CN103079566A - 作为组胺h3受体配体的杂环基化合物 - Google Patents
作为组胺h3受体配体的杂环基化合物 Download PDFInfo
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- CN103079566A CN103079566A CN2010800689118A CN201080068911A CN103079566A CN 103079566 A CN103079566 A CN 103079566A CN 2010800689118 A CN2010800689118 A CN 2010800689118A CN 201080068911 A CN201080068911 A CN 201080068911A CN 103079566 A CN103079566 A CN 103079566A
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- China
- Prior art keywords
- cyclobutyl
- oxygen base
- thiazole
- piperidin
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 229940127285 new chemical entity Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 208000035824 paresthesia Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 230000004224 protection Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- 238000006462 rearrangement reaction Methods 0.000 description 1
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- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及式(I)杂环基化合物和其可药用盐以及含有它们的组合物。本发明还涉及用于制备上述新化合物和其可药用盐的方法。所述式(I)化合物可用于治疗与组胺H3受体有关的多种疾病,例如认知障碍、睡眠障碍、肥胖和疼痛。
Description
技术领域
本发明涉及式(I)的杂环基化合物和它们的可药用盐、其制备方法以及含有它们的组合物,其用于治疗与组胺H3受体有关的多种疾病。
背景技术
组胺H3受体是G蛋白偶联受体(G-protein coupled receptor,GPCR)并且是组胺家族四种受体中的一种。组胺H3受体在1983年被鉴定出,其克隆和表征在1999年进行。组胺H3受体在中枢神经系统中以较大的程度表达而在周围神经系统以较小的程度表达。
文献证据表明,可将组胺H3受体用于治疗认知障碍(British Journalof Pharmacology,2008,154(6),1166-1181)、睡眠障碍(Trends inPharmacology Science,2004,25(12),618-625)、肥胖症(MolecularInterventions,2006,6(2),77-88)和疼痛(Pain,2008,138(1),61-69)。
专利/专利申请US4695575、EP0151826、WO2010026113、WO2004022060和WO2003004480公开了作为组胺H3受体之配体的一系列化合物。虽然已经公开了一些组胺H3受体配体,但是在本研究领域的市场上至今没有推出化合物,因而仍存在发现新药的需要和眼界,该药具有新的化学结构用于治疗受组胺H3受体影响的疾病。
发明内容
本发明涉及新的式(I)的组胺H3受体配体或其可药用盐;
其中,
R1是-C(O)-R4、-S(O)2-R4、取代的或未取代的环烷基、芳基或杂芳基;其中取代基可以是一个或更多个并且独立选自氢、羟基、卤素、烷基、烷氧基、卤烷基或卤烷氧基;
R4是取代的或未取代的烷基、环烷基、环烷基烷基、芳基、杂芳基、杂环基或杂环基烷基;其中取代基可以是一个或更多个并且独立选自氢、羟基、卤素、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、烷基或环烷基;
在每种情况下,R3独立选自氢、卤素、烷基或烷氧基;
R2是氢、取代的或未取代的烷基或环烷基;其中取代基可以是一个或更多个并且独立选自氢、羟基、卤素、烷基、烷氧基、卤烷基或卤烷氧基;
X是S、N或O;
Y是C或N;
“p”是0至2的整数;
“q”是0至2的整数;
“r”是0至1的整数。
本发明涉及治疗有效量的式(I)化合物在制备用于治疗与组胺H3受体有关的多种疾病的药物中的用途。
特别地,本发明的化合物可用于治疗多种疾病,例如认知障碍、睡眠障碍、肥胖症和疼痛。
在另一个方面中,本发明涉及含有治疗有效量的至少一种式(I)化合物及其可药用盐与可药用赋形剂混合的药物组合物。
在又一个方面中,本发明涉及用于使用式(I)化合物的方法。
在再一个方面中,本发明还涉及用于制备式(I)化合物及其可药用盐的方法。
本发明的代表性化合物包括以下详述的那些及其可药用盐。本发明不应解释为限于此:
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮酒石酸盐;
N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-6-基]-丙酰胺;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环丙基-甲酮酒石酸盐;
环丁基-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(2-氟-苯基)-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-3-甲基-丁-1-酮酒石酸盐;
环丁基-[2-(1-异丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮;
环丙基-[2-(1-异丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
环丙基-[2-(1-环丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
环丁基-[2-(1-环丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-吗啉-4-基-乙酮酒石酸盐;
[4-(5-环丁基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-1-基]-环丙基-甲酮酒石酸盐;
[3-(5-环丁基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-1-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-3-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吡啶-4-基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(4-甲氧基-苯基)-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-哌啶-1-基-乙酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-环丙基-乙酮;
2-(1-环丁基-哌啶-4-基氧基)-5-(2-氟-苯磺酰基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-甲磺酰基-6,7-二氢-4H-噻唑并[5,4-c]吡啶;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-甲基-丙-1-酮酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-(2-三氟甲基-吡啶-5-基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶;
