CN1993319A - 作为maob抑制剂的苄氧基衍生物 - Google Patents
作为maob抑制剂的苄氧基衍生物 Download PDFInfo
- Publication number
- CN1993319A CN1993319A CNA2005800258332A CN200580025833A CN1993319A CN 1993319 A CN1993319 A CN 1993319A CN A2005800258332 A CNA2005800258332 A CN A2005800258332A CN 200580025833 A CN200580025833 A CN 200580025833A CN 1993319 A CN1993319 A CN 1993319A
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- Prior art keywords
- compound
- formula
- benzyloxy
- fluoro
- perhaps
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 title description 3
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 title description 2
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 229940052764 dopaminergic anti-parkinson drug mao b inhibitors Drugs 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 230000001404 mediated effect Effects 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 24
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- -1 diazole-3-yl Chemical group 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
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- 239000003480 eluent Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明涉及通式(I)的化合物以及它们的可药用盐,其中R1为卤素;R2为-C(O)NH2、-C(NH2)=N-OH、-C(O)CH2Br、-C(O)N(CH3)OCH3或-C(O)-低级烷基,或者为含有2或3个选自N、O或S的杂原子的5-元杂芳基,其任选被R3取代,其中R3为低级烷基、-NR′R″或-C(O)R;R为NR′R″、低级烷基或低级烷氧基;R′/R″独立地为氢或低级烷基,它们用于治疗由单胺氧化酶B抑制剂介导的疾病,例如阿尔茨海默病和老年性痴呆。
Description
本发明涉及通式I的苄氧基衍生物
其中
R1 为卤素;
R2 为-C(O)NH2、-C(NH2)=N-OH、-C(O)CH2Br、-C(O)N(CH3)OCH3或-C(O)-低级烷基,或者为含有2或3个选自N、O或S的杂原子的5-元杂芳基,其任选地被低级烷基、-NR′R″或-C(O)R取代;
R 为NR′R″、低级烷基或低级烷氧基;
R′/R″独立地为氢或低级烷基;以及它们的可药用盐。
本发明包括式I化合物的单个异构体以及其外消旋的和非外消旋的混合物。
式I化合物的单个异构体以及其外消旋和非外消旋混合物形式的式l化合物和它们的可药用盐(下文:所述药用化合物)具有药理学活性,可用作药物。具体地,所述药用化合物抑制单胺氧化酶B的活性。
单胺氧化酶(MAO)是一种含黄素酶,负责内源性单胺神经递质如多巴胺、5-羟色胺、肾上腺素或去甲肾上腺素和痕量胺例如苯乙胺以及许多胺外源物的氧化脱氨。该酶以两种形式存在,即MAO-A和MAO-B,它们由不同的基因编码(A.W.Bach等,Proc.Natl.Acad.Sci.USA 1988,85,4934-4938),并且在组织分布、结构和底物特异性方面有差异。MAO-A对5-羟色胺、章鱼胺、肾上腺素和去甲肾上腺素具有更高的亲和性;而MAO-B的天然底物是苯乙胺和酪胺。认为这两种同工型均可氧化多巴胺。MAO-B广泛分布于包括脑在内的多个器官中(A.M.Cesura和A.Pletscher,Prog.Drug Research 1992,38,171-297)。脑MAO-B的活性似乎随年龄增长而增加。该活性增加已被归因于与衰老相关的神经胶质增生(C.J.Fowler等,J.Neural. Transm.1980,49,1-20)。