CN1582168A - 用于治疗血管性疾病的固醇吸收抑制剂与心血管药剂的组合 - Google Patents
用于治疗血管性疾病的固醇吸收抑制剂与心血管药剂的组合 Download PDFInfo
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- CN1582168A CN1582168A CNA028042190A CN02804219A CN1582168A CN 1582168 A CN1582168 A CN 1582168A CN A028042190 A CNA028042190 A CN A028042190A CN 02804219 A CN02804219 A CN 02804219A CN 1582168 A CN1582168 A CN 1582168A
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Abstract
本发明提供了可用于治疗血管性疾病、肥胖症、糖尿病和降低血浆固醇水平的组合物、治疗组合和方法,其中包括:(a)至少一种固醇吸收抑制剂;和(b)至少一种不同于所述固醇吸收抑制剂的心血管药剂。
Description
相关申请的交叉参考
本申请要求下列申请的优先权:于2001年9月21日提交的第60/323,842号美国临时专利申请;于2001年1月26日提交的第60/264,396号美国临时专利申请;于2001年1月26日提交的第60/264,600号美国临时专利申请;和于2001年1月26日提交的第60/264,275号美国临时专利申请,每一上述申请都引入本发明以作参考。
发明领域
本发明涉及用于治疗哺乳动物动脉粥样硬化、冠状动脉疾病和其它血管性疾病的方法、组合物和治疗组合,其中包含一些心血管药剂和固醇吸收抑制剂。
发明背景
血管性疾病是一个术语,从广义上来说,其包括所有的血管一包括小和大的动脉和静脉以及血流的病症。血管性疾病的最常见形式是动脉硬化,这是与动脉壁增厚和硬化有关的一种病症。大血管动脉硬化称为动脉粥样硬化。动脉粥样硬化是血管性疾病例如冠状动脉疾病、主动脉瘤、下肢动脉疾病和脑血管疾病的主要致病因素。
动脉硬化的一个主要危险因素是高血清胆固醇。超过225-250mg/dl的总胆固醇水平会使血管性疾病、特别是冠心病的危险性显著增高。
胆固醇酯是动脉粥样硬化损害的主要成分,并且是胆固醇在动脉壁细胞中的主要贮存形式。胆固醇酯的形成还是饮食胆固醇肠吸收中的一个步骤。因此,抑制胆固醇酯形成和减少血清胆固醇可抑制动脉粥样硬化损害形成的进行,降低胆固醇酯在动脉壁中的积聚,以及阻断饮食胆固醇的肠吸收。
在哺乳动物和动物中,全身胆固醇体内平衡的调节涉及饮食胆固醇的调节以及胆固醇生物合成、胆汁酸生物合成和含有胆固醇的血浆脂蛋白代谢的调节。肝脏是进行胆固醇生物合成和代谢的主要器官,因此,肝脏是血浆胆固醇水平的主要决定因素。肝脏是极低密度脂蛋白(VLDL)的合成和分泌位点,极低密度脂蛋白随后在循环中代谢成低密度脂蛋白(LDL)。LDL是血浆中携带胆固醇的主要脂蛋白,并且其浓度增加与动脉粥样硬化增加有关。当无论通过什么手段减少肠胆固醇吸收时,就有较少的胆固醇被递送到肝脏中。这种作用的结果是减少了肝脏脂蛋白(VLDL)生成,并增加了血浆胆固醇一主要作为LDL的肝脏清除率。因此,抑制肠胆固醇吸收的净作用是血浆胆固醇水平下降。
U.S.专利5,767,115、5,624,920、5,668,990、5,656,624和5,688,787分别公开了用于在哺乳动物动脉壁中降低胆固醇和/或抑制含有胆固醇的损害的形成的羟基取代的氮杂环丁烷酮化合物和取代的β-内酰胺化合物。U.S.专利5,846,966和5,661,145分别公开了用于预防或治疗动脉粥样硬化和降低血浆胆固醇水平的与HMG CoA还原酶抑制剂联合使用的羟基取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物。
PCT专利申请WO 00/38725公开了心血管治疗组合,其中包括回肠胆汁酸转运抑制剂或胆固醇酯转运蛋白抑制剂与纤维酸(fibric acid)衍生物、烟酸衍生物、微粒体甘油三酯转运蛋白抑制剂、胆固醇吸收拮抗剂、植物甾醇、stanol、抗高血压剂或胆汁酸螯合剂。
U.S.专利5,698,527公开了作为胆固醇吸收抑制剂的被二糖取代的麦角甾烷酮衍生物,它们单独使用或者与可用于治疗高胆固醇血症和相关病症的一些其它降胆固醇剂联合使用。
其它血管性疾病经常与和动脉粥样硬化有关的胆固醇水平共存。这些血管性疾病可包括高血压、心绞痛和/或心律失常。例如在男性和女性中高血压作为动脉粥样硬化、心血管和脑血管疾病危险因素的相关性已经在大量流行病学研究中得到了印证。
使用心血管药剂,包括例如钙通道阻断剂,进行的降血压临床试验已经在早期动脉粥样硬化损伤的治疗中表现出了有益作用(参见例如Lichtien,P.R.等人:Lancet,335:1109-1113(1990)和Waters,D.等人,Circulation 82:1940-1953(1990))。Scott(PCT专利申请WO 99/11260)描述了用于治疗动脉粥样硬化和其它血管性疾病危险症状的HMGCoA还原酶抑制剂与抗高血压剂的组合。此外,Egon等人(PCT专利申请WO 96/40255)描述了用于治疗心血管疾病的抗高血压剂,包括eplerenone,与血管紧张素II拮抗剂的组合。
尽管最近在血管性疾病的治疗中取得了改善,但是本领域仍然需要用于动脉粥样硬化、其它血管性疾病和与血管性疾病有关的病症例如高血压、动脉粥样硬化和高脂血症的改善的组合物和治疗。
发明概述
在一个实施方案中,本发明提供了组合物,其中包含(a)至少一种固醇吸收抑制剂或其可药用盐或溶剂化物,或者该至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和(b)至少一种用于治疗血管性疾病、糖尿病、肥胖症和/或降低哺乳动物血浆固醇浓度的不同于所述至少一种固醇吸收抑制剂的心血管药剂。
本发明还提供了治疗组合,其中包含(a)第一个量的至少一种固醇吸收抑制剂或其可药用盐或溶剂化物,或者该至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和(b)第二个量的至少一种用于治疗哺乳动物血管性疾病的不同于所述至少一种固醇吸收抑制剂的心血管药剂,其中所述第一个量与所述第二个量一起构成了治疗或预防血管性疾病、糖尿病、肥胖症和/或降低哺乳动物血浆固醇浓度的治疗有效量。
本发明还提供了用于治疗或预防血管性疾病、肥胖症、糖尿病和/或降低哺乳动物血浆固醇浓度的药物组合物,其中包含治疗有效量的上述组合物或治疗组合与可药用载体。
本发明还提供了用于治疗或预防血管性疾病、肥胖症、糖尿病或降低哺乳动物血浆固醇浓度的方法,包括给需要这样的治疗的哺乳动物施用有效量的上述组合物或治疗组合的步骤。
应当理解,除了在操作实施例中,或者除非另有说明,否则在说明书和权利要求书中所有表示组分的量、反应条件等的数字在所有情况下都以术语“约”修饰。
发明详述
在一个实施方案中,本发明涉及组合物、药物组合物、治疗组合、药盒和使用它们的治疗方法,其中包含(a)至少一种(一种或多种)固醇吸收抑制剂,例如但不限于在下文中详细描述的取代的氮杂环丁烷酮固醇吸收抑制剂或取代的β-内酰胺固醇吸收抑制剂,或其可药用盐或溶剂化物,或者该至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和(b)至少一种(一种或多种)不同于固醇吸收抑制剂(组分(a))的心血管药剂。
本发明组合物和治疗组合可以以治疗有效量施用给需要这样的治疗的哺乳动物,以治疗血管性疾病例如动脉粥样硬化、高脂血症(包括但不限于高胆固醇血症、高甘油三酯血症、谷固醇血症)、高血压、血管炎症、心绞痛、心律失常、中风以及糖尿病、肥胖症,和/或降低血浆中固醇水平。本发明组合物和治疗可通过使得这些化合物与体内作用位点例如哺乳动物或人血浆、肝脏或小肠内作用位点接触的任何适当手段来施用。
本文所用的可用于治疗本发明所述的血管性疾病、肥胖症或糖尿病和/或降低血浆固醇水平的“心血管药剂”是不同种类的药剂,包括钙通道阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素II受体拮抗剂、利尿剂,肾上腺素能阻断剂,包括β-肾上腺素能受体阻断剂和α-肾上腺素能受体阻断剂,肾上腺素能刺激剂、冠状血管舒张剂、抗高血压剂、利尿剂、抗心绞痛剂及其组合。本文所用术语“心血管药剂”不包括HMGCoA还原酶抑制剂。上文定义的心血管药剂在化学或结构上与下述固醇吸收抑制剂不同,例如,与下述固醇吸收抑制剂相比,它们含有一个或多个不同的原子、具有不同的原子排列或者具有不同数目的一个或多个原子。
可使用的“肾上腺素能阻断剂”包括是β-受体抑制剂和/或α-受体抑制剂的化合物。是β-受体抑制剂的肾上腺素能阻断剂包括拮抗儿茶酚胺在高血压、心绞痛和心律失常中的心血管作用的一类药物。β-肾上腺素能受体阻断剂包括但不限于盐酸布诺洛尔(1(2H)-萘酮,5-[3-(1,1-二甲基乙基)氨基]-2-羟基丙氧基]-3,4-二氢-,盐酸盐,CAS RN 31969-05-8,可得自Parke-Davis);醋丁洛尔(±N-[3-乙酰基-4-[2-羟基-3-[(1-甲基乙基)氨基]丙氧基]苯基]-丁酰胺,或(±)-3’-乙酰基-4’-[2-羟基-3-(异丙基氨基)丙氧基]丁酰苯胺);盐酸醋丁洛尔(例如N-[3-乙酰基-4-[2-羟基-3-[1-甲基-乙基)氨基]丙氧基]苯基]-,一盐酸盐,(±-;-3’-乙酰基-4’-[2-羟基-3-(异丙基氨基)丙氧基]丁酰苯胺一盐酸盐,例如得自Wyeth-Ayerst的SECTRAL胶囊);盐酸阿普洛尔(2-丙醇,1-[(1-甲基乙基)氨基]-3-[2-(2-丙烯基)苯氧基]-,盐酸盐,CAS RN 13707-88-5,参见第6,605,692号荷兰专利申请);阿替洛尔(例如苯乙酰胺4-[2’-羟基-3’-[(1-甲基乙基)氨基]丙氧基]-,例如得自AstraZeneca的TENORMIN静脉注射剂);盐酸卡替洛尔(例如5-[3-[(1,1-二甲基乙基)氨基]-2-羟基丙氧基]-3,4-二氢-2(1H)-喹啉酮一盐酸盐,例如得自Abbott的CartrolFilmtab片剂);盐酸塞利洛尔(3-[3-乙酰基-4-[3-(叔丁基氨基)-2-羟基丙氧基]苯基]-1,1-二乙基脲一盐酸盐,CAS RN 57470-78-7,还参见US专利4,034,009);盐酸塞他洛尔(乙酰胺,2-[2-[3-[(1,1-二甲基乙基)氨基]-2-羟基丙氧基]-苯氧基]-N-甲基-,一盐酸盐,CAS RN 77590-95-5,还参见US专利4,059,622);盐酸拉贝洛尔(例如5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]水杨酰胺一盐酸盐,例如得自Schering的NORMODYNE片剂);盐酸艾司洛尔(对-[2-羟基-3-(异丙基氨基)丙氧基]氢化肉桂酸(±)-甲酯盐酸盐,例如得自Baxter的BREVIBLOC注射剂);盐酸左倍他洛尔(例如(S)-1-[对-[2-(环丙基甲氧基)乙基]苯氧基]-3-(异丙基氨基)-2-丙醇盐酸盐,例如得自Alcon的BETAXON眼用悬浮液);盐酸左布诺洛尔(例如(-)-5-[3-(叔丁基氨基)-2-羟基丙氧基]-3,4-二氢-1(2H)-萘酮盐酸盐,例如得自Allergan的具有C CAPCompliance Cap的BETAGANLiquifilm);纳多洛尔(例如1-(叔丁基氨基)-3-[(5,6,7,8-四氢-顺式-6,7-二羟基-1-萘基)氧基]-2-丙醇,例如得自Mylan的纳多洛尔片剂);普拉洛尔(乙酰胺,N-[4-[2-羟基-3-[1-甲基乙基)氨基]-丙氧基]苯基]-,CAS RN 6673-35-4,还参见US专利3,408,387);盐酸普萘洛尔(1-(异丙基氨基)-3-(1-萘基氧基)-2-丙醇盐酸盐,CAS RN 318-98-9);盐酸索他洛尔(例如d,l-N-[4-[1-羟基-2-[(1-甲基乙基)氨基]乙基]-苯基]甲烷-磺酰胺一盐酸盐,例如得自Berlex的BETAPACE AFTM片剂);噻吗洛尔(2-丙醇,1-[(1,1-二甲基乙基)氨基]-3-[[4-4(4-吗啉基)-1,2,5-噻二唑-3-基]氧基]-,半水合物,(S)-,CAS RN 91524-16-2);马来酸噻吗洛尔((S)-1-[(1,1-二甲基乙基)氨基]-3-[[4-(4-吗啉基)-1,2,5-噻二唑-3-基]氧基]-2-丙醇(Z)-2-丁烯二酸(1∶1)盐,CAS RN 26921-17-5);比索洛尔(2-丙醇,1-[4-[[2-(1-甲基乙氧基)乙氧基]-甲基]苯氧基]-3-[(1-甲基乙基)氨基]-,(±),CAS RN 66722-44-9);富马酸比索洛尔(例如(±)-1-[4-[[2-(1-甲基乙氧基)乙氧基]甲基]苯氧基]-3-[(1-甲基乙基)氨基]-2-丙醇(E)-2-丁烯二酸(2∶1)(盐),例如得自Lederle Consumer的ZEBETATM片剂);奈必洛尔(2H-1-苯并吡喃-2-甲醇,αα’-[亚氨基二(亚甲基)]二[6-氟-3,4-二氢-,CAS RN99200-09-6,还参见US专利4,654,362);盐酸环丙洛尔(例如2-丙醇,1-[4-[2-(环丙基甲氧基)乙氧基]苯氧基]-3-[1-甲基乙基)氨基]-,盐酸盐,A.A.S.RN 63686-79-3);和盐酸右普萘洛尔(2-丙醇,1-[1-甲基乙基)氨基]-3-(1-萘基氧基)盐酸盐(CAS RN 13071-11-9);盐酸二醋洛尔(乙酰胺,N-[3-乙酰基-4-[2-羟基-3-[(1-甲基-乙基)氨基]丙氧基][苯基]-,一盐酸盐,CAS RN 69796-04-9);盐酸地来洛尔(苯甲酰胺,2-羟基-5-[1-羟基-2-[1-甲基-3-苯基丙基)氨基]乙基]-,一盐酸盐,CAS RN 75659-08-4);盐酸己丙洛尔(2-丙醇,1-(2-环己基苯氧基)-3-[(1-甲基乙基)氨基]-,盐酸盐CAS RN 59333-90-3);硫酸氟司洛尔(苯甲酸,2-氟-3-[[2-[氨基羰基)氨基]-1-二甲基乙基]氨基]-2-羟基丙基酯,(±)-硫酸盐(1∶1)(盐),CAS RN88844-73-9);盐酸美他洛尔(甲磺酰胺,N-[4-[1-羟基-2-(甲基氨基)丙基]苯基]-,一盐酸盐,CAS RN 7701-65-7);美托洛尔(2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[1-甲基乙基)氨基]-;CAS RN 37350-58-6);酒石酸美托洛尔(例如2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[(1-甲基乙基)氨基]-,例如得自Novartis的LOPRESSOR);硫酸帕马洛尔(氨基甲酸,[2-[4-[2-羟基-3-[(1-甲基乙基)氨基]丙氧基]苯基]-乙基]-,甲酯,(±)硫酸盐(盐)(2∶1),CAS RN 59954-01-7);硫酸喷布洛尔(2-丙醇,1-(2-环戊基苯氧基)-3-[1,1-二甲基乙基)氨基]1,(S)-,硫酸盐(2∶1)(盐),CAS RN 38363-32-5);普拉洛尔(乙酰胺,N-[4-[2-羟基-3-[(1-甲基乙基)氨基]丙氧基]苯基]-,CAS RN 6673-35-4);盐酸替普洛尔(丙醇,1-[(1-甲基乙基)氨基]-3-[2-(甲硫基)-苯氧基]-,盐酸盐,(±),CAS RN 3983243-4);妥拉洛尔(苯甲酰胺,4-[2-[[2-羟基-3-(2-甲基苯氧基)丙基]氨基]乙氧基]-,CAS RN 38103-61-6)。
是α-受体抑制剂的肾上腺素能受体抑制剂阻断内源性儿茶酚胺引起的血管收缩。所带来的周围阻力下降导致人血压下降。该作用的大小取决于在施用拮抗剂时的交感紧张程度。
是α-受体抑制剂的合适的肾上腺素能受体抑制剂包括但不限于盐酸fenspiride(可按照US专利3,399,192中公开的方法制得,引入本发明以作参考);普罗克生(CAS RN 3374396-3);盐酸阿夫唑嗪(CAS RN:81403-68-1);及如上所述的盐酸拉贝洛尔或其混合物。
可用于本发明的具有α和β受体抑制剂活性的肾上腺素阻断剂包括但不限于托西溴苄铵(CAS RN:61-75-6);甲磺双氢麦角胺(例如麦角烷-3’,6’,18-三酮,9,10-二氢-12’-羟基-2’-甲基-5’-(苯基甲基)-,(5’(α))-,一甲磺酸盐,例如得自Novartis的DHE 45注射剂);卡维地洛(例如(±)-1-(咔唑-4-基氧基)-3-[[2-(邻甲氧基苯氧基)乙基]氨基]-2-丙醇,例如得自SmithKline Beecham的COREG片剂);拉贝洛尔(例如5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]水杨酰胺一盐酸盐,例如得自Schering的NORMODYNE片剂);托西溴苄铵(苯甲铵,2-溴-N-乙基-N,N-二甲基-,与4-甲基苯磺酸成的盐(1∶1),CAS RN 61-75-6);甲磺酸酚妥拉明(苯酚,3-[[(4,5-二氢-1H-咪唑-2-基)甲基](4-甲基苯基)氨基]-,一甲磺酸盐(盐)CAS RN 65-28-1);酒石酸索立哌汀(5H-1,3-二氧杂环戊烯并[4,5-f]吲哚,7-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-,(2R,3R)-2,3-二羟基丁二酸盐(1∶1)CAS RN 5591-43-5);盐酸佐勒汀(哌嗪,1-苯基-4-[2-(1H-四唑-5-基)乙基]-,一盐酸盐(8Cl,9Cl)CAS RN 7241-94-3)。
高血压引起或加重血管性疾病。高血压定义为持续的高血压。一般情况下,对于成人,当收缩血压持续地在140mmHg以上或者当舒张血压持续地在90mmHg时,其被归为高血压。心血管死亡长期危险的增加与持续的高血压有直接关系。可用于本发明的抗高血压剂的合适的实例包括阿尔噻嗪(2H-1,2,4-苯并噻二嗪-7-磺酰胺,6-氯-3,4-二氢-3-[(2-丙烯基硫基)甲基]-,1,1-二氧化物,CAS RN 5588-16-9);苄噻嗪(2H-1,2,4-苯并噻二嗪-7-磺酰胺,6-氯-3-[[(苯基甲基)硫基]甲基]-,1,1-二氧化物,CAS RN 91-33-8);卡托普利(L-脯氨酸,1-[(2S)-3-巯基-2-甲基-1-氧代丙基]-,CAS RN 62571-86-2);卡维地洛(2-丙醇,1-(9H-咔唑-4-基氧基)-3-[[2-(2-甲氧基苯氧基)乙基]氨基]-CAS RN 72956-09-3);氯噻嗪(2-丙醇钠,1-(9H-咔唑-4-基氧基)-3-[[2-(2-甲氧基苯氧基)乙基]氨基]-CASRN 72956-09-3);盐酸可乐定(1H-咪唑-2-胺,N-(2,6-二氯苯基)-4,5-二-氢-,一盐酸盐CAS RN 4205-91-8);环噻嗪(2H-1,2,4-苯并噻二嗪-7-磺酰胺,3-二环[2.2.1]庚-5-烯-2-基-6-氯-3,4-二氢-,1,1-二氧化物,CAS RN2259-96-3);盐酸地拉普利(2H-1,2,4-苯并噻二嗪-7-磺酰胺,3-二环[2.2.1]庚-5-烯-2-基-6-氯-3,4-二氢-,1,1-二氧化物,CAS RN 2259-96-3);盐酸地来洛尔(2H-1,2,4-苯并噻二嗪-7-磺酰胺,3-二环[2.2.1]庚-5-烯-2-基-6-氯-3,4-二氢-,1,1-二氧化物CAS RN 2259-96-3);盐酸地拉普利(甘氨酸,N-[(1S)-1-(乙氧基羰基)-3-苯基丙基]-L-丙氨酰基-N-(2,3-二氢-1H-茚-2-基)-,一盐酸盐CAS RN 83435-67-0);甲磺酸多沙唑嗪(哌嗪,1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(2,3-二氢-1,4-苯并二噁嗪-2-基)羰基]-,一甲磺酸盐CAS RN 77883-43-3);福辛普利钠(L-脯氨酸,4-环己基-1-[[(R)-[(1S)-2-甲基-1-(1-氧代丙氧基)丙氧基);盐酸莫昔普利(3-异喹啉甲酸,2-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-6,7二甲氧基-,一盐酸盐,(3S)-CAS RN 82586-52-5);马来酸莫那匹尔(1-哌嗪丁酰胺,N-(6,11-二氢二苯并(b,e)硫杂环庚三烯-11-基)-4-(4-氟苯基)-,(±)-,(Z)-2-丁烯二酸盐(1∶1)(±)-N-(6,11-二氢二苯并(b,e)硫杂环庚三烯-11-基)-4-(对氟苯基)-1-哌嗪丁酰胺马来酸盐(1∶1)CAS RN 132046-06-1);琥珀酸美托洛尔(丁二酸与1-[4-(2-甲氧基乙基)苯氧基]-3-[(1-甲基乙基)氨基]-2-丙醇的化合物(1∶2)CAS RN 98418-47-4);盐酸胍法辛(苯乙酰胺,N-(氨基亚氨基甲基)-2,6-二氯-,一盐酸盐,CAS RN 29110-48-3);甲基多巴(L-酪氨酸,3-羟基-α-甲基-CAS RN555-30-6);喹普利拉(3-异喹啉甲酸,2-[(2S)-2-[[(1S)-1-羧基-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-,(3S)-CAS RN 82768-85-2);盐酸喹那普利(3-异喹啉甲酸,2-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-,一盐酸盐,(3S)-CAS RN 82586-55-8);普米洛尔(2,4(1H,3H)-嘧啶二酮,1-[2-[[2-羟基-3-(2-甲基苯氧基)丙基]氨基]乙基]-5-甲基-CAS RN 67227-55-8);盐酸哌唑嗪(哌嗪,1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-(2-呋喃基羰基)-,一盐酸盐CAS RN 19237-84-4);盐酸培兰色林(2,4(1H,3H)-喹唑啉二酮,3-[3-(4-苯基-1-哌嗪基)丙基]-,一盐酸盐CAS RN 42877-18-9);盐酸酚苄明(苯甲胺,N-(2-氯乙基)-N-(1-甲基-2-苯氧基乙基)-,盐酸盐CAS RN 63-92-3);坎地沙坦cilexeti](1H-苯并咪唑-7-甲酸,2-乙氧基-1-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-,1-[[(环己基氧基)羰基]氧基]乙酯CAS RN 145040-37-5);替米沙坦([1,1’-联苯]-2-甲酸,4’-[(1,4’-二甲基-2’-丙基[2,6’-联-1H-苯并咪唑]-1’-基)甲基]-CAS RN 144701-48-4);坎地沙坦(1H-苯并咪唑-7-甲酸,2-乙氧基-1-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-CASRN 139481-59-7);苯磺酸氨氯地平(3,5-吡啶二甲酸,2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-,3-乙基5-甲基酯,一苯磺酸盐CAS RN 111470-99-6);马来酸氨氯地平(3,5-吡啶二甲酸,2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-,3-乙基5-甲基酯,(2Z)-2-丁烯二酸盐(1∶1)CAS RN 88150-47-4);盐酸特拉唑嗪(哌嗪,1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢-2-呋喃基)羰基]-,一盐酸盐CAS RN63074-08-8);盐酸贝凡洛尔(2-丙醇,1-[[2-(3,4-二甲氧基苯基)乙基]氨基]-3-(3-甲基苯氧基)-,盐酸盐CAS RN 42864-78-8);雷米普利(环戊烷并[b]吡咯-2-甲酸,1-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]八氢-,(2S,3aS,6aS)-CAS RN 87333-19-5)。
