CN1330660A - 环四肽化合物及其用途 - Google Patents
环四肽化合物及其用途 Download PDFInfo
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- CN1330660A CN1330660A CN99814383A CN99814383A CN1330660A CN 1330660 A CN1330660 A CN 1330660A CN 99814383 A CN99814383 A CN 99814383A CN 99814383 A CN99814383 A CN 99814383A CN 1330660 A CN1330660 A CN 1330660A
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
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Abstract
本发明描述了环四肽化合物及其用途。特别地,本发明描述了一种通过在营养培养基中培养产生WF27082的属于支顶孢属的菌株并从培养肉汤中回收所述化合物而生产所述化合物的方法;一种含有所述化合物作为活性组分和药物上可接受的基本上无毒性的载体或赋形剂的药物组合物;所述化合物作为药剂的用途;所述化合物在制备用于抑制组蛋白脱酰基酶的药剂中的用途;所述化合物在制备用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)、原虫感染、器官移植排斥、自身免疫病或肿瘤的药剂中的用途;组蛋白脱酰基酶抑制剂作为免疫抑制剂或抗肿瘤药的用途;以及组蛋白脱酰基酶抑制剂在制备用于治疗或预防器官移植排斥、自身免疫病或肿瘤的药剂中的用途。
Description
技术领域
本发明涉及一种用作药剂的环四肽化合物、涉及用于生产该化合物的方法并涉及含有该化合物的药物组合物。
背景技术
已知组蛋白脱酰基酶在调节基因表达的转录机中起主要作用,且组蛋白脱酰基酶抑制剂诱导组蛋白乙酰化过度并影响所述的基因表达。因此,将组蛋白脱酰基酶抑制剂用作由基因表达异常所导致的几种疾病的治疗剂或预防剂,所述的疾病诸如炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)、原虫感染等。
在这方面,可以用作抗肿瘤药的环四肽化合物公开在JP-A-196686中,但是在该公开文献中没有关于对组蛋白脱酰基酶的作用和对上述各种疾病的作用的记载。
发明公开内容
本发明涉及一种用作药剂的新型环四肽化合物WF27082,涉及该化合物的制备方法并涉及含有该化合物的药物组合物。
更具体地说,本发明涉及一种对组蛋白脱酰基酶活性具有有效抑制作用的环四肽化合物。
本发明的发明者还发现诸如WF27082这样的组蛋白脱酰基酶抑制剂具有有效的免疫抑制作用和有效的抗肿瘤作用。因此,将诸如WF27082这样的组蛋白脱酰基酶抑制剂用作免疫抑制剂和抗肿瘤药的活性组分并用作器官移植排斥、自身免疫病、肿瘤等的治疗剂或预防剂。
因此,本发明的一个目的是提供一种具有如上所述的生物活性的化合物。
本发明的另一个目的是提供一种用于生产WF27082的方法,该方法通过在营养培养基中发酵产生WF27082的属于支顶孢属(Acremonium)的菌株来完成。
本发明的另一个目的是提供一种含有WF27082作为活性组分的药物组合物。
本发明的另一个目的是提供诸如WF27082这样的组蛋白脱酰基酶抑制剂用于治疗或预防上述疾病的用途。
因此,本发明提供的技术方案如下。
其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基,条件是当R3是氢时,R2是乙基。
(2)一种上述(1)的WF27082化合物,其中R3是甲基,R2是乙基,R3是甲基且R4是羟基。
(3)一种属于支顶孢属的真菌菌株,它具有的保藏号为FERMBP-6539且它产生一种具有组蛋白脱酰基酶抑制活性的化合物。
(4)一种具有组蛋白脱酰基酶抑制活性的化合物,它通过在营养培养基中培养上述(3)的真菌菌株并从其培养肉汤中回收所述化合物来获得。
(5)一种用于生产上述(1)的WF27082化合物的方法,该方法包括在营养培养基中培养产生WF27082的属于支顶孢属的菌株并从其培养肉汤中回收所述化合物的步骤。
(6)上述(5)的方法,其中所述的产生WF27082的属于支顶孢属的菌株是上述(3)的真菌菌株。
(7)一种药物组合物,它含有上述(1)的WF27082化合物作为活性组分和药物上可接受的基本上无毒性的载体或赋形剂。
(8)一种用作药剂的上述(1)的化合物。
(9)一种用于生产具有组蛋白脱酰基酶抑制活性的化合物的方法,该方法包括在营养培养基中培养属于支顶孢属的真菌菌株并回收所述化合物的步骤,其中所述的真菌菌株可产生一种具有组蛋白脱酰基酶抑制活性的化合物。
(10)一种具有组蛋白脱酰基酶抑制活性的化合物,它通过在营养培养基中培养属于支顶孢属的真菌菌株并从其培养肉汤中回收所述化合物来获得,其中所述的属于支顶孢属的真菌菌株可产生一种具有组蛋白脱酰基酶抑制活性的化合物。
其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基。
(12)一种用于抑制组蛋白脱酰基酶的方法,该方法包括使用上述(11)中所用的化合物(I)的步骤。
(13)一种上述(11)中所用的化合物(I)在制备用于抑制组蛋白脱酰基酶的药剂中的用途。
(14)一种用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)、器官移植排斥或自身免疫病的药物组合物,它含有通式(I)的化合物作为活性组分,其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基。
(15)一种用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)或器官移植排斥、自身免疫病的方法,该方法包括对人或动物给予上述(14)中所用的化合物(I)的步骤。
(16)一种上述(14)中所用的化合物(I)在制备用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)、器官移植排斥或自身免疫病的药剂中的用途。
(17)一种用于治疗或预防原虫感染或肿瘤的方法,该方法包括对人和动物给予上述(1)中所用的化合物WF27082的步骤。
(18)一种上述(1)中所用的化合物WF27082在制备用于治疗或预防原虫感染或肿瘤的药剂中的用途。
(19)一种组蛋白脱酰基酶抑制剂作为免疫抑制剂或抗肿瘤药的用途。
(20)一种组蛋白脱酰基酶抑制剂在制备用于治疗或预防器官移植排斥、自身免疫病或肿瘤的药剂中的用途。
