CN104520307B - 用于治疗神经疾病的泛酸酯衍生物 - Google Patents
用于治疗神经疾病的泛酸酯衍生物 Download PDFInfo
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- CN104520307B CN104520307B CN201380033271.0A CN201380033271A CN104520307B CN 104520307 B CN104520307 B CN 104520307B CN 201380033271 A CN201380033271 A CN 201380033271A CN 104520307 B CN104520307 B CN 104520307B
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical class OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Chemical compound [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000009492 vitamin B5 Nutrition 0.000 description 1
- 239000011675 vitamin B5 Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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Abstract
本公开内容涉及用于治疗神经疾病(如泛酸激酶相关的神经变性)的泛酸酯衍生物、包含这样的化合物的药物组合物,以及它们在治疗神经疾病中的用途。
Description
本申请要求于2012年4月27日提交的美国临时申请号61/639,602的权益,将其全部内容通过引用结合于此。
发明领域
本发明涉及用于治疗神经疾病(如泛酸激酶(pantothenate kinase)相关的神经变性)的泛酸酯衍生物(泛酸衍生物,pantothenate derivatives),包含这样的化合物的药物组合物,及它们在治疗神经疾病中的用途。
背景技术
泛酸激酶相关的神经变性(PKAN)是具有脑铁积累的神经变性(脑内铁沉积性神经变性,neurodegeneration with brain iron accumulation)(NBIA)的一种形式(被认为负责半数),其引起锥体外系功能失常(例如,张力失常(dystonia)、僵直(rigidity)、舞蹈手足徐动症(choreoathetosis))(A.M.Gregory和S.J.Hayflick,“Neurodegeneration WithBrain Iron Accumulation(具有脑铁积累的神经变性)”,Orphanet Encyclopedia,2004年9月)。PKAN被认为是由酶泛酸激酶缺乏导致的遗传疾病,泛酸激酶负责将泛酸酯(维生素B-5)转化为4′-磷酸泛酸酯。4′-磷酸泛酸酯随后被转化为辅酶A(CoA)(如以下所示)(R.Leonardi,Y.-M.Zhang,C.O.Rock,以及S.Jackowski,“Coenzyme A:Back In Action”,Progress in Lipid Research,2005,44,125-153)。
具体地,泛酸经由酶泛酸激酶(PANK)转化为4′-磷酸泛酸,4′-磷酸泛酸经由酶4′-磷酸泛酰半胱氨酸合酶(PPCS)转化为4′-磷酸泛酰半胱氨酸,并且随后由4′-磷酸泛酰半胱氨酸脱羧酶(PPCDC)脱去羧基成为4′-磷酸泛酰巯基乙胺。4′-磷酸泛酰巯基乙胺然后通过磷酸泛酰巯基乙胺腺嘌呤转移酶(PPAT)的作用连接到腺苷从而产生脱磷酸CoA,脱磷酸CoA最后经由脱磷酸-CoA激酶(DPCK)转化为辅酶A(CoA)。
典型的PKAN通常出现在儿童的头十到十五年,尽管也存在非典型的形式,其可能一直到40岁发生。PKAN是进行性变性疾病,其导致肌肉骨骼功能丧失,对生活品质具有毁灭性影响。
治疗PKAN的一种方法可以是使用酶反应的产物,即4′-磷酸泛酸酯。该方法已在文献中被提及,但是已经认识到高度带电荷的分子不能够透过亲脂性细胞膜(C.J.Balibar,M.F.Hollis-Symynkywicz,和J.Tao,“Pantethine RescuesPhosphopantothenoylcysteine Synthetase And Phospho-pantothenoylcysteineDecarboxylase Deficiency In Escherichia Coli But Not In PseudomonasAeruginosa(泛酰巯基乙胺在大肠杆菌中但不在铜绿假单胞菌中拯救磷酸泛酰半胱氨酸合酶和磷酸泛酰半胱氨酸脱羧酶缺乏)”,J.Bacteriol.,2011,193,3304-3312)。
发明概述
本发明涉及4′-磷酸泛酸酯(4′-磷酸泛酸,4′-phosphopantothenate)的前药或4′-磷酸泛酸酯的代用品。这些前药具有比4’-磷酸泛酸酯更大的细胞渗透性。不希望受制于任何特别的理论,据信4’-磷酸泛酸酯的替代,或其代用品的使用,将允许身体合成CoA或其活性变体。因此,这些前药可用于治疗由4’-磷酸泛酸酯和/或CoA缺乏导致的疾病。
本发明的一个实施方案是4′-磷酸泛酸酯的前药(3-{[(2R)-2-羟基-3,3-二甲基-4-(膦酰氧基)丁酰基]氨基}丙酸)。所述前药可以具有与4’-磷酸泛酸酯连接的一个或多个前药部分。优选地,这些前药部分减少化合物的电荷,由此增强其细胞渗透性。在一个实施方案中,一个或多个前药部分连接到4’-磷酸泛酸酯的羧基和/或膦酰基。在一个优选的实施方案中,所述前药具有一个与羧基相连的前药部分和与膦酰基相连的两个前药部分。在一个更优选的实施方案中,膦酰部分的一个羟基上的氢被前药部分替代,并且膦酰部分的另一个羟基被氨基替代(例如,氨基酸,通过其氨基连接到磷原子)。
在一个实施方案中,本发明涉及4′-磷酸泛酸酯的前药或在生理pH(例如,在约7.3至约7.5的pH,如在约7.3至约7.4的pH,如在约7.4的pH或在约7.365的pH)不形成离子的本发明的其他化合物。
在另一个实施方案中,本发明涉及4′-磷酸泛酸酯的前药或pKa值为约7的本发明的其他化合物。
本发明的另一个实施方案是一种具有下式的化合物或其药用盐:
其中
X是羟基,卤素,-OR6,或-SR6(其中R6是C1-C6烷基,C2-C6烯基,或C2-C6炔基,如甲基,乙基,正丙基,异丙基,正丁基,仲丁基);
Q是羧酸(-COOH),亚磺酸(-SOOH),磺酸(SOOOH),或它们的酯(即,-COOR1,-SOOR1,-SOOOR1);
R1选自取代或未取代的C1-C6烷基,取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;
