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WO2025140409A1 - Inhibiteur d'aldostérone synthétase, son procédé de préparation et son utilisation - Google Patents

Inhibiteur d'aldostérone synthétase, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025140409A1
WO2025140409A1 PCT/CN2024/142727 CN2024142727W WO2025140409A1 WO 2025140409 A1 WO2025140409 A1 WO 2025140409A1 CN 2024142727 W CN2024142727 W CN 2024142727W WO 2025140409 A1 WO2025140409 A1 WO 2025140409A1
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substituted
unsubstituted
alkyl
membered
alkoxy
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Chinese (zh)
Inventor
吴俊军
陆银锁
杨钊
肖瑛
李洪超
宋泽楠
杨洋
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Shenzhen Salubris Pharmaceuticals Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the invention belongs to the technical field of chemical medicines and provides an aldosterone synthase inhibitor and a preparation method and use thereof.
  • Aldosterone is a steroid hormone with mineralocorticoid activity. It is mainly produced by the adrenal zona glomerulosa in response to angiotensin II, adrenocorticotropic hormone and increased serum potassium content. The main physiological role of aldosterone in the kidney is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal nephron. However, aldosterone has also been shown to be a pro-inflammatory and pro-fibrotic hormone in blood vessels, heart and kidneys. The effect of aldosterone on gene expression is regulated by binding to the mineralocorticoid receptor (MR) and the typical nuclear hormone receptor pathway.
  • MR mineralocorticoid receptor
  • CYP11B2 (aldosterone synthase) is a cytochrome P450 enzyme, known as an enzyme that catalyzes a series of reactions from 11-deoxycorticosterone (i.e., aldosterone precursor) to aldosterone.
  • CYP11B2 is mainly expressed in the zona glomerulosa of the adrenal cortex, and the aldosterone in the plasma is regulated by the activity of the enzyme in the adrenal gland.
  • the expression of aldosterone has also been confirmed in the positions other than the adrenal glands such as the cardiovascular system, kidney, adipose tissue, and brain, and the discovery that the aldosterone produced locally in each organ is related to organ dysfunction has received attention.
  • CYP11B2 inhibitors can suppress the production of aldosterone in the research using enzymes and cultured cells, and have the effect and therapeutic effect of suppressing the production of aldosterone in the research using various experimental animal models.
  • CYP11B2 inhibitors show the effect and hypotensive effect of reducing the aldosterone level in the plasma and urine in hypertensive patients and primary aldosteronism patients. Finding a means to inhibit the biosynthetic pathway of aldosterone is a highly feasible approach for establishing effective treatments for various aldosterone-related diseases.
  • CYP11B2 aldosterone synthase
  • patent application CN103827101B reports a bicyclic dihydroquinoline-2-one derivative. Although the compound has good CYP11B2 inhibitory activity, its selectivity is poor.
  • CN114853755A also reports an aldosterone synthase inhibitor, but the compound is a chiral compound and is relatively difficult to synthesize. In addition, the side effects are large. In addition, the existing CYP11B2 inhibitors have the problems of poor activity, difficulty in synthesis, poor stability, and low bioavailability. Therefore, there is an urgent need to provide more CYP11B2 inhibitors.
  • the present invention provides an aldosterone synthase inhibitor and a preparation method and use thereof to solve the problems existing in the prior art.
  • the present invention provides an aldosterone synthase inhibitor, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof.