血管紧张素系统抑制剂是干扰血管紧张素II的功能、合成或分解代谢的药剂。可用于本发明中的这些药剂包括但不限于血管紧张素转化酶(ACE)抑制剂、血管紧张素II拮抗剂、血管紧张素II受体拮抗剂、激活血管紧张素II分解代谢的药剂和阻止最终由其衍生出血管紧张素I的合成的药剂。肾素-血管紧张素系统参与血流动力学以及水与电解质平衡的调控。降低血容量、肾灌注量或血浆Na+浓度的因素往往会激活该系统,而增加这些参数的因素往往会抑制其功能。血管紧张素I和血管紧张素II是通过酶促肾素-血管紧张素途径合成的。当肾素作用于血管紧张素原—血浆中的一种假球蛋白,合成过程就被启动,生成cecapeptide血管紧张素I。血管紧张素I被血管紧张素转化酶(ACE)转化成血管紧张素II。血管紧张素II是活性增压物质,其在不同的哺乳动物中作为诱因物质参与几种形式的高血压。
“血管紧张素II受体拮抗剂”是通过与血管紧张素II受体结合并干扰其活性而阻碍血管紧张素II活性的化合物。可用于本发明的众所周知的血管紧张素II受体拮抗剂包括肽类化合物和非肽类化合物。血管紧张素II受体拮抗剂的非限制性实例包括:坎地沙坦cilexetil(1H-苯并咪唑-7-甲酸,2-乙氧基-1-[[2’-(1H-四唑-5-基)[1,1’-联苯]4-基]甲基]-,1-[[(环己基氧基)羰基]氧基]乙酯)CAS RN 145040-37-5);替米沙坦([1,1’-联苯]-2-甲酸,4’-[(1,4’-二甲基-2’-丙基[2,6’-联-1H-苯并咪唑]-1’-基)甲基]-CAS RN 144701-48-4);坎地沙坦(1H-苯并咪唑-7-甲酸,2-乙氧基-1-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-CAS RN 139481-59-7);洛沙坦钾(1H-咪唑-5-甲醇,2-丁基-4-氯-1-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-,一钾盐);依贝沙坦(1,3-二氮杂螺[4-4]壬-1-烯-4-酮,2-丁基-3-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-CAS RN 138402-11-6)。
血管紧张素转化酶(ACE)”是催化血管紧张素I转化成血管紧张素II的酶。可用于本发明的ACE抑制剂包括通过抑制ACE活性,并由此降低或消除增压物质血管紧张素II形成来干涉肾素-血管紧张素系统的氨基酸及其衍生物,肽,包括二肽和三肽,和ACE的抗体。ACE抑制剂已经在医疗上用于治疗高血压、充血性心力衰竭、心肌梗塞和肾病。合适的ACE抑制剂包括但不限于盐酸贝那普利(例如3-[[1-(乙氧基羰基)-3-苯基-(1S)-丙基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-(3S)-苯并氮杂-1-乙酸一盐酸盐,例如得自Novartis的LOTREL胶囊);卡托普利(例如1-[(2S)-3-巯基-2-甲基丙酰基]-L脯氨酸,例如得自Mylan的卡托普利片剂);福辛普利(例如L-脯氨酸,4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)氧膦基]乙酰基]-,钠盐,反式-,例如得自Bristol-Myers Squibb的MONOPRIL片剂);盐酸莫昔普利(例如[3S-[2[R*(R*)],3R*]]-2-[2-[[1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-6,7-二甲氧基-3-异喹啉甲酸,一盐酸盐,例如得自Schwarz的UNIRETIC片剂);培哚普利erbumine(例如2S,3aS,7aS)-1-[(S)-N-[(S)-1-羧基丁基]丙氨酰基]六氢-2-二氢吲哚甲酸,1-乙酯,与叔丁胺的化合物(1∶1),例如得自Solvay的ACETON片剂);喹那普利(例如[3S-[2[R*(R*)],3R*]]-2-[2-[[1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-3-异喹啉甲酸,一盐酸盐,例如得自Parke-Davis的ACCURETIC片剂);雷米普利(例如2-氮杂-二环[3.3.0]-辛烷-3-甲酸衍生物,例如得自Monarch的ALTACE胶囊);马来酸依那普利(例如(S)-1-[N-[1-(乙氧基羰基)-3-苯基丙基]-L-丙氨酰基]-L-脯氨酸,(Z)-2-丁烯二酸盐(1∶1),例如得自Merck的VASOTEC片剂);赖诺普利(例如(S)-1-[N-2-(1-羧基-3-苯基丙基)-L-赖氨酰基]-L-脯氨酸二水合物,例如得自Merck的PRINZIDE片剂);地拉普利(可按照US专利4,385,051中公开的方法制得);和螺普利(可按照US专利4,470,972中公开的方法制得);贝那普利拉(1H-1-苯并氮杂-1-乙酸,3-[[(1S)-1-羧基-3-苯基丙基]氨基]-2,3,4,5-四氢-2-氧代-,(3S)-CAS RN 86541-78-8);盐酸地拉普利(甘氨酸,N-[(1S)-1-(乙氧基羰基)-3-苯基丙基]-L-丙氨酰基-N-(2,3-二氢-1H-茚-2-基)-,一盐酸盐CAS RN 83435-67-0);福辛普利钠(L-脯氨酸,4-环己基1-[[(R)-[(1S)-2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)氧膦基]乙酰基]-,钠盐,(4S)-CAS RN 88889-14-9);赖苯普利(1H-1-苯并氮杂-1-乙酸,3-[[(1S)-5-氨基-1-羧基戊基]氨基]-2,3,4,5-四氢-2-氧代-,(3S)-CAS RN 109214-55-3);喷托普利(1H-吲哚-1-戊酸,2-羧基-2,3-二氢-α,γ-二甲基-δ-氧代-,α-乙酯,(αR,γR,2S)-CAS RN 82924-03-6);培哚普利(1H-吲哚-2-甲酸,1-[(2S)-2-[[(1S)-1-(乙氧基羰基)丁基]氨基]-1-氧代丙基]八氢-,(2S,3aS,7aS)-CAS RN 82834-16-0);盐酸喹那普利(3-异喹啉甲酸,2-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-,一盐酸盐,(3S)-CAS RN 82586-55-);喹普利拉(3-异喹啉甲酸,2-[(2S)-2-[[(1S)-1-羧基-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-,(3S)-CAS RN 82768-85-2);盐酸螺普利(1,4-二硫杂-7-氮杂螺[4.4]壬烷-8-甲酸,7-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧代丙基]-,一盐酸盐,(8S)-CAS RN 94841-17-5);螺普利拉(1,4-二硫杂-7-氮杂螺[4.4]壬烷-8-甲酸,7-[(2S)-2-[[(1S)-1-羧基-3-苯基丙基]氨基]-1-氧代丙基]-,(8S)-CAS RN 83602-05-5);替普罗肽(缓激肽增强剂BPP9a CAS RN 35115-60-7);赖诺普利(L-脯氨酸,N2-[(1S)-1-羧基-3-苯基丙基]-L-赖氨酰基-CAS RN 76547-98-3);佐芬普利(L-脯氨酸,1-[(2S)-3-(苯甲酰基硫基)-2-甲基-1-氧代丙基]-4-(苯硫基)-,钙盐(2∶1),(4S)-CAS RN 81938-43-4)。
“钙通道阻断剂”是在化学上不同的一类化合物,其在控制多种疾病,包括几种心血管疾病例如高血压、心绞痛和心律失常中具有重要治疗价值(Fleckenstein,Cir.Res.V.52(suppl.1),p.13-16(1983);Fleckenstein,Experimental Facts and Therapeutic Prospects,JohnWiley,New York(1983);McCall,D.,Curr.Pract Cardio.,v.10,p.1-11(1985),上述文献分别引入本发明以作参考)。钙通道阻断剂是一组不同的通过控制细胞钙通道来阻止或减缓钙进入细胞内的药物(Remington,The Science and Practice of Pharmacy,Nineteenth Edition,MackPublishing Company,Eaton,PA,p.963(1995),将其引入本发明以作参考)。可用于本发明的钙通道阻断剂包括但不限于氨氯地平的苯磺酸盐(例如3-乙基-5-甲基-2-(2-氨基乙氧基甲基)-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二甲酸酯苯磺酸盐,例如得自Pfizer的NORVASC);马来酸克仑硫(1,5-苯并硫杂氮杂-4(5H)-酮,3-(乙酰基氧基)-8-氯-5-[2-(二甲基氨基)乙基]-2,3-二-氢-2-(4-甲氧基苯基)-(2S-顺式)-,(Z)-2-丁烯二酸盐(1∶1),还参见U.S.专利4,567,195);伊拉地平(3,5-吡啶二甲酸,4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-,甲基1-甲基乙酯,(±)-4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-3,5-吡啶二甲酸酯,还参见US专利4,466,972);尼莫地平(例如1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸异丙酯(2-甲氧基乙基)酯,例如得自Bayer的NIMOTOP);非洛地平(例如4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二甲酸甲酯乙酯,例如得自AstraZeneca LP的PLENDIL缓释片剂);尼伐地平(3,5-吡啶二甲酸,2-氰基-1,4-二氢-6-甲基-4-(3-硝基苯基)-,3-甲基5-(1-甲基乙基)酯,还参见US专利3,799,934);硝苯地平(例如3,5-吡啶二甲酸,1,4二氢-2,6-二甲基-4-(2-硝基苯基)-,二甲酯,例如得自Pfizer的PROCARDIA XL缓释片剂);盐酸地尔硫(例如1,5-苯并硫杂氮杂-4(5H)-酮,3-(乙酰基氧基)-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-,一盐酸盐,(+)-顺式,例如得自Forest的TIAZAC胶囊);盐酸维拉帕米(例如苯乙腈,(α)[[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-(α)-(1-甲基乙基)盐酸盐,例如得自Knoll Labs的ISOPTINSR片剂);盐酸替鲁地平(3,5-吡啶二甲酸,2-[(二甲基氨基)甲基]-4-[2-[(1E)-3-(1,1-二甲基乙氧基)-3-氧代-1-丙烯基]苯基]-1,4-二氢-6-甲基-,二乙酯,一盐酸盐)CAS RN 108700-03-4);贝磷地尔(膦酸,[2-(2-苯氧基乙基)-1,3-丙二基]二-,四丁基酯CAS RN 103486-79-9);福司地尔(膦酸,[[4-(2-苯并噻唑基)苯基]甲基]-,二乙酯CAS RN75889-62-2)。
还起“抗心绞痛剂”作用的本发明心血管药剂可用于本发明。心绞痛包括当可利用的心肌氧不能满足心肌氧需求时所发生的症状。这些药剂的非限制性实例包括:盐酸雷诺嗪(1-哌嗪乙酰胺,N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-,二盐酸盐CAS RN 95635-56-6);盐酸倍他洛尔(2-丙醇,1-[4-[2-(环丙基甲氧基)乙基]苯氧基]-3-[(1-甲基乙基)氨基]-,盐酸盐CAS RN 63659-19-8);盐酸布托丙茚(甲酮,[4-[3-(二丁基氨基)丙氧基]苯基](2-乙基-3-吲嗪基)-,一盐酸盐CASRN 62134-34-3);马来酸桂哌酯(1-哌嗪乙酸,4-[1-氧代-3-(3,4,5-三甲氧基苯基)-2-丙烯基]-,乙酯,(2Z)-2-丁烯二酸盐(1∶1)CAS RN 50679-07-7);托西芬(苯磺酰胺,4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]-CAS RN 32295-18-4);盐酸维拉帕米(苯乙腈,α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-,一盐酸盐CAS RN 152-11-4);吗多明(1,2,3-噁二唑鎓,5-[(乙氧基羰基)氨基]-3-(4-吗啉基)-,内盐CAS RN 25717-80-0);盐酸雷诺嗪(1-哌嗪乙酰胺,N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-,二盐酸盐CASRN 95635-56-6);托西芬(苯磺酰胺,4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]-CAS RN 32295-18-4)。
“冠状血管舒张剂”可通过增加对心脏的氧供应来减轻心绞痛系统。可用于本发明的冠状血管舒张剂包括但不限于盐酸地尔硫(例如1,5-苯并硫杂氮杂-4(5H)-酮,3-(乙酰基氧基)-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-,一盐酸盐,(+)-顺式,例如得自Forest的TIAZAC胶囊);硝酸异山梨酯(例如1,4:3,6-二脱水-D-山梨醇2,5-二硝酸酯,例如得自Wyeth-Ayerst的ISORDILTITRADOSE片剂);单硝酸异山梨酯(例如1,4:3,6-二脱水-D-山梨醇5-硝酸酯,一种有机硝酸酯,例如得自Wyeth-Ayerst的Ismo片剂);硝酸甘油(例如2,3-丙三醇三硝酸酯,例如得自Parke-Davis的NITROSTAT片剂);盐酸维拉帕米(例如苯乙腈,(±)-(α)[[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-(α)-(1-甲基乙基)盐酸盐,例如得自Searle的COVERA HS缓释片剂);卡波罗孟(可按照US专利3,282,938中公开的方法制得);氯硝甘油(Annalen 1870 155);盐氢普拉明(可按照德国专利2,521,113中公开的方法制得);利多氟嗪(可按照US专利3,267,104中公开的方法制得);普尼拉明(可按照US专利3152173中公开的方法制得);丙帕硝酯(可按照法国专利1,103,113中公开的方法制得);盐酸米氟嗪(1-哌嗪乙酰胺,3-(氨基羰基)-4-[4,4-二(4-氟苯基)丁基]-N-(2,6二氯苯基)-,二氢盐酸盐CAS RN 83898-67-3);米克昔定(苯乙胺,3,4-二甲氧基-N-(1-甲基-2-亚吡咯烷基)-吡咯烷,2-[(3,4-二甲氧基苯乙基)亚氨基]-1-甲基-1-甲基-2-[(3,4-二甲氧基苯乙基)亚氨基]吡咯烷CAS RN 27737-38-8);吗多明(1,2,3-噁二唑鎓,5-[(乙氧基羰基)氨基]-3-(4-吗啉基)-,内盐CASRN 25717-80-0);单硝酸异山梨酯(D-山梨醇,1,4:3,6-二脱水-,5-硝酸酯CAS RN 16051-77-7);丁四硝酯(1,2,3,4-丁四醇,四硝酸酯,(2R,3S)-rel-CAS RN 7297-25-8);氯硝甘油(1,2-丙二醇,3-氯-,二硝酸酯(7Cl,8Cl,9C1)CAS RN 2612-33-1);双嘧达莫乙醇,2,2’,2”,2-[(4,8-二-1-哌啶基嘧啶并[5,4-d]嘧啶-2,6-二基)二次氮基]四-CAS RN 58-32-2);尼可地尔(CAS RN 65141-46-0 3-);尼索地平(吡啶甲酰胺,(N-[2-(硝基氧基)乙基]-3,5-吡啶二甲酸,1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-,甲基2-甲基丙基酯CAS RN 63675-72-9);硝苯地平(3,5-吡啶二甲酸,1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-,二甲酯CAS RN 21829-25-4);马来酸哌克昔林(哌啶,2-(2,2-二环己基乙基)-,(2Z)-2-丁烯二酸盐(1∶1)CAS RN 6724-53-4);盐酸氧烯洛尔(2-丙醇,1-[(1-甲基乙基)氨基]-3-[2-(2-丙烯基氧基)苯氧基]-,盐酸盐CAS RN 6452-73-9);戊硝醇(1,3-丙二醇,2,2-二[(硝基氧基)甲基]-,一硝酸酯(酯)CAS RN 1607-17-6);维拉帕米(苯乙腈,α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-CAS RN 52-53-9)。
术语“利尿剂”包括增加溶质(主要是NaCl)和水分泌的化合物。一般情况下,利尿剂治疗的主要目标是减少细胞外液体体积以降低血压或清除过量间质液体(水肿)。可在本发明范围内使用的利尿剂的非限制性实例包括阿尔噻嗪(可按照英国专利902,658中描述的方法制得);苄噻嗪(可按照U.S.专利3,108,097中公开的方法制得);布噻嗪(可按照英国专利861,367中公开的方法制得);氯噻嗪(可按照U.S.2,809,194中公开的方法制得);螺内酯(CAS号52-01-7);和氨苯蝶啶(CAS号396-01-0)。
可在本发明中用作心血管药剂的“肾上腺素能刺激剂”包括但不限于盐酸胍法辛(例如N-脒基-2-(2,6-二氯苯基)乙酰胺盐酸盐,例如得自Robins的TENEX片剂);甲基多巴-氢氯噻嗪(例如左旋-3-(3,4-二羟基苯基)-2-甲基丙氨酸)与氢氯噻嗪(例如6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺酰胺1,1-二氧化物的复方药物,例如得自Merck的ALDORIL片剂);甲基多巴-氯噻嗪(例如6-氯-2H-1,2,4-苯并噻二嗪-7-磺酰胺1,1-二氧化物与如上所定义的甲基多巴,例如得自Merck的ALDOCLORr片剂);盐酸可乐定(例如2-(2,6-二氯苯基氨基)-2-咪唑啉盐酸盐和氯噻酮(例如2-氯-5-(1-羟基-3-氧代-1-异二氢吲哚基)苯磺酰胺),例如得自Boehringer Ingelheim的COMBIPRES片剂);盐酸可乐定(例如2-(2,6-二氯苯基氨基)-2-咪唑啉盐酸盐,例如得自Boehringer Ingelheim的CATAPRES片剂);可乐定(1H-咪唑-2-胺,N-(2,6-二氯苯基)-4,5-二氢-CAS RN 4205-90-7)。
通常,上述药剂或药物的总剂量可以为1-3,000mg/天,优选为约1-1,000mg/天,更优选为约1-200mg/天,每天分1次或2-4次施用。
施用治疗有效量的可用于治疗血管性疾病的心血管药剂来治疗特定病症,例如日剂量优选为约1-约3000mg/天,更优选为约5-约200mg/天,每天分1次或2-4次施用。然而,确切剂量是由临床医师决定的,并取决于诸如所施用的化合物的效力、患者年龄、体重、健康状况和反应这样的因素。