(a)Z是膦酸酯(-CH2P(O)OR2),磷酸酯(-OP(O)OR3R4),硫代膦酸酯(-CH2P(S)OR2),硫代磷酸酯(-OP(S)OR3R4),
R2、R3和R4独立地选自取代或未取代的C1-C6烷基,取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;
R5选自取代或未取代的C1-C6烷基(如未取代的C1-C6烷基),取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;
Y是下式的天然或非天然氨基酸酯:
R7选自取代或未取代的C1-C6烷基(如未取代的C1-C6烷基),取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;
R8和R9独立地选自氢,氨基酸侧链,C1-C6烷基,取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;
前提是R8和R9不都是氢。
在一个优选的实施方案中,R8和R9的定义中的氨基酸侧链是天然氨基酸(例如,L-氨基酸)的侧链。在式F中,R8和R9可以连接至所示的碳以使该碳具有R或S绝对构型(D或L相对构型)。在一个更优选的实施方案中,R8和R9中的一个是氢而另一个是氨基酸侧链(优选地,天然L-氨基酸如蛋白氨基酸的氨基酸侧链)。
另一个实施方案是一种具有下式的化合物或其药用盐:
其中
R是氨基酸侧链;
R’选自C1-C6烷基取代或未取代的C1-C6烷基(如未取代的C1-C6烷基),取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代或未取代的C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基;并且
R”选自取代或未取代的C1-C6烷基,取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C3-C8环烷基(C1-C6烷基),取代的或未取代C3-C8环烯基(C1-C6烷基),取代或未取代的芳基,取代或未取代的芳基烷基,取代或未取代的杂环基,取代或未取代的杂芳基,取代和未取代的杂环基烷基,以及取代和未取代的杂芳基烷基.
在一个优选的实施方案中,R的定义中的氨基酸侧链是天然氨基酸(例如,天然L-氨基酸)的侧链。R可以连接到所示的碳以使该碳具有R或S绝对构型(D或L相对构型)。在一个更优选的实施方案中,R是蛋白氨基酸的侧链。在一个优选的实施方案中,R基团的立体化学为使得所述分子具有以下立体化学:
在式G的化合物的一个实施方案中,R’是C1-C6烷基(例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基),苄基,环己基,和甲基环丙基。
在式G的化合物的一个实施方案中,R”是C1-C6烷基(例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基),苄基,环己基,和甲基环丙基。
另一个实施方案是具有下式的化合物或其药用盐:
其中
R是氨基酸侧链;
X是卤素(例如,F);
n是0,1,2,3,4或5(例如,0,1或2);
R’选自C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烯基,C3-C8环烷基(C1-C6烷基),C3-C8环烯基(C1-C6烷基),芳基,芳基烷基,杂环基,杂芳基,杂环基烷基,和杂芳基烷基;其各自任选地被一个或多个卤素(例如,氟)取代;并且
R”选自C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烯基,C3-C8环烷基(C1-C6烷基),C3-C8环烯基(C1-C6烷基),芳基,芳基烷基,杂环基,杂芳基,杂环基烷基,和杂芳基烷基;其各自任选地被一个或多个卤素(例如,氟)取代。
在一个优选的实施方案中,n是0。在另一个优选的实施方案中,n是1。
在一个优选的实施方案中,R的定义中的氨基酸侧链是天然氨基酸(例如,天然L-氨基酸)的侧链。R可以连接至所示的碳以使该碳具有R或S绝对构型(D或L相对构型)。在一个更优选的实施方案中,R是蛋白氨基酸的侧链。在一个优选的实施方案中,R基团的立体化学为使得所述分子具有以下立体化学:
在式H的化合物的一个实施方案中,R’是C1-C6烷基(例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,或叔丁基),苄基,环己基,或甲基环丙基,其各自任选地被一个或多个卤素(例如,氟)取代。
在式H的化合物的一个实施方案中,R”是C1-C6烷基(例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,或叔丁基),苄基,环己基,或甲基环丙基,其各自任选地被一个或多个卤素(例如,氟)取代。
本发明的优选化合物包括具有下式的那些或其药用盐:
其中
(其中Bn是苄基,Cy是环己基,Et是乙基,hex是己基,iBu是异丁基,iPr是异丙基,Me是甲基,MeCyPr是甲基环丙基(即,-CH2-环丙基,并且MeIndole是(1H-吲哚-3-基)甲基)。在一个实施方案中,上述化合物具有以下立体化学:
另一个实施方案是一种包含本发明的化合物和药用赋形剂的药物组合物。在一个实施方案中,所述药物组合物包含有效量的所述化合物以用于治疗神经疾病。所述药物组合物可以是单位剂量形式,如片剂或胶囊。
另一个实施方案是一种治疗受试者的与泛酸激酶、4′-磷酸泛酸酯或辅酶A的缺乏相关的疾病的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种治疗受试者的泛酸激酶相关的神经变性的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。所述受试者可以患有具有脑铁积累的神经变性。
另一个实施方案是一种治疗受试者的帕金森病(Parkinson’s disease)的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种处理(治疗,treating)受试者的涉及特征在于异常的神经元功能的病状的细胞或组织的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。所述病状可以选自张力失常,锥体外系作用(extrapyramidal effects),吞咽困难(dysphagia),肢体僵直和/或僵硬(rigidity and/or stiffness of limbs),舞蹈手足徐动症(choreoathetosis),颤抖(tremor),痴呆(dementia),痉挛状态(spasticity),肌无力(muscle weakness),和癫痫发作(seizure).
