CN101675049A - 作为α7-神经元烟碱样乙酰胆碱受体(NNRS)的选择性调节剂的氨基甲基氮杂金刚烷衍生物及其用途 - Google Patents
作为α7-神经元烟碱样乙酰胆碱受体(NNRS)的选择性调节剂的氨基甲基氮杂金刚烷衍生物及其用途 Download PDFInfo
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- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- PCFIPYFVXDCWBW-UHFFFAOYSA-N tricyclo[3.3.1.03,7]nonane Chemical compound C1C(C2)C3CC2CC1C3 PCFIPYFVXDCWBW-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000002071 ventral thalamic nuclei Anatomy 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
- 238000004260 weight control Methods 0.000 description 1
- 230000037221 weight management Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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Abstract
本发明涉及式(I)的取代的氨基甲基氮杂金刚烷衍生物,包含这类化合物的组合物,以及这类化合物和组合物在治疗或预防由α7烟碱样乙酰胆碱受体、α4β2烟碱样乙酰胆碱受体或α7和α4β2烟碱样乙酰胆碱受体两者调节的病症、疾病或缺陷的用途,其中所述病症、疾病或缺陷选自记忆疾病、认知障碍、神经变性和神经发育疾病。
Description
技术领域
[0001]本发明涉及氨基甲基氮杂金刚烷衍生物,包含这些化合物的组合物,以及使用这些化合物和组合物预防或治疗病症和疾病的方法。
相关技术的描述
[0002]烟碱样乙酰胆碱受体(nAChR,nicotinic acetylcholinereceptors),属于配体门控离子通道(LGIC)的超家族,广泛分布于整个中枢神经***(CNS)和外周神经***(PNS)中,并且门控阳离子流,受乙酰胆碱(ACh)控制。nAChR可以分为肌肉接头(NMJ)的烟碱样受体和神经元nAChR或神经元烟碱样受体(NNR)。所述NNR被理解为在调节CNS功能和释放许多神经传递介质中起重要作用,包括,但不是必须限于乙酰胆碱、去甲肾上腺素、多巴胺、5-羟色胺和GABA。因此,烟碱样受体调节非常宽范围的生理作用,并且是治疗有关认知功能、学习和记忆、神经变性、疼痛和炎症、精神和感觉门控、情绪和情感等疾病的靶标。
[0003]许多NNR亚型存在于CNS和***神经***中。每种亚型在调节整体生理功能方面具有不同作用。
[0004]典型地,NNR是由五倍体亚单位蛋白组装构成的离子通道。到目前为止已经报道了16种nAChR亚单元,其被确定为α2-α10、β1-β4、γ、δ和ε。在这些亚单元当中,9种亚单元,α2至α7以及β2至β4,主要存在于哺乳动物脑中。还存在许多功能不同的nAChR络合物,例如五种α7亚单元可以构成同质功能性五聚体形式的受体或者在α4β2和α3β4受体的情况下不同亚单元的组合可以络合在一起(例如,参见Vincler,M.,McIntosh,J.M.,Targeting the α9α10 nicotinicacetylcholine receptor to treat severe pain,Exp.Opin.Ther.Targets,2007,11(7):891-897;Paterson,D.and Nordberg,A.,Neuronal nicotinicreceptors in the human brain,Prog.Neurobiol.2000,61:75-111;Hogg,R.C.,Raggenbass,M.,Bertrand,D.,Nicotinic acetylcholine receptors:from structure to brain function,Rev.Physiol.,Biochem.Pharmacol.,2003,147:1-46;Gotti,C.,Clementi,F.,Neuronal nicotinic receptors:from structure to pathology,Prog.Neurobiol.,2004,74:363-396)。这些亚单元提供各种同质和异质组合,其构成不同的受体亚型。
[0005]通常,所述NNR涉及各种认知功能,例如学习、记忆、注意力,由此涉及CNS疾病,即,阿尔茨海默氏病(Alzheimer’sdisease)(AD)、帕金森病(PD)、注意力不集中的过度反应症(attentiondeficit hyperactivity disorder)(ADHD)、图雷特综合征、精神***症、双相性精神障碍、疼痛和烟草依赖(例如,参见,Keller,J.J.,Keller,A.B.,Bowers,B.J.,Wehner,J.M.,Performance of alpha7 nicotinic receptornull mutants is impaired in appetitive learning measured in a signalednose poke task,Behav.Brain Res.,2005,162:143-52;Gundish,D.,Nicotinic acetylcholine receptor ligands as potential therapeutics,ExpertOpin.Ther.Patents,2005,15(9):1221-1239;De Luca,V.,Likhodi,O.,Van Tol,H.H.,Kennedy,J.L.,Wong,A.H.,Regulation ofalpha7-nicotinic receptor subunit and alpha7-like gene expression in theprefrontal cortex of patients with bipolar disorder and schizophrenia,Acta Psychiatr.Scand.,2006,114:211-5)。
[0006]该同质α7受体与α4β2受体一起在人脑中是最丰富的烟碱样受体之一,它在海马、脑皮层、丘脑核、腹侧被盖区和黑质中大量表达(例如,参见,Broad,L.M.,Sher,E.,Astles,P.C.,Zwart,R.,O’Neill,M.J.,Selective α7 nicotinic acetylcholine receptor ligands forthe treatment of neuropsychiatric diseases,Drugs of the Future,2007,32(2):161-170)。
[0007]α7NNR在CNS中的神经元信号作用也已经被积极地研究(例如,参见,Couturier,S.,Bertrand,D.,Matter,J.M.,Hernandez,M.C.,Bertrand,S.,Millar,N.,Valera,S.,Barkas,T.,Ballivet,M.,A neuronalnicotinic acetylcholine receptor subunit(alpha 7)is developmentallyregulated and forms a homo-oligomeric channel blocked by alpha-BTX,Neuron,1990,5:847-56)。现已表明,在细胞损伤的实验性体外模型中,所述α7NNR调节中间神经元兴奋性、调节刺激性和抑制性递质的释放、以及引起神经保护作用(例如,参见,Alkondon,M.,Albuquerque,E.X.,The nicotinic acetylcholine receptor subtypes and their function inthe hippocampus and cerebral cortex,Prog.Brain Res.,2004,145:109-20)。
[0008]生物物理学研究表明,当在异种表达***中表达时,由α7亚单元组成的离子通道迅速被激活和脱敏,并且此外,与其它NNR组合相比,表现出相对更高的钙渗透性(例如,参见,Dajas-Bailador,F.,Wonnacott,S.,Nicotinic acetylcholine receptors and the regulation ofneuronal signaling,Trends Pharmacol.Sci.,2004,25:317-24).
[0009]所述NNR配体还与吸烟戒断(smoking cessation)、体重控制和潜在的镇痛作用有关(例如,参见,Balbani,A.P.S.,Montovani,J.C.,Recent developments for smoking cessation and treatment of nicotinedependence,Exp.Opin.Ther.Patents,2003,13(7):287-297;Gurwitz,D.,The therapeutic potential of nicotine and nicotinic agonists for weightcontrol,Exp.Opin.Invest.Drugs,1999,8(6):747-760;Vincler,M.,Neuronal nicotinic receptors as targets for novel analgesics,Exp.Opin.Invest.Drugs,2005,14(10):1191-1198;Bunnelle,W.H.,Decker,M.W.,Neuronal nicotinic acetylcholine receptor ligands as potential analgesics,Exp.Opin.Ther.Patents,2003,13(7):1003-1021;Decker,M.W.,Meyer,M.D.,Sullivan,J.P.,The therapeutic potential of nicotinic acetylcholinereceptor agonists for pain control,Exp.Opin.Invest.Drugs,2001,10(10):1819-1830;Vincler,M.,McIntosh,J.M.,Targeting the α9α10 nicotinicacetylcholine receptor to treat severe pain,Exp.Opin.Ther.Targets,2007,11(7):891-897)。
[0010]现已表明,α7和α4β2NNR在增强认知功能中表现出显著的作用,包括学习、记忆和注意力方面(Levin,E.D.,J.Neurobiol.53:633-640,2002)。例如,α7NNR涉及下面的病症和疾病,包括与注意缺陷障碍(attention deficit disorder)、ADHD、AD、轻度认知缺损(mildcognitive impairment)、老年性痴呆(senile dementia)、与莱维体有关的痴呆(dementia associated with Lewy bodies)、与唐氏综合征有关的痴呆(dementia associated with Down ′s syndrome)、AIDS痴呆(AIDSdementia)、皮克病(Pick′s disease)、以及与精神***症有关的认知缺损(cognitive deficits associated with schizophrenia)(CDS)、其它全身性活动有关的病症和疾病。所述α4β2受体亚型与注意力、认知、癫痫和疼痛控制有关(Paterson,D.和Nordberg,A.,Neuronal nicotinic receptorsin the human brain,Prog.Neurobiol.2000,61:75-111)。
[0011]某些化合物,如植物碱尼古丁,与所有已知的nAChR亚型都发生相互作用,说明这种化合物的深远的生理作用。已知当给予尼古丁时,可提高注意力和认知性能,减少焦虑,提高感觉门控,以及痛觉丧失和神经保护作用。这些作用通过尼古丁的非选择性作用对各类烟碱样受体亚型进行调节。但是,公知尼古丁也产生不利的结果,例如治疗剂量时的心血管和胃肠道问题,及其上瘾性质和急性毒性。因此,需要发现亚型选择性的化合物,其引起尼古丁的有益作用,同时消除或减少尼古丁的副作用。