环丙基-[2-(1-异丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(2-三氟甲基-吡啶-5-基)-甲酮;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吡啶-3-基-甲酮酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-吡啶-3-基-6,7-二氢-4H-噻唑并[5,4-c]吡啶酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(四氢-吡喃-4-基)-甲酮;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吗啉-4-基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-哌啶-1-基-甲酮盐酸盐;
6-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-烟酰胺;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环戊基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-环丙基-甲酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-丙-1-酮;
环丁基-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-甲酮;
N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-7-基]-丙酰胺;
N-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-4H-环戊并噻唑-5-基]-丙酰胺;
1-[2-(1-环丁基-哌啶-4-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-吡咯并[3,2-d]噻唑-4-基]-丙-1-酮;
N-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-4H-环戊并噻唑-6-基]-丙酰胺;
1-[2-(1-环丁基-哌啶-4-基氧基)-4,6-二氢-吡咯并[4,3-d]唑-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-4-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-7-氟-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-7-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-6-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-3-甲基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-3-氟-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-环丁基-4-(5-丙酰基-4,5,6,7-四氢-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-3-甲腈;
1-[2-(1-环丁基-氮杂环庚-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-氮杂环庚-4-基氧基)-4,5,7,8-四氢-噻唑并[5,4-d]氮杂-6-基]-丙-1-酮;
1-[2-(1-环丁基-吡咯烷-3-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-[2-(1-环丁基-氮杂环庚-4-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-{2-[1-(2-羟基-乙基)-哌啶-4-基氧基]-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基}-丙-1-酮;
1-[2-(1-乙氧甲基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-{2-[1-(2,2,2-三氟-乙基)-哌啶-4-基氧基]-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基}-丙-1-酮;
1-[2-(1-环丁基-氮杂环丁-3-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;及其可药用盐。
发明详述
除非另有所指,否则在本说明书和权利要求书中使用的以下术语具有以下给出的含义:
术语“卤素”意指氟、氯、溴或碘。
术语“烷基”意指直链或支链碳氢基团,其仅由碳和氢原子组成,不包括不饱和,具有1至8个碳原子并且通过单键连接至其余分子。示例性“烷基”包括甲基、乙基、正丙基、异丙基等。
术语“烷氧基”意指经由氧连接与分子其余部分相连接的烷基。示例性“烷氧基”包括甲氧基、乙氧基、丙氧基、异丙基氧基等。
术语“卤烷基”意指含有1至3个碳原子的直链或支链烷基基团。示例性“卤烷基”包括氟甲基、二氟甲基、三氟甲基、三氟乙基、氟乙基、二氟乙基等。
术语“卤烷氧基”意指含有1至3个碳原子的直链或支链烷氧基基团。示例性“卤烷氧基”包括氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、氟乙氧基、二氟乙氧基等。
术语“环烷基”意指3至8个碳原子的非芳香单环。示例性“环烷基”包括环丙基、环丁基、环戊基等。
术语“环烷基烷基”意指直接键合至烷基的环烷基环基团。
术语“芳基”意指来源于简单芳香环的任何官能团或取代基,示例性“芳基”包括苯基、萘基等。
术语“杂芳基”意指包含环结构的有机化合物,该环结构含有除碳之外的原子(例如硫、氧或氮)作为环的部分,这些额外的原子可在环中重复多于一次。这些环可以是简单芳香环。示例性“杂芳基”包括吡啶、嘧啶、苯并呋喃基、苯并噻吩、呋喃基、二氧戊环基(dioxalanyl)、吡咯基、唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、吲哚基等。
术语“杂环基”意指2至7个碳原子的非芳香单环,其环结构包含1至3个杂原子,这些额外的原子可在环中重复多于一次。示例性“杂环基”包括吡咯烷基、哌啶基、哌嗪基、吗啉基等。
术语“杂环基烷基”意指直接键合至烷基的杂环基环基团。
术语“治疗”包括所有的含义,例如预防性的、保护性的和缓解性的。
短语“可药用盐”指所述物质或组合物必须在化学和/或毒物学上与其他成分(包括制剂)、所治疗的哺乳动物相容。
短语“治疗有效量”定义为本发明的化合物用于以下时的量:(i)治疗或预防特定疾病、病症或障碍,(ii)使特定疾病、病症或障碍的一种或更多种症状减弱、减轻或消除,(iii)预防或延缓本文中描述的特定疾病、病症或障碍的一种或更多种症状发作。
在不进一步纯化的情况下使用商业试剂。室温指25-40℃。除非另有所指,否则使用ESI条件进行所有的质谱。采用Bruker仪器在400MHz记录1H-NMR谱。将氘化氯仿(99.8%D)、甲醇或二甲亚砜用作溶剂。将TMS用作内参标准。化学位移值表示为百万分之一(δ)值。以下缩写用于NMR信号的多重性:s=单峰,bs=宽单峰,d=双峰,t=三重峰,q=四重峰,qui=五重峰,h=七重峰,dd=双二重峰,dt=双三重峰,tt=三重三重峰,m=多重峰。色谱法指使用100-200目硅胶进行的并且在氮气压力(快速色谱)条件下进行的柱色谱法。
由使用Chem Draw Ultra 7.0产生化合物命名。
药物组合物
为了在治疗中使用式(I)化合物,一般将它们根据标准制药实践配制成药物组合物。
可使用一种或更多种可药用赋形剂以常规方式配制本发明的药物组合物。可药用赋形剂是载体或稀释剂。因此,可配制本发明的活性化合物用于口服、鼻内或肠胃外(例如,静脉内、肌肉内或皮下)。此类药物组合物和制备其的方法为本领域所公知(参见,例如,Remington:TheScience and Practice of Pharmacy(D.B.Troy编),第21版,Lippincott,Williams&Wilkins,2006年)。
活性化合物的剂量可有赖于一些因素(例如施用途径、患者的年龄和重量、待治疗疾病的性质和严重性等类似因素)而改变。因此,本文中对药理有效量的通式(I)化合物的任何参考指的是上述因素。