另一个实施方案是一种处理(治疗)涉及特征在于由与酶泛酸激酶相关的基因的误调节(misregulation)引起的功能失常的神经元细胞的病状的细胞或组织的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种治疗受试者的特征在于由与酶泛酸激酶相关的基因的误调节引起的功能失常的神经元细胞的病状的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种处理(治疗)涉及特征在于由与酶泛酸激酶相关的基因的表达的误调节引起的功能失常的神经元细胞的病状的细胞或组织的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种治疗受试者的特征在于由与酶泛酸激酶相关的基因的表达的误调节引起的功能失常的神经元细胞的病状的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
另一个实施方案是一种治疗具有铁过度积累的神经元细胞的受试者的方法。所述方法包括向所述受试者施用有效量的本发明的化合物。
在上述方法中,所述受试者可以是儿童(例如,10至15岁)或成人。
另一个实施方案是一种通过以下步骤制备式G或H的化合物的方法:
(a)保护泛酸的两个羟基;
(b)酯化经保护的泛酸的酸部分以形成下式的化合物:
其中各个Pg独立地表示保护基团,并且R”如以上关于式G或H所定义;
(c)对所述羟基去保护;
(d)用下式的化合物磷酸化经去保护的化合物:
其中L是离去基团(例如,卤素如氯),并且R和R’如以上关于式G或H所定义;以及
(e)任选地,形成在步骤(d)中所形成的化合物的盐。
另一个实施方案是一种通过以下步骤制备式G或H的化合物的方法:
(a)利用式R”OH的醇来酯化泛酸以形成下式的化合物:
其中R”是如以上关于式G或H所定义的;
(b)用下式的化合物磷酸化经酯化的化合物:
其中L是离去基团(例如,卤素),并且R和R’如以上关于式G或H所定义;并且
(c)任选地,形成在步骤(b)中所形成的化合物的盐。步骤(a)中的酯化可以通过使泛酸经受费歇尔(Fischer)酯化条件进行。
附图简述
图1是直方图,其显示在用实施例2、5、7和12的化合物处理后通过质谱测量的人HEK 293T细胞中的乙酰CoA的水平。
图2是直方图,其显示在未经处理的Pank1+/+小鼠(WT)、未经处理的Pank1-/-敲除小鼠(panklKO)和施用实施例2的化合物后的PANK敲除小鼠(Pank KO+实施例2)中的mBBr CoA的水平。
发明详述
定义
如在本文中使用的,某些项可以具有以下限定含义。
如在说明书和权利要求中使用的,除非上下文明确另有所指,单数的“一个”、“一种”以及“该”包括复数指代。例如,术语“一个细胞”包括多个细胞,包括其混合物。类似地,除非上下文明确另有所指,如本文所述的将“一种化合物”用于治疗或药物制备考虑了将本发明的一种或多种化合物用于这样的治疗或制备。
如在本文中使用的,术语“包含(或包括)”意在指所述组合物和方法包括列出的要件,但是不排除其他。因此,基本上由如本文所定义的要件组成的组合物将不排除来自分离和纯化方法的痕量污染物以及药用载体,如磷酸盐缓冲盐水、防腐剂等。“由……组成”是指排除其他成分的超过痕量元素和用于施用本发明的组合物的基本(或实质性)方法步骤。由各个过渡术语限定的实施方案在本发明的范围内。
术语“烷基”是指仅由碳和氢原子组成的不含不饱和度的直链或支链烃链基团。除非另有说明,术语“烷基”是指具有一至八个碳原子(例如,一至六个碳原子或一至四个碳原子)的基团,并且其通过单键连接至分子的剩余部分。烷基的实例包括,但不限于,甲基,乙基,正丙基,异丙基,正丁基,叔丁基,仲丁基,正戊基,和仲戊基。
术语“烯基“是指含有碳碳双键的脂肪烃基团并且其可以是直链或支链或支化链。除非另有说明,术语“烯基”是指具有2至约10个碳原子的基团,例如,乙烯基,1-丙烯基,2-丙烯基(烯丙基),异丙烯基,2-甲基-1-丙烯基,1-丁烯基,和2-丁烯基。
术语“炔基”是指具有至少一个碳碳三键的直链或支链烃基团。除非另有说明,术语“炔基”是指具有2直至约12个碳原子(例如,2至102至10个碳原子)的基团,例如,乙炔基,丙炔基,和丁炔基。
术语“环烷基”是指约3至12个碳原子的非芳族的单环或多环环系统,如环丙基,环丁基,环戊基,和环己基。
术语“环烷基烷基”是指与烷基直接相连的包含约3至8个碳原子的含环状环的基团(所述烷基然后在该烷基中的任意碳处连接至主要结构,产生一个稳定的结构),如环丙基甲基,环丁基乙基,和环戊基乙基。
术语“芳基”是指具有6至20个碳原子的单环或多环芳族基团,如苯基,萘基,四氢萘基,茚满基,和联苯基。
术语“芳基烷基”是指与如上所定义的烷基直接连接的如上所定义的芳基,例如,-CH2C6H5和-C2H5C6H5。
术语“杂环基”是指非芳族的3至15元环基团,其由碳原子和选自氮、磷、氧和硫中的至少一个杂原子组成。杂环基团可以是单环、二环、三环或四环系统,其可以包括稠合、桥接或螺环系统,并且杂环基团中的氮、磷、碳、氧或硫原子可以被任选地被氧化成各种氧化态。此外,氮原子可以任选地被季铵化。
术语“杂环基烷基”是指与如上所定义的烷基直接连接的如上所定义的杂环基。
术语“杂芳基”是指任选取代的5-14元芳族环,其具有一个或多个选自N、O和S中的杂原子作为环原子。杂芳基可以是单环、二环或三环系统。这样的杂芳基环基团的实例包括但不限于唑基,噻唑基,咪唑基,吡咯基,呋喃基,吡啶基,嘧啶基,吡嗪基,苯并呋喃基,吲哚基,苯并噻唑基,苯并唑基,咔唑基,喹啉基和异喹啉基。