术语“治疗有效量”是指组合物的治疗剂例如心血管药剂、固醇吸收抑制剂和下述其它药物或治疗剂的量,这样的量能引起由施用人员(例如研究人员、医师或兽医)寻找的组织、系统、动物或哺乳动物的生物或医疗反应,包括减轻所治疗病症或疾病的症状,和预防、减缓或停止病症(例如上述血管性疾病)的发展。
本文所用的“联合治疗”或“治疗组合”是指施用两种或更多种治疗剂例如心血管药剂和固醇吸收抑制剂以预防或治疗血管性疾病例如高脂血症(例如动脉粥样硬化、高胆固醇血症或谷固醇血症)、中风、糖尿病、肥胖症和/或降低血浆固醇水平。如本文所用的“血管”包括心血管、脑血管及其组合。这样的给药包括将这些治疗剂以基本上同时的方式一起给药,例如在具有固定的活性组分比例的单一片剂或胶囊中给药,或者在多个分别填充有各种治疗剂的胶囊中给药。这样的给药还包括以顺序方式施用各种治疗剂。对于任一种情况,使用联合治疗都将在如上所述的血管性疾病和其它病症的治疗中提供有益效果。本文所公开的联合治疗的可能优点可以是降低有效地治疗血管性疾病所需的单个治疗化合物的量或治疗化合物的总量。与单一治疗相比,通过使用治疗剂的组合,可减轻单个化合物的副作用,从而可改善患者的配合性。还可以选择治疗剂来提供较宽范围的互补作用或互补作用方式。
如上所述,本发明组合物、药物组合物和治疗组合包含一种或多种固醇吸收抑制剂,例如在下文中详细说明的取代的氮杂环丁烷酮固醇吸收抑制剂或取代的β-内酰胺固醇吸收抑制剂。本文所用的“固醇吸收抑制剂”是指,当以治疗有效(固醇吸收抑制)量施用给哺乳动物或人时,能够抑制一种或多种固醇吸收的化合物,所述固醇包括但不限于胆固醇、植物甾醇(例如谷甾醇、菜油甾醇、豆甾醇和avenosterol)、5α-stanols(例如胆甾烷醇、5α-campestanol、5α-sitostanol)及其混合物。
在优选的实施方案中,可用于本发明组合物、治疗组合和方法的固醇吸收抑制剂由下式(I)代表:
或式(I)化合物的异构体,或式(I)化合物或式(I)化合物的异构体的可药用盐或溶剂化物,或式(I)化合物或式(I)化合物的异构体、盐或溶剂化物的前药,其中在上式(I)中:
Ar1和Ar2独立地选自芳基和R4-取代的芳基;
Ar3是芳基或R5-取代的芳基;
X、Y和Z独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
R和R2独立地选自-OR6、-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7;
R1和R3独立地选自氢、低级烷基和芳基;
q是0或1;r是0或1;m、n和p独立地选自0、1、2、3或4;条件是:q和r当中至少有一个是1,且m、n、p、q和r的总和为1、2、3、4、5或6;以及条件是:当p是0,且r是1时,m、q和n的总和为1、2、3、4或5;
R4是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6、-CH=CH-COOR6、-CF3、-CN、-NO2和卤素;
R5是1-5个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6和-CH=CH-COOR6;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;且
R9是低级烷基、芳基或芳基-取代的低级烷基。
R4优选是1-3个独立地选择的取代基,且R5优选是1-3个独立地选择的取代基。
本文所用的术语“烷基”或“低级烷基”是指具有1-6个碳原子的直链或支链烷基链,“烷氧基”是指具有1-6个碳原子的烷氧基。低级烷基的非限制性实例包括例如甲基、乙基、丙基和丁基。
“链烯基”是指在链中具有一个或多个共轭或非共轭双键的直链或支链碳链。类似地,“炔基”是指在链中具有一个或多个叁键的直链或支链碳链。当烷基、链烯基或炔基链连接两个变量并因此是二价的时,使用术语亚烷基、亚链烯基和亚炔基。
“环烷基”是指具有3-6个碳原子的饱和碳环,“亚环烷基”是指相应的二价环,其中与其它基团的连接位点包括所有位置异构体。
“卤素”是指氟、氯、溴或碘。
“芳基”是指苯基、萘基、茚基、四氢萘基和二氢茚基。
“亚苯基”是指二价苯基,包括邻位、间位和对位取代。
其中例如说明R、R1、R2和R3独立地选自一组取代基的陈述是指,R、R1、R2和R3是独立地选择的,以及当R、R1、R2和R3变量在分子中出现多于一次时,每次出现都是独立地选择的(例如,如果R是-OR6,其中R6是氢,R2可以是-OR6,其中R6是低级烷基)。本领域技术人员将认识到,取代基的大小和性质将影响可存在的取代基的数目。
本发明化合物具有至少一个不对称碳原子,因此式(I-XI)化合物的所有异构体,包括对映体、立体异构体、旋转异构体、互变异构体和外消旋体(当它们存在时)都是本发明一部分。本发明包括纯形式和混合物形式(包括外消旋混合物)的d和l异构体。异构体可使用常规技术,通过用旋光纯的或富含旋光物的原料反应,或者通过分离式I-XI化合物的异构体来制得。例如当存在双键时,异构体还可以包括几何异构体。
本领域技术人员应当理解,对于某些式I-XI化合物,一种异构体将表现出强于其它异构体的药理活性。
具有氨基的本发明化合物可以与有机酸和无机酸形成可药用盐。适于成盐的酸的实例有盐酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸和其它本领域已知的无机酸以及羧酸。盐是通过将游离碱形式与足量的所需酸接触以生成盐来制得的。游离碱形式可通过用合适的稀的碱水溶液例如稀的碳酸氢钠水溶液处理盐来再生。游离碱形式与其各自的盐形式在一些物理性质例如在极性溶剂中的溶解度方面多少有几分不同,但是对于本发明目的来说,盐与其各自的游离碱形式是等同的。
一些本发明化合物是酸性的(例如具有羧基的化合物)。这些化合物与无机和有机碱形成可药用盐。这样的盐的实例有钠盐、钾盐、钙盐、铝盐、金盐和银盐。还包括与可药用胺例如氨、烷基胺、羟基烷基胺、N-甲基葡糖胺等形成的盐。
本文所用的“溶剂化物”是指溶剂分子或离子与溶质(例如一种或多种式I-XI化合物、式I-XI化合物的异构体或式I-XI化合物的前药)的分子或离子配合物。可使用的溶剂的非限制性实例包括极性质子溶剂例如水和/或醇(例如甲醇)。
本文所用的“前药”是指这样的化合物,它们是药物前体,施用给患者后,它们在体内通过一些化学或生理过程释放出药物(例如由于在生理pH下或者通过酶的作用,前药转化成所需的药物形式)。
优选的式(I)化合物是定义如下的那些:其中Ar1是苯基或R4-取代的苯基,更优选为(4-R4)-取代的苯基。Ar2优选为苯基或R4-取代的苯基,更优选为(4-R4)-取代的苯基。Ar3优选为R5-取代的苯基,更优选为(4-R5)-取代的苯基。当Ar1是(4-R4)-取代的苯基时,R4优选为卤素。当Ar2和Ar3分别是R4-和R5-取代的苯基时,R4优选为卤素或-OR6,且R5优选为-OR6,其中R6是低级烷基或氢。尤其优选的是其中每个Ar1和Ar2是4-氟苯基,且Ar3是4-羟基苯基或4-甲氧基苯基的化合物。
X、Y和Z分别优选为-CH2-。R1和R3分别优选为氢。R和R2优选为-OR6,其中R6是氢,或易于代谢成羟基的基团(例如如上所定义的-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7)。
m、n、p、q和r的总和优选为2、3或4,更优选为3。优选其中m、n和r分别是0,q是1,且p是2的化合物。
其中p、q和n分别是0,r是1,且m是2或3的式(I)化合物也是优选的。定义如下的化合物是更优选的:其中m、n和r分别是0,q是1,p是2,Z是-CH2-,且R是-OR6,R6尤其是氢。
定义如下的式(I)化合物也是更优选的:其中p、q和n分别是0,r是1,m是2,X是-CH2-,且R2是-OR6,R6尤其是氢。
另一组优选的式(I)化合物是定义如下的那些:其中Ar1是苯基或R4-取代的苯基,Ar2是苯基或R4-取代的苯基,且Ar3是R5-取代的苯基。定义如下的化合物也是优选的:其中Ar1是苯基或R4-取代的苯基,Ar2是苯基或R4-取代的苯基,Ar3是R5-取代的苯基,且m、n、p、q和r的总和是2、3或4,更优选是3。定义如下的化合物是更优选的:其中Ar1是苯基或R4-取代的苯基,Ar2是苯基或R4-取代的苯基,Ar3是R5-取代的苯基,且m、n和r分别是0,q是1,且p是2,或者p、q和n分别是0,r是1,且m是2或3。
在一个优选的实施方案中,可用于本发明组合物、治疗组合和方法的式(I)固醇抑制剂是由下式(II)代表(ezetimibe):
或式(II)化合物的可药用盐或溶剂化物,或式(II)化合物或式(II)化合物的盐或溶剂化物的前药。
式I化合物可通过本领域技术人员众所周知的各种方法制得,例如在U.S.专利5,631,365、5,767,115、5,846,966、6,207,822,于2001年3月28日提交的第60/279,288号U.S.临时申请,和PCT专利申请WO93/02048(以上各个专利引入本发明以作参考)中公开的方法,以及在下文实施例中描述的方法。例如,合适的式I化合物可通过包含下列步骤的方法制得:
(a)用强碱处理式A或B的内酯:
其中R’和R2’分别是R和R2,或者是适当保护的羟基;Ar10是Ar1、适当保护的羟基-取代的芳基或适当保护的氨基-取代的芳基;其余变量如上文对式I所定义,条件是:在式B内酯中,当n和r分别是0时,
p是1-4;
(b)将步骤(a)中的产物与下式所示的亚胺反应
其中Ar20是Ar2,适当保护的羟基-取代的芳基或适当保护的氨基-取代的芳基;且Ar30是Ar3、适当保护的羟基-取代的芳基或适当保护的氨基-取代的芳基;
c)用酸中止该反应;
d)当存在时,任选将保护基从R’、R2’、Ar10、Ar20和Ar30上除去;和
e)任选将在R、R2、Ar1、Ar2和Ar3上的羟基或氨基取代基官能化。
使用上述内酯,如下所示获得了式IA和IB化合物:
其中变量如上所定义;和
其中变量如上所定义。
或者,可用于本发明组合物、治疗组合和方法的固醇吸收抑制剂由下式(III)代表:
或式(III)化合物的异构体,或式(III)化合物或式(III)化合物的异构体的可药用盐或溶剂化物,或式(III)化合物或式(III)化合物的异构体、盐或溶剂化物的前药,其中在上式(III)中:
Ar1是R3-取代的芳基;
Ar2是R4-取代的芳基;
Ar3是R5-取代的芳基;
Y和Z独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
A选自-O-、-S-、-S(O)-或-S(O)2-;
R1选自-OR6、-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7;R2选自氢、低级烷基和芳基;R1与R2一起是=O;
q是1、2或3;
p是0、1、2、3或4;
R5是1-3个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR9、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2-低级烷基、-NR6SO2-芳基、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2-烷基、S(O)0-2-芳基、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、邻位卤素、间位卤素、邻位低级烷基、间位低级烷基、-(低级亚烷基)-COOR6和-CH=CH-COOR6;
R3和R4独立地为1-3个独立地选自下列的取代基:R3、氢、对位低级烷基、芳基、-NO2、-CF3和对位卤素;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;且R9是低级烷基、芳基或芳基-取代的低级烷基。
优选的式I化合物包括定义如下的那些:其中Ar1是R3-取代的苯基,尤其是(4-R3)-取代的苯基。Ar2优选是R4-取代的苯基,尤其是(4-R4)-取代的苯基。Ar3优选是R5-取代的苯基,尤其是(4-R5)-取代的苯基。Ar1、Ar2和Ar3分别优选是单取代的。
Y和Z分别优选是-CH2-。R2优选是氢。R1优选为-OR6,其中R6是氢,或易于代谢成羟基的基团(例如如上所定义的-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7)。其中R1和R2一起是=O的化合物也是优选的。
q和p的总和优选为1或2,更优选为1。其中p是0,且q是1的化合物是优选的。定义如下的化合物是更优选的:其中p是0,q是1,Y是-CH2-,且R1是-OR6,R6尤其是氢。
另一组优选的化合物是定义如下的那些:其中Ar1是R3-取代的苯基,Ar2是R4-取代的苯基,且Ar3是R5-取代的苯基。
定义如下的化合物也是优选的:其中Ar1是R3-取代的苯基,Ar2是R4-取代的苯基,Ar3是R5-取代的苯基,且p和q的总和为1或2,尤其是1。定义如下的化合物是更优选的:其中Ar1是R3-取代的苯基,Ar2是R4-取代的苯基,Ar3是R5-取代的苯基,p是0,且q是1。
A优选为-O-。
R3优选为-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2-烷基、S(O)0-2芳基、NO2或卤素。R3更优选的定义是卤素,尤其是氟或氯。
R4优选为氢、低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CO)NR6R7、-NR6R7、COR6或卤素,其中R6和R7优选独立地为氢或低级烷基,且R9优选为低级烷基。R4更优选的定义是氢或卤素,尤其是氟或氯。
R5优选为-OR6、-O(CO)R6、-O(CO)OR9、-O(CO)NR6R7、-NR6R7、-(低级亚烷基)-COOR6或-CH=CH-COOR6,其中R6和R7优选独立地为氢或低级烷基,且R9优选为低级烷基。R5的更优选定义是-OR6、-(低级亚烷基)-COOR6或-CH=CH-COOR6,其中R6优选为氢或低级烷基。
制备式III化合物的方法是本领域技术人员众所周知的。合适的方法的非限制性实例公开在U.S.专利5,688,990中,将其引入本发明以作参考。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇吸收抑制剂由下式(IV)代表:
或式(IV)化合物的异构体,或式(IV)化合物或式(IV)化合物的异构体的可药用盐或溶剂化物,或式(IV)化合物或式(IV)化合物的异构体、盐或溶剂化物的前药,其中在上式(IV)中:
A选自R2-取代的杂环烷基、R2-取代的杂芳基、R2-取代的苯并稠合的杂环烷基和R2-取代的苯并稠合的杂芳基;
Ar1是芳基或R3-取代的芳基;
Ar2是芳基或R4-取代的芳基;
Q是一个键,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
;且
R1选自:
-(CH2)q-,其中q是2-6,条件是:当Q形成螺合环时,q还可以是0或1;
-(CH2)e-G-(CH2)r-,其中G是-O-、-C(O)-、亚苯基、-NR8-或-S(O)0-2-,e是0-5,且r是0-5,条件是:e和r的总和是1-6;
-(C2-C6亚链烯基)-;和
-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1-5,且g是0-5,条件是:f和g的总和是1-6;
R5选自:
R6和R7独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R5与相邻的R6一起,或者R5与相邻的R7一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为0、1、2或3,条件是二者不能同时为0;条件是:当R6是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;条件是:当R7是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;条件是:当a是2或3时,R6可相同或不同;以及条件是:当b是2或3时,R7可相同或不同;
并且当Q是一个键时,R1还可以选自:
其中M是-O-、-S-、-S(O)-或-S(O)2-;
X、Y和Z独立地选自-CH2-、-CH(C1-C6烷基)-和-C(二-(C1-C6)烷基);
R10和R12独立地选自-OR14、-O(CO)R14、-O(CO)OR16和-O(CO)NR14R15;
R11和R13独立地选自氢、(C1-C6)烷基和芳基;或者R10与R11一起是=O,或者R12与R13一起是=O;
d是1、2或3;
h是0、1、2、3或4;
s是0或1;t是0或1;m、n和p独立地为0-4;条件是:s和t当中至少有一个是1,并且m、n、p、s和t的总和是1-6;条件是:当p是0,且t是1时,则m、s和n的总和为1-5;以及条件是,当p是0,且s是1时,m、t和n的总和为1-5;
v是0或1;
j和k独立地为1-5,条件是j、k和v的总和为1-5;
R2是1-3个选自下列的在环碳原子上的取代基:氢、(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C6)环烷基、(C3-C6)环烯基、R17-取代的芳基、R17-取代的苄基、R17-取代的苄氧基、R17-取代的芳氧基、卤素、-NR14R15、NR14R15(C1-C6亚烷基)-、NR14R15C(O)(C1-C6亚烷基)-、-NHC(O)R16、OH、C1-C6烷氧基、-OC(O)R16、-COR14、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、NO2、-S(O)0-2R16、-SO2NR14R15和-(C1-C6亚烷基)COOR14;当R2是在杂环烷基环上的取代基时,R2如上所定义,或者是=O或
并且,当R2是在可取代的环氮原子上的取代基时,其是氢、(C1-C6)烷基、芳基、(C1-C6)烷氧基、芳氧基、(C1-C6)烷基羰基、芳基羰基、羟基、-(CH2)1-6CONR18R18,
其中J是-O-、-NH-、-NR18-或-CH2-;
R3和R4独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR14、-O(CO)R14、-O(CO)OR16、-O(CH2)1-5OR14、-O(CO)NR14R15、-NR14R15、-NR14(CO)R15、-NR14(CO)OR16、-NR14(CO)NR15R19、-NR14SO2R16、-COOR14、-CONR14R15、-COR14、-SO2NR14R15、S(O)0-2R16、-O(CH2)1-10-COOR14、-O(CH2)1-10-CONR14R15、-(C1-C6亚烷基)-COOR14、-CH=CH-COOR14、-CF3、-CN、-NO2和卤素;
R8是氢、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R14或-COOR14;
R9和R17独立地为1-3个独立地选自下列的基团:氢、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR14R15、OH和卤素;
R14和R15独立地选自氢、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;
R16是(C1-C6)烷基、芳基或R17-取代的芳基;
R18是氢或(C1-C6)烷基;且
R19是氢、羟基或(C1-C6)烷氧基。
如在上面的式(IV)中所使用的,“A”优选为R2-取代的含有1或2个氮原子的6元杂环烷基环。优选的杂环烷基环是哌啶基、哌嗪基和吗啉基。环“A”优选经由环氮原子连接在苯环上。优选的R2取代基是氢和低级烷基。R19优选为氢。
Ar2优选为苯基或R4-苯基,尤其是(4-R4)-取代的苯基。
R4的优选定义是低级烷氧基,尤其是甲氧基,和卤素,尤其是氟。
Ar1优选为苯基或R3-取代的苯基,尤其是(4-R3)-取代的苯基。
对于变量组合-R1-Q-,有几个优选的定义:
Q是一个键,且R1是低级亚烷基,优选亚丙基;
Q是如上所定义的螺合基团,其中优选地,R6和R7分别是亚乙基,且R5是
Q是一个键,且R1是
其中选择变量使得R1是-O-CH2-CH(OH)-;
Q是一个键,且R1是
其中选择变量使得R1是-CH(OH)-(CH2)2-;和
Q是一个键,且R1是
其中选择变量使得R1是-CH(OH)-CH2-S(O)0-2-。
制备式IV化合物的方法是本领域技术人员众所周知的。合适的方法的非限制性实例公开在U.S.专利5,656,624中,其引入本发明以作参考。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇吸收抑制剂由下式(V)代表:
或式(V)化合物的异构体,或式(V)化合物或式(V)化合物的异构体的可药用盐或溶剂化物,或式(V)化合物或式(V)化合物的异构体、盐或溶剂化物的前药,其中在上式(V)中:
Ar1是芳基、R10取代的芳基或杂芳基;
Ar2是芳基或R4-取代的芳基;
Ar3是芳基或R5-取代的芳基;
X和Y独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
R是-OR6、-O(CO)R6、-O(CO)OR9或-O(CO)NR6R7;R1是氢、低级烷基或芳基;或者R和R1一起是=O;
q是0或1;
r是0、1或2;
m和n独立地为0、1、2、3、4或5;条件是m、n和q的总和为1、2、3、4或5;
R4是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6和-CH=CH-COOR6;
