CN1486302A - 作为抗冠状动脉疾病或动脉硬化的abca-1加强化合物的取代1,3,5-三嗪和嘧啶 - Google Patents
作为抗冠状动脉疾病或动脉硬化的abca-1加强化合物的取代1,3,5-三嗪和嘧啶 Download PDFInfo
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- CN1486302A CN1486302A CNA018220541A CN01822054A CN1486302A CN 1486302 A CN1486302 A CN 1486302A CN A018220541 A CNA018220541 A CN A018220541A CN 01822054 A CN01822054 A CN 01822054A CN 1486302 A CN1486302 A CN 1486302A
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- alkyl
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- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 title 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
- C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
- C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明提供了提高ABCA-1基因的细胞表达,促进胆固醇从细胞流出,增加哺乳动物特别是人的血浆中的HDL水平的化合物。该化合物用于治疗冠状动脉疾病。
Description
本申请要求以2000年11月7日递交的序列号为60/251916和2001年8月17日递交的序列号为60/313274的美国临时申请为优先权。
发明领域
本发明涉及用于提高哺乳动物细胞中ABCA-1产量的化合物,以及利用这类化合物治疗冠状动脉疾病的方法。本发明也涉及制备这类化合物的方法,以及涉及含有它们的药物组合物。
发明背景
胆固醇是高等生物体生长和生存所必需的。它是调节真核生物膜流体性的脂,是甾类激素如黄体酮,睾丸激素等等的前体。胆固醇可以从饮食中得到,或在肝中和肠中内部合成。胆固醇在体液中通过脂蛋白运输到特定的靶,而脂蛋白是根据密度的增加来分类的。例如,低密度的脂蛋白胆固醇(LDL)负责运输胆固醇进出肝,以及将胆固醇运输到周边组织细胞,其中LDL受体结合LDL,并介导它进入细胞。
虽然胆固醇是哺乳动物中许多生物过程所必需的,但提高血清中LDL的水平是不需要的,因为他们会在布满身体的动脉上形成动脉粥样硬化斑,能导致例如冠状动脉疾病的发展。与此相反,根据人的临床数据和动脉模型系统,人们已经发现提高高密度脂蛋白胆固醇(HDL-C)的水平将能阻止冠状动脉疾病的发展。
通常,通过包括高密度脂蛋白(HDL)的途径可以从身体中除去过量的胆固醇。胆固醇通过两个过程之一从细胞中“流出”——或被动地转移到成熟的HDL,或主动地转移到载脂蛋白A--1。后一过程是通过已知为ATP结合盒子运输器1(ABC-1,或称为ABCA--1)的蛋白质来介导的。在后一过程中,脂少的HDL前体获得了磷脂和胆固醇,导致成熟HDL颗粒的血浆水平升高。HDL胆固醇基本上是在一个已知为“反向胆固醇运输”的过程中运输到肝的,在此它作为胆汁进行再循环或分泌。
一个目的是减少动脉中动脉粥样硬化斑形成危险的治疗方法,涉及到降低血浆的脂水平。这样的一个方法包括饮食的变化和/或用药物来治疗,如纤维酸(氯贝特(clofibrate),吉非罗齐(gemfibrozil)和降脂异丙酯(fenofibrate)),烟酸,和HMG--CoA还原酶抑制剂,如莫维诺林(mevinolin),美伐他汀(mevastatin),普伐他汀(pravastatin),simuvastatin,氟伐他汀(fluvastatin),和洛伐他汀(lovastatin),它们可以通过抑制胆固醇的细胞内合成或抑制LDL受体的吸收来降低血浆LDL胆固醇的水平。另外,胆酸结合树脂,如cholestyrine,考来替泊(colestipol)和普罗布考(Probucol)通过降低肠的吸收和提高肝中的LDL胆固醇的分解代谢来降低LDL胆固醇的水平。
人们需要可选择的治疗方法,目的在于降低在动脉中形成动脉粥状硬化斑的危险,特别是对那些通过HDL途径从动脉壁除去胆固醇存在缺陷的个体。既然HDL水平通常涉及ABCA--1的表达,提高HDL水平的一个方法将为加强ABCA--1的表达。因此,需要提供一种化合物,其为对哺乳动物中ABCA--1表达的潜在刺激剂化合物,从而增大胆固醇的流出,以及提高血液中的HDL胆固醇水平。这将用于低HDL水平特征的各种疾病状态特别是冠状动脉疾病的治疗。
业已表明,降低LDL胆固醇水平的药物和提高HDL胆固醇的药物相结合是有益的;参见例如,Arterioscler.,Thromn.,Vasc.Biol.(2001),21(8),1320-1326,Marian C.Cheung et al。因此,也需要提供刺激ABCA-1表达的化合物和降低LDL胆固醇水平的化合物的结合体。
应该注意的是,业已表明在巨噬细胞中提高ABCA--1产量局部地降低了冠状动脉中胆固醇的储存,但没有明显提高血浆HDL胆固醇。在这种情况下,提高ABCA-1的表达甚至在没有提高HDL胆固醇的情况下也是有益的。
发明概述
因此,本发明的目的是提供提高哺乳动物中ABCA-1基因的细胞表达的化合物。在第一方面,本发明涉及了用于提高ABCA-1表达的通式I化合物:
式I
其中:
m,n和p分别是0或1;
A是-C(Z1)-,-C(Z1)-NH-,SO2或共价键;
其中Z1是氧或硫;
R1是氢,选择性取代的烷基,选择性取代的烯基,选择性取代的炔基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
R2是氢,烷基或环烷基;或者
R1,R2和A与他们连接的氮原子一起形成含氮的杂环;
R3为选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环,选择性取代的芳基,或选择性取代的杂芳基;
R4是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环,选择性取代的芳基,或选择性取代的杂芳基;
T是-O-,-S(O)q或-NR5-;
其中q是0,1,或2,R5是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
X1,X2,X3分别为-CR6或氮,其中R6是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
条件是X1,X2,和X3中至少一个是氮;
Y1是低级亚烷基或羰基;
Y2是低级亚烷基或氧;以及
Z是硫,氧或-NR5-,
包括对需要的哺乳动物给予治疗有效量的通式I的化合物。这样的疾病包括但不限于动脉疾病,特别是冠状动脉疾病。
在第二方面,本发明涉及利用通式I化合物治疗哺乳动物的疾病或症状的的方法,这类疾病可以用提高HDL胆固醇血清水平的化合物进行有效治疗,该方法包括对需要的哺乳动物给予治疗有效量的通式I的化合物。这样的疾病包括但不限于动脉疾病,特别是冠状动脉疾病。
在第三个方面,本发明涉及利用通式I化合物治疗哺乳动物的疾病或症状的方法,这类疾病可以用促进胆固醇从细胞流出的化合物进行有效治疗,该方法包括对需要的哺乳动物给予治疗有效量的通式I的化合物。这样的疾病包括但不限于动脉疾病,特别是冠状动脉疾病。
在第四个方面,本发明涉及利用通式I化合物治疗哺乳动物的以低HDL-C为特征的疾病或症状的方法,这类疾病可以利用提高HDL-C血清水平的化合物进行有效治疗,该方法包括对需要的哺乳动物给予治疗有效量的通式I的化合物。这样的疾病包括但不限于动脉疾病,特别是冠状动脉疾病。
在第五个方面,本发明涉及利用通式I化合物治疗哺乳动物与冠状动脉疾病相关的症状的方法,这类疾病可以用提高血清HDL胆固醇水平的化合物和降低LDL胆固醇的化合物相结合来进行治疗,该方法包括对需要的哺乳动物给予治疗有效量的通式I的化合物和降低LDL胆固醇的化合物。
本发明的第六方面涉及一种药物制剂,其包含治疗有效量的通式I化合物和至少一种药学上可接受的赋形剂。
本发明的第七方面涉及制备通式I化合物的方法。
定义和常用参数
术语“烷基”指具有1到20个碳原子的单基枝化或未枝化的饱和烃基链。这一术语的例子有甲基,乙基,n-丙基,异丙基,n-丁基,异丁基,t-丁基,n-戊基,2-甲基丁基,n-己基,n-葵基,四葵基等等基团。
术语“取代烷基”指:
1)如上定义的烷基基团,具有1到5个取代基,优选1到3个取代基,所述的取代基选自包括烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧羰基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧烷基,芳硫基,杂芳硫基,杂环硫基,硫基,烷硫基,芳基,芳氧基,杂芳基,氨磺酰基,氨基羰基氨基,氨基硫基羰基氨基(aminothiocarbonylamino),氨基硫基羰基氨基(aminothiocarbonylamio),杂芳氧基,杂环基,杂环氧基,羟氨基,烷氧氨基,硝基,-SO-烷基,SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和-SO2-杂芳基。除非被定义所限制之外,所有取代基可以选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2;或
2)如上定义的烷基基团,被1-5个分别选自氧,硫和-NRa-的原子或基团所中断,其中Ra选自氢,烷基,环烷基,烯基,环烯基,炔基,芳基,杂芳基和杂环基。所有取代基可以选择性地进一步被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2;或
3)如上定义的烷基基团,具有如上定义的1到5个取代基,并且也是被如上定义的1-5个原子或基团打断。
术语“低级烷基”指具有1到6个碳原子的单基枝化或未枝化的饱和烃基链。该术语的例子有甲基,乙基,n-丙基,异丙基,n-丁基,异丁基,t-丁基,n-己基等等基团。
术语“取代的低级烷基”指如上定义的低级烷基,其具有1到5个,优选1到3个如上取代烷基定义中的取代基;或被如上定义的低级烷基,其被1-5个如上取代烷基定义中的原子中断;或如上定义的低级烷基,其既具有如上定义的1到5个取代基,同时也被如上定义的1-5个原子中断。
术语“亚烷基”指枝化的或未枝化的饱和烃基链的双基,优选具有1到20个碳原子,进一步优选1-10个碳原子,更优选1-6个碳原子。该术语的例子如亚甲基(-CH2-),亚乙基(-CH2CH2-),亚丙基异构体(例如,-CH2CH2CH2-和-CH(CH3)CH2-)等等基团。
术语“低级亚烷基”指枝化或未枝化的饱和烃基链的双基,优选地具有1到6个碳原子。
术语“取代亚烷基”指:
(1)如上定义的亚烷基基团,其具有1到5个取代基,所述的取代基选自烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羧基,烷氧基羧基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧基烷基,芳基硫基,杂芳基硫,杂环硫,硫,烷基硫,芳基,芳氧基,杂芳基,氨基磺酰基,氨基羰基氨基,氨基硫羰基氨基,杂芳氧基,杂环基,杂环氧基,羟氨基,烷氧氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和-SO2-杂芳基。除非受定义的限制,所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2;
(2)如上定义的亚烷基基团,被1-5独立选自氧,硫和NRa-的原子或基团中断,其中Ra选自氢,选择性取代的烷基,环烷基,环烯基,芳基,杂芳基和杂环基;或选自羰基,羧基酯,羧基酰胺和磺酰基的基团中断;或
(3)如上定义的亚烷基基团,具有如上定义的1到5个取代基,同时被如上定义的1-20个原子中断。
取代亚烷基的例子有氯亚甲基(-CH(Cl)-),氨基亚乙基(-CH(NH2)CH2-),甲基氨基亚乙基(-CH(NHMe)CH2-),2-羧基亚丙基异构体(-CH2CH(CO2H)CH2-),乙氧基乙基(-CH2CH2O-CH2CH2-),乙基甲基氨基乙基(-CH2CH2N(CH3)CH2CH2-),1-乙氧基-2-(2-乙氧基-乙氧基)乙烷(-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2-),等等。
术语“芳烷基”指与亚烷基基团共价连接的芳基基团,其中芳基和亚烷基的定义如本文所述。“选择性取代的芳烷基”指与选择性取代的亚烷基基团共价地连接选择性取代的芳基基团。这样的芳烷基的例子有苄基,苯乙基,3-(4-甲氧基苯基)丙基,等等。
术语“烷氧基”指基团R-O-,其中R是选择性取代的烷基,或选择性取代的环烷基,或R是基团-Y-Z,其中Y是选择性取代的亚烷基,Z是选择性取代的烯基,选择性取代的炔基;或者选择性取代的环烯基,其中烷基,烯基,炔基,环烷基和环烯基如本文所定义。优选的烷氧基基团为选择性取代的烷基-O-并且包括甲氧基,乙氧基,n-丙氧基,异丙氧基,n-丁氧基,叔丁氧基,sec-丁氧基,n-戊氧基,n-己氧基,1,2-二甲基丁氧基,三氟甲氧基等等。
术语“烷硫基”指基团R-S-,其中R如烷氧基中所定义。
