CN105102447A - 双环取代的嘧啶类pde-5抑制剂的前药 - Google Patents
双环取代的嘧啶类pde-5抑制剂的前药 Download PDFInfo
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- CN105102447A CN105102447A CN201480019442.9A CN201480019442A CN105102447A CN 105102447 A CN105102447 A CN 105102447A CN 201480019442 A CN201480019442 A CN 201480019442A CN 105102447 A CN105102447 A CN 105102447A
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- 239000002590 phosphodiesterase V inhibitor Substances 0.000 title claims abstract description 15
- 229940002612 prodrug Drugs 0.000 title abstract description 33
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- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 2
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- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 claims description 2
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Pulmonology (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims (1)
- 权 利 要 求1、 通式 ( I ) 所示的 体异构体:其中, R1选自任选被 1-4个取代基取代的 6-7元的含氮稠杂环基、 7-12元的含氮螺杂环 基或 7-12元的含氮桥杂环基, R1通过 N原子连接到式 (I) 的嘧啶环上,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 d_6烷基、 卤代 d_6烷基、 羟基 d_6烷基、 d_6烧氧基、 d_6烧基羰基或 d_6烧氧基羰基;R2选自氢原子, 羟基, 氨基, 氰基, _6烷基氨基, 二 ( _6烷基)氨基, _6烷基, 卤代 _6 垸基, 羟基 C"垸基或 d_6垸氧基;R3、 R4分别独立的为氢, 或任选被 1-3个选自卤素原子、 羟基、 羧基取代的 d_6烷基; m为 0-3;Z为氢, 或为能与磷酸形成盐的无机碱或有机碱的阳离子;R5、 R6分别独立地代表氢原子或 -Q-R7.,Q代表键, 或任选被取代基取代的 _6亚烷基, 所述取代基选 S卤素原子、 羟基、 C "烷 基、 氨基、 氰基、 硝基或 d_6垸氧基;R7选自任选被 1-4个取代基取代的 6-14元芳基、 5-7元杂环基或 8-10元稠环基, 所述取代基选自卤素原子、羟基、 _6烷基、 卤代 _6烷基、羧基 Q_6烷基、 C2_6烯基、 C2_6 炔基、 C^烷氧基、 卤代 烷氧基、 氨基、 烷基氨基、 二 (C^烷基)氨基、 氰基、 硝基、 烷基羰基、 磺酰氨基或 烷基磺酰氨基。2、 如权利要求 1所述的化合物、 其药学上可接受的盐或其立体异构体:其中, R2选自氢原子, 羟基或甲基;R6代表氢原于。3、 如权利要求 2所述的化合物、 其药学上可接受的盐或其立体异构体:其中, R3、 R4分别独立的为氢;m为 0、 1或 2;Z为氢, 或钠离子;4、 如权利耍求 3所述的化合物、 其药学上可接受的盐或其立体异构体: 其中, R5代表 -Q-R7,Q选自 C^亚垸基,R7选自任选被 1-4个取代基取代的 6-10元芳基、 5-7元杂环基或 8-10元稠环基, 所述取代基选自卤素原子、 羟基、 C^烷基、 卤代 C^烷基、 羧基 C"烷基、 C^烷氧基、 卤代 d_6烷氧基、 氨基、 d_6烷基氨基、 二 (d_6烷基)氨基、 氰基、 硝基、 d_6烷基羰基、 磺酰 氨基或 烷基磺酰氨基。5、 如权利要求 4所述的化合物、 其药学上可接受的盐或其立体异构体:其中, R1选自任选被 1-4个取代基取代的 6-7元的含氮稠杂环基、 7-12元的含氮螺杂环 基或 7-12元的含氮桥杂环基, R1通过 N原子连接到式 (I) 的嘧啶环上,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 _6垸基、 卤代 _6垸基、 羟基 _6垸基、 d_6垸氧基、 d_6垸基羰基或 d_6垸氧基羰基。6、 如权利要求 5所述的化合物、 其药学上可接受的盐或其立体异构体:其中, R1选自任选被 1-3个取代基取代的 6-7元含氮稠杂环基、 7-10元含氮螺杂环基或 7-8元含氮桥杂环基, R1通过 N原子连接到式 (I) 的嘧啶环上,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 d_4烷基、 卤代 d_4烷基、 羟基 d_4垸基 或 d_4.烧氧基;R3、 R4分别独立的为氢;m为 0、 1或 2;Z为氢, 或钠离子;R5代表 -Q-R7,Q选自 CM亚烷基,R7选自任选被 1-3个取代基取代的苯基、 5-7元杂环基或 8-10元稠环基,所述取代基选自卤素原子、 甲基、 三氟甲基、 甲氧基、 乙氧基、 三氟甲氧基、 二甲氨基 或羧甲基;R2选自氢原于;R6选自氢原子。7、 如权利要求 6所述的化合物、 其药学上可接受的盐或其立体异构体:其中, R1选自任选被 1-3个取代基取代的 6-7元含氮稠杂环基或 7-10元含氮螺杂环基, R1通过 N原子连接到式 (I) 的嘧啶环上,所述取代基选自卤素原子、 氰基、 氨基、 羟基、 CM垸基、 卤代 d_4垸基、 羟基 d_4垸基 或 CM烷氧基; R3、 R4分别独立的为氢;m为 0、 1或 2;Z为氢, 或钠离子;R5代表 -Q-R7,Q选自亚甲基或亚乙基,R7选自任选被 1-3个取代基取代的苯基、 吡咯基、 呋喃基、 吡啶基、 噻唑基、 萘基、 苯 并吡咯基、 茚基、 喹啉基或吲哚基,所述取代基选自氟原子、 氯原子、 氰基、 氨基、 羟基、 d_4烷基、 卤代 d_4烷基、 羟基 CM ¾基或 CM烷氧基。