制备方法
通过下述方案I制备式(I)化合物。
方案I
在上述方案I中,p是1;q是1;r是1;Y是N;X是S;R1是-C(O)-R4、-S(O)2-R4、取代的或未取代的环烷基、芳基或杂芳基,并且所有其他符号如上所述。
将式(1)化合物与式(2)化合物相偶联以形成式(3)化合物。使式(3)化合物脱保护以形成式(4)化合物。将式(4)化合物与式(5)化合物相偶联以形成式(I)化合物。
在上述制备的第一步骤中,将式(1)化合物与式(2)化合物相偶联以形成式(3)化合物。优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、三乙胺、二甲基甲酰胺等或其混合物)中进行该反应并且优选通过使用四氢呋喃。所述反应可在碱(例如氢化钠、碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠或其混合物)的存在下发生并且优选通过使用氢化钠。反应在室温下进行。反应可持续4至8小时,优选5至7小时。
在上述制备的第二步骤中,使式(3)化合物脱保护以形成式(4)化合物。优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、乙腈、1,4-二乙双酮、二甲基甲酰胺等或其混合物)中进行该反应并且优选通过使用二氯甲烷。所述反应可在酸(例如三氟乙酸、硫酸、醋酸、高氯酸、盐酸等或其混合物)的存在下发生并且优选通过使用三氟乙酸。反应在60℃至85℃的温度下进行并且优选65℃至75℃的温度。反应可持续2至6小时,优选3至5小时。
在上述制备的第三步骤中,将式(4)化合物与式(5)化合物相偶联以形成式(I)化合物。优选在溶剂(例如二氯甲烷、四氢呋喃、甲苯、乙酸乙酯、二甲基甲酰胺等或其混合物)中进行该反应并且优选通过使用二氯甲烷。所述反应可在碱(例如三乙胺、碳酸钾、二异丙基乙胺和吡啶)的存在下发生并且优选通过使用三乙胺。反应在室温下进行。反应可持续15分钟至45分钟,优选25分钟至35分钟。
式(1)、式(2)和式(5)化合物可商购或者可使用已知过程通过常规方法或通过修饰进行制备。
还可通过使用下述方案II制备式(I)化合物。
方案II
在上述方案II中,p是1;q是2;r是1;Y是N;X是S;R1是-C(O)-R4、-S(O)2-R4、取代的或未取代的环烷基、芳基或杂芳基,并且所有其他符号如上述。
将式(6)化合物与式(5)化合物相偶联以形成式(7)化合物。使式(7)化合物溴化以形成式(8)化合物。使式(8)化合物环化以形成式(9)化合物。使式(9)化合物重氮化以形成式(10)化合物。将式(10)化合物与式(2)化合物相偶联以形成式(I)化合物。
在上述制备的第一步骤中,将式(6)化合物与式(5)化合物相偶联以形成式(7)化合物。优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、二甲基甲酰胺等或其混合物)中进行该反应并且优选通过使用二氯甲烷。所述反应可在碱(例如三乙胺、碳酸钾、二异丙基乙胺和吡啶)的存在下发生并且优选通过使用三乙胺。反应在室温下进行。反应可持续15分钟至45分钟,优选25分钟至35分钟。
在上述制备的第二步骤中,使式(7)化合物溴化以形成式(8)化合物。所述反应可在酸(例如硫酸、醋酸、高氯酸、盐酸等或其混合物)的存在下发生并且优选通过使用醋酸。所述反应可在溴化剂(例如溴、溴化铜(II)、氢溴酸、N-溴代丁二酰亚胺、过溴化氢溴酸吡啶、四溴甲烷等或其混合物)的存在下发生并且优选通过使用溴。反应在室温下进行。反应可持续16小时至20小时,优选17小时至19小时。
在上述制备的第三步骤中,使式(8)化合物环化以形成式(9)化合物。该反应优选在溶剂(例如异丙醇、四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、三乙胺、二甲基甲酰胺等或其混合物)中进行并且优选通过使用异丙醇。所述反应可在尿素或硫脲的存在下发生。反应在60℃至85℃的温度下进行并且优选65℃至75℃的温度。反应可持续15分钟至45分钟,优选25分钟至35分钟。
在上述制备的第四步骤中,使式(9)化合物重氮化以形成式(10)化合物。该反应优选在溶剂(例如乙腈、四氢呋喃、异丙醇、甲苯、乙酸乙酯、二氯甲烷、三乙胺、二甲基甲酰胺等或其混合物)中进行并且优选通过使用乙腈。所述反应可在溴化剂(例如溴化铜(II)、氢溴酸、N-溴代丁二酰亚胺、过溴化氢溴酸吡啶、四溴甲烷等或其混合物)的存在下发生并且优选通过使用溴化铜(II)。所述反应可在亚硝酸烷基酯的存在下发生并且优选通过使用亚硝酸叔丁酯。反应在室温下进行。反应可持续15分钟至45分钟,优选25分钟至35分钟。
在上述制备的第五步骤中,将式(10)化合物与式(2)化合物相偶联以形成式(I)化合物。该反应优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、三乙胺、二甲基甲酰胺等或其混合物)中进行并且优选通过使用四氢呋喃。所述反应可在碱(例如氢化钠、碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠或其混合物)的存在下发生并且优选通过使用氢化钠。所述反应可在尿素或硫脲的存在下发生。反应在60℃至85℃的温度下进行并且优选65℃至75℃的温度。反应可持续12至18小时,优选14至16小时。
式(2)、式(5)和式(6)化合物可商购或者可使用已知过程通过常规方法或通过修饰进行制备。
还可通过使用下述方案III制备式(I)化合物
方案III
将式(11)化合物与式(5)化合物相偶联以形成式(12)化合物。将式(12)化合物与式(2)化合物相偶联以形成式(I)化合物。
在上述制备的第一步骤中,将式(11)化合物与式(5)化合物相偶联以形成式(12)化合物。该反应优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、二甲基甲酰胺等或其混合物)中进行并且优选通过使用二氯甲烷。所述反应可在碱(例如三乙胺、碳酸钾、二异丙基乙胺和吡啶)的存在下发生并且优选通过使用三乙胺。反应在室温下进行。反应可持续15分钟至45分钟,优选25分钟至35分钟。
在上述制备的第二步骤中,将式(12)化合物与式(2)化合物相偶联以形成式(I)化合物。该反应优选在溶剂(例如四氢呋喃、甲苯、乙酸乙酯、二氯甲烷、三乙胺、二甲基甲酰胺等或其混合物)中进行并且优选通过使用二甲基甲酰胺。所述反应可在碱(例如氢化钠、碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠或其混合物)的存在下发生并且优选通过使用氢化钠。反应在室温下进行。反应可持续45至51小时,优选47至49小时。
式(2)、式(5)和式(11)化合物可商购或者可使用已知过程通过常规方法或通过修饰进行制备。
如果有必要,可进行以下步骤中的任何一个或多于一个,
i)将式(I)化合物转化成另一式(I)化合物或者
ii)形成可药用盐。
可使用公知反应通过进一步化学修饰进行过程(i),这些反应是例如氧化、还原、保护、脱保护、重排反应、卤化、羟基化、烷基化、烷硫基化、脱甲基化、O-烷基化、O-酰化、N-烷基化、N-烯基化、N-酰化、N-氰化、N-磺酰化、使用过渡金属的偶联反应等。
在过程(ii)中,可通过与适当的酸或酸衍生物反应常规地制备可药用盐。
合适的可药用盐对本领域技术人员而言将是明显的并且包括在J.Pharm.Sci.,1977,66,1-19中描述的那些,例如与无机酸(例如盐酸、氢溴酸、硫酸、硝酸或磷酸)和有机酸(例如琥珀酸、马来酸、醋酸、富马酸、柠檬酸、苹果酸、酒石酸、苯甲酸、对甲基苯甲酸、对甲苯磺酸、甲基磺酸或萘磺酸)形成的酸加成盐。
实施例
使用适当的材料和适当的条件,根据以下实验程序制备本发明的新化合物。
制备1:2-溴-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯的制备
步骤(i):3-溴-4-氧代-哌啶-1-羧酸叔丁酯的制备
将4-氧代-哌啶-1-羧酸叔丁酯(10克,50mmol)和氯化铝(0.67克,5mmol)在四氢呋喃(30mL)和乙醚(30mL)中的溶液冷却至0℃,之后用溴(2.6mL,50mmol)处理30分钟。使反应物料在0-5℃搅拌24小时。反应完成后,过滤获得的固体,接着在真空下浓缩母液。用乙醚将获得的粗物质磨碎,过滤固体并在真空下干燥,从而获得标题化合物(10克)。
1H-NMR(δppm):1.51(9H,s),2.42-2.48(1H,m),3.04(1H,m),3.59-3.74(2H,m),3.97(2H,m),4.33(1H,m);
Mass(m/z):278(M+H)+,280(M+3H)+.
