氧基、甲基、乙基、甲氧基、乙氧基、乙烯基、烯丙基、乙炔基、甲酰基、乙酰基、甲酰氨基、乙酰基氨基、乙酰氧基、甲基氨基、二甲基氨基、N-甲基氨基甲酰基、N,N-二甲基氨基甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、N-甲基氨磺酰基、N,N-二甲基氨磺酰基、N-甲基氨磺酰基氨基和N,N-二甲基氨磺酰基氨基;
R20、R24、R26、R30、R35和R38独立地选自C1-6烷基、C1-6烷酰基、C1-6烷基磺酰基、C1-6烷氧基羰基、氨基甲酰基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)氨基甲酰基、苄基、苄氧基羰基、苯甲酰和苯基磺酰基。
适合的具有上述结构的IBAT抑制剂选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-羟基-1-(3,4-二羟基苯基)丙-2-基]氨基甲酰基}苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,2,5-苯并硫二氮杂(两种对映异构体);
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-{N-[(R)-α-(N-{2-(S)-[N-(氨基甲酰基甲基)氨基甲酰基]吡咯烷-1-基羰基甲基}氨基甲酰基)苄基]氨基甲酰基甲氧基}-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-[N-((R)-α-{N-[2-(3,4,5-三羟基苯基)乙基]氨基甲酰基}苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;或
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-(R)-3-(S)-4-(S)-5-(R)-3,4,5,6-四羟基四氢吡喃-2-基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
进一步适合的IBAT抑制剂是具有以下结构的化合物或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药:
其中:
R1和R2独立地选自C1-4烷基;
R3是氢、羟基或卤素;
R4是任选被羟基、甲氧基和甲基S(O)a取代的C1-4烷基,其中a为0-2;
R5是羟基或HOC(O)CH(R6)NH-;
R6选自氢和任选被羟基、甲氧基和甲基S(O)a取代的C1-3烷基,其中a为0-2;
条件是当R1和R2均为丁基时,R5是羟基,且R4是甲硫基甲基、甲基亚磺酰基甲基、2-甲硫基乙基、羟基甲基、甲氧基甲基;R3不是氢;以及条件是当R1和R2均为丁基时,R5是HOC(O)CH(R6)NH-,R6是羟基甲基,且R4是羟基甲基;R3不是氢。
适合的具有上述结构的IBAT抑制剂选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基丁基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲基丁基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲基丁基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-羟基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲磺酰基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲基磺酰基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲磺酰基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N{(R)-α-[N′-((S)-1-羧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-羟基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氨杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-羟基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲硫基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲基亚磺酰基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲磺酰基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-2-甲氧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲硫基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲基磺酰基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;或
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基-3-甲磺酰基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;
或它们的可药用盐、溶剂化物、可药用盐的溶剂化物、或前药。
具有上述结构的另外适合的IBAT抑制剂选自:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂;或
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂。
其它适合的IBAT抑制剂是具有以下结构的化合物或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药:
其中
M1是-CH2-或-NR21-;
M2是-CR22R23-或-NR24-;条件是如果M1是-NR21-,则M2为-CR22R23-;
R1和R2之一选自氢、C1-6烷基或C2-6烯基,另外一个选自C1-6烷基或C2-6烯基;