[0012]通过给予亚型选择性NNR配体,可以改变或调节对NNR的活性。所述配体可以表现出拮抗剂、激动剂、或部分激动剂性质,因此具有治疗各种认知障碍的潜能。
[0013]虽然已知非选择性对烟碱样受体亚型(包括α4β2和α7NNR)表现出活性的化合物,但是与其它亚型相比,提供与含α7神经元NNR、α4β2NNR、或α7和α4β2NNR两者选择性相互作用的化合物是有益的。
发明概述
[0014]本发明涉及氨基甲基氮杂金刚烷衍生物,包含这些化合物的组合物,以及使用这些化合物和组合物的方法。
[0015]本发明的一方面涉及式(I)的化合物
(I);
其中
R1是氢或C1-6烷基;
R2是-C(O)-A、-A、-(CRxRy)t-A或-C(O)-(CRxRy)t-A;
A是芳基、杂芳基、杂环、环烷基或环烯基;
t在每次出现时是1、2、3、4或5;和
Rx和Ry在每次出现时独立地是氢、卤素、烷基或卤代烷基;
或其药学上可接受的盐、酰胺、酯或前药。
[0016]另一方面,本发明涉及包含本发明化合物的药物组合物。这些组合物可以根据本发明的方法给药,典型地作为治疗方案的一部分用于治疗或预防与NNR活性相关的病症和疾病,更特别是与α7NNR活性、α4β2NNR活性、或α7NNR活性和α4β2NNR活性二者相关的病症和疾病。
[0017]另一方面,本发明涉及一种调节α7NNR活性、α4β2NNR活性、α7NNR活性和α4β2NNR活性二者的方法。所述方法可用于在哺乳动物中治疗、预防或治疗和预防与α7NNR活性、α4β2NNR活性或α7NNR活性和α4β2NNR活性二者相关的病症和疾病。更特别地,所述方法可用于与注意缺陷障碍(attention deficit disorder)、ADHD、AD、帕金森氏病(Parkinson′s disease)、图雷特综合征(Tourette′s syndrome)、精神***症、精神***症的认知缺乏(CDS)、轻度认知缺损(mild cognitiveimpairment)、与年龄有关的记忆缺陷(AAMI,age-associated memoryimpairment)、老年性痴呆(senile dementia)、AIDS痴呆(AIDS dementia)、皮克病(Pick′s disease)、与莱维体有关的痴呆(dementia associated withLewy bodies)、与唐氏综合征有关的痴呆(dementia associated with Down′ssyndrome)、肌萎缩性侧索硬化(amyotrophic lateral sclerosis)、亨廷顿舞蹈病(Huntington′s disease)、与创伤性脑损伤有关的CNS功能减弱(diminishedCNS function associated with traumatic brain injury)、急性疼痛(acute pain)、术后痛(post-surgical pain)、慢性痛(chronic pain)、炎性痛(inflammatorypain)、神经性疼痛(neuropathic pain)、吸烟戒断(smoking cessation)、局部缺血(ischemia)、脓毒症(sepsis)、创伤愈合(wound healing)、以及与糖尿病有关的其它并发症、其它全身性和神经免疫调节活性相关的病症和疾病。
[0018]本文还描述了化合物、包含化合物的组合物、使用化合物的方法、以及制备化合物的方法以及在这些方法中获得的中间体。
发明的详细说明
术语的定义
[0019]对于在任何取代基中或在本发明的化合物或本文任何其它通式化合物中出现不止一次的变量来说,其每次出现时的定义是相互独立的。取代基的组合是允许的,条件是这些组合产生稳定的化合物。稳定化合物是可以从反应混合物中以可使用纯度分离得到的化合物。
[0020]在本说明书和所附权利要求书中,以下术语具有下列含义:
[0021]在此所使用的术语″链烯基″是指含有2-10个碳并且含有至少一个通过除去两个氢形成的碳-碳双键的直链或支链烃。链烯基的代表性例子包括,但不局限于,乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基和3-癸烯基。
[0022]在此所使用的术语″烷氧基″是指如在此所定义的通过一个氧原子附着于母体分子部分的烷基。烷氧基的代表性例子包括,但不局限于,甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基和己氧基。
[0023]在此所使用的术语″烷氧基烷基″是指如在此所定义的烷氧基,其通过在此所定义的烷基附着于母体分子部分。烷氧基烷基的代表性例子包括,但不局限于,叔丁氧基甲基、2-乙氧基乙基、2-甲氧基乙基和甲氧基甲基。
[0024]在此所使用的术语″烷氧羰基″是指如上所定义的烷氧基,其通过如在此定义的羰基与母体分子部分相连接。烷氧羰基的代表性例子包括,但不局限于,甲氧羰基、乙氧羰基和叔丁氧羰基。
[0025]在此所使用的术语″烷基″是指含有1-10个碳原子的直链或支链烃。烷基的代表性例子包括,但不局限于,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲戊基、2,3-二甲戊基、正庚基、正辛基、正壬基和正癸基。
[0026]在此所使用的术语″C1-6烷基″是指含有1-6个碳原子的直链或支链烃。
[0027]在此所使用的术语″烷基羰基″是指如在此所定义的烷基,其通过如在此定义的羰基与母体分子部分相连接。烷基羰基的代表性例子包括,但不局限于,乙酰基、1-氧代丙基、2,2-二甲基-1-氧代丙基、1-氧代丁基和1-氧代戊基。
[0028]在此所使用的术语″亚烷基″是指来源于1-10个碳原子的直链或支链烃的二价基团。亚烷基的代表性例子包括,但不局限于,-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-和-CH2CH(CH3)CH2-。
[0029]在此所使用的术语″炔基″是指含有2-10个碳原子并且含有至少一个碳-碳三键的直链或支链烃基。炔基的代表性例子包括,但不限于,乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基和1-丁炔基。
[0030]在此所使用的术语″芳基″是指苯基、双环芳基或三环芳基。双环芳基是萘基,或是与单环环烷基稠合的苯基,或是与单环环烯基稠合的苯基。所述双环芳基的代表性例子包括,但不局限于,二氢茚基、茚基、萘基、二氢萘基和四氢萘基。三环芳基是与单环环烷基稠合的双环芳基,或是与单环环烯基稠合的双环芳基,或是与苯基稠合的双环芳基。三环芳环的代表性例子包括,但不局限于,蒽、菲、二氢蒽基、芴基和四氢菲基。本发明的芳基可以是未取代的或取代的并且通过环体系内包含的任何碳原子附着于母体分子部分上。
[0031]在此所使用的术语″芳烷基″是指如在此所定义的芳基,其通过如在此所定义的烷基与母体分子部分相连接。芳烷基的代表性例子包括,但不局限于,苄基(苯基甲基)、2-苯基乙基和3-苯基丙基。
[0032]在此所使用的术语″羰基″是指-C(O)-基团。
[0033]在此所使用的术语″氰基″是指-CN基团。
[0034]在此所使用的术语″氰基烷基″是指如在此所定义的氰基,其通过如在此所定义的烷基与母体分子部分相连接。氰基烷基的代表性例子包括,但不局限于,氰基甲基、2-氰基乙基和3-氰基丙基。
[0035]在此所使用的术语″环烯基″是指含有3-8个碳并且含有至少一个通过除去两个氢形成的碳-碳双键的环烃。环烯基的代表性例子包括,但不局限于,2-环己烯-1-基、3-环己烯-1-基、2,4-环己二烯-1-基和3-环戊烯-1-基。
[0036]在此所使用的术语″环烷基″或″环烷烃″是指单环的、双环的和三环的环烷基。所述单环环烷基是指含有3-8个碳原子、0个杂原子和0个双键的单环碳环系。单环体系的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。所述双环环烷基是指与单环环烷基环稠合的单环环烷基,或是指桥连单环体系,其中所述单环的两个非相邻碳原子通过一个、两个、三个或四个碳原子的亚烷基桥连接。双环体系的代表性例子包括,但不局限于,二环[3.1.1]庚烷、二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷、二环[3.3.1]壬烷和二环[4.2.1]壬烷。三环环烷基例如是指与单环环烷基稠合的双环环烷基,或是指桥连双环环烷基,其中所述双环体系的两个非相邻碳原子通过1-4个碳原子的亚烷基桥连接。三环-环体系的代表性例子包括,但不局限于,八氢-2,5-亚甲基并环戊二烯(methanopentalene)(三环[3.3.1.03,7]壬烷或去甲金刚烷(noradamantane))和三环[3.3.1.13.7]癸烷(金刚烷)。所述单环的、双环的和三环的环烷基可以是未取代的或取代的并且通过所述环体系内包含的任何可替换原子附着于母体分子部分上。
[0037]在此所使用的术语″甲酰基″是指-C(O)H基团。
[0038]在此所使用的术语″卤代″或″卤素″是指-Cl、-Br、-I或-F。
[0039]在此所使用的术语″卤代烷基″是指在此所定义的至少一种卤素,其通过在此所定义的烷基连接于母体分子部分。卤代烷基的代表性例子包括,但不局限于,氯甲基、2-氟乙基、三氟甲基、五氟乙基和2-氯-3-氟戊基。
[0040]在此所使用的术语″卤代烷氧基″是指在此所定义的至少一种卤素,通过在此所定义的烷氧基连接于母体分子部分。卤代烷氧基的代表性例子包括,但不局限于,氯甲氧基、2-氟乙氧基、三氟甲氧基和五氟乙氧基。
[0041]在此所使用的术语″杂芳基″是指单环杂芳基或双环杂芳基。单环杂芳基是指五元环或六元环。所述五元环含有两个双键。所述5元环可以含有一个选自O或S的杂原子;或四个氮原子;或一个、两个或三个氮原子以及任选一个氧或硫原子。所述六元环含有三个双键以及一个、两个、三个或四个氮原子。单环杂芳基的代表性例子包括,但不局限于,呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、1,3-噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、***基和三嗪基。所述双环杂芳基的例子是指与苯基稠合的单环杂芳基,或是指与单环环烷基稠合的单环杂芳基,或是指与单环环烯基稠合的单环杂芳基,或是指与单环杂芳基稠合的单环杂芳基,或是指与单环杂环稠合的单环杂芳基。双环杂芳基的代表性例子包括,但不限于,苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并咪唑基、苯并噁二唑基、6,7-二氢-1,3-苯并噻唑基、咪唑并[1,2-a]吡啶基、吲唑基、吲哚基、异吲哚基、异喹啉基、萘啶基、吡啶并咪唑基、喹啉基、噻唑并[5,4-b]吡啶-2-基、噻唑并[5,4-d]嘧啶-2-基、噻吩并[2,3-c]吡啶基和5,6,7,8-四氢喹啉-5-基。本发明的单环的和双环的杂芳基可以是未取代的或取代的并且通过所述环体系内包含的任何可替换碳原子或任何可替换氮原子附着于母体分子部分上。
[0042]本发明的被羟基取代的杂芳基可以以互变异构体的形式存在。本发明的杂芳基包括所有互变异构体,包括非芳香族的互变异构体。
