CN1100539C - 抗真菌组合物 - Google Patents
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Abstract
本发明涉及一种组合物的用途及相应的药物组合物、制备方法和治疗方法,所述的组合物由角鲨烯环氧化酶抑制剂特比萘芬和一种唑类14α-甲基去甲酶抑制剂组成。
Description
本发明与人类真菌感染的治疗有关,涉及一类包含特比萘芬和一种唑类14α-甲基去甲基酶抑制剂(如唑类药物氟康唑和/或伊曲康唑)的抗真菌组合物,它可用于治疗由唑类药物抗性酵母菌株所引起的真菌感染。
虽然,真菌(尤其是念珠菌属)在健康人体的消化道中呈现为良性的共生物,但是它们在受害宿主中能引起广泛严重的疾病。此类真菌感染疾病明显在上升,在人类免疫性缺陷病毒(HIV)感染的患者中,口咽念珠菌病是最常见的真菌感染病。直到口服后可被生物利用的唑类真菌剂的利用,才有了治疗严重念珠菌属感染病的方法。酮康唑成为第一个可用的唑类抗真菌剂,并且很快发现它在处理慢性粘膜和皮肤念珠菌病有效。然而,这种药物使用不久,就有因长期使用酮康唑治疗引起酮康唑最低抑制浓度(MICs)升高而造成临床失败的报道。这种问题在随后氟康唑的使用变得更加突出,氟康唑是一种水溶性的三唑类化合物,口服后90%以上能被生物利用,它可广泛用于治疗很大范围内的念珠菌感染,尤其是,它广泛的用于治疗具有高度HIV感染和AIDS患者的口咽念珠菌病,虽然口咽念珠菌病通常对氟康唑很敏感,但要完全根除是很困难,并且在治疗完成后的几个月内易复发,正是这个原因,许多AIDS患者都要持续地或经过很长一段时间间隔地接受氟康唑治疗。
氟康唑已形成的抗性比其他唑类药物的抗性更大,并逐渐成为显著的临床问题,这已通过分离法,尤其是从大量抗性念珠菌菌株的AIDS患者的分离结果中得到证实(参见:如D.Law等,
J.Antimicrob.Chemother.34 1994 659-688)。
现已出人意外地发现,角鲨烯环氧化酶抑制剂特比萘芬和一种唑类14α-甲基去甲基酶抑制剂(如氟康唑和/或伊曲康唑)的组合物对唑类药物抗性真菌菌株具有活性。利用化合物的这种组合,可为治疗由唑类药物抗性真菌菌株引起的人类真菌感染提供了一种方法。
合适的唑类14α-甲基去甲基酶抑制剂尤其是咪唑和三唑类抗真菌剂。
优选的咪唑类抗真菌剂包括:克霉唑(
Arzneim.-Forsch.22[1972]280);咪康唑(
Arzneim.-forsch.21[1971]256);益康唑(
Arzneim.-Forsch.25[1975]224);异康唑(
Arzneim.-Forsch.29[1979]1344);噻康唑(trioconazole)(《抗微生物药剂化学治疗法》[
Antimicobial Agents Chemotherapy]15[1979]597-602);硫康唑(
Eumycetes and Mycosis23[1982]314-317);奥昔康唑(
Arzneim.-forsch.32[1982]17-24);氯康唑(《医学化学杂志》[
J.Med.Chem.]26(1983)768-770);联苯苄唑(
Arzneim.-Forsch.23[1982]517-524);布康唑(《医学化学杂志)》[
J.Med.Chem,]21[1978]840);芬替康唑(
Arzneim.-Forsch.31[1981]2127);齐诺康唑(《医学化学杂志》[
J.Med Chem.]26[1983]442-445);酮康唑(《医学化学杂志》[J.Med.Chem.]22[1979]1003-1005)。
优选的三唑类抗真菌剂包括:特康唑(《医学化学杂志》[J.Med.Chem.]26[1983]611-613);伊曲康唑(《抗微生物药剂和化学治疗法》[
Antimicrobial Agents and Chemotherapy]26[1984]5-9);唯必三唑(Vibunazole)(
Arzneim.-Forsch.33[1983]546);氟康唑(《抗微生物药剂和化学治疗法》[
Antimicrobial Agents and Chemotherapy]27[1985]815-818)和(R)(-)-α-(4-氯苯基)-α-(1-环丙基-1-甲基乙基)-1H-1,2,4-三唑-1-乙醇的游离形式或盐形式或金属配合物的形式(GB 2′161′483)。(在下文中将游离形式简称为“化合物A”)。
