WO2023063851A1 - Inhibiteurs de l'aldostérone synthase humaine (cyp11b2) - Google Patents

Inhibiteurs de l'aldostérone synthase humaine (cyp11b2) Download PDF

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Publication number
WO2023063851A1
WO2023063851A1 PCT/RU2022/050316 RU2022050316W WO2023063851A1 WO 2023063851 A1 WO2023063851 A1 WO 2023063851A1 RU 2022050316 W RU2022050316 W RU 2022050316W WO 2023063851 A1 WO2023063851 A1 WO 2023063851A1
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Prior art keywords
alkyl
optionally substituted
cycloalkyl
halogen
hydrogen
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PCT/RU2022/050316
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English (en)
Inventor
Andrei Aleksandrovich GILEP
Natallia Vladimirovna STRUSHKEVICH
George Pascal
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«Target Medicals» Limited Liability Company
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Priority claimed from RU2021129717A external-priority patent/RU2783521C1/ru
Application filed by «Target Medicals» Limited Liability Company filed Critical «Target Medicals» Limited Liability Company
Publication of WO2023063851A1 publication Critical patent/WO2023063851A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • 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
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to organic chemistry, pharmacology, medicine, namely the invention relates to compounds for use in inhibiting the activity of human cytochrome 11 B2 (CYP1 1 B2) and their use in the treatment and/or prevention of various diseases and disorders that are mediated or supported by the activity of the hormone aldosterone.
  • the present invention also relates to pharmaceutical compositions containing the compounds of the invention and methods for preparing these compounds.
  • Aldosterone is a steroid hormone whose main physiological role is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal nephron, which in turn leads to an increase in blood pressure.
  • aldosterone is also involved in the pathogenesis of diseases or pathological conditions caused (primary hyperaldosteronism) and/or accompanied by its hypersynthesis (secondary hyperaldosteronism), including a number of diseases of the cardiovascular system, kidneys and metabolic syndrome.
  • renin-angiotensin- aldosterone system Modern standards of medical care are represented by such classes of drugs as renin inhibitors (IRs), angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), and mineralocorticoid receptor (MR) blockers.
  • IRs renin inhibitors
  • ARBs angiotensin II receptor blockers
  • ACEIs angiotensin-converting enzyme inhibitors
  • MR mineralocorticoid receptor
  • aldosterone has a so-called “rapid effect”, leading to apoptosis and preventing the proliferation of vascular endothelial and smooth muscle cells [Namsolleck et aL, 2014, Nephrology, Dialysis, Transplantation, 29 (SuppL 1 ), i62— i68), impaired vasoconstriction (Feldman et aL, 2013, Clinical and Experimental Pharmacology & Physiology, 40, 916-921 ), and endothelial inflammation [Ziwei Tang et aL, 2021 , International Journal of Endocrinology, Volume 2021 , Article ID 5575927],
  • aldosterone also through GPCR activation, enhances CYP1 1 B2 gene expression and therefore enhances its own biosynthesis and release (Caroccia et aL, 2019, The Journal of Clinical Endocricri
  • aldosterone has demonstrated a non-genomic endothelium-independent vasoconstrictor effect, also mediated through the AT1 receptor (Yamada et aL, 2008, Cardiovasc Res, 79(1 ):169-78).
  • Aldosterone is synthesized by a single enzyme, CYP11 B2 (aldosterone synthase), which catalyzes a 3-step conversion of 1 1 -deoxycorticosterone (1 1 -DOC) to aldosterone via corticosterone and 18-hydroxycorticosterone, so CYP11 B2 is a potential therapeutic target for inhibition of aldosterone synthesis, which may have an excellent pharmacodynamic profile, from that observed in other RAAS modulators.
  • CYP11 B2 aldosterone synthase
  • agents capable of inhibiting CYP11 B2 can be used to treat and/or prevent a disease or condition that is mediated or maintained by hypersynthesis of aldosterone.
  • Translation of data from in vitro studies on aldosterone synthase inhibition to in vivo results in both rodents and primates has been demonstrated for at least 7 compounds with different chemical structures, and moreover, 3 of them have shown an aldosterone-lowering effect in clinical trials: LCI699 (Novartis), RO6836191 (Roche) and LY3045697 (Ely Lilly)
  • Aldosterone synthase inhibitors for cardiovascular diseases A comprehensive review of preclinical, clinical and in silico data.
  • a CYP1 1 B2-specific molecule can be used as a diagnostic marker for various diseases associated with CYP1 1 B2 overexpression.
  • PMID 34137616].
  • the present invention provides novel chemicals capable of inhibiting the activity of the human CYP1 1 B2 enzyme, and their biological activity has been investigated.
  • the invention relates to compounds, pharmaceutical compositions containing these compounds, the use of the compounds, methods of their use in the treatment of various diseases and disorders, as well as methods for obtaining these compounds.
  • the compounds disclosed herein inhibit the activity of the human CYP1 1 B2 enzyme and their biological activity has been investigated.