其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基。
其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基,条件是当R3是氢时,R2是乙基。
具有通式(I)的本发明化合物,其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基,条件是当R3是氢时,R2是乙基,也称作WF27082。
下面具体解释上述特定的定义及其优选的实施方案。
除非另有说明,本说明书中所用的术语“低级”指的是1-6个碳原子。
合适的羟基保护基可以包括:
1-(低级烷硫基)(低级)烷基诸如低级烷硫基甲基(例如甲硫基甲基、乙硫基甲基、丙硫基甲基、异丙硫基甲基、丁硫基甲基、异丁硫基甲基、己硫基甲基等)等,其中优选的可以是C1-C4烷硫基甲基且最优选的可以是甲硫基甲基;
三取代的甲硅烷基诸如三(低级)烷基甲硅烷基(例如三甲基甲硅烷基、三乙基甲硅烷基、三丁基甲硅烷基、叔丁基二甲基甲硅烷基、三叔丁基甲硅烷基等)、低级烷基-二芳基甲硅烷基(例如甲基-二苯基甲硅烷基、乙基-二苯基甲硅烷基、丙基-二苯基甲硅烷基、叔丁基-二苯基甲硅烷基等)等,其中优选的可以是三(C1-C4)烷基甲硅烷基和C1-C4烷基-二苯基甲硅烷基且最优选的可以是叔丁基-二甲基甲硅烷基和叔丁基-二苯基甲硅烷基;
酰基诸如脂族酰基、芳香族酰基和被芳香基取代的脂族酰基等,它们由羧酸和磺酸衍生。
脂族酰基可以包括可以带有一个或多个诸如羧基这样的合适的取代基的低级链烷酰基(例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、羧基乙酰基、羧基丙酰基、羧基丁酰基、羧基己酰基等)、可以带有一个或多个诸如低级烷基这样的合适的取代基的环(低级)烷氧基(低级)链烷酰基(例如环丙基氧基乙酰基、环丁基氧基丙酰基、环庚基氧基丁酰基、基氧基乙酰基、基氧基丙酰基、基氧基丁酰基、基氧基庚酰基、基氧基己酰基等)、樟脑磺酰基等。
芳香族酰基可以包括可以带有一个或多个诸如硝基这样的合适的取代基的芳酰基(例如苯甲酰基、甲苯酰基、二甲苯酰基、萘酰基、硝基苯基、二硝基苯基、硝基萘酰基等)、可以带有一个或多个诸如卤素这样的合适的取代基的芳基磺酰基(例如苯磺酰基、甲苯磺酰基、二甲苯磺酰基、萘磺酰基、氟苯磺酰基、氯苯磺酰基、溴苯磺酰基、碘苯磺酰基等)等。
被芳香基取代的脂族酰基可以包括可以带有一个或多个诸如低级烷氧基和三卤代(低级)烷基这样的合适的取代基的芳基(低级)链烷酰基(例如苯乙酰基、苯丙酰基、苯丁酰基、2-三氟甲基-2-甲氧基-2-苯乙酰基、2-乙基-2-三氟甲基-2-苯乙酰基、2-三氟甲基-2-丙氧基-2-苯乙酰基等)等。
当上述通式(I)的化合物具有立体异构体时,这类异构体也包括在本发明中。通式(I)的化合物可以成盐,它也包括在本发明中。例如,当分子中存在诸如氨基这样的碱性基团时,酸加成盐(例如与诸如盐酸、氢溴酸、硫酸等这样的无机酸形成的盐;与诸如甲磺酸、富马酸、马来酸、扁桃酸、柠檬酸、水杨酸等这样的有机酸形成的盐)是典型的;而当存在诸如羧基这样的酸性基团时,碱性盐(例如与诸如钠、钾、钙、镁、铝等这样的金属形成的盐;与诸如赖氨酸等这样的氨基酸形成的盐)是典型的。此外,其溶剂化物诸如水合物、乙醇酸盐等也包括在本发明中。
在本说明书中,为了方便而使用下列特殊化合物的命名。化合物名称 R1 R2 R2 R4WF27082 B -CH3 -CH2CH3 -CH3 -OHWF27082 E -CH3 -CH2CH3 -H -OHWF27082 F -CH3 -CH3 -CH3 -OHFR235220 CH3 -CH3 -H -OH
WF27082 B具有下列物化特性:分子式:
C30H44N4O6分子量:
ESI-MS(+):m/z 557(M+H)+
ESI-MS(-):m/z 555(M-H)-比旋:
[α]D(23℃)-129℃(c=0.5,在氯仿中)紫外吸收光谱:
λmax(甲醇): 235(sh)
λmax(甲醇+0.01N HCl): 235(sh)
λmax(甲醇+0.01N NaOH):235(sh)溶解性:
可溶于:甲醇、氯仿、乙酸乙酯、二甲亚砜
不溶于:己烷显色反应:
阳性:硫酸铈反应、碘蒸气反应、德拉根道夫反应
阴性:茚三酮反应、氯化铁反应、莫里什氏反应、埃尔利希反应薄层色谱(TLC):
固定相 展开剂 Rf值
Silica Gel 60 氯仿∶甲醇 0.58
F254* (20∶1,v/v)
*由E.Merck制造高效液相色谱(HPLC):条件:
流动相:乙腈∶水=50∶50
柱:YMC ODS AM-303**(250mm长×4.6mm内径)
流速:1.0ml/分钟
检测:210nm处的UV检测
保留时间:10.2分钟
**由YMC Co.,Ltd.制造红外光谱:
vmax(净):3300、2960、2940、2880、1715、1680、1660、1630、1510、1440、1380、1250、1060cm-1 1H核磁共振光谱:
(500MHz,CDCl3)δH7.52(1H,d,J=10Hz,可互换),7.30-7.17(5H,m),7.17(1H,d,J=10Hz,
可互换),5.81(1H,s,可互换),5.16(1H,m),4.67(1H,m),4.26-4.16(2H,m),4.05(1H,dd,J=10&7.5Hz),3.56(1H,d,J=5Hz,可互换),3.24(1H,dd,J=13.5&10Hz),2.96(1H,dd,J=13.5&6Hz),2.73(1H,dd,J=10&8Hz),2.62(1H,m),2.54-2.29(4H,m),2.16(1H,m),1.82(1H,m),1.66-1.56(3H,m),1.38(3H,d,J=7Hz),1.41-1.27(5H,m),1.28(3H,s),0.88(3H,d,J=6.5Hz),0.84(3H,t,J-7Hz).13C核磁共振光谱:
(125 MHz,CDCl3)δC212.4(s),175.6(s),174.1(s),173.1(s),171.9(s),137.0(s),129.0(d)x2,128.6(d)x2,126.7(d),72.6(d),63.0(s),58.0(d),54.4(d),53.8(t),53.3(d),37.2(t),35.7(t),33.0(t),32.8(d),28.8(t),28.8(t),27.8(t),25.3(t),23.2(t),22.4(q),19.8(q),18.1(q),8.4(q).物质性质:
中性物质
WF27082 E具有下列物化特性:分子式:
C29H42N4O6分子量:
ESI-MS(+):m/z 543(M+H)+比旋:
[α]D(23℃)-137℃(c=0.2,在氯仿中)紫外吸收光谱:
λmax(甲醇):235(sh)
λmax(甲醇+0.01N HCl):235(sh)
λmax(甲醇+0.01N NaOH):235(sh)溶解性:
可溶于:甲醇、氯仿、乙酸乙酯、二甲亚砜显色反应:
阳性:硫酸铈反应、碘蒸气反应、德拉根道夫反应
阴性:茚三酮反应、氯化铁反应、莫里什氏反应、埃尔利希反应薄层色谱(TLC):
固定相 展开剂 Rf值
Silica Gel 60 氯仿∶甲醇 0.46
F254* (20∶1,v/v)
*由E.Merck制造高效液相色谱(HPLC):条件:
流动相:乙腈∶水=50∶50
柱:YMC ODS AM-303**(250mm长×4.6mm内径)
流速:1.0ml/分钟
检测:210nm处UV检测
保留时间:7.6分钟
**由YMC Co.,Ltd.制造红外光谱:
vmax(净):3300、2940、1720、1690、1660、1630、1530、1460、1420、1380、1320、1250、1150、1060cm-1 1H核磁共振光谱:
(500 MHz,CDCl3)δH7.54(1H,d,J=10Hz,可互换),7.29-7.17(5H,m),7.10(1H,d,J=10Hz,
可互换),5.82(1H,s,可互换),5.19(1H,m),4.67(1H,m),4.26-4.17(2H,m),3.85(1H,m),3.54(1H,br.s,可互换),3.30-3.20(2H,m),2.96(1H,dd,J=14&6Hz),2.54-2.38(2H,m),2.36-2.28(2H,m),2.18-2.12(2H,m),1.84-1.72(3H,m),1.67-1.57(3H,m),1.38(3H,d,J=7Hz),1.37-1.23(4H,m),1.28(3H,s),0.83(3H,t,J=7z)13C核磁共振光谱:
(125MHz,CDCl3)δC212.4(s),175.6(s),174.1(s),172.8(s),171.8(s),137.0(s),129.0(d)x2,128.6(d)x2,126.7(d),72.6(d),63.1(s),57.8(d),54.4(d),53.3(d),47.0(t),37.3(t),35.8(t),28.8(t),28.7(t),27.9(t),25.3(t),25.0(t),24.7(t),23.2(t),22.4(q),19.8(q),8.4(q).物质性质:
中性物质
WF27082 F具有下列物化特性:分子式:
C29H42N4O6分子量:
ESI-MS(+):m/z 543(M+H)+比旋:
[α]D(23℃)-114℃ (c=0.3,在氯仿中)紫外吸收光谱:
λmax(甲醇): 235(sh)
λmax(甲醇+0.01N HCl): 235(sh)
λmax(甲醇+0.01N NaOH):235(sh)溶解性:
可溶于:甲醇、氯仿、乙酸乙酯、二甲亚砜显色反应:
阳性:硫酸铈反应、碘蒸气反应、德拉根道夫反应
阴性:茚三酮反应、氯化铁反应、莫里什氏反应、埃尔利希反应薄层色谱(TLC):
固定相 展开剂 Rf值
Silica Gel 60 氯仿∶甲醇 0.47
F254* (20∶1,v/v)
*由E.Merck制造高效液相色谱(HPLC):条件:
流动相:乙腈∶水=50∶50
柱:YMC ODS AM-303**(250mm长×4.6mm内径)
流速:1.0ml/分钟
检测:210nm处UV检测
保留时间:7.6分钟
**由YMC Co.,Ltd.制造红外光谱:
vmax(净):3300、2930、1720、1690、1660、1630、1530、1440、1390、1280、1180、1120、1060cm-1 1H核磁共振光谱:
(500MHz,CDCl3)δH7.47(1H,d,J=10Hz,可互换),7.30-7.18(5H,m),7.17(1H,d,J=10Hz,
可互换),5.88(1H,s,可互换),5.14(1H,m),4.66(1H,m),4.26-4.14(2H,m),4.05(1H,dd,J=10&8Hz),3.54(1H,d,J=5Hz,可互换),3.27(1H,dd,J=14&10Hz),2.94(1H,dd,J=14&6Hz),2.70(1H,dd,J=10&8Hz),2.61(1H,m),2.53-2.35(3H,m),1.80(1H,m),1.78(3H,s),1.70-1.57(3H,m),1.40-1.25(5H,m),1.38 (3H,d,J=7Hz),1.34(3H,s),0.86(3H,d,J=7Hz)13C核磁共振光谱:
(125 MHz,CDCl3)δC212.4(s),175.6(s),174.3(s),173.0(s),171.9(s),137.0(s),129.0(d)x2,128.6(d)x2,126.7(d),72.6(d),58.8(s),57.9(d),54.3(d),53.9(t),53.5(d),37.3(t),35.7(t),33.0(t),32.8(d),28.8(t),28.7(t),26.5(q),25.2(t), 23.5(q),23.2(t),19.8(q),18.1(q).物质性质:
中性物质
如上所述根据上述物化特性和广泛研究,分别确定WF27082 B、E和F的化学结构。
通过在营养肉汤中培养产生WF27082的属于支顶孢属的菌株诸如支顶孢属27082号菌株且如果必要使用化学修饰(例如引入羟基保护基等)可以生产WF27082。
例如,通过将羟基保护基引入化合物(其中R4是羟基)可以制备其中R4是带有羟基保护基的羟基的WF27082。
在该反应中使用的羟基保护基的合适的引导剂可以是:一种常用的物质诸如二(低级)烷基亚砜,例如低级烷基甲基亚砜(例如二甲亚砜、乙基甲基亚砜、丙基甲基亚砜、异丙基甲基亚砜、丁基甲基亚砜、异丁基甲基亚砜、己基甲基亚砜等);三取代的甲硅烷基化合物诸如三(低级)烷基甲硅烷基卤(例如三甲基甲硅烷基氯、三乙基甲硅烷基溴、三丁基甲硅烷基氯、叔丁基二甲基甲硅烷基氯等);低级烷基-二芳基甲硅烷基卤(例如甲基-二苯基甲硅烷基氯、乙基-二苯基甲硅烷基溴、丙基-二甲苯基甲硅烷基氯、叔丁基-二苯基甲硅烷基氯等)和能够引入如上所述的酰基的诸如羧酸、磺酸及其反应衍生物例如酰基卤、酸酐、活性酰胺、活性酯等这样的酰化剂。这类反应衍生物的优选实例可以包括酰基氯;酰基溴;与诸如取代磷酸(例如二烷基磷酸、苯基磷酸、二苯基磷酸、二苄基磷酸、卤化磷酸等)这样的酸形成的混合酸酐;二烷基亚磷酸;亚硫酸;硫代硫酸;硫酸;碳酸烷基酯(例如碳酸甲酯、碳酸乙酯、碳酸丙酯等);脂族羧酸(例如新戊酸、戊酸、异戊酸、2-乙基丁酸、三氯乙酸、三氟乙酸等);芳香羧酸(例如苯甲酸等);一种对称酸酐;一种与含有亚氨基官能基的诸如咪唑、4-取代咪唑、二甲基吡唑、三唑和四唑这样的杂环化合物形成的活性酰胺;一种活性酯(例如对硝苯基酯、2,4-二硝苯基酯、三氯苯基酯、五氯苯基酯、甲磺酰基苯基酯、苯基苯偶氮基酯、苯基硫酯、对硝苯基硫酯、对甲苯基硫酯、羧甲基硫酯、吡啶基酯、哌啶基酯、8-喹啉基硫酯或与诸如N,N-二甲基羟基胺、1-羟基-2-(1H)-吡啶酮、N-羟基琥珀酰亚胺、N-羟基苯邻二甲酰亚胺、1-羟基苯并三唑、1-羟基-6-氯苯并三唑等这样的N-羟基化合物形成的酯)等。