尤其优选的唑类药物是伊曲康唑和氟康唑。
抗真菌药物的组合物并不是都表现为协同或相加效果,拮抗效果在文献中也有报道,例如E.martin等在《抗微生物药剂和化学治疗法》[
Antimicrobial Agents and Chemotherapy]38[1994]1331-1338)就报道了氟康唑拮抗两性霉素B的抗念珠菌效果,在
Abstr.Ann.meeting soc. Microbiol.87[1987]392中报道过:特比萘芬和酮康唑在白色念珠菌上使用,抗真菌活性并没有提高。在
Eur.J.Clin.Mircobiol Infect.Dis.7[1988]732-735]中也提到特比萘芬在体外条件下与唑类药物似乎有拮抗作用。在Drugs Today 24[1988]705-715中也提及联合疗法,以及抗真菌药物的组合并不都表现协同或相加效果。
因此,抗真菌剂联合疗法的效果似乎极其不可预测。
这样,从理论上说,在两个不同步骤中抑制同一生物合成途径的药理活性成分的组合的效果通常期望比仅在同一步骤中作用于同一生物合成途径的组合的效果更好,并且例如特比萘芬和唑类药物(如氟康唑或伊曲康唑)的组合应该至少具有相加效果。非常出人意外的是,这样的组合物甚至在唑类药物抗性己经出现的情况下仍然有效,也就是说,在真菌菌株已对唑类药物产生抗性的情况下,协同效果仍然能够保持,具体原因还不清楚。
本发明的组合物包括唑类药物14α-甲基去甲基酶抑制剂(如氟康唑或伊曲康唑)和下式的芳甲胺角鲨烯环氧化酶抑制剂特比萘芬,所述组合物可用于治疗由唑类药物抗性真菌菌株引起的真菌感染,其中特比萘芬可以是游离碱式或酸加成盐形式(如盐酸盐形式)。
最优选的唑类药物是氟康唑。特比萘芬优选地是药物学上可接受的形式,尤其是盐酸盐形式。优选的真菌是酵母,如优选地是有念珠属菌,则更优选的是白色念珠菌属。由唑类药物抗性诱导的真菌病可以是体表的,也可是全身的,尤其是口咽的。上述真菌病对皮肤和粘膜都有害。
唑类药物抗性可能是一种交叉抗性,它与多种唑类药物有关。
本发明的抗真菌组合物是将式I的芳甲基胺与唑类药物14α-甲基去甲基酶抑制性抗真菌剂(如氟康唑或伊曲康唑)合并来制备。
本发明于是涉及一种包含如上定义的特比萘芬和唑类药物14α-甲基去甲基酶抑制剂(如氟康唑或伊曲康唑)的抗真菌组合物,用于治疗由唑类药物抗性真菌菌株引起的真菌感染,防止或控制有害唑类药物抗性诱导的真菌病。
本发明进一步涉及包含如上所述的特比萘芬和唑类药物14α-甲基去甲基酶抑制剂(如氟康唑或伊曲康唑)的抗真菌组合物在药剂制备中的应用,所述药剂用于治疗因唑类药物抗性真菌菌株引起的真菌感染,防止或控制有害的唑类药物抗性在受这种唑类药物抗性损害的患者中诱导的真菌病。
本发明进一步涉及如上定义的抗真菌组合物的制备方法,包括将如上定义的特比萘芬和唑类药物14α-甲基去甲基酶抑制性抗真菌剂(如氟康唑或伊曲康唑)合并。
本发明进一步涉及一种治疗因唑类药物抗性真菌菌株引起的唑类药物抗性真菌感染的治疗方法,用于防止或控制有害的唑类药物抗性诱导的真菌病,该方法包括给需要此治疗的患者施用用如上所述的治疗有效量的抗真菌组合物。
在本发明的抗真菌组合物中,唑类抗真菌剂与芳甲基胺抗真菌剂的重量比可在很大范围内变动,但优选范围在100∶1至1∶500之内,更优选的范围为25∶1至1∶125。通过将唑类抗真菌剂与芳甲基胺抗真菌剂特比萘芬按如上重量比进行混合,在治疗由唑类药物抗性真菌菌株引起的真菌病方面将会获得很好的效果,所述真菌尤其是酵母菌,例如念珠菌菌株中的白色念珠菌、Candida glabrata、克鲁斯氏念珠菌、热带念珠菌;隐球酵母菌株中的新型隐球酵母;或者发癣菌菌株如须发癣菌;尤其是念珠菌菌株又特别是白色念珠菌菌。
本发明的组合物可单独用于局部施药,也能在大范围内(通常重量百分比从0.1%至10%)与常用药剂载体混合制备成一种制剂。本发明组合物可以以片剂、胶囊或液体形式进行口服,也可以以皮下、肌内或静脉注射等非口服形式使用。因此,正常情况下该组合物是一个固定的组合,然而,各种活性剂也可以自由组合的形式(即单独例如以任何顺序依次)进行给药。
