CN102119142A - 作为烟碱α7调节剂的水杨酰胺衍生物 - Google Patents
作为烟碱α7调节剂的水杨酰胺衍生物 Download PDFInfo
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- CN102119142A CN102119142A CN2009801310854A CN200980131085A CN102119142A CN 102119142 A CN102119142 A CN 102119142A CN 2009801310854 A CN2009801310854 A CN 2009801310854A CN 200980131085 A CN200980131085 A CN 200980131085A CN 102119142 A CN102119142 A CN 102119142A
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- phenyl
- methoxyl group
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
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- 210000000214 mouth Anatomy 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
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- 201000000585 muscular atrophy Diseases 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- YBSZEWLCECBDIP-UHFFFAOYSA-N n-[bis(dimethylamino)phosphoryl]-n-methylmethanamine Chemical compound CN(C)P(=O)(N(C)C)N(C)C.CN(C)P(=O)(N(C)C)N(C)C YBSZEWLCECBDIP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 230000001242 postsynaptic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- 230000008961 swelling Effects 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000002700 tablet coating Substances 0.000 description 1
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- 230000002123 temporal effect Effects 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 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
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- 230000008733 trauma Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/62—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Abstract
本申请公开了式I的化合物:其中Q1、Q2、R1、R2、R3和n如本文所定义。还提供了主题化合物的药物组合物、其使用方法和制备方法。
Description
发明领域
本发明涉及烟碱乙酰胆碱受体(nAChR),且特别涉及7nAChR亚型的正变构调节剂和这种化合物的制备方法和使用方法。
发明背景
烟碱乙酰胆碱受体(nAChR)是配体门控离子通道家族的成员。当被激活时,通过烟碱离子通道的离子电导增加。烟碱α7受体(α7nAChR)在体外形成高度可透过钙离子的同型五聚化通道。α7nAChR各自具有四个跨膜结构域,称作M1、M2、M3和M4。已经提示M2结构域形成内衬通道的壁。序列对比显示α7nAChR在进化过程中是高度保守的。沿通道排列的M2结构域与从小鸡到人的蛋白质序列相同。α7nAChR由如下文献描述:Revah等人(1991),Nature,353,846-849;Galzi等人(1992),Nature 359,500-505;Fucile等人(2000),PNAS 97(7),3643-3648;Briggs等人(1999),Eur.J.Pharmacol.366(2-3),301-308;和Gopalakrishnan等人(1995),Eur.J.Pharmacol.290(3),237-246。
α7nAChR通道在不同脑区域中表达并且认为牵连中枢神经系统(CNS)中的许多重要生物过程,包括学习、记忆力和注意力(Levin等人,Psychopharmacology(1998),138,217-230)。α7nAChR位于突触3前和突触后末端上并且已经提示它们涉及调节突触传递。已经显示α7nAChR激动剂改善阿尔茨海默病和注意缺陷障碍中的注意力和认知(Wilens等人,Am.J.Psychiatry(1999),156(12),1931-1937)。
长期以来已知烟碱的镇痛作用。已经显示α7nAChR受体激动剂调节促炎细胞因子产生,包括白细胞介素(ILs)、肿瘤坏死因子(TNF)α和高速泳动族框(HMGB-1),并且抑制CNS中的炎症信号传导(de Jonge等人,Br.J.Pharmacol.(2007),1-15)。α7nAChR受体在调节CNS疼痛传递中起作用,并且α7nAChR激动剂已经在急性疼痛模型中显示镇痛效果(Damaj等人,Neuropharmacol.(2000)39,2785-2791。
由于乙酰胆碱(ACh)是α7nAChR的内源性激动剂,所以在与ACh相同部位起作用的激动剂可以刺激并且可能通过脱敏和竞争性阻断过程阻断受体活性(Forman等人,Biophysical J.(1988),54(1),149-158),且导致延长的受体失活(Buisson等人,J.Neuroscl.(2001),21(6),1819-1829)。脱敏限制离子通道在激动剂施用过程中保持活化的期限。因此,这种激动剂提供的α7nAChR活性促进还会增加与ACh竞争,且由此限制激动剂作为药物的有用性。
烟碱α7受体通道的正变构调节剂促进Ach和其他烟碱α7受体激动剂活性。当中枢神经系统中存在足够的Ach时,正变构调节剂活化α7nAChR。α7nAChR的正变构调节剂由此用于治疗CNS、疼痛和炎性疾病或病症,调节CNS功能,例如认知、学习、情绪、情感和注意力,并且控制与疼痛和炎性病症相关的促炎细胞因子产生。因此,对烟碱α7受体通道的新颖的正变构调节剂存在需求。
发明概述
本申请提供了式I的化合物:
其中:
Q1是[CH2]q;
q是0、1或2;
Q2是[CH2]r;
r是1或2;
R1是R1’或R1”;
R1’是任选被卤素取代的苯基;
R1”是任选被炔基取代的环烷基;
R2是R2’或R2”;
R2’是任选被低级烷氧基取代的苯基;
R2”是环烷基;
R3是低级烷氧基或低级烷基;且
n是0、1或2。
在式I的一个实施方案中,Q1是亚甲基。
在式I的一个实施方案中,R1是R1”。
在式I的一个实施方案中,Q1是亚甲基,R1是R1”。
在式I的一个实施方案中,R1”是环丙基。
在式I的一个实施方案中,R1”是环丙基,Q1是亚甲基。
在式I的一个实施方案中,Q2是亚甲基。
在式I的一个实施方案中,R2是苯基。
在式I的一个实施方案中,R2是苯基,Q2是亚甲基。
在式I的一个实施方案中,R2是4-甲氧基-苯基。
在式I的一个实施方案中,q是0。
在式I的一个实施方案中,R1是环戊基。
在式I的一个实施方案中,q是0,R1是环戊基。