在该反应中,就将二(低级)烷基亚砜用作羟基保护基的引导剂(introducing agent)的情况而言,该反应通常在有诸如乙酐这样的低级链烷酸酐存在的情况下进行。
此外,就将三取代甲硅烷基化合物用作羟基保护基的引导剂的情况而言,该反应优选在有诸如咪唑等这样的常用缩合剂存在的情况下进行。
此外,就将酰化剂用作羟基保护基的引导剂的情况而言,该反应优选在有下列物质存在的情况下进行:有机或无机碱诸如碱金属(例如锂、钠、钾等)、碱土金属(例如钙等)、碱金属氢化物(例如氢化钠等)、碱土金属氢化物(例如氢化钙等)、碱金属氢氧化物(例如氢氧化钠、氢氧化钾等)、碱金属碳酸盐(例如碳酸钠、碳酸钾等)、碱土金属碳酸氢盐(例如碳酸氢钠、碳酸氢钾等)、碱金属醇盐(例如甲醇钠、乙醇钠、叔丁醇钾等)、碱金属链烷酸盐(例如乙酸钠等)、三烷基胺(例如三乙胺等)、吡啶化合物(例如吡啶、卢剔啶、甲基吡啶、4-N,N-二甲氨基吡啶等)、喹啉等。
就在该反应中使用游离形式或其盐形式的酰化剂的情况而言,该反应优选在有下列常用缩合剂存在的情况下进行诸如:碳化二亚胺化合物[例如N,N’-二环己基碳化二亚胺、N-环己基-N’-(4-二乙氨基环己基)碳化二亚胺、N,N’-二乙基碳化二亚胺、N,N’-二异丙基碳化二亚胺、N-乙基-N’-(3-二甲氨基丙基)碳化二亚胺等];乙烯酮亚胺化合物(例如N,N’-羰基双(2-甲基咪唑)、五亚甲基乙烯酮-N-环己基亚胺、二苯基乙烯酮-N-环己基亚胺等);烯或炔醚化合物(例如乙氧基乙炔、β-环乙烯基乙基醚);N-羟基苯并三唑衍生物的磺酸酯[例如1-(4-氯苯磺酰氧基)-6-氯-1H-苯并三唑等]等。
该反应通常在不会对反应产生不利影响的常规溶剂中进行,诸如水、丙酮、二氯甲烷、醇(例如甲醇、乙醇等)、四氢呋喃、吡啶、N,N-二甲基甲酰胺等或其混合物;而另外就碱和羟基保护基的引导剂是液体的情况而言,也可以将它用作溶剂。
反应温度并不关键且该反应通常在冷却至加热的条件下进行。生产菌株27082的特征
真菌菌株27082号最初土壤样品分离、保藏在日本的Akita-shi,Akita-ken。该生物体在各种培养基上生长得极为有限并形成淡黄色至暗棕色菌落。该菌株产生由单纯瓶梗产孢细胞和粘液质头中的分生孢子组成的分生孢子结构,而它不在培养基上形成有性型。其真菌特征如下。
将各种琼脂培养基上的培养物特征概括在表1中。马铃薯右旋糖琼脂上的培养物生长得极为有限,在25℃下的4周后达到1.5-2.5cm直径。该菌落表面中心升高、起毛、呈放射状沟槽至皱纹状、有渗出物、黄褐色至灰棕色、而边缘处呈淡黄色。在培养基上没有观察到分生孢子结构。反色是暗棕色并产生棕色可溶性色素。在相同条件下玉米粉琼脂上的菌落以与马铃薯右旋糖琼脂上类似的速度发散。表面平坦、薄、粉状、中心呈橄榄色而边缘呈淡黄色。大量形成分生孢子结构。反色在中心呈暗棕色而边缘呈淡黄色至灰棕色,并观察到淡桔黄色可溶性色素。
根据Miura’s LCA平板(Miura,K.和M.Kudo:《日本真菌学协会学报》(Trans.Mycol.Soc.Japan)11:116-118,1970)上的培养物确定形态特征。分生孢子梗几乎不存在、微线形(micronematous)、短、贯基且有时是轮生的。产孢细胞是离散的、顶生、瓶梗且线形(nematogenous)至具绞旋线形(plectonematogenous)。它们是透明的、稍粗糙、刺状至尖锥状、带有模糊的领部、长21-40μm、顶端距至基底部从(1.5-)2-2.5μm减小至1-2(-2.5)μm且产生粘液滴形式的分生孢子。分生孢子开始是透明的、在成熟时逐渐变成深橄榄色、平滑、单细胞、宽椭圆体至椭圆体、有时呈梨形、顶端成环形、基底部上带有小突出物且大小为3.5-5(-6)×2.5-3(-3.5)μm。营养菌丝是透明的、平滑、有隔膜且有分支。菌丝细胞呈圆柱形、2-3μm宽。没有观察到厚壁孢子。
27082号菌株能够在2-26℃的温度范围内生长,在21-22℃下生长最佳。在马铃薯右旋糖琼脂(由NISSUI制造)上测定这些温度数据。
以与von Arx(J.A.von Arx:《真菌属-纯培养物中形成孢子》(The Genera of Fungi-Sporulating in Pure Culture)第3版315页,J.Cramer,Vaduz,1974)和Domsch等(K.H.Domsch,W.Gams和T.-H.Anderson:《土壤真菌概要》(Compendium of SoilFungi)第1卷859页,Academic Press,London,1980)的真菌分类标准相比较的形态特征为基础,将27082号菌株看作属于丝状菌属的Acremonium Link(1809)。因此,我们将这种分离物鉴定为支顶孢属的一种菌株并将其命名为支顶孢属27082号。已经将该菌株保藏在工业科学和技术部国立生命科学和人体技术研究所(NationalInstitute of Bioscience and Human-Technology,Agency ofIndustrial Science and Technology),1-3,Higashi 1-chome,Tsukuba-shi,Ibaraki-ken,305-8566,Japan,给予其保藏号为FERM BP-6539(保藏日:1998年10月2日)。表1.27082号菌株的培养物特征
培养基 培养物特征
麦芽汁琼脂* G:极为有限,1.5-2.5cm
S:环状、平坦、毡状至起毛状、形
成一定的分生孢子结构、中心呈橄榄
褐色(4D3-4E3)、边缘呈淡黄色
(6A2)或浅桔黄色(6B4-6B5)
R:中心成褐色(7E8)、边缘呈浅桔
黄色(5A3)马铃薯右旋糖琼脂(Difco G:极为有限,1.5-2.5cm
0013) S:环状、中心升高、起毛、呈发散
沟槽状至皱纹状、有渗出物、不形成
分生孢子结构、浅黄褐色(7C4)至
灰棕色(7D3)且边缘呈淡黄色(6A2)
R:深棕色(7F7-7F8)并产生棕色可
溶性色素
Czapek氏溶液琼脂* G:极为有限,1.5-2.5cm
S:环状至不规则状、平坦至中心升
高、边缘沉没、不形成分生孢子结
构、中心呈深棕色(7F6)或淡黄色
(6A2)、边缘呈浅黄色(4A2)且中
部呈棕色(6E6-6E8)
R:深棕色(6F5-6F7)且边缘呈浅黄