R5是1-5个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-CF3、-CN、-NO2、卤素、-(低级亚烷基)COOR6和-CH=CH-COOR6;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;
R9是低级烷基、芳基或芳基-取代的低级烷基;且
R10是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、-S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-CF3、-CN、-NO2和卤素。
在式V化合物的范围中,包括两个优选的结构。在式VA中,q是0,且其余变量如上所定义,在式VB中,q是1,且其余变量如上所定义:
R4、R5和R10分别优选为1-3个独立地选择的如上所述的基团。定义如下的式(V)化合物是优选的:其中Ar1是苯基、R10-取代的苯基或噻吩基,尤其是(4-R10)-取代的苯基或噻吩基。Ar2优选为R4-取代的苯基,尤其是(4-R4)-取代的苯基。Ar3优选为苯基或R5-取代的苯基,尤其是(4-R5)-取代的苯基。当Ar1是R10-取代的苯基时,R10优选为卤素,尤其是氟。当Ar2是R4-取代的苯基时,R4优选为-OR6,其中R6尤其是氢或低级烷基。当Ar3是R5-取代的苯基时,R5优选为卤素,尤其是氟。定义如下的式(V)化合物是尤其优选的:其中Ar1是苯基、4-氟苯基或噻吩基,Ar2是4-(烷氧基或羟基)苯基,且Ar3是苯基或4-氟苯基。
X和Y分别优选为-CH2-。m、n和q的总和优选为2、3或4,更优选为2。当q是1时,n优选为1-5。
优选的是,X、Y、Ar1、Ar2和Ar3在式(VA)和(VB)各式中是相同的。
在式(VA)化合物中,m和n的总和优选为2、3或4,更优选为2。其中m和n的总和是2,且r是0或1的化合物也是优选的。
在式(VB)化合物中,m和n的总和优选为1、2或3,更优选为1。其中m是0,且n是1的化合物是尤其优选的。
R1优选为氢,且R优选为-OR6,其中R6是氢,或易于代谢成羟基的基团(例如如上所定义的-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7),或者R和R1一起形成=O基团。
制备式V化合物的方法是本领域技术人员众所周知的。合适的方法的非限制性实例公开在U.S.专利5,624,920中,其引入本发明以作参考。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇吸收抑制剂由下式(VI)代表:
或式(VI)化合物的异构体,或式(VI)化合物或式(VI)化合物的异构体的可药用盐或溶剂化物,或式(VI)化合物或式(VI)化合物的异构体、盐或溶剂化物的前药,其中:
R1是
R2和R3独立地选自:-CH2-、-CH(低级烷基)-、-C(二低级烷基)-、-CH=CH-和-C(低级烷基)=CH-;或者R1与相邻的R2一起,或者R1与相邻的R3一起形成-CH=CH-或-CH=C(低级烷基)-;
u和v独立地为0、1、2或3,条件是二者不能同时为0;条件是:当R2是-CH=CH-或-C(低级烷基)=CH-时,v是1;条件是:当R3是CH=CH-或-C(低级烷基)=CH-时,u是1;条件是:当v是2或3时,R2可相同或不同;以及条件是:当u是2或3时,R3可相同或不同;
R4是B-(CH2)mC(O)-,其中m是0、1、2、3、4或5;B-(CH2)q-,其中q是0、1、2、3、4、5或6;B-(CH2)e-Z-(CH2)r-,其中Z是-O-、-C(O)-、亚苯基、-N(R8)-或-S(O)0-2-,e是0、1、2、3、4或5,且r是0、1、2、3、4或5,条件是e和r的总和为0、1、2、3、4、5或6;
B-(C2-C6亚链烯基)-;B-(C4-C6亚链二烯基)-;B-(CH2)t-Z-(C2-C6亚链烯基)-,其中Z如上所定义,t是0、1、2或3,条件是t与亚链烯基链中的碳原子数目的总和为2、3、4、5或6;B-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1、2、3、4或5,且g是0、1、2、3、4或5,条件是f与g的总和是1、2、3、4、5或6;B-(CH2)t-V-(C2-C6亚链烯基)-或B-(C2-C6亚链烯基)-V-(CH2)t-,其中V和t如上所定义,条件是t与亚链烯基链中的碳原子数目的总和为2、3、4、5或6;B-(CH2)a-Z-(CH2)b-V-(CH2)d-,其中Z和V如上所定义,且a、b和d独立地为0、1、2、3、4、5或6,条件是a、b和d的总和为0、1、2、3、4、5或6;或T-(CH2)s-,其中T是具有3-6个碳原子的环烷基,且s是0、1、2、3、4、5或6;或者
R1和R4一起形成
B选自二氢茚基、茚基、萘基、四氢萘基、杂芳基或W-取代的杂芳基,其中杂芳基选自吡咯基、吡啶基、嘧啶基、吡嗪基、三嗪基、咪唑基、噻唑基、吡唑基、噻吩基、噁唑基和呋喃基,对于含氮杂芳基,还包括其N-氧化物,或
对于在环碳原子上的取代,W是1-3个独立地选自下列的基团:低级烷基、羟基低级烷基、低级烷氧基、烷氧基烷基、烷氧基烷氧基、烷氧基羰基烷氧基、(低级烷氧基亚氨基)-低级烷基、低级烷二酰基、低级烷基低级烷二酰基、烯丙氧基、-CF3、-OCF3、苄基、R7-苄基、苄氧基、R7-苄氧基、苯氧基、R7-苯氧基、二氧杂环戊烷基、NO2、-N(R8)(R9)、N(R8)(R9)-低级亚烷基-、N(R8)(R9)-低级链烯氧基-、OH、卤素、-CN、-N3、-NHC(O)OR10、-NHC(O)R10、R11O2SNH-、(R11O2S)2N-、-S(O)2NH2、-S(O)0-2R8、叔丁基二甲基-甲硅烷氧基甲基、-C(O)R12、-COOR19、-CON(R8)(R9)、-CH=CHC(O)R12、-低级亚烷基-C(O)R12、R10C(O)(低级链烯氧基)-、N(R8)(R9)C(O)(低级链烯氧基)-和
以及
当存在时,在取代的杂芳基环氮原子上的取代基选自低级烷基、低级烷氧基、-C(O)OR10、-C(O)R10、OH、N(R8)(R9)-低级亚烷基-、N(R8)(R9)-低级链烯氧基-、-S(O)2NH2和2-(三甲基甲硅烷基)-乙氧基甲基;
R7是1-3个独立地选自下列的基团:低级烷基、低级烷氧基、-COOH、NO2、-N(R8)(R9)、OH和卤素;
R8和R9独立地选自H或低级烷基;
R10选自低级烷基、苯基、R7-苯基、苄基或R7-苄基;
R11选自OH、低级烷基、苯基、苄基、R7-苯基或R7-苄基;
R12选自H、OH、烷氧基、苯氧基、苄氧基、
-N(R8)(R9)、低级烷基、苯基或R7-苯基;
R13选自-O-、-CH2-、-NH-、-N(低级烷基)-或-NC(O)R19;
R15、R16和R17独立地选自H和对W定义的基团;或者R15是氢,且
R16和R17与它们所连接的相邻碳原子一起形成二氧杂环戊烷基环;
R19是H、低级烷基、苯基或苯基低级烷基;且
R20和R21独立地选自苯基、W-取代的苯基、萘基、W-取代的萘基、二氢茚基、茚基、四氢萘基、苯并二氧杂环戊烯基(benzodioxolyl)、杂芳基、W-取代的杂芳基、苯并稠合的杂芳基、W-取代的苯并稠合的杂芳基和环丙基,其中杂芳基如上所定义。
一组优选的式VI化合物是定义如下的那些:其中R21选自苯基、W-取代的苯基、二氢茚基、苯并呋喃基、苯并二氧杂环戊烯基、四氢萘基、吡啶基、吡嗪基、嘧啶基、喹啉基或环丙基,其中W是低级烷基、低级烷氧基、OH、卤素、-N(R8)(R9)、-NHC(O)OR10、-NHC(O)R10、NO2、-CN、-N3、-SH、-S(O)0-2-(低级烷基)、-COOR19、-CON(R8)(R9)、-COR12、苯氧基、苄氧基、-OCF3、-CH=C(O)R12或叔丁基二甲基甲硅烷氧基,其中R8、R9、R10、R12和R19如对式IV所定义。当W是2或3个取代基时,取代基可相同或不同。
另一组优选的式VI化合物是定义如下的那些:其中R20是苯基或W-取代的苯基,其中W的优选含义如上文中对R21的优选定义中所定义。
定义如下的式VI化合物是更优选的:其中R20是苯基或W-取代的苯基,且R21是苯基、W-取代的苯基、二氢茚基、苯并呋喃基、苯并二氧杂环戊烯基、四氢萘基、吡啶基、吡嗪基、嘧啶基、喹啉基或环丙基;W是低级烷基、低级烷氧基、OH、卤素、-N(R8)(R9)、-NHC(O)OR10、-NHC(O)R10、NO2、-CN、-N3、-SH、-S(O)0-2-(低级烷基)、-COOR19、-CON(R8)(R9)、-COR12、苯氧基、苄氧基、-CH=CHC(O)R12、-OCF3或叔丁基-二甲基-甲硅烷氧基,其中当W是2或3个取代基时,取代基可相同或不同,并且R8、R9、R10、R12和R19如对式IV所定义。
其中R1是
或
的式VI化合物也是优选的。
另一组优选的式VI化合物是定义如下的那些:其中R2和R3分别是-CH2-,且u和v的总和是2、3或4,u=v=2是更优选的。
R4优选为B-(CH2)q-或B-(CH2)e-Z-(CH2)r-,其中B、Z、q、e和r如上所定义。B优选为
其中R16和R17分别是氢,其中R15优选为H、OH、低级烷氧基,尤其是甲氧基,或卤素,尤其是氯。
Z优选为-O-,e是0,且r是0。
q优选为0-2。
R20优选为苯基或W-取代的苯基。
对于R20,优选的W取代基是低级烷氧基,尤其是甲氧基和乙氧基,OH和-C(O)R12,其中R12优选为低级烷氧基。
R21优选选自苯基、低级烷氧基-取代的苯基和F-苯基。
定义如下的式VI化合物是特别优选的,其中R1是
R2和R3分别是-CH2-、u=v=2,R4是B-(CH2)q-,其中B是苯基或被低级烷氧基或氯取代的苯基,q是0-2,R20是苯基、OH-苯基、低级烷氧基-取代的苯基或低级烷氧基羰基-取代的苯基,且R21是苯基、低级烷氧基-取代的苯基或F-苯基。
制备式VI化合物的方法是本领域技术人员众所周知的。合适的方法的非限制性实例公开在U.S.专利5,698,548中,将其引入本发明以作参考。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇抑制剂由下式(VIIA)和(VIIB)代表:
和
或式(VIIA)或(VIIB)化合物的异构体,或式(VIIA)或(VIIB)化合物或式(VIIA)或(VIIB)化合物的异构体的可药用盐或溶剂化物,或式(VIIA)或(VIIB)化合物或式(VIIA)或(VIIB)化合物的异构体、盐或溶剂化物的前药,其中在上式(VIIA)或(VIIB)中:
A是-CH=CH-、-C≡C-或-(CH2)p-,其中p是0、1或2;
B是
B’是
D是-(CH2)mC(O)-或-(CH2)q-,其中m是1、2、3或4,且q是2、3或4;
E是C10-C20烷基或-C(O)-(C9-C19)-烷基,其中烷基是直链或支链的,是饱和的或者含有一个或多个双键;
R是氢、饱和或含有一个或多个双键的直链或支链C1-C15烷基或B-(CH2)r-,其中r是0、1、2或3;
R1、R2、R3、R1’、R2’和R3’独立地选自氢、低级烷基、低级烷氧基、羧基、NO2、NH2、OH、卤素、低级烷基氨基、二低级烷基氨基、-NHC(O)OR5、R6O2SNH-和-S(O)2NH2;
R4是
其中n是0、1、2或3;
R5是低级烷基;且
R6是OH、低级烷基、苯基、苄基或取代的苯基,其中取代基是1-3个独立地选自下列的基团:低级烷基、低级烷氧基、羧基、NO2、NH2、OH、卤素、低级烷基氨基和二低级烷基氨基。
其中R是氢、饱和或单不饱和C1-C10烷基或苯基的式(VIIA)化合物是优选的。另一组优选的式(VIIA)化合物是定义如下的那些:其中D是丙基(即-(CH2)q-,且q是3)。第三组优选的式(VIIA)化合物是定义如下的那些:其中R4是对甲氧基苯基或2,4,6-三甲氧基苯基。另一组优选的式(VIIA)化合物是定义如下的那些:其中A是亚乙基或一个键(即-(CH2)p-,其中p是0)。R1’、R2’和R3’优选分别是氢,且R1优选为氢、羟基、硝基、低级烷氧基、氨基或叔丁氧基羰基-氨基,且R2和R3分别是氢。
定义如下的式(VIIA)化合物是更优选的:其中R1’、R2’和R3’分别是氢;R1是氢、羟基、硝基、低级烷氧基、氨基或叔丁氧基羰基-氨基,且R2和R3分别是氢;R是氢、乙基或苯基;D是丙基;R4是对甲氧基苯基或2,4,6-三甲氧基苯基;且A是亚乙基或一个键。
其中B’是苯基的优选的式(VIIA)化合物如下表所示:
D | R | A | B | R4 |
-(CH2)3--CH2C(O)--(CH2)3--(CH2)3--(CH2)3--(CH2)3--(CH2)3--(CH2)3--(CH2)3--(CH2)3--(CH2)3- | H苯基HHHH乙基苯基乙基甲基H | ------------亚乙基------------------ | p-MeO-苯基苯基苯基p-OH-苯基p-MeO-苯基3-MeO-苯基苯基苯基苯基苯基p-NH2-苯基 | p-MeO-苯基p-MeO-苯基p-MeO-苯基p-MeO-苯基p-MeO-苯基p-MeO-苯基p-MeO-苯基p-MeO-苯基2,4,6-三-MeO-苯基p-MeO-苯基p-MeO-苯基 |
在上表中首先列出的具有(3R,4S)绝对立体化学的化合物是更优选的。
优选的式(VIIB)化合物是其中R是氢、甲基、乙基、苯基或苯基丙基的那些。另一组优选的式(VIIB)化合物是其中R4是对甲氧基苯基或2,4,6-三甲氧基苯基的那些。另一组优选的式(VIIB)化合物是其中A是亚乙基或一个键的那些。另一组优选的式(VIIB)化合物是定义如下的那些:其中E是癸基、油酰基或7-Z-十六碳烯基。R1、R2和R3优选分别是氢。
更优选的式(VIIB)化合物是定义如下的那些:其中R是氢、甲基、乙基、苯基或苯基丙基;R4是对甲氧基苯基或2,4,6-三甲氧基苯基;A是亚乙基或一个键;E是癸基、油酰基或7-Z-十六碳烯基;且R1、R2和R3分别是氢。
优选的式(VIIB)化合物是定义如下的那些:其中E是癸基,R是氢,B-A是苯基,且R4是对甲氧基苯基。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇抑制剂由下式(VIII)代表:
或式(VIII)化合物的异构体,或式(VIII)化合物或式(VIII)化合物的异构体的可药用盐或溶剂化物,或式(VIII)化合物或式(VIII)化合物的异构体、盐或溶剂化物的前药,其中在上式(VIII)中:
R26是H或OG1;
G和G1独立地选自
和
条件是:当R26是H或OH时,G不是H;
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)-烷氧基或-W-R30;
W独立地选自-NH-C(O)-、-O-C(O)-、-O-C(O)-N(R31)-、-NH-C(O)-N(R31)-和-O-C(S)-N(R31)-;
R2和R6独立地选自H、(C1-C6)烷基、芳基和芳基(C1-C6)烷基;
R3、R4、R5、R7、R3a和R4a独立地选自H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)(C1-C6)烷基和-C(O)芳基;
R30选自R32-取代的T、R32-取代的-T-(C1-C6)烷基、R32-取代的-(C2-C4)链烯基、R32-取代的-(C1-C6)烷基、R32-取代的-(C3-C7)环烷基和R32-取代的-(C3-C7)环烷基(C1-C6)烷基;
R31选自H和(C1-C4)烷基;
T选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、苯并噻唑基、噻二唑基、吡唑基、咪唑基和吡啶基;
R32独立地选自1-3个独立地选自下列的取代基:卤素、(C1-C4)烷基、-OH、苯氧基、-CF3、-NO2、(C1-C4)烷氧基、亚甲二氧基、氧代基、(C1-C4)烷硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、-N(CH3)2、-C(O)-NH(C1-C4)烷基、-C(O)-N((C1-C4)烷基)2、-C(O)-(C1-C4)烷基、-C(O)-(C1-C4)烷氧基和吡咯烷基羰基;或者R32是共价键,并且R31、其所连接的氮与R32一起形成吡咯烷基、哌啶基、N-甲基-哌嗪基、二氢吲哚基或吗啉基,或者(C1-C4)烷氧基羰基-取代的吡咯烷基、哌啶基、N-甲基哌嗪基、二氢吲哚基或吗啉基;
Ar1是芳基或R10-取代的芳基;
Ar2是芳基或R11-取代的芳基;
Q是一个键,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
且
R1选自
-(CH2)q-,其中q是2-6,条件是:当Q形成螺环时,q还可以是0或1;
-(CH2)e-E-(CH2)r-,其中E是-O-、-C(O)-、亚苯基、-NR22-或-S(O)0-2-,e是0-5,且r是0-5,条件是e与r的总和是1-6;
-(C2-C6)亚链烯基-;和
-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1-5,且g是0-5,条件是f与g的总和是1-6;
R12是
R13和R14独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R12与相邻的R13一起,或R12与相邻的R14一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为0、1、2或3,条件是二者不能同时为0;
条件是:当R13是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;
条件是:当R14是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;
条件是:当a是2或3时,R13可相同或不同;以及
条件是:当b是2或3时,R14可相同或不同;
并且当Q是一个键时,R1还可以是:
M是-O-、-S-、-S(O)-或-S(O)2-;
X、Y和Z独立地选自-CH2-、-CH(C1-C6)烷基-和-C(二-(C1-C6)烷基);
R10和R11独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR19、-O(CO)R19、-O(CO)OR21、-O(CH2)1-5OR19、-O(CO)NR19R20、-NR19R20、-NR19(CO)R20、-NR19(CO)OR21、-NR19(CO)NR20R25、-NR19SO2R21、-COOR19、-CONR19R20、-COR19、-SO2NR19R20、S(O)0-2R21、-O(CH2)1-10-COOR19、-O(CH2)1-10CONR19R20、-(C1-C6亚烷基)-COOR19、-CH=CH-COOR19、-CF3、-CN、-NO2和卤素;
R15和R17独立地选自-OR19、-O(CO)R19、-O(CO)OR21和-O(CO)NR19R20;
R16和R18独立地选自H、(C1-C6)烷基和芳基;R15和R16一起是=O,或者R17和R18一起是=O;
d是1、2或3;
h是0、1、2、3或4;
s是0或1;t是0或1;m、n和p独立地为0-4;
条件是:s和t当中至少有一个是1,且m、n、p、s和t的总和是1-6;
条件是:当p是0,且t是1时,m、s和n的总和是1-5;以及条件是:当p是0,且s是1时,m、t和n的总和是1-5;
v是0或1;
j和k独立地为1-5,条件是j、k和v的总和是1-5;
并且当Q是一个键时,且R1是
时,Ar1还可以是吡啶基、异噁唑基、呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、噻唑基、吡嗪基、嘧啶基或哒嗪基;
R19和R20独立地选自H、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;
R21是(C1-C6)烷基、芳基或R24-取代的芳基;
R22是H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R19或-COOR19;
R23和R24独立地为1-3个独立地选自下列的基团:H、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR19R20、-OH和卤素;且
R25是H、-OH或(C1-C6)烷氧基。
Ar2优选为苯基或R11-苯基,尤其是(4-R11)-取代的苯基。R11的优选定义是低级烷氧基,尤其是甲氧基,和卤素,尤其是氟。
Ar1优选为苯基或R10-取代的苯基,尤其是(4-R10)取代的苯基。R10优选为卤素,更优选为氟。
对于-R1-Q-变量组合,有几个优选的定义:
Q是一个键,且R1是低级亚烷基,优选亚丙基;
Q是如上所定义的螺合基团,其中优选地,R13和R14分别是亚乙基,且R12是
且R1是-(CH2)q,其中q是0-6;
Q是一个键,且R1是
其中选择变量使得R1是-O-CH2-CH(OH)-;
Q是一个键,且R1是
其中选择变量使得R1是-CH(OH)-(CH2)2-;和
Q是一个键,且R1是
其中选择变量使得R1是-CH(OH)-CH2-S(O)0-2-。
因此,优选的式(VIII)化合物是定义如下的那些:其中G和G1如上所定义,且其余变量具有下列定义:
Ar1是苯基或R10-取代的苯基,其中R10是卤素;
Ar2是苯基或R11-苯基,其中R11是1-3个独立地选自C1-C6烷氧基和卤素的取代基;
Q是一个键,且R1是低级亚烷基;Q与氮杂环丁烷酮的3-位环碳原子一起形成基团
其中优选地,R13和R14分别是亚乙基,且a和b分别是1,其中R12是