另外,MAO-B的活性在阿尔茨海默病患者的脑中显著更高(P.Dostert等,Biochem.Pharmacol. 1989,38,555-561),并且已经发现其在老年斑周围的星形胶质细胞中被高度表达(Saura等,Neuroscience 1994,70,755-774)。在此方面,由于MAO对伯单胺的氧化脱氨作用产生NH3、醛和H2O2,均为具有已确定的或潜在毒性的物质,因此这表明用选择性MAO-B抑制剂治疗痴呆和帕金森病具有理论依据。抑制MAO-B导致多巴胺的酶失活减少,从而使多巴胺能神经元中的神经递质的有效性延长。与衰老、阿尔茨海默病和帕金森病相关的变性过程也可归因于由于MAO活性增加及因此由MAO-B导致的H2O2形成增加所造成的氧化应激。因此,MAO-B抑制剂可通过减少氧自由基的形成和升高脑内单胺水平来发挥作用。
考虑到在上述神经障碍中涉及MAO-B,人们对获得可控制该酶活性的有效和选择性抑制剂非常关注。一些已知的MAO-B抑制剂的药理学例如被D.Bentué-Ferrer等在CNS Drugs 1996,6,217-236中讨论。不可逆性和非选择性MAO抑制剂活性的一个主要限制是需要遵守饮食注意事项,因为当摄入食用酪胺时存在诱发高血压危象的危险并且存在与其它药物相互作用的可能(D.M.Gardner等,J.Clin.Psychiatry 1996,57,99-104),而这些不良事件较少与MAO、特别是MAO-B的可逆性和选择性抑制剂相关。因此,需要对该酶具有高选择性且无低选择性的不可逆性MAO抑制剂的典型不良副作用的MAO-B抑制剂。
因此,所述药用化合物作为单胺氧化酶B的选择性抑制剂可用于例如治疗或预防单胺氧化酶B活性在其中发挥作用或其中牵涉单胺氧化酶B活性的疾病和病症。这类病症特别包括急性和/或慢性神经障碍。
急性和/或慢性神经障碍包括精神病、精神***症、阿尔茨海默病、认知障碍和记忆缺陷(memory deficit)如轻度认知功能损害、与年龄相关的认知功能减退(cognitive decline)、血管性痴呆、帕金森病、与抑郁或焦虑相关的记忆损害(memory impairement)、唐氏综合征、中风、外伤性脑损伤和注意力缺陷障碍。其它可治疗的适应症有由旁路手术或移植导致的脑功能受限(restricted brain function)、脑供血不足、脊髓损伤、头损伤、妊娠导致的缺氧、心脏停搏和低血糖。其它可治疗的适应症有急性和慢性疼痛、亨廷顿舞蹈病、肌萎缩性侧索硬化(ALS)、AIDS导致的痴呆、眼损伤、视网膜病变、特发性帕金森综合征(idiopathic parkinsonism)或药物导致的帕金森综合征,以及引起谷氨酸缺乏功能的病症例如肌肉痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、精神病发作、阿片成瘾、焦虑、呕吐、运动障碍和抑郁。
在一个实施方案中,急性和/或慢性神经障碍是阿尔茨海默病。在另一个实施方案中,急性和/或慢性神经障碍是轻度认知功能损害或老年性痴呆。
因此,本发明的目的是提供必须具有上述有利性质的化合物。已经发现本发明的式I化合物和它们的可药用盐表现出作为高选择性MAO-B抑制剂的潜能。本发明的主题还有基于本发明的式I化合物的药物、制备式I化合物和它们可药用盐的方法以及式I化合物在控制或预防由单胺氧化酶B抑制剂介导的疾病中的用途和分别在制备相应药物中的用途。
无论所述的术语是单独出现还是组合出现,本专利申请中所用的通用术语的以下定义均适用。必须注意的是,除非上下文中明确指出,否则说明书和所附权利要求书中所用的单数形式也包括复数形式。
本申请中所用的术语“低级烷基”表示含有1至6个碳原子、优选含有1至4个碳原子的直链或支链的饱和烃基,如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等。
术语“卤素”表示氟、氯、溴和碘。
“低级烷氧基”意指残基-O-R,其中R为本文中所定义的低级烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基等。
术语“含有2或3个选自N、O或S的杂原子的5-元杂芳基”意指杂芳族环系,其选自[1.2.4]二唑基、1,3-噻唑基、咪唑基、吡唑基或异唑基。优选的基团是[1.2.4]二唑基、1,3-噻唑基或咪唑基。
化合物的“可药用盐”意指药学可接受的盐,它们通常安全、无毒且在生物学上或其它方面符合需要,并且具有所需的母体化合物的药理学活性。这些盐衍生自无机或有机的酸或碱。
这类盐包括:
(1)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐;或者与有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、羟基乙酸、羟基萘甲酸、2-羟基乙烷磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰基-L-酒石酸、酒石酸、对甲苯-磺酸、三甲基乙酸、2,2,2-三氟乙酸等形成的酸加成盐;或