  • the invention relates to compounds, pharmaceutical compositions containing these compounds, the use of these compounds, methods of their use in the treatment of various diseases and disorders, as well as methods for obtaining these compounds.
  • a disease selected in the group consisting in primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy , arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, heart and vascular remodeling,
  • Conse's syndrome primary hyperaldosteronism
  • chronic heart failure chronic heart failure with preserved ejection fraction
  • left ventricular dysfunction left ventricular hypertrophy
  • arterial hypertension resistant arterial hypertension
  • pulmonary arterial hypertension coronary heart disease
  • liver cirrhosis metabolic syndrome
  • chronic kidney disease glomerulosclerosis
  • glomerulonephritis glomerulonephritis
  • nephritic syndrome focal segmental glomerulosclerosis
  • SUBSTITUTE SHEETS postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, and insulin resistance.
  • RO represents a group selected from; wherein;
  • R1 represents a group selected from:
  • C1-C3)-alkyl partially or fully halogenated (C1 -C5)-alkyl, which may be optionally substituted with a nitrile group or with a (C1 -C3)-alkylsulfonyl,
  • R3 independently represents hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 -C3)-alkyl;
  • R6' independently represents hydrogen, (C1 -C3)-alkyl or (C3-C7)-cycloalkyl or
  • R7' independently represents hydrogen, (C1 -C3)-alkyl or (C3-C7)-cycloalkyl or
  • R6" independently represents hydrogen, (C1 -C3)-alkyl or (C3-C7)-cycloalkyl or
  • R7" independently represents hydrogen, (C1 -C3)-alkyl or (C3-C7)-cycloalkyl or
  • n 1 or 2.
  • Q1 represents a nitrogen or a carbon atom optionally substituted with a halogen.
  • Q2 represents a carbon atom.
  • Q3 represents a carbon atom optionally substituted with a trifluoromethyl.
  • Q4 represents a carbon atom.
  • Q5 represents a carbon atom
  • Q1 represents a nitrogen atom or a carbon atom optionally substituted with a halogen
  • Q2 represents a carbon atom
  • Q3 represents a carbon atom optionally substituted with a trifluoromethyl
  • Q4 represents a carbon atom
  • Q5 represents a carbon atom.
  • R1 represents a group selected from;
  • R1 represents bicyclic ring consisting of a phenyl ring connected with a 5-membered heterocycle containing 1 -2 nitrogen atoms (in particular an indolinyl group), and optionally substituted with 1 -2 R5 substituents, and
  • R1 represents a phenyl optionally substituted with 1 -3 R4 substituents
  • R6’, R7’, R6” and R7 are as defined above.
  • n is 1 , 2 or 3 (in particular 1 or 2),
  • R1 represents a 5-6 membered heteroaryl comprising one or two of nitrogen or sulfur atom, optionally substituted with 1 -2 R3 substituents.
  • R3 independently represents hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 -C3)-alkyL
  • R1 represents a group selected from:
  • n 1
  • R0 is defined above
  • R1 is as defined above.
  • n 2
  • R0 is defined above and R1 is as defined above.
  • ent in the compounds of formula (I) as defined above, n is 1
  • R0 is as defined above and R1 is as defined above.
  • n 1 , 2 or 3, and in particular 1 or 2, R1 represents a group (a) or (b)
  • Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8 and Z9 independently represent nitrogen, oxygen, sulfur or carbon and said carbon being optionally substituted with one to three groups selected from deuterium, halogen, (C1 -C3)-alkyl, partially or fully halogenated (C1 -C3)-alkyl, dashed bonds mean the ring is aromatic.
  • RO is as defined above and R1 is as defined above.
  • R1 represents a group selected from morpholinyl
  • the present invention includes a compound of Formula (la)
  • R1, n, Q1 , Q2, Q3, Q4, Q5 are as defined above.
  • the present invention includes a compound of Formula (Ila):
  • Q1 , Q2, Q3, Q4, Q5 are as described above in the description of formula (I); n is independently 1 , 2 or 3;
  • the present invention includes a compound of Formula (Ilb1 ) or Formula (Ilb2):
  • Z1 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z2 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z3 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z4 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z5 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z6 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z7 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z8 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl;
  • Z9 is independently represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1 -C3)-alkyl or partially or fully halogenated (C1 - C3)-alkyl.
  • the present invention includes a compound of Formula (He):
  • Q1 , Q2, Q3, Q4, Q5 are as described above in the description of Formula (I); n is independently selected and is 1 , 2 or 3;
  • R8 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1 -C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SC>2NR6'R7', -CONR6"R7", (C1-C3)-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)-alkyloxy;
  • R9 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1-C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SC>2NR6'R7', -CONR6"R7", (C1-C3)-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;
  • R10 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1-C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SC>2NR6'R7', -CONR6"R7", (C1-C3)-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;
  • R11 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1-C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SC>2NR6'R7', - CONR6"R7",
  • R6' is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R7' is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7 cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, when R6' is methyl, then R7' is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl, alternatively, R6' and R7' together with the nitrogen atom to which they are attached may form a 5-7 membered heterocycle containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur;
  • R6" is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R7" is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, when R6" is hydrogen, then R7" is (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, R6" and R7" together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur; dotted bonds mean the rings are aromatic.