Q是一个键,且R1是-O-CH2-CH(OH)-;Q是一个键,且R1是-CH(OH)-(CH2)2-;或者Q是一个键,且R1是-CH(OH)-CH2-S(O)0-2-。
对于下列各式所示的基团G和G1,
优选的变量如下:
R2、R3、R4、R5、R6和R7独立地选自H、(C1-C6)烷基、苄基和乙酰基。
对于下式所示的基团G或G1,
优选的变量如下:
R3、R3a、R4和R4a选自:H、(C1-C6)烷基、苄基和乙酰基;
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)烷氧基和-W-R30,
其中W是-O-C(O)-或-O-C(O)-NR31-,R31是H,且R30是(C1-C6)烷基、-C(O)-(C1-C4)烷氧基-(C1-C6)烷基、T、T-(C1-C6)烷基、或T或T-(C1-C6)烷基,其中T被一个或两个卤素或(C1-C6)烷基取代。
优选的R30取代基选自:2-氟苯基、2,4-二氟苯基、2,6-二氯苯基、2-甲基苯基、2-噻吩基甲基、2-甲氧基-羰基乙基、噻唑-2-基-甲基、2-呋喃基、2-甲氧基羰基丁基和苯基。
R、Ra和Rb的优选组合如下:
1)R、Ra和Rb独立地为-OH或-O-C(O)-NH-R30,尤其其中Ra是-OH,且R和Rb是-O-C(O)-NH-R30,R30选自上述优选的取代基,或者其中R和Ra分别是-OH,且Rb是-O-C(O)-NH-R30,其中R30是2-氟苯基、2,4-二氟苯基、2,6-二氯苯基;
2)Ra是-OH、卤素、叠氮基或(C1-C6)-烷氧基(C1-C6)烷氧基,Rb是H、卤素、叠氮基或(C1-C6)烷氧基(C1-C6)-烷氧基,且R是-O-C(O)-NH-R30,尤其其中Ra是-OH,Rb是H,且R30是2-氟苯基的化合物;
3)R、Ra和Rb独立地为-OH或-O-C(O)-R30,R30是(C1-C6)烷基、T或被一个或两个卤素或(C1-C6)烷基取代的T,尤其是其中R是-OH,且Ra和Rb是-O-C(O)R30,其中R30是2-呋喃基的化合物;和
4)R、Ra和Rb独立地为-OH或卤素。另外3类优选的化合物是定义如下的那些:其中C1’异头氧是β,其中C2’异头氧是β,和其中R基团是α。
G和G1优选选自:
和
其中Ac是乙酰基,且Ph是苯基。
R26优选为H或OH,更优选为H。-O-G取代基优选在其所连接的苯环的4-位上。
在另一个实施方案中,可用于本发明组合物、治疗组合和方法的固醇抑制剂由下式(IX)代表:
或式(IX)化合物的异构体,或式(IX)化合物或式(IX)化合物的异构体的可药用盐或溶剂化物,或式(IX)化合物或式(IX)化合物的异构体、盐或溶剂化物的前药,其中在上式(IX)中:
R26选自:
a)OH;
b)OCH3;
c)氟和
d)氯。
R1选自
H,
天然和非天然氨基酸。
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)-烷氧基和-W-R30;
W独立地选自-NH-C(O)-、-O-C(O)-、-O-C(O)-N(R31)-、-NH-C(O)-N(R31)-和-O-C(S)-N(R31)-;
R2和R6独立地选自H、(C1-C6)烷基、芳基和芳基(C1-C6)烷基;
R3、R4、R5、R7、R3a和R4a独立地选自H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)(C1-C6)烷基和-C(O)芳基;
R30独立地选自R32-取代的T、R32-取代的-T-(C-C6)烷基、R32-取代的-(C2-C4)链烯基、R32-取代的-(C-C6)烷基、R32-取代的-(C3-C7)环烷基和R32-取代的(C3-C7)环烷基(C1-C6)烷基;
R31独立地选自H和(C1-C4)烷基;
T独立地选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、苯并噻唑基、噻二唑基、吡唑基、咪唑基和吡啶基;
R32独立地选自1-3个独立地选自下列的取代基:H、卤素、(C1-C4)烷基、-OH、苯氧基、-CF3、-NO2、(C1-C4)烷氧基、亚甲二氧基、氧代基、(C1-C4)烷硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、-N(CH3)2、-C(O)-NH(C1-C4)烷基、-C(O)-N((C1-C4)烷基)2、-C(O)(C1-C4)烷基、-C(O)-(C1-C4)烷氧基和吡咯烷基羰基;或者R32是共价键,并且R31、其所连接的氮原子和R32一起形成吡咯烷基、哌啶基、N-甲基-哌嗪基、二氢吲哚基或吗啉基,或(C1-C4)烷氧基羰基-取代的吡咯烷基、哌啶基、N-甲基哌嗪基、二氢吲哚基或吗啉基;
Ar1是芳基或R10-取代的芳基;
Ar2是芳基或R11-取代的芳基;
Q是-(CH2)q-,其中q是2-6,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
R12是
R13和R14独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R12与相邻的R13一起,或者R12与相邻的R14一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为O、1、2或3,条件是二者不能同时为0;条件是:当R13是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;条件是:当R14是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;条件是:当a是2或3时,R13可相同或不同;以及条件是:当b是2或3时,R14可相同或不同;
R10和R11独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR19、-O(CO)R19、-O(CO)OR21、-O(CH2)1-5OR19、-O(CO)NR19R20、-NR19R20、-NR19(CO)R20、-NR19(CO)OR21、-NR19(CO)NR20R25、-NR19SO2R21、-COOR19、-CONR19R20、-COR19、-SO2NR19R20、S(O)0-2R21、-O(CH2)1-10-COOR19、-O(CH2)1-10CONR19R20、-(C1-C6亚烷基)-COOR19、-CH=CH-COOR19、-CF3、CN、-NO2和卤素;
Ar1还可以是吡啶基、异噁唑基、呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、噻唑基、吡嗪基、嘧啶基或哒嗪基;
R19和R20独立地选自H、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;R21是(C1-C6)烷基、芳基或R24-取代的芳基;
R22是H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R19或-COOR19;
R23和R24独立地为1-3个独立地选自下列的基团:H、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR19R20、-OH和卤素;且
R25是H、-OH或(C1-C6)烷氧基。
Ar2优选为苯基或R11-苯基,尤其是(4-R11)-取代的苯基。R11的优选定义是低级烷氧基,尤其是甲氧基,和卤素,尤其是氟。
Ar1优选为苯基或R10-取代的苯基,尤其是(4-R10)取代的苯基。R10的优选定义是卤素,尤其是氟。
优选地,Q是低级烷基或如上所定义的螺合基团,其中优选地,
R13和R14分别是亚乙基,且R12是
因此,优选的式IX化合物是定义如下的那些:其中R1如上所定义,且其余变量具有下列定义:
Ar1是苯基或R10-取代的苯基,其中R10是卤素;
Ar2是苯基或R11-苯基,其中R11是1-3个独立地选自C1-C6烷氧基和卤素的取代基;
Q是低级烷基(即C-1至C-2),其中Q=C-2是优选的,或者Q与氮杂环丁烷酮的3-位环碳原子一起形成基团
其中优选地,R13和R14分别是亚乙基,且a和b分别是1,其中R12是
或
对于下列各式所示的R1基团
优选的变量如下:
R2、R3、R4、R5、R6和R7独立地选自H、(C1-C6)烷基、苄基和乙酰基。
对于下式所示的R1基团
优选的变量如下:
R3、R3a、R4和R4a选自:H、(C1-C6)烷基、苄基和乙酰基;
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)烷氧基和-W-R30,其中W是-O-C(O)-或-O-C(O)-NR31-,R31是H,且R30是(C1-C6)烷基、-C(O)-(C1-C4)烷氧基-(C1-C6)烷基、T、T-(C1-C6)烷基、或T或T-(C1-C6)烷基,其中T被一个或两个卤素或(C1-C6)烷基取代。
优选的R30取代基选自:2-氟苯基、2,4-二氟苯基、2,6-二氯苯基、2-甲基苯基、2-噻吩基甲基、2-甲氧基-羰基乙基、噻唑-2-基-甲基、2-呋喃基、2-甲氧基羰基丁基和苯基。R、Ra和Rb的优选组合如下:(1)R、Ra和Rb独立地为-OH或-O-C(O)-NH-R30,尤其其中Ra是-OH,且R和Rb是-O-C(O)-NH-R30,R30选自上述优选的取代基,或者其中R和Ra分别是-OH,且Rb是-O-C(O)-NH-R30,其中R30是2-氟苯基、2,4-二氟苯基、2,6-二氯苯基;(2)Ra是-OH、卤素、叠氮基或(C1-C6)-烷氧基(C1-C6)烷氧基,Rb是H、卤素、叠氮基或(C1-C6)烷氧基(C1-C6)-烷氧基,且R是-O-C(O)-NH-R30,尤其其中Ra是-OH,Rb是H,且R30是2-氟苯基的化合物;(3)R、Ra和Rb独立地为-OH或-O-C(O)-R30,R30是(C1-C6)烷基、T或被一个或两个卤素或(C1-C6)烷基取代的T,尤其其中R是-OH,且Ra和Rb是-O-C(O)R30,其中R30是2-呋喃基的化合物;和(4)R、Ra和Rb独立地为-OH或卤素。另外3类优选的化合物是定义如下的那些:其中C1’异头氧是β,其中C2’异头氧是β,和其中R基团是α。
R1优选选自:
和
其中Ac是乙酰基,且Ph是苯基。
有用的本发明化合物的一个实例由式X代表:
或式(X)化合物的可药用盐或溶剂化物,或式(X)化合物或式(X)化合物的盐或溶剂化物的前药,其中R1如上所定义。
更优选的化合物由式XI代表:
或式(XI)化合物的可药用盐或溶剂化物,或式(XI)化合物或式(XI)化合物的盐或溶剂化物的前药。
在另一个实施方案中,本发明提供了如上所述的组合物、药物组合物、治疗组合、药盒和治疗方法,其中包括:(a)第一个量的至少一种心血管药剂;和(b)第二个量的至少一种固醇吸收抑制剂或其可药用盐或溶剂化物,或者所述的固醇吸收抑制剂或固醇吸收抑制剂的盐或溶剂化物的前药;其中所述第一个量和第二个量一起在其总体上(不论是并行给药还是依次连续给药)构成了治疗或预防血管性疾病、糖尿病、肥胖症或降低哺乳动物血浆固醇浓度或水平的治疗有效量。合适的固醇吸收抑制剂包括取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物,例如在上文式I-XI中描述的任何化合物,取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物的异构体,取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物或取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物的异构体的盐或溶剂化物,或取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物或取代的氮杂环丁烷酮化合物或取代的β-内酰胺化合物的异构体、盐或溶剂化物的前药。其它有用的取代的氮杂环丁烷酮化合物包括N-磺酰基-2-氮杂环丁烷酮化合物,例如在U.S.专利4,983,597中公开的那些,和4-(2-氧代氮杂环丁烷-4-基)苯氧基链烷酸乙酯,例如在Ram等人,Indian J.Chem.Sect.B.29B,12(1990),p.1134-7中公开的那些,将这两篇文献引入本发明以作参考。
式I-XI化合物可通过已知方法制得,包括上述方法,并且例如WO93/02048中描述了其中-R1-Q-是亚烷基、亚链烯基或被杂原子间断的亚烷基、亚苯基或亚环烷基的化合物的制备;WO 94/17038中描述了其中Q是螺合基团的化合物的制备;WO 95/08532中描述了其中-R1-Q-是羟基-取代的亚烷基的化合物的制备;PCT/US95/03196中描述了其中-R1-Q-是经由-O-或-S(O)0-2-连接在Ar1上的羟基-取代的亚烷基的化合物;1995年6月5日提交的第08/463,619号U.S.申请描述了其中-R1-Q-是通过-S(O)0-2-连接在氮杂环丁烷酮环上的羟基-取代的亚烷基的化合物的制备。
固醇吸收抑制剂的日剂量为约0.1-约1000mg/天,优选为约0.25-约50mg/天,更优选为约10mg/天,每天分1次或2-4次施用。然而,确切剂量是由临床医师决定的,并取决于施用的化合物的效力、患者年龄、体重、健康状况和反应。
当施用的是上述化合物的可药用盐时,上述重量是指由该盐衍生出的酸同等物或碱同等物的重量。
在一个本发明实施方案中,组合物或治疗组合还可以包含一种或多种药理或治疗剂或药物例如下述胆固醇生物合成抑制剂和/或降脂剂。
用于本发明组合物、治疗组合和方法的胆固醇生物合成抑制剂的非限制性实例包括HMG CoA还原酶—胆固醇生物合成中的限速步骤—的竞争性抑制剂、角鲨烯合成酶抑制剂、角鲨烯环氧酶抑制剂及其混合物。合适的HMG CoA还原酶抑制剂的非限制性实例包括他汀类药物(statins)例如洛伐他汀(例如得自Merck&Co.的MEVACOR)、普伐他汀(例如得自Bristol Meyers Squibb的PRAVACHOL)、氟伐他汀、辛伐他汀(例如得自Merck&Co.的ZOCOR)、阿伐他汀(atorvastatin)、cerivastatin、rosuvastatin、rivastatin(7-(4-氟苯基)-2,6-二异丙基-5-甲氧基甲基吡啶-3-基)-3,5-二羟基-6-庚酸钠CI-981)和pitavastatin(例如Negma Kowa of Japan的NK-104);HMG CoA合成酶抑制剂例如L-659,699((E,E)-11-[3’R-(羟基-甲基)-4’-氧代-2’R-氧杂环丁烷基]-3,5,7R-三甲基-2,4-十一碳二烯酸);角鲨烯合成抑制剂例如squalestatin 1;和角鲨烯环氧酶抑制剂例如NB-598((E)-N-乙基-N-(6,6-二甲基-2-庚烯-4-炔基)-3-[(3,3’-联噻吩-5-基)甲氧基]苯-甲胺盐酸盐)和其它固醇生物合成抑制剂例如DMP-565。优选的HMG CoA还原酶抑制剂包括洛伐他汀、普伐他汀和辛伐他汀。最优选的HMG CoA还原酶抑制剂是辛伐他汀。
胆固醇生物合成抑制剂的总日剂量一般可以为约0.1-约160mg/天,优选为约0.2-约80mg/天,每天分1次或2-3次施用。
在另一个优选的实施方案中,组合物或治疗包括与一种或多种心血管药剂和一种或多种胆固醇生物合成抑制剂组合的式(II)化合物。胆固醇生物合成抑制剂优选包括一种或多种HMG CoA还原酶抑制剂例如洛伐他汀,普伐他汀和/或辛伐他汀。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的烟酸(尼克酸)和/或其衍生物。
本文所用的“烟酸衍生物”是指包含吡啶-3-甲酸结构或吡嗪-2-甲酸结构,包括酸形式、盐、酯、两性离子和互变异构体(如果能获得的话)的化合物。烟酸衍生物的实例包括烟酸戊四醇酯、烟呋糖酯和阿西莫司(5-甲基吡嗪-2-甲酸4-氧化物)。烟酸及其衍生物抑制VLDL及其代谢物LDL在肝脏中的生成,并提高HDL和apo A-1水平。合适的烟酸产品的一个实例是得自Kos的NIASPAN(烟酸缓释片剂)。
烟酸或其衍生物的总日剂量一般可以为约500-约10,000mg/天,优选为约1000-约8000mg/天,更优选为约3000-约6000mg/天,每天分1次或多次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的可降低LDL和HDL水平的一种或多种酰基CoA:胆固醇O-酰基转移酶(“ACAT”)抑制剂。ACAT是酯化过量细胞内胆固醇的酶,并且降低VLDL-胆固醇酯化产物—的合成以及含有apo B-100的脂蛋白的过度生成。
有用的ACAT抑制剂的非限制性实例包括avasimibe([[2,4,6-三(1-甲基乙基)苯基]乙酰基]氨基磺酸,2,6-二(1-甲基乙基)苯基酯,以前称为CI-1011)、HL-004、来西贝特(DuP-128)和CI-277082(N-(2,4-二氟苯基)-N-[[4-(2,2-二甲基丙基)苯基]甲基]-N-庚基脲)。参见P.Chang等人,“异常脂血症和动脉粥样硬化的目前、新的和将来的治疗”,Drugs 2000Jul;60(1);55-93,将其引入本发明以作参考。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的可降低LDL水平的普罗布考或其衍生物(例如AGI-1067以及在U.S.专利6,121,319和6,147,250中公开的其它衍生物)。
普罗布考或其衍生物的总日剂量一般可以为约10-约2000mg/天,优选为约500-约1500mg/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的低密度脂蛋白(LDL)受体激活剂。合适的LDL-受体激活剂的非限制性实例包括HOE-402,这是一种直接刺激LDL受体活性的咪唑烷基嘧啶衍生物。参见M.Huettinger等人,“HOE-402的降血脂活性是通过刺激LDL受体途径来介导的”,Arterioscler.Thromb.1993;13:1005-12。
LDL受体激活剂的总日剂量一般可以为约1-约1000mg/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的鱼油,其含有ω3脂肪酸(3-PUFA),可降低VLDL和甘油三酯水平。鱼油或ω3脂肪酸的总日剂量一般可以为约1-约30克/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的可降低胆固醇水平的天然水溶性纤维例如欧车前(psyllium)、瓜尔胶、燕麦和果胶。天然水溶性纤维的总日剂量一般可以为约0.1-约10克/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的可降低胆固醇水平的植物甾醇、植物stanols和/或植物stanols的脂肪酸酯例如在BENECOL人造奶油中使用的sitostanol酯。植物甾醇、植物stanols和/或植物stanols的脂肪酸酯的总日剂量一般可以为约0.5-约20克/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的抗氧化剂例如普罗布考、生育酚、抗坏血酸、β-胡萝卜素和硒,或维生素例如维生素B6或维生素B12。抗氧化剂或维生素的总日剂量一般可以为约0.05-约10克/天,每天分一次或2-4次施用。
在另一个实施方案中,本发明组合物、治疗组合或方法还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的一种或多种胆汁酸螯合剂(不溶性阴离子交换树脂)。
胆汁酸螯合剂结合肠中的胆汁酸,中断胆汁酸的肠肝循环,并引起粪便中分泌的甾族化合物增多。由于其非全身作用方式,使用胆汁酸螯合剂是理想的。胆汁酸螯合剂可减少肝脏内胆固醇,并促进apo B/E(LDL)受体合成,而apo B/E(LDL)受体结合血浆中的LDL,从而进一步降低血液中的胆固醇水平。
合适的胆汁酸螯合剂的非限制性实例包括考来烯胺(能够结合胆汁酸的含有季铵阳离子的苯乙烯-二乙烯基苯共聚物,例如得自Bristol-Myers Squibb的QUESTRAN或QUESTRAN LIGHT考来烯胺)、考来替泊(二亚乙基三胺与1-氯-2,3-环氧丙烷的共聚物,例如得自Pharmacia的COLESTID片剂)、colesevelam盐酸盐(例如得自Sankyo的WetChol片剂(用环氧氨丙烷交联且用1-溴癸烷和(6-溴己基)三甲基溴化铵烷基化的聚(烯丙基胺盐酸盐))、水溶性衍生物例如3,3-ioene、N-(环烷基)烷基胺和聚氨葡糖、不溶性季铵化聚苯乙烯、皂甙及其混合物。其它有用的胆汁酸螯合剂公开在PCT专利申请WO 97/11345和WO 98/57652以及U.S.专利3,692,895和5,703,188中,将其引入本发明以作参考。合适的无机胆固醇螯合剂包括水杨酸铋加蒙脱石粘土、氢氧化铝和碳酸钙解酸剂。
胆汁酸螯合剂的总日剂量一般可以为约1-约50克/天,优选为约2-约16克/天,每天分一次或2-4次施用。
还可包含至少一种(一种或多种)过氧物酶体增殖子激活受体(PPAR)的激活剂的组合物或治疗组合也可用于本发明。这些激活剂起过氧物酶体增殖子激活受体的激动剂的作用。已经鉴定出了三种PPAR亚型,它们称为过氧物酶体增殖子激活受体α(PPARα)、过氧物酶体增殖子激活受体γ(PPARγ)和过氧物酶体增殖子激活受体δ(PPARδ)。应当注意,PPARδ在文献中还称为PPARβ和NUC1,这些名称都指相同的受体。
PPARα调控脂质的代谢。PPARα可由fibrates和多种中链和长链脂肪酸激活,并且参与刺激脂肪酸的β-氧化。PPARγ受体亚型参与激活脂肪细胞分化过程,并且不参与刺激肝脏中的过氧物酶体增殖。已经鉴定出PPARδ可用于提高人高密度脂蛋白(HDL)水平。参见例如WO97/28149。