[0043]在此所使用的术语″杂环″或″杂环基″是指单环的、双环的或三环的杂环环体系,条件是所述杂环不是1,3-苯并二氧杂环戊基(benzodioxolyl)、2,3-二氢-1,4-苯并二噁英、萘并[2,3-d][1,3]间二氧杂环戊烯(dioxole)或2,3-二氢萘并[2,3-b][1,4]二噁英。所述单环杂环是含有至少一个杂原子的3、4、5、6或7元环,所述杂原子独立地选自O、N和S。所述3或4元环含有零个或一个双键以及一个选自O、N和S的杂原子。所述5元环含有零个或一个双键以及一个、两个或三个选自O、N和S的杂原子。所述6元环含有零个、一个或两个双键以及一个、两个或三个选自O、N和S的杂原子。所述7元环含有零个、一个、两个或三个双键以及一个、两个或三个选自O、N和S的杂原子。单环杂环的代表性例子包括,但不局限于,氮杂环丁烷基(azetidinyl)、氮杂环庚烷基(azepanyl)、氮丙啶基(aziridinyl)、二氮杂环庚烷基(diazepanyl)、1,3-二噁烷基(dioxanyl)、1,3-二氧戊环基(dioxolanyl)、1,3-二硫代戊基(dithiolanyl)、1,3-二噻烷基(dithianyl)、咪唑啉基(imidazolinyl)、咪唑烷基(imidazolidinyl)、异噻唑啉基(isothiazolinyl)、异噻唑烷基(isothiazolidinyl)、异噁唑啉基(isoxazolinyl)、异噁唑烷基(isoxazolidinyl)、吗啉基(morpholinyl)、噁二唑啉基(oxadiazolinyl)、噁二唑烷基(oxadiazolidinyl)、噁唑啉基(oxazolinyl)、噁唑烷基(oxazolidinyl)、哌嗪基(piperazinyl)、哌啶基(piperidinyl)、吡喃基(pyranyl)、吡唑啉基(pyrazolinyl)、吡唑烷基(pyrazolidinyl)、吡咯啉基(pyrrolinyl)、吡咯烷基(pyrrolidinyl)、四氢呋喃基(tetrahydrofuranyl)、四氢噻吩基(tetrahydrothienyl)、四氢吡喃基(tetrahydropyranyl)、噻二唑啉基(thiadiazolinyl)、噻二唑烷基(thiadiazolidinyl)、噻唑啉基(thiazolinyl)、噻唑烷基(thiazolidinyl)、硫代吗啉基(thiomorpholinyl)、1,1-二氧代硫代吗啉基(dioxidothiomorpholinyl)(硫代吗啉砜(thiomorpholine sulfone))、硫代吡喃基(thiopyranyl)和三噻烷基(trithianyl)。所述双环杂环是与苯基稠合的单环杂环,或与单环环烷基稠合的单环杂环,或与单环环烯基稠合的单环杂环,或与单环杂环稠合的单环杂环,或桥连单环杂环环体系其中所述环的两个非相邻原子通过含有一个、两个、三个或四个碳原子的亚烷基桥连接。双环杂环的代表性例子包括,但不局限于,苯并吡喃基、苯并硫代吡喃基、2,3-二氢苯并呋喃基、2,3-二氢苯并噻吩基和2,3-二氢-1H-吲哚基。三环杂环的例子是与苯基稠合的双环杂环,或与单环环烷基稠合的双环杂环,或与单环环烯基稠合的双环杂环,或与单环杂环稠合的双环杂环,或桥连双环杂环其中所述双环的两个非相邻原子通过包含一个、两个、三个或四个碳原子的亚烷基桥连接。三环杂环的例子是氮杂-金刚烷例如1-氮杂三环[3.3.1.13,7]癸烷。所述单环的、双环的和三环的杂环通过该环体系内包含的任何可替换碳或氮原子与母体分子部分连接,并且可以是未取代的或取代的。
[0044]在此所使用的术语″杂环烷基″是指如在此所定义的杂环,其通过如在此所定义的烷基与母体分子部分相连接。
[0045]在此所使用的术语″羟基″是指-OH基团。
[0046]术语″羟基-保护基″或″O-保护基″是指一种取代基,其在合成步骤期间保护羟基不发生不希望的反应。羟基-保护基的例子包括,但不局限于,取代的甲醚,例如,甲氧基甲基、苄氧基甲基、2-甲氧基乙氧基甲基、2-(三甲基甲硅烷基)-乙氧基甲基、苄基和三苯甲基;四氢吡喃基醚;取代***,例如,2,2,2-三氯乙基和叔丁基;甲硅烷基醚,例如,三甲基甲硅烷基,叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基;环状缩醛和缩酮,例如,亚甲基缩醛,丙酮化合物(acetonide)和亚苄基缩醛;环状原酸酯,例如,甲氧基亚甲基;环状碳酸酯;和环状硼酸酯。通常使用的羟基-保护基在T.W.Greene andP.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,JohnWiley&Sons,New York(1999)中公开。
[0047]在此所使用的术语″氮保护基″是指那些基团,其在合成步骤期间保护氨基不发生不希望的反应。优选的氮保护基是乙酰基、苯甲酰基、苄基、苄氧羰基(Cbz)、甲酰基、苯磺酰基、叔丁氧羰基(Boc)、叔丁基乙酰基、三氟乙酰基和三苯甲基(trityl)。
[0048]在此所使用的术语″硝基″是指-NO2基团。
[0049]在此所使用的术语″NZ1Z2″是指两个基团,Z1和Z2,其通过氮原子附着于母体分子部分。Z1和Z2每个独立地是氢、烷基、烷基羰基、烷氧羰基、芳基、芳烷基、甲酰基或(NZ5Z6)羰基。在本发明的某些情况中,Z1和Z2与它们相连的氮原子一起形成杂环。NZ1Z2的代表性例子包括,但不局限于,氨基、甲基氨基、乙酰氨基、乙酰甲基氨基、苯基氨基、苄基氨基、氮杂环丁烷基、吡咯烷基和哌啶基。
[0050]在此所使用的术语″NZ3Z4″是指两个基团,Z3和Z4,其通过氮原子附着于母体分子部分。Z3和Z4每个独立地是氢、烷基、芳基或芳烷基。NZ3Z4的代表性例子包括,但不局限于,氨基、甲基氨基、苯基氨基和苄基氨基。
[0051]在此所使用的术语″NZ5Z6″是指两个基团,Z5和Z6,其通过氮原子附着于母体分子部分。Z5和Z6每个独立地是氢、烷基、芳基或芳烷基。NZ5Z6的代表性例子包括,但不局限于,氨基、甲基氨基、苯基氨基和苄基氨基。
[0052]在此所使用的术语″(NZ3Z4)羰基″是指如在此所定义的NZ3Z4基团,其通过如在此所定义的羰基与母体分子部分相连接。(NZ3Z4)羰基的代表性例子包括,但不局限于,氨基羰基、(甲基氨基)羰基、(二甲氨基)羰基和(乙基甲基氨基)羰基。
[0053]在此所使用的术语″(NZ5Z6)羰基″是指如在此所定义的NZ5Z6基团,其通过如在此所定义的羰基与母体分子部分相连接。(NZ5Z6)羰基的代表性例子包括,但不局限于,氨基羰基、(甲基氨基)羰基、(二甲氨基)羰基和(乙基甲基氨基)羰基。
[0054]在此所使用的术语″氧代″是指=O部分。
[0055]在此所使用的术语″肠胃外″是指给药方式,其包括静脉内、肌内、腹膜内、胸骨内、皮下和关节内注射和输液。
[0056]在此所使用的术语″药学上可接受的载体″是指任何类型的无毒的、惰性固体、半固体或液体填充剂、稀释剂、包封材料或制剂辅剂。可以用作药学上可接受的载体的物质的一些实例是糖例如乳糖、葡萄糖和蔗糖;淀粉例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉末西黄蓍胶;麦芽;明胶;滑石粉;可可脂和栓剂石蜡(supposity waxes);油类例如花生油、棉子油、红花子油、芝麻油、橄榄油、玉米油和大豆油;二醇类,例如丙二醇;酯例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂例如氢氧化镁和氢氧化铝;褐藻酸;无热原的水;等渗盐水;林格(Ringer)溶液;乙醇;和磷酸盐缓冲液;以及其它无毒相容润滑剂;例如月桂基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂,防腐剂和抗氧化剂也可以存在于该组合物中,根据制剂领域熟练技术人员的判断。
[0057]在此所使用的术语″药学上可接受的盐、酯和酰胺″包括式(I)化合物的盐、两性离子、酯和酰胺,其在合理医学判断的范围内,适合用于与没有过分毒性、刺激、***反应等的人和低等动物组织接触,具有合理的益处/风险比,并且对于它们指定的用途是有效的。
[0058]术语″药学上可接受的盐″是指那些盐,其在合理医学判断的范围内适合于与人和低等动物的组织接触,并且没有过度的毒性、刺激性、***反应等,并且具有合理的益处/风险比。药学上可接受的盐是本领域公知的。所述盐可以在本发明化合物最终分离和提纯期间原位制备或通过游离碱官能团与合适有机酸反应而单独地制备。
[0059]代表性酸加成盐包括但不限于乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(羟乙基磺酸盐)、乳酸盐、马来酸盐、苹果酸盐(malate)、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一酸盐。
[0060]术语“药学上可接受的前药”或“前药”用于本文时,代表本发明化合物的那些前药,在合理医学判断的范围内,适用于接触人和低等动物的组织,无异常毒性、刺激性、***反应等,具有合理的效益/危险比率,有效完成其预期用途。
[0061]在此所使用的术语″互变异构体″是指质子从化合物一个原子移动到该相同化合物的另一个原子上,其中两个或多个结构不同的化合物互相平衡。
[0062]除非另有说明,在此所使用的关于本发明的芳基、环烷基、环烯基、杂环或杂芳基部分的术语″未取代的或取代的″作为取代基或作为取代基的一部分每个独立地是指未取代的或被如下文所述的1、2、3、4或5个取代基取代。该任选的取代基选自烷基、链烯基、炔基、卤素、氰基、氧代、-G1,-NO2,-OR1a,-OC(O)R1a,-OC(O)N(Rb)(R3a),-SR1a,-S(O)2R2a,-S(O)2N(Rb)(R3a),-C(O)R1a,-C(O)OR1a,-C(O)N(Rb)(R3a),-N(Rb)(R3a),-N(Ra)C(O)R1a,-N(Ra)C(O)O(R1a),-N(Ra)C(O)N(Rb)(R3a),-(CR4aR5a)m-NO2,-(CR4aR5a)m-OR1a,-(CR4aR5a)m-OC(O)R1a,-(CR4aR5a)m-OC(O)N(Rb)(R3a),-(CR4aR5a)m-SR1a,-(CR4aR5a)m-S(O)2R2a,-(CR4aR5a)m-S(O)2N(Rb)(R3a),-(CR4aR5a)m-C(O)R1a,-(CR4aR5a)m-C(O)OR1a,-(CR4aR5a)m-C(O)N(Rb)(R3a),-(CR4aR5a)m-N(Rb)(R3a),-(CR4aR5a)m-N(Ra)C(O)R1a,-(CR4aR5a)m-N(Ra)C(O)O(R1a),-(CR4aR5a)m-N(Ra)C(O)N(Rb)(R3a),-(CR4aR5a)m-G1,氰基烷基和卤代烷基;其中
R1a和R3a,在每次出现时,独立地是氢、烷基、卤代烷基、G1或-(CR6R7)n-G1;
R2a,在每次出现时,独立地是烷基、卤代烷基、G1或-(CR6R7)n-G1;
R4a、R5a、R6和R7,在每次出现时,每个独立地是氢、卤素、烷基或卤代烷基;
Ra和Rb,在每次出现时,每个独立地是氢、烷基或卤代烷基;
m和n,在每次出现时,每个独立地是1、2、3、4或5;
G1是芳基、杂芳基、杂环或环烷基,其中每个G1独立地是未取代的或被1、2、3、4或5个取代基取代,所述取代基选自烷基、链烯基、炔基、卤素、氰基、氧代、-NO2、-OR1b,-OC(O)R1b,-OC(O)N(Rb)(R3b),-SR1b,-S(O)2R2b,-S(O)2N(Rb)(R3b),-C(O)R1b,-C(O)OR1b,-C(O)N(Rb)(R3b),-N(Rb)(R3b),-N(Ra)C(O)R1b,-N(Ra)C(O)O(R1b),-N(Ra)C(O)N(Rb)(R3b),-(CR4bR5b)m-NO2,-(CR4bR5b)m-OR1b,-(CR4bR5b)m-OC(O)R1b,-(CR4bR5b)m-OC(O)N(Rb)(R3b),-(CR4bR5b)m-SR1b,-(CR4bR5b)m-S(O)2R2b,-(CR4bR5b)m-S(O)2N(Rb)(R3b),-(CR4bR5b)m-C(O)R1b,-(CR4bR5b)m-C(O)OR1b,-(CR4bR5b)m-C(O)N(Rb)(R3b),-(CR4bR5b)m-N(Rb)(R3b),-(CR4bR5b)m-N(Ra)C(O)R1b,-(CR4bR5b)m-N(Ra)C(O)O(R1b),-(CR4bR5b)m-N(Ra)C(O)N(Rb)(R3b),氰基烷基和卤代烷基;
R1b和R3b,在每次出现时,每个独立地是氢、烷基或卤代烷基;
R2b,在每次出现时,独立地是烷基或卤代烷基;和
R4b和R5b,在每次出现时,每个独立地是氢、卤素、烷基或卤代烷基。
[0063]在化学结构中使用波浪键表示必须考虑单独的或混合物形式的所有可能的非对映异构体。
本发明的化合物
[0064]本发明的化合物可以具有式(I)的结构,
(I);
其中
R1是氢或C1-6烷基;
R2是-C(O)-A、-A、-(CRxRy)t-A或-C(O)-(CRxRy)t-A;
A是未被取代的或被取代的芳基、杂芳基、杂环、环烷基或环烯基;
t在每次出现时是1、2、3、4或5;和
Rx和Ry在每次出现时独立地是氢、卤素、烷基或卤代烷基;
或其药学上可接受的盐、酰胺或前药。
[0065]在一种实施方案中,本发明是式(I)的化合物,其中R1是氢或C1-6烷基,以及R2是-C(O)-A,或其药学上可接受的盐、酰胺或前药。A可以更特别地选自具有下面结构的基团
其中X1是N或CRX1,X2是N或CRX2,X3是N或CRX3,X4是N或CRX4,以及RX1、RX2、RX3和RX4每个独立地是氢、烷基、烷氧基、烷氧基烷基、烷氧羰基、烷基羰基、氰基、卤代、卤代烷氧基、卤代烷基、羟基、硝基、-NZ1Z2或(NZ3Z4)羰基;条件是仅X1、X2、X3或X4之一可以是N,以及其余不是N;Y1是CRY1或N;Y2是CRY2或N;Y3是NH、O或S,以及RY1和RY2每个独立地是氢、烷基、烷氧基、烷氧基烷基、烷氧羰基、烷基羰基、氰基、卤代、卤代烷氧基、卤代烷基、羟基、硝基、-NZ1Z2或(NZ3Z4)羰基。优选地,A是吲哚基。
[0066]在另一种实施方案中,本发明的化合物可以具有式(I)的结构,其中R1是氢或C1-6烷基以及R2是-A,或其药学上可接受的盐、酰胺或前药。在式(I)的化合物中,A可以更特别地选自芳基或杂芳基。