在式I的一个实施方案中,Q2是亚乙基。
在式I的一个实施方案中,R2是苯基。
在式I的一个实施方案中,R2是苯基,Q2是亚乙基。
在式I的一个实施方案中,n是2。
在式I的一个实施方案中,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,Q1是亚乙基。
在式I的一个实施方案中,R1是R1’。
在式I的一个实施方案中,Q1是亚乙基,R1是R1’。
在式I的一个实施方案中,R1’是2-氟-苯基。
在式I的一个实施方案中,Q1是亚乙基,R1’是2-氟-苯基。
在式I的一个实施方案中,Q2是亚甲基。
在式I的一个实施方案中,R2是R2’。
在式I的一个实施方案中,Q2是亚甲基,R2是R2’。
在式I的一个实施方案中,R2是R2”。
在式I的一个实施方案中,Q2是亚甲基,R2是R2”。
在式I的一个实施方案中,n是1。
在式I的一个实施方案中,R3是甲氧基。
在式I的一个实施方案中,n是1,R3是甲氧基。
在式I的一个实施方案中,n是2。
在式I的一个实施方案中,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,R2是R2”,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,Q2是亚甲基,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,R2是R2”,Q2是亚甲基,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,q是0。
在式I的一个实施方案中,R1是R1”。
在式I的一个实施方案中,q是0,R1是R1”。
在式I的一个实施方案中,R1”是1-乙炔基-环己基。
在式I的一个实施方案中,q是0,R1”是1-乙炔基-环己基。
在式I的一个实施方案中,Q2是亚甲基。
在式I的一个实施方案中,R2是环丙基。
在式I的一个实施方案中,Q2是亚甲基,R2是环丙基。
在式I的一个实施方案中,R2是环丙基,n是2,R3各自独立地是甲基或甲氧基。
在式I的一个实施方案中,Q2是亚甲基,R2是环丙基,n是2,R3各自独立地是甲基或甲氧基。
本申请还提供了选自如下的式I的化合物:
4-苄氧基-2′-甲氧基-联苯-3-甲酸环丙基甲基-酰胺;
4-苄氧基-2′-甲氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺;
4′-甲氧基-2′-甲基-4-苯乙氧基-联苯-3-甲酸环戊基酰胺;
4′-甲氧基-2′-甲基-4-苯乙氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺;
4′-甲氧基-4-(4-甲氧基-苄氧基)-2′-甲基-联苯-3-甲酸环丙基甲基-酰胺;
4-环丙基甲氧基-4′-甲氧基-2′-甲基-联苯-3-甲酸(1-乙炔基-环己基)-酰胺;和
4-环丙基甲氧基-4′-甲氧基-2′-甲基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺。
本申请还提供了对需要的个体促进认知的方法,该方法包含对所述个体施用有效量的式I的化合物。
本申请还提供了上述方法,其中所述个体具有阿尔茨海默病。
本申请还提供了药物组合物,其包含式I的化合物与至少一种药学可接受的载体、稀释剂或赋形剂。
发明详述
本申请提供了式I的化合物:
其中Q1、Q2、R1、R2、R3和n如本文所定义。还提供了主题化合物的药物组合物、其使用方法和制备方法。
定义
除非另有描述,否则如下本申请包括说明书和权利要求书中所用的术语具有如下所述的定义。必须注意,除非另有描述,否则本说明书和待批权利要求中所用的术语“一个(a)”、“一种(an)”和“所述的(the)”包括一个(种)或多个(种)复数对应物。
“激动剂”意指促进另一种化合物或受体部位活性的化合物。
“烷基”意指仅由碳和氢组成的具有1-12个碳原子的一价直链或支链饱和烃部分。“低级烷基”意指含有1-6个碳原子的烷基,即C1-C6烷基。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基等。″支链烷基″意指异丙基、异丁基、叔丁基。
本文所用的术语“亚烷基”或“亚烷基(alkylenyl)”意指1-6个碳原子的直链饱和二价烃基或3-6个碳原子的支链饱和二价烃基,例如亚甲基、亚乙基、2,2-二甲基亚乙基、亚丙基、2-甲基亚丙基、亚丁基、亚戊基等。
“烷氧基”是指式-OR的部分,其中R是如本文所定义的烷基部分。烷氧基部分的实例包括但不限于甲氧基、乙氧基、异丙氧基、叔丁氧基等。“低级烷氧基”意指式-OR的部分,其中R是如本文所定义的烷基部分。低级烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、叔丁氧基等。
“炔基”单独或与其他基团组合表示包含三键和至多12个、优选至多6个碳原子的直链或支链烃残基,例如乙炔基或2-丙炔基。
″氨基″意指式-NRR’的部分,其中R和R’各自独立地是氢或如本文所定义的烷基。
“拮抗剂”意指减少或防止另一种化合物或受体部位作用的化合物。
“芳基”意指由一-、二-或三环芳族环组成的一价环状芳族烃部分。芳基可以任选如本文所定义的那样被取代。芳基的实例包括但不限于苯基、萘基、菲基、芴基、茚基、并环戊二烯基、甘菊环基、氧基二苯基、联苯、亚甲二苯基、氨基二苯基、二苯基硫基、二苯基磺酰基、二苯基亚异丙基、苯并二噁烷基、苯并呋喃基、苯并间二氧杂环戊烯基(benzodioxylyl)、苯并吡喃基、苯并噁嗪基、苯并噁嗪酮基、苯并哌啶基、苯并哌嗪基、苯并吡咯烷基、苯并吗啉基、亚甲二氧基苯基、亚乙二氧基苯基等,包括其部分氢化的衍生物,它们各自可以任选被取代。优选的芳基包括任选取代的苯基和任选取代的萘基。优选的芳基是任选取代的苯基。
″芳基烷基″和″芳烷基″可以互换使用,其意指基团-RaRb,其中Ra是亚烷基,Rb是如本文所定义的芳基;例如苯基,例如苄基、苯基乙基、3-(3-氯苯基)-2-甲基戊基等苯基烷基是芳基烷基的实例。
“环烷基”意指由一-或二环组成的一价饱和碳环部分。环烷基可以任选被一个或多个取代基取代,其中除非另有具体指示,否则每个取代基独立地是羟基、烷基、烷氧基、卤素、卤代烷基、氨基、一烷基氨基或二烷基氨基。环烷基部分的实例包括、但不限于环丙基、环丁基、环戊基、环己基、环庚基等,包括其部分不饱和的衍生物。
“环烷基烷基”意指式-R’-R”的部分,其中R’是亚烷基,R”是如本文所定义的环烷基。
″杂烷基″意指如本文所定义的烷基,包括支链C4-C7-烷基,其中1、2或3个氢原子被独立地选自-ORa、-NRbRc和S(O)nRd(其中n是0-2的整数)的取代基替代,其中可以理解杂烷基的连接点通过碳原子,其中Ra是氢、酰基、烷基、环烷基或环烷基烷基;Rb和Rc彼此独立地是氢、酰基、烷基、环烷基或环烷基烷基;并且当n是0时,Rd是氢、烷基、环烷基或环烷基烷基,而当n是1或2时,Rd是烷基、环烷基、环烷基烷基、氨基、酰基氨基、一烷基氨基或二烷基氨基。有代表性的实例包括、但不限于2-羟基乙基、3-羟基丙基、2-羟基-1-羟基甲基乙基、2,3-二羟基丙基、1-羟基甲基乙基、3-羟基丁基、2,3-二羟基丁基、2-羟基-1-甲基丙基、2-氨基乙基、3-氨基丙基、2-甲基磺酰基乙基、氨基磺酰基甲基、氨基磺酰基乙基、氨基磺酰基丙基、甲基氨基磺酰基甲基、甲基氨基磺酰基乙基、甲基氨基磺酰基丙基等。
“杂芳基”意指具有至少1个芳族环的5-12个环原子的单环、二环或三环基团,所述至少一个芳族环包含1、2或3个选自N、O或S的环杂原子,其余的环原子是C,其中可以理解杂芳基的连接点在芳族环上。杂芳基环可以任选如本文所定义的那样被取代。杂芳基部分的实例包括、但不限于咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、吡嗪基、噻吩基、噻吩基、呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、苯并呋喃基、苯并噻吩基、苯并硫代吡喃基、苯并咪唑基、苯并噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、苯并吡喃基、吲哚基、异吲哚基、三唑基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、喹嗪基、萘啶基、蝶啶基、咔唑基、氮杂基、二氮杂基、吖啶基等,包括其部分氢化的衍生物,它们各自可以任选被取代。优选的杂芳基包括吲哚基、吡啶基、嘧啶基、噻吩基、呋喃基、吡咯基、咪唑基和吡唑基,它们各自可任选被取代。