R3选自卤素、硝基、氰基、羟基、氨基、羧基、氨基甲酰基、巯基、氨磺酰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷酰基、C1-6烷酰氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷酰基氨基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、其中a为0-2的C1-6烷基S(O)a、C1-6烷氧基羰基、N-(C1-6烷基)氨磺酰基和N,N-(C1-6烷基)2氨磺酰基;
v是0-5;
R5和R6之一是式(IA)所示基团:
R4和R7以及R5和R6中的另一个独立地选自氢、卤素、硝基、氰基、羟基、氨基、羧基、氨基甲酰基、巯基、氨磺酰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷酰基、C1-4烷酰氧基、N-(C1- 4烷基)氨基、N,N-(C1-4烷基)2氨基、C1-4烷酰基氨基、N-(C1-4烷基)氨基甲酰基、N,N-(C1-4烷基)2氨基甲酰基、其中a为0-2的C1-4烷基S(O)a、C1-4烷氧基羰基、N-(C1-4烷基)氨磺酰基和N,N-(C1-4烷基)2氨磺酰基;其中R4和R7以及R5和R6中的另一个可任选在碳原子上被一个或多个R25取代;
Z是-O-、-N(Ra)-、-S(O)b-或-CH(Ra)-;其中Ra是氢或C1-6烷基,且b为0-2;
R8是氢、C1-4烷基、碳环基或杂环基;其中R8可以任选被一个或多个选自R26的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R27的基团取代;
R9是氢或C1-4烷基;
R10和R11独立地选自氢、C1-4烷基、碳环基或杂环基;或者R10和R11一起形成C2-6亚烷基;其中R10和R11或R10和R11在一起可以任选独立地在碳上被一个或多个选自R28的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被一个或多个R29取代;
R12是氢、C1-4烷基、碳环基或杂环基;其中R12可以任选在碳上被一个或多个选自R30的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被一个或多个R31取代;
R13是氢、卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷氧基羰基、C1-10烷酰基、C1-10烷酰氧基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、N,N,N-(C1-10烷基)3铵基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、C1-10烷氧基羰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)e-R32-(C1-10亚烷基)f-或杂环基-(C1-10亚烷基)g-R33-(C1-10亚烷基)h-;其中R13可以任选在碳上被一个或多个选自R36的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R37的基团取代;或者R13是式(IB)所示基团:
其中:
X是-N(R38)-、-N(R38)C(O)-、-O-和-S(O)a-;其中a为0-2,且R38是氢或C1-4烷基;
R14是氢或C1-4烷基;
R15和R16独立地选自氢、卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷酰基、C1-6烷酰氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷酰基氨基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、其中a为0-2的C1-6烷基S(O)a、C1-6烷氧基羰基、N-(C1-6烷基)氨磺酰基、N,N-(C1-6烷基)2氨磺酰基、碳环基或杂环基;其中R15和R16可以任选独立地在碳上被一个或多个选自R41的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R42的基团取代;
R17选自氢、卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷酰基、C1-10烷酰氧基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、C1-10烷氧基羰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)e-R43-(C1-10亚烷基)f-或杂环基-(C1-10亚烷基)g-R44-(C1-10亚烷基)h-;其中R17可以任选在碳上被一个或多个选自R47的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R48的基团取代;或者R17是式(IC)所示基团:
其中:
R18选自氢或C1-4烷基;
R19选自氢、卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷酰基、C1-6烷酰氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、C1-6烷酰基氨基、N-(C1-6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、其中a为0-2的C1-6烷基S(O)a、C1-6烷氧基羰基、N-(C1-6烷基)氨磺酰基、N,N-(C1-6烷基)2氨磺酰基、碳环基或杂环基;其中R19可以任选在碳上被一个或多个选自R51的取代基取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R52的基团取代;
R20选自卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷氧基羰基、C1-10烷酰基、C1-10烷酰氧基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、N,N,N-(C1-10烷基)3铵基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、C1-10烷氧基羰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)e-R53-(C1-10亚烷基)f-或杂环基-(C1-10亚烷基)g-R54-(C1-10亚烷基)h-;其中R20可以任选在碳上被一个或多个R57取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R58的基团取代;
