CN1124135C - 雷帕霉素衍生物在血管病和异种移植中的应用 - Google Patents
雷帕霉素衍生物在血管病和异种移植中的应用 Download PDFInfo
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- CN1124135C CN1124135C CN97193278A CN97193278A CN1124135C CN 1124135 C CN1124135 C CN 1124135C CN 97193278 A CN97193278 A CN 97193278A CN 97193278 A CN97193278 A CN 97193278A CN 1124135 C CN1124135 C CN 1124135C
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Abstract
利用权利要求中所定义的式I雷帕霉素衍生物来预防或治疗血管病和异种移植排斥现象。
Description
技术领域
本发明涉及一种新的用途,尤其是涉及游离型或可药用盐或配合物形式的雷帕霉素衍生物的新用途。
X为(H、H)或O;
Y为(H、OH)或O;
R1和R2独立地选自H、烷基、芳烷基、羟基烷基、二羟基烷基、羟基烷氧基羰基烷基、羟基烷基芳烷基、二羟基烷基芳烷基、酰氧基烷基、氨基烷基、烷基氨基烷基、烷氧基羰基氨基烷基、酰基氨基烷基、芳基磺酰氨基烷基、烯丙基、二羟基烷基烯丙基、二氧戊环基烯丙基、二烷基-二氧戊环基烷基、二(烷氧基羰基)-***基-烷基和羟基-烷氧基-烷基;其中“烷基”为C1-6支链或直链烷基;“芳基”为苯基或甲苯基;并且酰基为由羧酸衍生的基团;并且
R4为甲基或者
R4和R1一起形成C2-6烷基;
条件是R1和R2不都为氢;并且羟基烷氧基烷基不为羟基烷氧基甲基。
背景技术
在WO94/09010中公开了这些化合物,将该文献的内容特别是关于该化合物的内容引入本文供参考。
优选地,可以在R1或R2中存在的酰基为RaCO-,其中Ra为C1-6烷基、C2-6链烯基、C3-6环烷基、芳基、芳基C1-6烷基(其中芳基如上定义)或杂芳基,例如由含N、S或O作为杂原子并且不含或含1个或2个N作为另一个杂原子的5或6元杂环衍生的基团。例如,适宜的杂芳基包括吡啶基、吗啉代、哌嗪基和咪唑基。
该化合物的实例包括:
1、40-O-苄基-雷帕霉素
2、40-O-(4’-羟甲基)苄基-雷帕霉素
3、40-O-〔4’(1,2-二羟基乙基)〕苄基-雷帕霉素
4、40-O-烯丙基-雷帕霉素
5、40-O-〔3’(2,2-二甲基-1,3-二氧戊环-4(S)-基)-丙-2’-烯-1’-基〕-雷帕霉素
6、(2’E,4’S)-40-O-(4’,5’-二羟基戊-2’-烯-1’-基)-雷帕霉素
7、40-O-(2-羟基)乙氧基羰基甲基-雷帕霉素
8、40-O-(2-羟基)乙基-雷帕霉素
9、40-O-(3-羟基)丙基-雷帕霉素
10、40-O-(6-羟基)己基-雷帕霉素
11、40-O-〔2-(2-羟基)乙氧基〕乙基-雷帕霉素
12、40-O-〔(3S)-2,2-二甲基二氧戊环-3-基〕甲基-雷帕霉素
13、40-O-〔(2S)-2,3-二羟基丙-1-基〕-雷帕霉素
14、40-O-(2-乙酰氧基)乙基-雷帕霉素
15、40-O-(2-烟酰氧基)乙基-雷帕霉素
16、40-O-〔2-(N-吗啉代)乙酰氧基〕乙基-雷帕霉素
17、40-O-(2-N-咪唑基乙酰氧基)乙基-雷帕霉素
18、40-O-〔2-(N-甲基-N’-哌嗪基)乙酰氧基〕乙基-雷帕霉素
19、39-O-去甲基-39,40-O,O-亚乙基-雷帕霉素
20、(26R)-26-二氢-40-O-(2-羟基)乙基-雷帕霉素
21、28-O-甲基-雷帕霉素
22、40-O-(2-氨基乙基)-雷帕霉素
23、40-O-(2-乙酰氨基乙基)-雷帕霉素
24、40-O-(2-烟酰氨基乙基)-雷帕霉素
25、40-O-(2-(N-甲基-咪唑-2’-基甲酰氨基)乙基)-雷帕霉素