除了别的作用以外,PPARα激活剂化合物可用于降低甘油三酯水平、中等程度地降低LDL水平和提高HDL水平。PPARα激活剂的有用实例包括上述fibrates。
可用于实施本发明的PPARα激活剂的其它实例包括:如在U.S.6,028,109中公开的合适的氟苯基化合物,将其引入本发明以作参考;如在WO 00/75103中公开的一些取代的苯基丙酸化合物,将其引入本发明以作参考;和如在WO 98/43081中公开的PPARα激活剂化合物,将其引入本发明以作参考。
合适的PPARγ激活剂的非限制性实例包括glitazones或噻唑烷二酮的衍生物例如曲格列酮(例如在商业上得自Parke Davis的REZULIN;曲格列酮(-5-[[4-[3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基]苯基]甲基]-2,4-噻唑烷二酮));rosiglitazone(例如在商业上得自SmithKline Beecham的AVANDIArosiglitazone马来酸盐(-5-[[4-[2-(甲基-2-吡啶基氨基)乙氧基]苯基]甲基]-2,4-噻唑烷二酮,(Z)-2-丁烯二酸盐)(1∶1))和吡格列酮(例如在商业上得自TakedaPharmaceuticals的ACTOSTM吡格列酮盐酸盐(5-[[4-[2-(5-乙基-2-吡啶基)乙氧基]苯基]甲基]-2,4-]噻唑烷二酮一盐酸盐))。其它有用的噻唑烷二酮类药物包括环格列酮、恩格列酮、达格列酮和如在WO 98/05331中公开的BRL 49653,将其引入本发明以作参考;在WO 00/76488中公开的PPARγ激活剂化合物,将其引入本发明以作参考;和在U.S.专利5,994,554中公开的PPARγ激活剂化合物,将其引入本发明以作参考。
其它有用的PPARγ激活剂化合物包括如在U.S.专利5,859,051中公开的一些乙酰基苯酚化合物,将其引入本发明以作参考;如在WO99/20275中公开的一些喹啉苯基化合物,将其引入本发明以作参考;如在WO 99/38845中公开的芳基化合物,将其引入本发明以作参考;如在WO 00/63161中公开的一些1,4-二取代的苯基化合物;如在WO01/00579中公开的一些芳基化合物,将其引入本发明以作参考;如在WO 01/12612和WO 01/12187中公开的一些苯甲酸化合物,将其引入本发明以作参考;和如在WO 97/31907中公开的取代的4-羟基-苯基alconic acid化合物,将其引入本发明以作参考。
除了别的作用以外,PPARδ化合物可用于降低甘油三酯水平或增高HDL水平。PPARδ激活剂的非限制性实例包括合适的噻唑和噁唑衍生物例如在WO 01/00603中公开的C.A.S.登记号317318-32-4,将其引入本发明以作参考);如在WO 97/28149中公开的一些氟、氯或硫代苯氧基苯基乙酸化合物,将其引入本发明以作参考;如在U.S.专利5,093,365中公开的合适的非-β-可氧化的脂肪酸类似物,将其引入本发明以作参考;如在WO 99/04815中公开的PPARδ化合物,将其引入本发明以作参考。
此外,具有激活PPARα、PPARγ和PPARδ的各种组合的多个功能的化合物也可用于实施本发明。非限制性实例包括如在下列专利中公开的一些取代的芳基化合物:U.S.专利6,248,781;WO 00/23416;WO00/23415;WO 00/23425;WO 00/23445;WO 00/23451;和WO00/63153,所有这些专利都描述了有用的PPARα和/或PPARγ激活剂化合物,将它们引入本发明以作参考。有用的PPARα和/或PPARγ激活剂化合物的其它非限制性实例包括如在WO 97/25042中公开的激活剂化合物,将其引入本发明以作参考;如在WO 00/63190中公开的激活剂化合物,将其引入本发明以作参考;如在WO 01/21181中公开的激活剂化合物,将其引入本发明以作参考;如在WO 01/16120中公开的联芳-噁(噻)唑化合物,将其引入本发明以作参考;如在WO 00/63196和WO 00/63209中公开的化合物,将其引入本发明以作参考;如在U.S.专利6,008,237中公开的取代的5-芳基-2,4-噻唑烷二酮化合物,将其引入本发明以作参考;如在WO 00/78312和WO 00/78313G中公开的芳基噻唑烷二酮和芳基噁唑烷二酮化合物,将其引入本发明以作参考;如在WO 98/05331中公开的GW2331或(2-(4-[二氟苯基]-1-庚基脲基)乙基]苯氧基)-2-甲基丁酸化合物,将其引入本发明以作参考;如在U.S.专利6,166,049中公开的芳基化合物,将其引入本发明以作参考;如在WO01/17994中公开的噁唑化合物,将其引入本发明以作参考;和如在WO01/25225和WO 01/25226中公开的二硫杂环戊烷化合物,将其引入本发明以作参考。
其它有用的PPAR激活剂化合物包括如在WO 01/14349、WO01/14350和WO/01/04351中公开的取代的苄基噻唑烷-2,4-二酮化合物,将其引入本发明以作参考;如在WO 00/50392中公开的巯基羧酸化合物,将其引入本发明以作参考;如在WO 00/53563中公开的壳二孢呋喃酮化合物,将其引入本发明以作参考;如在WO 99/46232中公开的羧酸化合物,将其引入本发明以作参考;如在WO 99/12534中公开的化合物,将其引入本发明以作参考;如在WO 99/15520中公开的苯化合物,将其引入本发明以作参考;如在WO 01/21578中公开的邻甲氧基苯甲酰胺化合物,将其引入本发明以作参考;和如在WO01/40192中公开的PPAR激活剂化合物,将其引入本发明以作参考。
将过氧物酶体增殖子激活受体激活剂以治疗有效量给药以治疗特定病症,例如以优选为约50-约3000mg/天、更优选为约50-约2000mg/天的日剂量施用,每天分一次或2-4次施用。然而,确切剂量是由临床医师决定的,并取决于诸如施用的化合物的效力、患者年龄、体重、健康状况和反应这样的因素。
本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的一种或多种回肠胆汁酸运输(“IBAT”)抑制剂(或顶点(apical)共同依赖于钠的胆汁酸运输(“ASBT”)抑制剂)。IBAT抑制剂可抑制胆汁酸运输,从而降低LDL胆固醇水平。合适的IBAT抑制剂的非限制性实例包括苯并硫杂环庚三烯化合物,例如在PCT专利申请WO 00/38727(将其引入本发明以作参考)中公开的包含2,3,4,5-四氢-1-苯并硫杂环庚三烯1,1-二氧化物结构的治疗化合物。
IBAT抑制剂的总日剂量一般可以为约0.01-约1000mg/天,优选为约0.1-约50mg/天,每天分一次或2-4次施用。
本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的一种或多种胆固醇酯转移蛋白(“CETP”)抑制剂。CETP的作用是携带HDL的胆固醇酯与VLDL中的甘油三酯的胆固醇酯的交换或转移。
合适的CETP抑制剂的非限制性实例公开在PCT专利申请WO00/38721和U.S.专利6,147,090中,将其引入本发明以作参考。胰腺胆固醇酯水解酶(pCEH)抑制剂例如WAY-121898也可以与上述过氧物酶体增殖子激活受体激活剂和固醇吸收抑制剂共同给药或联合给药。
CETP抑制剂的总日剂量一般可以为约0.01-约1000mg/天,优选为约0.5-约20mg/天,每天分一次或多次施用。
本发明组合物或治疗还可以包含与上述心血管药剂和固醇吸收抑制剂共同给药或联合给药的可降低LDL和HDL水平的普罗布考或其衍生物(例如AGI-1067以及在U.S.专利6,121,319和6,147,250中公开的其它衍生物)。
本发明组合物或治疗还可以包含单核细胞和巨噬细胞抑制剂例如多不饱和脂肪酸(PUFA),甲状腺激素,包括甲状腺素类似物例如CGS-26214(一种具有氟代环的甲状腺素化合物)、基因治疗和使用重组蛋白例如重组apo E。这些药剂的总日剂量一般可以为约0.01-约1000mg/天,每天分一次或2-4次施用。
还包含激素替代剂和组合物的组合物或治疗组合也可用于本发明。可用于本发明激素替代治疗的激素剂和组合物包括雄激素类、雌激素类、孕激素类、它们的可药用盐和衍生物。这些激素剂和组合物的组合也是可以使用的。
雄激素和雌激素的组合的剂量在约1mg-约4mg雄激素和约1mg-约3mg雌激素之间按照需要改变。实例包括但不限于雄激素和雌激素组合,例如以商品名Estratest得自Solvay Pharmaceuticals,Inc.,Marietta,GA的酯化雌激素(雌酮硫酸钠和马烯雌酮硫酸钠)与甲睾酮(17-羟基-17-甲基-,(17B)-雄烷-4-烯-3-酮)的组合。
雌激素和雌激素组合的剂量可以为约0.01mg至最高达8mg,理想地为约0.3mg-约3.0mg。有用的雌激素和雌激素组合的实例包括:
(a)九(9)种合成的雌激素物质的混合物,这9种雌激素物质包括雌酮硫酸钠、马烯雌酮硫酸钠、17α-二氢马烯雌酮硫酸钠、17α-雌二醇硫酸钠、17β-二氢马烯雌酮硫酸钠、17α-二氢马萘雌酮硫酸钠、17β-二氢马萘雌酮硫酸钠、马萘雌酮硫酸钠和17β-雌二醇硫酸钠;以商品名Cenestin得自Duramed Pharmaceuticals,Inc.,Cincinnati,OH;
(b)乙炔基雌二醇(19-去甲-17α-孕烷-1,3,5(10)-三烯-20-炔-3,17-二醇;以商品名Estinyl得自Schering Plough Corporation,Kenilworth,NJ;
(c)酯化雌激素组合例如雌酮硫酸钠与马烯雌酮硫酸钠;以商品名Estratab得自Solvay,以及以商品名Menest得自MonarchPharmaceuticals,Bristol,TN;
(d)estropipate(哌嗪雌烷-1,3,5(10)-三烯-17-酮,3-(磺基氧基)-雌酮硫酸盐);以商品名Ogen得自Pharmacia&Upjohn,Peapack,NJ,以及以商品名Ortho-Est得自Women First Health Care,Inc.,San Diego,CA;和
(e)结合型雌激素(17α-二氢马烯雌酮,17α-雌二醇,和17β-二氢马烯雌酮);以商品名Premarin得自Wyeth-Ayerst Pharmaceuticals,Philadelphia,PA。
也可以以不同剂量施用孕激素类和雌激素类,剂量一般为约0.05mg-约2.0mg孕激素与约0.001mg-约2mg雌激素,理想地为约0.1mg-约1mg孕激素和约0.01mg-约0.5mg雌激素。可在剂量和方案方面改变的孕激素与雌激素的组合的实例包括:
(a)雌二醇(雌烷-1,3,5(10)-三烯-3,17β-二醇半水合物)和炔诺酮(17β-乙酰氧基-19-去甲-17α-孕烷-4-烯-20-炔-3-酮)的组合;其以商品名Activella得自Pharmacia&Upjohn,Peapack,NJ;
(b)左炔诺孕酮(d(-)-13β-乙基-17α-乙炔基-17β-羟甾烷-4-烯-3-酮)和乙炔基雌二醇的组合;以商品名Alesse得自Wyeth-Ayerst,以商品名Levora和Trivora得自Watson Laboratories,Inc.,Corona,CA,以商品名Nordette得自Monarch Pharmaceuticals,和以商品名Triphasil得自Wyeth-Ayerst;
(c)双醋炔诺醇(19-去甲-17α-孕烷-4-烯-20-炔-3β,17-二醇二乙酸盐)和乙炔基雌二醇的组合;以商品名Demulen得自G.D.Searle&Co.,Chicago,IL,以商品名Zovia得自Watson;
(d)去氧孕烯(13-乙基-11-亚甲基-18,19-二去甲-17α-孕烷-4-烯-20-炔-17-醇)和乙炔基雌二醇的组合;以商品名Desogen和Mircette得自Organon,以商品名Ortho-Cept得自Ortho-McNeil Pharmaceutical,Raritan,NJ;
(e)炔诺酮与乙炔基雌二醇的组合;以商品名Estrostep和femhrt得自Parke-Davis,Morris Plains,NJ,以商品名Mierogestin、Necon和Tri-Norinyl得自Watson,以商品名Modicon和Ortho-Novum得自Ortho-McNeil,以商品名Ovcon得自Warner Chilcott Laboratories,Rockaway,NJ;
(f)炔诺孕酮((±)-13-乙基-17-羟基-18,19-二去甲-17α-孕烷-4-烯-20-炔-3-酮)和乙炔基雌二醇的组合;以商品名Ovral和Lo/Ovral得自Wyeth-Ayerst,和以商品名Ogestrel和Low-Ogestrel得自Watson;
(g)炔诺酮、乙炔基雌二醇和美雌醇(3-甲氧基-19-去甲-17α-孕烷-1,3,5(10)-三烯-20-炔-17-醇)的组合;以商品名Brevicon和Norinyl得自Watson;
(h)17β-雌二醇(雌烷-1,3,5(10)-三烯-3,17β-二醇)和微粉化诺孕酯(17α-17-(乙酰氧基)-13-乙基-18,19-二去甲-孕烷-4-烯-20-炔-3-酮3-肟)的组合;以商品名Ortho-Prefest得自Ortho-McNeil;
(i)诺孕酯(18,19-二去甲-17-孕烷-4-烯-20-炔-3-酮,17-(乙酰氧基)-13-乙基-,肟,(17(a)-(+)-)和乙炔基雌二醇;以商品名Ortho Cyclen和OrthoTri-Cyclen得自Ortho-McNeil;和
(j)结合型雌激素(雌酮硫酸钠和马烯雌酮硫酸钠)与醋酸甲羟孕酮(20-二酮,17-(乙酰氧基)-6-甲基-,(6(a))-孕烷-4-烯-3)的组合;以商品名Premphase和Prempro得自Wyeth-Ayerst。
一般情况下,如果施用微粉化的孕酮,孕激素的剂量可以为约0.05mg-约10mg或最高达约200mg。孕激素的实例包括炔诺酮;以商品名Aygestin得自ESI Lederle,Inc.,Philadelphia,PA,以商品名Micronor得自Ortho-McNeil,和以商品名Nor-QD得自Watson;炔诺孕酮;以商品名Ovrette得自Wyeth-Ayerst;微粉化的孕酮(孕烷-4-烯-3,20-二酮);以商品名Prometrium得自Solvay;和醋酸甲羟孕酮;以商品名Provera得自Pharmacia&Upjohn。
本发明的组合物、治疗组合或方法还可以包含一种或多种肥胖控制药物。有用的肥胖控制药物包括但不限于降低能量摄取或抑制食欲的药物,增加能量消耗的药物和营养分配剂。合适的肥胖控制药物包括但不限于去甲肾上腺素能剂(例如安非拉酮、马吲哚、苯丙醇胺、芬特明、苯甲曲秦、phendamine tartrate、脱氧麻黄碱、苯甲曲秦和酒石酸盐);血清素能剂(例如西布曲明、芬氟拉明、右芬氟拉明、氟西汀、氟伏沙明和帕罗西汀);生热剂(例如麻黄碱、咖啡因、茶碱和选择性β3-肾上腺素能激动剂);α-阻断剂;钾盐镁矾或AMPA受体拮抗剂;leptin-脂解刺激的受体;磷酸二酯酶抑制剂;具有桃花心木基因的核苷酸序列的化合物;成纤维细胞生长因子-10多肽;单胺氧化酶抑制剂(例如贝氟沙通、吗氯贝胺、溴法罗明、酚黄素、乙磺普隆、befol、托洛沙酮、吡吲哚、阿米夫胺、sercloremine、巴嗪普令、拉扎贝胺、米拉醋胺和卡罗沙酮);增加脂质代谢的化合物(例如吴茱更碱化合物);和脂肪酶抑制剂(例如奥利司他)。上述肥胖控制药物的总剂量一般可以为1-3,000mg/天,理想地为约1-1,000mg/天,更优选为约1-200mg/天,每天分一次或2-4次施用。
本发明的组合物、治疗组合或方法还可以包含一种或多种血液调节剂,所述血液调节剂在化学或结构上不同于上述的固醇吸收抑制剂(例如上述化合物(I-XI)和心血管药剂,例如,与上述固醇吸收抑制剂和心血管药剂相比,它们含有一个或多个不同的原子、具有不同的原子排列或者具有不同数目的一个或多个原子。各种血液调节剂包括但不限于抗凝血剂(阿加曲班、bivalirudin、达肝素钠、地西卢定、双香豆素、阿朴酸钠、甲磺酸萘莫司他、苯丙香豆素、亭扎肝素钠、华法林钠);抗血栓形成剂(盐酸阿那格雷、bivalirudin、西洛他唑、达肝素钠、danaparoid sodium、盐酸达唑氧苯、硫酸efegatran、依诺肝素钠、氟瑞托芬、ifetroban、ifetroban sodium、lamifiban、盐酸lotrafiban、napsagatran、乙酸orbofiban、乙酸roxifiban、sibrafiban、亭扎肝素钠、三苯格雷、阿昔单抗、阿佐莫单抗);血纤蛋白原受体拮抗剂(乙酸roxifiban、fradafiban、orbofiban、盐酸lotrafiban、tirofiban、xemilofiban、单克隆抗体7E3、sibrafiban);血小板抑制剂(西洛他唑、二硫酸氯吡格雷、依前列醇、依前列醇钠、盐酸噻氯吡啶、阿司匹林、布洛芬、萘普生、舒林酸、idomethacin、甲芬那酸、哚昔康、双氯芬酸、磺吡酮、吡罗昔康、双嘧达莫);血小板聚集抑制剂(阿卡地新、贝前列素、贝前列素钠、西前列烯钙、伊他格雷、利法利嗪、盐酸lotrafiban、乙酸orbofiban、氧格雷酯、fradafiban、orbofiban、tirofiban、xemilofiban);出血剂(己酮可可碱);脂蛋白结合凝固抑制剂;因子VIIa抑制剂(4H-3,1-苯并噁嗪-4-酮、4H-3,1-苯并噁嗪-4-硫酮、喹唑啉-4-酮、喹唑啉-4-硫酮、苯并噻嗪-4-酮、咪唑基-硼酸衍生的肽类似物、TFPI-衍生的肽、萘-2-磺酸{1-[3-(氨基亚氨基甲基)-苄基]-2-氧代-吡咯烷-3-(S)-基}酰胺三氟乙酸盐、二苯并呋喃-2-磺酸{1-[3-(氨基甲基)-苄基]-5-氧代-吡咯烷-3-基}-酰胺、甲苯-4-磺酸{1-[3-(氨基亚氨基甲基)-苄基]-2-氧代-吡咯烷-3-(S)-基}-酰胺三氟乙酸盐、3,4-二氢-1H-异喹啉-2-磺酸{1-[3-(氨基亚氨基甲基)-苄基]-2-氧代-吡咯啉-3-(S)-基}-酰胺三氟乙酸盐);因子Xa抑制剂(二取代的吡唑啉化合物、二取代的三唑啉化合物、取代的N-[(氨基甲基)苯基]丙基酰胺化合物、取代的N-[(氨基亚氨基甲基)苯基]丙基酰胺化合物、组织因子通道抑制剂(TFPI)、低分子量肝素、磺酸脂粘多糖、苯并咪唑啉化合物、苯并噁唑啉酮化合物、苯并哌嗪酮化合物、二氢茚酮化合物、二元(脒基芳基)丙酸衍生物、脒基苯基吡咯烷化合物、脒基苯基吡咯啉化合物、脒基苯基异噁唑烷化合物、脒基吲哚化合物、脒基唑类化合物、二芳基磺酰基氨基苯甲酰胺衍生物、肽类因子Xa抑制剂)。
本发明组合物、治疗组合或方法还可以包含一种或多种用于降低人中血糖水平的抗糖尿病剂。不同的抗糖尿病药物包括但不限于降低能量摄取或抑制食欲的药物,增加能量消耗的药物和营养分配剂。合适的抗糖尿病药物包括但不限于磺酰脲类(例如醋磺己脲、氯磺丙脲、格列胺脲、格列齐特、格列美脲、格列吡嗪、格列苯脲、优降糖、妥拉磺脲和甲苯磺丁脲)、meglitinide(例如瑞格列奈和nateglinide)、双胍类(例如甲福明和丁福明)、噻唑烷二酮类(例如曲格列酮、rosiglitazone、吡格列酮、环格列酮、恩格列酮和达格列酮)、α-糖苷酶抑制剂(例如阿卡波糖、米格列醇、卡格列波糖和伏格列波糖)、一些肽(例如amlintide、pramlintide、exendin和GLP-1激动性肽)和用于经肠递送的口服胰岛素或胰岛素组合物。上述抗糖尿病药物的总剂量可以为0.1-1,000mg/天,每天分一次或2-4次施用。
上述任何药理或治疗剂的混合物可用于本发明这些其它实施方案的组合物和治疗组合中。
本发明的组合物和治疗组合可以以治疗有效量施用给需要这样的治疗的哺乳动物,以治疗血管性疾病例如高血压。本发明组合物和治疗可通过使得这些化合物与体内作用位点例如哺乳动物或人血浆、肝脏或小肠内作用位点接触的任何适当手段来施用。
上述各种组合物和治疗组合的日剂量可按照需要作为一次剂量或分为多个亚剂量施用给患者。亚剂量每天可施用例如2-6次。可使用缓释剂型。当心血管药剂和固醇吸收抑制剂是在单独的剂型中施用时,每一组分在每天的给药次数可能无需相同,例如,一个组分可具有更长的活性持续时间,因此不需要太频繁地给药。
本发明治疗组合物和治疗组合还可以包含一种或多种可药用载体、一种或多种赋形剂和/或一种或多种添加剂。可药用载体的非限制性实例包括固体和/或液体例如乙醇、甘油、水等。载体在治疗组合物中的量可以为占治疗组合物或治疗组合总重量的约5%-约99%重量。合适的可药用赋形剂和添加剂的非限制性实例包括无毒相容的填充剂、粘合剂例如淀粉、崩解剂、缓冲剂、防腐剂、抗氧化剂、润滑剂、矫味剂、增稠剂、着色剂、乳化剂等。赋形剂或添加剂的量可以为占治疗组合物或治疗组合总重量的约0.1-约90%重量。本领域技术人员应当理解,载体、赋形剂和添加剂(如果存在的话)的量可以改变。
本发明治疗组合物可以以任何常规剂型,优选口服剂型例如胶囊、片剂、粉剂、扁囊剂、悬浮液或溶液的形式施用。制剂和药物组合物可用常规可药用技术制得。下面提供制备制剂的几个实例。
下列制剂举例说明了本发明的一些剂型。在每个制剂中,术语“活性化合物I”是指上述固醇吸收抑制剂,术语“活性化合物II”是指上述心血管药剂。
实施例
片剂
序号 组分 mg/片
1 活性化合物I 10
2 乳糖一水合物NF 55
3 微晶纤维素NF 20
4 聚维酮(K29-32)USP 4
5 交联羧甲基纤维素钠NF 8
6 十二烷基硫酸钠 2
7 硬脂酸镁NF 1
总共 100
在本发明中,可将上述片剂与含有一定剂量活性化合物II例如上述心血管药剂的片剂、胶囊等共同给药。
制备方法