色(4A2)沙氏葡糖琼脂(Difco 0190) G:极为有限,1.5-2.0cm
S:环状、中心升高、毡状、呈发散
沟槽状至皱纹状、不形成分生孢子结
构、中心呈浅桔黄色(6B4-6B5)且
边缘呈浅棕色(6D6)至棕色(6E6)
R:棕色(7E7)至深棕色(7F7)并
产生棕色可溶性色素埃默森Yp Ss琼脂(Difco G:极为有限,1.5-2.5cm
0739) S:环状、平坦、毡状、有渗出物、
不形成分生孢子结构、浅黄色(5A2)
且边缘呈浅棕色(6D6-6D7)
R:浅棕色(6D7)至深棕色(6F7)玉米粉琼脂(Difco 0386) G:极为有限,1.5-2.5cm
S:环状、平坦、薄、粉状、形成大
量分生孢子结构、中心呈橄榄色
(3F5-3F6)且边缘呈淡黄色(6A2)
R:中心呈深棕色(7F7),边缘呈浅
桔黄色至浅棕色(5D3)并产生浅桔
黄色可溶性色素
MY20琼脂* G:极为有限,1.5-2.5cm
S:环状、中心升高、起毛至絮状、
呈发散沟槽状、不形成分生孢子结
构、中心呈浅桔黄色(6B4-6B6)且
边缘呈淡黄色(5A2)
R:浅棕色(6D7-6D8)且边缘呈浅桔
黄色(5A5)燕麦粉琼脂(Difco 0552) G:极为有限,1.5-2.5cm
S:环状、平坦、毡状至起毛、呈发
散沟槽状、形成一定的分生孢子结
构、中心呈暗绿色(30D4-30E4)、
边缘呈淡黄色(6A2)并产生浅棕色
可溶性色素
缩写G:生长,测定的以直径计的菌落大小;
S;菌落表面,R:反向。
*:麦芽汁琼脂、Czapek氏溶液琼脂和MY20琼脂的组成均以JCM菌株目录为基础(Nakase,T.,第6版617页,日本微生物保藏中心(Japan Collection of Microorganisms),物理和化学研究所(the Institute of Physical and Chemical Research),Saitama,1995)。
在25℃下培养28天后观察到了这些特征。颜色描述以《Methuen颜色手册》(Methuen Handbook of Colour)(Kornerup,A.和J.H. Wanscher第3版252页,Methuen,London,1978)为基础。
可以理解的是WF27082的生产并不限于本文所述的特定生物体的应用,它仅用于解释的目的。本发明还包括能够产生WF27082的所有突变体的应用,所述的突变体包括天然突变体和可以由所述生物体通过常规方法产生的人工突变体,所述的常规方法诸如重组DNA技术;X线照射;紫外线照射;用N-甲基-N’-硝基-N-亚硝基胍、2-氨基嘌呤处理等。WF27082的生产
在上述通式(I)的化合物中,当产生WF27082的属于支顶孢属的菌株在需氧条件下生长在含有可同化碳和氮源的营养培养基中时(例如摇合培养、浸没培养等),产生了WF27082。
在营养培养基中优选的碳源是诸如葡萄糖、蔗糖、淀粉、果糖或甘油等这样的碳水化合物。
优选的氮源是花生粉、酵母提取物、牛肉提取物、胨、聚胨、谷蛋白粉、棉子粉、大豆粉、大豆粗粉、玉米浆、干酵母、麦胚等以及诸如铵盐(例如硝酸铵、硫酸铵、磷酸铵等)、脲或氨基酸等这样的无机和有机氮化合物。
尽管以组合形式使用是有利的,但是并不要求使用纯形式的碳和氮源,因为含有微量生长因子和相当数量的矿物营养物的纯度较低的物质也适合使用。
如果需要,可以向培养基中加入无机盐诸如碳酸钠或碳酸钙、磷酸钠或磷酸钾、氯化钠或氯化钾、碘化钠或碘化钾、镁盐、铜盐、锌盐、铁盐或钴盐等。
如果必要,尤其是当培养基严重起泡时,可以加入消泡剂诸如液体石蜡、脂肪油、植物油、矿物油、硅氧烷等。
可以按照各种方式诸如通过螺旋桨或类似的机械搅拌设备进行搅拌、通过旋转或振摇发酵罐等来完成对培养混合物的搅拌和通气。
发酵过程通常在约10℃-40℃、优选20℃-30℃的温度下进行约50小时-150小时,它可以根据发酵条件和规模而改变。
然后为回收WF27082而使所得的培养肉汤进行用于回收和纯化生物活性物质所通常使用的各种步骤,例如用合适的溶剂或某些溶剂的混合物进行溶剂提取、层析或从合适的溶剂或其混合物中重结晶。
例如,可以按照JP-A-7-196686中所述的方法制备通式(I)化合物中的所述化合物,其中R1是甲基、R2是甲基、R3是氢且R4是羟基或被保护的羟基(例如FR235220)。通过如上所述制备WF27082并修饰其必要的部分也可以获得所述化合物。这种修饰方法可以按照本身公知的方法来进行。
WF27082可以是溶剂化物形式,它属于本发明的范围。该溶剂化物优选包括水合物和乙醇盐。
作为表现出上述通式(I)化合物的生物活性的实例,将某些生物数据列在下面。
试验1.对淋巴细胞种质遗传(blastogenesis)反应的作用
将WF27082和FR235220用作测试化合物。
在带有孔的微量滴定平板中进行淋巴细胞种质遗传试验,所述的各孔内的0.1ml RPMI-1640培养基中含有1×105个Balb/c小鼠的脾细胞,所述的培养基用10%胎牛血清(FBS)、50mM 2-巯基乙醇、青霉素(100个单位/ml)和链霉素(100μg/ml)进行了补充,向其中加入抗-CD3抗体(2C11)(1μm/ml)。在37℃下和5% CO2加湿气体中将细胞培养72小时。培养期后,通过MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓溴化物(MTT)]染料还原试验对淋巴细胞种质遗传中测试样品的抑制活性进行定量。
将WF27082 B溶于甲醇并进一步稀释入RPMI-1640培养基并加入到培养物中至终浓度为50ng/ml或50ng/ml以下。将WF235220溶于甲醇并进一步稀释入RPMI-1640培养基并加入到培养物中至终浓度为500ng/ml或500ng/ml以下。分别将结果列在表2和表3中。
正如表2和3中所示,WF27082 B和WF235220以一种剂量依赖性方式抑制由抗-CD3抗体诱导的鼠淋巴细胞种质遗传。发现WF27082B具有特别强的作用。表2 WF27082 B对由抗-CD3抗体诱导的鼠淋巴细胞种质遗传的作用浓度 50 25 12.5 6.3 3.1 1.6 0.8(ng/ml)抑制(%)113.5 114.1 111.7 86.6 46.1 19.3 4.4表3 FR235220对由抗-CD3抗体诱导的鼠淋巴细胞种质遗传的作用浓度 500 250 125 63 31 16 8 4(ng/ml)抑制(%)126.0 126.0 127.2 125.3 106.0 45.1 -1.3 -23.4试验2.WF27082 B对小鼠体内DTH(延缓型过敏性)反应的作用