26、40-O-(2-乙氧基羰基氨基乙基)-雷帕霉素
27、40-O-(2-甲苯磺酰氨基乙基)-雷帕霉素
28、40-O-〔2-(4’,5’-二乙氧羰基-1’,2’,3’-***-1’-基)-乙基〕-雷帕霉素
优选的化合物是例如40-O-(2-羟基)乙基-雷帕霉素(以下称作化合物A)。
基于所观察到的活性,例如,WO94/09010中所描述的与macrophilin-12(也称作FK-506结合蛋白或FKBP-12)的结合,已发现式I化合物可在治疗急性同种移植物排斥中用作免疫抑制剂。
目前,正逐步进行肝、肾、肺和心脏的器官移植来用于治疗内脏器官的疾病。由于目前缺少可移植性同种移植物的人类供体,人们将注意力集中到用异种移植物进行移植的可能性上(种间移植)。在人类中,成功移植异种移植物的主要障碍之一是免疫学问题。
同种和异种移植中的另一个障碍是慢性排斥,因此,对于不可逆转的器官疾病来说,器官移植在临床上仍不是可行的解决办法。
表现为移植物逐渐且不可逆机能障碍的慢性排斥是器官移植失败的主要原因,在某些情况下,这种现象发生在手术一年以后。从移植存活时间可知,慢性排斥的临床问题是显而易见的;在移植后5年内,大约有一半的肾同种移植物失败,并且在心脏同种移植物的病人中可见到类似的情况。
慢性排斥可看作是多因素过程,其中不仅对移植物的免疫反应,而且移植器官的血管壁对损伤的反应(“对损伤的应答”反应)也起作用。最坏预后的慢性排斥是动脉硬化样改变,也称作移植物血管病、移植物脉管病、移植物动脉硬化、移植物冠状疾病等。该血管损伤的特点是平滑肌细胞的迁移和增殖,也许是受内皮细胞合成的生长因子等的影响。这导致内膜增生和增厚,平滑肌细胞肥大修复,并最终逐渐导致腔体消失(血管重建vascular remodelling)。这似乎也通过宿主抗体或抗原-抗体复合物等诱导的重复性内皮损伤来产生;也称作非免疫学因素如高血压、高血脂、高血胆固醇等所产生的作用。
慢性排斥似乎是无法抑制的和不可控制的,因为没有已知的有效的治疗或预防方法。因此,对有效地用于预防、控制或逆转慢性移植物血管病的治疗方法,一直存在着需求。
也一直存在对预防或治疗由血管手术如血管成形术诱导的内膜平滑肌细胞增殖和迁移引起的再狭窄或血管闭塞的需求。
发明内容
本发明现在意外地发现,式I化合物可抑制血管病如血管重建,尤其是可预防或对抗移植器官的慢性排斥。
根据本发明的具体发现,现提供:
1、一种预防或治疗患者新内膜增生和增厚的方法,它包括给予所述患者治疗有效量的式I化合物。
在一系列其它特定的或改变的实施方案中,本发明也提供:
2.1、一种预防或对抗移植器官或组织受体慢性排斥现象的方法,它包括给予所述受体治疗有效量的式I化合物。
2.2、一种预防或对抗移植器官或组织的受体移植物脉管病如移植物血管病、动脉硬化或动脉粥样硬化的方法,它包括给予所述受体治疗有效量的式I化合物。
慢性排斥现象是指由抗移植物的免疫反应和上述移植器官或组织血管壁的应答产生的状况。式I化合物可用于减轻慢性排斥现象或减轻由慢性排斥引起的疾病。
器官或组织移植可由同种或不同种供体移植给同种或不同种的受体。这些移植器官或组织的实例包括心、肝、肾、脾、肺、小肠和胰腺,或上述任何器官或组织的组合。
在其它实例中,本发明提供:
3、一种预防或治疗患者内膜平滑肌细胞增殖和迁移,例如血管损伤如血管成形术后再狭窄和/或血管闭塞的方法,它包括给予所述患者治疗有效量的式I化合物。
在其它实例中,本发明也提供:
4、一种预防或对抗移植器官或组织异种移植物受体急性或慢性排斥的方法,它包括给予所述受体治疗有效量的式I化合物。
例如,异种器官或组织移植物包括心、肝、肾、脾、肺、小肠、胰腺(全部或部分,例如胰岛)、皮肤或骨髓异种移植物。
或者,本发明也提供:
5、用于在上述1-4所定义的任何方法的式I化合物;或
6、式I化合物在制备用于在上述1-4所定义的任何方法的药物组合物中的应用;或
7、用于上述1-4所定义的任何方法的、含式I化合物和一种或多种可药用稀释剂或载体的药物组合物。