有益活性可通过体外条件下使用各种唑类药物抗性菌株来证实,这种测定实验可在96孔、平底的微型稀释板上铺上PRMI1640培养基进行,采用交错药物稀释法。特比萘芬(以盐酸盐形式)和唑类药物所采用的浓度范围在0.006μg/ml与100μg/ml之间,经过在37℃ 48小时的培养,最低杀菌浓度(MIC)即可确定。最低杀真菌浓度在药物处理细胞转移到无药物的培养基后24小时进行评价。用于MIC测定的终点可采用100%抑制作用(如表1和表4),也可采用(常常采用)80%抑制作用(如表2和表3)。
表1体外测定特比萘芬和氟康唑联合作用于对氟康唑产生抗性的白色念珠菌、C.glabrata、克鲁斯氏念珠菌和热带念珠菌的结果:
菌株 | 100%抑制的最低抑制浓度(μg/ml) | |||
单独作用 | 联合作用 | |||
特比萘芬 | 氟康唑 | 特比萘芬 | 氟康唑 | |
白色念珠菌 | >100 | >100 | 12.5 | 6.25 |
白色念珠菌 | >100 | >100 | 12.5 | 12.5 |
白色念珠菌 | >100 | >100 | 12.5 | 6.25 |
白色念珠菌 | >100 | >100 | 3.13 | 12.5 |
热带念珠菌 | >100 | >100 | >100 | >100 |
C.glabrata | >100 | >100 | 3.13 | 25.0 |
白色念珠菌 | >100 | >100 | 3.13 | 50.0 |
克鲁斯氏念珠菌 | >100 | 50.0 | 3.13 | 50.0 |
以氟康唑和特比萘芬单独作用真菌作对照,当特比萘芬和氟康唑联合作用于以上几种菌株时,除一种菌株外,其他菌株的真菌全部100%的被抑制。对其中四个菌株,两种药物中任何一个单独作用的效果都不如两种药物都低于100μg/ml的浓度下联合作用效果好。
表2体外测定特比萘芬和氟康唑联合作用于对氟康唑产生抗性的念珠菌分离菌的结果:
菌株 | 80%抑制的最低抑制浓度(μg/ul) | |||
单独作用 | 联合作用 | |||
氟康唑 | 特比萘芬 | 氟康唑 | 特比萘芬 | |
白色念珠菌 | >16 | >1 | 0.25 | 0.1 |
白色念珠菌 | >16 | >1 | 16 | 0.5 |
热带念珠菌 | >16 | >1 | >0.125 | 0.06 |
C.glabrata | >16 | >1 | 16 | 0.125 |
表3体外测定特比萘芬和伊曲康唑联合作用于对伊曲康唑产生抗性的念珠菌分离菌的结果
菌株 | 80%抑制的最低抑制浓度(μg/ul) | |||
单独作用 | 联合作用 | |||
伊曲康唑 | 特比萘芬 | 伊曲康唑 | 特比萘芬 | |
白色念珠菌 | >4 | >1 | ≤0.03 | 0.03 |
热带念珠菌 | >4 | >1 | ≤0.03 | 0.03 |
表4体外测定特比萘芬和化合物A联合作用于对氟康唑产生抗性的念珠菌分离菌的结果
菌株 | 100%抑制的最低抑制浓度(μg/ul) | |||
单独作用 | 联合作用 | |||
化合物A | 特比萘芬 | 化合物A | 特比萘芬 | |
白色念珠菌 | >100 | >100 | 0.4 | 3.13 |
白色念珠菌 | 100 | >100 | 0.4 | 3.13 |
白色念珠菌 | 100 | >100 | 1.56 | 3.13 |
白色念珠菌 | 100 | >100 | 0.8 | 3.13 |
表5唑类药物抗性真菌的概述,其中已发现特比萘芬和唑类药物的组合有活性并且已出现唑类药物抗性
真菌种类 | 唑类药物 | 表现出有活性的菌株比例 |
白色念珠菌 | 氟康唑 | 5/10 |
白色念珠菌 | 伊曲康唑 | 9/10 |
热带念珠菌 | 氟康唑 | 2/2 |
克鲁斯氏念珠菌 | 氟康唑 | 1/4 |
C.paratropicalis | 氟康唑 | 1/1 |
C.glabrata | 氟康唑 | 1/2 |
新型隐球酵母 | 氟康唑 | 3/10 |
白包念珠菌 | 化合物A | 4/4 |
Claims (4)
1.一种包含以游离碱或酸加成盐的形式存在的式I的特比萘芬和唑类药物14α-甲基去甲基酶抑制剂的抗真菌组合物在制备用于治疗因唑类药物抗性真菌菌株引起的真菌感染,防止或控制有害的唑类药物抗性在受这种唑类药物抗性损害的人类患者中诱导的真菌病的药物中的应用。
2.根据权利要求1的应用,其中特比萘芬以盐酸盐形式存在。
3.根据权利要求1的应用,其中唑类药物是氟康唑。
4.根据权利要求1的应用,其中唑类药物是(R)-(-)-α-(4-氯苯基)-α-(1-环丙基-1-甲基乙基)-1H-1,2,4,-三唑-1-乙醇,它是游离形式、盐或金属配合物形式。