  • the structure of the aldosterone synthase inhibitor is shown in general formula I or general formula IA:
  • said R1 or R2 are independently selected from: H, halogen, hydroxyl, cyano, substituted or unsubstituted C1 - C8 alkyl, substituted or unsubstituted C1 - C8 alkoxy, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, C1 - C6 alkylsulfonyl, substituted or unsubstituted C6 - C12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;
  • the R 5 is independently selected from: substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted 5-12 membered heteroaryl;
  • the ring A is independently selected from: 5-12 membered fused heteroaryl or C 10 -C 12 aryl;
  • the substituents in the "substituted" are independently selected from the group consisting of C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkoxy, -NR 3 R 4 , hydroxy, oxo, carboxyl, cyano, halogen, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylacyl, C 1 -C 6 alkylamido, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C 3 -C 8 cycloalkyl substituted C 1 -C 8 alkoxy, C 6 -C 12 aryl, C 6 -C 12 aryloxy, C 1 -C 8 alkyl substituted C 6 -C 12 ary
  • the R 3 and R 4 are independently selected from: H or C 1 -C 8 alkyl
  • n, p or q are independently selected from integers of 0, 1, 2 or 3.
  • the present invention also provides an aldosterone synthase inhibitor, or its isomer, or its racemate, or its pharmaceutically acceptable salt, wherein the structure of the aldosterone synthase inhibitor is shown in the general formula IB:
  • said R1 or R2 are independently selected from: H, halogen, cyano, substituted or unsubstituted C1 - C8 alkyl, substituted or unsubstituted C1 - C8 alkoxy, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6 - C12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;
  • the R 5 is independently selected from: substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted 5-12 membered heteroaryl;
  • the ring A is independently selected from: 5-12 membered fused and heteroaryl;
  • the substituents in the "substituted" are independently selected from the group consisting of C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkoxy, -NR 3 R 4 , hydroxy, oxo, carboxyl, cyano, halogen, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamido, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C 3 -C 8 cycloalkyl substituted C 1 -C 8 alkoxy, C 6 -C 12 aryl, C 6 -C 12 aryloxy, C 1 -C 8 alkyl substituted C 6 -C 12 aryloxy, C 1 -C 8 alkoxy
  • n, p or q are independently selected from integers of 0, 1, 2 or 3.
  • the R1 or R2 is independently selected from: H, halogen, cyano, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl or substituted or unsubstituted 5-10 membered heteroaryl;
  • the R 5 is independently selected from: substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl;
  • the ring A is independently selected from: 6-10 membered fused and heteroaryl;
  • the substituents in the "substituted" are independently selected from the group consisting of C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -NR 3 R 4 , hydroxy, oxo, carboxyl, cyano, halogen, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamido, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C 3 -C 8 cycloalkyl substituted C 1 -C 6 alkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 1 -C 6 alkyl substituted C 6 -C 10 aryloxy, C 1 -C 6 alkoxy
  • the R1 or R2 is independently selected from: H, halogen, cyano, substituted or unsubstituted C1 - C3 alkyl, substituted or unsubstituted C1 - C3 alkoxy, substituted or unsubstituted C3 - C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6- C8 aryl or substituted or unsubstituted 5-8 membered heteroaryl;
  • the R 5 is independently selected from: substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 1 -C 3 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 8 aryl, or substituted or unsubstituted 5-8 membered heteroaryl;
  • the ring A is independently selected from: 6-9 membered fused and heteroaryl;
  • the substituents in the "substituted" are independently selected from the group consisting of C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, -NR 3 R 4 , hydroxy, oxo, carboxyl, cyano, halogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamido, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyloxy, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkoxy, C 6 -C 8 aryl, C 6 -C 8 aryloxy, C 1 -C 3 alkyl substituted C 6 -C 8 aryloxy, C 1 -C 3 alkoxy
  • the R 3 and R 4 are independently selected from: H or C 1 -C 3 alkyl
  • n, p or q are independently selected from integers of 0, 1, 2 or 3.
  • the present invention also provides an aldosterone synthase inhibitor, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the aldosterone synthase inhibitor is shown in the general formula IIA or IIB:
  • R 1 , R 2 , ring A, n, p and q are the same as those mentioned above.
  • the present invention also provides an aldosterone synthase inhibitor, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the aldosterone synthase inhibitor is shown in the general formula IIIA, IIIB, IIIC or IIID:
  • R 1 , R 2 , ring A, n, p and q are the same as those mentioned above.