  • the present invention includes a compound of Formula (lid):
  • Q1, Q2, Q3, Q4, Q5 are as described above in the description of Formula (I); n is independently 1 , 2 or 3;
  • the present invention includes a compound of Formula (He):
  • R1e is independently selected from:
  • Q1, Q2, Q3, Q4, Q5 are as described above in the description of Formula (I); n is independently 1 , 2 or 3.
  • the present invention includes a compound of Formula (III):
  • R1, Q1, Q2, Q3, Q4, Q5 are as described above in the description of Formula (I).
  • the present invention includes a compound of Formula (Illa):
  • Q1, Q2, Q3, Q4, Q5 are as described above in the description of Formula (I);
  • X5 is independently selected and represents a carbon or nitrogen atom
  • the present invention includes a compound of Formula (II Ib1 ) or Formula (Illb2):
  • the present invention includes a compound of Formula (I lie):
  • R8, R9, R10, R11 are as defined above in the description of Formula (He);
  • Q1, Q2, Q3, Q4, Q5 are as described above in the description of Formula (I);
  • the present invention includes a compound of Formula (Hid):
  • A1 , A2, A3 are as described above in the description of Formula (Hd).
  • the present invention includes a compound of Formula (Hie):
  • R1e is as described above in the description of Formula (lie);
  • Q1 , Q2, Q3, Q4, Q5 are as described above in the description of Formula (I); n is 1 ,2 or 3.
  • the present invention includes a compound of Formula (IV):
  • R1 , Q1 , Q2, Q3, Q4, Q5 are as described above in the description of Formula (I).
  • the present invention includes a compound of Formula (IVa):
  • X 5 and X 6 are as described above in the description of Formula (Illa); t and m are chosen independently from 0, 1 , 2, with t+m ⁇ 4.
  • the present invention includes a compound of Formula (IVb1 ) or
  • Z1 , Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 are as described above in the description of Formula
  • the present invention includes a compound of Formula (IVc):
  • the present invention includes a compound of Formula (IVd):
  • the present invention includes a compound of Formula (IVe):
  • the present invention includes a compound of Formula (V-1):
  • R1 is as described above in the description of Formula (I); n is independently selected from 1 , 2 or 3.
  • the present invention includes a compound of Formula (V-2):
  • R1 is as described above in the description of Formula (I); n is independently selected from 1 , 2 or 3.
  • the present invention includes a compound of Formula (Va-1 ):
  • X 5 and X 6 are as described above in the description of Formula (Illa); t and m are chosen independently from 0, 1 , 2, with t+m ⁇ 4.
  • the present invention includes a compound of Formula (Va-2):
  • X 5 and X 6 are as described above in the description of Formula (Illa); t and m are chosen independently and are 0, 1 , 2, with t+m ⁇ 4.
  • the present invention includes a compound of Formula (Vb-1-1 ) or Formula (Vb-1-2):
  • Z1 , Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 are as described above in the description of formulas Ilb1 and Ilb2; n is independently selected from 1 , 2 or 3.
  • the present invention includes a compound of Formula Vb-2-1 or Formula Vb-2-2:
  • Z1 , Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 are as described above in the description of Formulas Ilb1 and Ilb2; n is independently selected and is 1 , 2 or 3.
  • the present invention includes a compound of Formula (Vc-1):
  • R8, R9, R10, R11 are as described above in the description of Formula (He); n is independently selected from 1 , 2 or 3; dashed bonds mean the ring is aromatic.
  • the present invention includes a compound of Formula (Vc-2):
  • R8, R9, R10, R11 are as described above in the description of Formula (He); n is independently selected and is 1 , 2 or 3; dashed bonds mean the ring is aromatic.
  • the present invention includes a compound of Formula (Vd-1 ):
  • A1 , A2, A3 are as described above in the description of Formula (lid); n is independently selected from 1 , 2 or 3.
  • the present invention includes a compound of Formula (Vd-2):
  • SUBSTITUTE SHEETS (RULE 26) A1 , A2, A3 are as described above in the description of Formula (lid); n is independently selected froml , 2 or 3.
  • the present invention includes a compound of Formula (Ve-1 ):
  • R1e are as described above in the description of Formula (He).
  • the present invention includes a compound of Formula (Ve-2):
  • R1e are as described above in the description of Formula (He).