″杂芳基烷基″和″杂芳烷基″可以互换使用,其意指基团-RaRb,其中Ra是亚烷基,Rb是如本文所定义的杂芳基。
术语“卤素(halo)”和“卤素(halogen)”可以互换使用,其意指取代基氟、氯、溴或碘。
“卤代烷基”意指如本文所定义的烷基,其中一个或多个氢被相同或不同的卤素替代。典型的卤代烷基包括CH2Cl、CH2CF3、CH2CCl3、全氟烷基(例如CF3)等。
“杂环基”或“杂环烷基”意指由1-3个环组成的一价饱和部分,其掺入了1、2、3或4个杂原子(选自氮、氧或硫)。杂环基可以任选如本文所定义的那样被取代。杂环基的实例包括、但不限于任选取代的哌啶基、哌嗪基、高哌嗪基、氮杂基、吡咯烷基、吡唑烷基、咪唑啉基、咪唑烷基、吡啶基、哒嗪基、嘧啶基、噁唑烷基、异噁唑烷基、吗啉基、噻唑烷基、异噻唑烷基、奎宁环基、喹啉基、异喹啉基、苯并咪唑基、噻二唑烷基、苯并噻唑烷基、benzoazolylidinyl、二氢呋喃基、四氢呋喃基、二氢吡喃基、四氢吡喃基、噻吗啉基、噻吗啉亚砜、噻吗啉砜、二氢喹啉基、二氢异喹啉基、四氢喹啉基、四氢异喹啉基等。
″任选取代的″在与″芳基″、″苯基″、″杂芳基″(包括吲哚基,例如吲哚-1-基、吲哚-2-基和吲哚-3-基、2,3-二氢吲哚基,例如2,3-二氢吲哚-1-基、2,3-二氢吲哚-2-基和2,3-二氢吲哚-3-基,吲唑基,例如吲唑-1-基、吲唑-2-基和吲唑-3-基,苯并咪唑基,例如苯并咪唑-1-基和苯并咪唑-2-基,苯并呋喃基,例如苯并呋喃-2-基和苯并呋喃-3-基,苯并噻吩基,例如苯并噻吩-2-基和苯并噻吩-3-基,苯并噁唑-2-基、苯并噻唑-2-基、噻吩基、呋喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噁唑基、噻唑基、异噁唑基、异噻唑基、咪唑基、吡唑基和喹啉基)″或″杂环基″结合使用时,意指芳基、苯基、杂芳基或杂环基,其任选独立地被1-4个取代基、优选1或2个取代基取代,所述取代基选自烷基、环烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、氰基、硝基、杂烷基、氨基、一-烷基氨基、二-烷基氨基、羟基烷基、烷氧基烷基、烷基磺酰基、烷基磺酰氨基、苄氧基、环烷基烷基、环烷氧基、环烷基烷氧基、烷基磺酰氧基、任选取代的噻吩基、任选取代的吡唑基、任选取代的吡啶基、吗啉代羰基、(CH2)q-S(O)rRf;-(CH2)q-NRgRh;-(CH2)q-C(=O)-NRgRh;-(CH2)q-C(=O)-C(=O)-NRgRh;-(CH2)q-SO2-NRgRh;-(CH2)q-N(Rf)-C(=O)-Ri;-(CH2)q-C(=O)-Ri;或-(CH2)q-N(Rf)-SO2-Rg;其中q是0或1,r是0-2,Rf、Rg和Rh各自独立地是氢或烷基,且Ri各自独立地是氢、烷基、羟基或烷氧基。″芳基″、苯基″、″杂芳基″、″环烷基″或″杂环基″的一些优选的任选取代基包括烷基、卤素、卤代烷基、烷氧基、氰基、氨基、氨基磺酰基和烷基磺酰基。更优选的取代基是甲基、氟、氯、三氟甲基、甲氧基、氨基、氨基磺酰基和甲磺酰基。
“离去基”意指具有通常与之相关的在合成有机化学中的含义的基团,即在取代反应条件下可被替代的原子或基团。离去基的实例包括、但不限于卤素、烷-或亚芳基磺酰氧基,例如甲磺酰氧基、乙磺酰氧基、硫代甲基、苯磺酰氧基、甲苯磺酰氧基和噻吩基氧基、二卤代膦酰氧基、任选取代的苄氧基、异丙氧基、酰基氧基等。
“调节剂”意指与靶标相互作用的分子。相互作用包括、但不限于如本文所定义的激动剂、拮抗剂等。
“任选的”或“任选地”意指随后描述的结果或情况可能但不一定发生,并且该描述包括结果或情况发生的例子及其不发生的例子。
″疾病″和“疾病状态”意指任意的疾病、病症、症状、障碍或适应征。
“惰性有机溶剂”或“惰性溶剂”意指在与之相关所述的反应条件下溶剂是惰性的,包括,例如苯、甲苯、乙腈、四氢呋喃、N,N-二甲基甲酰胺、氯仿、二氯甲烷(ethylene chloride)或二氯甲烷(dichloromethane)、二氯乙烷、乙醚、乙酸乙酯、丙酮、甲基乙基酮、甲醇、乙醇、丙醇、异丙醇、叔丁醇、二噁烷、吡啶等。除非有相反的指示,否则本发明反应中使用的溶剂是惰性溶剂。
“药学可接受的”意指用于制备药物组合物的,它们一般是安全的、无毒性的并且既无生物学上的、也非其他不期望的,并且包括对兽医和人体药物应用而言均为可接受的。
化合物的“药学可接受的盐”意指如本文所定义的药学可接受的,并且具有母体化合物的期望的药理学活性。这种盐包括:与无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与有机酸形成的酸加成的盐,所述有机酸例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对-甲苯磺酸、三甲基乙酸等;或当存在于母体化合物上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替代时形成的盐;或与无机或有机碱形成的配位化合物。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。优选的药学可接受的盐是由乙酸、盐酸、硫酸、甲磺酸、马来酸、磷酸、酒石酸、柠檬酸、钠、钾、钙、锌和镁形成的盐。应理解所有涉及的药学可接受的盐包括如本文所定义的相同酸加成盐的溶剂加成形式(溶剂合物)或晶型(多晶型物)。
“保护基”或“保护基团”意指选择性阻断多官能团化合物上的一个反应位点的基团,使得化学反应选择性地在通常与之相关的合成化学含义中的另一个未被保护的反应位点上进行。本发明的一些方法依赖于阻断反应剂中存在的反应氮和/或氧原子。例如,术语“氨基-保护基”和“氮保护基”在本文中可以互换使用并且意指那些指定防止氮原子在合成操作中发生不期望的反应的有机基团。典型的氮保护基包括、但不限于三氟乙酰基、乙酰氨基、苄基(Bn)、苄氧羰基(苄氧羰基,CBZ)、对-甲氧基苄氧羰基、对-硝基苄氧羰基、叔-丁氧羰基(BOC)等。本领域技术人员已知如何选择易于除去和能够进行接下来的反应的基团。
“溶剂合物”意指包含化学计算或非化学计算量的溶剂的溶剂加成形式。一些化合物具有俘获结晶固态的溶剂分子的固定摩尔比的趋向,由此形成溶剂合物。如果溶剂是水,则形成的溶剂合物是水合物;当溶剂是醇时,形成的溶剂合物是醇化物。通过组合一个或多个水分子与水保持其分子状态如H2O的物质之一形成水合物,这种组合能够形成一种或多种水合物。
“个体”意指哺乳动物和非哺乳动物。哺乳动物意指哺乳动物种类的任意成员,包括、但不限于人类;非人的灵长类,例如黑猩猩和其他猿类和猴子种类;农场动物,例如牛、马、绵羊、山羊和猪;家养动物,例如家兔、狗和猫;实验室动物,包括啮齿动物,例如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括、但不限于鸟类等。术语“个体”不表示具体年龄或性别。
本文所用的“疼痛”和疼痛病症(状态)意指与任意各种原因相关的疼痛,包括、但不限于炎性痛、手术疼痛、内脏痛、牙痛、月经前疼痛、中枢性痛、因烧伤导致的疼痛、偏头痛或丛集性头疼、神经损伤、神经炎、神经痛、中毒、缺血损伤、间质性膀胱炎、癌症疼痛、病毒、寄生虫或细菌感染、创伤后损伤(包括骨折和体育运动损伤)和与功能性肠紊乱相关的疼痛例如肠易激综合征。
“炎症”意指任意病理过程,其特征在于因细胞反应、化学反应或其他原因导致的组织损伤或破坏。炎症可以表现为疼痛、发热、发红、肿胀和功能缺失的征候。炎症适应征包括、但不限于细菌、真菌或病毒感染、类风湿性关节炎、骨关节炎、手术、膀胱感染或特发性膀胱炎、过度使用、老年或营养缺乏、前列腺炎和结膜炎。