步骤(ii):2-氨基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯的制备
将3-溴-4-氧代-哌啶-1羧酸叔丁酯(10克,35mmol,在上述步骤中获得的)和硫脲(3.28克,42mmol)在异丙醇(100mL)中的悬液回流1小时。反应完成后,浓缩反应物料并用乙醚(50mL)将所得粗物质磨碎,过滤固体并在真空下干燥,从而获得标题化合物(10克)。
1H-NMR(δppm):1.39(9H,s),2.52(2H,m),3.56-3.59(2H,t),4.30(2H,s),7.10(2H,bs);Mass(m/z):256(M+H)+.
步骤(iii):2-溴-6,7-氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯的制备
将2-氨基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯(10克,40mmol,在上述步骤中获得的)和溴化铜(II)(9.6克,43mmol)在乙腈(50mL)中的溶液冷却至0℃。在0℃下经30分钟逐滴添加亚硝酸叔丁酯(5.1mL,43mmol)。使反应物料搅拌30分钟,然后用6N盐酸溶液淬灭反应物料。用乙酸乙酯(3×100mL)萃取产物,用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(乙酸乙酯/正己烷,0.5/9.5)纯化获得的残余物,从而获得标题化合物(3.0克)。
1H-NMR(δppm):1.49(9H,s),2.85(2H,m),3.72(2H,m),4.56(2H,s);
Mass(m/z):319.3(M+H)+,321.3(M+H)+.
制备2:(2-溴-4,5,6,7-四氢-苯并噻唑-6-基)-氨基甲酸叔丁酯的制备
步骤(i):(3-溴-4-氧代-环己基)-氨基甲酸叔丁酯的制备
将(4-氧代-环己基)-氨基甲酸叔丁酯(10克,46mmol)和氯化铝(0.25克,2mmol)在四氢呋喃(30mL)和乙醚(30mL)中的溶液冷却至0℃,之后用溴(2.4mL,46mmol)处理30分钟。使反应物料在0-5℃搅拌24小时。反应完成后,过滤获得的固体,接着在真空下浓缩下面的滤液。用乙醚将获得的粗物质磨碎,过滤所得固体并在真空下干燥,从而获得标题化合物(9.0克)。
Mass(m/z):292.3(M+H)+,294.3(M+3H)+.
步骤(ii):2-氨基-4,5,6,7-四氢-苯并噻唑-6-基)-氨基甲酸叔丁酯的制备
将3-溴-4-氧代-哌啶-1-羧酸叔丁酯(9克,31mmol,在上述步骤中获得的)和硫脲(2.4克,31mmol)在异丙醇(100mL)中的悬液回流1小时。反应完成后,浓缩反应物料并用乙醚(50mL)将所得粗物质磨碎,过滤固体并在真空下干燥,从而获得标题化合物(9克)。
1H-NMR(δppm):1.38(9H,s),1.61-1.71(1H,m),1.84-1.86(1H,m),2.29-2.35(1H,m),2.53-2.57(2H,m),2.71-2.76(1H,m),3.71-3.76(1H,m),9.11(2H,s),12.86-12.93(1H,bs);
Mass(m/z):270.3(M+H)+.
步骤(iii):(2-溴-4,5,6,7-四氢-苯并噻唑-6-基)-氨基甲酸叔丁酯的制备
将2-氨基-4,5,6,7-四氢-苯并噻唑-6-基)-氨基甲酸叔丁酯(9克,33mmol,在上述步骤中获得的)和溴化酮(II)(8.3克,37mmol)在乙腈(70mL)中的溶液冷却至0℃。在0℃下将所得物料用亚硝酸叔丁酯(4.5mL,37mmol)处理30分钟。使反应物料搅拌30分钟,然后用6N盐酸溶液淬灭。用乙酸乙酯(3×100mL)萃取产物,用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(乙酸乙酯/正己烷,0.5/9.5)纯化残余物,从而获得标题化合物(2.3克)。
1H-NMR(δppm):1.45(9H,s),1.89-1.93(1H,m),2.03-2.07(1H,m),2.59-2.63(1H,m),2.85-2.91(1H,m),3.09-3.13(1H,m),4.05-4.09(1H,m),4.63-4.66(1H,m),12.36-12.42(1H,bs);
Mass(m/z):333.1(M+H)+,335.3(M+3H)+.
实施例1:1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮酒石酸盐的制备
步骤(i):2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯的制备
用冷却的并搅拌的氢化钠(0.9克,18mmol)在四氢呋喃(20mL)中的悬液缓慢处理四氢呋喃(20mL)中的1-环丁基-哌啶-4-醇(1.6克,10mmol)30分钟;使反应混合物搅拌1小时。经15分钟逐滴添加2-溴-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯(3克,9mmol,在制备1中获得的)在四氢呋喃(30mL)中的溶液并使反应物回流6小时。用冰冷的水淬灭反应物料,然后用乙酸乙酯(3×50mL)萃取产物。用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(乙酸乙酯/正己烷,1/1)纯化残余物,从而获得标题化合物(2.0克)。
1H-NMR(δppm):1.48(9H,s),1.65-1.72(2H,m),1.85-1.92(4H,m),2.01-2.07(4H,m),2.18-2.19(2H,m),2.57(2H,m),2.62-2.66(2H,m),2.71-2.75(1H,m),3.70(2H,m),4.43(2H,m),4.93(1H,m);
Mass(m/z):394.2(M+H)+.