术语“烯基”指枝化或未枝化的不饱和烃基基团的单基,优选具有2到20个碳原子,更优选地具有2到10个碳原子,甚至更优选地具有2到6个碳原子,以及具有1-6个,特别优选具有1个双键(乙烯基)。优选的烯基基团包括乙烯基(-CH=CH2),1-丙烯基或烯丙基(-CH2CH=CH2),异丙烯基(-C(CH3)=CH2),双环[2.2.1]庚烯,等等。在烯基与氮连接的情况下,双键不能在氮的α位上。
术语“低级烯基”指如上定义的烯基,具有2到6个碳原子。
术语“取代烯基”指如上定义的烯基基团,具有1到5个,优选地具有1到3个取代基,所述取代基选自下面的基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧羰基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧烷基,芳基硫,杂芳基硫,杂环基硫,硫基,烷基硫,芳基,芳氧基,杂芳基,氨基磺酰基,氨基羰基氨基,氨基硫羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和-SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“炔基”指不饱和烃的单基,其具有优选2到20个,更优选2到10个,进一步优选2到6个碳原子,且至少具有1个,优选地具有1-6个乙炔(三键)不饱和位位置。优选的炔基基团包括乙炔,(-C≡CH),炔丙基(或丙-1-炔-3-基基,-CH2C≡CH),等等。当炔基与氮相连接时,三键不能在氮的α位上。
术语“取代炔基“指如上定义的炔基,具有1到5个取代基,优选地具有1到3个取代基,所述取代基选自以下基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰基氨基,酰氧基,氨基,氨基羰基,烷氧基羰基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧烷基,芳硫基,杂芳硫基,杂环硫基,硫基,烷硫基,芳基,芳氧基,杂芳基,氨磺酰基,氨基羰基氨基,氨基硫羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧基氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和-SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基或杂芳基,n是0,1或2。
术语“氨基羰基”指基团-C(O)NRR,其中每个R独立地为氢,烷基,芳基,杂芳基,杂环基,或其中两个R基团连接形成杂环基团(例如,吗啉基)。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“酰氨基”指基团-NRC(O)R,其中每个R独立为氢,烷基,芳基,杂芳基,或杂环基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“酰氧基”指基团-O(O)C-烷基,-O(O)C-环烷基,-O(O)C-芳基,-O(O)C-杂芳基,和-O(O)C-杂环基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“芳基”指具有6到20个碳原子的芳香碳环基团,具有单个环(例如,苯基),或多个环(例如,联苯基),或多个稠合(融合)环(例如,萘基或蒽基)。优选的芳基包括苯基,萘基等等。
除非受芳基取代基定义的限制,这样的芳基基团可以选择性地被1到5个取代基,优选1到3个取代基取代,这些取代基选自以下基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧基羰基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧基烷基,芳基硫基,杂芳基硫基,杂环基硫基,硫基,烷硫基,芳基,烷氧基,杂芳基,氨基磺酰基,氨基羰基氨基,氨基硫基羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧基氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“芳氧基”指基团芳基-O-,其中芳基基团如上定义,并包括如上定义的选择性取代的芳基。术语“芳硫基”指R-S-,其中R定义为芳基。
术语“氨基”指基团-NH2。
术语“取代氨基”指基团-NRR,其中每个R独立选自以下基团:氢,烷基,环烷基,羧基烷基(例如,苄氧基羰基),芳基,杂芳基,和杂环基,条件是两个R基团不同时是氢或基团-Y-Z,其中Y是选择性取代的亚烷基,Z是烯基,环烯基,或炔基,所有取代基可进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“羧基烷基”指基团-C(O)O-烷基-,-C(O)O-环烷基-,其中烷基和环烷基的定义如本文所述,且可进一步选择性地被烷基,烯基,炔基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R为烷基,芳基或杂芳基,n为0,1或2。
术语“环烷基”指具有3到20个碳原子的环烷基基团,其具有单环或多个稠合环。这样的环烷基基团包括,例如,单环结构,如环丙基,环丁基,环戊基,环葵基等等,或多个环结构,如金刚烷环,和双环[2.2.1]庚烷,或与芳基基团稠合的环烷基基团,例如二氢茚等等。
术语“取代环烷基”指具有1到5个取代基,优选具有1到3个取代基的环烷基基团,所述取代基,选自下列基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧基羰基氨基,迭氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧基烷基,芳基硫基,杂芳基硫基,杂环基硫基,硫基,烷硫基,芳基,芳氧基,杂芳基,氨磺酰基,氨基羰基氨基,氨基硫基羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧基氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,-SO2-芳基,和-SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。
术语“卤素”或“卤基”指氟,氯,溴和碘。
术语“酰基”指基团-C(O)R,其中R是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,以及选择性取代的杂芳基。
术语“杂芳基”指芳香基团(即,不饱和的),含有1到15个碳原子,且至少在1个环中具有1到4个选自氧,氮和硫的杂合原子。
除非受到杂芳基取代基的定义限制,这样的杂芳基可以选择性地被1到5个取代基,优选1到3个取代基取代,所述取代基选自下列基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧基羰基氨基,叠氮基,氰基,卤素,氢,羟基,酮,硫羰基,羧基,羧基烷基,芳硫基,杂芳硫基,杂环硫基,硫基,烷基硫基,芳基,芳氧基,杂芳基,氨磺酰基,氨基羰基氨基,氨基硫基羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧基氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和-SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。这样的杂芳基基团可以有一个单环(例如,吡啶基或呋喃基),或多个稠合环(例如,中氮茚基(indolizinyl),苯丙噻唑基,或苯并噻吩基)。氮杂环和杂芳基的例子包括但不限于,吡咯,咪唑,吡唑,吡啶,吡嗪,嘧啶,哒嗪,中氮茚,异吲哚,吲哚,吲唑,嘌呤,喹嗪,异喹啉,喹啉,酞嗪,萘吡啶,喹喔啉,喹唑啉,噌啉,喋啶,咔唑,咔啉,菲啶,丫啶,菲咯啉,异噻唑,吩嗪,异噁唑,吩吩噁嗪,酚噻嗪,咪唑啶(imidazolidine),咪唑啉,等等,以及含有杂芳基化合物的N-烷氧基-氮。
术语“杂芳氧基”指基团杂芳基-O-。
术语“杂环基”指具有单环或多个稠合环的饱和或部分不饱和基团的单基,其具有1到40个碳,且环内具有1到10个,优选1到4个选自氮,硫,磷和/或氧的杂合原子。
除非受到杂环取代基的定义限制,这样的杂环基团可以选择性地被1到5个,优选1到3个取代基取代,所述取代基选自下列基团:烷基,烯基,炔基,烷氧基,环烷基,环烯基,酰基,酰氨基,酰氧基,氨基,氨基羰基,烷氧基羰基氨基,叠氮基,氰基,卤素,羟基,酮,硫羰基,羧基,羧基烷基,芳硫基,杂芳基硫基,杂环基硫基,硫基,烷基硫基,芳基,芳氧基,杂芳基,氨磺酰基,氨基羰基氨基,氨基硫基羰基氨基,杂芳氧基,杂环基,杂环氧基,羟基氨基,烷氧基氨基,硝基,-SO-烷基,-SO-芳基,-SO-杂芳基,-SO2-烷基,SO2-芳基和SO2-杂芳基。所有取代基可以进一步选择性地被烷基,烷氧基,卤素,CF3,氨基,取代氨基,氰基,或-S(O)nR取代,其中R是烷基,芳基,或杂芳基,n是0,1或2。杂环基基团可以具有单环或多个稠合环。优选的杂环包括四氢呋喃,吗啉,吡啶等等。
这些定义包括特征:当R1,R2和A一起与氮原子连接时,形成含氮的杂环。该定义指当R1,R2和A一起与氮原子连接时,代表了以下通式的5,6或7元环酰胺,环脲,环硫酰胺,环硫脲,或环氨磺酰:
或
其中R是C(O),C(S)或SO2,D是-C-或-NH-,和R7,R8,R9和R10分别是氢或低级烷基。
术语“硫基”指基团-SH。
术语“取代烷基硫基”指基团-S-取代烷基。
术语“杂芳基硫基”指基团-S-杂芳基,其中杂芳基基团如上定义,包括也是如上定义的选择性取代的杂芳基基团。
术语“亚砜”指基团-S(O)R,其中R是烷基,芳基,或杂芳基。“取代亚砜”指基团-S(O)R,其中R是取代烷基,取代芳基,或取代杂芳基,如上定义。
术语“砜”指基团-S(O)2R,其中R是烷基,芳基,或杂芳基。“取代砜”指基团-S(O)2R,其中R是取代烷基,取代芳基,或取代杂芳基,如上定义。
术语“酮”指基团-C(O)-。术语“硫羰基”指基团-C(S)-。术语“羧基”指基团-C(O)-OH。
“选择性的”或“选择性地”指随后叙述的事件或情况可以或可以不发生,该叙述包括所述事件或情况发生的情况和不发生的情况。
术语“通式I的化合物”包括公开的本发明的化合物,和药学上可接受的盐,药学上可接受的酯,以及此类化合物的前药物。另外,本发明的化合物可以具有一个或几个不对称中心,并且可以作为外消旋混合物或作为单个的对映体或非对映异构体来产生。通式I的任何给定的化合物中存在的立体异构体的数目取决于存在的不对称中心的数目(有2n可能的立体异构体,其中n是不对称中心的数目)。个别的立体异构体可以通过在合成的某些适当时期分辨外消旋或非外消旋的中间产物混合物得到,或通过常规方法分辨通式I的混合物来得到。立体异构体(包括个别的对映体和非对映异构体)以及外消旋和非外消旋立体异构体的混合物是包括在本发明的范围内的,除非特别说明,所有这些是用本申请书的结构来描述的。
“异构体”是具有相同分子通式的不同的化合物。“立体异构体”是原子只在空间排列上有所不同的异构体。
“对映体”是一对立体异构体,其是相互非重叠的镜象。1∶1的一对对映体的混合物是“外消旋”混合物。术语“±”用于命名合适的外消旋混合物。
“非对映异构体”是立体异构体,至少具有两个非对称原子,但不是相互呈镜象的。
纯粹的立体化学是根据Cahn-Ingold-Prelog R-S系统详细说明的。当化合物是纯的对映体时,每个手性碳的立体化学可以用R或S来指定。对于绝对构型未知的被分辨化合物,根据它们在钠D谱线波长的极光下旋转面的方向(右旋或左旋),来命名该化合物为(+)或(-)。
术语“治疗有效量”指通式I的化合物的量是如下定义,当对需要治疗的哺乳动物给药时,其量是足以有效治疗的。治疗的有效量将根据受试者和待治疗的疾病症状,受试者的体重和年龄,疾病症状的严重程度,给药的方式等等而改变,这可以由本领域的普通技术人员来确定。
术语“冠状动脉疾病”指冠状动脉存在“硬化”(粥样硬化)的慢性疾病。
术语“粥样硬化”指动脉硬化的一种形式,其中黄色的斑的沉积物中含有胆固醇,脂物质,和噬脂细胞,它们是在大的和中等大小的动脉的内膜和内部介质中形成的。
术语“治疗”或“在治疗”指治疗哺乳动物的疾病。包括:(i)预防疾病,即使疾病的临床症状不发生;
(ii)抑制疾病,即阻止临床症状的发展;和/或
(iii)缓解疾病,即使临床症状退解。
在许多情况中,本发明的化合物能够借助胺和/或羧基基团或相似基团的存在来形成酸和/或碱盐。术语“药学上可接受的盐”指保留通式I的化合物的生物效力和特性,但不是生物学或其他方面不需要的盐。药学上可接受的碱添加盐可以从无机和有机碱中制备。起源于无机碱的盐包括例如,钠,钾,锂,铵,钙和镁盐。起源于有机碱的盐包括例如,伯,仲和叔胺的盐,如烷基胺,二烷基胺,三烷基胺,取代烷基胺,双(取代烷基)胺,三(取代烷基)胺,烯基胺,二烯基胺,三烯基胺,取代烯基胺,双(取代烯基)胺,三(取代烯基)胺,环烷基胺,双(环烷基)胺,三(环烷基)胺,取代环烷基胺,双取代环烷基胺,三取代环烷基胺,环烯基胺,双(环烯基)胺,三(环烯基)胺,取代环烯基胺,双取代环烯基胺,三取代环烯基胺,芳基胺,二芳基胺,三芳基胺,杂芳基胺,二杂芳基胺,三杂芳基胺,杂环基胺,二杂环基胺,三杂环基胺,混合的二和三胺,其中胺上的至少两个取代基是不同的,并且选自下列基团:烷基,取代烷基,烯基,取代烯基,环烷基,取代环烷基,环烯基,取代环烯基,芳基,杂芳基,杂环基等等。同时包括的是两个或三个取代基和氨基氮形成杂环或杂芳基基团的胺。