  • the ring A is selected from:
  • the ring A is selected from:
  • the ring B is selected from 5-10 membered heteroaryl or C 6 -C 10 aryl; and the X, Y, Z 1 , Z 2 or Z 3 are independently selected from C or N.
  • the ring A is selected from: Wherein, the ring B is selected from 5-10 membered heteroaryl; and the X or Y is independently selected from C or N.
  • the ring A is selected from: wherein the ring B is selected from a 5-10 membered heteroaryl group; and the X or Y is independently selected from C or N.
  • the ring B is selected from a 5-10 membered heteroaryl group, preferably a 5-8 membered heteroaryl group; more preferably a 5-6 membered heteroaryl group, and examples of the ring B include but are not limited to: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, triazinyl, isoxazolyl, and isothiazolyl.
  • the ring A is selected from: benzothiophenyl, benzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, imidazopyridinyl, naphthyridinyl, and naphthyl.
  • the ring A is selected from:
  • the R1 or R2 is independently selected from: H, hydroxyl, halogen, cyano, C1 - C6 alkyl, halogenated C1 - C6 alkyl, C1 -C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, C3 - C8 cycloalkyloxy, C1 - C6 alkylsulfonyl, C1 - C6 alkylacyl, 3-8 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; further, as a preferred technical solution of the present invention, the R1 or R2 is independently selected from: H, halogen, cyano, C1 - C3 alkyl, halogenated C1 - C3 alkyl, C1 - C3 alkoxy, halogenated C1 -C3 alkoxy, C
  • the R 1 or R 2 is independently selected from: H, hydroxyl, F, Cl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, cyclopropyl, cyclopropyloxy, methylsulfonyl, ethylsulfonyl, formyl or acetyl;
  • the R 1 or R 2 is independently selected from: H, F, Cl, cyano, methyl, methoxy, trifluoromethyl.
  • the C1 - C8 alkoxy group is preferably C1 - C2 , C1 - C3 , C1- C4 , C1 - C5 or C1 - C6 alkoxy group.
  • examples of the alkoxy group include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • the C 3 - C 8 cycloalkyl group is preferably selected from: C 3 - C 6 cycloalkyl group or C 3 - C 5 cycloalkyl group, and the cycloalkyl group is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the C 3 - C 8 cycloalkoxy group is preferably selected from: C 3 - C 6 cycloalkoxy group or C 3 - C 5 cycloalkoxy group, and the cycloalkyl group is specifically selected from cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
  • the heterocycloalkyl group is selected from 3-12 membered heterocycloalkyl groups, preferably: 3-10 membered heterocycloalkyl groups, 3-8 membered heterocycloalkyl groups, 3-6 membered heterocycloalkyl groups or 3-5 membered heterocycloalkyl groups, and examples of the heterocycloalkyl groups include: aziridine, oxirane, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , thiomorpholinyl, 1,1-dioxo
  • heterocycloalkyl examples include dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl; preferred examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl. More preferred examples of heterocycloalkyl are pyrrolidinyl,
  • the halogenated C1 - C8 alkyl or halogenated C1 - C8 alkyl preferably halogenated C1 - C2 , C1 - C3 , C1 - C4 , C1 - C5 or C1 - C6 alkyl or C1 - C2 , C1 - C3 , C1 - C4 , C1 - C5 or C1 - C6 haloalkyl
  • examples of the halogenated alkyl include: fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl
  • special halogenated alkyl are trifluoromethyl and trifluoroethyl.
  • the substituted or unsubstituted C 6 -C 12 aryl group is preferably: a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted C 6 -C 8 aryl group, a substituted or unsubstituted C 6 -C 12 aryl group, and examples of the substituted or unsubstituted aryl group include: phenyl, o-tolyl, m-tolyl, p-tolyl, phenol, xylyl, chlorophenyl, dichlorophenyl, nitrophenyl, cyanophenyl or naphthyl.