术语“杂芳基烷基”是指与如上所定义的烷基直接连接的如上所定义的杂芳基,例如,-CH2C6H4N和-C2H5C6H4N。
术语“卤素”包括F,Cl,Br,和I。
术语“氨基酸侧链”是指式H2N-CH(R)-COOH的α氨基酸的侧链R。例如,丙氨酸的侧链是甲基,甘氨酸的侧链是氢,缬氨酸的侧链是异丙基,而色氨酸的侧链是(1H-吲哚-3-基)甲基。本发明的化合物中的合适的氨基酸侧链包括天然氨基酸(包括蛋白氨基酸)的侧链。天然氨基酸的非限制性实例包括标准氨基酸或蛋白氨基酸,其包括但不限于丙氨酸,精氨酸,天冬酰胺,天冬氨酸,半胱氨酸,谷氨酸,谷氨酰胺,甘氨酸,组氨酸,异亮氨酸,亮氨酸,赖氨酸,甲硫氨酸,苯丙氨酸,脯氨酸,吡咯赖氨酸,硒半胱氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸和缬氨酸。
术语“取代的”,除非另有说明,是指被以下取代基中的任一个或以下取代基的任意组合取代:氢,羟基,卤素,羧基,氰基,硝基,氧代(=O),硫代(=S),烷基,烷氧基,烯基,炔基,芳基,芳基烷基,环烷基,环烯基,芳基,杂环基,杂芳基,-COORx,-C(O)Rx,-C(S)Rx,-C(O)NRxRy,-C(O)ONRxRy,-NRyRz,-NRxCONRyRz,-N(Rx)SORy,-N(Rx)SO2Ry,-(=N-N(Rx)Ry),-NRxC(O)ORy,-NRxRy,-NRxC(O)Ry-,-NRxC(S)Ry-NRxC(S)NRyRz,-SONRxRy-,-SO2NRxRy-,-ORx,-ORxC(O)NRyRz,-ORxC(O)ORy-,-OC(O)Rx,-OC(O)NRxRy,-RxNRyC(O)Rz,-RxORy,-RxC(O)ORy,-RxC(O)NRyRz,-RxC(O)Rx,-RxOC(O)Ry,-SRx,-SORx,-SO2Rx,和-ONO2,其中以上基团中各自的Rx、Ry和Rz可以是氢原子,烷基,烷氧基,烯基,炔基,芳基,芳基烷基,环烷基,环烯基,氨基,芳基,杂芳基,杂环基,或者Rx、Ry和Rz中的任意两个可以结合而形成饱和或不饱和的3-10元环,所述环可以任选地包括杂原子,所述杂原子可以是相同的或不同的并且选自O、NH或S。在一个实施方案中,术语取代的是指被一个或多个卤素(例如,氟)取代。
术语“受试者(对象,subject)”是指哺乳动物,如家养宠物(例如,狗或猫),或人。优选地,所述受试者是人。
短语“有效量”是指当施用于受试者或患者以用于治疗疾病时,足以实现对所述疾病的这样的治疗的量。
″治疗″或″处理″包括(1)抑制经历或显示疾病的病状或症状的受试者或患者中的所述疾病(例如,阻止病状和/或症状的进一步发展),(2)改善经历或显示疾病的病状或症状的受试者或患者中的所述疾病(例如,反转病状和/或症状),和/或(3)实现经历或显示疾病的病状或症状的受试者或患者中的所述疾病的任何可测量的下降。
药物制剂和施用途径
本发明的化合物可以通过多种途径施用,所述途径包括经口和通过注射(例如皮下、静脉内和腹膜内)。
所述化合物可以以固体或液体剂量形式经口施用。在这两种情况中,所述化合物都可以用材料涂覆以保护其免受酸及可能使所述化合物失活的其他自然条件的作用。所述化合物可以被配制成水溶液,液体分散体,(可摄取的)片剂,颊含片,含片,胶囊,酏剂,混悬剂,糖浆和薄片。口服剂型可以包含本领域中已知的赋形剂,如粘合剂,崩解剂,调味剂,抗氧化剂和防腐剂。液体剂型可以包含稀释剂如盐水或水性缓冲液。
所述化合物也可以通过注射施用。适用于注射的制剂可以包括无菌水溶液(在水可溶的情况下)或分散体,以及用于临时制备无菌的可注射溶液或分散体的无菌粉末。所述组合物可以是无菌的并且是流动的,达到容易注射的程度。其在制备和储存条件下可以是稳定的并且被保护以免受微生物如细菌和真菌的污染作用。载体可以是溶剂或分散介质,包括,例如,水,乙醇,多元醇(如,甘油,丙二醇,和液体聚乙二醇),其合适的混合物,以及植物油。可以例如通过使用包衣如卵磷脂,通过保持所需的粒度(在分散体的情况中),以及通过使用表面活性剂来保持适当的流动性。可以通过多种抗细菌剂和抗真菌剂,例如,对羟基苯甲酸酯类,氯丁醇,苯酚和抗坏血酸,来实现防止微生物的作用。在许多情况中,优选的是在组合物包含等张剂,例如,糖,氯化钠,或多元醇如甘露醇和山梨醇。可以通过在组合物中包含延迟吸收的试剂(例如,单硬脂酸铝或明胶)来产生可注射组合物的延长吸收。
可以通过以下方式制备无菌注射液:将所需量的治疗化合物与(当需要时)以上列举的成分之一或组合一起混合到合适的溶剂中,之后过滤灭菌。通常,通过以下方式制备分散体:将治疗化合物与来自以上列举的那些的所需其他成分混合到含有基本分散介质的无菌载体中。在用于制备无菌注射液的无菌粉末的情况中,制备方法包括真空干燥和冻干,其产生活性成分(即,治疗化合物)和来自其之前无菌过滤的溶液的任何额外的所需成分的粉末。
向受试者施用的化合物的实际剂量可以由医生以及生理因素如年龄,性别,体重,病症的严重性,所治疗的疾病的类型,之前或同时的治疗干预,受试者的自发病以及施用途径决定。这些因素可以由技术人员确定。负责给药的医生通常确定组合物中活性成分的浓度以及用于个体受试者的合适剂量。
在一个实施方案中,人受试者被施用约0.01mg/kg至约100mg/kg的日剂量。