合适的胺的特定例子包括例如,异丙胺,三甲胺,二乙胺,三(异丙)胺,三(n-丙基)胺,乙醇胺,2-二甲基胺乙醇,三甲胺,赖氨酸,精氨酸,组氨酸,咖啡因,普鲁卡因,氢巴胺(hydrabamine),胆碱,甜菜碱,乙烯二胺,葡糖胺,N-烷基葡糖胺,可可碱,嘌呤,哌嗪,哌啶,吗啉,N-乙基哌啶等等。
药学上可接受的酸添加盐可以从无机和有机酸制备。无机酸起源的盐包括盐酸,氢溴酸,硫酸,硝酸,磷酸等等。起源于有机酸的盐包括乙酸,丙酸,乙醇酸,丙酮酸,草酸,苹果酸,丙二酸,琥珀酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,苦杏仁酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸等等。
如本文所用,“药学上可接受的载体”包括任何和所有溶剂,分散介质,包衣剂,杀菌剂,和杀真菌剂,等渗剂和吸收延迟剂等等。这样的介质和试剂对药学活性物质的用途是本领域公知的。除了那些与活性成分不相容的常规介质或试剂之外,它在治疗组合物中的用途受到关注。补充的活性成分也可以掺入组合物中。
名称
本发明的化合物的名称和数目是用通式I的代表化合物来说明的,其中X1,X2和X3是N,Z是硫,R1和R2是氢,R3是4(叔-丁基)苯基,R4是n-戊基,A是共价键,T是氧,在(Y1)n中,n是O,(Y1)n是亚甲基。
名称:6-{[4-(叔-丁基)苯氧基]甲基}-4-戊硫基-1,3,5-三嗪-2-基胺。
合成反应参数
术语“溶剂”,“惰性有机溶剂”或“惰性溶剂”指在待叙述的反应条件下呈惰性的溶剂[包括例如,苯,甲苯,乙腈,四氢呋喃(“THF”),二甲基甲酰胺(“DMF”),氯仿,亚甲基氯(或二氯甲烷),二乙基醚,甲醇,吡啶等等]。除非特别相反地指出,用于本发明反应中的溶剂是惰性有机溶剂。
术语“q.s”指加入足够量以达到规定的功能,例如,使溶液达到需要的体积(即,100%)的量。
通式I化合物的合成
制备通式I化合物的方法的一个例子表示在反应路线I中。
反应路线I
其中R3A代表R3-Y1-T-Y2-,其中Hal是氯,溴或碘。
步骤1-制备通式(2)化合物
通式(2)的化合物是通过通式(1)的化合物(2-亚氨-4-硫代双脲),一个可购买到的化合物与R4Hal的反应制备得到,其中R4是如上定义的,并且Hal是氯,溴,或碘。反应在室温下,惰性溶剂中,例如四氢呋喃中进行10-48个小时。当反应基本完成时,不进行纯化即可进行余下的反应。
步骤2-制备通式(3)化合物
通式(3)的化合物是通过通式(2)的化合物与通式R3AC(O)Cl的酰基氯(其中R3A代表如上定义的R3-Y1-T-Y2),在存在碱,优选存在叔-有机碱的条件下反应制备而得。在惰性溶剂中,优选四氢呋喃中加入酰基氯,接着在大致室温下加入叔碱,然后将混合物搅拌10到48小时。当反应基本完成时,用常规方法分离通式(3)的产物,例如在减压下除去溶剂,并在硅胶上层析残留物。
起始物质
上面的步骤(2)中需要的通式R3AC(O)Cl的许多化合物是可以市场购买的,或者可以通过本领域公知的方法来制备。例如,通式R3AC(O)Cl化合物的制备方法表示在反应路线II中,其中R3-Y1-T-Y2是苯氧甲基(即,R3是苯基,Y1是共价键,T是氧,Y2是亚甲烷)。
反应路线II
相似的反应序列可以用于制备通式R3AC(O)Cl化合物,其用于制备通式I的化合物,其中T是硫。
制备其中T是氮的通式I化合物
制备其中T是氮的通式I化合物,需要不同的反应顺序,如反应路线III所示。
步骤1-制备通式(3)化合物
在存在碱,优选叔碱的情况下,通过通式(2)的化合物与氯乙酰氯的反应可以制备通式(3)的化合物。在惰性溶剂中,优选四氢呋喃中加入盐酸,接着在室温下加入叔碱,然后将混合物搅拌10到48小时。当反应基本完成时,用常规方法分离通式(3)的产物,例如在减压下除去溶剂,并在硅胶上层析残留物。
步骤2-制备T是NR5的通式I化合物
通式(3)的化合物与通式R3R5NH的胺,在存在碱,优选存在叔-有机碱的情况下,在惰性溶剂优选四氢呋喃中进行反应。反应在50-100℃下进行约10-48小时,优选16小时。当反应基本完成时,用常规方法例如在减压下除去溶剂,并在硅胶上层析残留物分离通式I的产物。
制备其中T是氧或硫的通式I化合物
其中Z是氧或硫的通式I化合物通过如反应路线IIIA制备而得。
反应路线IIIA
其中Z’是氧或硫。
起始原料通式(5)化合物是本领域公知的,也可以如YakugakiZassshi(1975),95(5),521-30中所述制备。通式(5)化合物与例如通过与氢化钠反应形成的通式R4Z’H化合物的阴离子,在惰性溶剂中进行反应,优选地取代环上的氯以得到通式(3A)的化合物。中间产物可以进一步进行如反应路线III中所示的反应,得到通式I的化合物,其中T是氮。或者,通式(3A)与通式R3-(Y1)nOH或R3-(Y1)nSH的阴离子反应得到通式I的化合物,其中T是氧或硫,R1和R2是氢,A是共价键。通式(3A)的化合物可以进一步转变成通式I的化合物,其中R1不是氢,如上面的反应路线所示。
制备其中X1
和X2
是氮,X3是CH的通式I化合物
制备其中X2和X3是氮,X1是CH的通式I化合物的反应顺序如反应路线IV所示。
反应路线IV
通式(4)的化合物是市场可购买到的,与强碱优选氢化钠反应,接着在存在碱,优选叔-有机碱的条件下,在惰性溶剂优选四氢呋喃中与通式R3C(O)Halo的酰基氯反应。反应在50-100℃进行10-48小时,优选16小时。当反应基本完成时,用常规方法分离通式I产物,例如在减压下除去溶剂,并在硅胶上层析残留物。
制备其中A是-C(Z1)-的通式I化合物
制备其中A是-C(Z1)-,Z1是氧或氢的通式I化合物的反应顺序如反应路线V所示。
反应路线V
其中A是共价键,R1是氢的通式I化合物最初与强碱优选氢化钠反应。反应是在惰性溶剂优选四氢呋喃中,在约0℃的温度下进行约1-30分钟。然后加入通式R1C(X1)Cl化合物,其中X1是氧或硫,使混合物升温到约室温下维持约8-24小时。当反应基本完成时,用常规方法分离其中A是-C(X1)-的通式I产物,例如在减压下除去溶剂,接着在硅胶上层析残留物。
制备其中A是-C(Z1)-NH-的通式I的化合物
制备A是-C(Z1)-NH-的通式I化合物的顺序如反应路线VI所示,其中Z1是氧或硫。
反应路线VI
其中A是共价键,R1是氢的通式I化合物与通式R1NCX1的异氰酸盐或异硫氰酸盐在存在催化量的4-二甲基氨基吡啶(DMAP)和叔碱优选三乙基胺的条件下反应,其中X1是氧或硫。反应在惰性溶剂例如乙腈中,在约0-30℃的温度优选室温下进行约4-24小时。当反应基本上完成时,用常规方法分离A是-C(X1)-NH-的通式I产物,例如在减压下除去溶剂,接着在硅胶上层析残留物。
用途,实验和给药
一般的用途
通式I的化合物刺激哺乳动物细胞中ABCA-1的表达,所以提高了胆固醇的流出,提高了血浆中的HDL水平。因此,通式I的化合物用于治疗与哺乳动物中高胆固醇/低HDL水平相关的疾病,包括但不限于冠状动脉疾病。该类疾病包括由糖尿病产生的疾病等等。
实验
如上面参考的那些专利和专利说明书中所述,在下面的实施例通过本领域技术人员公知的方法来进行活性实验。
药物组合物
通式I的化合物通常以药物组合物的形式给药。因此本发明提供了一种药物组合物,含有作为活性成分的一个或几个通式I的化合物,或其药学上可接受的盐或酯,以及一个或几个药学上可接受的赋形剂,载体,包括惰性固体稀释剂和填充剂,稀释剂,包括无菌的水溶液和各种有机溶剂,渗透性增强剂,增溶剂和佐剂。通式I的化合物可以单独或结合其他治疗剂来给药。这类组合物是以药物技术中已知的方法来制备的(参见例如,Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelophia,PA 17th Ed.(1985)和“Modern Pharmaceutics”,MarcelDekker,Inc.3rd Ed.(G.S.Banker&C.T.Rhodes,Eds)。
给药
通式I的化合物可以以单或多剂量,以具有相似用途的可接受的给药形式进行给药,如在那些列为参考的专利和专利申请中所述,包括直肠,口腔,鼻内和经皮的途径,通过动脉内注射,静脉内,腹膜内,肠胃外,肌肉内、皮下,口服,局部,作为吸入剂,或通过浸渗或包衣设备如支架,或如动脉插入圆筒多聚物来给药。
给药的一个方式是肠胃外的,特别是通过注射。本发明新的组合物可以通过以包括水溶液或油悬浮液,或乳液的注射形式,与芝麻油,玉米油,棉籽油,或花生油,以及酏剂,甘露醇,葡聚糖或无菌的水溶液,以及相似的药物载体共同给药。盐水溶液也常规地用于注射,但在本发明中不优选。也可利用乙醇,甘油,丙二醇,液体聚乙二醇,等等(和其合适的混合物),环糊精衍生物,和蔬菜油。合适的流体性可以利用包衣,如卵磷脂,通过在分散的情况下维持需要的颗粒大小,也可利用表面活性剂来维持。可以由各种抗细菌和抗真菌剂阻止微生物行为,例如parabens,氯丁醇,酚,山梨酸,硫柳汞等等。
无菌可注射溶液是通过在适当溶剂中掺入需要量的通式I化合物和如上所枚举的各种其他成分,接着过滤灭菌来制备的。通常,分散液是通过在含有基本分散介质的无菌载体中掺入各种无菌活性成分和来自上面枚举的那些所需要的其他成分来制备。对用于无菌可注射溶液制备的无菌粉末,优选的制备方法是用真空干燥或冻干技术生产粉末,该粉末为来自前面所述的无菌过滤溶液的活性成分和任何其他需要的成分的混合物。
口服给药是通式I化合物的另一个给药途径。给药可以通过胶囊或肠衣片等等。在制造包括至少一个通式I的化合物的药物组合物时,活性成分通常是通过赋形剂稀释和/或包埋在胶囊,香袋,纸或其他容器等形式的载体中。当赋形剂作为稀释剂时,其可以是固体,半固体,或液体物质(如上所述),作为活性成分的载物、载体,或介质。因此,组合物可以是片剂形式,小丸形式,粉末,锭剂,香袋,扁囊剂(cachets),酏剂,悬浮液,乳液,溶液,糖浆,气雾剂(作为固体或在液体介质中),含有例如高达10%重量的活性化合物的油膏,软和硬的明胶胶囊,无菌的可注射溶液,以及无菌的包装粉末。
一些适当的赋形剂的例子包括乳糖,葡聚糖,蔗糖,山梨醇,甘露醇,淀粉,阿拉伯树胶,磷酸钙,藻酸盐,黄芪胶,明胶,硅酸钙,微晶纤维素,聚乙烯吡咯烷酮,纤维素,无菌水,糖浆和甲基纤维素。该制剂另外可以包括:润滑剂如滑石、硬脂酸镁和矿质油;加湿剂;乳化和悬浮剂;防腐剂如甲基和丙羟基苯甲酸盐;甜味剂和调味剂。
利用本领域公知的方法,可将本发明的组合物配制成对病人给药后快速释放,持续释放或延迟释放活性成分的方式。用于口服给药的控制释放的药物递送系统包括等渗泵系统和含有聚合物包衣的储存囊或药物聚合物基质配方的双溶液系统。控制释放系统的例子在美国专利3,845,770;4,326,525;4,902514和5,616,345中有描述。用于本发明方法中的另一个制剂利用了经皮的传输装置(“膏药”)。此类经皮的膏药可使控制量的本发明化合物连续或不连续地侵入。用于药物试剂传输的经皮膏药的构成和使用是本领域已知的,参见例如,美国专利号,5,023,252;4,992,445和5,001,139。此类膏药可制成连续的,搏动地或按照要求传输药物试剂。
组合物优选地以单位剂量形式配制。术语“单位剂量形式”指适于人和其他哺乳动物受试者的单一剂量的物理上不连续的单位,每个单位含有与适当的药物赋形剂(例如,片剂,胶囊,安瓿)相结合的,计算产生需要的治疗效果的预定量的活性物质。通式I的化合物在宽剂量范围内是有效的,并通常以药物有效量给药。优选地,对于口服给药,每个剂量单位含有10mg到2g通式I的化合物,更优选是10到700mg,对于肠胃外的给药,优选是10到700mg的通式I化合物,更优选50到200mg。但是,可以理解通式I化合物的真正给药量通常是医生根据相关的情况,包括待治疗的症状,给药的选择途径,给药的实际化合物和它的相关活性,年龄,体重,和个别病人的反应,病人症状的严重程度等等来确定的。
为了制备固体组合物如片剂,将基本活性成分与药物赋形剂混合形成固体的配制前体组合物,其中含有本发明化合物的均一混合物。这些配制前组合物为均一的,是指活性成分完全均匀分散在组合物中,以使组合物可以容易地被分成相等的有效剂量单位形式如片剂,丸剂和胶囊。
本发明的片剂或丸剂可以被包衣或被配制从而提供具有延迟作用优点的剂量形式,或保护其不受胃的酸性条件的干扰。例如,片剂或丸剂可以含有内剂和外剂成分,后者是前者的包被形式。两个成分可以通过肠衣层分开,作用是抵抗胃中的分解,允许内部成分完整地通过十二指肠,或延迟释放。对于这样的肠衣层或包衣可以利用各种物质,这样的物质包括大量的具有虫胶,十六烷基醇和乙酸纤维素物质的聚合物酸和聚合物酸的混合物。
吸入剂或喷剂的组合物包括药学上可接受的水溶液或有机溶剂或其混合物,以及粉末的溶液和悬浮液。液体或固体组合物可以含有如上所述的适当的药学上可接受的赋形剂。组合物优选地可以通过口或鼻呼吸途径给药,产生局部或系统的效果。优选的药学上可接受的溶剂中的组合物可以利用惰性气体气雾化。气雾化溶液可以直接从气雾装置吸入,或气雾化装置可以附着在面罩或间歇正压呼吸机器上。溶液,悬浮液或粉末组合物可以优选地口服或通过鼻从输送制剂的装置中以适当的方式给药。
下面的实施例是证实本发明的优选实施方案的。令本领域的技术人员满意的是,这些实施例公开的技术是本发明人公开的代表技术,在本发明的实践中很好地起作用,所以可以认为其构成了实践的优选模式。但是,本领域的技术人员应该明白,在本公开的启示下,可以在公开的特定实施方案中进行许多变化,且仍然可以得到相似的结果而不脱离本发明的精神范围。
实施例1
制备通式(2)化合物
A.制备R4 是戊基的通式(2)化合物