  • the substituted or unsubstituted 5-12 membered heteroaryl is preferably: a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 5-7 membered heteroaryl, a substituted or unsubstituted 5-6 membered heteroaryl, and examples of the substituted or unsubstituted heteroaryl include: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl , thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl
  • Particular heteroaryl includes pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl.
  • heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, indazolyl, isoxazolyl and isothiazolyl.
  • the 5-12 membered fused heteroaryl is preferably: 5-10 membered fused heteroaryl, 6-10 membered fused heteroaryl, 6-9 membered fused heteroaryl, 6-8 membered fused heteroaryl;
  • the fused heteroaromatic hydrocarbon group include but are not limited to: benzothiophenyl, benzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, imidazopyridyl, naphthy
  • the C 6 -C 12 aryl group is preferably a C 6 -C 10 aryl group or a C 10 -C 12 aryl group.
  • the C 6 -C 10 aryl group is preferably a C 6 -C 8 aryl group, and more preferably a phenyl group.
  • the C 10 -C 12 aryl group is more preferably a naphthyl group.
  • the halogen is selected from fluorine, chlorine, bromine and iodine.
  • the aldosterone synthase inhibitor, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from:
  • the present invention also provides a deuterated compound of the aforementioned aldosterone synthase inhibitor, or its isomer, or its racemate, or its pharmaceutically acceptable salt. Further, as a preferred technical solution of the present invention, the deuterated compound is selected from the following structures:
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an aldosterone synthase inhibitor of formula I, IA, IB, IIA, IIB, IIIA, IIIB, IIIC or IIID, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, and one or more pharmaceutically acceptable excipients and/or carriers.
  • the present invention further provides a method for preparing a drug for treating or preventing diseases related to elevated CYP11B2 activity levels, including chronic kidney disease, congestive heart failure, hypertension, diabetic nephropathy, primary aldosteronism and Cushing's syndrome, comprising an aldosterone synthase inhibitor of formula I, IA, IB, IIA, IIB, IIIA, IIIB, IIIC or IIID, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition thereof.
  • diseases related to elevated CYP11B2 activity levels including chronic kidney disease, congestive heart failure, hypertension, diabetic nephropathy, primary aldosteronism and Cushing's syndrome, comprising an aldosterone synthase inhibitor of formula I, IA, IB, IIA, IIB, IIIA, IIIB, IIIC or IIID, or an isomer thereof, or a racemate thereof, or
  • the related diseases caused by the increased activity level of CYP11B2 are selected from: hypertension and the like.
  • the aldosterone synthase inhibitor of the present invention can selectively inhibit CYP11B2 and weakly inhibit CYP11B1, and has better CYP11B2 inhibitory activity.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention, which are prepared by reacting the compounds discovered in the present invention with specified substituents and a pharmaceutically acceptable acid or base.
  • compounds provided by the present invention also exist in prodrug forms.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms.
  • the alkyl group contains 1 to 8 carbon atoms, and more preferably, the alkyl group contains 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof.
  • Examples of monocyclic saturated heterocycloalkyl groups are aziridine, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinyl.
  • excipient generally refers to a carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
  • Step B Synthesis of methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate
  • Methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (31.5 g, 110.87 mmol) was dissolved in 300 ml of hydrochloric acid (6 M), and the mixture was heated to 105° C. and refluxed with stirring for 16 hours.
  • Step D Synthesis of (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-ylidene)-2-methylpropane-2-sulfonamide
  • Step E Synthesis of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-2-methylpropane-2-sulfonamide
  • Step G Synthesis of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide
  • Step H Synthesis of (R)-N-(4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide
  • Step D Synthesis of (R)-N-(1'-cyano-5,6,7,8-tetrahydro-[4,6'-diisoquinolinyl]-8-yl)propanamide
  • 1,6-Dichloroisoquinoline 450 mg, 2.27 mmol
  • sodium methanesulfinate 348 mg, 3.41 mmol
  • potassium carbonate 784 mg, 5.67 mmol
  • dimethyl sulfoxide 10 ml
  • Step B 1-(Methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
  • the synthesis method is as follows: Referring to step C of example 26, 1-(methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline is obtained.