将序号4组分在合适的混合器中与纯水混合以形成粘合剂溶液。在流化床加工器中将该粘合剂溶液和水依次喷雾到序号1、2、6组分和一部分序号5组分上以将各组分制粒。连续进行流化以将湿的颗粒干燥。将干燥后的颗粒过筛并与序号3组分和剩余的序号5组分混合。加入序号7组分并混合。在合适的压片机上将混合物压缩至合适的尺寸和重量。
对于在分开的片剂或胶囊中共同给药,包含固醇吸收抑制剂例如上述固醇吸收抑制剂的代表性制剂是本领域众所周知的,包含心血管药剂例如上述心血管药剂的代表性制剂是本领域众所周知的。可以理解,当两种活性组分是作为单一组合物给药时,可容易地使用本领域技术人员的知识对上面公开的关于固醇吸收抑制剂的剂型作改动。
因为本发明涉及通过用活性组分的组合治疗来降低血浆固醇(尤其是胆固醇)浓度或水平或治疗血管性疾病、中风或肥胖症,其中活性组分可分别给药,所以本发明还涉及将分别的药物组合物以药盒的形式组合起来。也就是说,本发明涉及药盒,其中组合了两个单独的单位:包含至少一种心血管药剂的药物组合物与包含至少一种如上所述的固醇吸收抑制剂的另一单独的药物组合物。药盒优选包括施用单独组分的说明书。当单独的组分必须以不同剂型(例如口服和非胃肠道给药剂型)给药或者以不同给药间隔施用时,药盒形式是特别有利的。
如下述实施例所示,本发明治疗组合物和治疗组合可抑制哺乳动物中胆固醇的肠吸收,并且可用于在哺乳动物、特别是人中治疗和/或预防血管性疾病例如血管炎症、动脉粥样硬化、高胆固醇血症和谷固醇血症、中风、肥胖症和降低血浆胆固醇水平。
在另一个本发明实施方案中,本发明组合物和治疗组合可抑制固醇吸收或降低至少一种选自下列的固醇的血浆浓度:植物甾醇(例如谷甾醇、菜油甾醇、豆甾醇和avenosterol)、5α-stanols(例如胆甾烷醇、5α-campestanol、5α-sitostanol)、胆固醇及其混合物。可通过给需要这样的治疗的哺乳动物施用有效量的包含至少一种上述心血管药剂和至少一种固醇吸收抑制剂的至少一种治疗组合物或治疗组合来降低血浆浓度。固醇血浆浓度的降低可以为约1-约70%、优选约10-约50%。测定血清总血液胆固醇和总LDL胆固醇的方法是本领域技术人员众所周知的,并且包括例如在PCT WO 99/38498第11页中描述的那些,将其引入本发明以作参考。测定血清中其它固醇的水平的方法公开在H.Gylling等人,“在轻度高胆固醇血症人群中在食用Stanol酯期间的血清固醇”,J.Lipid Res.40:593-600(1999),将其引入本发明以作参考。
下述实施例举例说明了本发明,然而,不应当认为其将本发明限制为它们的详细内容。除非另有说明,否则在下述实施例以及整个说明书中所有份数和百分比都是按重量计的。
实施例
制备式(II)化合物
步骤1):向(S)-4-苯基-2-噁唑烷二酮(41g,0.25mol)在CH2Cl2(200ml)内的溶液中加入4-二甲基氨基吡啶(2.5g,0.02mol)和三乙胺(84.7ml,0.61mol),并将该反应混合物冷却至0℃。用1小时滴加4-(氯甲酰基)丁酸甲酯(50g,0.3mol)在CH2Cl2(375ml)中的溶液,并将该反应温热至22℃。17小时后,加入水和H2SO4(2N,100ml),并分离各层,依次用NaOH(10%)、NaCl(饱和)和水洗涤有机层。用硫酸镁将有机层干燥,并浓缩,获得了半结晶产品。
步骤2):在0℃向TiCl4(18.2ml,0.165mol)在CH2Cl2(600ml)内的溶液中加入异丙醇钛(16.5ml,0.055mol)。15分钟后,加入步骤1产物(49.0g,0.17mol)在CH2Cl2(100ml)中的溶液。5分钟后,加入二异丙基乙胺(DIPEA)(65.2ml,0.37mol),将该反应混合物在0℃搅拌1小时,将该反应混合物冷却至-20℃,加入固体形式的4-苄氧基亚苄基(4-氟)苯胺(114.3g,0.37mol)。将该反应混合物在-20℃剧烈搅拌4小时,然后用15分钟滴加乙酸在CH2Cl2中的溶液,将该反应混合物温热至0℃,加入H2SO4(2N)。将该反应混合物再搅拌1小时,分离各层,用水洗涤,分离,将有机层干燥。将粗产物从乙醇/水中结晶,以获得纯的中间体。
步骤3):在50℃向步骤2产物(8.9g,14.9mmol)在甲苯(100ml)内的溶液中加入N,O-二(三甲基甲硅烷基)乙酰胺(BSA)(7.50ml,30.3mmol)。0.5小时后,加入固体TBAF(0.39g,1.5mmol),将该反应混合物在50℃再搅拌3小时。将该反应混合物冷却至22℃,加入CH3OH(10ml)。将该反应混合物用HCl(1N)、NaHCO3(1N)和NaCl(饱和)洗涤,用MgSO4干燥有机层。
步骤4):向步骤3产物(0.94g,2.2mmol)在CH3OH(3ml)内的溶液中加入水(1ml)和LiOH·H2O(102mg,2.4mmol)。将该反应混合物在22℃搅拌1小时,然后再加入LiOH·H2O(54mg,1.3mmol)。总共2小时后,加入HCl(1N)和EtOAc,分离各层,将有机层干燥,并真空浓缩。在22℃向所得产物(0.91g,2.2mmol)在CH2Cl2内的溶液中加入ClCOCOCl(0.29ml,3.3mmol),将该混合物搅拌16小时。将溶剂真空蒸发。
步骤5):在4℃向由4-氟苯基溴化镁(1M的THF溶液,4.4ml,4.4mmol)和ZnCl2(0.6g,4.4mmol)制得的4-氟苯基氯化锌(4.4mmol)的充分搅拌的悬浮液中加入四(三苯基膦)钯(0.25g,0.21mmol),然后加入步骤4产物(0.94g,2.2mmol)在THF(2ml)中的溶液。将该反应在0℃搅拌1小时,然后在22℃搅拌0.5小时。加入HCl(1N,5ml),用EtOAc萃取该混合物。将有机层浓缩至油状物,通过硅胶色谱纯化,获得了1-(4-氟苯基)-4(S)-(4-羟基苯基)-3(R)-(3-氧代-3-苯基丙基)-2-氮杂环丁烷酮:HRMS:C24H19F2NO3的计算值=408.1429,实测值为408.1411。
步骤6):向在THF(3ml)内的步骤5产物(0.95g,1.91mmol)中加入(R)-四氢-1-甲基-3,3-二苯基-1H,3H-吡咯并-[1,2-c][1,3,2]氧杂氮杂硼杂环戊二烯(oxazaborole)(120mg,0.43mmol),将该混合物冷却至-20℃。5分钟后,用0.5小时滴加氢硼化物-二甲基硫醚配合物(2M的THF溶液,0.85ml,1.7mmol)。总共1.5小时后,加入CH3OH,然后加入HCl(1N),用EtOAc萃取该混合物,获得了1-(4-氟苯基)-3(R)-[3(S)-(4-氟苯基)-3-羟基丙基)]-4(S)-[4-(苯基甲氧基)苯基]-2-氮杂环丁烷酮(化合物6A-1),为油状物。1H(CDCl3)d H3=4.68。J=2.3Hz。Cl(M+H)500。
使用(S)-四氢-1-甲基-3,3-二苯基-1H,3H-吡咯并-[1,2-c][1,3,2]氧杂氮杂硼杂环戊二烯,获得了相应的3(R)-羟基丙基氮杂环丁烷酮(化合物6B-1)。1H(CDCl3)d H3=4.69。J=2.3Hz。Cl(M+H)500。
向化合物6A-1(0.4g,0.8mmol)在乙醇(2ml)内的溶液中加入10%Pd/C(0.03g),将该反应混合物在一定压力(60psi)的氢气氛下搅拌16小时。将该反应混合物过滤,将溶剂浓缩,获得了化合物6A。Mp 164-166℃;Cl(M+H)410。[a]25 D=-28.1°(c3,CH3OH)。元素分析:C24H22F2NO3的计算值:C 70.41;H 5.17;N 3.42;实测值:C 70.25;H 5.19;N 3.54。
按照类似方法处理6B-1,获得了化合物6B。Mp 129.5-132.5℃;Cl(M+H)410。元素分析:C24H21F2NO3的计算值:C 70.41;H 5.17;N3.42;实测值:C 70.30;H 5.14;N 3.52。
步骤6′(供选择的):向步骤5产物(0.14g,0.3mmol)在乙醇(2ml)内的溶液中加入10%Pd/C(0.03g),将该反应混合物在一定压力(60psi)的氢气氛下搅拌16小时。将该反应混合物过滤,将溶剂浓缩,获得了化合物6A与6B的1∶1混合物。
本领域技术人员应当理解,在不背离本发明实质的情况下,可对上述实施方案作各种改变。因此应当理解,本发明不限于所公开的特定实施方案,而是包括在如通过权利要求书所限定的本发明实质和范围内的改变。
Claims (49)
1.组合物,其中包含:
(a)至少一种固醇吸收抑制剂或其可药用盐或溶剂化物,或者该至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和
(b)至少一种不同于上述组分(a)的用于治疗血管性疾病的心血管药剂。
2.权利要求1的组合物,其中至少一种固醇吸收抑制剂由式(I)代表:
或其异构体,或式(I)化合物或其异构体的可药用盐或溶剂化物,或式(I)化合物或其异构体、盐或溶剂化物的前药,
其中:
Ar1和Ar2独立地选自芳基和R4-取代的芳基;
Ar3是芳基或R5-取代的芳基;
X、Y和Z独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
R和R2独立地选自-OR6、-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7;
R1和R3独立地选自氢、低级烷基和芳基;
q是0或1;
r是0或1;
m、n和p独立地选自0、1、2、3或4;条件是:q和r当中至少有一个是1,且m、n、p、q和r的总和为1、2、3、4、5或6;以及条件是:当p是0,且r是1时,m、q和n的总和为1、2、3、4或5;
R4是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6、-CH=CH-COOR6、-CF3、-CN、-NO2和卤素;
R5是1-5个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6和-CH=CH-COOR6;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;
且
R9是低级烷基、芳基或芳基-取代的低级烷基。
3.权利要求2的组合物,其中所述固醇吸收抑制剂由下(II)代表:
或其可药用盐或溶剂化物,或者式(II)化合物或其盐或溶剂化物的前药。
4.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(III)代表:
或其异构体,或式(III)化合物或其异构体的可药用盐或溶剂化物,或式(III)化合物或其异构体、盐或溶剂化物的前药,其中在上式(III)中:
Ar1是R3-取代的芳基;
Ar2是R4-取代的芳基;
Ar3是R5-取代的芳基;
Y和Z独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
A选自-O-、-S-、-S(O)-或-S(O)2-;
R1选自-OR6、-O(CO)R6、-O(CO)OR9和-O(CO)NR6R7;R2选自氢、
低级烷基和芳基;R1与R2一起是=O;
q是1、2或3;
p是0、1、2、3或4;
R5是1-3个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR9、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2-低级烷基、-NR6SO2-芳基、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2-烷基、S(O)0-2-芳基、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、邻位卤素、间位卤素、邻位低级烷基、间位低级烷基、-(低级亚烷基)-COOR6和-CH=CH-COOR6;
R3和R4独立地为1-3个独立地选自下列的取代基:R5、氢、对位低级烷基、芳基、-NO2、-CF3和对位卤素;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;
且
R9是低级烷基、芳基或芳基-取代的低级烷基。
5.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(IV)代表:
或其异构体,或式(IV)化合物或其异构体的可药用盐或溶剂化物,或式(IV)化合物或其异构体、盐或溶剂化物的前药,其中在上式(IV)中:
A选自R2-取代的杂环烷基、R2-取代的杂芳基、R2-取代的苯并稠合的杂环烷基和R2-取代的苯并稠合的杂芳基;
Ar1是芳基或R3-取代的芳基;
Ar2是芳基或R4-取代的芳基;
Q是一个键,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
且
R1选自:
-(CH2)q-,其中q是2-6,条件是:当Q形成螺合环时,q还可以是0或1;
-(CH2)e-G-(CH2)r-,其中G是-O-、-C(O)-、亚苯基、-NR8-或-S(O)0-2-,e是0-5,且r是0-5,条件是:e和r的总和是1-6;
-(C2-C6亚链烯基)-;和
-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1-5,且g是0-5,条件是:f和g的总和是1-6;
R5选自:
或
R6和R7独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R5与相邻的R6一起,或者R5与相邻的R7一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为0、1、2或3,条件是二者不能同时为0;条件是:当R6是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;条件是:当R7是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;条件是:当a是2或3时,R6可相同或不同;以及条件是:当b是2或3时,R7可相同或不同;
并且当Q是一个键时,R1还可以选自:
其中M是-O-、-S-、-S(O)-或-S(O)2-;
X、Y和Z独立地选自-CH2-、-CH(C1-C6烷基)-和-C(二-(C1-C6)烷基);
R10和R12独立地选自-OR14、-O(CO)R14、-O(CO)OR16和-O(CO)NR14R15;
R11和R13独立地选自氢、(C1-C6)烷基和芳基;或者R10与R11一起是=O,或者R12与R13一起是=O;
d是1、2或3;
h是0、1、2、3或4;
s是0或1;t是0或1;m、n和p独立地为0-4;条件是:s和t当中至少有一个是1,并且m、n、p、s和t的总和是1-6;条件是:当p是0,且t是1时,则m、s和n的总和为1-5;以及条件是,当p是0,且s是1时,m、t和n的总和为1-5;
v是0或1;
j和k独立地为1-5,条件是j、k和v的总和为1-5;
R2是1-3个选自下列的在环碳原子上的取代基:氢、(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C6)环烷基、(C3-C6)环烯基、R17-取代的芳基、R17-取代的苄基、R17-取代的苄氧基、R17-取代的芳氧基、卤素、-NR14R15、NR14R15(C1-C6亚烷基)-、NR14R15C(O)(C1-C6亚烷基)-、-NHC(O)R16、OH、C1-C6烷氧基、-OC(O)R16、-COR14、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、NO2、-S(O)0-2R16、-SO2NR14R15和-(C1-C6亚烷基)COOR14;当R2是在杂环烷基环上的取代基时,R2如上所定义,或者是=O或
并且,当R2是在可取代的环氮原子上的取代基时,其是氢、(C1-C6)烷基、芳基、(C1-C6)烷氧基、芳氧基、(C1-C6)烷基羰基、芳基羰基、羟基、-(CH2)1-6CONR18R18,
其中J是-O-、-NH-、-NR18-或-CH2-;
R3和R4独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR14、-O(CO)R14、-O(CO)OR16、-O(CH2)1-5OR14、-O(CO)NR14R15、-NR14R15、-NR14(CO)R15、-NR14(CO)OR16、-NR14(CO)NR15R19、-NR14SO2R16、-COOR14、-CONR14R15、-COR14、-SO2NR14R15、S(O)0-2R16、-O(CH2)1-10-COOR14、-O(CH2)1-10-CONR14R15、-(C1-C6亚烷基)-COOR14、-CH=CH-COOR14、-CF3、-CN、-NO2和卤素;
R8是氢、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R14或-COOR14;
R9和R17独立地为1-3个独立地选自下列的基团:氢、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR14R15、OH和卤素;
R14和R15独立地选自氢、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;
R16是(C1-C6)烷基、芳基或R17-取代的芳基;
R18是氢或(C1-C6)烷基;且
R19是氢、羟基或(C1-C6)烷氧基。
6.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(V)代表:
或其异构体,或式(V)化合物或其异构体的可药用盐或溶剂化物,或式(V)化合物或其异构体、盐或溶剂化物的前药,其中在上式(V)中:
Ar1是芳基、R10-取代的芳基或杂芳基;
Ar2是芳基或R4-取代的芳基;
Ar3是芳基或R5-取代的芳基;
X和Y独立地选自-CH2-、-CH(低级烷基)-和-C(二低级烷基)-;
R是-OR6、-O(CO)R6、-O(CO)OR9或-O(CO)NR6R7;R1是氢、低级烷基或芳基;或者R和R1一起是=O;
q是0或1;
r是0、1或2;
m和n独立地为0、1、2、3、4或5;条件是m、n和q的总和为1、2、3、4或5;
R4是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-(低级亚烷基)COOR6和-CH=CH-COOR6;R5是1-5个独立地选自下列的取代基:-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-CF3、-CN、-NO2、卤素、-(低级亚烷基)COOR6和-CH=CH-COOR6;
R6、R7和R8独立地选自氢、低级烷基、芳基和芳基-取代的低级烷基;
R9是低级烷基、芳基或芳基-取代的低级烷基;且
R10是1-5个独立地选自下列的取代基:低级烷基、-OR6、-O(CO)R6、-O(CO)OR9、-O(CH2)1-5OR6、-O(CO)NR6R7、-NR6R7、-NR6(CO)R7、-NR6(CO)OR9、-NR6(CO)NR7R8、-NR6SO2R9、-COOR6、-CONR6R7、-COR6、-SO2NR6R7、-S(O)0-2R9、-O(CH2)1-10-COOR6、-O(CH2)1-10CONR6R7、-CF3、-CN、-NO2和卤素。
7.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由下式(VI)代表:
或其异构体,或式(VI)化合物或其异构体的可药用盐或溶剂化物,或式(VI)化合物或其异构体、盐或溶剂化物的前药,其中:
R1是
R2和R3独立地选自:-CH2-、-CH(低级烷基)-、-C(二低级烷基)-、-CH=CH-和-C(低级烷基)=CH-;或者R1与相邻的R2一起,或者R1与相邻的R3一起形成-CH=CH-或-CH=C(低级烷基)-;
u和v独立地为0、1、2或3,条件是二者不能同时为0;条件是:当R2是-CH=CH-或-C(低级烷基)=CH-时,v是1;条件是:当R3是CH=CH-或-C(低级烷基)=CH-时,u是1;条件是:当v是2或3时,R2可相同或不同;以及条件是:当u是2或3时,R3可相同或不同;
R4选自B-(CH2)mC(O)-,其中m是0、1、2、3、4或5;
B-(CH2)q-,其中q是0、1、2、3、4、5或6;
B-(CH2)e-Z-(CH2)r-,其中Z是-O-、-C(O)-、亚苯基、-N(R8)-或-S(O)0-2-,e是0、1、2、3、4或5,且r是0、1、2、3、4或5,条件是e和r的总和为0、1、2、3、4、5或6;
B-(C2-C6亚链烯基)-;
B-(C4-C6亚链二烯基)-;
B-(CH2)r-Z-(C2-C6亚链烯基)-,其中Z如上所定义,并且其中t是0、1、2或3,条件是t与亚链烯基链中的碳原子数目的总和为2、3、4、5或6;
B-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1、2、3、4或5,且g是0、1、2、3、4或5,条件是f与g的总和是1、2、3、4、5或6;
B-(CH2)t-V-(C2-C6亚链烯基)-或B-(C2-C6亚链烯基)-V-(CH2)t-,其中V和t如上所定义,条件是t与亚链烯基链中的碳原子数目的总和为2、3、4、5或6;
B-(CH2)a-Z-(CH2)b-V-(CH2)d-,其中Z和V如上所定义,且a、b和d独立地为0、1、2、3、4、5或6,条件是a、b和d的总和为0、1、2、3、4、5或6;或T-(CH2)s-,其中T是具有3-6个碳原子的环烷基,且s是0、1、2、3、4、5或6;或者
R1和R4一起形成
B选自二氢茚基、茚基、萘基、四氢萘基、杂芳基或W-取代的杂芳基,其中杂芳基选自吡咯基、吡啶基、嘧啶基、吡嗪基、三嗪基、咪唑基、噻唑基、吡唑基、噻吩基、噁唑基和呋喃基,以及对于含氮杂芳基,其N-氧化物,或