8、 如权利要求 7所述的化合物、 其药学上可接受的盐或其立体异构体:R1选自选自下列基团:R3、 R4分别独立的为氢;m为 0或 1 ;Z为钠离子;5选自下列基团:9、如权利要求 1所述的化合物、其药学上可接受的盐或其立体异构体,所述化合物选自:9Z LO/nOZ D/13d 89ΐ^ΐ/Η0∑: O 3610、 药物制剂, 含有权利要求 1所述的化合物、 其药学上可接受的盐或其立体异构体, 以及一种或多种药用载体和 /或稀释剂。11、含有权利要求 1所述的化合物、其药学上可接受的盐或其立体异构体的药物组合物, 其特征在于, 进一步包含一种或多种第二治疗活性剂, 选自血管扩张剂, 前列腺素 E1 , 前列 环素, α-肾上腺素受体阻滞剂, 混合的 α,β-阻断剂, a-阻断剂, 5oc-还原酶抑制剂, α2-肾上腺 素受体阻滞剂, ACE抑制剂, NEP抑制剂, 中枢多巴胺剂, 血管活性肠肽, 钙通道阻滞剂, 噻嗪类, 或它们的混合物。12、 权利要求 1所述的化合物、 其药学上可接受的盐或其立体异构体在制备药物中的应 用, 所述的药物为 PDE-5抑制剂, 用于治疗和 /或预防性功能障碍疾病及下尿路症状的疾病。13、 权利要求 1所述的化合物、 其药学上可接受的盐或其立体异构体在制备药物中的应 用, 所述的药物治疗和 /或预防选自下述的疾病: 高血压、 心力衰竭、 肺动脉高压、 勃起功能 障碍、 膀胱过度活化、 前列腺增生以及女性性功能障碍。14、权利要求 12或 13所述的应用, 其中所述的疾病是勃起功能障碍, 膀胱过度活化及良 性前列腺增生。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1223170A1 (en) * | 1999-10-12 | 2002-07-17 | Takeda Chemical Industries, Ltd. | Pyrimidine-5-carboxamide compounds, process for producing the same and use thereof |
CN1374953A (zh) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | 含氮的6-员芳香环化合物 |
CN102887889A (zh) * | 2011-07-21 | 2013-01-23 | 山东轩竹医药科技有限公司 | 杂环取代的嘧啶类化合物 |
WO2014026467A1 (zh) * | 2012-08-14 | 2014-02-20 | 山东轩竹医药科技有限公司 | 双环取代的嘧啶类化合物 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3637961B2 (ja) * | 1999-09-16 | 2005-04-13 | 田辺製薬株式会社 | 芳香族含窒素六員環化合物 |
JP2001233875A (ja) * | 1999-10-12 | 2001-08-28 | Takeda Chem Ind Ltd | ピリミジン−5−カルボキサミド化合物、その製造法およびその用途 |
US20080027037A1 (en) * | 2000-04-28 | 2008-01-31 | Tanabe Seiyaku Co., Ltd. | Cyclic compounds |
US7273868B2 (en) * | 2000-04-28 | 2007-09-25 | Tanabe Seiyaku Co., Ltd. | Pyrazine derivatives |
MXPA02010693A (es) * | 2000-04-28 | 2003-03-10 | Tanabe Seiyaku Co | Compuestos ciclicos. |
EP2556820A4 (en) * | 2010-04-05 | 2015-01-21 | Sk Chemicals Co Ltd | COMPOSITION CONTAINING PDE5 INHIBITOR FOR MITIGATION OF SKIN WRINKLES |
CN102372697A (zh) * | 2010-08-19 | 2012-03-14 | 山东轩竹医药科技有限公司 | 取代的嘧啶类化合物 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1374953A (zh) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | 含氮的6-员芳香环化合物 |
EP1223170A1 (en) * | 1999-10-12 | 2002-07-17 | Takeda Chemical Industries, Ltd. | Pyrimidine-5-carboxamide compounds, process for producing the same and use thereof |
CN102887889A (zh) * | 2011-07-21 | 2013-01-23 | 山东轩竹医药科技有限公司 | 杂环取代的嘧啶类化合物 |
WO2014026467A1 (zh) * | 2012-08-14 | 2014-02-20 | 山东轩竹医药科技有限公司 | 双环取代的嘧啶类化合物 |
Non-Patent Citations (1)
Title |
---|
JARKKO RAUTIO ET AL.,: "Prodrugs: design and clinical applications", 《NATURE REVIEWS DRUG DISCOVERY》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111406053A (zh) * | 2017-12-11 | 2020-07-10 | 轩竹(海南)医药科技有限公司 | 磷酸二酯酶-5抑制剂的晶型 |
CN111433199A (zh) * | 2017-12-11 | 2020-07-17 | 轩竹(海南)医药科技有限公司 | 磷酸二酯酶-5抑制剂的晶型 |
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US9527876B2 (en) | 2016-12-27 |
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BR112015025033A2 (pt) | 2017-07-18 |
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