[0067]在另一种实施方案中,本发明是式(I)的化合物,其中R1是氢或C1-6烷基,以及R2是-(CRxRy)t-A,或其药学上可接受的盐、酰胺或前药。A可以更特别地是芳基或杂芳基;以及Rx和Ry优选是氢或烷基。
[0068]在另一种实施方案中,本发明是式(I)的化合物,其中R1是氢或C1-6烷基,以及R2是-C(O)-(CRxRy)t-A,或其药学上可接受的盐、酰胺或前药。A可以更特别地是芳基或杂芳基;以及Rx和Ry优选是氢或烷基。
[0069]本发明的具体实施方案包括,但不局限于,式(I)的化合物,例如:
[0070]N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氯-1H-吲哚-2-甲酰胺;
[0071]N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氯-1H-吲哚-2-甲酰胺;
[0072]N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氟-1H-吲哚-2-甲酰胺;
[0073]N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲酰胺;和
[0074]N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲酰胺;
[0075]或其药学上可接受的盐、酰胺、酯或前药。
[0076]在此公开的化合物可以含有不对称取代的碳或硫原子,因此其可以以单一立体异构体(例如单一对映异构体或单一非对映异构体)、立体异构体的混合物(例如对映异构体或非对映异构体的任何混合物)或其外消旋混合物的形式存在和分离。所述化合物的单个的光学活性形式例如可以通过由光学活性的起始原料的合成、通过手性合成、通过酶拆分、通过生物转化或通过色谱分离制得。可以理解,本发明包含任何外消旋形式、光学活性形式、立体异构形式或其各种比例的混合物,所述形式具有在调节NNR(特别是α7NNR、α4β2NNR或α7和α4β2NNR两者)活性中有用的性能。当本文所示化学结构中存在的手性中心的立体化学没有标出时,该化学结构用来包含含有每个手性中心立体异构体的化合物以及它们的混合物。
[0077]例如,式(Ia)和(Ib)代表式(I)化合物所具有的某些立体异构体形式:
[0078]异构体(Ia)和异构体(Ib)的氮杂金刚烷部分不是手性的,但是,C-4碳取代时被认为是假不对称的。式(Ia)和(Ib)表示的化合物是非对映异构体。根据在Synthesis,1992,1080,Becker,D.P.;Flynn,D.L.中的示例,式(Ia)结构的构型排布(configurational assignment)被称为4s,并且如在Stereochemistry of Organic Compounds,E.L.Eliel,S.H.Wilen;John Wiley and Sons,Inc.1994中定义。此外,使用相同的方法,式(Ib)结构的构型排布被称为4r。预计式(I)的化合物包含式(Ia)、式(Ib)的化合物以及各个比例的式(Ia)和式(Ib)化合物的混合物。
[0079]该异构体(Ia)和(Ib)由方案4中所述的相应的腈前体合成。在方案4中所示的该腈化合物可如实施例1A和2A中所述进行色谱分离。
[0080]当立体异构体的混合物用于合成中时,所述异构体(Ia)和(Ib)可以一起合成,然后通过色谱法从两种异构体的混合物中可以分离得到各个异构体。所述异构体的混合物还可以通过包含在式(I)化合物中的胺盐分级结晶分离得到,所述胺盐通过酸制得。
[0081]预计可以使用两种异构体的混合物来调节NNR的作用。此外,预计可以单独使用式(Ia)和(Ib)的单个异构体来调节NNR的作用。因此,预计式(Ia)和(Ib)化合物的混合物或由式(Ia)或(Ib)化合物表示的单独的各个异构体在调节NNR作用中是有效的,更特别是α7和/或α4β2NNR并因此在本发明的范围内。
[0082]几何异构体可以存在于本发明的化合物中。本发明考虑各种几何异构体及其混合物,其通过碳-碳双键、碳-氮双键、环烷基或杂环基团周围的取代基分布获得。碳-碳双键或碳-氮键周围的取代基被称为Z或E构型,环烷基或杂环周围的取代基被称为顺式或反式构型。
[0083]可以理解,在此公开的化合物可以表现出互变异构体现象。
[0084]在化合物或通式的命名过程中,本说明书中的化合物可能仅给出可能的互变异构体、几何异构体或立体异构体形式之一。但是,可以理解,本发明包含任何互变异构体、几何异构体或立体异构体形式、及它们的混合物形式,并且不仅限于在化合物或通式的命名中所使用的任何一种互变异构体、几何异构体或立体异构体形式。
酰胺、酯和前药
[0085]前药是活性药物的药理学上非活性的衍生物,其被设计成用于改善一些已经确定的、不希望的物理或生物学性质。所述物理性质通常是溶解度(对脂溶性或水溶性过高或过低)或相关的稳定性,还包括有问题的生物学特性包括本身可能与物理化学性质有关的过快代谢或差的生物利用度。
[0086]前药通常通过如下制备:a)制备该活性药物的酯、半酯、碳酸酯、硝酸酯、酰胺、异羟肟酸(hydroxamic acid)、氨基甲酸酯、亚胺、曼尼希碱和烯胺(enamine),b)用偶氮、糖苷、肽和醚官能团对该药物进行官能化反应,c)使用该药物的聚合物、盐、络合物、磷酰胺、缩醛、半缩醛和缩酮形式。例如,参见Andrejus Korolkovas`s,″Essentials of MedicinalChemistry″,John Wiley-Interscience Publications,John Wiley and Sons,NewYork(1988),pp.97-118,其在此整个引入作为参考。
[0087]酯可以由含有羟基或羧基的式(I)的底物通过本领域熟练技术人员已知的一般方法制备。这些化合物的典型反应是所述杂原子之一被另一个原子代替,例如:
方案1
[0088]酰胺可以由含有氨基或羧基的式(I)的底物以类似方式制备。酯还可以与胺或氨反应以制备酰胺。
方案2
[0089]由式(I)的化合物制备酰胺的另一方法是将羧酸类化合物和胺类化合物一起进行加热。
方案3
[0090]在方案2和3中,R和R′独立地是式(I)的底物、烷基或氢。本发明的式(I)的各种实施方案,其是前药、酰胺和酯的底物,包括,但不局限于,实施例1、2、3、4和5。
本发明的组合物
[0091]本发明还提供包含本发明化合物或其药学上可接受的盐、酰胺、酯、前药或前药的盐的药物组合物,其与一种或多种药学上可接受的载体一起进行配制。
[0092]通过上文所述的方法鉴定的化合物可以作为单独的药物制剂给药,或者可以与一种或多种其它药物试剂一起联合给药,其中所述联用不会引起无法接受的副作用。例如,本发明的化合物可以与非典型抗精神病药(antipsychotics)联用。适宜的非典型抗精神病药(antipsychotics)的具体实例包括,但不局限于,氯氮平(clozapine)、利哌利酮(risperidone)、奥兰氮平(olanzapine)、quietapine、齐拉西酮(ziprasidone)、苯噻庚乙胺(zotepine)、伊潘立酮(iloperidone)等。因此,本发明还包括含有治疗有效量的通过在此所述的方法确认的化合物或其药学上可接受的盐、前药或前药的盐、在上文所公开的一种或多种药物试剂以及一种或多种药学上可接受的载体的药物组合物。
[0093]本发明的药物组合物可以口服、直肠、胃肠外、脑池内、***内、腹膜内、局部(例如用粉剂、膏剂、滴剂)、口腔或口服或鼻喷入给予人以及其它哺乳动物。所述药物组合物可以配制成固体、半固体或液体形式用于口服给药。
[0094]适于肠胃外注射的药物组合物包含药学上可接受的无菌含水或非水溶液、分散液、悬浮液或乳液和临用前用于构对无菌注射溶液或分散体的无菌粉剂。合适的含水和非水载体、稀释剂、溶剂或赋形剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等,及其适宜的混合物)、植物油(例如橄榄油)以及可注射的有机酯例如油酸乙酯,或其适宜的混合物。例如,通过使用一种包衣例如卵磷脂,在分散液的情况中通过保持所需的粒径,和通过使用表面活性剂,可以将该组合物保持适宜的的流动性。
[0095]这些组合物还可以含有助剂例如防腐剂、润湿剂、乳化剂和分散剂。通过各种抗菌剂和抗真菌剂,例如帕拉贝(parabens)、氯代丁醇、苯酚、山梨酸等,可以确保防止微生物作用。理想地,还可以包含等渗剂,例如糖、氯化钠等。通过使用吸收延迟试剂,例如单硬脂酸铝和明胶,可以使可注射的药物形式的吸收延长。
[0096]在一些情况中,为了延长药物的作用,通常希望减缓药物由皮下注射或肌内注射所引起的吸收。这可以通过使用弱水溶性的晶体或无定形物质的液体悬浮液来实现。药物的吸收速率可能取决于它的溶解速度,其,反过来,可以取决于晶体大小和晶体形式。或者,胃肠外给药的药物形式可以通过将该药物溶解或悬浮在油赋型剂中给药。
[0097]悬浮液,除活性化合物外,可以含有悬浮剂,例如,乙氧基化的异硬脂基醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏铝酸(aluminum metahydroxide)、膨润土、琼脂和西黄蓍胶,及其混合物。
[0098]如果需要的话,并且为了更有效的分布,本发明的化合物可以与缓释或靶标给药体系例如聚合物基质、脂质体(liposome)和微球体结合。例如,它们可以通过截留细菌的过滤器进行过滤来灭菌,或者加入无菌固体组合物的形式的灭菌剂来灭菌,所述无菌固体组合物可以在临用前将其溶于无菌水或某些其它无菌可注射介质中。
[0099]注射用长效形式(injectable depot forms)通过将在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成该药物的微胶囊基质来制备。取决于药物与聚合物的比例以及所使用的具体聚合物的性质,可以控制药物的释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。注射用长效制剂(depot injectable formulation)还通过将药物包埋在脂质体或与身体组织匹配的微乳剂进行制备。
[00100]例如,所述可注射制剂可通过截留细菌的过滤器过滤,或者通过结合无菌固体组合物形式的灭菌剂来进行灭菌,所述无菌固体组合物可在临用前溶解或分散在无菌水或其它无菌可注射介质中。
[00101]可注射的制剂,例如,无菌可注射含水或含油悬浮液可以根据本领域已知技术使用适宜的分散剂或润湿剂和悬浮剂进行配制。该无菌可注射制剂还可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如一种在1,3-丁二醇中的溶液。在所述可接受的赋形剂和溶剂当中,可以使用的是水、林格溶液、U.S.P.以及等渗氯化钠溶液。此外,无菌不挥发油(fixed oil)通常用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发油,包括合成的甘油一酯和甘油二酯。此外,在可注射制剂的制备中使用脂肪酸例如油酸。
[00102]用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和粒剂。在这些固体剂型中,本发明的一种或多种化合物与至少一种惰性药学上可接受的载体例如柠檬酸钠或磷酸二钙和/或a)填充剂或膨胀剂例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和水杨酸;b)粘合剂,例如,羧甲基纤维素、褐藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶;c)润湿剂例如甘油;d)崩解剂例如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂例如石蜡(paraffin);f)吸收促进剂例如季铵化合物;g)润湿剂例如鲸蜡醇和单硬脂酸甘油酯;h)吸收剂例如高岭土和膨润土;和i)润滑剂例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物混合。在胶囊、片剂和丸剂的情况中,所述剂型还可以包含缓冲剂。
[00103]类似类型的固体组合物还可以在使用乳糖(lactose/milksugar)以及高分子量聚乙二醇的软或硬填充明胶胶囊中被用作填料。
[00104]片剂、糖衣丸、胶囊、丸剂和粒剂的固体剂型可以用包衣和外壳如肠溶衣以及药物制剂领域中公知的其它包衣来制备。它们可以任选含有遮光剂并且还可以是一种组合物,该组合物以缓释方式仅仅或优先在胃肠道的某一部分中释放活性组分。可用于活性剂的缓释材料的例子可以包括聚合物和石蜡(waxes)。