  • the present invention includes a compound of Formula (VI):
  • R12 is independently selected and is:
  • the present invention includes a compound of Formula (VII):
  • R13 is independently selected from: cyclopropyl
  • the present invention includes a compound of Formula (ll-l);
  • R1 is chosen independently from:
  • C1 -C4-alkyl partially or fully halogenated C1 or (C3-C4) alkyl, C2-alkyl optionally substituted with one or 3 halogens, 2 chlorine atoms, 2 bromine atoms or 2 iodine atoms;
  • R4 is independently deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2 - C3) alkynyl, -(C1 -C3)-alkoxy, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SC>2NR6’R7’, -CONR6”R7”, (C1- C3)-alkoxy-(C1 -C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)-alkyloxy;
  • R6’ is independently hydrogen, (C1 -C3)-alkyl, (C3-C7)-cycloalkyl, or (C3-C7) -cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R7’ is independently hydrogen, (C1 -C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl; alternatively, R6’ and R7’ together with the nitrogen atom to which they are attached may form a 5-7 membered heterocycle, containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur;
  • R6 is independently hydrogen, (C2-C3) alkyl, (C3-C7)-cycloalkyl or (C3-C7) cycloalkyl substituted with one (C1-C3)-alkyl;
  • R7 is independently hydrogen, (C2-C3) alkyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, when R6” is methyl, then R7” is (C1-C3)-alkyl, (C3-C7)-cycloalkyl, or (C3- C7) -cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, R6” and R7” together with the nitrogen atom to which they are attached may form a 5-7 membered heterocycle containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur.
  • the present invention includes a compound of Formula (ll-lla):
  • X'1 is independently a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium or halogen;
  • the present invention includes a compound of Formula (ll-llb):
  • R'8 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1 -C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SC>2NR6'R7', - CONR6”R7”, (C1 -C3)-alkyl-O-(C1 -C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)- alkyloxy;
  • R'9 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogens, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1 -C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SC>2NR'4R'5, - CONR'6R'7, (C1 -C3)-alkoxy-(C1 -C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)- alkyloxy;
  • R'10 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1 -C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SC>2NR6'R7', - CONR6”R7”, (C1 -C3)-alkyl-O-(C1 -C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)- alkyloxy;
  • R'11 is independently hydrogen, deuterium, halogen, (C1 -C3)-alkyl optionally substituted with 1 -7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1 -C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SC>2NR6'R7', - CONR6”R7”, (C1 -C3)-alkoxy-(C1 -C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1 -C3)- alkyloxy;
  • R6' is independently hydrogen, (C1 -C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R7' is independently hydrogen, (C1 -C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7 cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R6' and R7' together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur;
  • R6 is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl;
  • R7 is independently hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, when R6” is methyl, then R7” is (C1 -C3)-alkyl, (C3-C7)-cycloalkyl or (C3- C7)-cycloalkyl substituted with one (C1 -C3)-alkyl; alternatively, R6” and R7”, together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1 -3 heteroatoms selected from nitrogen, oxygen and/or sulfur; dotted bonds mean the rings are aromatic.
  • the present invention includes a compound of Formula (ll-l) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R1 is selected independently from:
  • C1 -C4)-alkyl C1 - or (C3-C4)-alkyl, optionally partially or completely substituted with halogens, C2-alkyl optionally substituted with one or 3 halogens, 2 chlorine atoms, 2 bromine atoms, 2 iodine atoms,
  • the present invention includes a compound of Formula (ll-l) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R1 is selected independently from:
  • the present invention provides a compound of general Formula (Ill-I):
  • Ri is independently selected from:
  • the present invention includes a compound of general Formula
  • Ri is independently selected from:
  • the present invention includes compounds selected from the group (names given in accordance with IUPAC):
  • SUBSTITUTE SHEETS (RULE 26)
  • the compounds of the invention may exist as various stereoisomers, diastereomers or enantiomers or mixtures thereof. All of these forms are part of the invention.
  • This invention also relates to the use of the compounds of the invention for the inhibition of CYP11 B2.
  • the present invention also relates to the use of the compounds of the invention to lower the level of aldosterone in a subject.
  • the subject is a human.
  • the present invention also relates to the use of the compounds of the invention in the manufacture of CYP11 B2 inhibitor.
  • the present invention also relates to the use of the compounds of the invention in the manufacture of agent for the lowering the level of aldosterone in a subject.
  • the present invention also relates to the use of the compounds of the invention in the manufacture of a pharmaceutical composition for the treatment and/or prevention of a disease or condition that is mediated or maintained by aldosterone hypersynthesis, comprising a therapeutically or prophylactically effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the invention also includes a pharmaceutical composition for the treatment and/or prevention of a disease or condition that is mediated or maintained by aldosterone hypersynthesis, comprising a therapeutically or prophylactically effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is a carrier, adjuvant and/or solvent.
  • the disease is selected from the group including primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, heart and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.
  • Cons syndrome primary hyperaldosteronism
  • chronic heart failure chronic heart failure with preserved ejection fraction
  • left ventricular dysfunction left ventricular hypertrophy
  • arterial hypertension resistant arterial hypertension
  • pulmonary arterial hypertension coronary heart disease
  • liver cirrhosis metabolic syndrome
  • chronic kidney disease glomerulosclerosis
  • glomerulonephritis
  • primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second type, aldosterone-producing carcinoma, and aldosteronectopic.