(2)当母体化合物中存在的酸性质子被金属离子例如碱金属离子、碱土金属离子或铝离子代替时形成的盐;或者与有机或无机碱的配合物。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨基丁三醇等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
应当理解的是,所有对可药用盐的指代均包括该酸加成盐的溶剂加成形式(溶剂合物)或晶体形式(多晶型物)。
“可药用的”如可药用的载体、赋形剂等意指药理学可接受的且对被施用特定化合物的对象基本上无毒的。
“治疗有效量”意指可有效预防、减轻或改善疾病的症状或延长被治疗对象的存活期的量。
而且,本文所用的需要治疗急性和/或慢性神经障碍的哺乳动物意指患有急性和/或慢性神经障碍或具有罹患急性和/或慢性神经障碍危险的哺乳动物,例如人。
当被应用于急性和/或慢性神经障碍时,本文所用的术语“治疗”等是指减慢、改善、减轻或逆转当前困扰施用对象的这类障碍或与所述障碍相关的任何症状的方法,以及预防这类障碍或其任何症状发生的方法。
在本发明的化合物中,某些式I化合物或其可药用盐是优选的。
优选其中各基团定义如下的式I化合物:R2为含有2或3个选自N、O或S的杂原子的5-元杂芳基,其任选地被R3取代,R3为低级烷基、-NR′R″或-C(O)R。以下结构包括这类化合物。
式IA的化合物是例如下列化合物:
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(5-甲基-[1,2,4]二唑-3-基)-吡咯烷-2-酮,3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酸乙酯,3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酰胺,
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(2-甲基-噻唑-4-基)-吡咯烷-2-酮或
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(1H-咪唑-4-基)-吡咯烷-2-酮。
另外的式I化合物是其中各基团定义如下的那些式I化合物:R2为-C(O)NH2、-C(NH2)=N-OH、-C(O)CH2Br、-C(O)N(CH3)OCH3或-C(O)-低级烷基,例如
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酰胺,
(R)-1-[4-(3-氟-苄氧基)-苯基]-N-羟基-5-氧代-吡咯烷-3-甲脒,
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸甲氧基甲基酰胺或
(R)-4-乙酰基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮。
本发明通式I的化合物和它们的可药用盐可以通过本领域已知的方法、例如通过下文所述的方法制备,该方法包括:
a)将式II的化合物
与乙酸铵在缩合试剂例如CDI(1,1′-羰基-二咪唑)的存在下进行反应,得到式I-1的化合物,
其中R1如上文所述,或者
b)将式I-1的化合物
与亚硫酰氯进行反应,得到式III的化合物,
其中R1如上文所述,或者
c)将式III的化合物
与羟胺进行反应,得到式I-2的化合物,
其中R1如上文所述,或者
d)将式I-2的化合物
与乙酰氯在碱的存在下进行反应,得到式I-3的化合物,
其中R1如上文所述,或者
e)将式I-2的化合物
与草酰氯单乙酯(ethyl oxalyl chloride)进行反应,得到式I-4的化合物,
其中R1如上文所述,或者
f)将式I-4的化合物
与NH4OH进行反应,得到式I-5的化合物,
其中R1如上文所述,或者
g)将式II的化合物
与亚硫酰氯在N,N′-二甲基甲酰胺和三甲基硅烷基重氮甲烷和HBr的存在下进行反应,得到式I-6的化合物,
其中R1如上文所述,或者
h)将式I-6的化合物
与甲酰胺进行反应,得到式I-8的化合物,
其中R1如上文所述,或者
i)将式I-6的化合物
与硫代乙酰胺在THF中进行反应,得到式I-7的化合物,
其中R1如上文所述,或者
j)将式II的化合物
与N,O-二甲基羟胺盐酸盐和CDI进行反应,得到式I-9的化合物,
其中R1如上文所述,或者
k)将式I-9的化合物
与MeMgBr在THF中进行反应,得到式I-10的化合物,
其中R1如上文所述,并且如果需要,将获得的式I化合物转化为具有药学活性的酸加成盐。
根据本发明,制备通式I化合物的可能性如流程图1和2中所示。