  • Step C Synthesis of (R)-N-(1'-(methylsulfonyl)-5,6,7,8-tetrahydro-[4,6'-diisoquinolinyl]-8-yl)propanamide
  • 3-Fluoro-6-methoxyquinoline (400.0 mg, 2.26 mmol) was dissolved in dichloromethane (5 ml), and a dichloromethane solution of boron tribromide (23.0 ml, 1 mol) was added under nitrogen and reacted at room temperature for 12 hours.
  • Step B Synthesis of 3-fluoroquinolin-6-yl trifluoromethanesulfonate
  • Step D Synthesis of (R)-N-(4-(3-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide
  • 6-aminoquinoline-5-carbonitrile 600 mg, 3.55 mmol
  • cuprous bromide 609 mg, 4.26 mmol
  • acetonitrile 12 mL
  • a solution of tert-butyl nitrite 474 mg, 4.61 mmol
  • acetonitrile 1 mL
  • the temperature was raised to 60°C for reaction for 8 hours, and then the temperature was moved to room temperature for reaction overnight.
  • 1N hydrochloric acid aqueous solution 5 mL was added and the reaction was continued for 3 hours.
  • Step D (R)-N-(4-(5-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide
  • 8-Bromo-6-chloroquinoline 500 mg, 2.05 mmol
  • zinc cyanide 145 mg, 1.23 mmol
  • tetrakis(triphenylphosphine)palladium 235 mg, 0.21 mmol
  • Step B Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-8-carbonitrile
  • 6-Bromoquinoline-5-carbonitrile 190 mg, 1.01 mmol
  • pinacol diboron 381 mg, 1.50 mmol
  • chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 79 mg, 0.10 mmol
  • 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 48 mg, 0.10 mmol
  • potassium acetate 294 mg, 3.00 mmol
  • Step C (R)-N-(4-(8-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide
  • the inventors herein use the H295R Steroidogenesis Assay System to test the enzymatic activity of human CYP11B1, human CYP11B2, etc.
  • the in vitro H295R Steroidogenesis Assay System utilizes a human adrenal cancer cell line (NCI-H295R cells) to constitute a Level 2 "in vitro assay providing mechanistic data" for screening and prioritization purposes.
  • NCI-H295R cells human adrenal cancer cell line
  • the development and standardization of the method is performed in a multi-step process for screening chemistries for steroidogenesis, and the H295R assay has been optimized and validated according to the OECD test guideline (Test Guideline No. 456 H295R Steroidogenesis Assay).
  • DMSO was diluted 3 times in a series of gradients, with a total of 10 concentration points.
  • the 10 concentration points were diluted 10 times with DMEM:F12 (1:1) blank medium, with a starting concentration of 10mM.
  • 1.5uL of different concentrations of compounds were added to the cells, with a final DMSO concentration of 0.1% and a starting compound concentration of 100uM.
  • 40uL of the cell supernatant was collected and the aldosterone and cortisol levels were analyzed by LCMS.
  • Inhibition rate% (Peak Area Avg SCs-Peak Area cmpd)/(Peak Area Avg SCs-Peak Area blank) ⁇ 100
  • Selectivity CYP11B1Ki (nM) / CYP11B2Ki (nM); where A indicates a selectivity value between 0-50, B indicates a selectivity value between 51-100, C indicates a selectivity value between 101-150, and D indicates a selectivity value above 151;
  • the compounds of the present invention have a good inhibitory effect on CYP11B2, and the effect is better than that of the control compound Baxdrostat.