对于在环碳原子上的取代,W是1-3个独立地选自下列的基团:低级烷基、羟基低级烷基、低级烷氧基、烷氧基烷基、烷氧基烷氧基、烷氧基羰基烷氧基、(低级烷氧基亚氨基)-低级烷基、低级烷二酰基、低级烷基低级烷二酰基、烯丙氧基、-CF3、-OCF3、苄基、R7-苄基、苄氧基、R7-苄氧基、苯氧基、R7-苯氧基、二氧杂环戊烷基、NO2、-N(R8)(R9)、N(R8)(R9)-低级亚烷基-、N(R8)(R9)-低级链烯氧基-、OH、卤素、-CN、-N3、-NHC(O)OR10、-NHC(O)R10、R11O2SNH-、(R11O2S)2N-、-S(O)2NH2、-S(O)0-2R8、叔丁基二甲基-甲硅烷氧基甲基、-C(O)R12、-COOR19、-CON(R8)(R9)、-CH=CHC(O)R12、-低级亚烷基-C(O)R12、R10C(O)(低级链烯氧基)-、N(R8)(R9)C(O)(低级链烯氧基)-和
当存在时,在取代的杂芳基环氮原子上的取代基选自低级烷基、低级烷氧基、-C(O)OR10、-C(O)R10、OH、N(R8)(R9)-低级亚烷基-、N(R8)(R9)-低级链烯氧基-、-S(O)2NH2和2-(三甲基甲硅烷基)-乙氧基甲基;
R7是1-3个独立地选自下列的基团:低级烷基、低级烷氧基、-COOH、NO2、-N(R8)(R9)、OH和卤素;
R8和R9独立地选自H或低级烷基;
R10选自低级烷基、苯基、R7-苯基、苄基或R7-苄基;
R11选自OH、低级烷基、苯基、苄基、R7-苯基或R7-苄基;
R12选自H、OH、烷氧基、苯氧基、苄氧基、
-N(R8)(R9)、低级烷基、苯基或R7-苯基;
R13选自-O-、-CH2-、-NH-、-N(低级烷基)-或-NC(O)R19;
R15、R16和R17独立地选自H和对W定义的基团;或者R15是氢,且
R16和R17与它们所连接的相邻碳原子一起形成二氧杂环戊烷基环;
R19是H、低级烷基、苯基或苯基低级烷基;且
R20和R21独立地选自苯基、W-取代的苯基、萘基、W-取代的萘基、二氢茚基、茚基、四氢萘基、苯并二氧杂环戊烯基、杂芳基、W-取代的杂芳基、苯并稠合的杂芳基、W-取代的苯并稠合的杂芳基和环丙基,其中杂芳基如上所定义。
8.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(VIIA)或(VIIB)代表:
和
或其异构体,或式(VIIA)或(VIIB)化合物或其异构体的可药用盐或溶剂化物,或式(VIIA)或(VIIB)化合物或其异构体、盐或溶剂化物的前药,其中在上式(VIIA)或(VIIB)中:
A是-CH=CH-、-C≡C-或-(CH2)p-,其中p是0、1或2;
B是
B’是
D是-(CH2)mC(O)-或-(CH2)q-,其中m是1、2、3或4,且q是2、3或4;
E是C10-C20烷基或-C(O)-(C9-C19)-烷基,其中烷基是直链或支链的,是饱和的或者含有一个或多个双键;
R是氢、饱和或含有一个或多个双键的直链或支链C1-C15烷基或B-(CH2)r-,其中r是0、1、2或3;
R1、R2、R3、R1’、R2,和R3,独立地选自氢、低级烷基、低级烷氧基、羧基、NO2、NH2、OH、卤素、低级烷基氨基、二低级烷基氨基、-NHC(O)OR5、R6O2SNH-和-S(O)2NH2;
R4是
其中n是0、1、2或3;
R5是低级烷基;且
R6是OH、低级烷基、苯基、苄基或取代的苯基,其中取代基是1-3个独立地选自下列的基团:低级烷基、低级烷氧基、羧基、NO2、NH2、OH、卤素、低级烷基氨基和二低级烷基氨基。
9.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(VIII)代表:
或其异构体,或式(VIII)化合物或其异构体的可药用盐或溶剂化物,或式(VIII)化合物或其异构体、盐或溶剂化物的前药,其中在上式(VIII)中:
R26是H或OG1;
G和G1独立地选自
和
条件是:当R26是H或OH时,G不是H;
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)-烷氧基或-W-R30;
W独立地选自-NH-C(O)-、-O-C(O)-、-O-C(O)-N(R31)-、-NH-C(O)-N(R31)-和-O-C(S)-N(R31)-;
R2和R6独立地选自H、(C1-C6)烷基、芳基和芳基(C1-C6)烷基;
R3、R4、R5、R7、R3a和R4a独立地选自H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)(C1-C6)烷基和-C(O)芳基;
R30选自R32-取代的T、R32-取代的-T-(C1-C6)烷基、R32-取代的-(C2-C4)链烯基、R32-取代的-(C1-C6)烷基、R32-取代的-(C3-C7)环烷基和R32-取代的-(C3-C7)环烷基(C1-C6)烷基;
R31选自H和(C1-C4)烷基;
T选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、苯并噻唑基、噻二唑基、吡唑基、咪唑基和吡啶基;
R32独立地选自1-3个独立地选自下列的取代基:卤素、(C1-C4)烷基、-OH、苯氧基、-CF3、-NO2、(C1-C4)烷氧基、亚甲二氧基、氧代基、(C1-C4)烷硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、-N(CH3)2、-C(O)-NH(C1-C4)烷基、-C(O)-N((C1-C4)烷基)2、-C(O)-(C1-C4)烷基、-C(O)-(C1-C4)烷氧基和吡咯烷基羰基;或者R32是共价键,并且R31、其所连接的氮与R32一起形成吡咯烷基、哌啶基、N-甲基-哌嗪基、二氢吲哚基或吗啉基,或者(C1-C4)烷氧基羰基-取代的吡咯烷基、哌啶基、N-甲基哌嗪基、二氢吲哚基或吗啉基;
Ar1是芳基或R10-取代的芳基;
Ar2是芳基或R11-取代的芳基;
Q是一个键,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
且
R1选自
-(CH2)q-,其中q是2-6,条件是:当Q形成螺环时,q还可以是0或1;
-(CH2)e-E-(CH2)r-,其中E是-O-、-C(O)-、亚苯基、-NR22-或-S(O)0-2-,e是0-5,且r是0-5,条件是e与r的总和是1-6;
-(C2-C6)亚链烯基-;和
-(CH2)f-V-(CH2)g-,其中V是C3-C6亚环烷基,f是1-5,且g是0-5,条件是f与g的总和是1-6;
R12是
R13和R14独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R12与相邻的R13一起,或R12与相邻的R14一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为0、1、2或3,条件是二者不能同时为0;
条件是:当R13是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;
条件是:当R14是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;
条件是:当a是2或3时,R13可相同或不同;以及
条件是:当b是2或3时,R14可相同或不同;
并且当Q是一个键时,R1还可以是:
或
M是-O-、-S-、-S(O)-或-S(O)2-;
X、Y和Z独立地选自-CH2-、-CH(C1-C6)烷基-和-C(二-(C1-C6)烷基);
R10和R11独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR19、-O(CO)R19、-O(CO)OR21、-O(CH2)1-5OR19、-O(CO)NR19R20、-NR19R20、-NR19(CO)R20、-NR19(CO)OR21、-NR19(CO)NR20R25、-NR19SO2R21、-COOR19、-CONR19R20、-COR19、-SO2NR19R20、S(O)0-2R21、-O(CH2)1-10-COOR19、-O(CH2)1-10CONR19R20、-(C1-C6亚烷基)-COOR19、-CH=CH-COOR19、-CF3、-CN、-NO2和卤素;
R15和R17独立地选自-OR19、-O(CO)R19、-O(CO)OR21和-O(CO)NR19R20;
R16和R18独立地选自H、(C1-C6)烷基和芳基;R15和R16一起是=O,或者R17和R18一起是=O;
d是1、2或3;
h是0、1、2、3或4;
s是0或1;t是0或1;m、n和p独立地为0-4;
条件是:s和t当中至少有一个是1,且m、n、p、s和t的总和是1-6;
条件是:当p是0,且t是1时,m、s和n的总和是1-5;以及条件是:当p是0,且s是1时,m、t和n的总和是1-5;
v是0或1;
j和k独立地为1-5,条件是j、k和v的总和是1-5;
并且当Q是一个键时,且R1是
时,Ar1还可以是吡啶基、异噁唑基、呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、噻唑基、吡嗪基、嘧啶基或哒嗪基;
R19和R20独立地选自H、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;
R21是(C1-C6)烷基、芳基或R24-取代的芳基;
R22是H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R19或-COOR19;
R23和R24独立地为1-3个独立地选自下列的基团:H、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR19R20、-OH和卤素;且
R25是H、-OH或(C1-C6)烷氧基。
10.权利要求1的组合物,其中所述的至少一种固醇吸收抑制剂由式(IX)代表:
或其异构体,或式(IX)化合物或其异构体的可药用盐或溶剂化物,或式(IX)化合物或其异构体、盐或溶剂化物的前药,其中在上式(IX)中:
R26选自:
a)OH;
b)OCH3;
c)氟和
d)氯;
R1选自
-SO3H;
天然和非天然氨基酸;
R、Ra和Rb独立地选自H、-OH、卤素、-NH2、叠氮基、(C1-C6)烷氧基(C1-C6)-烷氧基和-W-R30;
W独立地选自-NH-C(O)-、-O-C(O)-、-O-C(O)-N(R31)-、-NH-C(O)-N(R31)-和-O-C(S)-N(R31)-;
R2和R6独立地选自H、(C1-C6)烷基、芳基和芳基(C1-C6)烷基;
R3、R4、R5、R7、R3a和R4a独立地选自H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)(C1-C6)烷基和-C(O)芳基;
R30独立地选自R32-取代的T、R32-取代的-T-(C-C6)烷基、R32-取代的-(C2-C4)链烯基、R32-取代的-(C-C6)烷基、R32-取代的-(C3-C7)环烷基和R32-取代的(C3-C7)环烷基(C1-C6)烷基;
R31独立地选自H和(C1-C4)烷基;
T独立地选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、苯并噻唑基、噻二唑基、吡唑基、咪唑基和吡啶基;
R32独立地选自1-3个独立地选自下列的取代基:H、卤素、(C1-C4)烷基、-OH、苯氧基、-CF3、-NO2、(C1-C4)烷氧基、亚甲二氧基、氧代基、(C1-C4)烷硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、-N(CH3)2、-C(O)-NH(C1-C4)烷基、-C(O)-N((C1-C4)烷基)2、-C(O)(C1-C4)烷基、-C(O)-(C1-C4)烷氧基和吡咯烷基羰基;或者R32是共价键,并且R31、其所连接的氮原子和R32一起形成吡咯烷基、哌啶基、N-甲基-哌嗪基、二氢吲哚基或吗啉基,或(C1-C4)烷氧基羰基-取代的吡咯烷基、哌啶基、N-甲基哌嗪基、二氢吲哚基或吗啉基;
Ar1是芳基或R10-取代的芳基;吡啶基、异噁唑基、呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、噻唑基、吡嗪基、嘧啶基或哒嗪基;
Ar2是芳基或R11-取代的芳基;
Q是-(CH2)q-,其中q是2-6,或者与氮杂环丁烷酮的3-位环碳原子一起形成螺合基团
R12是
R13和R14独立地选自-CH2-、-CH(C1-C6烷基)-、-C(二-(C1-C6)烷基)、-CH=CH-和-C(C1-C6烷基)=CH-;或者R12与相邻的R13一起,或者R12与相邻的R14一起形成-CH=CH-或-CH=C(C1-C6烷基)-;
a和b独立地为0、1、2或3,条件是二者不能同时为0;条件是:当R13是-CH=CH-或-C(C1-C6烷基)=CH-时,a是1;条件是:当R14是-CH=CH-或-C(C1-C6烷基)=CH-时,b是1;条件是:当a是2或3时,R13可相同或不同;以及条件是:当b是2或3时,R14可相同或不同;R10和R11独立地选自1-3个独立地选自下列的取代基:(C1-C6)烷基、-OR19、-O(CO)R19、-O(CO)OR21、-O(CH2)1-5OR19、-O(CO)NR19R20、-NR19R20、-NR19(CO)R20、-NR19(CO)OR21、-NR19(CO)NR20R25、-NR19SO2R21、-COOR19、-CONR19R20、-COR19、-SO2NR19R20、S(O)0-2R21、-O(CH2)1-10-COOR19、-O(CH2)1-10CONR19R20、-(C1-C6亚烷基)-COOR19、-CH=CH-COOR19、-CF3、CN、-NO2和卤素;
R19和R20独立地选自H、(C1-C6)烷基、芳基和芳基-取代的(C1-C6)烷基;
R21是(C1-C6)烷基、芳基或R24-取代的芳基;
R22是H、(C1-C6)烷基、芳基(C1-C6)烷基、-C(O)R19或-COOR19;
R23和R24独立地为1-3个独立地选自下列的基团:H、(C1-C6)烷基、(C1-C6)烷氧基、-COOH、NO2、-NR19R20、-OH和卤素;且
R25是H、-OH或(C1-C6)烷氧基。
11.权利要求1的组合物,其中所述至少一种用于治疗血管性疾病的心血管药剂选自通道阻断剂、肾上腺素能阻断剂、肾上腺素能刺激剂、血管紧张素转化酶(ACE)抑制剂、抗高血压剂、血管紧张素II受体拮抗剂、抗心绞痛剂、冠状血管舒张剂、利尿剂及其组合。
12.权利要求11的组合物,其中所述至少一种心血管药剂是肾上腺素能阻断剂。
13.权利要求12的组合物,其中所述肾上腺素能阻断剂是选自下列的α-受体抑制剂:盐酸芬司匹利、盐酸拉贝洛尔、普罗克生、盐酸阿夫唑嗪及其组合。
14.权利要求12的组合物,其中所述肾上腺素能阻断剂是选自下列的β-受体抑制剂:醋丁洛尔、盐酸醋丁洛尔、盐酸阿普洛尔、阿替洛尔、盐酸布诺洛尔、盐酸卡替洛尔、盐酸塞利洛尔、盐酸塞他洛尔、盐酸环丙洛尔、盐酸右普萘洛尔、盐酸二醋洛尔、盐酸地来洛尔、盐酸艾司洛尔、盐酸己丙洛尔、硫酸fiestolol、盐酸拉贝洛尔、盐酸左倍他洛尔、盐酸左布诺洛尔、盐酸美他洛尔、美托洛尔、酒石酸美托洛尔、纳多洛尔、硫酸帕马洛尔、硫酸喷布洛尔、普拉洛尔、盐酸普萘洛尔、盐酸索他洛尔、噻吗洛尔、马来酸噻吗洛尔、盐酸替普洛尔、妥拉洛尔、比索洛尔、富马酸比索洛尔、萘必洛尔及其组合。
15.权利要求12的组合物,其中所述肾上腺素能阻断剂选自托西溴苄铵、甲磺双氢麦角胺、甲磺酸酚妥拉明、酒石酸索立哌汀、盐酸佐勒汀、卡维地洛、盐酸拉贝洛尔及其组合。
16.权利要求11的组合物,其中所述至少一种心血管药剂是钙通道阻断剂。
17.权利要求16的组合物,其中所述钙通道阻断剂选自马来酸克仑硫、苯磺酸氨氯地平、伊拉地平、尼莫地平、非洛地平、尼伐地平、硝苯地平、盐酸替鲁地平、盐酸地尔硫、贝磷地尔、盐酸维拉帕米、福司地尔及其组合。
18.权利要求11的组合物,其中所述至少一种心血管药剂是血管紧张素转化酶(ACE)抑制剂。
19.权利要求18的组合物,其中所述血管紧张素转化酶抑制剂选自盐酸贝那普利、贝那普利拉、卡托普利、盐酸地拉普利、福辛普利钠、赖苯普利、盐酸莫昔普利、喷托普利、培哚普利、盐酸喹那普利、喹普利拉、雷米普利、盐酸螺普利、螺普利拉、替普罗肽、马来酸依那普利、赖诺普利、佐芬普利钙、培哚普利erbumine及其组合。
20.权利要求11的组合物,其中所述至少一种心血管药剂是肾上腺素能刺激剂。
21.权利要求20的组合物,其中所述肾上腺素能刺激剂选自氯噻嗪与甲基多巴的组合产品、氢氯噻嗪与甲基多巴的组合产品、盐酸可乐定、可乐定、氯噻酮与盐酸可乐定的组合产品、胍法辛盐酸盐及其组合。
22.权利要求11的组合物,其中所述至少一种心血管药剂是抗高血压剂。
23.权利要求22的组合物,其中所述抗高血压剂选自阿尔噻嗪、苄噻嗪、卡托普利、卡维地洛、氯噻嗪钠、盐酸可乐定、环噻嗪、盐酸地拉普利、盐酸地来洛尔、甲磺酸多沙唑嗪、福辛普利钠、胍法辛盐酸盐、甲基多巴、琥珀酸美托洛尔、盐酸莫昔普利、马来酸莫那匹尔、盐酸培兰色林、盐酸酚苄明、盐酸哌唑嗪、普米洛尔、盐酸喹那普利、喹普利拉、雷米普利、盐酸特拉唑嗪、坎地沙坦、坎地沙坦cilexetil、替米沙坦、苯磺酸氨氯地平、马来酸氨氯地平、盐酸贝凡洛尔及其组合。
24.权利要求11的组合物,其中所述至少一种心血管药剂是血管紧张素II受体拮抗剂。
25.权利要求24的组合物,其中所述血管紧张素II受体拮抗剂选自坎地沙坦、依贝沙坦、洛沙坦钾、坎地沙坦cilexetil、替米沙坦及其组合。
26.权利要求11的组合物,其中所述至少一种心血管药剂是抗心绞痛剂。
27.权利要求26的组合物,其中所述抗心绞痛剂选自苯磺酸氨氯地平、马来酸氨氯地平、倍他洛尔盐酸盐、盐酸贝凡洛尔、盐酸布托丙茚、卡维地洛、马来酸桂哌酯、琥珀酸美托洛尔、吗多明、马来酸莫那匹尔、普米洛尔、盐酸雷诺嗪、托西芬、维拉帕米盐酸盐及其组合。
28.权利要求11的组合物,其中所述至少一种心血管药剂是冠状血管舒张剂。
29.权利要求28的组合物,其中所述冠状血管舒张剂选自福司地尔、盐酸氮氯嗪、盐酸卡波罗孟、氯硝甘油、盐酸地尔硫、双嘧达莫、盐氢普拉明、丁四硝酯、硝酸异山梨酯、单硝酸异山梨酯、利多氟嗪、盐酸米氟嗪、米克昔定、吗多明、尼可地尔、硝苯地平、尼索地平、硝酸甘油、氧烯洛尔盐酸盐、戊硝醇、马来酸哌克昔林、普尼拉明、丙帕硝酯、盐酸特罗地林、妥拉洛尔、维拉帕米及其组合。
30.权利要求11的组合物,其中所述至少一种心血管药剂是利尿剂。
31.权利要求30的组合物,其中所述利尿剂选自氢氯噻嗪与螺内酯的组合产品以及氢氯噻嗪与氨苯蝶啶的组合产品。
32.权利要求1的组合物,其中所述至少一种心血管药剂是盐酸拉贝洛尔。
33.权利要求1的组合物,其中用于治疗血管性疾病的至少一种心血管药剂是以约50-约3000毫克心血管药剂/天的量施用给哺乳动物。
34.权利要求1的组合物,其中至少一种固醇吸收抑制剂以约0.1-约1000毫克固醇吸收抑制剂/天的量施用给哺乳动物。
35.权利要求1的组合物,其中所述组合物还包含至少一种胆固醇生物合成抑制剂。
36.权利要求35的组合物,其中所述至少一种胆固醇生物合成抑制剂包括至少一种HMG CoA还原酶抑制剂。
37.权利要求36的组合物,其中至少一种HMG CoA还原酶抑制剂包括洛伐他汀、普伐他汀、氟伐他汀、辛伐他汀、阿伐他汀、rosuvastatin,rivastatin、cerivastatin及其混合物。
38.权利要求37的组合物,其中至少一种HMG CoA还原酶抑制剂包括辛伐他汀。
39.权利要求1的组合物,其中所述组合物还包含至少一种胆汁酸螯合剂。
40.权利要求1的组合物,其中所述组合物还包含至少一种酰基CoA:胆固醇O-酰基转移酶抑制剂。
41.权利要求1的组合物,其中所述组合物还包含普罗布考或其衍生物。
42.权利要求1的组合物,其中所述组合物还包含至少一种低密度脂蛋白受体激活剂。
43.权利要求1的组合物,其中所述组合物还包含至少一种ω3脂肪酸。
44.权利要求1的组合物,其中所述组合物还包含至少一种天然水溶性纤维。
45.权利要求1的组合物,其中所述组合物还包含至少一种抗氧化剂或维生素。
46.用于治疗或预防血管性疾病、肥胖症、糖尿病或降低哺乳动物血浆固醇浓度的药物组合物,其中包含治疗有效量的权利要求1的组合物与可药用载体。
47.治疗或预防血管性疾病、肥胖症、糖尿病或降低哺乳动物血浆固醇浓度的方法,包括给需要这样的治疗的哺乳动物施用下列组分的步骤:
(a)有效量的至少一种固醇吸收抑制剂或其可药用盐或溶剂化物,或者所述至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和
(b)有效量的至少一种不同于上述组分(a)的心血管药剂。
48.权利要求47的方法,其中所述血管性疾病是高脂血症。
49.治疗组合,其中包含:
(a)第一个量的至少一种固醇吸收抑制剂或其可药用盐或溶剂化物或所述至少一种固醇吸收抑制剂或其盐或溶剂化物的前药;和
(b)第二个量的至少一种不同于所述至少一种固醇吸收抑制剂的心血管药剂,
其中所述第一个量和第二个量一起构成治疗或预防血管性疾病、肥胖症、糖尿病或降低哺乳动物血浆固醇浓度的治疗有效量。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110141663A (zh) * | 2012-10-30 | 2019-08-20 | 法奈克斯公司 | 通过控制血糖水平用于治疗糖尿病及相关病症的组合物、方法以及用途 |
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