具体实施方式
例如,可在下文所描述动物试验中证明式I化合物在治疗上述疾病中的应用。A、慢性同种移植物的排斥
将雄性DA(RTIa)大鼠的肾正位移植给雄性Lewis(RT11)受体。所移植的动物总数为24只。从移植那天开始,将所有的动物用7.5mg/kg/天剂量的环孢菌素A治疗14天来预防急性细胞排斥。不进行对侧肾切除术。用不同剂量式I化合物治疗的试验组或空白组各含6只动物。
从移植后53-64天开始,受体动物口服69-72天式I化合物或安慰剂。在移植后的第14天,通过磁共振成像(MRI),用肾灌注测定法来评估动物的移植物(比较移植的肾和自身对侧的肾)。在移植后53-64天和在试验结束时重复进行。然后,将动物进行尸检。测定并通过统计学分析排斥参数如MRI评分、移植肾的相对灌注速度和肾同种移植物在细胞排斥和血管改变方面的组织学评分。在该鼠肾同种移植物模型中,给予0.5-2.5mg/kg剂量的式I化合物如化合物A使上述所有排斥参数减小。在该测定中,与安慰剂组动物比较,口服2.5mg/kg/天化合物A治疗的动物明显降低排斥的MRI评分、细胞排斥和血管改变的组织学评分并明显降低通过MRI测定的灌注速度。B、主动脉移植
在这种鼠主动脉移植模型中,移植物的同种(异体)反应不破坏移植物,但它引起类似于临床移植中慢性排斥的病理改变。这些包括向单核细胞(淋巴细胞、巨噬细胞、一些血浆细胞)外膜的浸润和内膜增厚。
将肾动脉分枝和尾肠系膜主动脉起始端之间、大约1cm长的供体主动脉从雄性DA(RT1a)鼠上取下来并正位移植到雄性Lewis(RT11)鼠上。移植后,每周记录体重。在尸检时,将移植物及移植物上下附带的受体主动脉部分取下来。将其用补加2%多聚甲醛和2.5%戊二醛的磷酸盐缓冲液离体灌注大约2分钟,然后通过在相同的溶液中浸没固定24小时,并在4%缓冲的***中固定。将移植物片以横断面和纵断面都是由移植的主动脉和受体自身的主动脉构成的方式包埋在石蜡中。将4μm厚的截面用苏木精-曙红、橡胶-von-Gieson染剂和高碘酸-Schiff试剂染色。除常规光学显微镜外,用聚焦激光扫描显微镜记录图象。各截面扫描4个区域,并在5个部位测定各区域的内膜和内膜+血管中层的厚度。在尸检时,将胸腺、脾、肝、肾、睾丸和精囊称重并进行组织学分析。
第一个试验包括4组,每组包含4只动物。一组进行同源移植(Lewis-Lewis),并且给予动物安慰剂微乳液;另一组含同种移植物,并且以给动物口服安慰剂微乳状液或2.5mg/kg/天剂量的微乳液中的式I化合物。在移植后的第7周终止试验。第二个试验包括4组,每组包含4只动物。在所有的试验组进行同种移植,并且口服安慰剂微乳液或以0.63,1.25,2.5或5.0mg/kg/天的剂量给予动物式I化合物的微乳液。在移植后的第11周终止试验。
在两组试验中,式I化合物,特别是化合物A明显地抑制移植物浸润和新内膜形成。C、血管成形术
在球囊导管损伤模型中进行血管成形术研究:基本上如Powell等所述(1989),在试验的当天进行球囊***术。在异氟醚麻醉下,将Fogarty2F导管通过颈外动脉***左颈总动脉中并充气(扩张≈10μlH2O)。将充气的球囊沿着颈总动脉抽动3次,后两次将球囊轻轻扭转以得到均一的脱内皮作用。然后将导管撤出,在颈外动脉结扎来防止出血并让动物苏醒。
将2组12只RoRo鼠(400g,大约24周大)用于研究中:一组为对照组,另一组为接受式I化合物组。小鼠在处理、试验和分析过程中是完全随机的。
在球囊损伤前3天(-3天)开始至研究结束,即球囊损伤后第14天(+14天),口服给予试验化合物(管饲法)。将鼠单个放置在笼中并任意进食和水。