  • the invention also relates to a method for lowering aldosterone levels in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
  • the invention also includes a method for treating and/or preventing a disease or condition that is mediated or maintained by aldosterone hypersynthesis in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of the invention.
  • the disease or condition is selected from the group including primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.
  • Cons syndrome primary hyperaldosteronism
  • chronic heart failure chronic heart failure with preserved ejection fraction
  • left ventricular dysfunction left ventricular hypertrophy
  • arterial hypertension resistant arterial hypertension
  • pulmonary arterial hypertension coronary heart disease
  • liver cirrhosis metabolic syndrome
  • chronic kidney disease glomerulosclerosis
  • primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second type, aldosterone-producing carcinoma, and aldosteronectopic.
  • the subject is a human.
  • the technical result of the present invention is to develop chemical compounds that are highly effective in inhibiting the activity of human cytochrome 1 1 B2 (CYP1 1 B2). These compounds are promising for the prevention and/or therapy of diseases or pathological conditions or disorders that are mediated or maintained by hypersynthesis of aldosterone.
  • alkyl as used herein, by itself or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the
  • SUBSTITUTE SHEETS (RULE 26) indicated number of carbon atoms, refers to groups typically having from one to ten carbon atoms.
  • (C1 -3)-alkyl means methyl, ethyl, propyl, etc.
  • alkenyl refers to a linear or branched hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms and at least an unsaturation. By way of examples, mention may be made of, but not limited to: vinyl group, and the like.
  • alkynyl refers to a linear or branched hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms and at least a triple bond.
  • alkynyl refers to a linear or branched hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms and at least a triple bond.
  • haloalkyl groups include, but are not limited to, the following groups: trifluoromethyl, trichloromethyl, -C(CF 3 ) 2 CH3 and the like.
  • (C1-C3)-alkylsulfonyl means a -SOs-alkyl where the alkyl group is as previously defined.
  • halogen by itself or in part of another term refers to a fluorine, chlorine, bromine or iodine atom.
  • aryl means mono - or bicyclic aromatic rings containing 5-12 carbon atoms, in accordance with the Huckel aromaticity rule: a cyclic, planar molecule has 4n+2 TT (Pi) electrons.
  • aryl specifically include phenyl, naphthyl.
  • alkoxy refers to alkyl groups as defined above, which are attached to the molecule via a bridging oxygen atom.
  • alkoxy means -O-alkyl, where the alkyl group contains from 1 to 3 carbon atoms in the form of a linear (straight) or branched chain.
  • alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, etc.
  • bicyclic ring or "bicyclic” as used herein means a bridged, fused or spirofused bicyclic ring system.
  • Bicyclic heterocycles contain from 9 to 11 atoms, preferably 9 to 10 atoms.
  • the bicyclic ring may contain one to four heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur.
  • phenyl ring fused with 5-membered heterocycle may be cited.
  • heteroaryl as used herein means a 5- or 7-membered aromatic ring according to Huckel's aromaticity rule: a cyclic, planar molecule has 4n+2 TT (Pi) electrons containing from one to 5 heteroatoms selected from nitrogen atoms, oxygen and/or sulfur.
  • heteroaryl include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, thiophenyl, furanyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isthiothiazolyl, triazolyl, tetrazolyl and the like.
  • heterocycle in the sense of the invention used here, means 3-7-membered non-aromatic ring containing from one to 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms. The definition also includes partially saturated rings. Examples of the heterocycle include azepine, pyrrolidine, piperidine, oxirane, tetrahydrofuran, tetrahydropyran, oxepan, piperazine, morpholine, thiomorpholine, diazepine, oxazepane, thiazepine, homopiperazine, homomorpholine and the like.
  • heterocycle “heterocyclyl” or “heterocyclic” also refers to rings, saturated or partially unsaturated, which may be substituted.
  • a stable or chemically possible compound is a compound whose stability is sufficient for its synthesis and analytical detection.
  • Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40°C in the absence of reactive conditions, for at least one week.
  • the structures of the compounds given in the application materials also imply all stereoisomers, that is, the R- and S-isomers for each asymmetric center.
  • individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds are also the subject of this invention.
  • the present invention embraces each diastereomer or enantiomer substantially free of other isomers (>90%; more preferably >95% molar purity), as well as a mixture of such isomers.
  • a particular optical isomer can be obtained by separating a racemic mixture according to a standard procedure, for example, by obtaining diastereomeric salts by treatment with an optically active acid or base, followed by separation of the mixture of diastereomers by crystallization, followed by isolating the optically active bases from these salts.
  • suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Another technique for separating optical isomers is to use a chiral chromatographic column.
  • another separation method involves the synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate.
  • the resulting diastereomers can be separated by conventional means, such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.
  • Optically active compounds of this invention can be obtained using optically active starting materials.
  • Such isomers may be in free acid, free base, ester or salt form.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex where the solvent molecules are water.