考虑了所述化合物的单个剂量或多个剂量。递送多个剂量的期望时间间隔可以由本领域技术人员仅仅采用常规实验确定。例如,可以以约12小时间隔每天向受试者施用两个剂量。在一些实施方案中,所述化合物每天施用一次。
所述化合物可以根据常规时间表施用。如在本文中使用的,常规时间表是指预定的指定时间段。常规时间表可以包括长度相同或不同的时间段,只要时间表是预定的。例如,常规时间表可以包括每天施用两次,每天施用一次,每两天施用一次,每三天施用一次,每四天施用一次,每五天施用一次,每六天施用一次,每周施用一次,每月施用一次或其间的任何设定的天数或周数。备选地,预定的常规时间表可以包括在第一周按照每天两次施用,之后按每日一次施用达若干周。在其他实施方案中,本发明提供所述药剂可以口服并且其时间安排取决于或不取决于食物摄取。因此,例如,可以在每个早晨和/或每个夜晚服用所述药剂,而不管受试者在何时进过食或将在何时进食。
联合疗法
除了被用作单一治疗以外,所述化合物也可以用于联合疗法。可以利用包含两种药剂的单一组合物或药物制剂,或利用同时施用的两种不同组合物或制剂(其中一个组合物包含本发明的化合物而另一个包含第二药剂)来实现有效的联合疗法。备选地,所述治疗可以以数分钟至数月的间隔在另一种药剂治疗之前或之后。
另外的一种或多种药剂可以选自可用于治疗神经疾病的任意一种或多种药剂,例如可用于治疗泛酸激酶、4′-磷酸泛酸酯或辅酶A缺乏的任意一种或多种药剂。在一个实施方案中,另外的一种或多种药剂可用于改善认知功能,例如,乙酰胆碱酯酶抑制剂,如毒扁豆碱(physostigmine),新斯的明(neostigmine),吡啶斯的明(pyridostigmine),阿伯农(ambenonium),demarcarium,利斯的明(rivastigmine),加兰他敏(galantamine),多奈哌齐(donezepil)及其组合。在另一个实施方案中,另外的一种或多种药剂是铁螯合剂,如去铁酮(deferiprone),去铁胺(deferoxamine),去铁斯若(deferasirox)及其组合。
合成磷酸泛酸酯衍生物
本发明的化合物可以制备自容易获得的泛酸(维生素B5)。泛酸的合成描述于例如美国专利号2,676,976和2,870,188中。
用于制备式G的化合物的以下合成可以适合于制备本发明的其他化合物,如式H的化合物。可以通过以下步骤制备式G的化合物:(a)保护泛酸的两个羟基,(b)酯化经保护的泛酸的酸部分以形成下式的化合物:
其中各个Pg独立地表示保护基团,并且R”是如以上关于式G所定义的,(c)对所述羟基去保护,(d)用下式的化合物磷酸化经去保护的化合物:
其中L是离去基团(例如,卤素),并且R和R’是如以上关于式G所定义的;以及(e)任选地,形成在步骤(d)中所形成的化合物的盐。以下显示该反应方案(其中L是Cl):
(注:最后一步中的R1可以是氢。)
保护步骤(a)可以通过用苯甲醛和氯化锌处理泛酸以产生相应的缩醛来进行(T.W.Green和P.G.M.Wuts,Protective Groups in Organic Synthesis(有机合成中的保护基),Wiley-Interscience,New York,1999,217-224,716-719)。泛酸也可以通过用丙酮和甲苯磺酸处理泛酸(M.Carmack和C.J.Kelley,“Synthesis of optically activeCleland′s reagent[(-)-1,4-dithio-L-threitol](光学活性Cleland试剂[(-)-1,4-二硫代-L-苏糖醇]的合成)”,J.Org.Chem.,1968,33,2171-2173)以产生相应的缩醛而被保护。在另一个实例中,将泛酸用氢化钠处理之后用苄基溴处理从而产生二-O-苄基化泛酸(T.W.Green等,同上)。
在羟基的二保护(diprotection)后,酯(R”)的形成可以通过例如将经二保护的泛酸与合适的醇以及二环己基二碳二亚胺(DCC)或二乙基偶氮二羧酸酯(DEAD)以及三苯基膦反应(Mitsunobu反应)来实现。备选地,经保护的泛酸可以被转化为相应的酰氯(例如,利用亚硫酰氯或草酰氯),之后用相应的醇处理。
去保护可以通过本领域中已知的任何方法进行,如在T.W.Green等(同上)中描述的。
作为步骤(a)至(c)的备选方案,泛酸可以用式R”OH的醇进行酯化,例如,通过使泛酸经历费歇尔酯化条件(即,过量的醇,以及催化性酸,在回流下)。
步骤(c)中形成的化合物上的伯醇羟基可以被选择性磷酸化。见J.D.Patrone,J.Yao,N.E.Scott和G.D.Dotson,“Selective Inhibitors of BacterialPhosphopantothenoylcysteine Synthetase(细菌磷酸泛酰半胱氨酸的选择性抑制剂)”,J.Am.Chem.Soc.,2009,131,16340-16341)。可以将在D.M.Lehsten,D.N.Baehr,T.J.Lobl和A.R.Vaino,“An Improved Procedure for the Synthesis of NucleosidePhosphoramidates(用于合成核苷氨基磷酸酯的改进方法)”,Organic Process Research&Development,2002,6,819-822中描述的条件用于该反应。
以下显示该方法以及用于制备磷酸化试剂的方法。
