WO2019223629A1 - 苯基取代的二氢萘啶类化合物及其用途 - Google Patents
苯基取代的二氢萘啶类化合物及其用途 Download PDFInfo
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- WO2019223629A1 WO2019223629A1 PCT/CN2019/087516 CN2019087516W WO2019223629A1 WO 2019223629 A1 WO2019223629 A1 WO 2019223629A1 CN 2019087516 W CN2019087516 W CN 2019087516W WO 2019223629 A1 WO2019223629 A1 WO 2019223629A1
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- 0 C*(C)(C(*)=C1*)C2=C(*)**C(*)=C2[C@]1c1c(*)c(*)c(*)c(*)c1* Chemical compound C*(C)(C(*)=C1*)C2=C(*)**C(*)=C2[C@]1c1c(*)c(*)c(*)c(*)c1* 0.000 description 3
- VOUXVCQFIMPXGT-UHFFFAOYSA-N CC1(COc2c(C(c(ccc(C#N)c3)c3[N+](C)(C3=O)[O-])C3=C(C)N3)c3c(C)cn2)CCC1 Chemical compound CC1(COc2c(C(c(ccc(C#N)c3)c3[N+](C)(C3=O)[O-])C3=C(C)N3)c3c(C)cn2)CCC1 VOUXVCQFIMPXGT-UHFFFAOYSA-N 0.000 description 1
- LVEPRVVSQKSMNW-UHFFFAOYSA-N Cc(c(F)nc(OCC1CC1)c1C2c(c([N+]3(C)[O-])c4)ccc4C#N)c1NC(C)=C2C3=O Chemical compound Cc(c(F)nc(OCC1CC1)c1C2c(c([N+]3(C)[O-])c4)ccc4C#N)c1NC(C)=C2C3=O LVEPRVVSQKSMNW-UHFFFAOYSA-N 0.000 description 1
- RJIQEPUITVEBSV-UHFFFAOYSA-N Cc(c(NC(C)=C1C2O)c3C1c(ccc(C#N)c1)c1[N+]2(C)[O-])cnc3OCc1cnc[s]1 Chemical compound Cc(c(NC(C)=C1C2O)c3C1c(ccc(C#N)c1)c1[N+]2(C)[O-])cnc3OCc1cnc[s]1 RJIQEPUITVEBSV-UHFFFAOYSA-N 0.000 description 1
- BRAXBDSJAIXVDL-UHFFFAOYSA-N Cc(cnc(OC1CC1)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O Chemical compound Cc(cnc(OC1CC1)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O BRAXBDSJAIXVDL-UHFFFAOYSA-N 0.000 description 1
- YMCPYEOEKVJZMV-UHFFFAOYSA-N Cc(cnc(OC1COCC1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O Chemical compound Cc(cnc(OC1COCC1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O YMCPYEOEKVJZMV-UHFFFAOYSA-N 0.000 description 1
- IIUBFSRWZQYKQM-HXUWFJFHSA-N Cc(cnc(OCCC1CC1)c1[C@@H]2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O Chemical compound Cc(cnc(OCCC1CC1)c1[C@@H]2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O IIUBFSRWZQYKQM-HXUWFJFHSA-N 0.000 description 1
- QTAVBHGJAQXKBC-UHFFFAOYSA-N Cc(cnc(OCc([s]1)ccc1Cl)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O Chemical compound Cc(cnc(OCc([s]1)ccc1Cl)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O QTAVBHGJAQXKBC-UHFFFAOYSA-N 0.000 description 1
- PKSNCKBQPUJTNQ-UHFFFAOYSA-N Cc(cnc(OCc1ccc[o]1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O Chemical compound Cc(cnc(OCc1ccc[o]1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O PKSNCKBQPUJTNQ-UHFFFAOYSA-N 0.000 description 1
- MHFLUWIQCZQRLN-UHFFFAOYSA-N Cc(cnc(OCc1ncc[s]1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O Chemical compound Cc(cnc(OCc1ncc[s]1)c1C2c(ccc(C#N)c3)c3OC)c1NC(C)=C2C(N)=O MHFLUWIQCZQRLN-UHFFFAOYSA-N 0.000 description 1
- JLPCXLISRMNPHM-UHFFFAOYSA-N Cc(nnc(OCC1CC1)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O Chemical compound Cc(nnc(OCC1CC1)c1C2c(ccc(C#N)c3)c3[N+]3(C)[O-])c1NC(C)=C2C3=O JLPCXLISRMNPHM-UHFFFAOYSA-N 0.000 description 1
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
- the invention belongs to the technical field of medicine, and particularly relates to a phenyl-substituted dihydronaphthyridine compound and use thereof, and further relates to a pharmaceutical composition containing the compound.