  • the compounds of the invention may exist in a radiolabeled form, i. e. these compounds may contain one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the most common natural isotopes.
  • Radioisotopes of hydrogen, carbon, phosphorus, chlorine include 3 H, 14 C, 32 P, 35 S, and 36 CI, respectively.
  • Compounds of this invention which contain such radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention.
  • Tritium, i.e. 3 H and carbon, i.e. 14 C radioisotopes are particularly preferred due to their ease of preparation and detection.
  • Labeled compounds can be obtained using methods well known to experts in this field. Labeled compounds can be prepared using the procedures described here, by simply replacing unlabeled reagents with the appropriate labeled reagents.
  • the compounds of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to those salts which, within the limits of medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable ratio of benefit, and risk.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be obtained in situ during the isolation or purification of the compounds of the invention, and can also be obtained separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively.
  • Examples of pharmaceutically acceptable, non-toxic acid salts are amino salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained other methods used in this field, for example, using ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained other methods used in this field, for example, using ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium, and others.
  • pharmaceutically acceptable salts may contain, if desired, non-toxic ammonium, quaternary ammonium and amine cations derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • SUBSTITUTE SHEETS (RULE 26)
  • therapeutically effective amount is meant that amount of a compound administered or delivered to a patient that is most likely to result in the desired response to treatment (prophylaxis) in the patient. The exact amount required may vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combination treatment with other drugs, and the like.
  • patient (or “subject”) embraces all mammalian, preferably human, species that use the compounds of this invention, either by self-administration and/or administration to a patient by another person, for the treatment and/or prevention of a disease or medical condition.
  • treatment cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) blocking (suspension) of the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.
  • prevention covers the elimination of risk factors, as well as the prophylactic treatment of subclinical stages of the disease in humans, aimed at reducing the likelihood of clinical stages of the disease.
  • Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increased risk of clinical stages of the disease compared with the general population.
  • Preventive therapy includes a) primary prevention and b) secondary prevention.
  • Primary prevention is defined as prophylactic treatment in patients who have not yet reached the clinical stage of the disease.
  • Secondary prevention is the prevention of the recurrence of the same or a close clinical condition of the disease.
  • risk reduction encompasses therapy that reduces the incidence of the clinical stage of the disease.
  • diseases risk reduction are primary and secondary disease prevention.
  • Table 1 shows specific examples of compounds of the invention that can be prepared by the methods described in the General Synthesis Schemes, Examples, and known methods in the art. The methods listed are not exhaustive and are subject to reasonable modifications. These reactions must be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. The compounds below are not to be considered as the only examples within the scope of the present invention, and in no way limit the invention.
  • the compounds of general Formula I are compounds N°1.1-1 .18 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula Ila are compounds N°1.4-1.5 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula I Ib1 M Ilb2 are compounds N21.6-1.10 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula He are compounds N°1.11-1 .16 and 1.18 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula lid are compounds N°1.1 and 1.17 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula ll-l are compounds N°2.1-2.4 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula ll-lla is compound N°2.1 listed in Table 1 below, as well as its pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula ll-llb are compounds N°2.2 and N°2.4 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula ll-l is compound N°2.3 listed in Table 1 below, as well as its pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula lll-l are compounds N°3.1-3.3 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • the compounds of general Formula Hi ll are compounds N°3.4-3.6 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.
  • Synthesis intermediates (general structure) and sulfonyl chloride derivatives are either commercially available or readily prepared by methods known to those skilled in the art.
  • dimethylaminopyridine or diisopropylethylamine (1 .0-4.4 eq.) is added to a solution of the intermediate (1 eq.) in dichloromethane or benzene, stirred for 15 min, and sulfonyl chloride (1 -1.2 eq.).
  • the reaction mixture was stirred at room temperature for 18-24 hours.
  • H 2 O is added and the reaction mixture is extracted.
  • the combined organic layers were washed with saturated aqueous NaHCOs and dried over NasSC . Filtration and removal of the solvent provides crude products, which are purified by liquid chromatography on silica gel to obtain the corresponding reaction products.
  • reaction conditions and reaction time may vary depending on the specific reagents used. Unless otherwise indicated, solvents, temperatures, pressures, and other reaction conditions can be freely chosen by one of skill in the art.
  • Intermediate X' (general structure) for synthesis and sulfonyl chloride derivatives (Intermediates Y') are either commercially available or readily prepared by methods known to those skilled in the art.
  • Compound 2.1 was prepared analogously to the procedure above, but using a- morpholine-4-sulfonyl chloride as the sulfonyl chloride derivative.
  • Compound 2.2 was prepared analogously to the procedure above, but using 4-(N,N- dimethylsulfamoyl)benzenesulfanyl chloride as the sulfonyl chloride derivative.
  • Compound 2.3 was prepared analogously to the procedure above, but using 2 methoxyethane-1 -sulfonyl chloride as the sulfonyl chloride derivative.