通式I的化合物可以通过以下方法制备:将式II的化合物与1,1′-羰基-二咪唑(CDI)在N,N′-二甲基甲酰胺(DMF)中进行反应,加入乙酸铵(流程图1),得到相应的式I-1的酰胺。可以通过用试剂如亚硫酰氯优选在90℃下脱水而由酰胺制备腈化合物。将式III化合物与羟胺盐酸盐在碱如N,N-二异丙基乙基胺的存在下进行反应,得到必需的式I-2的N-羟基-甲脒,将式I-2的化合物与乙酰氯在碱如吡啶的存在下进行反应,得到式I-4的化合物,或者将式I-2的化合物与草酰氯单乙酯进行反应,得到式I-3的化合物。可以与氨一起在溶剂如甲醇中加热而由酯制备式1-5的相应的酰胺。
流程图1
R1的定义如上文所述。
其它通式I化合物可以通过以下方法制备:将式II的化合物与亚硫酰氯在催化量的N,N′-二甲基甲酰胺的存在下进行反应,得到中间体酰氯,将酰氯与三甲基硅烷基重氮甲烷和33%的氢溴酸的乙酸溶液进行反应,得到2-溴乙酰基化合物I-6。其中R2代表咪唑的式I化合物(I-8)可以通过将式I-6的化合物与甲酰胺和水一起进行回流来制备。其中R2代表噻唑的式I化合物(I-7)可以通过将式I-6的化合物与硫代乙酰胺一起在溶剂如四氢呋喃中进行回流来制备。其中R2代表酰胺如甲氧基甲基酰胺的其它式I化合物(I-9)可以通过以下方法制备:将相应的式II的酸与1,1′-羰基-二咪唑(CDI)在N,N′-二甲基甲酰胺(DMF)中进行反应,得到活化的中间体,将其与相应的胺如甲氧基甲基胺反应。将甲氧基甲基酰胺I-9与亲核试剂如烷基溴化镁例如甲基溴化镁进行反应,得到相应的式I-10的酮。
流程图2
取代基R1具有上文所述的含义。
根据本身已知的方法并考虑待转化为盐的化合物的性质,可以容易地制备式I化合物的可药用盐。无机酸或有机酸如例如盐酸、氢溴酸、硫酸、硝酸、磷酸或柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲烷磺酸、对甲苯磺酸等适合用于形成碱性式I化合物的可药用盐。含有碱金属或碱土金属例如钠、钾、钙、镁等的化合物、碱性胺或碱性氨基酸适合用于形成酸性化合物的可药用盐。
正如以上已提及的,式I化合物和它们的可药用盐是单胺氧化酶B抑制剂,可用于治疗或预防MAO-B抑制剂对其可能有益的疾病。这些疾病包括急性和慢性神经障碍、认知障碍和记忆缺陷。可治疗的神经障碍有例如神经***的创伤性或慢性变性过程,如阿尔茨海默病、其它类型的痴呆、极微认知功能损害(minimal cognitive impairment)或帕金森病。其它适应症包括精神疾病如抑郁、焦虑、惊恐发作、社交恐怖、精神***症、进食和代谢障碍如肥胖症,以及预防和治疗滥用酒精、尼古丁和其它成瘾性药物诱发的戒断综合征。其它可治疗的适应症可以是奖赏缺陷综合征(rewarddeficiency syndrome)(G.M.Sullivan,国际专利申请No.WO 01/34172A2)、癌症化疗引起的外周神经病(G.Bobotas,国际专利申请No.WO97/33572 A1)或治疗多发性硬化(R.Y.Harris,国际专利申请No.WO96/40095 A1)和其它神经炎性疾病。
使用以下方法试验化合物的药理学活性:
所述药用化合物的药理学活性可以例如如下证明:
使用Schlaeger和Christensen[Cytotechnology,15:1-13(1998)]所述的操作方法,将编码人MAO-A和MAO-B的cDNA瞬时转染到EBNA细胞中。转染后,将细胞用Polytron匀浆器在含有0.5mM EGTA和0.5mM苯基甲烷磺酰氟的pH 8.0的20mM Tris HCl缓冲液中进行均化。通过在45,000×g下离心得到细胞膜,用含有0.5mM EGTA的pH 8.0的20mMTris HCl缓冲液洗涤两次后,最后将细胞膜重新混悬在上述缓冲液中,并将等分试样贮存在-80℃下备用。
使用由Zhou和Panchuk-Voloshina[Analytical Biochemistry,253:169-174(1997)]所述的方法改进得到的分光光度测定法在96孔板上测定MAO-A和MAO-B的酶活性。简言之,将膜的等分试样在pH 7.4的0.1M磷酸钾缓冲液中于37℃下温育30分钟,存在或不存在各种浓度的化合物。之后,通过加入MAO底物酪胺以及1U/ml的辣根过氧化物酶(RocheBiochemicals)和80μM N-乙酰基-3,7-二羟基吩嗪(Amplex Red,Molecular Probes)引发酶反应。将样品以200μl的终体积在37℃下再温育30分钟,然后使用SpectraMax读板仪(Molecular Devices)在570nm波长下测定吸收度。对于MAO-A在10μM的氯吉灵存在下或者对于MAO-B在10μM的L-盐酸司来吉兰存在下测定背景(非特异性)吸收。
通过用计算机程序将数据拟合为四参数逻辑方程由用一式两份的9个抑制剂浓度获得的抑制曲线确定IC50值。
本发明的化合物是特异性MAO-B抑制剂。在上述测定法中测得的式I化合物的IC50值为1μM或更小,理想地为0.1μM或更小。下表给出了为其对映体形式之一的式I化合物的示范性IC50值。
人MAO-B
实施例
[IC50(μM)]
3 0.018
4 0.016
5 0.043
6 0.429
8 0.387