步骤(ii):2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-噻唑并[5,4-c]吡啶的制备
在0℃下用三氟乙酸(5.0mL,50mmol)处理2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-羧酸叔丁酯(2.0克,5mmol,在上述步骤中获得的)在二氯甲烷(30mL)中的溶液。使反应物料搅拌4小时。反应完成后,在冰冷的水中淬灭反应物料并通过使用40%氢氧化钠水溶液将pH调节至10。用二氯甲烷(3×50mL)萃取产物,用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物,从而获得标题化合物(1.3克)。
1H-NMR(δppm):1.68-1.74(2H,m),1.85-1.93(4H,m),2.06(4H,m),2.19(2H,m),2.60-2.61(4H,m),2.73-2.80(1H,m),2.90-3.10(1H,m),3.13-3.16(2H,m),3.85(2H,s),4.90-4.93(1H,m);
Mass(m/z):294.2(M+H)+.
步骤(iii):1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮的制备
将2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-噻唑并[5,4-c]吡啶(1.3克,4mmol,在上述步骤中获得的)和三乙胺(1.9mL,13mmol)在二氯甲烷(30mL)中的溶液冷却至0℃。经15分钟逐滴添加二氯甲烷(5mL)中的丙酰氯(0.4mL,5mmol)并搅拌反应物30分钟。将反应物料倾倒至冰水上,然后用乙酸乙酯(3×50mL)萃取产物。用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(甲醇/氯仿,2/98)纯化残余物,从而获得标题化合物(1.0克)。
1H-NMR(δppm):1.17-1.21(3H,m),1.65-1.72(5H,m),1.87-1.91(4H,m),2.01-2.07(4H,m),2.22(1H,m),2.38-2.45(2H,m),2.45(1H,m),2.68-2.76(3H,m),3.72-3.74(1H,m),4.47-4.62(2H,m),4.92-4.94(1H,m).
Mass(m/z):350.4(M+H)+.
步骤(iv):1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮酒石酸盐的制备
在0℃下用L(+)-酒石酸(0.34克,2.3mmol)处理1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮(0.8克,2.3mmol,在上述步骤中获得的)在甲醇(10mL)中的溶液。使反应物料搅拌约1小时,然后在真空下蒸发溶剂至干。用乙醚洗涤固体并在真空下干燥,从而获得标题化合物(1.1克)。
1H-NMR(δppm):1.12-1.20(3H,m),1.82-1.87(2H,m),2.16-2.32(7H,m),2.45-2.55(2H,m),2.63-2.66(3H,m),2.72(1H,m),3.20(2H,m),3.47-3.50(1H,m),3.66-3.70(1H,m),3.81-3.88(2H,m),4.45(2H,s),4.60(2H,s),5.18(5H,m);
Mass(m/z):350.4(M+H)+.
步骤(i):1-环丙甲酰基-氮杂环庚-4-酮的制备
将氮杂环庚-4-酮(1.75克,15.3mmol)和三乙胺(6.45mL,3.1mmol)在二氯甲烷(15mL)中的溶液冷却至0℃。添加二氯甲烷(2mL)中的环丙酰氯(0.17mL,1.8mmol)并搅拌反应物30分钟。将反应物料倾倒至冰冷的水上,然后用二氯甲烷(3×15mL)萃取产物。用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物,从而获得标题化合物(2.7克)。
1H-NMR(δppm):0.66-0.69(4H,m),1.56-1.57(1H,m),1.71-1.75(1H,m),1.87-1.89(1H,m),2.45-2.49(1H,m),2.59-2.62(1H,m),3.57-3.91(4H,m);
Mass(m/z):182(M+H)+.
步骤(ii):5-溴-1-环丙甲酰基-氮杂环庚-4-酮的制备
将1-环丙甲酰基-氮杂环庚-4-酮(2.7克,14.9mmol,在上述步骤中获得的)在醋酸(30mL)中的溶液冷却至10℃,然后用溴(0.71mL,14.9mmol)处理15分钟。使所得浆液在氮气氛下搅拌18小时。反应完成后,将物料浓缩至干,从而获得标题化合物(3.87克)。
Mass(m/z):260,262(M+H)+.
将5-溴-1-环丙甲酰基-氮杂环庚-4-酮(3.87克,14.8mmol,在上述步骤中获得的)和硫脲(1.13克,14.8mmol)在异丙醇(40mL)中的悬液回流6小时。反应完成后,浓缩反应物料,然后通过快速色谱法(甲醇/氯仿,3/97)纯化获得的残余物,从而获得标题化合物(0.4克)。
1H-NMR(δppm):0.66-0.73(4H,m),1.95(1H,m),2.66-2.69(2H,m),2.75-2.76(2H,m),3.55-3.62(2H,m),3.79-3.86(2H,m),6.61(2H,bs);
Mass(m/z):238(M+H)+.
步骤(vi):(2-溴-4,5,7,8-四氢-噻唑并[5,4-d]氮杂-6-基)-环丙基-甲酮的制备
将(2-氨基-4,5,7,8-四氢-噻唑并[5,4-d]氮杂-6-基)-环丙基-甲酮(0.4克,1.68mmol,在上述步骤中获得的)和溴化铜(II)(0.37克,1.68mmol)在乙腈(40mL)中的溶液冷却至0℃。在0℃下经10分钟逐滴添加亚硝酸叔丁酯(0.2mL,1.68mmol)。使反应物料搅拌30分钟,然后用3N盐酸溶液淬灭反应物料。用乙酸乙酯(3×15mL)萃取产物,用水然后用盐水洗涤合并的有机层,接着经硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(乙酸乙酯/正己烷,7/3)纯化由此获得的残余物,从而获得标题化合物(0.053克)。
1H-NMR(δppm):0.71-0.75(4H,m),1.97(1H,m),2.86-2.92(2H,m),2.99-3.08(2H,m),3.61-3.86(2H,m),3.86-3.90(2H,m);
Mass(m/z):301(M+H)+.
用冷却的并搅拌的氢化钠(0.021克,0.51mmol)在四氢呋喃(8mL)中的悬液缓慢处理四氢呋喃(3mL)中的1-环丁基-哌啶-4-醇(0.04克,0.26mmol)5分钟,然后使反应混合物在室温下搅拌2小时。经5分钟逐滴添加(2-溴-4,5,7,8-四氢-噻唑并[5,4-d]氮杂-6-基)-环丙基-甲酮(0.053克,0.17mmol,在上述步骤中获得的)在四氢呋喃(3mL)中的溶液并回流15小时。在冰冷的水上淬灭反应物料,然后用乙酸乙酯(3×10mL)萃取产物。用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物。通过快速色谱法(甲醇/氯仿,3/97)纯化获得的残余物,从而获得标题化合物(0.05克)。
1H-NMR(δppm):0.84-0.86(4H,m),0.91(1H,m),1.73-1.76(2H,m),1.86-1.93(4H,m),2.07-2.08(5H,m),2.63(2H,m),2.80-2.84(2H,m),2.93-2.99(3H,m),3.74-3.79(2H,m),3.94-4.00(2H,m).