将1-溴戊烷(4.6g,3.8ml,30.4mmole)加入2-亚氨-4-硫代双脲(3g,25.4mmole)的干四氢呋喃(100ml)溶液中,并在室温下搅拌16小时,得到氨基(亚氨戊基硫代甲基)-羧基脒,即为其中R4是戊基的通式(2)化合物的四氢呋喃溶液。溶液不经纯化可进一步转化成通式I的化合物。
B.制备不同R4 的通式(2)化合物
同样,采用上面的1A过程,但使用其他通式R4Hal的化合物替代溴戊烷,制备出通式(2)的其他化合物,其中R4是甲基,乙基,n-丙基,异丙基,n-丁基,sec-丁基,t-丁基,3-甲基丙基,苯基,和4-t-丁基苯基。
C.制备不同R4 的通式(2)化合物
同样,采用上面的1A过程,但使用通式R4Hal的其他化合物替代溴戊烷,还制备出下面的通式(2)化合物:
氨基[亚氨(3-甲氧基丙基)硫代甲基]-羧基脒;
氨基[亚氨(3-羟基丙基)硫代甲基]-羧基脒;
氨基(亚氨环丙基硫代甲基)-羧基脒;
氨基(亚氨环戊基硫代甲基)-羧基脒;
氨基(亚氨环戊基甲基硫代甲基)-羧基脒;
氨基(亚氨环己基硫代甲基)-羧基脒;
氨基[亚氨(噻吩-2-基)硫代甲基]-羧基脒;
氨基[亚氨(异噁唑-3-基)硫代甲基]-羧基脒;
氨基[亚氨(呋喃-2-基)硫代甲基]-羧基脒;
氨基[亚氨(吡啶-2-基)硫代甲基]-羧基脒;
氨基{[2-(4-氯戊基)乙基硫代]亚氨甲基}-羧基脒;
氨基{[2-(4-叔-丁基苯氧基)乙基硫代]亚氨甲基}-羧基脒;
氨基{[2-(4-三氟甲基苯氧基)甲基硫代]亚氨甲基}-羧基脒;
氨基{[2-(4-氟苯氧基)乙基硫代]亚氨甲基}-羧基脒;和
氨基{[2-(3,5-二氯苯氧基)甲基硫代]亚氨甲基}-羧基脒;
D.制备不同R4 的通式(2)化合物
同样地,采用上面的1A方法,但用其他通式R4Hal的化合物替代溴戊烷,可以制备通式(2)的任何化合物。
实施例2
制备通式I化合物
A.制备通式I化合物,其中m是0,n和p是1,R1
和R2
是氢,R3是4-t-丁基戊基,R4
是戊基,T是氧,A是共价键,X1
,X2
和X3 都是氮,m是0,n和p都是1,Z是硫
1)在草酰氯的二氯甲烷溶液(25ml,2M)中加入如反应路线II所制备的4-t-丁基苯氧乙酸(5.2g,25mm ole),在冰浴中冷却。在溶液中加入无水N,N-二甲基甲酰胺(5滴),在0℃搅拌30分钟。使反应化合物升温至室温,搅拌直到气体蒸发终止,并且在减压下浓缩,将残留物与甲苯共沸两次得到2-(4-t-丁基苯氧基)乙酰氯的溶液。
在通式(2)化合物,氨基(亚氨戊基硫代甲基)-羧基脒的溶液中,加入2-(4-t-丁基苯氧基)乙酰氯的无水四氢呋喃溶液(25ml),接着加入无水的N,N-二异丙基乙基胺(9.75ml,56mmole),并且在室温下搅拌16小时得到混合物。在减压下浓缩得到混合物,在乙酸乙酯(150ml)中溶解残留物,用水(3×50ml),10%NaOH(2×25ml),盐水(1×50)洗涤,并且在无水硫酸钠中干燥。在减压下除去溶剂,利用己烷/乙酸乙酯梯度(10%到40%的乙基乙酸)在硅胶上纯化残留物,得到通式I的化合物,N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-戊基硫-1,3,5-三嗪-2-基胺,白色固体。(M+1)=361.2。
B.制备不同m,n,p,A,R1
,R2
,R3
,R4
,T,X1
,X2
,X3
,Y1和Y2 的通式I化合物
同样,按照上面的2A方法,但采用通式(2)的其他化合物替代氨基(亚氨戊基硫代甲基)-羧基脒,且用其他的酰基氯替代2-(4-t-丁基苯氧基)乙酰氯,制备得到通式I化合物:
4-甲基硫代-6-苯基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-三氟甲基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-氰基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(吡啶-3-基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-氟苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-t-丁基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-三氟甲基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(苯基硫代甲基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(2,4-二氯苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-甲基苯基)-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-戊基硫代-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(2-苯基环丙基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(1-苯氧基乙基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(2-氟苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-异丙基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(1,2-二氢环丁[1,2-a]苄基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(1,2,3,4,四氢萘基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-苯基丙基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-环己基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-二甲基氨基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(苯氧基甲基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-甲氧基苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-氟苯基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(2-苯基乙基)-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-氯苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-三氟苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-异丙基苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-t-丁基苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-(t-丁基苯基)甲基硫代-6-(4-甲氧基甲基)-1,3,5-三嗪-2-基胺;
4-(t-丁基苯基)甲基硫代-6-(4-t-丁基苯基)-1,3,5-三嗪-2-基胺;
4-苯基甲基硫代-6-(4-t-丁基苯基)-1,3,5-三嗪-2-基胺;
6-(茚满-5-基氧甲基)-4-甲基硫代-1,3,5-三嗪-基胺;
6-[(3,4-亚甲基二氧基苯氧基)甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-二甲基氨基-苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(4-乙基苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-异丙基苯氧基)甲基-1,3,5-三嗪-2-基胺;
6-{[(4-t-丁基苯基)硫代]甲基}-4-甲基硫代-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(萘基-2-基氧)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-(3-三氟甲基苯氧基)甲基-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[4-(咪唑-1-基苯氧基)甲基-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-乙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-丙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-异丙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-n-丁基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-sec-丁基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(3-甲基丙基)硫代-1,3,5-三嗪-2-基胺;和
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-苯基硫代-1,3,5-三嗪-2-基胺。
C.制备不同m,n,p,A,R1
,R2
,R3
,R4
,T,X1
,X2
,X3
,Y1和Y2 的通式I化合物
同样,按照上面2A的方法,但采用其他通式(2)的化合物替代氨基(亚氨戊基硫代甲基)-羧基脒,并选择性地用其他酰基氯取代2-(4-t-丁基苯氧基)乙酰氯,制备下面的通式I化合物:
基基基基基基基基基基基基基基基基N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(3-甲氧基丙基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(3-羟基丙基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-环丙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(3-甲氧基丙基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-环戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(环戊基甲基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-环己基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(噻吩-2-基甲基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(呋喃-3-基)硫代-1,3,5--三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(异噁唑-3-基甲基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-(吡啶-2-基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-[2-(4-氯苯基)乙基]硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-[2-(4-叔-丁基苯氧基)乙基]硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-[2-(4-三氟甲基苯基)乙基]硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-[2-(4-氟苯氧基)乙基]硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-[2-(3,5-二氯苯氧基)乙基]硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-氟苯氧基]甲基}-4-甲基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-甲基乙基]苯氧基}甲基)-4-甲基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[3-甲氧基苯氧基]甲基}-4-乙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{[3,5-二氯苯氧基]甲基}-4-n-丙基硫代-1,3,5-三嗪-2-基胺;
N-(6-{2-[4-氟苯氧基]乙基}-4-n-丁基硫代-1,3,5-三嗪-2-基胺;