“认知”意指与获取和保留知识相关的任意心理过程。“认知障碍”意指涉及思维、推理、判断和记忆的心理过程的任意障碍。认知障碍可以因如下情况导致或与之相关:帕金森氏病、亨廷顿舞蹈病、焦虑、抑郁症、躁狂忧郁、精神病、癫痫症、强迫性障碍、情绪障碍、偏头痛、阿尔茨海默病、睡眠障碍、进食障碍例如食欲减退、食欲亢进和肥胖、惊恐发作、静坐不能、注意力缺陷伴多动障碍(ADHD)、注意缺陷障碍(ADD)、从药物滥用例如可卡因、酒精、烟碱和苯二氮类的戒断、精神分裂症和与脊柱创伤和/或头部损伤例如脑积水相关的障碍。
“治疗有效量”意指在对个体施用以治疗疾病状态时足以进行这种对疾病状态治疗的化合物用量。“治疗有效量”根据化合物、所治疗的疾病状态、严重性或所治疗的疾病、个体年龄和相对健康状况、施用途径和形式、主治医师或兽医和其他因素的不同而改变。
术语“上述定义的那些”和“本文定义的那些”在涉及变量时作为涉及该变量广泛的定义和优选的、更优选和最优选的定义(如果有的话)引入。
“治疗(Treating)”或“治疗(treatment)”疾病状态包括:
(i)预防疾病状态,即导致疾病状态的临床症状在暴露或趋向于该疾病状态、但尚未发生或显示疾病状态症状的个体中不发生;
(ii)抑制疾病状态,即阻止疾病状态或其临床症状发生;或
(iii)缓解疾病状态,即导致疾病状态或其临床症状暂时或持久消退。
(iv)
术语“治疗”、“接触”和“反应”在涉及化学反应时意指在适合条件下添加或混合两种试剂,以产生所示和/或期望的产物。应理解产生所示和/或期望产物的反应不一定直接因组合两种最初添加的试剂导致,即可能存在两种或多种混合物中产生的中间体,最终导致形成所示和/或期望的产物。
命名和结构
一般而言,用于本申请的命名基于AUTONOMTM v.4.0,即用于IUPAC系统命名法生成的Beilstein Institute计算机化系统。使用ISIS2.2版制备本文所示的化学结构。本文结构上的碳、氧、硫或氮原子上出现的任何开放式化合价都指示存在氢原子。
手性碳原无论何时存在于化学结构上,都指定该结构包括与该手性碳相关的所有立体异构体。
将本文确定的全部专利和公开文献完整引入本文作为参考。
本发明方法有代表性的化合物如表1中所示。
表1
合成
可以通过如下所示和如下所述的示例性合成反应方案中所述的各种方法制备本发明的化合物。
用于制备这些化合物的原料和试剂一般购自商品供应商,例如Aldrich Chemical Co.,或通过本领域技术人员公知的方法、按照参考文献中举出的方法制备,所述的参考文献例如Fieser and Fieser’s Reagents for Organic Synthesis;Wiley & Sons:New York,1991,Volumes 1-15;Rodd’s Chemistry of Carbon Compounds,Elsevier Science Publishers,1989,Volumes 1-5 and Supplementals;和Organic Reactions,Wiley & Sons:New York,1991,Volumes 1-40。下列合成反应方案仅为一些方法的示例,通过这些方法可以合成本发明的化合物,且可以对这些合成反应方案进行各种改变并且在参照本申请中包含的公开内容的情况下可以启示本领域技术人员。
如果需要,可以使用常规技术分离和纯化合成反应路线的原料和中间体,包括但不限于过滤、蒸馏、结晶、色谱等。可以使用常规方式包括物理常数和光谱数据表征这种原料。
除非特别有相反的指示,否则本文所述反应优选在惰性气体气氛中、在大气压下、在约-78℃-约150℃、更优选约0℃-约125℃、且最优选和便利地在约室(环境)温、例如约20℃的反应温度范围内进行。
应用
本发明的化合物用于治疗与烟碱α7(α7nACh)受体相关的疾病或病症,包括精神病、神经变性疾病和牵连胆碱能系统功能障碍的认知损害,以及记忆力和/或认知损害病症,包括,例如精神分裂症、焦虑、躁狂、抑郁症、躁狂忧郁、图雷特综合征、帕金森病、亨廷顿舞蹈病、认知障碍(例如阿尔茨海默病、Lewy体痴呆、肌萎缩侧索硬化、记忆缺陷、记忆丧失、认知缺陷、注意缺陷、注意力缺陷伴多动障碍);和其他应用,例如治疗烟碱成瘾,包括戒烟、治疗疼痛(即止痛应用)、提供神经保护和治疗时差综合症。本发明的化合物用于提高阿尔茨海默病患者和具有与精神分裂症、焦虑、躁狂、抑郁症、躁狂忧郁、图雷特综合征、帕金森病、亨廷顿舞蹈病、Lewy体痴呆、肌萎缩侧索硬化、记忆缺陷、记忆丧失、认知缺陷、注意缺陷、注意力缺陷伴多动障碍相关的认知损害或认识病的患者的认知。
因此,本发明提供了治疗患有如下疾病的患者或个体、特别是哺乳动物且尤其是人的方法:精神病、神经变性疾病和牵连胆碱能系统功能障碍的认知损害,以及记忆力和/或认知损害病症,包括,例如精神分裂症、焦虑、躁狂、抑郁症、躁狂忧郁[精神病的实例]、图雷特综合征、帕金森病、亨廷顿舞蹈病[神经变性疾病的实例]和/或认知病(例如阿尔茨海默病、Lewy体痴呆、肌萎缩侧索硬化、记忆缺陷、记忆丧失、认知缺陷、注意缺陷、注意力缺陷伴多动障碍),该方法包含对所述患者施用有效量的本发明化合物。
神经变性障碍包括、但不限于治疗和/或预防阿尔茨海默病、皮克病、弥漫性Lewy体疾病、进行性核上麻痹(Steel-Richardson综合征)、多系统变性(Shy-Drager综合征)、运动神经元病包括肌萎缩侧索硬化、变性共济失调、皮质基底变性、ALS-关岛震颤麻痹痴呆综合征、亚急性硬化性全脑炎、亨廷顿病、帕金森病、共核蛋白病、原发进行性失语、纹状体黑质变性、马-约病/脊髓小脑共济失调3型、橄榄体脑桥小脑变性、日拉斯德拉图拉泰病、延髓、假性延髓麻痹、脊髓性肌萎缩、脊髓延髓肌萎缩(Kennedy病)、原发性侧索硬化症、家族性痉挛性截瘫、韦-霍病、库-韦病、Tay-Sach病、Sandhoff病、家族性痉挛性疾病、沃-库-韦病、痉挛性轻截瘫、进行性多病灶脑白质病、朊病毒病(例如克罗伊茨费尔特-雅各布病、病、库鲁病和家族致命性失眠症)和因脑缺血症或梗塞包括栓塞和血栓形成栓塞以及任意类型的颅内出血(包括、但不限于硬膜外、硬膜下、蛛网膜下腔和大脑内)和颅内和脊柱内损害(包括、但不限于挫伤、穿透、割伤、压迫和撕裂伤)导致的神经变性疾病。
此外,本发明的化合物可以用于治疗与年龄相关的痴呆和其他痴呆和具有记忆缺失的病症包括与年龄相关的记忆缺失、衰老、血管性痴呆、弥散性白质病(宾斯旺格病)、内分泌或代谢来源的痴呆、头损伤和弥撒性脑损害的痴呆、拳击员痴呆和额叶痴呆,因此,本发明提供了治疗患有与年龄相关的痴呆和其他痴呆和具有记忆缺失的病症的患者、尤其是人并且促进阿尔茨海默病患者认知记忆力的方法,包含对所述患者施用有效量的本发明化合物。
本发明提供了治疗患有记忆缺陷的个体的方法,所述记忆缺陷由于例如阿尔茨海默病、由于衰老造成的轻微认知损害、精神分裂症、帕金森病、亨廷顿舞蹈病、皮克病、克罗伊茨费尔特-雅各布病、抑郁症、老化、头损伤、中风、CNS缺氧、大脑衰老、多发性脑梗死痴呆和其他神经性疾病以及HIV和心血管疾病,该方法包括施用有效量的本发明化合物。
已知淀粉样前蛋白(APP)和衍生自它们的Aβ肽类例如Aβ1-40、Aβ1-42和其他片段牵连阿尔茨海默病的病理学。Aβ1-42肽类不仅牵连神经毒性,而且已知可抑制胆碱能递质功能。此外,已经确定Aβ肽类结合α7nACh受体。阻断Aβ肽类结合α-7nAChR的活性剂由此用于治疗神经变性疾病。此外,刺激7nACh受体可以防止神经元发生与Aβ肽类相关的细胞毒性。因此,本发明提供了治疗和/或预防阿尔茨海默病患者痴呆的方法,包括对该个体施用治疗有效量的式I的化合物,以抑制淀粉样蛋白β肽(优选Aβ1-42)结合nACh受体,优选α7nACh受体,最优选人α7nACh受体(和治疗和/或预防阿尔茨海默病的其他临床表现的方法,包括但不限于认知和语言缺陷、精神性失用症、抑郁症、妄想和其他神经精神症状和症候和运动和步态异常)。
本发明还提供了治疗其他淀粉样变性疾病的方法,例如遗传性大脑血管病、非神经病性遗传性淀粉样蛋白、唐氏综合征、巨球蛋白血症、继发性家族性地中海热、穆-韦综合征、多发性骨髓瘤、胰腺-和心脏-相关淀粉样变性、长期血液透析的人体疾病(chronic hemodialysis anthropathy)和芬兰和衣阿华淀粉样变性。