任选地,通过对终产物或合成步骤之间的中间体中之一进行手性分离可以获得光学纯的产物。
备选地,本发明的化合物可以通过B.S.Ross,P.G.Reddy,H.-R.Zhang,S.Rachakonda和M,J.Sofia,“Synthesis of Diastereomerically Pure NucleotidePhosphoramidates(合成非对映异构体纯的核苷氨基磷酸酯)”,J.Org.Chem.,2011,76,8311-8319中描述的途径制备。该途径可以在不进行最终手性分离步骤的情况下产生光学纯的产物。
实施例
实施例1
合成3-((2R)-4-(((((S)-1-乙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)-2-羟基-3,3-二甲基丁酰胺)丙酸乙酯
将L-丙氨酸乙酯盐酸盐(0.50g,3.25mmol)悬浮在10mL的CH2Cl2中并在-10℃并且在氮气氛下用二氯化磷酸苯酯(0.50mL,3.35mmol)处理。然后该充分搅拌的混合物用N-甲基咪唑(1.0mL,12.5mmol)逐滴地处理。1小时后,并且仍然在-10℃,缓慢加入在3mL的CH2Cl2中的泛酸乙酯(0.70g,2.8mmol)。允许该混合物温热至室温,并且在3小时后,加入2mL的甲醇。相继用1M HCl、水、5%NaHCO3和盐水进行萃取。将有机相干燥(Na2SO4),并且将溶剂蒸发,产生1.11g清澈无色的浆液。将该材料通过急骤柱色谱法纯化,使用30g的硅胶,并且利用1∶1 EtOAc/己烷(含5%EtOH)洗脱。重复该过程直至获得1.1g的氨基磷酸酯。HPLC显示产物为非对映异构体的1∶1混合物,具有97%的纯度。1H NMR(300MHz,CDCl3):δ1.08(s,3H,CH3),1.21(d,3H,J=2.7Hz,CH3),1.27(m,6H,CH3),1.35(t,3H,J=6.9Hz,CH3),2.53(q,2H,J=4.2Hz,CH2),3.50(m,2H,CH2),3.60(m,1H,CH),3.78(d,J=7.5Hz,CH),3.9(m,2H,CH2),4.10(m,6H,CH2),4.79(t,1H,J=6.5Hz,CH),7.15和7.40(2Ms,5H,Ph)。预期的分子量502.21,观察到的分子量503.09(M+H+]
实施例2
合成3-((2R)-2-羟基-4-(((((S)-1-甲氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)-3,3-二甲基丁酰胺)丙酸甲酯
将L-丙氨酸甲酯盐酸盐(1.35g,9.65mmol)悬浮在二氯甲烷(20mL)中,并且在-78℃在氩气氛下用二氯化磷酸苯酯处理(1.51mL,10.15mmol)。逐滴加入二异丙基乙基胺(2.6mL,20.27mmol)。将混合物在-78℃搅拌30分钟,然后使其温热至室温达1小时。将混合物冷却至-5℃并且逐滴加入在二氯甲烷中的泛酸甲酯(1.6mL,20.27mmol)。加入N-甲基咪唑(1.6mL,20.27mmol),并且在-5℃搅拌30分钟以及室温搅拌1小时后,加入2mL甲醇。将混合物相继用水(30mL)、5%柠檬酸(30mL)和盐水(10mL)洗涤。将有机相干燥(Na2SO4),并且在减压下除去溶剂。利用EtOAc∶己烷的1∶1混合物实现纯化,产生清澈无色油状的产物。(1.1g,24%收率)。HPLC显示产物为非对映异构体的1∶1混合物,具有97%的纯度。1H NMR(300MHz,CDCl3):δ1.11(s,3H,CH3),1.27,1.39和1.40(2Ss,3H,CH3),1.41(重叠的d,3H,J=1.2Hz,CHCH3),3.55(m,2H,CH2),3.60(m,1H,CH2),3.63(m,1H,CH),3.66和3.68(2Ss,3H,COCH3),3.70和3.74(2Ss,3H,COCH3),3.78(m,1HCH),4.03(m,1H,CH),4.17(m,1H,CH),7.16和7.35和7.40(2Ms,5H,Ph)。预期的分子量474.18,观察到的分子量475.03(M+H+]。
实施例3-14
根据实施例1和2中概述的合成方法,使用合适的起始物料,制备下表中显示的化合物。
实施例15:体外细菌测试
SJ16是需要添加泛酸以进行增殖的大肠杆菌(Escherichia coli)菌株(即,其具有使得泛酸无活性的突变)。因此,其在确定化合物是否可以拯救PANK不足(PKAN的病因)的生物方面用作有用的测定。测试本发明的化合物的毒性以及在允许条件和非允许条件下支持大肠杆菌K-12菌株SJ16(见,例如,Jackowski等,J.Bacteriol.,148,926-932,1981)和DV70(见,例如,Vallari等,J.Bacteriol.,169,5795-5800,1987)生长的能力。以8μM的终浓度将在溶剂(二甲亚砜,DMSO)中的测试化合物添加到生长介质中。以≤0.1%的终浓度将单独的溶剂(DMSO)添加到生长介质中作为对照。
将菌株SJ16在含有琼脂(1.5%)、M9最小必需盐(见,Miller,Experiments inMolecular Genetics(分子遗传学中的实验).Cold Spring Harbor Laboratory,ColdSpring Harbor,New York,1972)、葡萄糖(0.4%)、甲硫氨酸(50μg/ml)并且具有(允许)或不具有(非允许)泛酸钙(1μM)的固体培养基上在37℃培养18小时。在补充泛酸钙的情况下的缺乏生长指示毒性。在不补充泛酸钙的情况下的生长指示细菌代谢所述化合物从而产生泛酸酯或β-丙氨酸的能力。