Mass(m/z):376.4(M+H)+.
在0℃下用L(+)-酒石酸(0.031克,0.208mmol)处理[2-(4-环丁基-环己氧基)-4,5,7,8-四氢-噻唑并[5,4-d]氮杂-6-基]-环丙基-甲酮(0.078克,0.208mmol,在上述步骤中获得的)在甲醇(5mL)中的溶液。使反应物料搅拌约1小时,然后在真空下蒸发溶剂至干。用乙醚洗涤固体并在真空下干燥,从而获得标题化合物(0.1克)。
1H-NMR(δppm):0.84-0.99(4H,m),1.83-1.90(2H,m),2.00-2.02(1H,m),2.18-2.23(5H,m),2.32-2.41(2H,m),2.82-2.87(2H,m),2.95-2.99(2H,m),3.13-3.20(5H,m),3.62-3.66(1H,m),3.74-3.79(2H,m),3.95-3.99(2H,m),4.43(2H,s),5.13(1H,s).
Mass(m/z):376.4(M+H)+.
实施例3:N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-6-基]-丙酰胺的制备
步骤(i):2-溴-4,5,6,7-四氢-苯并噻唑-6-基胺的制备
在0℃下用三氟乙酸(1.1mL,15mmol)处理(2-溴-4,5,6,7-四氢-苯并噻唑-6-基)-氨基甲酸叔丁酯(0.50克,1.5mmol,在制备2中获得的)在二氯甲烷(30mL)中的溶液。使反应物料搅拌4小时。反应完成后,用冰冷的水淬灭物料,然后通过使用40%氢氧化钠水溶液将pH调节至10。用二氯甲烷(3×50mL)萃取产物,用水然后用盐水洗涤合并的有机层,接着经无水硫酸钠干燥。在真空下蒸发有机挥发物,从而获得标题化合物(0.36克)。
Mass(m/z):233.0(M+H)+,235.0(M+3H)+.
步骤(ii):N-(2-溴-4,5,6,7-四氢-苯并噻唑-6-基)-丙酰胺的制备
将2-溴-4,5,6,7-四氢-苯并噻唑-6-基胺(0.36克,1.5mmol,在上述步骤中获得的)和三乙胺(0.43mL,mmol)在二氯甲烷(15mL)中的溶液冷却至0℃。添加二氯甲烷(2mL)中的丙酰氯(0.17mL,1.8mmol),然后使反应物料搅拌30分钟。反应完成后,将物料倾倒至冰冷的水上,然后用乙酸乙酯(3×15mL)萃取产物。用水然后用盐水洗涤合并的有机层,经无水硫酸钠干燥,接着在真空下蒸发有机挥发物。通过快速色谱法(甲醇/氯仿,2/98)纯化残余物,从而获得标题化合物(0.4克)。
1H-NMR(δppm):0.81-0.85(1H,m),1.14-1.18(3H,m),1.20-1.28(2H,m),1.90-1.96(1H,m),2.02-2.05(1H,m),2.18-2.23(2H,m),2.57-2.63(1H,m),2.86-2.91(1H,m),3.10-3.15(1H,m);
Mass(m/z):289.2(M+H)+,291.2(M+3H)+.
步骤(iii):N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-6-基]-丙酰胺的制备
用冷却的并搅拌的氢化钠(0.1克,2.08mmol)在N,N-二甲基甲酰胺(10mL)中的悬液缓慢处理N,N-二甲基甲酰胺(5mL)中的1-环丁基-哌啶-4-醇(0.25克,1.6mmol)30分钟,然后使反应混合物再搅拌1小时。经10分钟逐滴添加N-2-溴-4,5,6,7-四氢-苯并噻唑-6-基)-丙酰胺(0.4克,1.3mmol,在上述步骤中获得的)在N,N-二甲基甲酰胺(5mL)中的溶液并使所得物料搅拌48小时。反应完成后,在冰冷的水上淬灭物料,然后用乙酸乙酯(3×15mL)萃取产物。用水然后用盐水洗涤合并的有机层,经无水硫酸钠干燥,接着在真空下蒸发有机挥发物。通过快速色谱法(乙酸乙酯/正己烷,1/1)纯化残余物,从而获得标题化合物(0.068克)。
1H-NMR(δppm):0.81-0.88(2H,m),1.14-1.18(3H,m),1.65-1.70(2H,m),1.89-1.91(5H,m),2.03-2.05(5H,m),2.17-2.23(3H,m),2.49-2.75(4H,m),2.96-3.01(2H,m),4.35-4.39(1H,m),4.90-3.96(1H,m),5.50-5.53(1H,m);
Mass(m/z):364.3(M+H)+.