通过皮下注射给雌性Balb/c小鼠免疫接种绵羊红细胞(1×108个)。从免疫接种前第1天开始将WF27082 B溶于10% HCO-60水溶液并口服连续给予8天。免疫接种后6天,将绵羊红细胞(1.25×108个)注入右后爪垫且在24小时后用刻度盘(Ozaki MFG CO.,Ltd.)测量爪垫的肿胀程度。将DTH的大小表示为受攻击的右爪垫与未处理的左爪垫的厚度之比。
正如表4中所示,爪垫的肿胀程度明显以剂量依赖性方式受到给予WF27082 B的抑制而没有任何体重减轻。表4.WF27082 B对小鼠体内DTH反应的作用
N 剂量 爪垫肿胀(抑制%) 体重增加(g)(mg/kg)未处理的 5 100*** 1.2±0.2预处理的 10 0 1.2±0.2WF27082 B 5 10 20 1.5±0.2
5 32 34** 1.5±0.3
5 100 47*** 1.1±0.3**:P<0.01 ***:P<0.001试验3.对部分纯化的人组蛋白脱酰基酶的作用
基本上如下所述按照Yoshida等提供的方法部分纯化人组蛋白脱酰基酶、制备[3H]乙酰基组蛋白并进行对组蛋白脱酰基酶活性的检测试验。
人脱酰基酶的部分纯化-从人T细胞白血病Jurkat细胞中部分纯化人脱酰基酶。将Jurkat细胞(5×108个细胞)悬浮于由15mM磷酸钾(pH7.5)、5%甘油和0.2mM EDTA组成的40ml HDA缓冲液中。在匀化后,通过离心(35,000×g,10分钟)收集细胞核并将其在20ml的用1M(NH4)2SO4补充的相同缓冲液中匀化。将粘性匀化物进行超声处理并通过离心(35,000×g,10分钟)使之澄清且通过将(NH4)2SO4的浓度升高至3.5M来沉淀脱酰基酶。将沉淀的蛋白质溶于10ml的HDA缓冲液并对4升的相同缓冲液进行透析。然后将透析液上用相同缓冲液平衡的DEAE-纤维素(Whatman DE52)柱(25×85mm)并用线性梯度(0-0.06M)的NaCl(300ml)洗脱。在0.3-0.4M NaCl之间洗脱组蛋白脱酰基酶活性的单峰级分。
[3H]乙酰基组蛋白的制备-为了获得[3H]乙酰基标记的组蛋白作为组蛋白脱酰基酶检测试验的底物,在37℃下、5%CO2-95%空气中和5μM丁酸钠存在的情况下,将75cm2烧瓶内用10%FBS、青霉素(50个单位/ml)和链霉素(50μg/ml)补充的20ml RPMI-1640培养基中的1×108个Jurkat细胞用300MBq[3H]乙酸钠培养30分钟、收集入离心管(50ml),通过以1000rpm离心10分钟收集并用磷酸缓冲盐水洗涤一次。将洗涤过的细胞悬浮于15ml的冰冷裂解缓冲液(10mMTris-HCl、50mM亚硫酸氢钠、1% Triton X-100、10mM MgCl2、8.6%蔗糖、pH 6.5)中。在杜恩斯匀化后(30个循环),通过以1000rpm离心10分钟收集细胞核、将其依次用15ml的裂解缓冲液洗涤3次并用15ml的冰冷洗涤缓冲液(10mM Tris-HCl、13mM EDTA、pH7.4)洗涤一次。使用混合器将沉淀悬浮于6ml的冰冷水中并将68ml的H2SO4加入到该混悬液中至得到0.4N的浓度。在4℃下培养1小时后,以15,000rpm将该混悬液离心5分钟并取出上清液且与60ml的丙酮混合。在-20℃下培养过夜后,通过微量离心收集凝固的物质、风干并储存在-8℃下。
组蛋白脱酰基酶活性检测试验-为了进行标准检测试验,将10μl[3H]乙酰基标记的组蛋白加入到90μl的酶级分中并在25℃下将该混合物培养30分钟。通过加入10μl的HCl而终止反应。将释放的[3H]乙酸用1ml的乙酸乙酯提取并将0.9ml的溶剂层溶于10ml的甲苯闪烁溶液中用于测定放射性。
正如表5中所示,WF27082 B、E和F以及FR235220以一种剂量依赖性方式有效抑制了部分纯化的人(Jurkat细胞)组蛋白脱酰基酶的活性。表5对部分纯化的人组蛋白脱酰基酶活性的作用浓度(ng/ml) 1000 100 10 1抑制(%) WF27082B 98.6 76.5 37.3 1.9
WF27082E 104.9 88.5 57.6 11.1
WF27082F 91.7 74.1 36.5 11.4
FR235220 94.6 74.6 33.7 -13.1试验4.WF27082 B对人肿瘤细胞系的抗肿瘤活性
如下在体外测定WF27082 B对人肿瘤细胞系的细胞毒性活性。通过将浓度的对数对所处理的细胞的生长率(控制百分比)作图来测试抑制50%细胞生长所需的化合物浓度(IC50;ng/ml)。在37℃下和5% CO2-95%空气中,在用10% FBS、青霉素(50个单位/ml)和链霉素(50μg/ml)补充的100μl RPMI-1640培养基中将人T细胞白血病Jurkat细胞(1×105个细胞/ml)和人结肠腺癌HT-29细胞(5×104个细胞/ml)用WF27082 B处理。按照如上所述的MTT方法在550nm处(和660nm作为参考)用比色方式测定细胞毒性。
结果如表6中所示。WF27082 B对Jurkat细胞和HT-29细胞具有有效抗肿瘤活性。
表6 WF27082 B对人肿瘤细胞系的抗肿瘤活性(体外)
IC50(ng/ml)
Jurkat HT-29
11 14
将含有诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的本发明药物组合物用作由异常基因表达所导致的疾病的治疗剂或预防剂,所述的疾病诸如炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)、原虫感染等。此外,将本发明的药物组合物用作预防以下列实例为典型的器官移植排斥和自身免疫病的抗肿瘤药和免疫抑制剂:
由诸如心脏、肾、肝、骨髓、皮肤、角膜、肺、胰、小肠、肢、肌肉、神经、锥间盘、气管、成肌细胞、软骨等这样的器官或组织移植所导致的排斥反应;骨髓移植后的移植物抗宿主反应;诸如类风湿性关节炎、全身性红斑狼疮、桥本甲状腺炎、多发性硬化症、重症肌无力、I型糖尿病等这样的自身免疫病;和由致病微生物(例如烟曲霉、尖孢镰孢、星形发癣菌等)所导致的感染。
此外,将含有诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的本发明药物组合物用于治疗或预防下列疾病:
炎症或皮肤过度增生性疾病或以免疫方式介导的疾病的皮肤表现(例如银屑病、特应性皮炎、接触性皮炎、湿疹样皮炎、脂溢性皮炎、扁平苔藓、天疱疮、大疱性天疤疮、大疱性表皮松解、荨麻疹、血管性水肿、脉管炎、红斑、皮肤嗜酸性粒细胞增多、红斑狼疮、痤疮和簇状脱发);
眼部自身免疫病(例如角结膜炎、春季结膜炎、与贝赫切特病相关的眼色素层炎、角膜炎、疱疹样角膜炎、圆锥形角膜炎、角膜上皮营养不良、角膜白斑、眼天疱疮(ocular premphigus)、莫伦溃疡、巩膜炎、格雷夫斯眼病、伏格特-小柳-原田综合征、干燥性角结膜炎(干眼)、水疱、虹膜睫状体炎、结节病、内分泌眼病等);
