MX2018005239A - Derivados de 2-fenil-3,4-dihidropirrolo[2,1-f][1,2,4]triazinona como inhibidores de fosfodiesterasa y sus usos. - Google Patents
Derivados de 2-fenil-3,4-dihidropirrolo[2,1-f][1,2,4]triazinona como inhibidores de fosfodiesterasa y sus usos.Info
- Publication number
- MX2018005239A MX2018005239A MX2018005239A MX2018005239A MX2018005239A MX 2018005239 A MX2018005239 A MX 2018005239A MX 2018005239 A MX2018005239 A MX 2018005239A MX 2018005239 A MX2018005239 A MX 2018005239A MX 2018005239 A MX2018005239 A MX 2018005239A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- optionally substituted
- ono2
- ono
- alkoxy
- Prior art date
Links
- HFBHPHBIBAUDNE-UHFFFAOYSA-N 2h-1,2,4-triazin-3-one Chemical compound O=C1N=CC=NN1 HFBHPHBIBAUDNE-UHFFFAOYSA-N 0.000 title 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 13
- 229910004679 ONO2 Inorganic materials 0.000 abstract 13
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 abstract 12
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract 9
- 125000000623 heterocyclic group Chemical group 0.000 abstract 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 6
- 125000001072 heteroaryl group Chemical group 0.000 abstract 5
- 229910052757 nitrogen Inorganic materials 0.000 abstract 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 4
- KPACBFJTZSMBKD-OAQYLSRUSA-N 2-[2-[(4-carbamimidoylphenyl)carbamoyl]-6-methoxypyridin-3-yl]-5-[[(2s)-1-hydroxy-3,3-dimethylbutan-2-yl]carbamoyl]benzoic acid Chemical compound C=1C=C(C(N)=N)C=CC=1NC(=O)C1=NC(OC)=CC=C1C1=CC=C(C(=O)N[C@H](CO)C(C)(C)C)C=C1C(O)=O KPACBFJTZSMBKD-OAQYLSRUSA-N 0.000 abstract 3
- -1 COO-C1-C3 alkyl Chemical group 0.000 abstract 3
- 125000002947 alkylene group Chemical group 0.000 abstract 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 3
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 3
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 abstract 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 abstract 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 2
- 125000005842 heteroatom Chemical group 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 abstract 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- QFCMBRXRVQRSSF-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole Chemical compound C1NCC2CNCC21 QFCMBRXRVQRSSF-UHFFFAOYSA-N 0.000 abstract 1
- UKHJNJFJCGBKSF-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CNC1C2 UKHJNJFJCGBKSF-UHFFFAOYSA-N 0.000 abstract 1
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- 125000003831 tetrazolyl group Chemical group 0.000 abstract 1
Classifications
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- 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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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- C07D207/50—Nitrogen atoms
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Abstract
La presente invención se refiere a compuestos de fórmula I (ver Fórmula) o una sal, solvato o hidrato farmacéuticamente aceptable del mismo, en donde: R1 es alquilo C1-C3 opcionalmente sustituido con F, cicloalquilo C3-C6, alcoxi C1-C3; X representa un enlace o alquileno C1-C3 opcionalmente sustituido con OH, ONO, ONO2; R2 is H, OH, ONO, ONO2, C(O)OH, C(O)O-alquilo C1-C3, CHO, CN, alkoxi C1-C3, OC(O)H, OC(O)-alquilo C1-C3, C(O)N(R6)OR7, O-alquileno C1-C3-C(O)OH, O-alquileno C1-C3-C(O)O-alquilo C1-C3, O-alquileno C1-C3-C(O)N(R6)OR7, S(O0-2) alquilo C1-C3, CR8=N-OR9, CR8=N-NR10R11, CR8=NR12 o CR8=N-ONO2; R3 es alquilo C1-C6 opcionalmente sustituido con F, OH, ONO, ONO2, alcoxi C1-C3, cicloalquilo C3-C6; ciclo-alquilo C3-C6, alquenilo C2-C6, alquinilo C2-C6; R4 es alquilo C1-C6 opcionalmente sustituido con cicloalquilo C3-C6, alcoxi C1-C6, F, ONO, ONO2; alquenilo C2-C6, alquinilo C2-C6, ciclo-alquilo C3-C6; R5 es