然后将鼠用异氟醚麻醉,将灌注导管通过左室***并固定在主动脉弓,将抽吸套管***右室中。将动物在150mmHg灌注压下,开始用0.1M磷酸缓冲盐溶液(PBS,PH7.4)灌注1分钟,然后,用2.5%戊二醛磷酸盐缓冲液(PH7.4)灌注15分钟。在套管末端,灌注压为150mmHg(在颈动脉,≈100mmHg),在预试验中,通过将安装在压力转换器上的套管***颈外动脉进行测定。然后,将颈动脉切下,与周围组织分离并浸没在含7%蔗糖的0.1M二甲胂酸盐缓冲液(PH7.4)中并在4℃下孵育过夜。在下一天,室温下将颈动脉在0.05%KMnO4的0.1M二甲胂酸盐溶液中浸没并振摇1h。然后将组织在一系列分级乙醇中脱水:在75%乙醇中脱水2×10分钟,在85%乙醇中脱水2×10分钟,在95%乙醇中脱水3×10分钟和在100%乙醇中脱水3×10分钟。然后,按照产品说明,将脱水的颈动脉包埋在Technovit7100中。将包埋介质在干燥器中、在氩气下聚合过夜,因为发现氧抑制栓塞物适当***。
在旋转切片机上,用硬金属刀从各颈动脉的中截面上切1-2um厚的截面并用Giemsa染剂染色。由此从各颈动脉制备大约5个截面并依靠图象分析***(MCID、Toronto、加拿大)通过形态测定法评估血管中层、新内膜和腔的横截面。
在该测定中,当每天以0.5-2.5mg/kg的剂量给予时,式I化合物抑制肌内膜增殖。与对照组动物相比,接受化合物A的大鼠,其血管内膜增厚现象明显降低,例如,在0.5mg/kg下,新内膜形成的抑制作用为50%,在2.5mg/kg下,其抑制作用为75%。D、体内心脏异种移植(仓鼠-大鼠)
仓鼠-大鼠异种移植物组合是所谓难一致性(concordant)组合。大鼠没有足够量的抗仓鼠天然抗体来产生如一致性组合中所见到的立即的超急性排斥;然而,由未治疗受体的抗体和补体产生的排斥作用发生在第3-4天内。在组织学上可见血管破坏、红细胞渗出和外渗和多形核粒细胞流入;经常有出血和血栓形成迹象。一旦通过有效地抑制抗体合成或补体灭活来克服该排斥作用,那么细胞排斥作用可随后出现。在组织学上可见单核细胞,包括淋巴细胞、成淋巴细胞和巨噬细胞的流入和肌细胞实质的渗出。抑制细胞排斥需要的免疫抑制作用比抑制同种移植物排斥更强。先天性无胸腺(rnu/rnu)大鼠缺少活性(胸腺依赖性)细胞免疫***并且通常不能排斥同种移植物。该种动物用与胸腺功能正常的大鼠类似的方式在第3-4天内排斥仓鼠异种移植物,这表明(至少部分)大鼠的抗仓鼠抗体合成在不依赖胸腺的B-细胞反应后发生。在仓鼠异种移植中使用该种受体来评估由不依赖胸腺的抗体介导的排斥。
通过供体和受体主动脉之间的吻合术和供体右肺动脉和受体下腔静脉之间的吻合术,将叙利亚仓鼠的心脏异种移植到雄性Lewis(RT1’)鼠的腹部。每天通过触摸腹部监测移植物。通过心跳停止推断发生排斥反应。将动物每周称重一次。在本系列试验中,终点确定在第28天。将动物进行尸体解剖,取出移植物,称重并将胸腺、脾、肝、精囊和睾丸进行组织学评估。采血并处理得到血清用于测定溶细胞性抗仓鼠红细胞抗体和溶血性补体活性。
在该测定中,式I化合物,例如化合物A延长无胸腺和胸腺机能正常受体移植物的存活时间。
实施本发明方法所需要的每日剂量将根据例如,所使用的式I化合物、宿主、给药方式和所治疗疾病的严重性而改变。优选的每日剂量范围大约为0.25-25mg,作为单剂量或分次剂量。给病人的适宜的每日剂量例如为0.2-25mg p.o.,优选5-25mg p.o.。可通过任何常规途径给予式I化合物,特别是通过肠道途径给予,例如,以片剂、胶囊剂、可饮用溶液剂形式通过口服给予,通过鼻、肺(通过吸入)给予,或者,例如,以可注射溶液或悬浮液的形式通过非肠道给予。适宜的口服给药单位剂量形式包括大约0.05-12.5mg,通常1-10mg活性组分,例如化合物A和一种或多种可药用稀释剂或载体。
当用于预防或治疗上述慢性排斥或异种移植排斥时,式I化合物可以以单一活性组分或与免疫调节方案中的其它药物一起给予。例如,式I化合物可以与环孢菌素或子囊霉素或其免疫抑制类似物,例如环孢菌素A、环孢菌素G、FK-506等;皮质类甾醇;环磷酰胺;硫唑嘌呤;氨甲喋呤;brequinar;来氟米特;咪唑立宾;麦考酚酸;摩非梯尔(mofetil)麦考酚酸盐;15-脱氧精胍菌素,免疫抑制性单克隆抗体,例如白细胞受体的单克隆抗体,例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD45或CD58或其配位体;或其它免疫调节化合物,例如CTLA4Ig联合使用。