  • Compound 2.4 was prepared analogously to the procedure above, but using 4 (morpholine-4-carbonyl)benzenesulfonyl chloride as the sulfonyl chloride derivative.
  • reaction conditions and reaction time may vary depending on the specific reagents used. Unless otherwise indicated, solvents, temperatures, pressures, and other reaction conditions can be freely chosen by one skilled in the art.
  • the authors of the present invention investigated the activity of the compounds according to the invention as inhibitors of CYP11 B2 when analyzed in a reconstructed system containing
  • SUBSTITUTE SHEETS (RULE 26) 0.5 m recombinant CYP11 B2, 0.3 pm human adrenodoxin reductase, 2 pm human adrenodoxin, 100 pm corticosterone as a control reaction to detect the formation of a product with using an HPLC system with a UV detector.
  • the test compound is added to the reaction mixture to a final concentration of ⁇ 2 pM.
  • the concentrated protein mixture was diluted with buffer to a final volume of 0.5 ml, pre-incubated for 10 min at 37°C, followed by the addition of the substrate.
  • Reactions are initiated by adding NADPH (nicotinamide adenine dinucleotide phosphate) to a final concentration of 0.25 mM with a regenerating system (glucose-6-phosphate and glucose-6- phosphate dehydrogenase) in 25 mM potassium phosphate buffer, pH 7.4, containing 0.1 mM DTT (dithiothreitol), 0.1% Tween-20.4 mM MgCh and incubated at 37°C. After 30 minutes of incubation, the reaction is stopped by adding 5 ml of dichloromethane. The organic phase is isolated by centrifugation, evaporation, dissolution in ethanol and transferred to a vial for HPLC studies. A C18 Luna 100 A 250x4, 6 mm column was used on an Agilent Technologies 1200 series instrument (USA) with ethanol as the mobile phase.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the level of inhibition of CYP11 B2 activity is expressed as a percentage, where 0% is defined as no inhibition in reactions without test compound and 100% is absolute inhibition by test compound.
  • Compounds of all embodiments of the invention are suitable for inhibiting CYP1 1 B2 activity, and a preferred subgroup includes compounds with inhibition of CYP1 1 B2 activity in the range of 1 -100% (+). Within this subgroup, there is another subgroup of more preferred compounds with inhibition of CYP11 B2 activity in the range of 20-100% (++). In the latter, there is another subgroup of more preferred compounds with inhibition of CYP1 1 B2 activity in the range of 35-100% for compounds 2.1 -2.4 and 3.1 -3.6 (+++) or 50-100% (+++) for compounds 1.1 -1.18. See Table 2.
  • the connection code numbers correspond to the earlier codes given in Table 1 .
  • the invention also relates to pharmaceutical compositions which contain a compound of general formula I, la, Ila, I Ib1 , Hb2, lie, lid, He, III, Illa, I Ilb1 , 1 Ilb2, 1 He, Hid, Hie, IV, IVa, I Vb1 , IVb2, IVc, IVd, IVe, V-1 , V-2, Va-1 , Va-2, Vb-1 -1 , Vb-2-1 , Vb-2-2, Vc-1 , Vc-2, Vd-1 , Vd-2, Ve-1 , Ve-2, VI, VII, H-l, H-lla, H-llb, Hl-I, lll-ll (or a pro-drug, pharmaceutically acceptable salt, or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, diluents, and/or excipients, such , which can be introduced into the patient's body together with the compound that is the essence of this invention, and which do not destroy the
  • SUBSTITUTE SHEETS (RULE 26) pharmacological activity of this compound, and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions of this invention contain the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, binders, lubricants, etc. suitable for the particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, binders, lubricants, etc. suitable for the particular dosage form.
  • Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, mono - and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, sesame, olive, corn and soybean oils and others; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer substances such as magnesium hydroxide and aluminum hydroxide; alginic acid; depyrogenated water; isotonic solution, Ringer's solution; alcohol and phosphate buffer solutions.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, filming agents, sweeteners, flavors and fragrances, preservatives and antioxidants may also be included in the composition.
  • the subject of the present invention are also dosage forms - a class of pharmaceutical compositions, the structure of which is optimized for a certain method of administration to the body in a therapeutically effective dose, for example, for administration to the body intravenously, intramuscularly, orally, subcutaneously, intraocularly, inhalation, intranasally and sublingually, in recommended dosages.
  • Dosage forms of this invention may contain structures obtained by liposomal methods, microencapsulation methods, methods for obtaining nanoforms of the drug, or other methods known in the pharmaceutical art.
  • the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, Arabic gum, mannitol, microcrystalline cellulose, hypromellose or similar compounds.
  • pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, Arabic gum, mannitol, microcrystalline cellulose, hypromellose or similar compounds.
  • Tablets may be coated with sucrose, cellulose derivatives, or other suitable coating agents. Tablets can be prepared in a variety of ways such as direct compression, dry or wet granulation, or hot doping.
  • a pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active principle with a solvent and filling the resulting mixture into soft or hard capsules.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, the compatible agents of which contain pharmacological agents such as propylene glycol or butylene glycol.