[00105]直肠或***给药的组合物优选是栓剂,其可以通过本发明的化合物与合适的无刺激性载体(例如,可可脂、聚乙二醇或在环境温度下是固体但是在体温下是液体的栓剂石蜡)混合进行制备,并因此在直肠或***中融化并释放所述活性化合物。
[00106]口服给药的液体剂型包括药学上可接受的乳液、微乳剂、溶液、悬浮液、糖浆和酏剂。除所述活性化合物外,所述液体剂型可以含有通常在本领域中使用的惰性稀释剂,例如,水或其它溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、丙三醇、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯,及其混合物。
[00107]除惰性稀释剂外,所述口服组合物还可以包括助剂,例如润湿剂、乳化剂、悬浮剂、甜味剂、调味剂和芳香剂。
[00108]本发明化合物的局部或经皮给药的剂型包括膏剂、糊剂、乳剂、洗剂、凝胶剂、粉剂、溶液、喷雾剂、吸入剂或贴片。在无菌条件下,将本发明的理想化合物与药学上可接受的载体以及视情况需要的任何防腐剂或缓冲剂掺合在一起。眼科制剂、耳内滴剂、眼膏、粉剂和溶液同样是在本发明所考虑的范围内。
[00109]所述膏剂、糊剂、乳剂和凝胶剂可以含有,除本发明的活性化合物外,动物和植物脂肪、油类、蜡类(waxes)、石蜡(paraffins)、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌,或其混合物。
[00110]粉剂和喷雾剂可以含有,除本发明的化合物外,乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。此外,喷雾剂可以含有常规的推进剂(propellants),例如氯氟烃类化合物。
[00111]本发明的化合物还可以以脂质体的形式给药。正如本领域已知的,脂质体通常来源于磷脂或其它脂质物质。脂质体通过分散在含水介质中的单层或多层水合液态晶体制得。任何能够形成脂质体的无毒、生理学上可接受的和可代谢的脂类都可使用。脂质体形式的本发明组合物除本发明的化合物外,还可以含有稳定剂、防腐剂等。优选的脂类是单独使用或一起使用的天然和合成磷脂和卵磷脂。
[00112]本领域已知脂质体的制备方法。参见,例如,Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.,(1976),p 33 et seq。
[00113]局部给予本发明化合物的剂型包括粉剂、喷雾剂、膏剂和吸入剂。所述活性化合物在无菌条件下与药学上可接受的载体以及任何所需的防腐剂、缓冲剂或推进剂一起混合。眼科制剂、眼膏、粉剂和溶液同样是在本发明所考虑的范围内。本发明的含水液体组合物是特别有用的。
[00114]本发明的化合物可以以药学上可接受的盐的形式使用,所述盐来源于无机或有机酸。
[00115]此外,含碱性氮原子的基团可以用以下试剂季铵化:低级烷基卤化物(例如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物);硫酸二烷基酯(例如二甲基、二乙基、二丁基和二戊基的硫酸酯);长链卤化物(例如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物);芳烷基卤化物(例如苄基和苯乙基的溴化物)等等。由此获得水溶性或油溶性的或可分散的产物。
[00116]可以用于制备药学上可接受的酸加成盐的酸的例子包括这些无机酸如盐酸、氢溴酸、硫酸和磷酸以及这些有机酸如苯磺酸、柠檬酸、葡糖酸、马来酸、草酸和琥珀酸。
[00117]在本发明化合物的最终分离和提纯期间,碱加成盐可以通过含羧酸部分与合适的碱或与氨或有机伯、仲或叔胺反应原位制备,所述合适的碱例如是药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐。药学上可接受的盐包括,但不局限于,基于碱金属或碱土金属的阳离子,例如锂、钠、钾、钙、镁和铝盐等,以及无毒季铵和胺阳离子包括铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺等。可用于制备碱加成盐的其它代表性的有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。
[00118]本发明的化合物可以以前药的形式存在。例如,通过在血液中水解,本发明的前药可以快速地在体内转化为本发明的母体化合物。详尽论述在T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,V.14 of the A.C.S.Symposium Series和在Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Associationand Pergamon Press(1987)中。
[00119]本发明还考虑药学上可接受的化合物,当给予需要的患者时,其可通过体内生物转化为式(I)的化合物。
本发明的方法
[00120]本发明的化合物和组合物可用于调节NNR作用,更特别是α7NNR、α4β2NNR、或α7和α4β2NNR两者。特别地,本发明的化合物和组合物可用于治疗或预防由α7NNR、α4β2NNR、或α7和α4β2NNR两者调节的疾病。典型地,这些疾病可以通过在哺乳动物中选择性调节α7NNR、α4β2NNR、或α7和α4β2NNR两者来得到改善,优选给予本发明的化合物或组合物,所述本发明的化合物或组合物单独地或与一种或多种其它药物试剂联合给药,例如作为治疗方案的一部分。
[00121]本发明方法的化合物,包括,但不局限于在实施例中指出的或具体命名的那些,可以调节NNR,并且通常具有对NNR的亲合力,更特别是α7NNR、α4β2NNR或α7和α4β2NNR两者。作为α7NNR、α4β2NNR、或α7和α4β2NNR两者的配体,本发明的化合物可以用于治疗或预防若干由α7NNR、α4β2NNR、或α7和α4β2NNR两者介导的疾病或病症。
[00122]可用于治疗或预防由α7、α4β2或α7和α4β2NNR两者介导的疾病或病症的化合物的具体实例包括,但不局限于,在本发明化合物部分中所述的化合物以及在实施例部分中所述的化合物。
[00123]在本发明的方法中可用的化合物的制备方法也可以在Iriepa,I,等.J.Molec.Struct.1999,509,105;Flynn,D.L.,等.Bioorganic&Medicinal Chemistry Letters,1992,2,1613;美国专利号4,816,453;WO94/00454;美国专利号5,280,028;美国专利号5,399,562;WO 92/15593;美国专利号5,260,303;美国专利号5,591,749;美国专利号5,434,151和美国专利号5,604,239中找到。
[00124]例如,α7NNR在增强认知功能中表现出显著的作用,包括学习、记忆和注意力方面(Levin,E.D.,J.Neurobiol.53:633-640,2002)。因而,α7配体适合于治疗与记忆和/或认知相关的病症和疾病,例如,包括,注意缺陷障碍(attention deficit disorder)、ADHD、AD、轻度认知缺损(mildcognitive impairment)、老年性痴呆(senile dementia)、AIDS痴呆(AIDSdementia)、皮克病(Pick′s disease)、与莱维体有关的痴呆(dementiaassociated with Lewy bodies)、以及与唐氏综合征有关的痴呆(dementiaassociated with Down′s syndrome)、以及CDS。
[00125]此外,已经显示含α7的NNR涉及烟碱在体外(Jonnala,R.B.和Buccafusco,J.J.,J.Neurosci.Res.66:565-572,2001)和体内(Shimohama,S.等,Brain Res.779:359-363,1998)的细胞保护作用。更具体来讲,神经退行性变是几种进行性CNS疾病(包括但不限于阿尔茨海默病、帕金森病、肌萎缩侧索硬化、亨廷顿舞蹈病(Huntington′s disease)、与莱维体有关的痴呆以及创伤性脑损伤引起的CNS功能减退)的基础。例如,与阿尔茨海默病有关的β-淀粉样蛋白肽(amyloid peptide)引起α7NNR的功能缺陷已被视为与疾病有关的认知缺陷发病的关键因素(Liu,Q.-S.,Kawai,H.,Berg,D.K.,Proc.Natl.Acad.Sci.USA 98:4734-4739,2001)。α7选择性配体可以影响神经保护通道,这导致tau蛋白的磷酸化作用降低,其过磷酸化(hyperphosphorylation)是在各种tau相关病理学如阿尔茨海默病和各种其它痴呆中神经纤维缠结形成所需要的(Bitner et al.,Soc.Neuroscience,2006 abst 325.6)。已经显示α7NNR的活化阻断这种神经毒性(Kihara,T.等,J.Biol.Chem.276:13541-13546,2001)。这样,提高α7活性的选择性配体可弥补阿尔茨海默病及其它神经变性疾病的缺陷。
[00126]α7NNR还涉及神经发育方面,如脑的神经发生。(Falk,L.等,Developmental Brain Research 142:151-160,2003;Tsuneki,H.等,J.Physiol.(London)547:169-179,2003;Adams,C.E.等,Developmental BrainResearch 139:175-187,2002)。这样,α7NNR可用于预防或治疗与神经发育受损有关的疾病或病症,如精神***症。(Sawa A.,Mol.Med.9:3-9,2003)。
[00127]现已表明,在与注意力缺陷/多动症(ADHD)有关的临床前模型中,一种核心症状为活动过强、注意力不集中和冲动行为的疾病,对α4β2NNR具有高亲合力的一些化合物可以改善注意力和认知性能。例如,ABT-418,一种α4β2NNR的完全激动剂,在多种临床前认知模型中是有效的。现已表明,在32名成人的对照临床试验中,经皮给药的ABT-418通常在治疗ADHD是有效的,特别是注意力/认知缺乏(Wilens,T.E.;Biederman,J.;Spencer,T.J.;Bostic,J.;Prince,J.;Monuteaux,M.C.;Soriano,J.;Fince,C.;Abrams,A.;Rater,M.;Polisner,D.The AmericanJournal of Psychiatry(1999)156(12),1931-1937.)。同样,在中试阿尔茨海默氏病(pilot Alzheimer′s disease)试验中,ABT-418表现出效力信号。现已表明,ABT-089,一种α4β2选择性部分激动剂,在啮齿动物和灵长目动物模型中改善注意力、学习和记忆缺损。ABT-089和另一种α4β2激动剂,ispronicline在中试临床试验中表现出效力(Wilens,T.E.;Verlinden,M.H.;Adler,L.A.;Wozniak,P.J.;West,S.A.Biological Psychiatry(2006),59(11),1065-1070.Geerts,H.,Curr.Opin.Invest.Drugs(2006),7(1),60-69.)。除认知外,与α4β2NNR相互作用的化合物例如ABT-594等等在疼痛的临床前和诊断模型中也是有效的。因而,调节α7和α4β2活性二者的配体在疾病状态中具有广泛的治疗效力,所述疾病状态例如涉及认知和注意力缺损、疼痛、神经变性疾病等等的那些。
[00128]精神***症是一种复杂的疾病,特征在于感知、认知和情感异常。有大量证据提示α7NNR涉及该疾病,包括在尸体解剖患者(post-mortem patients)中测量到这些受体的缺乏(Sawa A.,Mol.Med.9:3-9,2003;Leonard,S.Eur.J.Pharmacol.393:237-242,2000)。感觉加工(门控)的缺乏是精神***症的标志之一。这些缺乏可由作用于α7NNR的烟碱配体标化(Adler L.E等,Schizophrenia Bull.24:189-202,1998;Stevens,K.E.等,Psychopharmacology 136:320-327,1998)。最新研究表明,在感觉门控的DBA/2小鼠模型中,α4β2烟碱样受体刺激还促进尼古丁的作用(Radek等,Psychopharmacology(Berl).2006 187:47-55)。因此,α7和α7/α4β2配体证实在治疗精神***症中的潜能。
[00129]在脊髓中α7或α4β2 NNR种群调节与烟碱化合物镇痛作用有关的神经传递(Cordero-Erausquin,M.和Changeux,J.-P.Proc.Natl.Acad.Sci.USA 98:2803-2807,2001)。α7 NNR和/或α7/α4β2配体证实治疗疼痛包括急性疼痛(acute pain)、术后疼痛和慢性疼痛(包括炎性疼痛和神经性疼痛)的治疗潜能。