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GB9509631.9 | 1995-05-12 | ||
GBGB9509631.9A GB9509631D0 (en) | 1995-05-12 | 1995-05-12 | Antifungal combination |
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CN1184427A CN1184427A (zh) | 1998-06-10 |
CN1100539C true CN1100539C (zh) | 2003-02-05 |
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US (1) | US5985906A (zh) |
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PT (1) | PT824350E (zh) |
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TW (1) | TW464492B (zh) |
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Families Citing this family (16)
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US6187757B1 (en) | 1995-06-07 | 2001-02-13 | Ariad Pharmaceuticals, Inc. | Regulation of biological events using novel compounds |
ATE264863T1 (de) * | 1999-08-24 | 2004-05-15 | Ariad Gene Therapeutics Inc | 28-epirapaloge |
US7067526B1 (en) | 1999-08-24 | 2006-06-27 | Ariad Gene Therapeutics, Inc. | 28-epirapalogs |
GB0001315D0 (en) * | 2000-01-20 | 2000-03-08 | Novartis Ag | Organic compounds |
GB0003932D0 (en) * | 2000-02-18 | 2000-04-12 | Novartis Ag | Pharmaceutical compositions |
US6673373B2 (en) | 2001-02-01 | 2004-01-06 | Carlsbad Technology Inc. | Antifungal formulation and the methods for manufacturing and using the same |
US7244703B2 (en) | 2001-06-22 | 2007-07-17 | Bentley Pharmaceuticals, Inc. | Pharmaceutical compositions and methods for peptide treatment |
DE60331367D1 (de) | 2002-12-30 | 2010-04-01 | Angiotech Int Ag | Wirkstofffreisetzung von schnell gelierender polymerzusammensetzung |
ES2348303T3 (es) | 2003-12-08 | 2010-12-02 | Cpex Pharmaceuticals, Inc. | Composiciones farmacauticas y procedimientos de tratamiento con insulina. |
US20060078580A1 (en) * | 2004-10-08 | 2006-04-13 | Mediquest Therapeutics, Inc. | Organo-gel formulations for therapeutic applications |