烟碱性受体牵连在对酒精摄入的身体响应中起作用,并且本发明的化合物用于治疗酒精脱瘾和抗中毒疗法。
α7nACh受体亚型激动剂也可以用于对与中风和局部缺血和谷氨酸盐-诱导的兴奋性中毒的神经保护,且本发明由此提供了治疗患者的方法,以提供对涉及中风和局部缺血和谷氨酸盐-诱导的兴奋性中毒的神经保护,该方法包括对患者施用有效量的本发明化合物。
α7nACh受体亚型激动剂也可以用于治疗烟碱成瘾、诱导戒烟、治疗疼痛和治疗时差综合症、糖尿病和炎症,且本发明由此提供了治疗患有烟碱成瘾、疼痛、时差综合症、肥胖、糖尿病和/或炎症的患者的方法或诱导患者戒烟的方法,该方法包括对所述患者施用有效量的本发明化合物。
炎症反射是对炎症信号的自主神经系统响应。在感觉到炎症刺激时,自主神经系统经释放乙烯胆碱和活化巨噬细胞上的烟碱α7受体通过迷走神经起响应。这些巨噬细胞依次释放细胞因子。这种途径中的功能障碍牵连人体炎症疾病,包括类风湿性关节炎、糖尿病和脓毒症。巨噬细胞表达烟碱α7受体并且可能的情况是这种受体介导胆碱能抗炎应答。因此,本发明的化合物可以用于治疗患有炎症疾病或障碍的患者(例如哺乳动物,例如人),例如但不限于类风湿性关节炎、糖尿病或脓毒症。
预期本发明的化合物作为止痛药应用于治疗与因各种原因导致的疼痛相关的疾病和病症,包括但不限于炎性痛、手术疼痛、内脏痛、牙痛、月经前疼痛、中枢性痛、因烧伤导致的疼痛、偏头痛或丛集性头疼、神经损伤、神经炎、神经痛、中毒、缺血损伤、间质性膀胱炎、癌症疼痛、病毒、寄生虫或细菌感染、创伤后损伤(包括骨折和体育运动损伤)和与功能性肠紊乱相关的疼痛例如肠易激综合征。
本发明的化合物还用于治疗呼吸障碍,包括慢性梗阻性肺障碍(COPD)、哮喘、支气管痉挛等。
此外,因其对α7nACh受体的亲和力,所以式I化合物的标记衍生物(例如C11或F18标记的衍生物)可以用于对例如脑内的受体进行神经造影。因此,使用这种标记的试剂,可以使用例如PET成像在体内使受体成像。
本发明还提供了治疗患有如下疾病的患者的方法:例如轻度认知损害(MCI)、血管性痴呆(VaD)、与年龄相关的认知减退(AACD)、健忘症相关w/心脏直视手术、心搏聚停和/或全身麻醉、因麻醉剂早期接触导致的记忆缺失、睡眠剥夺诱发的认知损害、慢性疲劳综合征、发作性睡病、AIDS-相关痴呆、癫痫症-相关认知损害、唐氏综合征、酒精中毒相关痴呆、药物/物质诱发的记忆缺陷、拳击员痴呆(拳击员综合征)和动物痴呆(例如狗、猫、马等),该方法包括对所述患者施用有效量的本发明化合物。
本发明还涉及作为治疗活性物质的如上述所定义的化合物,治疗活性物质特别是用作治疗和/或预防与烟碱α7(α7nACh)受体相关的疾病的治疗活性物质。
本发明还涉及如上述所定义的化合物在制备用于治疗和/或预防性治疗与烟碱α7(α7nACh)受体相关的疾病的药物、特别是在制备用于认知增强的药物中的用途。
施用和药物组合物
本发明包括药物组合物,其包含至少一种本发明的化合物或其各异构体、异构体的外消旋或非外消旋混合物或药学可接受的盐或溶剂合物和至少一种药学可接受的载体并任选其他治疗和/或预防成分。
一般而言,可以以治疗有效量通过任意可接受的用于类似应用的活性剂的施用方式施用本发明的化合物。适合的剂量范围一般地在1-500mg/日,优选1-100mg/日,且最优选1-30mg/日,这取决于许多因素,例如所治疗疾病的严重性、个体年龄和相对健康状况、所用化合物的功效、施用途径和形式、施用的适应征和所涉的医务人员的偏好和经验。治疗这种疾病的本领域技术人员能够在不进行过度实验和信赖个人知识和本申请的公开内容的情况下确定用于指定疾病的本发明化合物的治疗有效量。
可以将本发明的化合物作为药物制剂进行施用,包括那些适合于口服(包括口含和舌下)、直肠、鼻部、局部、肺部、阴道或胃肠外(包括肌内、动脉内、鞘内、皮下和静脉内)施用的药物制剂或适合于通过吸入或吹入施用的形式。优选的施用方式一般是使用便利的每日剂量方案口服,可以根据病患的程度进行调整。
可以将本发明的化合物与一种或多种常用辅剂、载体或稀释剂制成药物组合物和单位剂量形式。药物组合物和单位剂型可以包含常规比例的常用成分与或不与其他活性化合物或成分,而单位剂型可以包含与指定使用范围的每日剂量相当的任意适合的有效量的活性成分。药物组合物可以作为固体使用,例如片剂或填充胶囊、半固体、粉末、缓释制剂;或作为液体使用,例如溶液、混悬液、乳剂、酏剂或用于口服使用的填充胶囊;或用于直肠或阴道施用的栓剂形式;或用于胃肠外应用的无菌可注射溶液形式。包含约一(1)毫克活性成分、或更广泛地约0.01-约一百(100)毫克/片的制剂由此是适合的有代表性的单位剂型。
可以将本发明的化合物配制成各种口服给药剂型。药物组合物和剂型可以包含本发明的化合物或其药学可接受的盐作为活性成分。药学可接受的载体可以是固体或液体。固体形式的制剂包括粉末、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散颗粒。固体载体可以是一种或多种还可以作为稀释剂、矫味剂、增溶剂、润滑剂、助悬剂、粘合剂、防腐剂、片剂崩解剂或包囊材料起作用的物质。在粉末中,载体一般是固体细粉,其为与活性成分细粉的混合物。在片剂中,一般将活性成分与具有必需粘合容量的载体按照适合比例混合并且压制成期望的形状和大小。粉末和片剂优选包含约一(1)-约七十(70)百分比的活性化合物。适合的载体包括、但不限于碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语“制剂”意指包括活性化合物与包囊材料作为载体的制剂,得到胶囊,其中活性成分与或不与载体周围包围有载体,与之混合。类似地,包括扁囊剂和锭剂。片剂、粉末、丸剂、扁囊剂和锭剂可以作为适合于口服施用的固体形式。
适合于口服施用的其他形式包括液体形式制剂,包括乳剂、糖浆剂、酏剂、水溶液、含水混悬液或指定在使用前即刻转化成液体形式制剂的固体形式制剂。可以用溶液制备乳剂,例如用丙二醇水溶液,或可以包含乳化剂,例如卵磷脂、失水山梨糖醇单油酸酯或阿拉伯树胶。可以通过将活性成分溶于水并且加入适合的着色剂、矫味剂、稳定剂和增稠剂制备水溶液。可以通过将活性成分细粉分散于含有粘性物质例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和其他众所周知的助悬剂的水中制备含水混悬液。固体形式制剂包括溶液、混悬液和乳剂并且除活性成分外还可以包含着色剂、矫味剂、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
可以为胃肠外施用配制本发明的化合物(例如通过注射,例如快速浓注或连续输注)并且可以将它们制成在安瓿、预装注射器、小体积输注液或在包含添加防腐剂的多剂量容器中的单位剂型。这些组合物可以采用在油或水媒介物中的混悬液、溶液或乳剂这样的形式,例如在聚乙二醇水溶液中的溶液。油或非水载体、稀释剂、溶剂或媒介物的实例包括丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射有机酯类(例如油酸乙酯),并且可以包含配制试剂,例如防腐剂、湿润剂、乳化剂或助悬剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,通过将无菌固体进行无菌分离或通过从在使用前用适合的媒介物例如无菌无热原水溶解的溶液冻干得到。
可以为对表皮局部施用将本发明的化合物配制成软膏剂、霜剂或洗剂或透皮贴剂。例如,可以使用添加了增稠剂和/或胶凝剂的水或油基质配制软膏剂和霜剂。可以用水或油基质配制洗剂并且一般还包含一种或多种乳化剂、稳定剂、分散剂、助悬剂、增稠剂或着色剂。适合于在口腔中局部施用的制剂包括锭剂,其包含在矫味基质通常是蔗糖和阿拉伯树胶或黄蓍胶中的活性剂;在惰性基质例如明胶和甘油或蔗糖和阿拉伯树胶中包含活性成分的软锭剂;和在适合的液体载体中包含活性成分的漱口剂。
可以为施用将本发明的化合物配制成栓剂。首先将低熔点蜡例如脂肪酸甘油酯类或可可脂的混合物熔化,并例如通过搅拌使活性成分均匀分散。然后将熔化的均匀混合物倾入便利大小的塑模,使其冷却并固化。
可以为阴道施用配制本发明的化合物。除活性成分外还包含这种载体的阴道环、棉塞、霜剂、凝胶、糊剂、泡沫或喷雾剂在本领域中被认为是适合的。