[00130]本发明的化合物特别可用于治疗和预防影响记忆、认知、神经变性、神经发育和精神***症的病症或疾病。
[00131]与精神***症有关的认知缺损(cognitive deficits associatedwith schizophrenia)(CDS)经常限制患者正常活动的能力,一种通过目前可利用的治疗(例如用非典型抗精神病药(antipsychotics)治疗)不能充分治疗的症状(Rowley,M.等,J.Med.Chem.44:477-501,2001)。这样认知缺损与烟碱样胆碱能***的功能障碍有关,特别是α7受体处活性降低。(Friedman,J.I.等,Biol.Psychiatry,51:349-357,2002)。因此,在正在用非典型抗精神病药(antipsychotics)治疗的精神***症患者中,α7受体激活剂可提供用于增强认知功能的有用的治疗。因此,α7NNR配体和一种或多种非典型抗精神病药(antipsychotics)的组合将提供改善治疗效用。适宜的非典型抗精神病药(antipsychotics)的具体实例包括,但不局限于,氯氮平(clozapine)、利哌利酮(risperidone)、奥兰氮平(olanzapine)、quietapine、齐拉西酮(ziprasidone)、苯噻庚乙胺(zotepine)、伊潘立酮(iloperidone)等。
[00132]本发明的化合物可以单独给药,或者与一种或多种其它药物试剂联合给药(即共同给药)。联合治疗包括给予单一药物剂量制剂,其含有一种或多种本发明的化合物以及一种或多种其它药物,以及在各自分开的药物剂量制剂中给予本发明的化合物和每一其它药物。例如,式(I)的化合物和一种或多种其它药物,以具有固定比率的每一活性组分的单一口服剂量组合物的形式可以共同给予患者,例如片剂或胶囊;或每一药物可以以分开口服剂量制剂的形式给药。
[00133]当采用分开的剂量制剂时,本发明的化合物和一种或多种其它药物可以基本上同时间(例如同时)或分别错开时间给药(例如依次)。
[00134]在本发明的药物组合物中,可以改变活性组分的实际剂量水平,以便获得对特定患者、特定组合物和特定给药方式有效达到所需治疗响应的活性化合物的数量。所选的剂量水平将取决于具体化合物的活性、给药途径、所治疗病症的严重程度以及所治疗患者之前的状况和病史。然而,本领域熟练技术人员已知,化合物的起始用药量要低于为达到所要求的效果所需之量,接着逐渐增大用药量直至达到所要求的疗效。
[00135]当用于以上或其它治疗时,可应用纯形或者(当此类形式存在时)药学上可接受的盐、酯、酰胺、前药或其前药的盐的形式的治疗有效量的本发明化合物之一。此外,可将本发明的化合物作为药用组合物给药,所述药用组合物包含与一种或多种药学上可接受的载体组合的感兴趣化合物。短语“治疗有效量”的本发明化合物指充分治疗疾病的量的化合物,以合理的效益/危险比率适用于任何医学治疗。然而,应理解本发明化合物和组合物每天总的用法将由主治医生在合理医学判断的范围内决定。对任何具体患者而言,具体的治疗有效剂量水平将取决于多种因素,包括正治疗的疾病和疾病的严重度;所用具体化合物的活性;所用具体组合物;患者的年龄、体重、一般状况、性别和饮食;所用具体化合物的给药时间、给药途径和***率;疗程;与所用具体化合物组合或同时使用的药物;以及医学领域熟知的类似因素。例如,本领域的常用方法是开始时给予低于实现所需治疗作用需要的剂量水平的化合物,逐渐增加剂量,直至实现所需作用。
[00136]给予人或低等动物的本发明化合物的总日剂量在约0.10μg/kg体重至约100mg/kg体重的范围内。更优选的剂量可以在约0.10μg/kg体重至约10mg/kg体重范围之内。如果需要的话,为了给药,所述有效日剂量可以被分成多剂量。因此,单次剂量组合物可以含有这样的数量或其约数以达到所述的日剂量。
本发明化合物的制备方法
[00137]本发明意图包括通过合成方法或代谢过程制得的本发明的化合物。通过代谢过程制备本发明的化合物包括在人或动物体内(体内)或体外出现的方法。
[00138]式(I)化合物的合成在方案4-7中举例说明,并且A、Rx、Ry和t如在发明概述部分中公开。
[00139]用于方案和实施例的描述时,某些缩写将具有下列含义:BSA表示牛血清白蛋白;BSS表示平衡盐液;HPLC表示高压液相色谱;OAc表示乙酰氧基,和Tris表示三(羟甲基)氨基甲烷。
[00140]方案中举例说明的反应在适合于所使用的试剂和原料以及适合于完成转化的溶剂中进行。根据分子上存在的官能团,所述转化可能需要改变合成步骤的顺序或者选择一种具体的加工方案而不是另一种加工方案,以获得本发明的所需化合物。
[00141]可用氮保护基保护在所述化合物中存在的胺基。此类方法和一些适宜的氮保护基描述于Greene和Wuts(Protective Groups InOrganic Synthesis,Wiley和Sons,1999)。例如,适宜的氮保护基包括,但不局限于,叔丁氧羰基(Boc)、苄氧羰基(Cbz)、苄基(Bn)、乙酰基和三氟乙酰基。更特别地,所述Boc保护基可以通过用酸处理除去,所述酸例如是三氟乙酸或盐酸。所述Cbz和Bn保护基可以通过催化氢化除去。所述乙酰基和三氟乙酰基保护基可以通过氢氧根离子除去。
方案4
[00142]如方案4中所列,式(1)的化合物(合成的描述可以在Becker,D.P.;Flynn,D.L.Synthesis,1992,1080-1082.中找到)通过与对甲苯磺酰基甲基异腈(isocyanide)和碱如叔丁醇钾反应,可以转化为式(2)的化合物。该反应典型地在1,2-二甲氧基乙烷和乙醇的溶剂混合物中进行。所述试剂典型地在-78℃下混合,然后将所述反应混合物温热至环境温度并在环境温度维持约5小时,此时加热至40℃约0.5小时,完成该反应。在此转化反应中,制得两种可能的非对映异构体,如果需要的话,可以通过柱色谱分离得到所述的非对映异构体。
方案5
[00143]通过在甲苯中用铝烷(alane)N,N-二甲基乙胺络合物处理,可以对式(2)的化合物进行还原,得到式(3)的化合物。该反应典型地在四氢呋喃中进行。该铝烷N,N-二甲基乙胺络合物典型地在-78℃下加入。随后,将该反应混合物典型地温热至环境温度约3小时,然后通过温热至60℃约1小时完成该反应。该反应典型地通过加入芒硝(Glauber′s salt)(十水硫酸钠)进行猝灭。
方案6
[00144]使用本领域熟练技术人员已知的羧酸与胺偶合生成酰胺的条件,将式(3)的化合物用羧酸处理,得到式(4)的化合物,其中R″是A或(RxRy)t-A,其是本发明的代表性化合物。由羧酸和胺的混合物生成酰胺的已知条件的例子包括但不局限于加入偶合试剂例如、但不局限于盐酸N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(EDCI,EDAC)、(1,3-二环己基碳二亚胺(DCC)、二(2-氧代-3-噁唑烷基)膦酰氯(phosphonic chloride))(BOPCl)、O-(7-氮杂苯并***-1-基)-N,N,N’,N’-四甲基脲鎓(uronium)六氟磷酸盐(HATU)、O-苯并***-1-基-N,N,N’,N’-四甲基脲鎓四氟硼酸盐(TBTU)。该偶合试剂可以以固体、溶液形式加入,或者以与固体载体树脂相结合的试剂形式加入。除该偶合试剂外,辅助偶合试剂可以促进该偶合反应。在该偶合反应中经常使用的辅助偶合试剂包括但不局限于4-二甲基氨基吡啶(DMAP)、1-羟基-7-氮杂苯并***(HOAT)和1-羟基苯并***(HOBT)。该偶合反应可以在溶剂例如但不局限于四氢呋喃、N,N-二甲基甲酰胺、吡啶和乙酸乙酯中进行。该反应可以在环境温度下或高温下进行。
[00145]或者,典型地,首先,通过将该羧酸悬浮在溶剂如二氯甲烷中,然后加入草酰氯(oxalyl chloride)和催化量的N,N-二甲基甲酰胺,所述羧酸转化为酰基氯。通过蒸发除去所述溶剂,接着将该酰基氯再溶解在吡啶中。在Hunig碱存在下加入式(3)的化合物,得到式(4)的化合物。该反应可以在环境温度下或在高温下在数小时至数天的期间内进行。
方案7
[00146]通过式(3)的化合物与醛和还原剂如氰基硼氢化钠或三乙酰氧基硼氢化钠反应,式(3)的化合物可以转化为式(5)的化合物,其中R″如方案6中所定义。典型的反应溶剂包括、但不局限于甲醇。该反应可以任选在酸如乙酸存在下进行。该反应可以在环境温度下或高温下进行。
[00147]或者,式(3)的化合物可以在交互偶合反应中与芳基卤化物、芳基磺酸酯、杂芳基卤化物或杂芳基磺酸酯反应,得到式(5)的化合物。该偶合反应典型地在金属催化剂如具有适宜配体的钯或铜存在下进行,碱、温度和溶剂建议在下面的参考文献中:Pd催化反应综述,参见:(a)Schlummer,B.;Scholz,U.Adv.Synth.Catal.2004,346,1599.(b)Jiang,L.;Buchwald,S.L.in Metal Catalyzed Cross-CouplingReactions,2nd ed.;de Meijere,A.;Diederich,F.;Eds.;John Wiley&Sons:Weinheim,2004。关于Cu催化反应的综述,参见(c)Ley,S.V.;Thomas,A.W.Angew.Chem.Int.Ed.2003,42,5400。
[00148]本发明的化合物和中间体可以用有机合成领域的熟练技术人员所公知的方法进行分离和提纯。分离和提纯化合物的常规方法的例子可以包括,但不局限于,固体载体如硅胶、氧化铝或用烷基硅烷基团衍生的二氧化硅上的色谱,通过在高或低温度下在用活性炭任选预处理下进行重结晶,薄层层析,在各种压力下蒸馏,在真空中升华,以及研磨,如″Vogel′s Textbook of Practical Organic Chemistry″,5thedition(1989),by Furniss,Hannaford,Smith,and Tatchell,pub.LongmanScientific&Technical,Essex CM20 2JE,England中所述那样。
[00149]本发明的化合物以及制备本发明化合物的方法通过参考下列实施例进行更好地理解,这些实施例仅仅是示范性并不对本发明的范围构成限制。
实施例
实施例1
[00150]N-[(4r)-1-氮杂三环[3.3.1.1 3,7 ]癸-4-基甲基]-5-氯-1H-吲哚 -2-甲酰胺
实施例1A
[00151](4r)-1-氮杂三环[3.3.1.1 3,7 ]癸烷-4-腈
[00152]将氮杂金刚烷-4-酮(3.76g,24.9mmol;参见Becker,D.P.;Flynn,D.L.Synthesis 1992,1080-1082.)和对甲苯磺酰基甲基异腈(TOSMIC,6.38g,32.3mmol)溶于1,2-二甲氧基乙烷(87mL)和乙醇(3.2mL)的混合物中并冷却至-78℃。在1分钟内,向该反应混合物中加入叔丁醇钾(6.70g,59.7mmol)。除去所述冷却浴,接着将所述反应混合物在25℃下搅拌5小时,然后在40℃下加热0.5小时。然后,将所述反应混合物冷却并通过玻璃料过滤。将所述滤液浓缩,残余物用硅胶色谱提纯(在乙腈中的10%浓NH4OH,Rf=0.25),得到标题化合物。然后,将等份该固体溶于10∶1***/甲醇中并用富马酸(在10∶1***/甲醇中的10mg/mL溶液)处理。滤出沉淀并在真空中干燥,得到富马酸盐形式的标题化合物,表征数据为:1H NMR(500MHz,甲醇-d4)δ2.07-2.14(m,2H),2.22-2.32(m,3H),2.47(s,2H),3.49-3.56(m,5H),3.59-3.66(m,2H),6.70ppm(s,2.8H;C4H4O4);MS(DCI/NH3)m/z163(M+H)+;计算值C10H14N2·1.45C4H4O4:C,57.41;H,6.04;N,8.48;实测值:C,57.26;H,6.04;N,8.87.
实施例1B
[00153](4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基胺
[00154]将实施例1A的游离碱产物(200mg,1.23mmol)溶于四氢呋喃(10mL)中,接着将该混合物冷却至-78℃。在5分钟内,向该反应混合物中缓慢加入铝烷N,N-二甲基乙胺络合物(在甲苯中的0.5M溶液,7.40mL,3.70mmol)。随后,该反应混合物在25℃搅拌3小时,然后在60℃搅拌1小时。向反应混合物分批加入芒硝(Na2SO4.10H2O)粉末,直到停止起泡为止。将所述反应混合物冷却并通过玻璃料过滤。将所述滤液在真空中进行浓缩,得到标题化合物,其在没有进一步提纯的情况下就使用:MS(APCI)m/z 167(M+H)+.