9 0.187
10 0.392
11 0.011
所述药用化合物可用作药物,例如以药物制剂的形式用作药物。所述药物制剂可以口服施用,例如以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊剂、溶液剂、乳剂或混悬剂的形式口服施用。但是,也可以直肠施用,例如以栓剂的形式直肠施用,或胃肠外施用,例如以注射用溶液剂的形式胃肠外施用。
可以将所述药用化合物用药学惰性的无机或有机载体进行加工以制备药物制剂。乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等可用作例如片剂、包衣片剂、糖衣丸和硬明胶胶囊剂的载体。用于软明胶胶囊剂的适宜载体有例如植物油、蜡、脂肪、半固体和液体多元醇等;但是,取决于活性物质的性质,对于软明胶胶囊剂,通常不需要载体。用于制备溶液剂和糖浆剂的适宜载体有例如水、多元醇、蔗糖、转化糖、葡萄糖等。辅剂如醇、多元醇、甘油、植物油等可用于式I化合物的水溶性盐的水性注射用溶液剂,但通常不是必需的。用于栓剂的适宜载体有例如天然或硬化油、蜡、脂肪、半液体或液体多元醇等。
另外,药物制剂可含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、甜味剂、着色剂、矫味剂、调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它治疗上有价值的物质。
剂量可以在宽的限度内变化,并且当然要符合每个特定病例中的个体需求。一般而言,用于口服或胃肠外施用的有效剂量为0.01-20mg/kg/天,优选的剂量为0.1-10mg/kg/天,适用于所有所述的适应症。对于体重70kg的成年人而言,日剂量相应地为每天0.7-1400mg,优选每天7至700mg。
提供以下实施例以举例说明本发明。它们不应被认为是对本发明范围的限制,而仅仅是本发明的代表。
实施例1
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酰胺
在氩气下将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸(1.5g,0.005mol)溶解在干燥的N,N-二甲基甲酰胺中,并冷却至0℃。向该混合物中加入1,1′-羰基-二咪唑(1.4g,0.009mol),将反应搅拌1小时,同时温度从0℃升至室温。加入乙酸铵(5.6g,0.073mol),将反应在室温下搅拌1小时。向混合物中滴加水,出现沉淀。过滤固体,用水洗涤,在真空下干燥,得到1.36g(0.0041mol,理论量的91%)标题化合物,为白色固体。MS(m/e)=329.3(M+H)+。
实施例2
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲腈
将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酰胺(0.400g,0.001mol)和亚硫酰氯(2.3ml,0.032mol)的混合物在氩气下回流3小时。将混合物冷却至室温,用5ml四氢呋喃稀释,在真空下浓缩,通过硅胶柱色谱法进行纯化,使用乙酸乙酯和己烷的2∶3混合物作为洗脱剂。将产物级分浓缩至干,得到(0.106g,理论量的28%)淡棕色油状物。MS(m/e)=311.1(M+H)+。
实施例3
(R)-1-[4-(3-氟-苄氧基)-苯基]-N-羟基-5-氧代-吡咯烷-3-甲脒
将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲腈(0.211g,0.001mol)和羟胺盐酸盐(0.047g,0.001mol)溶解在乙醇(4ml)中,加入N,N-二异丙基乙基胺(0.120ml,0.001mol)。将反应混合物在回流下搅拌3小时。将反应冷却至室温,蒸发溶剂,用二氯甲烷萃取残余物,通过硅胶柱色谱法进行纯化,使用二氯甲烷和甲醇的19∶1混合物作为洗脱剂,得到(0.220g,理论量的94%)黄色油状物。MS(m/e)=344.3(M+H)+。
实施例4
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(5-甲基-[1,2,4]二唑-3-基)-吡咯烷-2-酮
在0℃下,将(R)-1-[4-(3-氟-苄氧基)-苯基]-N-羟基-5-氧代-吡咯烷-3-甲脒(0.020g,0.58mmol)溶解在0.4ml吡啶的混合物中,缓慢加入乙酰氯(0.01ml,0.116mmol)。然后将混合物在70℃下搅拌过夜。加入冰水,将混合物搅拌1小时。用饱和氯化铵溶液和二氯甲烷萃取,得到粗产物,将其通过硅胶柱色谱法进行纯化,使用二氯甲烷和甲醇的19∶1混合物作为洗脱剂,获得标题化合物,为淡黄色固体(0.0197g,理论量的92%)。MS(m/e)=368.4(M+H)+。
实施例5
3-{(R)-1-[4-(3-氟-苄氧基)-苯基)-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酸乙酯