可以为鼻部施用配制主题化合物。通过常用装置,例如用滴管、吸液管或喷雾器将溶液或混悬液直接应用于鼻腔。可以将制剂制成单或多剂量形式。就后面的滴管或吸液管的情况而言,可以由患者施用适合的预定体积的溶液或混悬液进行。就喷雾剂而言,可以通过例如计量雾化喷雾泵进行。
可以为喷雾施用配制本发明的化合物,特别是对呼吸道施用且包括鼻内施用。化合物一般具有例如约五(5)微米或以下的小粒度。可以通过本领域公知的方式,例如通过微粉化得到这种粒度。将活性成分制成加压药包,其中包含适合抛射剂,例如氯氟化碳(CFC),例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷或二氧化碳或其他适合的气体。气雾剂还可以便利地包含表面活性剂,例如卵磷脂。药物剂量可以由计量阀控制。或者,可以将活性成分制成干粉形式,例如化合物在适合粉末基质例如乳糖、淀粉、淀粉衍生物例如羟丙基甲基纤维素和聚乙烯吡咯烷(PVP)中的粉末混合物。粉末载体在鼻腔中形成凝胶。可以将粉末组合物制成单位剂型,例如明胶的胶囊或药筒或可以通过吸入器施用粉末的泡罩包。
如果需要,可以用适合于活性成分缓释或控释施用的肠溶衣制备制剂。例如,可以将本发明的化合物配制成透皮或皮下递药装置。这些递送系统在化合物的缓释是必要的并且患者依从治疗方案是关键的情况下是有利的。透皮递送系统中的化合物通常与皮肤粘着固体支持物结合。还可以将所关注的化合物与透皮促进剂合并,例如氮酮(1-十二烷基氮杂环庚-2-酮)。通过手术或注射将缓释递送系统经皮下掺入皮下层。皮下植入物将化合物包封在脂溶性膜内,例如硅橡胶或生物可降解聚合物,例如聚乳酸。
药物制剂优选是单位剂型。在这种剂型中,制剂被再分成包含适量活性成分的剂量单位。单位剂型可以是包装制剂,该包装包含分散量的制剂,例如在小瓶或安瓿中的包装片、胶囊和粉末。此外,单位剂型可以是胶囊、片剂、扁囊剂或锭剂自身或可以是适当数量的任意这些包装形式。
其他适合的药用载体及其制剂描述在Remington:The Science and Practice of Pharmacy 1995,E.W.Martin编辑,Mack Publishing Company,第19版,Easton,Pennsylvania中。包含本发明的化合物的有代表性的药物制剂如下所述。
实施例
对本领域技术人员给出下列制备和实施例是为了更清楚地理解和实施本发明。不应将它们视为限定本发明的范围,而仅作为其示例和代表。可以在实施例中使用如下缩写。
缩写
CDI 1,1-羰基-二咪唑
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMAP 4-二甲氨基吡啶
EDCI 1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺
EtOAc 乙酸乙酯
EtOH 乙醇
tBuOH 叔丁醇
gc 气相色谱
HMPA 六甲基磷酰胺
HOAc 乙酸
HOBt N-羟基苯并三唑
hplc 高效液相色谱法
mCPBA 间-氯过苯甲酸
MeCN 乙腈
MeOH 甲醇
NMP N-甲基吡咯烷酮
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
LDA 二异丙胺锂
LHMDS 双(三甲代甲硅烷基)酰胺锂
TBAF 氟化四丁铵
TLC 薄层色谱法
一般而言,在四种合成操作中完成新酰胺类的制备。它们高度概括在反应方案1、2和3中。使-碘水杨酸甲酯(2,TCI)在甲醇的存在下接触Mitsunobo条件(在甲苯中的三苯膦-二异丙基偶氮二甲酸酯)。然后在钯催化下将具有侧链醚的芳基碘转化成联苯类。从钯催化条件得到母体联苯酸,并且还在标准皂化条件下生成。使用两种不同试剂在期望的胺对应物的存在下制备酰胺类:羰基二咪唑或氮杂苯并三唑-1-基)脲鎓盐(分别为实施例2或3)。
合成方案1.
实施例1.
将5-碘水杨酸甲酯(TCI,4.9g,17.5mmol)、环丙烷甲醇(Aldrich,1.15g,16mmol)和三苯膦(Aldrich,5.45g,21mmol)溶于无水甲苯(50mL),冷却至0℃。在15分钟内将偶氮二甲酸二异丙酯(Aldrich,4.1mL,21mmol溶于20mL甲苯)滴加到上述溶液中。在环境温度搅拌3天后,用己烷稀释该混合物,直接上硅胶垫。用5-20%乙酸乙酯的己烷溶液梯度洗脱所需的醚(3,4.63g,油状物),并显示与所需的物质一致的分光光度特性。
在加热的同时用氮气真空净化醚3(3.0g,9.0mmol)、4-甲氧基-2-甲基苯基硼酸(Combi-Blocks,1.65g,9.9mmol)、碳酸铯(Aldrich,7.3g,22.5mmol)、乙醇(5mL)、水(25mL)和甲苯(70mL)。加入四(三苯膦)钯(Strem,1.04g,0.9mmol),将该混合物加热至回流16小时,同时剧烈搅拌。在冷却至环境温度时,分离各相,用乙酸乙酯萃取水层。用无水硫酸钠储存合并的有机层。在除去挥发性物质时,通过硅胶色谱法分离所需的联苯(5,2.23g,油状物)(洗脱剂5-60%乙酸乙酯的己烷溶液),显示与指定结构一致的分光光度特性。
根据实施例1(在步骤1中用苄醇取代环丙烷甲醇,然后在步骤2中用2-甲氧基苯基硼酸取代4-甲氧基-2-甲基苯基硼酸),然后皂化实施例2;制备4-苄氧基-2’-甲氧基-联苯-3-甲酸(9,820mg,1.77mmol)。
将酸9(255mg,0.55mmol)溶于N-甲基-2-吡咯烷酮(5mL),用羰基二咪唑处理(90mg,0.55mmol,一次性加入)。将该溶液在环境温度剧烈搅拌10分钟。快速加入氨基甲基环丙烷(0.12mL,1.4mmol),将得到的金色溶液搅拌过夜。使该混合物分配在水(20mL)与己烷∶乙酸乙酯(1∶1,4x 25mL)之间,用新鲜水、盐水洗涤,用无水硫酸钠储存。通过硅胶色谱法分离所需的酰胺(10,86mg,油状物,MS m/z的母体离子M+1 388)(洗脱剂:10-80%乙酸乙酯的己烷溶液),分光光度特性与所示结构一致。
根据实施例1,通过用2-氟-β-苯乙胺取代氨基甲基环丙烷制备4-苄氧基-2′-甲氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]酰胺(I-2,241mg,油状物,MS m/z的母体离子M+1 456)。
实施例2
将酯6(根据实施例1制备,1.6g,4.1mmol)溶于四氢呋喃(60mL)和甲醇(5mL)。将该溶液放入冰浴,用氢氧化锂[(400mg,约10mmol)溶于水(20mL)]处理,在环境温度搅拌过夜。从该混合物中除去挥发性物质,使残余物分配在水(50mL)与乙醚(2x30mL)之间。用10%乙酸水溶液使水层猝灭,用乙酸乙酯(3x60mL)萃取,然后用无水硫酸钠储存。在过滤和除去挥发性物质后得到所需的酸(7,1.4g,mp 125-126℃,MS m/z的母体离子M-1 377),显示与指定结构一致的分光光度特性。将酸(255mg,0.67mmol)溶于N-甲基-2-吡咯烷酮(4mL),用羰基二咪唑(108mg,0.67mmol,一次性加入)处理。将该溶液在环境温度剧烈搅拌10分钟。快速加入氨基甲基环丙烷(0.12mL,1.4mmol),将得到的金色溶液搅拌过夜。使该混合物分配在水(20mL)与己烷∶乙酸乙酯(1∶1,4x25mL)之间,用新鲜水、盐水洗涤,用无水硫酸钠储存。通过硅胶色谱法分离所需的酰胺(8,185mg,mp115.6-116.5℃,MS m/z的母体离子M+1 432)(洗脱剂:10-80%乙酸乙酯的己烷溶液),分光光度特性与所示结构一致。
根据实施例1,通过用2-苯乙醇取代环丙烷甲醇,通过用环戊胺取代实施例2中的氨基甲基环丙烷制备4′-甲氧基-2′-甲基-4-苯乙氧基-联苯-3-甲酸环戊基酰胺(I-3,55mg,油状物,MS m/z的母体离子M+1 430)。
通过用2-苯乙醇取代环丙烷甲醇,通过用2-氟-β-苯乙胺取代实施例2中的氨基甲基环丙烷制备制备4′-甲氧基-2′-甲基-4-苯乙氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]酰胺(I-4,54mg,m.p.83-85℃,MS m/z的母体离子M+1 484)。
实施例3.