实施例4-34:
通过根据实施例1至3描述的程序(具有一些非关键性变化)制备实施例4-34的化合物。
实施例35-66:
本领域技术人员可根据上述程序制备实施例35-66的化合物。
生物测定
实施例67:人或大鼠组胺H3受体的结合和功能测定
可根据以下程序评估化合物。
材料和方法:
受体来源:大鼠脑额皮质或CHO细胞中表达的重组人cDNA
放射性配体:[3H]R-α-甲基组胺
最终配体浓度-[3.0nM]
非特异性决定因子:R-α-甲基组胺(100μM)
参照化合物:R-α-甲基组胺
阳性对照:R-α-甲基组胺
孵育条件:
在室温下将测试化合物或标准品与5mM MgCl2和50mM TRIS-HCl(pH7.4)中的膜受体和放射性配体一起孵育60分钟。通过快速真空过滤至玻璃纤维过滤器上来终止反应。确定在过滤器上捕获的放射性并且与对照值相比较,从而确定测试化合物与克隆的人或大鼠受体结合位点的任何相互作用。
实施例编号 | Ki(nM) |
1. | 3.83 |
2. | 2.0 |
3. | 26.67 |
4. | 7.2 |
5. | 3.3 |
6. | 13.4 |
7. | 10.5 |
8. | 7.69 |
9. | 9.94 |
10. | 5.43 |
11. | 11.98 |
12. | 8.44 |
14. | 23.6 |
16. | 33.55 |
17. | 21.2 |
18. | 6.96 |
19. | 12.28 |
20. | 7.4 |
21. | 22.6 |
22. | 9.5 |
23. | 0.3 |
25. | 35.33 |
26. | 32.54 |
27. | 0.75 |
28. | 38.96 |
29. | 11.3 |
30. | 4.19 |
31. | 1.62 |
32. | 4.6 |
33. | 15.45 |
34. | 15.6 |
文献参考:Millipore数据表
实施例68:啮齿动物药代动力学研究
将从NIN(国家营养学会(National Institute of Nutrition),Hyderabad,India)获得的雄性Wistar大鼠(230-280g)用作实验动物。在每只笼子中装有3只动物。使动物保持禁食过夜并且以12小时的明暗周期(light/dark cycle)维持。在第0天和第2天用新化学实体(New chemicalentity,NCE)对三只大鼠口服(3或10mg/kg)和静脉内(1或5mg/kg)给药。
在每个时间点,通过颈静脉采集血液。将血液贮存在2-8℃直到分析。使用LC-MS/MS法确定NCE化合物在血液中的浓度。预定时间点:给药前,给药后0.08、0.25、0.5、1、2、4、6、8和24小时(n=3)。使用乙腈沉淀技术通过部分验证的LC-MS/MS法(partially validatedLC-MS/MS method)在血液中定量NCE化合物。在血液中,在1-2000ng/mL的校准范围中定量NCE化合物。使用批次内校准样品和批次间品质对照样品来分析研究样品。
使用软件WinNonlin 5.0.1版通过非区室模型(non-compartmentalmodel)计算药代动力学参数。
实施例69:啮齿动物脑渗透研究
将从NIN(国家营养学会,Hyderabad,India)获得的雄性Wistar大鼠(230-280克)用作实验动物。在每只笼子中装有3只动物。整个实验随意给动物水和食物,并且以12小时的明暗周期维持。
将新化学实体(NCE)溶解在合适的载剂中并口服施用(3或10mg/kg)。在约Tmax(即,0.5小时、1.0小时和2.0小时)时处死动物。采集血液和脑组织并将脑匀浆化至产生20%w/v。将血液贮存在2-8℃和将脑匀浆在-20℃冷冻直到分析。使用LC-MS/MS法定量NCE在血液和脑中的浓度。
使用乙腈沉淀技术通过部分验证的LC-MS/MS法在血液和脑匀浆中定量NCE。在血液和脑匀浆中,在1-500ng/mL的校准范围中定量NCE化合物。使用批次内校准样品和批次间品质对照样品来分析研究样品。计算脑-血液比率的范围(Cb/Cp)。
实施例70:物体识别任务模型
通过使用该模型评估本发明化合物的认知增强特性。
将从N.I.N.(国家营养学会,Hyderabad,India)获得的雄性Wistar大鼠(230-280克)用作实验动物。在每只笼子中装有4只动物。在一天前使动物保持20%食物剥夺以及整个实验随意给动物水,并且以12小时的明暗周期维持。另外,在不存在任何物体的情况下使大鼠动物习惯各个场地(arena)1小时。
在熟悉(T1)和选择试验(T2)前1小时,使一组12只大鼠口服接受载剂(1mL/Kg)以及另一组动物口服或腹腔(i.p.)接受式(I)化合物。
在由丙烯酸制成的50×50×50cm旷场(open field)中进行实验。在熟悉阶段(T1),将大鼠各自放入旷场中3分钟,其中用黄色遮蔽胶带单独覆盖的两个相同的物体(塑料瓶,12.5cm高×5.5cm直径)(a1和a2)放置在两个毗连的角落,离墙有10cm。在长期记忆测试的(T1)试验的24小时后,将同一批大鼠放入如它们在T1试验被放入的同一场地中。选择阶段(T2),使得大鼠在熟悉的物体(a3)和一个新的物体(b)(琥珀色玻璃瓶,12cm高和5cm直径)的存在下探索旷场3分钟。熟悉的物体表现出类似的质地、颜色和尺寸。在T1和T2试验期间,通过秒表分开记录对每个物体的探索(其定义为嗅、舔、嚼或移动触须同时在少于1cm的距离使鼻子朝向物体)。坐在物体上不被认为是探索行为,然而极少被观察到。
T1是探索熟悉的物体(a1+a2)花费的总时间。
T2是探索熟悉的物体和新的物体(a3+b)花费的总时间。
通过Ennaceur,A.,Delacour,J.,1988,A new one-trial test forneurobiological studies of memory in rats-Behavioural data,Behav.Brain Res.,31,47-59所描述的那样进行物体识别测试。
实施例71:莫里斯(Morris)水迷宫
通过使用该模型评估本发明化合物的认知增强特性。
用水(24±2℃)充满由在黑色有机玻璃(Perspex)中构建的循环池(1.8m直径,0.6m高)组成的水迷宫装置(TSE systems,Germany)并将该装置放置在广角摄像机的下方以追踪动物。将位于水表面下1cm的10cm2有机玻璃平台放入四个虚构象限(imaginary quadrant)之一的中心,其对于所有的大鼠保持固定。用于构建迷宫和平台的黑色有机玻璃不提供指导脱逃行为的迷宫内线索。相比之下,训练室提供了数个强烈的迷宫外视觉线索以帮助形成脱逃学习必需的空间地图。使用自动追踪系统[Videomot2(5.51),TSE systems,Germany]。该程序经由数字摄像机和图像采集板分析取得的视频图像,从而确定在水迷宫的每个象限中路径长度、游泳速度和进入次数以及花费的游泳持续时间。
实施例编号 | 东莨菪碱诱导的健忘症的逆转 |
1. | ≤10mg/kg,经口 |
4. | ≤10mmg/kg,经口 |
5. | ≤3mmg/kg,经口 |
12. | ≥20mg/kg,经口 |
28. | ≥10mg/kg,经口 |
实施例72:食物摄取的抑制
通过使用该模型评估本发明化合物的抗肥胖症特性。
实验由6天组成。使大鼠适应18小时禁食和6小时饲喂模式。在配置有禁食栅格(fasting grill)的笼子中以3只一组装入动物并使动物禁食18小时。在18小时禁食后,将大鼠分开并单独放入笼子中。将经称重量的食物提供给大鼠6小时,并且在1小时、2小时、4小时和6小时测量食物摄取。
将大鼠再重新分组并禁食18小时。根据上述程序进行5天。计算最后3天大鼠的平均积累食物摄取。在动物之前3天的食物摄取的基础上将它们随机化。在实验当天,用测试化合物或载剂口服处理大鼠。60分钟后,给大鼠提供食物并在1小时、2小时、4小时和6小时测量食物摄取。通过使用非配对的t检验(Unpaired Student’s t test),将用测试化合物处理的大鼠的食物摄取与载剂处理组相比较。
实施例编号 | 食物摄取的抑制 |
4. | 20mmg/kg,p.o. |
Claims (14)
1.通式(I)的化合物或其可药用盐:
其中,
R4是取代的或未取代的烷基、环烷基、环烷基烷基、芳基、杂芳基、杂环基或杂环基烷基;其中取代基可以是一个或更多个并且独立地选自氢、羟基、卤素、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、烷基或环烷基;
在每种情况下,R3独立地选自氢、卤素、烷基或烷氧基;
R2是氢、取代的或未取代的烷基或环烷基;其中取代基可以是一个或更多个并且独立地选自氢、羟基、卤素、烷基、烷氧基、卤烷基或卤烷氧基;
X是S、N或O;
Y是C或N;
“p”是0至2的整数;
“q”是0至2的整数;
“r”是0至1的整数。
2.根据权利要求1所述的化合物,其中R2是烷基或环烷基。
3.根据权利要求1所述的化合物,其中R3是氢或烷基。
4.根据权利要求1所述的化合物,其中R4是烷基、环烷基、环烷基烷基、芳基、杂芳基、杂环基或杂环基烷基。
5.根据权利要求1所述的化合物,其中R5是氢。
6.根据权利要求1所述的化合物,其选自:
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮酒石酸盐;