p为1-3;其中R15的值可以相同或不同;
q为0-1;
r为0-3;其中R16的值可以相同或不同;
m为0-2;其中R12的值可以相同或不同;
n为1-2;其中R8的值可以相同或不同;
z为0-3;其中R19的值可以相同或不同;
R21选自氢或C1-6烷基;
R22和R23独立地选自氢、羟基、氨基、巯基、C1-6烷基、C1-6烷氧基、N-(C1-6烷基)氨基、N,N-(C1-6烷基)2氨基、其中a为0-2的C1-6烷基S(O)a;
R24选自氢、羟基、C1-6烷基、C1-4烷氧基和C1-6烷酰氧基;
R25选自卤素、硝基、氰基、羟基、氨基、羧基、氨基甲酰基、巯基、氨磺酰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷酰基、C1-4烷酰氧基、N-(C1-4烷基)氨基、N,N-(C1-4烷基)2氨基、C1-4烷酰基氨基、N-(C1-4烷基)氨基甲酰基、N,N-(C1-4烷基)2氨基甲酰基、其中a为0-2的C1-4烷基S(O)a、C1-14烷氧基羰基、N-(C1-4烷基)氨磺酰基和N,N-(C1-4烷基)2氨磺酰基;其中R25可以任选在碳上被一个或多个R67取代;
R26、R28、R30、R36、R41、R47、R51和R57独立地选自卤素、硝基、氰基、羟基、氨基、氨基甲酰基、巯基、氨磺酰基、羟基氨基羰基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷酰基、C1-10烷酰氧基、C1-10烷氧基羰基、N-(C1-10烷基)氨基、N,N-(C1-10烷基)2氨基、N,N,N-(C1-10烷基)3铵基、C1-10烷酰基氨基、N-(C1-10烷基)氨基甲酰基、N,N-(C1-10烷基)2氨基甲酰基、其中a为0-2的C1-10烷基S(O)a、N-(C1-10烷基)氨磺酰基、N,N-(C1-10烷基)2氨磺酰基、N-(C1-10烷基)氨磺酰基氨基、N,N-(C1-10烷基)2氨磺酰基氨基、C1-10烷氧基羰基氨基、碳环基、碳环基C1-10烷基、杂环基、杂环基C1-10烷基、碳环基-(C1-10亚烷基)e-R59-(C1-10亚烷基)f-或杂环基-(C1-10亚烷基)g-R60-(C1-10亚烷基)h-;其中R26、R28、R30、R36、R41、R47、R51和R57可以任选在碳上被一个或多个R63取代;并且其中如果所述杂环基包含-NH-基团,则氮可以任选被选自R64的基团取代;
R27、R29、R31、R37、R42、R48、R52、R58和R64独立地选自C1-6烷基、C1-6烷酰基、C1-6烷基磺酰基、氨磺酰基、N-(C1-6烷基)氨磺酰基、N,N-(C1-6烷基)2氨磺酰基、C1-6烷氧基羰基、氨基甲酰基、N-(C1- 6烷基)氨基甲酰基、N,N-(C1-6烷基)2氨基甲酰基、苄基、苯乙基、苯甲酰基、苯基磺酰基和苯基;
R32、R33、R43、R44、R53、R54、R59和R60独立地选自-O-、-NR65-、-S(O)x-、-NR65C(O)NR66-、-NR65C(S)NR66-、-OC(O)N=C-、-NR65C(O)-或-C(O)NR65-;其中R65和R66独立地选自氢或C1-6烷基,且x为0-2;
R63和R67独立地选自卤素、羟基、氰基、氨基甲酰基、脲基、氨基、硝基、氨基甲酰基、巯基、氨磺酰基、三氟甲基、三氟甲氧基、甲基、乙基、甲氧基、乙氧基、乙烯基、烯丙基、乙炔基、甲氧基羰基、甲酰基、乙酰基、甲酰氨基、乙酰基氨基、乙酰氧基、甲基氨基、二甲基氨基、N-甲基氨基甲酰基、N,N-二甲基氨基甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、N-甲基氨磺酰基和N,N-二甲基氨磺酰基;且
e、f、g和h独立地选自0-2。
另外的具有上述结构的适合的IBAT抑制剂选自:
(+/-)-反式-1,1-二氧代-3-乙基-3-丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
(+/-)-反式-1,1-二氧代-3-乙基-3-丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,4-苯并硫氮杂;
1,1-二氧代-3-乙基-3-丁基-4-羟基-5-苯基-7-(N-{α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]-2-氟苄基}氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂;或
1,1-二氧代-3-丁基-3-乙基-4-羟基-5-苯基-7-(N-{1-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]-1-(环己基)甲基}氨基甲酰基甲硫基)-2,3,4,5-四氢苯并硫杂。
在本发明一个特别的方面,IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药是IBAT抑制剂或其可药用盐。
上述化合物适合的可药用盐,例如是,具有足够碱性的本发明化合物的酸加成盐,例如,无机或有机酸例如盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、柠檬酸、乙酸或马来酸的酸加成盐。另外,具有足够酸性的化合物的适合的可药用盐是例如钠盐或钾盐的碱金属盐,例如钙盐或镁盐的碱土金属盐,铵盐或用可提供生理上可接受的阳离子的有机碱形成的盐,如用甲基胺、二甲基胺、三甲基胺、哌啶、吗啉或三-(2-羟基乙基)胺形成的盐。
本发明化合物可以以前药的形式给予,其在人体或动物体内分解为母体化合物。前药的实例包括可在体内水解的酯类和可在体内水解的酰胺类。
含有羧基或羟基的化合物的可在体内水解的酯是例如可药用酯,其在人体或动物体内水解产生母体酸或醇。对于羧基,适合的可药用酯包括C1-6烷氧基甲酯例如甲氧基甲酯、C1-6烷酰氧基甲酯例如新戊酰氧基甲酯、2-苯并[c]呋喃酮基酯、C3-8环烷氧基羰基氧基C1-6烷基酯例如1-环己基羰基氧基乙基酯;1,3-二氧杂环戊烯-2-酮基甲酯例如5-甲基-1,3-二氧杂环戊烯-2-酮基甲基酯;和C1-6烷氧基羰基氧基乙酯例如1-甲氧基羰基氧基乙基酯,并且可在化合物中任何羧基上形成酯。