将酯5(2.23g,6.8mmol)溶于四氢呋喃(60mL)和甲醇(5mL)。将该溶液放入冰浴,用氢氧化锂[(860mg,约20mmol)预先溶于水(20mL)]处理,在环境温度搅拌过夜。从该混合物中除去挥发性物质,使残余物分配在水(50mL)与乙醚(2x30mL)之间。用10%乙酸水溶液使水层猝灭,用乙酸乙酯(3x60mL)萃取,然后用无水硫酸钠储存。在过滤和除去挥发性物质后得到所需的酸(11,1.66g,mp 139-140.5℃,MS m/z的母体离子M+1 313),显示与指定结构一致的分光光度特性。将酸(314mg,1.0mmol)溶于N-甲基-2-吡咯烷酮(4mL),在N2气气氛中用O-(7-氮杂苯并三唑-1-基)脲鎓六氟磷酸盐(4210mg,1.1mmol)处理。即刻用三乙胺(0.28mL,2.0mmol)处理该溶液,将1-乙炔基环己基胺(0.28mL,2.1mmol)在环境温度搅拌16小时。然后使其分配在0.2M硫酸氢钾(15mL)与己烷∶乙酸乙酯(1∶1,3x 40mL)之间。用新鲜水、然后用盐水洗涤合并的有机层,用无水硫酸钠储存。使萃取物体积减小至残余物,对其进行硅胶色谱。所需的酰胺(12,235mg,油状物,MS m/z的母体离子M+1 418)显示与指定结构一致的分光光度特性。
根据实施例3、通过用2-氟-β-苯乙胺替代1-乙炔基环己胺制备酰胺13(155mg,油,MS m/z的母体离子M+1 434)。
制剂
如下表所示配制通过不同途径递送的药物制剂。表中使用的″活性成分″或″活性化合物″意指一种或多种式I的化合物。
用于口服施用的组合物
成分 | %wt./wt. |
活性成分 | 20.0% |
乳糖 | 79.5% |
硬脂酸镁 | 0.5% |
将各成分混合,分配到胶囊中,每粒胶囊含有约100mg;一粒胶囊约为总的日剂量。
用于口服施用的组合物
成分 | %wt./wt. |
活性成分 | 20.0% |
硬脂酸镁 | 0.5% |
交联羧甲基纤维素钠 | 2.0% |
乳糖 | 76.5% |
PVP(聚乙烯吡咯烷酮) | 1.0% |
将各成分合并,用溶剂如甲醇制粒。然后将制剂干燥,采用适当的压片机制成片剂(含有约20mg的活性化合物)。
用于口服施用的组合物
成分 | 量 |
活性化合物 | 1.0g |
富马酸 | 0.5g |
氯化钠 | 2.0g |
对羟基苯甲酸甲酯 | 0.15g |
对羟基苯甲酸丙酯 | 0.05g |
砂糖 | 25.5g |
山梨醇(70%溶液) | 12.85g |
硅酸镁铝K(Vanderbilt Co.) | 1.0g |
矫味剂 | 0.035ml |
着色剂 | 0.5mg |
蒸馏水 | 适量至100ml |
将各成分混合,形成用于口服施用的混悬液。
胃肠外制剂
成分 | %wt./wt. |
活性成分 | 0.25g |
氯化钠 | 适量至等渗 |
注射用水 | 100ml |
将活性成分溶于部分注射用水中。然后在搅拌下加入足量的氯化钠使溶液等渗。用剩余的注射用水将溶液调整至足量,通过0.2微米膜滤器过滤,在无菌条件下包装。
栓剂
成分 | %wt./wt. |
活性成分 | 1.0% |
聚乙二醇1000 | 74.5% |
聚乙二醇4000 | 24.5% |
将各成分一起熔融,在蒸气浴上混合,倒入模具中,其包含2.5g总重。
局部用制剂
成分 | 克 |
活性化合物 | 0.2-2 |
司盘60 | 2 |
吐温60 | 2 |
矿物油 | 5 |
凡士林油 | 10 |
对羟基苯甲酸甲酯 | 0.15 |
对羟基苯甲酸丙酯 | 0.05 |
BHA(丁羟茴醚) | 0.01 |
水 | 适量至100 |
将除水外的所有成分合并,在搅拌的同时加热至约60℃。然后在剧烈搅拌下在约60℃加入足量的水以乳化各成分,然后加水适量至约100g。
鼻腔喷雾剂
将包含约0.025-0.5%活性化合物的几种含水混悬液制备成鼻腔喷雾剂。该制剂任选包含无活性成分,例如微晶纤维素、羧甲基纤维素钠、葡萄糖等。可以加入盐酸以调整pH。可以通过鼻腔喷雾计量泵递送鼻腔喷雾剂,这种鼻腔喷雾计量泵一般每次启动递送约50-100微升制剂。典型给药方案是每4-12小时喷2-4次。
实施例4.烟碱α7调节测定
细胞培养
细胞培养生长培养基:通过将5μM的用H2O制备的储备溶液稀释50-倍将F10培养基(Invitrogen),2.5%胎牛血清(FBS,Summit Biotechnology);15%热灭活的供体马血清(Invitrogen),250μg/ml潮霉素B(Invitrogen);和100nM methyllicaconite(MLA,Sigma)加入到各新培养物中。
在37℃、在包含4%CO2的加湿气体中,在细胞培养生长培养基(上述)中培养稳定表达人烟碱α7WT受体(RPA克隆#34.7)的GH4C1细胞(大鼠垂体-衍生的细胞系)。用细胞以0.1-0.2x106/ml、50ml培养基/T225烧瓶启动新鲜细胞储备培养物,使其生长2或3天,然后用于FLIPR测定。启动储备烧瓶后2天采集的细胞一般地得到~25x106/T225烧瓶,启动储备烧瓶后3天后一般地得到~40x106/T225烧瓶。
在测定前1天,将细胞放入补充了100nM新鲜MLA的新鲜细胞培养生长培养基。为了进行培养基变化,除去培养物的细胞混悬液并且即刻将45ml新鲜细胞培养生长培养基(包含100nM新鲜MLA)加入到储备烧瓶中,因为大量细胞保持与表面粘附。然后通过离心采集混悬液形式的细胞,重新混悬于5ml新鲜细胞培养生长培养基,并返回到原始培养烧瓶中。
缓冲溶液
用于测定的缓冲溶液是HBSS FLIPR缓冲液(Invitrogen)、2mM CaCl2(Sigma)、10mM HEPES(Invitrogen)、2.5mM丙磺舒(Sigma)和0.1%BSA(Sigma)。
FLIPR测定
α7nAChR测定是为测定测试化合物直接活化烟碱受体通道和/或调节天然激动剂乙酰胆碱(ACh,Sigma)导致的活化效果而设计的基于细胞的功能性读出值。
在测定当天,使用1x-浓度的依地酸(Gibco,Cat-No.15040)浮起贴壁细胞,以混悬液形式与细胞合并,通过离心收集(5min,162xg)。将细胞沉淀以0.5x106/ml重新混悬于FLIPR缓冲液,将细胞以0.5x105细胞/孔配入96-孔聚-d-赖氨酸包被的黑色/澄清培养板(Becton Dickinson)的样品孔。然后给样品孔补充1μM最终测定浓度(FAC)的在FLIPR缓冲液中的FLUO-3AM染料(TefLabs,制备的在包含10%普卢兰尼克酸的无水DMSO中2.5mM的储备溶液)。通过在37℃、在包含4%CO2的加湿气体中孵育培养板1小时进行细胞荷载。为了除去胞外染料,用EL405培养板洗涤器洗涤FLIPR培养板,剩余残留体积0.1ml FLIPR缓冲液/梯品孔。
根据如FLUO-3荧光增加报道的细胞溶质[Ca2+]升高测量值、使用两种添加实验设计和FLIPRTM(Molecular Devices)测定测试化合物对α7烟碱受体通道活化的效果。30秒基线记录后,联机加入测试化合物(稀释方案如下),将细胞响应再记录5分钟。第二次添加ACh(30μM,FAC)后,再将培养板读取4分钟。
测试化合物制备
在每一96孔测定培养板上平行检验测试化合物的多种浓度。为了得到100μM(1.00E-4M)的测试化合物最高FAC,将24μl 10mM测试化合物储备溶液(100%DMSO)直接加入到576μl FLIPR缓冲液中(即最高[测试化合物]=0.4mM=4-倍FAC)。从0.4mM测试化合物样品开始,然后用FLIPR缓冲液依次稀释测试化合物(使用Biomek 2000),得到如下测试化合物FAC:媒介物、1.00E-4M、3.16E-5、1.00E-5M、3.16E-6、1.00E-6M、3.16E-7、1.00E-7M。在接触最高测试化合物FAC为100μM的样品孔中DMSO的最大值FAC=1%。阴性对照通过添加媒介物、然后添加Ach制成。阳性对照通过添加1μM PNU-120596、然后添加Ach制成。
化合物活性
使用ACTIVITYBASETM数据分析软件测定α7nAChR的IC50/EC50值、内在激动剂活性和正变构调节效果。就剂量响应数据而言,曲线拟合中点(偏转)或曲线通过阈值活性值(典型地50%对照)的点可以用于测定IC50/EC50。