  • the compounds of the present invention are inhibitors of CYP11 B2 (aldosterone synthase), and therefore they are useful agents for the therapy and/or prevention of diseases or conditions that can be alleviated by reducing the level of aldosterone. Due to their ability to inhibit aldosterone synthase, the compounds of the present invention are useful in the treatment and/or reduction of the risk of developing: primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, remodeling of the heart and blood vessels, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia and insulin
  • the compounds of the invention may be administered by pharmaceutical composition in any pharmaceutical dosage form by any route of administration.
  • Dosage forms generally include a pharmaceutically acceptable carrier suitable for the particular dosage form chosen.
  • the compound of the invention may be administered daily for a period of time necessary for the treatment and/or prevention of diseases relevant to the patient, including a course of therapy lasting days, months, years or the entire life of the patient.
  • Routes of administration include, but are not limited to, intravenous, intramuscular, oral, subcutaneous, intraocular, inhalation, intranasal, and sublingual. Preferred routes of administration are oral and intravenous.
  • the invention also relates to a pharmaceutical composition containing a daily dose of said compound in the form of a fixed dosage unit, and to a combination containing said pharmaceutical composition or said compound.
  • said composition for use according to the invention is administered once a day at a dosage of 1 mg or more of the selected compound of the invention.
  • the preferred dosage is 1 -500 mg.
  • the most preferred dosage is 10-200 mg.
  • One or more additional pharmacologically active agents may be administered in combination with a compound of formula I, la, Ila, I Ib1 , I Ib2, He, lid, He, III, Illa, 11 Ib1 , 11 Ib2, 11 Ic, Hid, Hie, IV, IVa, IVb1 , IVb2, IVc, IVd, IVe, V-1 , V-2, Va-1 , Va-2, Vb-1 -1 , Vb-2-1 , Vb-2-2, Vc-1 , Vc- 2, Vd-1 , Vd-2, Ve-1 , Ve-2, VI, VII, H-l, Il-Ila, ll-llb, Hl-I, lll-IL Generally, any additional single or
  • SUBSTITUTE SHEETS (RULE 26) multiple active agents other than a compound of formula I, la, Ila, Ilb1 , Ilb2, He, lid, He, HI, Illa, Hlb1 , Hlb2, lllc, Hid, Hie, IV, IVa, IVb1 , IVb2, IVc, IVd, IVe, V-1 , V-2, Va-1 , Va-2, Vb-1-1 , Vb-2-1 , Vb-2-2, Vc-1 , Vc-2, Vd-1 , Vd-2, Ve-1 , Ve-2, VI, VII, H-l, Il-Ila, ll-llb, Hl-I, lll-ll including but not limited to antihypertensive agents, antidiabetic agents, and/or antiobesity agents, may be used in any combination with a compound of formula I, la, Ha, I Ib1 , Hb2, He, Hd, lie, HI, Illa, 11 lb

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Abstract

La présente invention relève de la chimie organique, la pharmacologie, la médecine, et concerne des composés destinés à être utilisés pour inhiber l'activité du cytochrome 11B2 humain (CYP11B2) et leur utilisation dans le traitement et/ou la prévention de diverses maladies et troubles qui sont médiés ou pris en charge par l'activité de l'hormone aldostérone. Les composés sont caractérisés par la formule générale (I) : NN SOOR1R0[ ]n Formule (I), dans laquelle R0, n, R1 ont les significations indiquées dans la description. La présente invention concerne également des compositions pharmaceutiques contenant les composés selon l'invention et des procédés de préparation de ces composés.
PCT/RU2022/050316 2021-10-13 2022-10-07 Inhibiteurs de l'aldostérone synthase humaine (cyp11b2) WO2023063851A1 (fr)

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RU2021129717A RU2783521C1 (ru) 2021-10-13 Ингибиторы цитохрома 11В2 человека
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RU2022103062A RU2789610C1 (ru) 2022-02-08 Ингибиторы цитохрома 11В2 человека
RU2022103058 2022-02-08
RU2022103062 2022-02-08
RU2022103058A RU2800378C1 (ru) 2022-02-08 Ингибиторы цитохрома 11В2 человека

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024061371A1 (fr) * 2022-09-23 2024-03-28 广州威诺森医药科技有限公司 Inhibiteur de pyridine stéroïde synthétase annelée, son procédé de préparation et son utilisation
WO2024102026A1 (fr) * 2022-11-10 2024-05-16 «Target Medicals» Limited Liability Company Inhibiteurs de l'aldostérone synthase humaine (cyp11b2)

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WO2024061371A1 (fr) * 2022-09-23 2024-03-28 广州威诺森医药科技有限公司 Inhibiteur de pyridine stéroïde synthétase annelée, son procédé de préparation et son utilisation
WO2024102026A1 (fr) * 2022-11-10 2024-05-16 «Target Medicals» Limited Liability Company Inhibiteurs de l'aldostérone synthase humaine (cyp11b2)

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