在含有琼脂(1.5%)、M9最小必需盐、葡萄糖(0.4%)、甲硫氨酸(50μg/ml)和泛酸钙(1μM)的固体培养基上将菌株DV70在30℃(允许)或42℃(非允许)培养18小时。在30℃的缺乏生长指示毒性。在42℃的生长指示细菌代谢所述化合物并且随后将其转化为辅酶A。
实施例2、5、7和12的化合物的SJ16恢复结果显示在下表中。“是”结果指示细菌在18小时后是存活的。实施例2、5、7和12的化合物不导致DV70菌株的恢复。
实施例 | 使用的DMSO | SJ16恢复 |
2 | <10% | 是 |
5 | >50% | 是 |
7 | >60% | 是 |
12 | >70% | 是* |
*测试化合物沉淀
实施例16
在永生人细胞(HEK 293T)中测试实施例2、5、7和12的化合物。通过质谱测量施用实施例2、5、7和12的化合物后的乙酰-CoA的量(PANK的下游结果)。结果显示在图1中。
如在图1中可见,用200μM的实施例2的化合物处理HEK 293T细胞产生相对于基线的乙酰CoA增加42%(p<0.0005)。用20μM的实施例7的化合物处理HEK 293T细胞产生相对于基线的乙酰CoA增加38%(p<0.005)。
实施例17:体内测试
测试本发明的化合物在Pankl-/-小鼠(菌株129SvJxC57BL/6J背景)中的效力,将Pankl-/-小鼠与年龄相仿(8-12周龄)的Pankl+/+(菌株129SvJxC57BL/6J)同窝出生仔相比。将每只小鼠用编码的耳标识别并且在测试的第一天称重。通过腹膜内注射以1.2μmol/g体重的剂量将在5μL二甲亚砜中的每种化合物施用于4-5只小鼠,每天一次,持续5天,并且然后使小鼠禁食过夜,称重并且进行安乐死。未处理的小鼠接受5μL二甲亚砜,每天一次,持续5天,然后使其禁食过夜,然后称重并且进行安乐死。将肝从每只小鼠中切离,将等分试样在液氮中速冻,并且保存在-80℃。在7天内,将肝样品在冰上解冻,称重并且分析辅酶A含量,如下所述。效力由以下指示:Pankl-/-小鼠中的肝辅酶A水平与来自未经处理的Pankl-/-小鼠的肝相比在统计学上显著增加,并且与未经处理的Pankl+/+小鼠中的辅酶A水平相当。
CoA测量:成纤维细胞和肝的提取以及在高压液相色谱(HPLC)前的辅酶A的衍生化
通过改进之前所述的方法(见,Minkler等,Anal.Biochem.,376,275-276,2008)进行成纤维细胞或肝的提取。通过改进之前所述的方法(见,Shimada等,J.Chromatogr.BBiomed.Appl.,659,227-241,1994)进行辅酶A衍生化。
将肝(20-50mg)在2mL的1mM KOH中匀浆化,并利用0.25M KOH将pH调节至12。将成纤维细胞从培养皿刮下并且收集在1mL水中,将其转移到200μL的0.25M NaOH中。然后将肝匀浆在55℃温育2小时,并且将成纤维细胞在55℃温育1小时。利用1M Trizma-HCl将pH调节至pH 8,并在黑暗中在2小时内加入10μL的100mM单溴二胺(mBBr,Life Technologies,NY)。将反应用乙酸酸化,并且在500g离心15分钟。然后将上清液添加到用1mL的50%甲醇/2%乙酸平衡的2-(2-吡啶基)乙基柱(Supelco)。将所述柱用2x1mL 50%甲醇/2%乙酸和1mL水洗涤。样品用2x1mL在95%乙醇中的50mM甲酸铵洗脱。将样品在氮气下蒸发并且重悬在300μL的水中。使样品旋转通过Spin-X离心管过滤器(0.22μm乙酸纤维素,Costar)从而在HPLC之前除去任何沉淀物。
通过HPLC量化辅酶A
通过反相HPLC,使用来自Phenomenex(Torrance,CA)的Gemini C183μm柱(150x4.60mm)分离辅酶A的mBBr衍生物。所用的层析系统为Waters e2695分离模块,其具有UV/Vis检测器,并且由Empower 3软件控制。溶剂A是50mM磷酸钾pH 4.6,而溶剂B是100%乙腈。将20μL的样品注入柱中,并且流速为0.5mL/min。HPLC程序如下:起始溶剂混合物为90%A/10%B,0至2min无梯度的10%B,2至9min从10%B到25%B的线性梯度,9至23min从25%B到40%B的凹形梯度,23至25min从40%到10%的线性梯度,以及25至30min无梯度的10%B。将检测器设定在λ393nm。对在mBBr衍生化的辅酶A峰下方的面积进行积分并将其与由市售辅酶A制备的mBBr-辅酶A的标准浓度曲线比较。
图2显示施用实施例2的化合物后在PANK敲除小鼠中的mBBr CoA水平。如由图2可见的,实施例2的化合物将CoA水平恢复至在正常小鼠中观察到的水平。这也显示在下表中。
本文中引述的所有出版物、专利和专利申请通过引用结合于此。
Claims (20)
1.一种具有下式的化合物或其药用盐:
其选自由以下各项组成的组:
。
2.权利要求1所述的化合物,其中R、R’和R”是甲基。
3.权利要求1所述的化合物,其中R是甲基,R’是乙基并且R”是苄基。
4.权利要求1所述的化合物,其中R是甲基,并且R’和R”是甲基环丙基。
5.权利要求1所述的化合物,其中R是1H-吲哚-3基-甲基,R’是苄基并且R”是乙基。