N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-6-基]-丙酰胺;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环丙基-甲酮酒石酸盐;
环丁基-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(2-氟-苯基)-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-3-甲基-丁-1-酮酒石酸盐;
环丁基-[2-(1-异丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮;
环丙基-[2-(1-异丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
环丙基-[2-(1-环丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
环丁基-[2-(1-环丙基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-吗啉-4-基-乙酮酒石酸盐;
[4-(5-环丁基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-1-基]-环丙基-甲酮酒石酸盐;
[3-(5-环丁基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-1-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-3-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吡啶-4-基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(4-甲氧基-苯基)-甲酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-哌啶-1-基-乙酮酒石酸盐;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-环丙基-乙酮;
2-(1-环丁基-哌啶-4-基氧基)-5-(2-氟-苯磺酰基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-甲磺酰基-6,7-二氢-4H-噻唑并[5,4-c]吡啶;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-2-甲基-丙-1-酮酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-(2-三氟甲基-吡啶-5-基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶;
环丙基-[2-(1-异丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(2-三氟甲基-吡啶-5-基)-甲酮;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吡啶-3-基-甲酮酒石酸盐;
2-(1-环丁基-哌啶-4-基氧基)-5-吡啶-3-基-6,7-二氢-4H-噻唑并[5,4-c]吡啶酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-(四氢-吡喃-4-基)-甲酮;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-吗啉-4-基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-哌啶-1-基-甲酮盐酸盐;
6-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-烟酰胺;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-环戊基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-环丙基-甲酮酒石酸盐;
[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-环丙基-甲酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-丙-1-酮;
环丁基-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-5H-噻唑并[5,4-b]吡啶-4-基]-甲酮;
N-[2-(1-环丁基-哌啶-4-基氧基)-4,5,6,7-四氢-苯并噻唑-7-基]-丙酰胺;
1-[2-(1-环丁基-哌啶-4-基氧基)-6,7-二氢-4H-唑并[5,4-c]吡啶-5-基]-丙-1-酮;
N-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-4H-环戊并噻唑-5-基]-丙酰胺;
1-[2-(1-环丁基-哌啶-4-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-吡咯并[3,2-d]噻唑-4-基]-丙-1-酮;
N-[2-(1-环丁基-哌啶-4-基氧基)-5,6-二氢-4H-环戊并噻唑-6-基]-丙酰胺;
1-[2-(1-环丁基-哌啶-4-基氧基)-4-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-7-氟-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-7-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-哌啶-4-基氧基)-6-甲基-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-3-甲基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-3-氟-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-环丁基-4-(5-丙酰基-4,5,6,7-四氢-噻唑并[5,4-c]吡啶-2-基氧基)-哌啶-3-甲腈;
1-[2-(1-环丁基-氮杂环庚-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-[2-(1-环丁基-吡咯烷-3-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-[2-(1-环丁基-氮杂环庚-4-基氧基)-4,6-二氢-吡咯并[4,3-d]噻唑-5-基]-丙-1-酮;
1-{2-[1-(2-羟基-乙基)-哌啶-4-基氧基]-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基}-丙-1-酮;
1-[2-(1-乙氧甲基-哌啶-4-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;
1-{2-[1-(2,2,2-三氟-乙基)-哌啶-4-基氧基]-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基}-丙-1-酮;
1-[2-(1-环丁基-氮杂环丁-3-基氧基)-6,7-二氢-4H-噻唑并[5,4-c]吡啶-5-基]-丙-1-酮;及其可药用盐。
7.一种药物组合物,其包含权利要求1至6中任一项所述的化合物和可药用赋形剂。
8.根据权利要求7所述的药物组合物,其用于治疗临床病症,例如认知障碍、睡眠障碍、肥胖症和疼痛。
12.一种治疗认知障碍、睡眠障碍、肥胖症或疼痛的方法,其包括向有此需要的患者施用有效量的根据权利要求1至6中任一项所述的化合物或其可药用盐。
13.根据权利要求1至6中任一项所述的化合物在制备用于治疗组胺H3受体相关疾病的药物中的用途。
14.根据权利要求13所述的化合物的用途,其用于治疗临床病症,例如认知障碍、睡眠障碍、肥胖症和疼痛。
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EP3378477A1 (en) * | 2017-03-21 | 2018-09-26 | BIOPROJET Pharma | New therapeutical use of h3-ligands |
KR20200083551A (ko) | 2017-11-02 | 2020-07-08 | 아이쿠리스 게엠베하 운트 코. 카게 | B형 간염 바이러스 (hbv)에 활성인 신규 고활성 아미노-티아졸 치환된 인돌-2-카르복스아미드 |
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PH23995A (en) | 1984-01-09 | 1990-02-09 | Janssen Pharmaceutica Nv | 4((bicycle heterocyclyl)-methyl and hetero)piperidines |
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