可逆性阻塞性气道疾病[哮喘(例如支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘和粉尘哮喘),特别是慢性或慢性顽固性哮喘(例如晚期哮喘和气道响应过强)、支气管炎等];
粘膜或血管炎症(例如胃溃疡、局部缺血或血栓形成性血管损伤、局部缺血性肠病、肠炎、坏死性小肠结肠炎、与热烧伤相关的肠损伤、白细胞三烯B4介导的疾病);
肠炎症/过敏反应(例如腹腔疾病、直肠炎、嗜酸性胃肠炎、肥大细胞增生病、局限性回肠炎和溃疡性结肠炎);
具有远离胃肠道症状表现的与食物相关的过敏性疾病(例如偏头痛、鼻炎和湿疹);
肾脏疾病(例如肠肾炎、古德帕斯切特综合征、溶血性尿毒症综合征和糖尿病性肾病);
神经疾病(例如多发性肌炎、急性热病性多神经炎、梅尼埃病、多发性神经炎、孤立性神经炎、脑梗塞、阿尔茨海默病、帕金森病、肌萎缩性侧索硬化(ALS)和神经根病);
大脑局部缺血性疾病(例如头部损伤、大脑内出血(例如蛛网膜下出血、颅内出血)、脑血栓形成、脑栓塞、心动停止、中风、一过性缺血发作(TIA)和高血压性脑病);
内分泌疾病(例如甲状腺功能亢进和巴塞多病);
血液病(例如纯红细胞再生不良、再生障碍性贫血、发育不良性贫血、特发性血小板减少性紫癜、自身免疫性溶血性贫血、粒细胞缺乏症、恶性贫血、巨成红细胞贫血和红细胞发生不能);
骨疾病(例如骨质疏松症);
呼吸疾病(例如结节病、肺纤维化和特发性间质性肺炎);
皮肤病(例如皮肌炎、寻常性白斑病、寻常鱼鳞病、光敏感性和皮肤T细胞淋巴病);
循环疾病(例如动脉硬化、动脉粥样硬化、主动脉炎综合征、结节性多动脉炎和心肌病);
胶原病(例如硬皮病、韦格纳肉芽肿和斯耶格伦综合征);
肥胖症;
嗜酸性筋膜炎;
牙周疾病(例如牙龈、牙周组织、牙槽骨或牙骨质损伤);
肾病综合征(例如肾小球肾炎);
男性脱发、老年性脱发;
肌行为异常;
脓皮病和赛塞利综合征;
与染色体异常相关的疾病(例如唐氏综合征);
艾迪生病;
活性氧介导的疾病[例如与保藏、移植或局部缺血性疾病(例如血栓形成、心梗等)相关的器官(例如心脏、肝、肾、消化道等)损伤(器官局部缺血性循环障碍);肠疾病(例如内毒素休克、假膜性结肠炎和药物或辐射诱发的结肠炎);肾病(例如人局部缺血性急性肾功能不全、慢性肾衰);肺病(例如由肺氧或药物(例如泼尼松、博来霉素等)导致的中毒)、肺癌和肺气肿;眼部疾病(例如白内障、离子储存性疾病(眼球铁质沉着)、视网膜炎、眼点、老年斑、玻璃体斑;角膜碱性烧伤);皮炎(例如多形红斑、线性免疫球蛋白A大疱性皮炎、水泥皮炎);及其它疾病(例如牙龈炎、牙周炎、脓毒病、胰腺炎和由环境污染(例如空气污染)、老化、致癌物、癌转移和低气压病导致的疾病)];
由组胺释放或白细胞三烯C4释放导致的疾病;
血管成形术后的冠状动脉再狭窄和所预防的手术后粘连;
自身免疫病和炎症疾病(例如原发性粘膜水肿、自身免疫性萎缩性胃炎、早现性绝经、男性不育、青少年糖尿病、寻常性天疱疮、类天疱疮、交感神经眼炎、晶状体诱发性色素层炎、特发性白细胞减少、慢性肝炎活跃期、自发性肝硬化、盘状红斑狼疮、自身免疫性睾丸炎、关节炎(例如变形性关节炎)或多软骨炎);
人免疫缺陷病毒(HTV)感染、AIDS;
变应性结膜炎;
因外伤、烧伤或手术所导致的瘢痕增生和疤痕疙瘩。
因此,本发明的药物组合物用于治疗和预防肝病[例如免疫原性疾病(例如诸如自身免疫性肝病、原发性胆汁性肝硬变或原发性硬化性胆管炎这样的慢性自身免疫性肝病)、部分肝脏切除术、急性肝坏死(例如由毒素、病毒性肝炎、休克或缺氧症导致的坏死)、乙型肝炎、非甲非乙型肝炎、肝硬变和肝衰(例如暴发性肝炎、肝炎晚期发作和“慢性肝炎急性(acute-on-chronic)”肝衰(涉及慢性肝病的急性肝衰))]。
可以使用本发明药物组合物的药物制剂形式,例如固体、半固体或液体形式,它含有混合了适于外用、内部或非肠道给药的有机或无机栽体或赋形剂的诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂作为活性组分。例如可以将该活性组分与常用的无毒性的药物上可接受的栽体混合制成片剂、丸剂、胶囊、栓剂、溶液、乳剂、混悬剂、注射剂、软膏、涂抹剂、滴眼液、洗剂、凝胶、霜剂和任意其它适用的剂型。
可以使用的载体是水、葡萄糖、乳糖、阿拉伯胶、明胶、甘露糖醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶态硅石、马铃薯淀粉、脲和其它适用于制备固体、半固体或液体剂型制剂的载体;且还可以使用助剂、稳定剂、增稠剂、增溶剂和着色剂以及香料。
为了将该组合物施用于人体,优选通过静脉内、肌内、局部或口服给药形式施用它。尽管诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的治疗有效量的剂量随所治疗各患者的年龄和病情的不同而改变并取决于它们,但是当治疗患者时,一般用于治疗的给药量如下:就静脉内给药的情况而言,诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的每日剂量为0.01-10mg/kg人体重;就肌内给药的情况而言,诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的每日剂量为0.1-10mg/kg人体重;且就口服给药的情况而言,诸如通式(I)化合物这样的组蛋白脱酰基酶抑制剂的每日剂量为0.5-50mg/kg人体重。
给出的下列实施例用于更具体地解释本发明的目的。
实施例1(1)WF27082 B的发酵生产:
将含有4.0%蔗糖、1.0%葡萄糖、2.0%可溶性淀粉、3.0%棉子粉、1.5%大豆粉、1.0% KH2PO4、0.2% CaCO3、0.05% AdekanolLG-109(消泡剂,Asahi Denka Co.,Ltd.)和0.05% Silicone KM-70(消泡剂,Shin-Etsu Chemical Co.,Ltd.)的含水接种培养基(30ml)倾入100-ml锥瓶并在120℃下灭菌30分钟。从斜面培养物中将菌环量的27082号真菌菌株接种入所述锥瓶并在25℃下的旋转振荡器上以220rpm(5.1cm-投料量)培养4天。将接种培养基(6ml)接种30升小型发酵罐内的20升无菌生产培养基,该培养基由3.0%改性淀粉、2.0%棉子粉、0.2%麦胚、0.1%KH2PO4、0.1% NaCl、0.0005% ZnSO4·7H2O、0.05% Adekanol LG-109和0.05% Silicone KM-70(pH7.0)组成。发酵过程在25℃下和以20升/分钟通气量和以200-300rpm搅拌下进行4天。(分析型HPLC条件)
柱 YMC Pack ODS-AM AM303,S-5 120A(250mm
长×4.6内径,YMC Co.,Ltd.)
