CN106795160A - 取代的吲哚化合物及其使用方法和用途 - Google Patents
取代的吲哚化合物及其使用方法和用途 Download PDFInfo
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- CN106795160A CN106795160A CN201680002185.7A CN201680002185A CN106795160A CN 106795160 A CN106795160 A CN 106795160A CN 201680002185 A CN201680002185 A CN 201680002185A CN 106795160 A CN106795160 A CN 106795160A
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- compound
- alkoxy
- alkyl
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- present
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- -1 benzazolyl compounds Chemical class 0.000 title claims abstract description 105
- 238000000034 method Methods 0.000 title abstract description 40
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 52
- 230000004064 dysfunction Effects 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims description 57
- 239000003814 drug Substances 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 210000003169 central nervous system Anatomy 0.000 claims description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 239000000651 prodrug Substances 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 20
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052805 deuterium Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 10
- 239000002207 metabolite Substances 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
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- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 6
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 6
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 230000000116 mitigating effect Effects 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
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- 230000000697 serotonin reuptake Effects 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
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- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 3
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 3
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- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 claims description 3
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 claims description 3
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 3
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims description 3
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- 239000002671 adjuvant Substances 0.000 claims description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 claims description 3
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- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 3
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- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 3
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- 229960001058 bupropion Drugs 0.000 claims description 3
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 claims description 3
- 229960004596 cabergoline Drugs 0.000 claims description 3
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 claims description 3
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- IMYZQPCYWPFTAG-IQJOONFLSA-N mecamylamine Chemical compound C1C[C@@H]2C(C)(C)[C@@](NC)(C)[C@H]1C2 IMYZQPCYWPFTAG-IQJOONFLSA-N 0.000 claims description 3
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (10)
- 一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药,其中:X为CR2或N;W为CR3或N;V为CR4或N;U为CR5或N;前提条件是X、W、V和U中最多两个同时为N;各R1和Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基,其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基独立任选地被一个或多个Rw所取代;各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(=O)NH2、-COOH、-C(=O)CH3、-C(=O)OCH3、-O-(CH2)p-C(=O)NH2、-O-(CH2)p-C(=O)OH、-O-(CH2)p-C(=O)-(C1-C6烷基)、-O-(CH2)p-C(=O)-(C1-C6烷氧基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基或5-10个环原子组成的杂芳基,其中所述-C(=O)CH3、-C(=O)OCH3、-O-(CH2)p-C(=O)NH2、-O-(CH2)p-C(=O)OH、-O-(CH2)p-C(=O)-(C1-C6烷基)、-O-(CH2)p-C(=O)-(C1-C6烷氧基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基和5-10个环原子组成的杂芳基独立任选地被一个或多个Rw所取代;各Rw独立地为D、F、Cl、Br、I、-NO2、-CN、-N3、-NH2、-OH、-SH、氧代(=O)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、C1-C4烷硫基、NH2-(C1-C4亚烷基)-、HO-(C1-C4亚烷基)-、HS-(C1-C4亚烷基)-、(C1-C4烷氧基)-(C1-C4亚烷基)-、(C1-C4烷氨基)-(C1-C4亚烷基)-、(C1-C4烷硫基)-(C1-C4亚烷基)-、C3-C6环烷基、(C3-C6环烷基)-(C1-C4亚烷基)-、3-7个环原子组成的杂环基、(3-7个环原子组成的杂环基)-(C1-C4亚烷基)-、苯基、苯基-(C1-C4亚烷基)-、5-6个环原子组成的杂芳基或(5-6个环原子组成的杂芳基)-(C1-C4亚烷基)-;m为0、1、2或3;n为0、1、2、3或4;r为0、1或2;和p为1、2、3或4。
- 根据权利要求1所述的化合物,其中各R1和Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基,其中所述C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基独立任选地被一个或多个Rw所取代。
- 根据权利要求1所述的化合物,其中各R1和Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3或-OCF3。
- 根据权利要求1所述的化合物,其中各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(=O)NH2、-COOH、-C(=O)CH3、-C(=O)OCH3、-O-(CH2)p-C(=O)NH2、-O-(CH2)p-C(=O)OH、-O-(CH2)p-C(=O)-(C1-C4烷基)、-O-(CH2)p-C(=O)-(C1-C4烷氧基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、5-6个环原子组成的杂环基、苯基或5-6个环原子组成的杂芳基,其中所述-C(=O)CH3、-C(=O)OCH3、-O-(CH2)p-C(=O)NH2、-O-(CH2)p-C(=O)OH、-O-(CH2)p-C(=O)-(C1-C4烷基)、-O-(CH2)p-C(=O)-(C1-C4烷氧基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、5-6个环原子组成的杂环基、苯基和5-6个环原子组成的杂芳基独立任选地被一个或多个Rw所取代。
- 根据权利要求1所述的化合物,其中各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(=O)NH2、-COOH、-C(=O)CH3、-C(=O)OCH3、-O-CH2-C(=O)NH2、-O-(CH2)2-C(=O)NH2、-O-CH2-C(=O)OH、-O-(CH2)2-C(=O)OH、-O-CH2-C(=O)CH3、-O-CH2-C(=O)CH2CH3、-O-CH2-C(=O)CH(CH3)2、-O-(CH2)2-C(=O)CH3、-O-(CH2)2-C(=O)CH2CH3、-O-(CH2)2-C(=O)CH(CH3)2、-O-CH2-C(=O)OCH3、-O-CH2-C(=O)OCH2CH3、-O-CH2-C(=O)OCH(CH3)2、-O-(CH2)2-C(=O)OCH3、-O-(CH2)2-C(=O)OCH2CH3、-O-(CH2)2-C(=O)OCH(CH3)2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3、-CH2CF3、-OCF3、-OCH2CF3或-OCH2CF2CHF2。
- 根据权利要求1-5任意一项所述的化合物,其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药:
- 一种药物组合物,包含权利要求1-6任意一项所述的化合物;和所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。
- 根据权利要求7所述的药物组合物,其进一步地包含治疗中枢神经系统功能障碍的药物,所述治疗中枢神经系统功能障碍的药物为阿米替林、地昔帕明、米氮平、安非他酮、瑞波西汀、氟西汀、曲唑酮、舍曲林、度洛西汀、氟伏沙明、米那普仑、左旋米那普仑、去甲文拉法辛、维拉唑酮、文拉法辛、达泊西汀、奈法唑酮、非莫西汀、氯丙咪嗪、西酞普兰、艾司西酞普兰、帕罗西汀、碳酸锂、丁螺环酮、奥氮平、喹硫平、利培酮、齐拉西酮、阿立哌唑、哌罗匹隆、氯氮平、莫达非尼、美卡拉明、卡麦角林、金刚烷、丙咪嗪、普拉克索、甲状腺素、右美沙芬、奎尼丁、纳曲酮、samidorphan、丁丙诺啡、褪黑激素、阿普唑仑、匹泮哌隆、维替匹坦、利眠宁、奋乃静或它们的任意组合。
- 权利要求1-6任意一项所述的化合物或权利要求7-8任意一项所述的药物组合物在制备药物中的用途,所述药物用于预防、治疗或减轻中枢神经系统功能障碍。
- 权利要求1-6任意一项所述的化合物或权利要求7-8任意一项所述的药物组合物在制备药物中的用途,所述药物用于抑制5-羟色胺再摄取,和/或所述药物用于部分激动5-HT1A受体。
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