N-(6-{2-[4-甲基乙基]苯氧基}丙基)-4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-{4-[3-甲氧基苯氧基]丁基}4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-{1-[3,5-二氯苯氧基]乙基}4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-[(吡啶-2-基)甲基]-4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-(环己基甲基)-4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-[(2-羟基环戊基)甲基]-4-戊基硫代-1,3,5-三嗪-2-基胺;和
N-(6-(呋喃-3-基甲基)-4-戊基硫代-1,3,5-三嗪-2-基胺。
实施例3
制备通式(3)化合物
A
.制备R4 是甲基的通式(3)化合物
在2-亚氨-4-硫代双脲(3g,25.4mmole)的干四氢呋喃(100ml)悬浮液中加入碘甲烷(1.9ml,30.4mmole),在室温下搅拌16小时。在得到的溶液中加入氯乙酰氯的无水四氢呋喃溶液(25ml),接着加入无水N,N-二异丙基乙基胺(9.75ml,56mmole),在室温下搅拌混合物16小时。在减压下浓缩反应混合物,将残留物溶解在乙酸乙酯中(150ml),用水(3×50ml),10%NaOH(2×25ml),盐水(1×50)洗涤,在无水硫酸钠中干燥。在减压下除去溶剂,用己烷/乙酸乙酯梯度(10%到40%乙酸乙酯)在硅胶上纯化残留物得到通式(3)的化合物,6-(氯甲基-4-甲基硫代-1,3,5-三嗪-2-基胺。
B.制备不同R4 的通式(3)化合物
同样,按照上面3A的方法,但采通式R4Hal的其他化合物替代碘甲烷,制备得到通式(3)的其他化合物,其中R4是乙基,n-丙基,异丙基,n-丁基,sec-丁基,t-丁基,n-戊基,苄基,和4-t-丁基苄基。
实施例4
制备通式I的化合物
A.制备通式I化合物,其中R1
和R2
是氢,R3
是3-氯苯基,R4 是甲基,T是-NH-,A是共价键,X1
,X2
,和X3 是氮,m是0,n是1和Y2 是亚甲基,Z是硫。
在6-(氯甲基-4-甲基硫代-1,3,5-三嗪-2-基胺(75mg,0.39mmol)的干四氢呋喃(3ml)的溶液中加入3-氯苯胺(0.210ml,1.97mmol)的干四氢呋喃(1ml)溶液,接着加入无水N,N-二异丙基乙基胺(0.343ml,1.95mmol)。在回流下加热混合物1 6小时,然后蒸发溶剂。通过反相HPLC纯化残留物得到4-([(3-氯苯基氨基)甲基]-6-甲基硫代[1,3,5]三嗪-2-基胺。M+1=266.1。
B.制备通式I的化合物,其中T是-NR5-,A,m,n,p,R1
,R2,R3
,R4
,X1
,X2
,X3
,Y1
和Y2 取不同基团
同样,按照上面4A的方法,但用通式(3)的其他化合物替代6-(氯甲基-4-甲基硫代-1,3,5-三嗪-2-基胺,且选择性地用通式R3(Y1)nR5NH的其他胺替代3-氯苯胺,制备下面的通式I化合物,其中T是-NR5-;
4-甲基硫代-6-[4-(1,1,1,3,3,3-己氟丙-2-醇)苯基氨基甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(二环己基氨基)甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(二苄基氨基)甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(苄基异丙基氨基)甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(4-(嘧啶-2-基)哌嗪-1-基)甲基]-1,3,5-三嗪-2-基胺;
6-[4-(3,4-亚甲基-二氧苯基)哌嗪-1-基]甲基)-4-甲基硫代-1,3,5-三嗪-2-基胺;
6-{[4-((2E)-3-苯基丙-2-烯基)吡嗪-1-基]甲基}-4-甲基硫代-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(2,6-二甲基苯基)氨基-甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(3-氯苯基)氨基甲基]-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(3-氯苯基)氨基甲基]-1,3,5-三嗪-2-基胺;
6-[(4-甲基吡嗪-1-基)甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
6-[(4-3,4-二甲基苯基)吡嗪-1-基)甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
6-[(4-(2-氟苯基)吡嗪-1-基)甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
4-甲基硫代-6-[(4-哌啶基哌啶基)甲基]-1,3,5-三嗪-2-基胺;
N-{[(3,5-二甲氧基苯基)氨基甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
N-{[(4-氯苯基)氨基甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
6-[4-(4-甲基哌啶)甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
6-[4-(4-氟苯基)哌嗪-1-基]甲基]-4-甲基硫代-1,3,5-三嗪-2-基胺;
和
4-甲基硫代-6-[(2,4-二甲氧基苯基)氨基甲基]-1,3,5-三嗪-2-基胺。
C.制备通式I化合物,其中T是-NR5,A,m,n,p,R1
,R2
,R3 ,R4
,X1
, X2
,X3
,Y1
和Y2 取不同基团
同样,按照上面3A的方法,但选择性地用通式(3)的其他化合物替代6-(氯甲基-4-甲基硫代-1,3,5-三嗪-2-基胺,且选择性地用通式R3(Y1)nR5NH的其他胺替代3-氯苯胺,制备通式I的下面的化合物,其中T是-NR5-:
4-[(3-氯苯基氨基)甲基]-6-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(3-甲氧基丙基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(3-羟基苯基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(3-环丙基)硫代-[1,3,5]-三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-环戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-环戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(环戊基甲基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(噻吩-2-基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(呋喃-3-基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(异噁唑-3-基甲基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-(吡啶-2-基)硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-[2-(4-氯苯基)乙基]硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-[2-(4-叔-丁基苯氧基)乙基]硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-[2-(4-三氟甲基苯基)乙基]硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯苯基氨基)甲基]-6-[2-(3,5,-二氯苯氧基)乙基]硫代-[1,3,5]三嗪-2-基胺;
4-[(4-氟苯基氨基)甲基]-6-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(4-甲基乙基苯基氨基)甲基]-6-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(4-甲氧基苯基氨基)甲基]-6-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(3,5-二氯苯基氨基)甲基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(3-氯戊基氨基)甲基]-6-n-丁基硫代-[1,3,5]三嗪-2-基胺;
4-[(3-甲氧基苯基氨基)甲基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[2-(3,5-二氯苯基氨基)乙基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(吡啶-2-基氨基)甲基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(环己基氨基)甲基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;
4-[(2-羟基环戊基)氨基甲基]-6-n-戊基硫代-[1,3,5]三嗪-2-基胺;和
4-[(呋喃-3-基胺)甲基]-6-n-丁基硫代-[1,3,5]三嗪-2-基胺。
实施例5
制备通式I的化合物
A.制备通式I的化合物,其中R1
是2-噻吩,R2
是氢,R3 是4-叔丁基苯基,R4 是甲基,T是氧,A是-C(Z1),Z1
是氧,X1
,X2
和X3 都是氮,m是0,n是1,Y2 是亚甲基,p是1,Z是硫
在氮气氛下,在6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-基胺,通式I的化合物,其中A是共价键,R1和R2是氢(25mg,0.082mmol)的干四氢呋喃(5ml)溶液中,加入氢化钠(5.76mg,0.24mmol),在室温下搅拌1小时。在得到的悬浮液中加入干2-噻吩-2-酰氯(0.009ml,0.082mmol)的四氢呋喃(1ml)溶液,在室温下搅拌反应混合物16小时。用水淬灭反应,通过反相HPLC纯化混合物得到N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-噻吩羧酰胺。M+1=415.1。
B.制备通式I的化合物,其中R1
是烯丙基,R2
是氢,R3 是4-叔-丁基苯基,R4 是甲基,T是氧,A是-C(Z1),Z1
是氧,X1
,X2
和X3 都是氮,m是0,n是1,Y2 是亚甲基,p是1,Z是硫
氮气氛中,于0℃下滴加异氰酸烯丙基酯(0.028mL,0.3285mmol)至6-{[4-(叔丁基)-苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-基胺(100mg,0.328mmol)的四氢呋喃溶液中。将混合物升温到室温,保持16小时以上。蒸发除去溶剂,并用反相HPLC纯化得到N-(6-{[4-(叔-丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-基(丙-2-烯基氨基)羧酰胺。M+1=388.1
C.制备通式I化合物,其中R1
是苄基,R2
是氢,R3 是4-叔-丁基苯基,R4
是甲基,T是氧,A是共价键,X1
,X2
和X3 都是氮,m是0,n是1,Y2 是亚甲基,p是1,Z是硫
a)将氰尿酰氯(0.75g,4.07mmol)溶解于干的CH2Cl2(10ml)中,并冷却到0℃。在溶液中加入二异丙基乙基胺(777ul,4,47mmol),接着逐滴加入苄基胺(444ul,4.07mmol)。冷却的溶液在0℃下搅拌2小时,升温到室温过夜。在减压下浓缩反应混合物以提供(4,6-二氯(1,3,5-三嗪-2-基)苄基胺,无需要进一步纯化即用于下面的步骤。
b)将来自上面反应的产物溶解于甲醇中,接着加入固体甲醇钠(1equiv.),并且在室温下搅拌混合物过夜。反应物在减压下浓缩,在CH2Cl2中溶解,用水,盐水洗涤,在硫酸钠中干燥。除去溶剂,在硅胶上纯化残留物(100%己烷到1∶1的己烷∶BtOAc),得到6-氯-4-甲氧基(1,3,5-三嗪-2-基)苄基胺。
c)在干的DMF(10ml)中悬浮氢化钠(36.7mg,0.937mmol),接着加入4-叔丁基苄基醇(111ul,0.625mmol),搅拌30分钟。将b)步骤的产物(100mg,0.398mmol)溶解于干的DMF(1ml)中,加入到苯甲醇溶液中。在室温搅拌反应2小时,接着加热到90℃过夜。冷却反应物,用水稀释(30ml),用乙基乙酸萃取。合并有机部分,用水,盐水洗涤,在硫酸钠上干燥,在减压下浓缩。通过反相HPLC纯化残留物,得到目标产物,(6-{[4-(4-叔丁基苯基)甲氧基(1,3,5-三嗪-2-基)苄基胺。
D.同样,根据上面5A,5B或5C的方法,但使用其中R1
和R2 是氢, A是共价键的通式I的其他化合物替代6-{[4-(叔-丁基)苯氧基]甲基-4-甲基硫代-1,3,5三嗪-2-基胺,并选择性地使用通式R1C((O)CL,R1NCO和R1 Halo的其他化合物来替代2-噻吩-2-酰氯,异氰酸烯丙基酯和苄基 溴,制备了下面通式I的化合物:
N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基)(4-氯苯基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(苯基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(4-甲氧基苯基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(4-二甲基氨基苯基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))-2,2,二甲基丙酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(环己基氨)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(甲基乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(丙基-2-烯基氨基)羧酰胺;
N-(6-[4-(叔丁基)苯基]-4-甲基硫代-1,3,5-三嗪-2-基)胺;
N-(6-[4-(叔丁基)苯基甲氧基]-4-甲基硫代-(1,3,5-三嗪-2-基)苄基胺;
(4-氨基-6-甲基硫代)1,3,5-三嗪-2-基)甲基]-[2-(二乙基氨基)-乙基]乙基胺;
N-[4-甲基硫代-6-(2-苯基环丙基(1,3,5-三嗪-2-基))(2-苯基环丙基)羧酰胺;和
N-(4-氨基-6-甲基硫代(1,,3,5-三嗪-2-基)[4-t-丁基苯基]羧酰胺。
E.同样,根据上面的5A,5B或5C的方法,但使用其中R1
和R2 是氢,A是共价键的通式I的其他化合物替代6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-基胺,且选择性地使用通式R1C((O)Cl,R1NCO和R1 Halo的其他化合物来替代2-噻吩-2-酰氯,异氰酸烯丙基酯 和苄基溴,制备了下面的通式I化合物:
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-噻吩硫代羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)苯甲酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-3-呋喃羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(3-甲氧基丙基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(3-羟丙基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-环丙基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(3-甲氧基丙基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-环戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(环戊基甲基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-环己基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(噻吩-2-基甲基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(呋喃-3-基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(异噁唑-3-基甲基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(吡啶-2-基)硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(4-环苯基)乙基]硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(4-叔丁基苯氧基)乙基]硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(4-三氟甲基苯基)乙基]硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(4-氟苯氧基)乙基]硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(3,5-二氯苯氧基)乙基]硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-氟苯氧基]甲基}-4-甲基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[4-甲基乙基]苯氧基}甲基)-4-甲基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[3-甲氧基苯氧基]甲基}-4-乙基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{[3,5-二氯苯氧基]甲基}-4-n-丙基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{2-[4-氟苯氧基]乙基}-4-n-丁基硫代-1,3,5-三嗪-噻吩羧酰胺;
N-(6-{2-[4-甲基乙基]苯氧基}丙基)-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{4-[3-甲氧基苯氧基]丁基}-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-{1-[3,5-二氯苯氧基]乙基}-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-[(吡啶-2-基)甲基]-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-(环己基甲基)-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-[(2-羟基环戊基)甲基]-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
N-(6-(呋喃-3-基甲基)-4-戊基硫代-1,3,5-三嗪-2-噻吩羧酰胺;
4-[(3-氯苯基氨基)甲基]-6-甲基硫代-[1,3,5]三嗪-2-噻吩羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(丁基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代(1,3,5-三嗪-2-基)(戊基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)环己基氨基}羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(3-羟基戊基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(叔-2-烯基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(呋喃-3-基胺)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(苯基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(4-氟苯基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-(1,3,5-三嗪-2-基)(吡啶-4-基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基-4-(3-甲氧基丙基)硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}4-(3-甲氧基丙基)硫代-(1,3,5-三嗪2--基)(乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-环戊基硫代(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(噻吩-2-基甲基)硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(呋喃-3-基)硫代-(1,3,5-三嗪-2-基)(异丙基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(吡啶-2-基)硫代-1,3,5-三嗪-2-基胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-[2-(4-氯苯基)乙基]硫代-(1,3,5-三嗪-2-基)(丙-2-烯基氨基)羧酰胺;
N-(6-{[4-(叔丁基)苯氧基]甲基}-4-(2-(4-叔丁基苯氧基)乙基)硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-{[4-氟苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-{2-[4-甲基乙基]苯氧基}丙基)-4-戊基硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-[(吡啶-2-基)甲基]4-戊基硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;
N-(6-(呋喃-3-基甲基)-4-戊基硫代-N-(6-(环己基甲基)-4-戊基硫代-1,3,5-三嗪-2-基胺;
N-(6-[(2-羟基环戊基)甲基]-4-戊基硫代-1,3,5-三嗪-2-基胺;
实施例6
制备通式I化合物
A.制备通式I的化合物,其中R1
和R2
是氢,R3 是4-叔-丁基苯基,R4
是甲基,(T)n是NH,A是共价键,X2
和X3
是氮,X3是CH,Y1是-C(O)-和m是1,n是1,p是0,Z是硫
在4,6-二氨基-2-甲基氢硫基吡啶(50mg,0.032mmol)的无水四氢呋喃溶液中加入氢化钠,接着加入4-t-丁基苯甲酰基氯(0.084ml,0.32mmol)和N,N-二异丙基乙基胺。在50℃加热混合物16小时,然后进行水相工作。用乙基乙酸萃取产物,用HPLC纯化得到N-(6-氨基-2-甲基硫代嘧啶-4-基)[4-(叔-丁基)苯基]羧酰胺。M+1=317.3。
B.制备通式I的化合物,其中X2
和X3
是氮,X3是CH,A,m,n,R1
,R2
,R3
,R4
,A,(T)n,(Y
1
)n,(Y
2
)n和Z取不同基团
同样,按照上面6A的方法,但使用通式(4)的其他化合物替代4,6-二氨基-2-甲基氢硫基嘧啶,并选择性地用通式R1-(Y1)n-Halo替代4-t-丁基苯甲酰氯,制备出下面的通式I化合物:
N-(6-氨基-2-乙基硫代嘧啶-4-基)[4-(叔-丁基)苯基]羧酰胺;
N-(6-氨基-2-异丙基硫代嘧啶-4-基)[4-(叔丁基)苯基]羧酰胺;
N-(6-氨基-2-异丙基硫代嘧啶-4-基)[4-(叔丁基)苯基]羧酰胺;
N-(6-氨基-2-环戊基硫代嘧啶-4-基)[4-(叔丁基)苯基]-(乙基氨基)羧酰胺;和
N-(6-氨基-2-异丙基硫代嘧啶-4-基)[4-(叔丁基)苯基](2-噻吩)羧酰胺。
下面的实施例说明了含有通式I的化合物的代表性药物组合物的制备。
实施例7
制备含有以下成分的硬明胶胶囊:
成分
质量
(mg/胶囊)
活性成分 30.0
淀粉 305.0
硬脂酸镁 5.0
混合上面的成分,并填充进入硬的明胶胶囊中。
实施例8
利用下面的成分制备片剂:
成分
质量
(mg/片剂)
活性成分 25.0
纤维素,微晶体 200.0
胶体二氧化硅 10.0
硬脂酸 5.0
混合这些成分,压缩形成片剂。
实施例9
制备含有下面的成分的干粉吸入剂配方:
成分
重量%
活性成分 5
乳糖 95
将活性成分与乳糖混合,将混合物加入干粉吸入器装置中。
实施例10
如下制备含有各30mg活性成分的片剂:
成分
质量
(mg/片剂)
活性成分 30.0mg
淀粉 45.0mg
微结晶纤维素 35.0mg
聚乙烯吡咯烷酮
(作为10%的无菌水溶液) 4.0mg
羧甲基钠淀粉 4.5mg
硬脂酸镁 0.5mg
滑石粉 1.0mg
总共 120mg
将活性成分,淀粉和纤维素通过20号网孔的美国筛,并完全混合。将聚乙烯吡咯烷酮的溶液与得到的粉末混合,然后通过16号网孔的美国筛。将这样产生的颗粒在50℃到60℃干燥,并通过16网孔的美国筛。羧甲基钠淀粉,硬脂酸镁和滑石粉,先通过30号网孔的目美国筛,然后加入颗粒中混合,在片剂机器上压缩,得到每个称重为120mg的片剂。
实施例11
如下制造每个含有25毫克活性成分的栓剂:
成分
量
活性成分 25mg
饱和脂肪酸甘油 2,000mg
将活性成分通过60号网孔的美国筛,然后悬浮于事先用最小的热量溶化的饱和脂肪酸甘油酯中。然后,将混合物倒入名义上有2.0g容量的栓剂模中,并使之冷却。
实施例12
如下制造每5.0ml剂量含有50mg活性成分的悬浮液:
成分
量
活性成分 50.0mg
黄原胶 4.0mg
羧甲基纤维素钠(11%)
微结晶纤维素(89%) 50.0mg
蔗糖 1.75g
苯甲酸钠 10.0mg
口味和颜色 q.v.