H, SO2NR13R14, NHSO2NR13R14; R6 es H o alquilo C1-C3; R7 es H, alquilo C1-C3, alcoxi C1-C3, alquilo C1-C3 sustituido con fenilo, bencilo o un anillo heterocíclico, en donde dicho fenilo, bencilo o dicho anillo heterocíclico son independientemente opcionalmente sustituidos con alquilo C1-C3, F; R8 es H, CH3 o C2H5; R9 es H, alquilo C1-C3 opcionalmente sustituido con OH, ONO, ONO2, CN, COOH, COO-alquilo C1-C3, alcoxi C1-C3, OC(O)H, OC(O)-alquilo C1-C3, C(O)N(R6)OR7, O-alquileno C1-C3-C(O)OH, O-alquileno C1-C3-C(O)O-alquilo C1-C3, O-alquileno C1-C3-C(O)N(R6)OR7, S(O0-2) alquilo C1-C3; R10 y R11 son cada uno independientemente H, alquilo C1-C3 opcionalmente sustituido con OH, ONO, ONO2, CN, COOH, COO-alquilo C1-C3, alcoxi C1-C3, OC(O)H, OC(O)-alquilo C1-C3, C(O)N(R6)OR7, O-alquileno C1-C3-C(O)OH, O-alquileno C1-C3-C(O)O-alquilo C1-C3, O-alquileno C1-C3-C(O)N(R6)OR7, S (O0-2) alquilo C1-C3; o junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico, en donde preferiblemente dicho anillo heterocíclico se selecciona de aziridina, azetidina, pirrolidina, piperidina, morfolina, piperazina y homopiperazina, en donde dicho anillo heterocíclico está opcionalmente sustituido con alquilo C1-C3; R12 es alquilo C1-C3 opcionalmente sustituido con OH, ONO, ONO2, CN, COOH, COO-alquilo C1-C3, alcoxi C1-C3, OC(O)H, OC(O)-alquilo C1-C3, C(O)N(R6)OR7, O-alquileno C1-C3-C(O)OH, O-alquileno C1-C3-C(O)O-alquilo C1-C3, O-alquileno C1-C3-C(O)N(R6)OR7, S(O0-2) alquilo C1-C3; R13 y R14 son cada uno independientemente H o alquilo C1-C6 opcionalmente sustituido con F, OH, ONO, ONO2, COOH, alcoxi C1-C3, cicloalquilo C3-C6; o junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico, en donde preferiblemente dicho anillo heterocíclico se selecciona de aziridina, azetidina, pirrolidina, piperidina, morfolina, piperazina, homopiperazina, 2,5-diazabiciclo[2,2,1]heptano y 3,7-diazabiciclo[3,3,0]octano, en donde dicho anillo heterocíclico está opcionalmente sustituido con R15; R15 es alquilo C1-C6 opcionalmente sustituido con halógeno, OH, ONO, ONO2, alcoxi C1-C3, haloalcoxi C1-C3, COOR16, NR17R18, C=NR19, o con un grupo tetrazol que está opcionalmente sustituido con alquilo C1-C3; o un anillo heteroarilo que está opcionalmente sustituido con F, en donde el al menos un heteroátomo de dicho anillo heteroarilo es nitrógeno; R16 es H, o alquilo C1-C4 opcionalmente sustituido con F, OH, ONO, ONO2, NR17R18, o con un anillo heteroarilo, en donde el al menos un heteroátomo de dicho anillo heteroarilo es nitrógeno, y en donde preferiblemente dicho anillo heteroarilo se selecciona de pirrolidina, piperidina, piperazina, morfolina, pirrol e imidazol, en donde el átomo de nitrógeno está directamente unido a alquilo C1-C4; R17 y R18 son cada uno independientemente H o alquilo C1-C4 opcionalmente sustituido con ONO, ONO2; R19 es alquilo C1-C4 opcionalmente sustituido con F, ONO, ONO2; ciclo-alquilo C3-C6 y su uso en métodos para tratar o prevenir una enfermedad aliviada por la inhibición de PDE-5 en un mamífero humano o en un mamífero no humano.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15194727 | 2015-11-16 | ||
| PCT/EP2016/077720 WO2017085056A1 (en) | 2015-11-16 | 2016-11-15 | 2-phenyl-3,4-dihydropyrrolo[2,1 -f] [1,2,4]triazinone derivatives as phosphodiesterase inhibitors and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX2018005239A true MX2018005239A (es) | 2019-09-04 |
| MX380708B MX380708B (es) | 2025-03-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2018005239A MX380708B (es) | 2015-11-16 | 2016-11-15 | Derivados de 2-fenil-3,4-dihidropirrolo[2,1-f][1,2,4]triazinona como inhibidores de fosfodiesterasa y sus usos. |
Country Status (22)
| Country | Link |
|---|---|
| US (5) | US10570137B2 (es) |
| EP (1) | EP3377495B1 (es) |
| JP (1) | JP6868635B2 (es) |
| KR (1) | KR102862562B1 (es) |
| CN (1) | CN108290896B (es) |