在0℃下,将(R)-1-[4-(3-氟-苄氧基)-苯基]-N-羟基-5-氧代-吡咯烷-3-甲脒(0.020g,0.58mmol)溶解0.4ml吡啶的混合物中,缓慢加入草酰氯单乙酯(0.01ml,0.116mmol)。然后将混合物在70℃下搅拌半小时。加入冰水,将混合物搅拌1小时。用饱和氯化铵溶液和二氯甲烷萃取,得到粗产物,将其通过硅胶柱色谱法进行纯化,使用乙酸乙酯和己烷的2∶1混合物作为洗脱剂,获得标题化合物,为淡黄色固体(0.019g,理论量的77%)。MS(m/e)=426.3(M+H)+。
实施例6
3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酰胺
将3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酸乙酯(0.110g,0.25mmol)溶解在3.5ml氨(2M的甲醇溶液)中。将得到的混合物在50℃下搅拌半小时。将混合物冷却至0℃,沉淀出固体。过滤反应混合物,用己烷洗涤固体,在真空下干燥。将残余物混悬在乙酸乙酯中,加热至回流。加入***,将混悬液冷却至0℃,过滤,得到标题化合物,为淡棕色固体(0.045g,理论量的44%)。MS(m/e)=397.4(M+H)+。
实施例7
(R)-4-(2-溴-乙酰基)-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮
将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸(0.204g,0.62mmol)溶解在二氯甲烷(4ml)、亚硫酰氯(0.15ml,2.1mmol)和催化量N,N-二甲基甲酰胺的混合物中。将反应混合物在室温下搅拌半小时以形成中间体酰氯。此后,在减压下除去溶剂,将残余物混悬在甲苯中,在真空下浓缩并干燥。将得到的油状物溶解在乙腈(2ml)中,在氩气下加入三甲基硅烷基重氮甲烷(2M的己烷溶液)(1.55ml,3.1mmol)。将得到的黄色溶液在室温下搅拌半小时,直至能观察到重氮酮。将反应混合物冷却至0℃后,滴加氢溴酸(33%的乙酸溶液)(0.71ml,4mmol)。将得到的深色溶液在室温下搅拌半小时。加入碳酸氢钠(5ml),用二氯甲烷萃取混合物。将有机层用硫酸镁干燥,过滤并蒸发至干,得到残余物,将其通过硅胶柱色谱法进行纯化,使用乙酸乙酯和己烷的1∶1混合物作为洗脱剂,获得标题化合物,为淡黄色油状物(0.067g,理论量的67.5%)。MS(m/e)=407.3(M+H)+。
实施例8
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(2-甲基-噻唑-4-基)-吡咯烷-2-酮
将(R)-4-(2-溴-乙酰基)-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮(0.040g,0.098mmol)溶解在四氢呋喃(1ml)中,加入硫代乙酰胺(0.007g,0.098mmol),将混合物在40℃下搅拌24小时。蒸发四氢呋喃,将残余物通过硅胶柱色谱法进行纯化,首先使用乙酸乙酯和己烷的1∶1混合物、然后使用4∶1混合物作为洗脱剂,得到标题化合物,为淡黄色固体(0.030g,理论量的80%)。MS(m/e)=383.3(M+H)+。
实施例9
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(1H-咪唑-4-基)-吡咯烷-2-酮
将(R)-4-(2-溴-乙酰基)-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮(0.050g,0.123mmol)溶解在水(0.1ml)中,加入甲酰胺(0.6ml),将混合物在回流下搅拌6小时。加入2M HCl,用乙酸乙酯萃取混合物。将水层用氢氧化钠水溶液(10%)中和(pH 7-8),用乙酸乙酯再次萃取,得到粗品,将其用硅胶色谱法进行处理,使用二氯甲烷和甲醇的19∶1混合物作为洗脱剂。得到0.011g(理论量的25%)标题化合物,为无色固体。MS:m/e=352.4(M+H)+。
实施例10
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸甲氧基甲基酰胺
在氩气下将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸(0.200g,0.001mol)溶解在干燥的N,N-二甲基甲酰胺(1ml)中,将溶液冷却至0℃。向混合物中加入1,1′-羰基-二咪唑(0.108g,0.001mol),将反应搅拌半小时,同时温度从0℃升至室温。加入N,O-二甲基羟胺盐酸盐(0.063g,0.001mol)和吡啶(0.053ml,0.001mmol)后,将反应在室温下搅拌2小时。加入水(10ml)和盐酸(0.1N),用乙酸乙酯萃取混合物。将有机相用碳酸钠溶液(1M)洗涤,用乙酸乙酯再次萃取,得到0.225g(理论量的99%)产物。将由此获得的粗产物不经进一步纯化即用在下一步中。MS:m/e=373.4(M+H)+。