包含羟基的化合物的可在体内水解的酯包括无机酯例如磷酸酯和α-酰氧基烷基酯,以及作为体内酯分解后产生母体羟基的水解结果的相关化合物。α-酰氧基烷基酯的实例包括乙酰氧基甲氧基和2,2-二甲基丙酰氧基-甲氧基。对于羟基,可在体内水解的酯形成基团的选择包括烷酰基、苯甲酰基、苯基乙酰基和取代的苯甲酰基以及苯基乙酰基、烷氧基羰基(产生碳酸烷基酯)、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基(产生氨基甲酸酯)、二烷基氨基乙酰基和羧基乙酰基。苯甲酰基上取代基的实例包括吗啉代和哌嗪子基,其从环氮原子通过亚甲基连接到苯甲酰基环的3-或4-位上。
包含羧基的化合物的适合的可在体内水解的酰胺是例如N-C1-6烷基或N,N-二-C1-6烷基酰胺例如N-甲基、N-乙基、N-丙基、N,N-二甲基、N-乙基-N-甲基或N,N-二乙基酰胺。
实验
如上所述,在本发明中定义的化合物可用于治疗功能性便秘和C-IBS。这些特性可使用例如本领域已知的方法来评估:
·用于便秘的Buenos狗模型(Hepato-gasteroenterology,1980,27,381-389)。其中给狗喂低纤维/高蛋白饮食以诱导便秘;
·Niwa′s吗啡诱导的便秘模型(Bioscience Biotechnology andBiochemistry,2002,66,6,1233-1240);和
·在大鼠中取出盲肠据证明能诱导便秘。
一旦已经诱导出便秘,即给动物施用IBAT抑制剂以评估IBAT抑制剂缓减便秘的能力。
下列数据是用Buenos狗模型(在上述出版物中描述的方法)产生的,其中调整为给狗喂20g肉/kg狗/天。结果是这样计算的:在3天的治疗期间,相对于登记值(在开始用IBAT抑制剂治疗的前一天),粪便增加的平均值。如果每天的粪便量少于30克,则狗被视为便秘。
1)化合物1:1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂
给予的物质 | 动物数目 | 剂量μmol/kg | 结果 |
化合物1 | 3 | 5 | 38±7<sup>*</sup> |
仅载体 | 3 | 0 | 0±7 |
*显著性≤0.01
2)化合物2:1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂
给予的物质 | 动物数目 | 剂量μmol/kg | 结果 |
化合物2 | 2 | 1.5 | 23±11 |
仅载体 | 2 | 0 | -6±3 |
3)化合物3:1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂
给予的物质 | 动物数目 | 剂量μmol/kg | 结果 |
化合物3 | 2 | 1.5 | 39±2<sup>*</sup> |
仅载体 | 2 | 0 | 12±2 |
*显著性≤0.05
在Buenos便秘狗模型中产生的数据表明,所有测试的IBAT抑制剂都能够逆转该模型中的便秘。用化合物1、化合物2和化合物3治疗后,每只狗中粪便增加的量分别为38±7、23±11和39±2g/天。
根据本发明的一个方面,提供了用于治疗和/或预防便秘的药物组合物,所述组合物包含IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药和可药用稀释剂或载体。
本发明药物组合物可以呈适于口服给药的形式,例如片剂或胶囊,适于胃肠外注射(包括静脉内、皮下、肌内、血管内或输注)的形式,例如灭菌溶液、悬浮液或乳剂,用于局部给药的形式例如膏剂或霜剂,适于直肠给药的形式例如栓剂。一般情况下,上述组合物可使用常用赋形剂通过常规方法制得。
根据本发明的另一个方面,提供了IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药在制备用于治疗和/或预防温血动物如人的便秘的药物中的应用。
因此,根据本发明,提供了在需要这种治疗和/或预防的温血动物如人中治疗和/或预防便秘的方法,所述方法包括给所述动物施用IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药。
根据本发明的另一个方面,提供了IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药在治疗和/或预防温血动物如人的便秘中的应用。
IBAT抑制剂或其可药用盐、溶剂化物、可药用盐的溶剂化物或前药通常以单位剂量对温血动物给药,所述单位剂量为0.5-5000mg每平方米动物身体面积,即约0.001-50mg/kg,并且预计这可提供治疗有效剂量。单位剂型例如片剂或胶囊通常含有例如0.05-250mg活性组分。在本发明的一个方面,采用0.01-50mg/kg的日剂量。然而,日剂量需要根据所治疗的宿主、具体的给药途径以及所治疗疾病的严重程度而改变。因此,最佳剂量可由负责治疗任何具体患者的操作者来决定。
Claims (3)
1.选自下列组的化合物或其可药用盐、溶剂化物、可药用盐的溶剂化物或其体内可水解酯或者其体内可水解酰胺在制备用于治疗和/或预防温血动物包括人的便秘的药物中的应用:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲硫基-乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-磺基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲硫基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-羟基-1-羧基乙基)氨基甲酰基]丙基}氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-[N-((R)-α-羧基-4-羟基苄基)氨基甲酰基甲氧基]-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂;和
1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-五羟基己基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫二氮杂。
2.权利要求1的应用,其中所述便秘是功能性便秘。
3.权利要求1的应用,其中所述便秘是便秘为主要特征的肠易激综合征。
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