| AU (1) | AU2016355854B2 (es) |
| CY (1) | CY1125142T1 (es) |
| DK (1) | DK3377495T3 (es) |
| ES (1) | ES2912648T3 (es) |
| HR (1) | HRP20220475T1 (es) |
| IL (1) | IL259163B (es) |
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Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10533011B2 (en) | 2015-10-09 | 2020-01-14 | ACEA Therapeutics, Inc. | Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making same |
| MX2021001503A (es) * | 2018-08-06 | 2021-04-28 | Nicox Sa | Inhibidor de fosfodiesterasa tipo 5 con liberacion de oxido nitrico. |
| CN113166157B (zh) | 2018-11-28 | 2024-08-27 | 托帕杜制药公司 | 双作用模式可溶性鸟苷酸环化酶活化剂和磷酸二酯酶抑制剂及其用途 |
| WO2021094209A1 (en) | 2019-11-12 | 2021-05-20 | Bayer Aktiengesellschaft | Substituted pyrrolo triazine carboxamide derivatives as prostaglandin ep3 receptor antagonists |
| EP4100014B1 (en) | 2020-02-05 | 2024-01-03 | Nicox S.A. | Compositions for the treatment of glaucoma and ocular hypertension |
| CN118903419A (zh) * | 2020-02-10 | 2024-11-08 | 广州市妇女儿童医疗中心 | Pde抑制剂或其盐在制备用于预防和/或治疗胃肠道疾病的药物中的用途 |
| CN113493459B (zh) * | 2020-04-07 | 2022-12-13 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pde5抑制剂化合物及其制备方法和应用 |
| WO2021245192A1 (en) | 2020-06-04 | 2021-12-09 | Topadur Pharma Ag | Novel dual mode of action soluble guanylate cyclase activators and phosphodiesterase inhibitors and uses thereof |
| WO2022022669A1 (en) * | 2020-07-30 | 2022-02-03 | Biofront Therapeutics (Beijing) Co., Ltd. | Dual-functional compounds and methods of use |
| CA3187693A1 (en) * | 2020-07-30 | 2022-02-03 | Zheng Huang | Drug conjugates comprising apremilast, and a nitric oxide-releasing moiety and uses thereof |
| CN116456963A (zh) | 2020-11-02 | 2023-07-18 | 尼科斯股份有限公司 | 用于治疗干性年龄相关性黄斑变性、地图状萎缩和青光眼相关性神经变性的no-pde5抑制剂 |
| WO2023005180A1 (en) * | 2021-07-30 | 2023-02-02 | Biofront Therapeutics (Beijing) Co., Ltd. | Dual-functional compounds and methods of use |
| JP2024536047A (ja) | 2021-09-29 | 2024-10-04 | トパデュール ファルマ アーゲー | ２－フェニル－３，４－ジヒドロピロロ［２，ｌ－ｆ］［１，２，４］トリアジノン誘導体の局所組成物及びその使用 |
| CN113754612B (zh) * | 2021-10-26 | 2023-09-26 | 山东安舜制药有限公司 | 一种西地那非中间体的制备方法 |
| KR20230129639A (ko) * | 2022-03-02 | 2023-09-11 | 연세대학교 산학협력단 | 이중작용 pde5 억제제/질산유기에스터의 국소 혈류 증진을 위한 경피 투약 형태 |
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| GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| US5250534A (en) | 1990-06-20 | 1993-10-05 | Pfizer Inc. | Pyrazolopyrimidinone antianginal agents |
| CA2309332C (en) * | 1997-11-12 | 2002-12-03 | Bayer Aktiengesellschaft | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
| GB9823103D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
| KR100358083B1 (ko) * | 2000-02-17 | 2002-10-25 | 에스케이케미칼주식회사 | 피롤로피리미디논 유도체와 이의 제조방법, 그리고 이의용도 |
| GB0106661D0 (en) | 2001-03-16 | 2001-05-09 | Pfizer Ltd | Pharmaceutically active compounds |
| TW200407143A (en) * | 2002-05-21 | 2004-05-16 | Bristol Myers Squibb Co | Pyrrolotriazinone compounds and their use to treat diseases |
| US7102002B2 (en) | 2004-06-16 | 2006-09-05 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| TW200902019A (en) * | 2007-04-26 | 2009-01-16 | Ono Pharmaceutical Co | Dicyclic heterocyclic compound |
| EP2387404B1 (en) | 2009-01-17 | 2014-06-25 | Bayer Intellectual Property GmbH | Sgc stimulators and activators in combination with pde5 inhbitors for the treatment of erectile dysfunction |
| EP2512479B1 (en) | 2009-12-18 | 2016-03-30 | Exodos Life Sciences Limited Partnership | Compositions for treating peripheral vascular disease |
| HRP20161033T1 (hr) | 2012-05-04 | 2016-10-21 | Merck Patent Gmbh | Derivati pirolotriazinona |
| EP2909207A1 (en) | 2012-10-16 | 2015-08-26 | Almirall S.A. | Pyrrolotriazinone derivatives as pi3k inhibitors |
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2016
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