实施例11
(R)-4-乙酰基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮
在氩气下将(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸甲氧基甲基酰胺(0.050g,0.143mmol)溶解在四氢呋喃(1ml)中,在0℃下加入甲基溴化镁(0.188mmol,0.063ml)。将得到的溶液在0℃下搅拌2小时。在0℃下加入水,将混合物搅拌1小时。用乙酸乙酯萃取,得到残余物,将其用硅胶色谱法处理,使用乙酸乙酯和环己烷的9∶1混合物作为洗脱剂,得到0.040g(理论量的91%)标题化合物,为白色固体。MS:m/e=328.4(M+H)+。
实施例A
用常规方法制备以下组合物的片剂:
mg/片
活性成分 100
粉状乳糖 95
白玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
片重 250
实施例B
用常规方法制备以下组合物的片剂:
mg/片
活性成分 200
粉状乳糖 100
白玉米淀粉 64
聚乙烯吡咯烷酮 12
羧甲基淀粉钠 20
硬脂酸镁 4
片重 400
实施例C
制备以下组合物的胶囊剂:
mg/胶囊
活性成分 50
结晶乳糖 60
微晶纤维素 34
滑石粉 5
硬脂酸镁 1
胶囊填充重量 150
将具有适宜颗粒大小的活性成分、结晶乳糖和微晶纤维素彼此混合均匀,过筛,此后混合入滑石粉和硬脂酸镁。将终混合物填充到适宜大小的硬明胶胶囊中。
实施例D
注射用溶液剂可以具有以下组成,按照通常的方法制备。
活性物质 1.0mg
1N HCl 20.0μl
乙酸 0.5mg
NaCl 8.0mg
苯酚 10.0mg
1N NaOH 加入适量至pH 5
H2O 加入适量至1ml
Claims (13)
2.权利要求1的式IA化合物
其中R1和R3如权利要求1中所述。
3.权利要求2的式IA化合物,其中该化合物为
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(5-甲基-[1,2,4]二唑-3-基)-吡咯烷-2-酮,3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酸乙酯,
3-{(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-基}-[1,2,4]二唑-5-甲酰胺,
(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(2-甲基-噻唑-4-基)-吡咯烷-2-酮或(R)-1-[4-(3-氟-苄氧基)-苯基]-4-(1H-咪唑-4-基)-吡咯烷-2-酮。
4.权利要求1的式I化合物,其中R2为-C(O)NH2、-C(NH2)=N-OH、-C(O)CH2Br、-C(O)N(CH3)OCH3或-C(O)-低级烷基。
5.权利要求4的式I化合物,其中该化合物为
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酰胺,
(R)-1-[4-(3-氟-苄氧基)-苯基]-N-羟基-5-氧代-吡咯烷-3-甲脒,
(R)-1-[4-(3-氟-苄氧基)-苯基]-5-氧代-吡咯烷-3-甲酸甲氧基甲基酰胺或
(R)-4-乙酰基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮。
6.制备权利要求1的式I化合物的方法,该方法包括
a)将式II的化合物
与乙酸铵在缩合试剂例如CDI(1,1′-羰基-二咪唑)的存在下进行反应,得到式I-1的化合物,
其中R1如上文所述,或者
b)将式I-1的化合物
与亚硫酰氯进行反应,得到式III的化合物,
其中R1如上文所述,或者
c)将式III的化合物
与羟胺进行反应,得到式I-2的化合物,
其中R1如上文所述,或者
d)将式I-2的化合物
与乙酰氯在碱的存在下进行反应,得到式I-3的化合物,
其中R1如上文所述,或者
e)将式I-2的化合物
与草酰氯单乙酯进行反应,得到式I-4的化合物,
其中R1如上文所述,或者
f)将式I-4的化合物
与NH4OH进行反应,得到式I-5的化合物,
其中R1如上文所述,或者
g)将式II的化合物
与亚硫酰氯在N,N′-二甲基甲酰胺和三甲基硅烷基重氮甲烷和HBr的存在下进行反应,得到式I-6的化合物,
其中R1如上文所述,或者
h)将式I-6的化合物
与甲酰胺进行反应,得到式I-8的化合物,
其中R1如上文所述,或者
i)将式I-6的化合物
与硫代乙酰胺在THF中进行反应,得到式I-7的化合物,
其中R1如上文所述,或者
j)将式II的化合物
与N,O-二甲基羟胺盐酸盐和CDI进行反应,得到式I-9的化合物,