如果联合给予式I化合物和其它免疫抑制剂/免疫调节治疗剂来例如预防或治疗上述慢性排斥或异种移植排斥,那么联合给予免疫抑制剂或免疫调节化合物的剂量将依赖于所使用药物的类型,例如是甾类化合物还是环孢菌素,依赖于所使用的特定药物,依赖于所治疗的疾病等等。根据上文,本发明还进一步提供:
8、上述方法,它包括,例如同时或按先后顺序联合给予治疗有效量的式I化合物和第二种药物,所述第二种药物为如上所述的免疫抑制剂或免疫调节药物。制剂实施例:胶囊剂
乙醇 20.0mg
1,2-丙二醇 81.0mg
精制油 121.5mg
Cremophor RH40 202.5mg
化合物A 20.0mg
总量 500mg
在按照本发明应用中所需要的剂量下,式I化合物可以被很好地耐受。例如,在4周的毒性研究中,化合物A的NTEL为0.5mg/kg/天(大鼠)和1.5mg/kg/天(猴子)。
Claims (5)
1、40-O-(2-羟基乙基)雷帕霉素在制备预防或治疗新内膜增生和增厚的药物中的应用。
2、根据权利要求1的应用,所述药物用于预防或对抗移植器官或组织受体中慢性排斥现象。
3、根据权利要求1的应用,所述药物用于预防或治疗血管损伤后的再狭窄和/或血管闭塞。
4、根据权利要求1-3中任一项的应用,所述药物与麦考酚酸、摩非梯尔麦考酚酸盐、15-脱氧精胍菌素、CTLA4Ig或抗白细胞受体的单克隆抗体或其配位体联合使用。
5、根据权利要求4的应用,所述单克隆抗体为抗MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD45或CD58的单克隆抗体。
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AU2020226527A1 (en) | 2019-02-20 | 2021-10-14 | AI Therapeutics, Inc. | Topical rapamycin formulations and their use in treating facial angiofibromas and other skin disorders |
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US5747034A (en) * | 1992-07-09 | 1998-05-05 | Chiron Corporation | Methods and materials for the induction of T cell anergy |
US5283257A (en) * | 1992-07-10 | 1994-02-01 | The Board Of Trustees Of The Leland Stanford Junior University | Method of treating hyperproliferative vascular disease |
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US5362718A (en) * | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
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WO1996041807A1 (en) * | 1995-06-09 | 1996-12-27 | Novartis Ag | Rapamycin derivatives |
GB9606452D0 (en) * | 1996-03-27 | 1996-06-05 | Sandoz Ltd | Organic compounds |
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