US7740875B2 (en) * | 2004-10-08 | 2010-06-22 | Mediquest Therapeutics, Inc. | Organo-gel formulations for therapeutic applications |
ZA200708530B (en) | 2005-04-07 | 2009-04-29 | Toyama Chemical Co Ltd | Pharmaceutical composition and method using antifungal agent in combination |
CN101522195B (zh) | 2006-10-06 | 2012-01-18 | 富山化学工业株式会社 | 含有苯基脒衍生物的药物组合物和该药物组合物与抗真菌剂的联合使用方法 |
EP2121572A2 (en) * | 2006-12-08 | 2009-11-25 | Auspex Pharmaceuticals Inc. | Preparation and utility of substituted allylamines |
CA2711765A1 (en) | 2008-01-11 | 2009-07-16 | Massachusetts Eye & Ear Infirmary | Conditional-stop dimerizable caspase transgenic animals |
CN105283553B (zh) | 2013-06-11 | 2021-06-25 | 克隆技术实验室有限公司 | 蛋白质富集的微泡及其制备和使用方法 |
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GB2197194A (en) * | 1986-09-29 | 1988-05-18 | Merck & Co Inc | Controlling mycotic infections |
JPH0338521A (ja) * | 1989-07-05 | 1991-02-19 | Maruho Kk | 抗真菌性組成物 |
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GB2099818A (en) * | 1981-06-06 | 1982-12-15 | Pfizer Ltd | Triazoles |
JP2581707B2 (ja) * | 1987-10-02 | 1997-02-12 | 科研製薬株式会社 | 抗真菌剤組成物 |
CA2016738A1 (en) * | 1989-06-08 | 1990-12-08 | Philippe Guerry | Substituted aminoalkylbenzene derivatives |
JPH0338522A (ja) * | 1989-07-05 | 1991-02-19 | Maruho Kk | 抗真菌性組成物 |
US5214046A (en) * | 1989-07-27 | 1993-05-25 | Hoffmann-La Roche Inc. | Substituted aminoalkoxybenzene anti-fungicidal compositions and use |
CA2020888A1 (en) * | 1989-07-27 | 1991-01-28 | Philippe Guerry | Substituted aminoalkoxybenzene derivatives |
CA2044533A1 (en) * | 1990-06-29 | 1991-12-30 | Philippe Guerry | Substituted aminoalkylbiphenyl derivatives |
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JP3038522U (ja) | 1996-12-05 | 1997-06-20 | 秀俊 筬 | カード型紙箱ポプリ |
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