实施例1C
[00155]5-氯-1H-吲哚-2-碳酰氯
[00156]将5-氯吲哚-2-羧酸(59mg,0.30mmol)悬浮在二氯甲烷(10mL)中。加入草酰氯(41μL,0.45mmol)和N,N-二甲基甲酰胺(5μL),接着将所述反应混合物在25℃搅拌1小时。将所述混合物浓缩,残余物在高真空中干燥,得到一种粗产物,该粗产物在没有其它提纯的情况下就使用。
实施例1D
[00157]N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氯-1H-吲哚 -2-甲酰胺
[00158]将实施例1C的产物(64mg,0.30mmol)溶于吡啶(10mL)中。加入实施例1B的产物(40mg,0.24mmol)和Hunig碱(47mg,0.36mmol),然后将反应混合物浓缩并在60℃搅拌48小时。反应混合物用制备性HPLC在WatersC8柱(40mmx100mm,7μm粒径)上使用10%-100%乙腈:0.1%含水三氟乙酸梯度在12分钟内(15分钟运行时间)提纯,流速为70mL/min,得到标题化合物。将所述物质溶于10∶1***/甲醇(5mL)中并用富马酸(在10∶1***/甲醇中的10mg/mL溶液)处理。滤出沉淀并在真空中干燥,得到半富马酸盐形式的标题化合物:1H NMR(甲醇-d4,500MHz)δ1.86-1.92(m,2H),2.10(brs,3H),2.24-2.31(m,2H),2.34(t,J=7.48Hz,1H),3.41-3.48(m,4H),3.53-3.60(m,2H),3.64(d,J=7.63Hz,2H),6.66(s,1.2H;C4H4O4),7.02(s,1H),7.18(dd,J=8.70,1.98Hz,1H),7.41(d,J=8.85Hz,1H),7.59ppm(d,J=2.14Hz,1H);MS(DCI/NH3)m/z 344(M+H)+;计算值C19H22ClN3O·0.65C4H4O4:C,61.87;H,5.91;N,10.02;实测值:C,62.07;H,5.91;N,9.91.
实施例2
[00159]N-[(4s)-1-氮杂三环[3.3.1.1 3,7 ]癸-4-基甲基]-5-氯-1H-吲哚 -2-甲酰胺
实施例2A
[00160](4s)-1-氮杂三环[3.3.1.1 3,7 ]癸烷-4-腈
[00161]通过硅胶色谱进行实施例1A的提纯(在乙腈中的10%浓NH4OH,Rf=0.30),也得到灰白色固体形式的标题化合物的游离碱。将等份该固体溶于10∶1***/甲醇中并用富马酸(在10∶1***/甲醇中的10mg/mL溶液)处理。滤出沉淀并在真空中干燥,得到富马酸盐形式的标题化合物,表征数据为:1H NMR(D2O,300MHz)δppm1.96-2.06(m,2H),2.11-2.20(m,2H),2.23-2.30(m,1H),2.54-2.61(m,2H),3.41-3.47(m,1H),3.53-3.56(m,2H),3.57-3.64(m,2H),3.71-3.80(m,2H),6.67(s,2H;C4H4O4);MS(DCI/NH3)m/z 163(M+H)+;计算值C10H14N2·1.15C4H4O4·0.1H2O:C,58.94;H,6.37;N,9.42;实测值:C,58.64;H,6.72;N,9.64.
实施例2B
[00162](4s)-1-氮杂三环[3.3.1.1 3,7 ]癸-4-基甲基胺
[00163]实施例2A的游离碱产物如实施例1B中所述进行处理,得到标题化合物:MS(APCI)m/z 167M+H+.
实施例2C
[00164]N-[(4s)-1-氮杂三环[3.3.1.1 3,7 ]癸-4-基甲基]-5-氯-1H-吲哚 -2-甲酰胺
[00165]将实施例2B的产物和实施例1C的产物如实施例1D中所述进行处理,得到富马酸盐形式的标题化合物:1H NMR(甲醇-d4,500MHz)δ1.97-2.03(m,2H),2.12-2.27(m,6H),3.37-3.43(m,2H),3.51(br s,2H),3.62(d,J=7.93Hz,2H),3.76-3.82(m,2H),6.69(s,2.3H;C4H4O4),7.01(s,1H),7.18(dd,J=8.70,1.98Hz,1H),7.41(d,J=8.85Hz,1H),7.59ppm(d,J=1.83Hz,1H);MS(ESI)m/z 344(M+H)+;计算值C19H22ClN3O·1.2C4H4O4:C,59.17;H,5.59;N,8.7;实测值:C,59.28;H,5.91;N,8.47.
实施例3
[00166]N-[(4s)-1-氮杂三环[3.3.1.1 3,7 ]癸-4-基甲基]-5-氟-1H-吲哚 -2-甲酰胺
[00167]将实施例2B的产物(50mg,0.30mmol)溶于吡啶(5mL)中。将5-氟吲哚-2-羧酸(65mg,0.36mmol)、1-羟基苯并***(51mg,0.38mmol)、4-二(甲基氨基)吡啶(9.2mg,0.08mmol)和盐酸N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(86mg,0.45mmol)加入到所述反应混合物中。将反应在25℃下搅拌18小时。所述反应混合物通过玻璃料过滤。将滤液在真空中进行浓缩。所述残余物用制备性HPLC在WatersHR C18 6mm 药筒柱(40mm×100mm)上提纯,使用10%至100%乙腈的10mM乙酸铵水溶液梯度在12分钟内以70mL/min的流速洗脱,得到标题化合物的游离碱。将所述固体溶于10∶1***/甲醇(5mL)中并用富马酸(在10∶1***/甲醇中的10mg/mL溶液)处理。滤出沉淀并在真空中干燥,得到富马酸盐形式的标题化合物:1H NMR(甲醇-d4,500MHz)δ1.95-2.02(m,2H),2.11-2.20(m,4H),2.20-2.28(m,2H),3.37-3.43(m,2H),3.51(br s,2H),3.62(d,J=7.93Hz,2H),3.76-3.83(m,2H),6.69(s,2.6H;C4H4O4),7.00(dt,J=9.15,2.44Hz,1H),7.03(s,1H),7.26(dd,J=9.46,2.44Hz,1H),7.41ppm(dd,J=8.85,4.58Hz,1H);MS(ESI)m/z 328(M+H)+;计算值C19H22FN3O·1.3C4H4O4·0.1NH4OAc:C,60.3;H,5.79;N,8.93;实测值:C,59.98;H,5.76;N,9.19.
实施例4
[00168]N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲 酰胺
[00169]实施例1B的产物与吲哚-5-羧酸、盐酸N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺、1-羟基苯并***和4-二(甲基氨基)吡啶在吡啶中如实施例3中所述进行反应,得到标题化合物:1H NMR(甲醇-d4,500MHz)δ1.82-1.89(m,2H),1.96(brs,3H),2.22-2.28(m,2H),2.31(t,1H),3.31-3.36(m,2H),3.41-3.47(m,2H),3.60-3.66(m,2H),6.54(dd,J=3.20,0.76Hz,1H),7.22-7.28(m,1H),7.32(d,J=3.05Hz,1H),7.42(d,J=8.54Hz,1H),7.60-7.62(m,1H),7.64-7.70(m,1H),8.11ppm(d,J=1.22Hz,1H);MS(ESI)m/z 310(M+H)+.
实施例5
[00170]N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲 酰胺
[00171]实施例2B的产物与吲哚-5-羧酸、盐酸N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺、1-羟基苯并***和4-二(甲基氨基)吡啶在吡啶中如实施例3中所述进行反应,得到标题化合物:1H NMR(甲醇-d4,500MHz)δ1.91(br s,2H),1.94-2.01(m,3H),2.11-2.18(m,2H),2.24(t,J=7.93Hz,1H),3.16-3.21(m,2H),3.59-3.65(m,4H),6.54(dd,J=3.05,0.92Hz,1H),7.22-7.28(m,1H),7.32(d,J=3.05Hz,1H),7.41-7.44(m,1H),7.60(dd,J=8.54,1.83Hz,1H),7.63-7.70(m,1H),8.10ppm(d,J=1.83Hz,1H);MS(ESI)m/z 310(M+H)+.
生物学活性测定
[00172]为了确定本发明的代表性化合物作为α7NNR的功效,根据[3H]-DPPB结合测定或者[3H]-甲基牛扁碱(MLA)结合测定评估本发明化合物。为了确定本发明的代表性化合物作为α4β2NNR的功效,根据[3H]-野靛碱结合测定评估本发明化合物,所述测定如下描述进行。
[
3
H]-野靛碱结合
[00173]与α4β2NNR亚型结合根据以下条件测定,其修改自Pabreza L.A.,Dhawan,S.,Kellar K.J.,[3H]-Cytisine Binding to NicotinicCholinergic Receptors in Brain,Mol.Pharm.39:9-12,1991中描述的方法。将富含去小脑的大鼠脑成分的膜(ABS Inc.,Wilmington,DE)在4℃缓慢解冻,洗涤,再悬浮于30体积BSS-Tris缓冲液(120mM NaCl/5mM KCl/2mM CaCl2/2mM MgCl2/50mM Tris-Cl,pH 7.4,4℃)中。使含有100-200μg蛋白质和0.75nM[3H]-野靛碱(30Ci/mmol;PerkinElmer/NEN Life Science Products,Boston,MA)的样品以500μL的终体积在4℃培养75分钟。对七种对数稀释浓度的每种化合物进行双重测试。在10μM(-)-烟碱的存在下确定非特异性结合。用96孔过滤装置(Packard Instruments,Meriden,CT)通过真空过滤至预湿的玻璃纤维滤器板(Millipore,Bedford,MA)上,分离结合放射性,然后迅速用2mL冰冷的BSS缓冲液(120mM NaCl/5mM KCl/2mM CaCl2/2mM MgCl2)漂洗。将Packard闪烁合剂(40μL)加入各孔内,用Packard仪器确定放射性。通过Microsoft软件的非线性回归确定IC50值。根据Cheng-Prusoff公式用IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。
[3H]-甲基牛扁碱(MLA)结合
[00174]结合条件类似于[3H]-野靛碱结合的条件。将富含去小脑的大鼠脑成分的膜(ABS Inc.,Wilmington,DE)在4℃缓慢解冻,洗涤,再悬浮于30体积BSS-Tris缓冲液(120mM NaCl,5mM KCl,2mMCaCl2,2mM MgCl2和50mM Tris-Cl,pH 7.4,22℃)中。使含有100-200μg蛋白质、5nM[3H]-MLA(25Ci/mmol;Perkin Elmer/NEN Life ScienceProducts,Boston,MA)和0.1%牛血清白蛋白(BSA,Millipore,Bedford,MA)的样品以500μL的终体积在22℃培养60分钟。对七种对数稀释浓度的每种化合物进行双重测试。在10μM MLA的存在下确定非特异性结合。用96孔过滤装置(Packard Instruments,Meriden,CT)通过真空过滤至用2%BSA预湿的玻璃纤维滤器板上,分离结合放射性,然后迅速用2mL冰冷的BSS漂洗。将Packard闪烁合剂(40μL)加入各孔内,用Packard仪器确定放射性。通过Microsoft软件的非线性回归确定IC50值。根据Cheng-Prusoff公式用IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。
[3H]-DPPB结合
[00175]用富含去小脑的大鼠大脑或人皮质部分的膜(ABS Inc.,Wilmington,DE)测定与α7NNR亚型结合的[3H]-DPPB,[3H]-(S,S)-2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓(azonia)-双环[2.2.1]庚烷碘化物,如以下文献中所述,as described in Anderson,D.J.;Bunnelle,W.;Surber,B.;Du,J.;Surowy,C.;Tribollet,E.;Marguerat,A.;Bertrand,D.;Gopalakrishnan,M.J.Pharmacol.Exp.Ther.(2008),324,179-187,其引入作为参考。简要地,将颗粒物在4℃解冻、洗涤,用7套Polytron再悬浮于30体积BSS-Tris缓冲液(120mM NaCl,5mM KCl,2mMCaCl2,2mM MgCl2和50mM Tris-Cl,pH 7.4,4℃)中。将双份七种对数稀释浓度的包含100-200μg蛋白质的待测化合物和0.5nM[3H]-DPPB(62.8Ci/mmol;R46V,Abbott Labs)以500μl终体积在4℃培养75分钟。在10μM甲基牛扁碱的存在下确定非特异性结合。用Packard细胞收集器将结合放射性收集在用0.3%聚乙烯亚胺预浸渍的Millipore收集板FB上,用2.5ml冰冷缓冲液洗涤,用Packard TopCount微量板β计数器测定放射性。用Excel或Assay Explorer的非线性回归确定IC50值。根据Cheng-Prusoff公式用IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。根据下文描述的制备过程获得[3H]-DPPB。