纯化水至 5.0ml
将活性成分,蔗糖和黄原胶混合,通过10号网孔的美国筛,然后与预先在水中制造的微结晶纤维素和羧甲基纤维素钠溶液混合。将苯甲酸钠,调味剂,色素用一些水稀释后,搅拌加入。然后加入足够的水获得需要的体积。
实施例13
如下制备皮下用的配方:
成分
质量
活性成分 5.0mg
玉米油 1.0ml
实施例14
制备具有如下组成的注射制剂:
成分
量
活性成分 2.0mg/ml
甘露醇,USP 50mg/ml
葡糖酸,USP q.s.(pH5-6)
水(蒸馏水,无菌) q.s到1.0ml
氮气,NF q.s
实施例15
制备具有如下组成的局部用制剂:
成分
克数
活性成分 0.2-10
Span 60 2.0
Tween 60 2.0
矿质油 5.0
矿脂 0.10
羟苯甲酸甲酯 0.15
羟苯甲酸丙酯 0.05
BHA(丁化羟基苯甲醚) 0.01
水 q.s.到100
所有除了水之外的上面成分合在一起,加热到60℃,并且搅拌。然后,剧烈搅拌下在60℃加入足够量的水,乳化这些成分,然后加入水,q.s100g。
实施例16
持续释放组合物
成分
重量范围
优选范围
最优选
(%) (%)
活性成分 50-95 70-90 75
微结晶纤维素(填料) 1-35 5-15 10.6
甲基丙烯酸共聚物 1-35 5-12.5 10.0
氢氧化钠 0.1-1.0 0.2-0.6 0.4
羟基丙基甲基纤维素 0.5-5.0 1-3 2.0
硬脂酸镁 0.5-5.0 1-3 2.0
如下制备本发明的持续释放配方:仔细地混合化合物、由pH值决定的粘合剂和或选的赋形剂(干混合)。然后,在存在强碱水溶液时将干混合的混合物颗粒化,该碱溶液喷洒于混合的粉末中。干燥,筛选颗粒,选择性地与润滑剂混合(如滑石粉,或硬脂酸镁),并且压缩成片剂。优选的强碱水溶液是氢氧化碱金属溶液,如氢氧化钠或钾,优选氢氧化钠水溶液(选择性地含有高达25%的与水易混合的溶剂如低级醇)。
用任选的成膜剂包衣,用于鉴别和掩盖味道,并使吞咽容易。成膜剂存在的量通常为2%和4%的片剂重量。适当的成膜剂是本领域已知的,并且包括羟基丙基甲基纤维素,阳离子甲基丙烯酸酯共聚物(甲基丙烯酸二甲基氨基乙基酯/甲基丙烯酸甲基丁基酯共聚物-Eudragit_E-Rohm,Pharma)等等。这些成膜剂选择性地含有着色剂,增塑剂和其他补充成分。
压缩片剂优选地具有足以抵抗8Kp压力的硬度。片剂大小主要取决于片剂中的化合物的量。片剂将包括300到1100mg的化合物的游离碱。优选地,片剂包括的化合物游离碱的量范围是400-600mg,650-850mg,和900-1100mg。
为了影响溶解的速度,含有化合物的粉末的湿混合时间是被控制的。优选地,总的粉末混合时间,即粉末与氢氧化钠溶液接触的时间的范围是1到10秒,优选地是2到5秒。在颗粒化后,从造粒器中取出颗粒,放置于流动床干燥器中,在约60℃干燥。
实施例17
pGL3荧光素酶试验
这一实施例显示了本发明的化合物对ABCA-1基因表达的作用,采用pGL3荧光素酶报道载体系统(Promega,Madison,WI)产生重组质粒,在ABCA-1启动子的控制下检测报道基因的表达。
构建报道质粒
利用质粒pGL3-Basic(Promega,Madison,WI;Cat.#1751)作为含有无启动子荧光酶基因的对照质粒。含有BACA-1启动子和荧光酶基因的报道构建体是这样制成的:通过将来自ABCA-1基因5‘侧接区的基因片断(hAPR15’启动子,对应于SEQ ID NO:3的核苷酸1080-1643)克隆进GL3-Basic质粒的
SacI位点以产生质粒GL-6a。然后,用
SpeI和
Acc65L消化质粒GL-6a。从λ亚克隆切出
BsiWI-
SpeI片段,其代表对应于SEQ IDNO:3的核苷酸1-1534的ABCA-1基因组序列,使其连接入由这一消化产生的其余的载体/ABCA-1启动子片段。得到的质粒,pAPR1在人的1.75kb的ABCA-1启动子序列的转录控制下编码荧光酶报道基因。
报道构建体的转染:将上面所述的对照物或pAPR1质粒转染进RAW164.7细胞的融合培养物中,该细胞保存在含有10%的胎牛血清的DMEM中。用pGL3-Basic,pGL3-启动子或pAPR1DNA(1μg),荧光酶质粒DNA(1μg),和12μl的基因报道试剂(基因治疗系统,圣地亚哥,CA;Cat.#T201007)转染12孔盘的每个孔达5小时。另外,将0.1μg的pCMVβ质粒DNA(Clontech,Palo Alto,CA,Cat.#6177-1)作为转染效率的对照物加入。在5小时后,用存在或缺乏乙酰化LDL(100ug/ml)的无血清的DMEM/BSA替代培养基,温育24小时。
为了在高流通量的筛选中添加方便,可以用下面的方法,用报道质粒稳定地转染培养的细胞。首先,在60mm的盘中,用在10ml无血清的DMEM和50μl的基因报道转染试剂(基因治疗系统,San Diego,CA)中的pCMVscript(Stratagene,LaJolla,CA)和9μg pAPR1质粒转染5×106RAW 264.7细胞达5小时。随后,用完全培养基替代转染培养基,在37℃温育细胞过夜。随后,将细胞转移到分离的盘中,稀释度为1∶5到1∶1000,并且在含有800μg/ml G418的选择培养基(Life Technologies,Bethesda,MD)中温育20天。挑选可见的克隆,扩展,如下所述测试荧光酶活性。利用这一方法,鉴定出荧光酶活性阳性的5个克隆细胞系,用于高流通量试验。
荧光酶述验:在转染后,在70μl的1X细胞溶解剂(Promega,Madison,WI,Cat.#3971)中溶解每个孔中的细胞,进行一次冻融循环,在12,000g离心下清除溶解物5分钟。在离心后,将100μl的荧光酶试剂(Promega,Madison,WI;Cat.#E1501)加入到10μl的溶解物中。利用发光计将每个溶解物的荧光酶活性作为光单位来进行测量。另外,利用在Galacto-光试剂盒中的化学发光实验试剂(Tropix公司,Bedford,MA:Cat.#BL100G),根据制造商的说明测量每个溶解物的β-半乳糖苷酶活性。通过用确定的β-半乳糖苷酶值除(divide)荧光酶活性值,确定了每个溶解物的归一化荧光酶活性,并且报道为相关的光单位。
本试验中证实了本发明的化合物提高了ABCA-1基因的表达。
实施例18
mRNA试验
下面的实验中,测定了本发明的化合物对ABCA-1mRNA水平表达的调节。
定量的PCR
在DMEM/10%FBS中,将THP的培养物生长到亚融合,用DMEM/BSA替代DMEM/10%FBS,再生长24到80小时。RNA利用标准方法。
利用GeneAmp 5700序列检测系统(Perkin-Elmer Applied Biosystem,Foster City,CA)进行定量的PCR。简要地说,利用2.5μM的任意六联体引物逆转录500ngDNAse-处理的mRNA。利用SYBR绿核试剂盒(PEApplied Biosystems,Foster City,CA;Cat.#4304886)和人ABCA-1引物LF:5’-CCTCTCATTACACAAAAACCAGAC(SEQ ID NO:11)和LR:5’-GCTTTCTTTCACTTCTCATCCTG(SEQ ID NO:12)通过PCR扩增约5%的这一反应以产生对应于人ABCA-1的核苷酸7018-7099的82bp片段。PCR循环条件如下:95℃,10分钟;接着40个95℃,15秒的循环;以及60℃,60秒。通过检测SYBR绿与每个PCR循环中产生的双标准扩增产物相结合引起的荧光增加来定量每个样品中的mRNA。所有样品进行3份,对β-激动素mRNA归一化,在平行反应中利用引物激动素F:5’-TCACCCACACTGTGCCATCTACGA(SEQ ID NO:54)和激动素B:5’-CAGCGGAACCGCTCATTGCCAATGG(SEQ ID NO:55)来扩增。在相同的PCR平板上对ABCA-1和β-激动素做标准的曲线。
在mRNA水平的变化也可以利用RAW 264.7细胞和来自Bayer的QuantiGene_表达试剂盒一起来测定。
在此试验中,本发明的化合物调节ABCA-1mRNA水平的表达。
实施例19
脂流出试验
本实施例证明,质膜中ABCA-1蛋白质表达的增强是与脂的流出相关的。
将细胞表面标记和免疫沉淀用于测定质膜中ABCA-1蛋白质表达的增强是否与胆固醇流出的增强相关。细胞表面ABCA-1的相对量用以下方法测定:用膜不可渗透试剂硫-NHS-生物素在完整细胞上交联表面蛋白质,接着进行膜溶解,用ABC1抗体免疫沉淀,SDS-PAGE,以及用链霉生物素检测。
细胞培养:在控制条件和已知增强胆固醇流出的条件下培养成纤维原细胞(Oram,et al.,J.Lip.Res.,40:1769-1781(1999))。在DMEM/10%FBS中,使对照细胞生长到融合,然后,无添加物(对照物)的情况下,在DMEM/BSA中温育18小时。在DMEM/10%FBS中使cAMP-处理细胞生长到融合,然后在DMEM/BSA中与1mM 8-Br-cAMP(cAMP)温育18小时。在DMEM/10%FBS中使胆固醇-加载细胞生长到融合,然后,在DMEM/BSA中与30μg/ml胆固醇温育48小时,再在无添加物(胆固醇)的情况下生长18小时。用cAMP处理的胆固醇加载细胞在DMEM/10%FBS中生长到融合,然后在DMEM/BSA中与30ug/ml的胆固醇温育48小时,然后与1mM 8-Br-cAMP(胆固醇+cAMP)温育18小时。
细胞表面标记:为了选择标记质膜ABCA-1,在0℃将细胞与含有1mg/ml的硫-NHS生物素(Pierce,Rockford,IL;Cat.#21217)的PBS一起培养达30分钟,生物素化细胞表面的蛋白质(参见Walker et al.,生物化学,50:14009-14014(1993))。
免疫沉淀:生产对ABCA-1的兔抗血清,抵抗一种与定位于人ABCA-1C末端的推测的肽KNQTVVDAVLTSFLQDEKVKES相对应的合成肽。在含有1%的Triton X-100(Sigma,St.Louis,MO)和蛋白酶抑制剂亮抑蛋白酶肽(1mM),胃酶抑素(1mM)和抑酶肽(1mM)的PBS中溶解细胞进行免疫沉淀。在4℃,细胞萃取物与抗-ABCA-1抗血清以1∶200的稀释度一起过夜温育,再与5μl的蛋白质A-包衣的磁性小珠温育1小时(Dynal,Lake Success,NY;Cat.#1001.01)。用磁体沉淀抗体-抗原复合物,用1%的Triton-X/PBS洗涤小珠两次,用1%乙酸洗脱蛋白质。
检测ABCA-1蛋白质:将洗脱的生物素化的蛋白质进行SDS-PAGE(6%凝胶;150V,5小时),并转移到硝化纤维素膜(200mA,18小时)。用稀释了300倍的链霉抗生素辣根过氧化物酶(AmershamPharmacia,Piscataway,NJ;Cat.#RPN 1231)探测硝酸纤维素,并根据出售规范(Vendor’proctocol)(Amersham Pharmacia,Piscataway,NJ)用加强的化学荧光标记法(ECL)检测。为了测试细胞内蛋白质可能的生物素化,用细胞内的蛋白质β-COP的小鼠单克隆抗体处理免疫后沉淀的上清液,通过链霉抗生素印迹测试免疫沉淀生物素化的β-COP。
实施例20
在下面的实验中测定本发明的化合物刺激胆固醇从细胞流出的能力。
如Smith et al.,J.Biol.Chem.,271:30647-30655(1996)中所述,用胆固醇加载RAW264.7细胞。简要地说,在0.2ml的用4.5g/L蔗糖,0.1g/L丙酮酸钠和0.584g/L的谷氨酸,10%胎牛血清,50ug/ml的乙酰化低密度脂蛋白(AcLDL)和0.5μCi/ml的[3H]-胆固醇补充的0.2ml的DMEM中温育植入48孔盘中的半融合细胞。在18小时后,用含有1%BSA的PBS洗涤细胞2次,在DMEM/1%BSA中温育过夜(16-18小时),允许胆固醇库平衡。然后,用PBS/BSA漂洗细胞,在37℃用DMEM/BSA温育1小时。加入含有单独的白蛋白(对照),白蛋白加HDL(40μg蛋白质/ml),或白蛋白加apoA-I(20μg/ml,Biodesign International,Kennebunk,ME)的流培养基(DMEM/BSA),温育细胞4,24或48小时。
通过除去培养基,洗涤细胞层和萃取细胞测量胆固醇流。通过在0.5ml的0.2M NaOH中溶解(Smith et al.,生物化学杂志,271:30647-30655(1996))或在己烷∶异丙醇(3∶2v/v)中萃取后,如Francis et al.,Clin.Invest.,96:78-87(1995)中所述,可以测量细胞的放射性。在培养基中剩余的已标记的磷脂也可以通过液体闪烁计数来测定。胆固醇流表示成培养基中含氚的脂的计数占细胞和培养基中收到的含氚的总脂的计数(cpm培养基/cpm(培养基+溶解物)×100)的百分数。