6.一种药物组合物,所述药物组合物包含权利要求1-5中任一项的化合物,以及药用赋形剂。
7.权利要求6所述的药物组合物,其中所述药物组合物是单位剂量形式。
8.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于治疗受试者的与泛酸激酶、4′-磷酸泛酸酯或辅酶A缺乏相关的疾病。
9.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于治疗受试者的泛酸激酶相关的神经变性。
10.权利要求9所述的用途,其中所述受试者患有具有脑铁积累的神经变性。
11.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于处理受试者的涉及特征在于异常神经元功能的病状的细胞或组织。
12.权利要求11所述的用途,其中所述病状选自张力失常、锥体外系作用、吞咽困难、肢体僵直和/或僵硬、舞蹈手足徐动症、颤抖、痴呆、痉挛状态、肌无力和癫痫发作。
13.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于处理涉及受试者的特征在于由与酶泛酸激酶相关的基因的误调节引起的功能失常的神经元细胞的病状的细胞或组织。
14.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于治疗受试者的特征在于由与酶泛酸激酶相关的基因的误调节引起的功能失常的神经元细胞的病状。
15.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于处理受试者的涉及特征在于由与酶泛酸激酶相关的基因的表达的误调节引起的功能失常的神经元细胞的病状的细胞或组织。
16.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于治疗受试者的特征在于与酶泛酸激酶相关的基因的表达的误调节引起的功能失常的神经元细胞的病状。
17.权利要求1-5中任一项的化合物用于制备药物的用途,所述药物用于治疗具有铁过度积累的神经元细胞的受试者。
18.权利要求8-17中任一项所述的用途,其中所述受试者是儿童。
19.权利要求18所述的用途,其中所述儿童是10至15岁。
20.权利要求8-17中任一项所述的用途,其中所述受试者是成人。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US2676976A (en) | 1950-12-04 | 1954-04-27 | Nat Res Dev | Synthesis of pantothenic acid-4' phosphate |
US2870188A (en) | 1955-10-03 | 1959-01-20 | Hoffmann La Roche | Process for the manufacture of pantothenic acid 4'-phosphate and its salts |
RU2002110463A (ru) * | 1999-09-21 | 2004-02-27 | Басф Акциенгезелльшафт (De) | Способ и микроорганизмы для получения пантосоединений |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1639349A (zh) * | 2002-07-03 | 2005-07-13 | 巴斯福股份公司 | 用于提高泛酸产量的微生物和方法 |
Non-Patent Citations (3)
Title |
---|
"Prodrugs of Phosphates and Phosphonates";S.J. Hecker等;《J. Med. Chem.》;20080201;第51卷(第8期);第2328-2345页 * |
"Unraveling the Hallervorden-Spatz syndrome:pantothenate kinase-associated neurodegeneration is the name…";S. J. Hayflick;《Current Opinion in Pediatrics》;20031231;第15卷(第6期);第572-577页 * |
Pantethine Rescues Phosphopantothenoylcysteine Synthetase and Phosphopantothenoylcysteine Decarboxylase Deficiency in Escherichia coli but Not in Pseudomonas aeruginosa;C. J. Balibar等;《JOURNAL OF BACTERIOLOGY》;20110506;第193卷(第13期);第3304-3312页 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106977544A (zh) * | 2012-04-27 | 2017-07-25 | 雷特罗芬公司 | 用于治疗神经疾病的泛酸酯衍生物 |
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