KR20190049691A - 심부전의 치료 방법 - Google Patents
심부전의 치료 방법 Download PDFInfo
- Publication number
- KR20190049691A KR20190049691A KR1020197003599A KR20197003599A KR20190049691A KR 20190049691 A KR20190049691 A KR 20190049691A KR 1020197003599 A KR1020197003599 A KR 1020197003599A KR 20197003599 A KR20197003599 A KR 20197003599A KR 20190049691 A KR20190049691 A KR 20190049691A
- Authority
- KR
- South Korea
- Prior art keywords
- oxo
- pyrimidine
- dihydrothieno
- alkyl
- carboxylic acid
- 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.)
- Ceased
Links
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 56
- -1 thienopyrimidine compound Chemical class 0.000 claims abstract description 69
- 241000124008 Mammalia Species 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 23
- KXTOBOUEORHQTG-UHFFFAOYSA-N 2-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound O=C1NC(C)=NC2=C1C=C(C(O)=O)S2 KXTOBOUEORHQTG-UHFFFAOYSA-N 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 8
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 claims description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
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- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- OHWZRDHRORANHY-UHFFFAOYSA-N 2-[(3-chlorophenyl)methyl]-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C(N2)=O)=C1N=C2CC1=CC=CC(Cl)=C1 OHWZRDHRORANHY-UHFFFAOYSA-N 0.000 claims description 3
- NZPFNMZJSZYNLZ-UHFFFAOYSA-N 2-[(3-chlorophenyl)methyl]-5-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CC=CC(Cl)=C1 NZPFNMZJSZYNLZ-UHFFFAOYSA-N 0.000 claims description 3
- MNNQGRJYHHDZPP-UHFFFAOYSA-N 2-benzyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C(N2)=O)=C1N=C2CC1=CC=CC=C1 MNNQGRJYHHDZPP-UHFFFAOYSA-N 0.000 claims description 3
- IJHOVPDESGUYIJ-UHFFFAOYSA-N 4-oxo-2-(thiophen-2-ylmethyl)-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C(N2)=O)=C1N=C2CC1=CC=CS1 IJHOVPDESGUYIJ-UHFFFAOYSA-N 0.000 claims description 3
- PZXOKIIUCOXTAT-UHFFFAOYSA-N 4-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C(N2)=O)=C1N=C2CC1=CC=CC(C(F)(F)F)=C1 PZXOKIIUCOXTAT-UHFFFAOYSA-N 0.000 claims description 3
- LIQNVZZWECMHPS-UHFFFAOYSA-N 5-methyl-4-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CC=CC(C(F)(F)F)=C1 LIQNVZZWECMHPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
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- 239000000126 substance Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- LBSSCTYABOXXHX-UHFFFAOYSA-N 2-(cyclopenten-1-ylmethyl)-5-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CCCC1 LBSSCTYABOXXHX-UHFFFAOYSA-N 0.000 claims description 2
- SKVLWSYDTSHFQY-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)methyl]-5-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CC=C(Cl)C(Cl)=C1 SKVLWSYDTSHFQY-UHFFFAOYSA-N 0.000 claims description 2
- REQCEJMBROBVOU-UHFFFAOYSA-N 2-[(3-chloro-4-fluorophenyl)methyl]-5-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CC=C(F)C(Cl)=C1 REQCEJMBROBVOU-UHFFFAOYSA-N 0.000 claims description 2
- PREAJIFBSWKBRL-UHFFFAOYSA-N 2-[(5-chloro-2-fluorophenyl)methyl]-5-methyl-4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1C(=O)C=2C(C)=C(C(O)=O)SC=2N=C1CC1=CC(Cl)=CC=C1F PREAJIFBSWKBRL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 claims description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 claims description 2
- 208000009378 Low Cardiac Output Diseases 0.000 claims description 2
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 2
- 239000002170 aldosterone antagonist Substances 0.000 claims description 2
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- 239000002876 beta blocker Substances 0.000 claims description 2
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- VMQOKBQPYZLGEX-UHFFFAOYSA-N 4-oxo-3h-thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound S1C(C(=O)O)=CC2=C1N=CNC2=O VMQOKBQPYZLGEX-UHFFFAOYSA-N 0.000 description 7
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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| WO2020182076A1 (zh) | 2019-03-08 | 2020-09-17 | 南京药捷安康生物科技有限公司 | 磷酸二酯酶抑制剂的用途 |
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| US8299083B2 (en) * | 2004-08-17 | 2012-10-30 | The Johns Hopkins University | PDE5 inhibitor compositions and methods for treating cardiac indications |
| KR101288144B1 (ko) * | 2005-06-14 | 2013-07-18 | 아스카 세이야쿠 가부시키가이샤 | 티에노피리미딘 유도체 |
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| GB2465405A (en) * | 2008-11-10 | 2010-05-19 | Univ Basel | Triazine, pyrimidine and pyridine analogues and their use in therapy |
| UA111589C2 (uk) * | 2010-05-31 | 2016-05-25 | Аска Фармасьютікал Ко., Лтд. | Кристалічна форма похідної тієнопіримідину (варіанти) |
| JP2016532721A (ja) * | 2013-10-07 | 2016-10-20 | バイエル ファーマ アクチエンゲゼルシャフト | 環状チエノウラシルカルボキサミドおよびその使用 |
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2020
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| CA3030021A1 (en) | 2018-01-11 |
| US10870656B2 (en) | 2020-12-22 |
| AU2017292918A1 (en) | 2019-02-07 |
| US20190211028A1 (en) | 2019-07-11 |
| US20210261567A1 (en) | 2021-08-26 |
| EP3481399A4 (en) | 2020-04-01 |
| EP3481399A1 (en) | 2019-05-15 |
| AU2017292918B2 (en) | 2021-11-11 |
| WO2018009899A1 (en) | 2018-01-11 |
| JP2019521192A (ja) | 2019-07-25 |
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