其中R1如上文所述,或者
k)将式I-9的化合物
与MeMgBr在THF中进行反应,得到式I-10的化合物,
其中R1如上文所述,并且如果需要,将获得的式I化合物转化为具有药学活性的酸加成盐。
7.权利要求1至5中任意一项的式I化合物,其是用权利要求6的方法制备的。
8.用于治疗和预防由单胺氧化酶B抑制剂介导的疾病的含有一种或多种权利要求1至5中任意一项所述的化合物和可药用赋形剂的药物。
9.用于治疗和预防阿尔茨海默病和老年性痴呆的含有一种或多种权利要求1至5中任意一项所述的化合物和可药用赋形剂的药物。
10.用于治疗或预防疾病的权利要求1至5中任意一项的式I化合物以及其可药用盐。
11.权利要求1至5中任意一项的式I化合物以及其可药用盐在制备药物中的用途,所述药物用于治疗和预防由单胺氧化酶B抑制剂介导的疾病。
12.权利要求11的用途,其中所述疾病是阿尔茨海默病或老年性痴呆。
13.本文前面描述的发明。
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PCT/EP2005/008143 WO2006013049A2 (en) | 2004-08-02 | 2005-07-27 | Benzyloxy derivatives as maob inhibitors |
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US7501528B2 (en) * | 2005-03-15 | 2009-03-10 | Hoffmann-La Roche Inc. | Method for preparing enantiomerically pure 4-pyrrolidino phenylbenzyl ether derivatives |
KR101220182B1 (ko) * | 2009-02-25 | 2013-01-11 | 에스케이바이오팜 주식회사 | 치환된 아졸 유도체 화합물, 이를 포함하는 약제학적 조성물 및 이를 이용한 파킨슨씨 병 치료방법 |
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US5679715A (en) | 1995-06-07 | 1997-10-21 | Harris; Richard Y. | Method for treating multiple sclerosis |
JP3258027B2 (ja) | 1996-03-15 | 2002-02-18 | サマーセット・ファーマシューティカルズ・インコーポレイテッド | セレジリン投与による末梢ニューロパシーの予防および治療方法 |
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CN110240557B (zh) * | 2018-03-08 | 2023-05-09 | 广东东阳光药业有限公司 | 吡咯烷酰胺衍生物及其用途 |
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US7456210B2 (en) | 2008-11-25 |
AR050193A1 (es) | 2006-10-04 |
EP1776337A2 (en) | 2007-04-25 |
AU2005268894A1 (en) | 2006-02-09 |
TWI291349B (en) | 2007-12-21 |
CN100560566C (zh) | 2009-11-18 |
WO2006013049A2 (en) | 2006-02-09 |
TW200612912A (en) | 2006-05-01 |
JP4629105B2 (ja) | 2011-02-09 |
JP2008508335A (ja) | 2008-03-21 |
RU2378270C2 (ru) | 2010-01-10 |
AU2005268894B2 (en) | 2010-12-16 |
WO2006013049A3 (en) | 2006-06-22 |
NZ552649A (en) | 2010-05-28 |
MX2007001169A (es) | 2007-03-12 |
US20060025599A1 (en) | 2006-02-02 |
CA2575018A1 (en) | 2006-02-09 |
HK1108432A1 (en) | 2008-05-09 |
RU2007103236A (ru) | 2008-09-10 |
ZA200700537B (en) | 2008-05-28 |
BRPI0514077A (pt) | 2008-05-27 |
NO20070972L (no) | 2007-02-28 |
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