[甲基-3H]2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓(azonia)-双环[2.2.1]庚烷;碘化物制剂
[00176]根据以下过程制备用于以上[3H]-DPPB结合测定的[甲基-3H]2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓(azonia)-双环[2.2.1]庚烷;碘化物。
步骤1:(S,S)-5-(6-苯基-哒嗪-3-基)-2,5-二氮杂-双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
[00177]将三乙胺(20mL)加入(S,S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(3.43g,17.3mmol,Aldrich Chemical Company)和3-氯代-6-苯基哒嗪(3.30g,17.3mmol,Aldrich Chemical Company)在甲苯(50mL)中的混悬液内,在100℃和氮气下将混合物加热7天。将深色混合物冷却至室温,将所得沉淀物过滤分离,用甲苯(15mL)洗涤,真空干燥,得到呈灰白色固体的标题化合物。浓缩滤液,将残留物用硅胶柱层析纯化,用乙酸乙酯洗脱,得到附加产物:MS(DCI/NH3)m/z353(M+H)+。
步骤2:(S,S)-2-甲基5-(6-苯基-哒嗪-3-基)-2,5-二氮杂-双环[2.2.1]庚烷的制备
[00178]使步骤1所得产物(3.41g,9.7mmol)溶于甲酸(20mL)中,用***(37%重量,1.0g,12.3mmol)处理。将混合物在100℃加热1小时,使褐色溶液冷却至室温,真空浓缩。将残留物用硅胶柱层析纯化,用CH2Cl2-CH3OH-NH4OH(95∶5∶1)洗脱,得到标题化合物:MS(DCI/NH3)m/z 267(M+H)+。
步骤3:[3H]-(S,S)-2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓(azonia)-双环[2.2.1]庚烷碘化物([3H]-DPPB)的制备
[00179]使[3H]甲基碘/甲苯(250mCi在0.1mL中,85Ci/mmol,American Radiolabeled Chemicals,Inc.)与步骤2所得产物的二氯甲烷溶液(0.788mg,2.96μmol在0.45mL中)合并。盖上管形瓶的盖子,让混合物在室温下反应过夜。加入甲醇,蒸发溶剂,得到42mCi。用甲醇吸收产物进行HPLC纯化。
步骤4:高效液相层析(HPLC)纯化
[00180]将约7mCi[3H]-DPPB蒸发至干,使残留物溶于总计约4.5ml乙腈∶水∶三氟乙酸(15∶85∶0.1)中。用Agilent HPLC***每次注射约0.9mL至C18(2)柱(5微米,250mm×4.6mm ID)上。用20分钟内从10%B至20%B的梯度流动相洗脱[3H]-DPPB,其中流动相A=0.1%三氟乙酸/水,流动相B=0.1%三氟乙酸/乙腈,流速为约1mL/min。在275nm用Agilent可变波长UV检测器得到峰点检出和层析图。用Agilent级分收集器在约14分钟收集含[3H]-DPPB的部分。将各部分合并,真空蒸发溶剂。使残留物溶于200proof乙醇(2mL)中,得到0.7mCi。
步骤5:纯度和特异活性的确定
[00181]用Agilent 1100系列HPLC***测定[3H]-DPPB,该***由四元泵、自动采样器和光敏二极管阵列UV检测器组成。使PackardRadiomatic A 500放射性检测器连接HPLC***。放射性检测时,用500μL流动细胞和3∶1比率的Ultima-Flo M闪烁合剂:HPLC流动相。用C18(2)柱(5微米,250mm×4.6mm ID)进行分析。流动相由以下梯度组成:以10%B开始,20分钟内达到20%B,接着1分钟内达到90%B,在90%B维持9分钟,其中流动相A=0.1%三氟乙酸/水,流动相B=0.1%三氟乙酸/乙腈。将流速设定在约1mL/min,将UV检测设定在275nm。
[00182]当通过[3H]-MLA试验进行测试时,本发明的优选化合物具有约0.01纳摩尔-约10微摩尔的Ki值,许多具有小于1微摩尔的Ki。其它优选化合物表明,本发明化合物的[3H]-野靛碱结合值为约0.01纳摩尔-至少10微摩尔。其它优选化合物表明,本发明化合物的[3H]-DPPB结合值为约0.01纳摩尔-至少10微摩尔。最优选化合物对α7受体、或α4β2受体、或α7受体和α4β2受体两者具有在0.01-1000nM范围内的结合亲和力。一些优选化合物对α7受体比对α4β2受体表现出更大的效力。
[00183]本发明的化合物是α4β2、α7NNR、或α4β2和α7NNR两者的配体,其通过改变受体的活性或信号来调节α4β2、α7NNR、或α4β2和α7NNR两者的功能。所述化合物可以是抑制受体基础活性的反激动剂,或可以是完全阻滞受体-激活激动剂作用的拮抗剂。所述化合物还可以是部分激动剂,其部分阻滞或部分激活α4β2、α7、或α4β2和α7NNR受体,或者可以是激活所述受体的激动剂。与α4β2、α7、或α4β2和α7受体两者的结合还引起涉及多种激酶和磷酸酶和蛋白质-蛋白质相互作用的关键信号过程,其对记忆、细胞保护、基因转录和疾病改变是重要的。
[00184]本发明的化合物可以以放射性标记的形式存在,其含有一个或多个具有原子质量或质量数不同于在自然界中最丰富的原子质量或质量数的原子。原子如氢、碳、磷、硫、氟、氯和碘的放射性同位素分别包括,但不局限于,3H、14C、32p、35S、18F、36Cl和125I。含有这些和/或其它原子的其它放射性同位素的化合物在本发明的范围之内。通常,由于它们容易被制备和检测,含有氚(3H)和14C放射性同位素的化合物是优选的。本发明的放射性标记的化合物可以通过本领域常规熟练技术人员已知的一般方法进行制备。这些放射性标记的化合物可以方便地通过在上面实施例和方案中描述的步骤,通过用可容易得到的放射性标记的试剂代替非放射性标记的试剂来制备。在结合试验例如上述试验中,本发明的放射性标记的化合物可以用作标准用于测定α7NNR配体的效力。
[00185]应理解以上详细描述和附属实施例只用于举例说明,不应视为限制本发明的范围,所述范围由附属权利要求及其等同物单独限定。本领域技术人员将清楚对公开的实施方案的各种更改和修饰。可不脱离本发明的主题及其范围进行包括但不限于涉及化学结构、取代基、衍生物、中间体、合成、配制和/或使用方法的此类更改和修饰。
Claims (12)
2.权利要求1的化合物,其中
R2是-C(O)-A;
或其药学上可接受的盐、酰胺或前药。
3.权利要求1的化合物,其中
R2是-A;
或其药学上可接受的盐、酰胺或前药。
4.权利要求1的化合物,其中
R2是-(CRxRy)n-A;
或其药学上可接受的盐、酰胺或前药。
5.权利要求1的化合物,其中
R1是氢或C1-6烷基;和
R2是-C(O)-(CRxRy)t-A;
或其药学上可接受的盐、酰胺或前药。
6.权利要求1的化合物,其中所述化合物选自
N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氯-1H-吲哚-2-甲酰胺;
N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氯-1H-吲哚-2-甲酰胺;
N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-5-氟-1H-吲哚-2-甲酰胺;
N-[(4r)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲酰胺;和
N-[(4s)-1-氮杂三环[3.3.1.13,7]癸-4-基甲基]-1H-吲哚-5-甲酰胺;
或其药学上可接受的盐、酰胺或前药。
7.一种治疗或预防由α7烟碱样乙酰胆碱受体、α4β2烟碱样乙酰胆碱受体或α7和α4β2烟碱样乙酰胆碱受体两者调节的病症、疾病或缺陷的方法,其中所述病症、疾病或缺陷选自记忆疾病、认知障碍、神经变性和神经发育疾病,包括给予治疗有效量的权利要求1的化合物或其药学上可接受的盐、酰胺或前药。
8.一种选自轻度认知缺损、与年龄有关的记忆缺陷(AAMI)、老年性痴呆、AIDS痴呆、皮克病、与莱维体有关的痴呆、与唐氏综合征有关的痴呆、肌萎缩性侧索硬化、亨廷顿舞蹈病、吸烟戒断、情感***性精神障碍、双向和躁狂疾病、与创伤性脑损伤有关的CNS功能减弱、急性疼痛、术后痛、慢性痛和炎性痛的疾病的治疗方法,所述方法包括给予需要的患者权利要求1的化合物或其药学上可接受的盐、酰胺或前药的步骤。
9.一种选自注意缺陷障碍、注意力不集中的过度反应症(ADHD)、阿尔茨海默氏病(AD)、帕金森氏病、图雷特综合征、精神***症和与精神***症有关的认知缺损(CDS)的疾病的治疗方法,所述方法包括给予需要的患者权利要求1的化合物或其药学上可接受的盐、酰胺或前药的步骤。
10.一种选自精神***症和与精神***症有关的认知缺损(CDS)或其混合型的疾病的治疗方法,包括给予需要的患者权利要求1的化合物或其药学上可接受的盐、酰胺或前药以及一种或多种非典型抗精神病药的步骤。
11.药物组合物,其包含治疗有效量的权利要求1的化合物或其药学上可接受的盐、酰胺或前药以及一种或多种药学上可接受的载体。
12.权利要求11的药物组合物,进一步包含一种或多种非典型抗精神病药。
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US5840903A (en) | 1992-07-27 | 1998-11-24 | G. D. Searle & Co. | 4-aminomethyl-1-azaadamantane derived benzamides |
JP3235913B2 (ja) | 1993-07-30 | 2001-12-04 | エーザイ株式会社 | アミノ安息香酸誘導体 |
US5399562A (en) | 1994-02-04 | 1995-03-21 | G. D. Searle & Co. | Indolones useful as serotonergic agents |
US7897766B2 (en) | 2005-09-23 | 2011-03-01 | Abbott Laboratories | Amino-aza-adamantane derivatives and methods of use |
-
2008
- 2008-03-20 MX MX2009010173A patent/MX2009010173A/es active IP Right Grant
- 2008-03-20 EP EP08799662.5A patent/EP2129673B1/en active Active
- 2008-03-20 CN CN200880009484A patent/CN101675049A/zh active Pending
- 2008-03-20 CA CA002679885A patent/CA2679885A1/en not_active Abandoned
- 2008-03-20 EP EP12162114.8A patent/EP2505588B1/en active Active
- 2008-03-20 WO PCT/US2008/057652 patent/WO2008118747A1/en active Application Filing
- 2008-03-20 US US12/052,093 patent/US8168791B2/en not_active Expired - Fee Related
- 2008-03-20 JP JP2009554740A patent/JP5394940B2/ja not_active Expired - Fee Related
Also Published As
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JP5394940B2 (ja) | 2014-01-22 |
EP2129673A1 (en) | 2009-12-09 |
MX2009010173A (es) | 2009-10-12 |
CA2679885A1 (en) | 2008-10-02 |
EP2129673B1 (en) | 2013-11-06 |
EP2505588A1 (en) | 2012-10-03 |
US8168791B2 (en) | 2012-05-01 |
WO2008118747A1 (en) | 2008-10-02 |
US20080262023A1 (en) | 2008-10-23 |
EP2505588B1 (en) | 2013-11-13 |
JP2010522204A (ja) | 2010-07-01 |
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