洗脱剂 50%乙腈水溶液
流速 1ml/分钟
检测 在210nm处UV检测
保留时间 WF27082 B 10.4分钟(2)WF27082 B的分离:
通过间歇式混合用20L丙酮提取所培养的肉汤(20L:含有380mg的WF27082 B)。将丙酮提取物用硅藻土过滤并用相同体积的水稀释。使稀释的滤液通过Diaion HP-20柱(Mitsubishi Chemical Co.,Ltd.)。将该柱用水和70%甲醇水溶液洗涤并用甲醇洗脱。将洗脱液(1L)用2L水稀释并上用45%乙腈水溶液装填的YMC GEL ODS-AM 120-S50柱(YMC Co.,Ltd.)(180ml)。将该柱用45%乙腈水溶液洗脱并通过上述分析型HPLC监测洗脱情况。在真空中浓缩相当于WF27082 B的部分至得到含水残余物。将该残余物用乙酸乙酯提取并在真空中浓缩提取物至得到一种油状残余物(含有351mg的WF27082 B)。将该油状残余物溶于小体积的甲醇、与20ml的硅胶60(70-230目,MERCK)混合并浓缩至于。将干粉进行使用装填了氯仿的相同硅胶60(230ml)的柱层析。将该柱用氯仿洗脱并通过上述分析型HPLC监测洗脱情况。在真空中浓缩相当于纯化的WF27082 B的部分至得到230mg的无色油状物。
实施例2(1)WF27082 E和F的发酵生产:
基本上按照与实施例1(1)相同的方式获得培养的肉汤(20L)。(2)WF27082 E和F的分离:
通过间歇式混合用20L丙酮提取所培养的肉汤(20L)。将丙酮提取物用硅藻土过滤并用相同体积的水稀释。使稀释的滤液通过Diaion HP-20柱(1L)(Mitsubishi Chemical Co.,Ltd.)。将该柱用水和70%甲醇水溶液洗涤并用甲醇洗脱。将洗脱液(1L)用2L水稀释并上用45%乙腈水溶液装填的YMC GEL ODS-AM 120-S50柱(YMC Co.,Ltd.)(180ml)。将该柱用45%乙腈水溶液洗脱并通过下述分析型HPLC监测洗脱情况。将相当于WF27082 E和F混合物(500mL)的部分用500mL水稀释并上用60%甲醇水溶液装填的YMCGEL ODS-AM 120-S50柱(YMC Co.,Ltd.)(180ml)。将该柱用60%甲醇水溶液洗脱并在真空中浓缩相当于WF27082 E和F混合物的部分至得到含水残余物。将该残余物用乙酸乙酯提取并在真空中浓缩提取物至得到一种油状残余物。将该油状残余物溶于小体积的甲醇并进行制备型HPLC并上用40%甲醇水溶液作为流动相且流速为9.9ml/分钟的装填柱Fluofix 120E 1EW225(20mm×250mm,NEOS Co.,Ltd.)。在真空中浓缩相当于纯化的WF27082 E和F的部分(保留时间:WF27082 E;74.8分钟,WF27082 F;85.7分钟)至分别得到8mg和18mg的油状残余物。(分析型HPLC条件)
柱 YMC Pack ODS-AM AM303,S-5 120A(250mm
长×4.6内径,YMC Co.,Ltd.)
洗脱剂40%乙腈水溶液
温度 50℃
流速 1ml/分钟
检测 在210nm处UV检测
保留时间 WF27082 E 15.3分钟
WF27082 F 16.1分钟
本申请以在澳大利亚提交的申请号6469/1998和申请号9257/1999为基础,将这些文献的内容引入本文作为参考。
Claims (20)
2.一种权利要求1的WF27082化合物,其中R1是甲基,R2是乙基,R3是甲基且R4是羟基。
3.一种属于支顶孢属的真菌菌株,它具有的保藏号为FERM BP-6539且它产生一种具有组蛋白脱酰基酶抑制活性的化合物。
4.一种具有组蛋白脱酰基酶抑制活性的化合物,它通过在营养培养基中培养权利要求3的真菌菌株并从其培养肉汤中回收所述化合物来获得。
5.一种用于生产权利要求1的WF27082化合物的方法,该方法包括在营养培养基中培养产生WF27082的属于支顶孢属的菌株并从其培养肉汤中回收所述化合物的步骤。
6.权利要求5的方法,其中所述的产生WF27082的属于支顶孢属的菌株是权利要求3的真菌菌株。
7.一种药物组合物,它含有权利要求1的WF27082化合物作为活性组分和药物上可接受的基本上无毒性的载体或赋形剂。
8.一种权利要求1的化合物用作药剂的用途。
9.一种用于生产具有组蛋白脱酰基酶抑制活性的化合物的方法,该方法包括在营养培养基中培养属于支顶孢属的真菌菌株的步骤,其中所述的真菌菌株可产生一种具有组蛋白脱酰基酶抑制活性的化合物,并回收该化合物。
10.一种具有组蛋白脱酰基酶抑制活性的化合物,它通过在营养培养基中培养属于支顶孢属的真菌菌株并从其培养肉汤中回收所述化合物来获得,其中所述的真菌菌株可产生一种具有组蛋白脱酰基酶抑制活性的化合物。
11.一种含有通式(I)化合物的组蛋白脱酰基酶抑制剂:
其中R1是甲基,R2是甲基或乙基,R3是氢或甲基且R4是可以带有羟基保护基或不带有羟基保护基的羟基。
12.一种用于抑制组蛋白脱酰基酶的方法,该方法包括使用权利要求11中所用的化合物(I)的步骤。
13.一种权利要求11中所用的化合物(I)在制备用于抑制组蛋白脱酰基酶的药剂中的用途。
15.一种用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓性白血病(APL)或器官移植排斥、自身免疫病的方法,该方法包括对人或动物给予权利要求14中所用的化合物(I)的步骤。
16.一种权利要求14中所用的化合物(I)在制备用于治疗或预防炎症疾病、糖尿病、糖尿病并发症、纯合型地中海贫血症、纤维变性、肝硬变、急性前髓细性白血病(APL)、器官移植排斥或自身免疫病的药剂中的用途。
17.一种用于治疗或预防原虫感染或肿瘤的方法,该方法包括对人和动物给予权利要求1中所用的化合物WF27082的步骤。
18.一种权利要求1中所用的化合物WF27082在制备用于治疗或预防原虫感染或肿瘤的药剂中的用途。
19.一种组蛋白脱酰基酶抑制剂作为免疫抑制剂或抗肿瘤药的用途。
20.一种组蛋白脱酰基酶抑制剂在制备用于治疗或预防器官移植排斥、自身免疫病或肿瘤的药剂中的用途。
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AUPP9257A AUPP925799A0 (en) | 1999-03-16 | 1999-03-16 | Novel compound WF27082 |
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- 1999-10-08 JP JP2000575884A patent/JP2002527449A/ja not_active Abandoned
- 1999-10-08 TR TR2001/01049T patent/TR200101049T2/xx unknown
- 1999-10-08 CN CN99814383A patent/CN1330660A/zh active Pending
- 1999-10-08 HU HU0103985A patent/HUP0103985A2/hu unknown
- 1999-10-08 KR KR1020017004664A patent/KR20010080142A/ko not_active Application Discontinuation
- 1999-10-08 CZ CZ20011342A patent/CZ20011342A3/cs unknown
- 1999-10-08 US US09/806,500 patent/US6656905B1/en not_active Expired - Fee Related
- 1999-10-08 PL PL99348648A patent/PL348648A1/xx not_active Application Discontinuation
- 1999-10-08 WO PCT/JP1999/005597 patent/WO2000021979A2/en not_active Application Discontinuation
- 1999-10-11 TW TW088117518A patent/TW536544B/zh not_active IP Right Cessation
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2002
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102153622A (zh) * | 2010-12-25 | 2011-08-17 | 中国水产科学研究院珠江水产研究所 | 一种免疫增强剂脯氨酸-甘氨酸环四肽(c14h20n4o4)及应用 |
CN107141335A (zh) * | 2017-04-12 | 2017-09-08 | 宁波大学 | 一种环肽化合物及其制备方法和应用 |
CN107141335B (zh) * | 2017-04-12 | 2020-10-20 | 宁波大学 | 一种环肽化合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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JP2002527449A (ja) | 2002-08-27 |
BR9914779A (pt) | 2001-07-03 |
PL348648A1 (en) | 2002-06-03 |
EP1123309A2 (en) | 2001-08-16 |
HK1042308A1 (zh) | 2002-08-09 |
US6656905B1 (en) | 2003-12-02 |
HUP0103985A2 (hu) | 2002-02-28 |
IL142531A0 (en) | 2002-03-10 |
KR20010080142A (ko) | 2001-08-22 |
TW536544B (en) | 2003-06-11 |
CA2346943A1 (en) | 2000-04-20 |
WO2000021979A2 (en) | 2000-04-20 |
CZ20011342A3 (cs) | 2001-09-12 |
TR200101049T2 (tr) | 2002-01-21 |
WO2000021979A3 (en) | 2000-07-20 |
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