胆固醇流也可以在THP细胞中测定。利用所述的方法在48孔的盘中植入复制的THP细胞培养物(参见Kritharides et al Thrombo Vasc Biol18,1589-1599,1998)。以起始密度为500,000个细胞/孔植入细胞。在加入PMA(100ng/ml)后,在37℃温育培养物48小时。抽吸培养基,并用含有2mg/ml的FAFA,50μg/ml的乙酰化LDL和3μCi/ml放射性标记的胆固醇的RPMI-1640培养基替代。温育过夜后,抽吸培养基,用PBS广泛洗涤孔。在每个孔中加入含有2mg/ml FAFA的0.2ml RPMI-1640培养基。加入需要的化合物到最后浓度为10uM。4小时后,在一些孔中加入阿朴脂蛋白A1(10μg/ml),温育培养物24小时。收获培养基,并测试放射性。通过加入0.2ml 2M NaOH并且计数溶解的细胞来测定细胞层中放射活性的量。如上所述计算胆固醇流的百分数。
此实验中,本发明的化合物刺激了胆固醇流。
实施例21
ABCA-1表达和HDL水平之间的关系在下面的体内实验中测定。
通过腹膜内注射或通过在10%的Cremaphore(BASF)/盐的管饲法,以预定剂量,每日对7星期大的雄性C57B1/6小鼠给予预定剂量的候选化合物,该化合物可增加体外ABCA-1表达,有药物活性且在体内有效。在最后注射后3到4小时,收集EDTA-血浆和适当的组织用于分析。通过磷钨酸沉淀(Sigma)分离血浆HDL,采用试剂盒用酶方法确定HDL胆固醇,总胆固醇和三乙酰甘油(Roche Diagnostics)。利用与胆固醇系列连接的两个Superose6/30柱,通过FPLC,在学检测的洗脱部分中进一步分析HDL胆固醇和大小的变化。通过对从候选组织分离的RNA进行RT-PCR分析,可进一步证实ABCA-1基因表达的体内变化。
此实验中观察到了ABCA-1表达和HDL水平之间的关系。
Claims (63)
1.一种治疗能用增强ABCA-1表达的试剂治疗缓和的哺乳动物疾病状态的方法,包括对需要的哺乳动物给予治疗有效剂量的通式I化合物:
通式I
其中:m,n和p分别是0或1;
A是-C(Z1)-,-C(Z1)-NH-,SO2或共价键;
其中Z1是氧或硫;
R1是氢,选择性取代的烷基,选择性取代的烯基,选择性取代的炔基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
R2是氢,烷基或环烷基;或
R1,R2和A与和它们连接的氮原子一起形成含氮的杂环;
R3为选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
R4是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
T是-O-,-S(O)q,or-NR5-;
其中q是0,1或2,R5是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
X1,X2和X3分别是-CR6或氮,其中R6是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;条件是X1,X2,和X3中的至少一个是氮;
Y1是低级亚烷基或羰基;
Y2是低级亚烷基或氧;
以及
Z是硫,氧,或-NR5-。
2.如权利要求1所述的方法,其中X1,X2,和X3都是氮。
3.如权利要求2所述的方法,其中R2是氢,R4为选择性取代的烷基,Z是硫。
4.如权利要求3所述的方法,其中R3是选择性取代的芳基或选择性取代的杂芳基。
5.如权利要求4所述的方法,其中m是0,n是1,p是1。
6.如权利要求5所述的方法,其中A是共价键,R1是氢。
7.如权利要求6所述的方法,其中R3是选择性取代的苯基,Y2是亚甲基。
8.如权利要求7所述的方法,其中R4是具有1-8个碳原子的烷基,T是氧。
9.如权利要求8所述的方法,其中R3是4-t-丁基苯基,R4是甲基,称为6-{[4-(叔-丁基)苯氧基]甲基}-4-戊基硫代-1,3,5-三嗪-2-基胺。
10.如权利要求8所述的方法,其中R3是4-t-丁基苯基,R4是n-戊基,称为6-{[4-(叔-丁基)苯氧基]甲基}-4-戊基硫代-1,3,5-三嗪-2-基胺。
11.如权利要求7所述的方法,其中R4具有1-8个碳原子的烷基,T是氧。
12.如权利要求11所述的方法,其中R3是3-氯苯基,R4是甲基,R5是氢,称为4-{(3-氯苯基氨基)甲基}-6-甲基硫代-[1,3,5]三嗪-2-基胺。
13.如权利要求11的方法,其中R3是2,4-二甲氧基苯基,R4是甲基,R5是氢,称为N-{[3,5-二甲氧基苯基]氨基甲基}-4-甲基硫代-1,3,5-三嗪-2-基胺;
14.如权利要求5所述的方法,其中A是-C(O)NH-,R1是氢,选择性取代的烷基,选择性取代的烯基,选择性取代的环烷基,或选择性取代的杂环基。
15.如权利要求14所述的方法,其中R3为选择性取代的苯基,Y2是亚甲基。
16.如权利要求15所述的方法,其中R4是具有1-8个碳原子的烷基,T是氧。
17.如权利要求16所述的方法,其中R1是具有1-6个碳原子的烷基,或具有1-6个碳原子的烯基。
18.如权利要求17所述的方法,其中R1是甲基,乙基,异丙基或烯丙基,R3是4-叔-丁基苯基。
19.如权利要求18所述的方法,选自N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫基-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基)(甲基乙基氨基)-羧酰胺;和N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基))(丙-2-烯基氨基)羧酰胺。
20.如权利要求5所述的方法,其中A是-C(O)-,R2是氢,R4是具有1-8个碳原子的烷基。
21.如权利要求20所述的方法,其中T是氧,R1是具有1-6个碳原子的烷基或杂环基,R3为选择性取代的苯基。
22.如权利要求21所述的方法,其中R1是2-硫代苯基,R4是甲基,称为N-(6-{[4-(叔-丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-噻吩基羧酰胺。
23.如权利要求1所述的方法,其中X2和X3是氮,X1是-CH-。
24.如权利要求23所述的方法,其中R2是氢,R4是选择性取代的烷基,Z是硫。
25.如权利要求24所述的方法,其中R3是选择性取代的芳基或选择性取代的杂芳基。
26.如权利要求25所述的方法,其中m是0,n是1,p是1。
27.如权利要求26所述的方法,其中R3是选择性取代的苯基,Y2是亚甲基,A是共价键,R1是氢。
28.一种治疗能用提高HDL胆固醇的血清水平的化合物来治疗的哺乳动物疾病或症状的方法,包括对需要治疗的哺乳动物给予治疗有效量的通式I化合物。
29.如权利要求28所述的方法,其中所述的疾病状态或症状是冠状动脉疾病或动脉硬化。
30.一种治疗与低HDL胆固醇水平相关的哺乳动物疾病或症状的方法,包括对需要的哺乳动物给予治疗有效量的通式I化合物。
31.如权利要求30所述的方法,其中所述疾病状态或症状是冠状动脉疾病或动脉硬化。
32.一种治疗能用促进胆固醇从细胞流出的化合物来治疗的哺乳动物疾病或症状的方法,包括对需要的哺乳动物给予治疗有效量的通式I化合物。
33.如权利要求32所述的方法,其中所述疾病状态或症状是冠状动脉疾病或动脉硬化。
34.一种治疗与冠状动脉疾病相关的,能利用提高HDL胆固醇的血清水平的化合物和降低LDL胆固醇的化合物相结合来治疗的哺乳动物症状的方法,包括对需要的哺乳动物给予治疗有效量的通式I化合物和降低LDL胆固醇的化合物。
35.如权利要求34的方法,其中降低LDL胆固醇的化合物是选自氯贝特,吉非罗齐,和降脂异丙酯,烟酸,莫维诺林,美伐他汀,普伐他汀,simuvastatin,氟伐他汀,洛伐他汀,cholestyrine,考来替泊,和普罗布考。
36.通式I化合物:
其中:
m,n和p分别是0或1;
A是-C(Z1)-,-C(Z1)-NH-,SO2或共价键;
其中Z1是氧或硫;
R1是氢,选择性取代的烷基,选择性取代的烯基,选择性取代的炔基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
R2是氢,烷基或环烷基;或
R1,R2和A与它们连接的氮原子一起形成含氮的杂环;
R3是选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
R4是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
T是-O-,S(O)q或者-NR5-;
其中q是0,1或2,R5是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;
X1,X2,和X3分别是-CR6或氮,其中R6是氢,选择性取代的烷基,选择性取代的环烷基,选择性取代的杂环基,选择性取代的芳基,或选择性取代的杂芳基;条件是X1,X2和X3中的至少一个是氮。
Y1是低级亚烷基或羰基;
Y2是低级亚烷基或氧;
和
Z是硫,氧,或-NR5-,
条件是当A是共价键,R1和R2都是氢,且Z是-NH-时,m,n和p不能都为0;且
当m为0,Y2是亚甲基,Z是-NH-时,R3不能是低级烷基;且
当Z是-NH-时,R4不能是苯基乙基;且
当A是共价键,R1和R2都是氢,Y2是亚甲基,且R4是甲基或乙基时,R3不能是低级烷基或者未取代的苯基;且
当A是共价键,R1和R2都是氢,T是氧,Z是氮,且Y2是亚甲基时,R4不能是环烷基或未取代的苯基。
37.如权利要求36所述的化合物,其中X1,X2和X3都是氮。
38.权利要求37所述的化合物,其中R2是氢,R4是选择性取代的烷基,Z是硫。
39.如权利要求38的化合物,其中R3是选择性取代的芳基或选择性取代的杂芳基。
40.如权利要求39所述的化合物,其中m是0,n是1,p是1。
41.如权利要求40所述的化合物,其中A是共价键,R1是氢。
42.如权利要求41所述的化合物,其中R3是选择性取代的苯基,Y2是亚甲基。
43.如权利要求42所述的化合物,其中R4是具有1-8个碳原子的烷基,T是氧。
44.如权利要求43所述的化合物,其中R3是4-t-丁基苯基,R4是甲基,称为6-{[4-(叔丁基)苯氧基]甲基}-4-戊基硫代-1,3,5三嗪-2-基胺。
45.如权利要求43所述的化合物,其中R3是4-t-丁基苯基,R4是n-戊基,称为6-{[4-(叔丁基)苯氧基]甲基}-4-戊基硫代-1,3,5-三嗪-2-基胺。
46.如权利要求43所述的化合物,其中R3是3-氯苯基,R4是甲基,R5是氢,称为4-{(3-氯苯基氨基)甲基}-6-甲基硫代-[1,3,5]三嗪-2-基胺。
47.如权利要求43所述的化合物,其中R3是2,4-二甲氧基苯基,R4甲基,R5是氢,称为N-{(3,5-二甲氧基戊基)氨基甲基}-4-甲基硫代-1,3,5三嗪-2-基胺。
48.如权利要求41所述的化合物,其中A是-C(O)NH-,R1是氢,选择性取代的烷基,选择性取代的烯基,选择性取代的环烷基,或选择性取代的杂环基。
49.如权利要求48所述的化合物,其中R3是选择性取代的苯基,Y2是亚甲基。
50.如权利要求49所述的化合物,其中R4是具有1-8个碳原子的烷基,T是氧。
51.如权利要求50的化合物,其中R1是具有1-6个碳原子的烷基或具有1-6个碳原子的烯基。
52.如权利要求51所述的化合物,其中R1是甲基,乙基,异丙基或烯丙基,R3是4-叔丁基苯基。
53.如权利要求52的化合物,选自N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基)(乙基氨基)羧酰胺;N-(6-{[4-(叔丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5三嗪-2-基)(甲基乙基氨基)-羧酰胺;和N-(6-{[4-(叔-丁基)苯氧基]甲基}-4-甲基硫代-(1,3,5-三嗪-2-基)(丙基-2-烯基氨基)羧酰胺。
54.如权利要求40所述的化合物,其中A是-C(O)-,R2是氢,R4是具有1-8个碳原子的烷基。
55.如权利要求54所述的化合物,其中T是氧,R1是具有1-6个碳原子的烷基或杂环基,R3是选择性取代的苯基。
56.如权利要求55所述的化合物,其中R1是2-硫代苯基,R4是甲基,称为N-(6-{[4-(叔丁基)苯氧基]甲基-4-甲基硫代-1,3,5-三嗪-2-噻吩基羧酰胺。
57.如权利要求3 5所述的化合物,其中X2和X3是氮,X1是-CH-。
58.如权利要求57所述的化合物,其中R2是氢,R4是选择性取代的烷基,Z是硫。
59.如权利要求58所述的化合物,其中R3是选择性取代的烷基或选择性取代的杂芳基。
60.如权利要求59所述的化合物,其中m是0,n是1,p是1。
61.如权利要求60所述的化合物,其中R3是选择性取代的苯基,Y2是亚甲基,A是共价键,R1是氢。
62.一种药物组合物,含有至少一个药学上可接受的赋形剂和治疗有效量的权利要求1的化合物。
63.一种药物组合物,含有至少一个药学上可接受的赋形剂和治疗有效量的权利要求36的化合物。
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CNA018200311A Pending CN1478085A (zh) | 2000-12-07 | 2001-12-06 | 用于治疗冠状动脉疾病或动脉粥样硬化的abca-1提高化合物 |
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