使用上述测定法,测定本发明化合物是α7nAChR的正变构调节剂。例如,化合物4-环丙基甲氧基-4′-甲氧基-2′-甲基-联苯-3-甲酸(1-乙炔基-环己基)-酰胺显示EC50为220nM和255%的正变构调节效果。得到如下数据:
实施例编号 | EC50[nM] |
I-1 | 743 |
I-2 | 1520 |
I-3 | 9.88 |
I-4 | 10'000 |
I-5 | 363 |
I-6 | 220 |
I-7 | 547 |
实施例5.福尔马林疼痛试验
将雄性Sprague Dawley大鼠(180-220g)放入各树脂玻璃圆筒并且使其适应测试环境30min。以5ml/kg皮下施用媒介物、药物或阳性对照(吗啡2mg/kg)。给药后15min,使用26-号针头将福尔马林(5%,在50μl中)注入右后爪的跖面。即刻将大鼠放回到观察室内。室周围放置的反射镜能够不受阻碍的观察福尔马林-注射的爪。由双盲的观察者使用自动化行为定时器记录每只动物的伤害感受行为期限。在5min间隔分别记录舔后爪和摇动/举起,总计60min。将0-5min花费在舔爪或摇动的按秒计的时间总和视为早期,而晚期被视为在15-40min花费在舔爪或摇动的秒数的总和。采集血浆样品。
实施例6.认知增强
本发明的化合物增强认知的特性可以是在动物认知模型中:新的物体认知任务模型。使用4-月-龄雄性Wistar大鼠(Charles River,The Netherlands)。每日制备化合物并且溶于生理盐水且以三种剂量测试。在T1前始终进行i.p.施用(注射体积1ml/kg)60分钟。在化合物注射后30分钟注射氢溴酸东莨菪碱。两个等同的测试组由24只大鼠构成并且由两位实验者测试。随机测定剂量的测试顺序。使用双盲方案进行实验。将全部大鼠用每一剂量条件处理一次。物体认知试验如Ennaceur,A.,Delacour,J.,1988,A new one-trial test for neurobiological studies of memory in rats.1:Behavioral data.Behav.Brain Res.31,47-59所述进行。
尽管已经参照具体实施方案描述了本发明,但是本领域技术人员应理解可以在不脱离本发明精神和范围的情况下进行各种改变和替代等效方案。此外,可以进行许多变型以使具体情况、材料、物质组成、方法、工艺步骤适应于本发明的目的精神和范围。指定所有这些变型均在待批权利要求的范围内。
Claims (34)
2.权利要求1的化合物,其中Q1是亚甲基。
3.权利要求2的化合物,其中R1是R1”。
4.权利要求3的化合物,其中R1”是环丙基。
5.权利要求4的化合物,其中Q2是亚甲基。
6.权利要求5的化合物,其中R2是苯基。
7.权利要求5的化合物,其中R2是4-甲氧基-苯基。
8.权利要求1的化合物,其中q是0。
9.权利要求8的化合物,其中R1是环戊基。
10.权利要求9的化合物,其中Q2是亚乙基。
11.权利要求10的化合物,其中R2是苯基。
12.权利要求11的化合物,其中n是2。
13.权利要求12的化合物,其中R3各自独立地是甲基或甲氧基。
14.权利要求1的化合物,其中Q1是亚乙基。
15.权利要求14的化合物,其中R1是R1’。
16.权利要求15的化合物,其中R1’是2-氟-苯基。
17.权利要求16的化合物,其中Q2是亚甲基。
18.权利要求17的化合物,其中R2是R2’。
19.权利要求18的化合物,其中R2是R2”。
20.权利要求18的化合物,其中n是1且R3是甲氧基。
21.权利要求19的化合物,其中n是2且R3各自独立地是甲基或甲氧基。
22.权利要求1的化合物,其中q是0且R1是R1”。
23.权利要求22的化合物,其中R1”是1-乙炔基-环己基。
24.权利要求23的化合物,其中Q2是亚甲基且R2是环丙基。
25.权利要求24的化合物,其中n是2且R3各自独立地是甲基或甲氧基。
26.权利要求1的化合物,其选自:
4-苄氧基-2′-甲氧基-联苯-3-甲酸环丙基甲基-酰胺;
4-苄氧基-2′-甲氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺;
4′-甲氧基-2′-甲基-4-苯乙基氧基-联苯-3-甲酸环戊基酰胺;
4′-甲氧基-2′-甲基-4-苯乙基氧基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺;
4′-甲氧基-4-(4-甲氧基-苄氧基)-2′-甲基-联苯-3-甲酸环丙基甲基-酰胺;
4-环丙基甲氧基-4′-甲氧基-2′-甲基-联苯-3-甲酸(1-乙炔基-环己基)-酰胺;和
4-环丙基甲氧基-4′-甲氧基-2′-甲基-联苯-3-甲酸[2-(2-氟-苯基)-乙基]-酰胺。
27.在需要其的个体中促进认知的方法,所述方法包括对所述个体施用有效量的权利要求1的化合物。
28.权利要求27的方法,其中所述个体具有阿尔茨海默病。
29.药物组合物,其包含权利要求1的化合物和至少一种药学可接受的载体、稀释剂或赋形剂。
30.权利要求1-26的任意项的用作治疗活性物质的化合物。
31.权利要求1-26的任意项的化合物,其用作治疗和/或预防与烟碱α7(α7nACh)受体相关的疾病的治疗活性物质。
32.根据权利要求1-26的任意项的化合物在制备治疗和/或预防性治疗与烟碱α7(α7nACh)受体相关的疾病的药物中的用途。
33.根据权利要求1-26的任意项的化合物在制备用于认知促进的药物中的用途。
34.如上所定义的本发明。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05239005A (ja) * | 1992-02-28 | 1993-09-17 | Kitsuen Kagaku Kenkyu Zaidan | N−(2−アミノエチル)ベンズアミド類およびその新規中間体 |
CN101124224A (zh) * | 2004-12-22 | 2008-02-13 | 记忆药物公司 | 烟碱性α-7受体配体及其制备和用途 |
Non-Patent Citations (2)
Title |
---|
DANIELA GUNDISCH: "Nicotinic acetylcholine receptor ligands as potential therapeutics", 《EXPERT OPIN. THER. PATENTS》 * |
KENJI HASHIMOTO ET AL.: "Alpha-7 Nicotinic Receptor Agonists as Potential Therapeutic Drugs for Schizophrenia", 《CURR. MED. CHEM.-CENTRAL NERVOUS SYSTEM AGENTS》 * |
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KR101333401B1 (ko) | 2013-11-28 |
ES2386760T3 (es) | 2012-08-29 |
US20100041763A1 (en) | 2010-02-18 |
WO2010018095A1 (en) | 2010-02-18 |
AU2009281243A1 (en) | 2010-02-18 |
CA2728451A1 (en) | 2010-02-18 |
IL209732A0 (en) | 2011-02-28 |
EP2323971A1 (en) | 2011-05-25 |
BRPI0917803A2 (pt) | 2019-09-03 |
KR20110028652A (ko) | 2011-03-21 |
US8198332B2 (en) | 2012-06-12 |
MX2011000841A (es) | 2011-02-25 |
EP2323971B1 (en) | 2012-05-09 |
CN102119142B (zh) | 2013-12-04 |
JP2011530560A (ja) | 2011-12-22 |
ATE556998T1 (de) | 2012-05-15 |
JP5341190B2 (ja) | 2013-11-13 |
CA2728451C (en) | 2013-09-24 |
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