  • the compounds of the present invention have excellent selectivity for CYP11B2 and can selectively inhibit CYP11B2, while weakly inhibiting CYP11B1.
  • SD rats male, 180-250 g, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
  • DMSO dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • normal saline normal saline
  • heparin normal saline
  • acetonitrile formic acid
  • propranolol internal standard
  • 25 ⁇ L of the test sample or positive drug working solution was added to 475 ⁇ L of liver microsome working solution and mixed evenly.
  • 150 ⁇ L of internal standard acetonitrile solution was added to the 0min sample to precipitate the protein, and then 15 ⁇ L of NADPH solution was added and placed in a 4°C refrigerator. After the other samples were pre-incubated at 37°C for 10min, 15 ⁇ L of NADPH solution was added to the 20min and 60min samples to start the reaction.
  • 15 ⁇ L of potassium phosphate buffer solution was added to the samples without NADPH, and they were placed together at 37°C for incubation. After the reaction time was reached, 150 ⁇ L of internal standard acetonitrile solution was added to precipitate the protein.

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Abstract

La présente invention appartient au domaine technique des produits pharmaceutiques chimiques. La présente invention concerne un inhibiteur de l'aldostérone synthétase, son procédé de préparation et son utilisation.
PCT/CN2024/142727 2023-12-29 2024-12-26 Inhibiteur d'aldostérone synthétase, son procédé de préparation et son utilisation Pending WO2025140409A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103958478A (zh) * 2011-11-30 2014-07-30 霍夫曼-拉罗奇有限公司 新双环二氢异喹啉-1-酮衍生物
WO2024109885A1 (fr) * 2022-11-23 2024-05-30 上海翰森生物医药科技有限公司 Inhibiteur de composé polycyclique de pyridine, son procédé de préparation et son utilisation
WO2024213042A1 (fr) * 2023-04-11 2024-10-17 上海翰森生物医药科技有限公司 Inhibiteur de composé cyclique benzo-fusionné, son procédé de préparation et son utilisation
CN118852103A (zh) * 2023-04-28 2024-10-29 长春金赛药业有限责任公司 Cyp11b2抑制剂化合物、药物组合物及其应用
CN118852196A (zh) * 2023-04-28 2024-10-29 长春金赛药业有限责任公司 Cyp11b2抑制剂化合物、药物组合物及其应用
WO2024222814A1 (fr) * 2023-04-28 2024-10-31 长春金赛药业有限责任公司 Composé inhibiteur de cyp11b2, composition pharmaceutique et utilisation de celui-ci
WO2024235165A1 (fr) * 2023-05-12 2024-11-21 南京明德新药研发有限公司 Composé hétérocyclique contenant de l'azote et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103958478A (zh) * 2011-11-30 2014-07-30 霍夫曼-拉罗奇有限公司 新双环二氢异喹啉-1-酮衍生物
WO2024109885A1 (fr) * 2022-11-23 2024-05-30 上海翰森生物医药科技有限公司 Inhibiteur de composé polycyclique de pyridine, son procédé de préparation et son utilisation
WO2024213042A1 (fr) * 2023-04-11 2024-10-17 上海翰森生物医药科技有限公司 Inhibiteur de composé cyclique benzo-fusionné, son procédé de préparation et son utilisation
CN118852103A (zh) * 2023-04-28 2024-10-29 长春金赛药业有限责任公司 Cyp11b2抑制剂化合物、药物组合物及其应用
CN118852196A (zh) * 2023-04-28 2024-10-29 长春金赛药业有限责任公司 Cyp11b2抑制剂化合物、药物组合物及其应用
WO2024222814A1 (fr) * 2023-04-28 2024-10-31 长春金赛药业有限责任公司 Composé inhibiteur de cyp11b2, composition pharmaceutique et utilisation de celui-ci
WO2024235165A1 (fr) * 2023-05-12 2024-11-21 南京明德新药研发有限公司 Composé hétérocyclique contenant de l'azote et son utilisation

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