TWI731842B - 醛固酮合成酶抑制劑 - Google Patents
醛固酮合成酶抑制劑 Download PDFInfo
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- TWI731842B TWI731842B TW104133758A TW104133758A TWI731842B TW I731842 B TWI731842 B TW I731842B TW 104133758 A TW104133758 A TW 104133758A TW 104133758 A TW104133758 A TW 104133758A TW I731842 B TWI731842 B TW I731842B
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- Prior art keywords
- alkyl
- compound
- substituted
- unsubstituted
- heterocyclic group
- Prior art date
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- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 108010009911 Cytochrome P-450 CYP11B2 Proteins 0.000 claims description 20
- 102100024329 Cytochrome P450 11B2, mitochondrial Human genes 0.000 claims description 19
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 19
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 18
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 17
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 13
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 208000017169 kidney disease Diseases 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 230000002861 ventricular Effects 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- WSXNRJXPTNQJBH-UHFFFAOYSA-N 5,6-dihydro-4h-thiazine Chemical compound C1CSN=CC1 WSXNRJXPTNQJBH-UHFFFAOYSA-N 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 208000016998 Conn syndrome Diseases 0.000 claims description 5
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 claims description 5
- 208000034189 Sclerosis Diseases 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 208000013846 primary aldosteronism Diseases 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 208000008253 Systolic Heart Failure Diseases 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims description 3
- 206010020565 Hyperaemia Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229940099472 immunoglobulin a Drugs 0.000 claims 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 44
- 238000000034 method Methods 0.000 abstract description 44
- 208000037765 diseases and disorders Diseases 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 239000000203 mixture Substances 0.000 description 88
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- 239000000243 solution Substances 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 238000003818 flash chromatography Methods 0.000 description 43
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
- 239000010410 layer Substances 0.000 description 29
- -1 morpholine -4-yl Chemical group 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 25
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 22
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 22
- 229960002478 aldosterone Drugs 0.000 description 22
- 238000004808 supercritical fluid chromatography Methods 0.000 description 22
- 239000012267 brine Substances 0.000 description 19
- 238000010828 elution Methods 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
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- 230000000694 effects Effects 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 15
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
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- 125000003118 aryl group Chemical group 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 210000003734 kidney Anatomy 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
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- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
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- 239000002253 acid Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 7
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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| WO2016089800A1 (en) * | 2014-12-02 | 2016-06-09 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors |
| CA3055292A1 (en) * | 2016-12-29 | 2018-07-05 | Selenity Therapeutics (Bermuda), Ltd. | Metalloenzyme inhibitor compounds |
| CN113767095A (zh) | 2019-05-01 | 2021-12-07 | 勃林格殷格翰国际有限公司 | (r)-4-溴苯磺酸(2-甲基环氧乙烷-2-基)甲酯 |
| AU2021341508A1 (en) | 2020-09-10 | 2023-05-25 | Precirix N.V. | Antibody fragment against fap |
| AU2022415313A1 (en) | 2021-12-14 | 2024-05-02 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors for treating chronic kidney disease |
| WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
| AU2023264245A1 (en) | 2022-05-02 | 2024-12-19 | Precirix N.V. | Pre-targeting |
| CN121181527A (zh) * | 2024-06-21 | 2025-12-23 | 江苏豪森药业集团有限公司 | 双稠环类化合物、及其制备方法和应用 |
| WO2026093586A1 (en) | 2024-11-04 | 2026-05-07 | AstraZeneca Ireland Limited | Combination of a aldosterone synthase inhibitor (asi) and a sodium-glucose co-transporter 2 inhibitor (sglt2i) for use in methods of reducing the risk of cardiovascular and heart failure events in a subject |
Citations (3)
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|---|---|---|---|---|
| WO2010042477A1 (en) * | 2008-10-07 | 2010-04-15 | Schering Corporation | Benzodioxan analogues as alpha2c adrenergic receptor modulators |
| US20100292225A1 (en) * | 2009-05-15 | 2010-11-18 | Sylvie Chamoin | Aryl pyridine as aldosterone synthase inhibitors |
| WO2014055595A1 (en) * | 2012-10-05 | 2014-04-10 | Merck Sharp & Dohme Corp. | Indoline compounds as aldosterone synthase inhibitiors related applications |
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| MX350717B (es) * | 2011-11-30 | 2017-09-14 | Hoffmann La Roche | Nuevos derivados biciclicos de dihidroisoquinolin-1-ona. |
| JP2016516004A (ja) * | 2013-02-22 | 2016-06-02 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | 抗糖尿病二環式化合物 |
| WO2014179186A1 (en) * | 2013-04-30 | 2014-11-06 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors |
| ES2684050T3 (es) * | 2014-07-24 | 2018-10-01 | Boehringer Ingelheim International Gmbh | Inhibidores de aldosterona sintasa |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010042477A1 (en) * | 2008-10-07 | 2010-04-15 | Schering Corporation | Benzodioxan analogues as alpha2c adrenergic receptor modulators |
| US20100292225A1 (en) * | 2009-05-15 | 2010-11-18 | Sylvie Chamoin | Aryl pyridine as aldosterone synthase inhibitors |
| WO2014055595A1 (en) * | 2012-10-05 | 2014-04-10 | Merck Sharp & Dohme Corp. | Indoline compounds as aldosterone synthase inhibitiors related applications |
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