- the compound or the pharmaceutical composition can be used as a mineralocorticoid receptor antagonist.
- MR Mineralocorticoid Receptor
- MR Mineralocorticoid Receptor
- aldosterone-activated nuclear hormone receptor that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease.
- the increase in circulating aldosterone increases blood pressure through its effect on urinary sodium excretion, while potentially affecting the brain, heart, and vascular systems.
- aldosterone excess is associated with many of the disease physiological processes that lead to kidney and cardiovascular disease.
- aldosteronism is usually caused by aldosterone-producing adenomas, patients with refractory hypertension often have elevated levels of aldosterone, often called "aldosterone escape" due to serum potassium Increased content or residual AT1R activity.
- MR antagonists have been shown to be effective antihypertensive agents and are also effective in treating heart failure and primary aldosterone overdose disease.
- MR antagonists have also proven effective in pre-clinical models of nephropathy and can be used in combination with standard therapies to reduce proteinuria in patients with kidney disease, such as chronic kidney disease, including diabetic nephropathy.
- Aldosterone is a steroid hormone formed in the adrenal cortex. Its production is greatly indirectly regulated by renal blood flow. Any reduction in renal blood flow results in the release of renin in the kidneys and into the circulating blood. This in turn activates the formation of angiotensin II, which on the one hand has a contractile effect on arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex.
- the kidney is used as a blood pressure sensor in the blood circulation and indirectly as a volume sensor, and the severe loss of volume is offset by the renin-angiotensin-aldosterone system, which is achieved by increasing blood pressure Effect II), on the other hand, it is achieved by increasing the reabsorption of sodium and water in the kidneys to rebalance the filling state of the vascular system (aldosterone effect).
- the control system may be pathologically damaged in various ways. For example, a chronic decrease in renal blood flow (for example, due to heart failure and the resulting blockage of blood in the venous system) results in excessive release of aldosterone.
- aldosterone is also considered to be the cause of many myocardial remodeling processes commonly observed in heart failure. Therefore, aldosterone hyperemia is the key to the pathogenesis and prognosis of heart failure, which is initially induced by various types of injury, such as myocardial infarction, myocardial inflammation, or hypertension.
- This hypothesis is supported by the fact that in extensive clinical studies of patients with chronic heart failure and acute myocardial infarction treated with aldosterone antagonists, patients' overall mortality has been significantly reduced (B.Pitt, F. Zannad, WJ Remme et al., N. Engl. J. Med. ML 709-717 (1999); B. Pitt, W. Remme, F. Zannad et al., N. Engl. J. Med 1309-1321 (2003) ).
- MR MR regulates sodium retention, potassium excretion, and water balance in response to aldosterone.
- the expression of MR in the brain also seems to play a cognitive role in controlling neuronal excitability, negative feedback regulation of the hypothalamus-pituitary adrenal axis, and behavioral performance (Castren et al., J. of Neuroendocrinology, 3,461-66 (1993 )).
- Increased aldosterone levels or overstimulation of mineralocorticoid receptors are associated with a number of physiological disorders or pathological conditions, including Conn (S) syndrome, primary and secondary aldosteronism, sodium retention Increased magnesium and potassium excretion (polyuria), increased water retention, hypertension (isolated systolic hypertension and combined systolic / diastolic hypertension, etc.), arrhythmia, myocardial fibrosis, myocardium Infarction, Bard's syndrome, and conditions related to excessive catecholamine levels (Hadley, ME, ENDOCRINOLOGY, 2nd Ed., Pp366-81, (1988); and Brilla et al., Journal of Molecular and Cellular Cardiology, 25 (5) pp563-75 (1993)).
- Compounds and / or pharmaceutical compositions having MR antagonistic effects have therapeutic value for any of the above conditions.
- the present invention addresses those needs by providing compounds and compositions that can be used to treat or prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular disorders, and other aldosterone disorders.
- the present invention provides a phenyl-substituted dihydronaphthyridine compound having a mineralocorticoid receptor (MR) antagonistic effect and a pharmaceutical composition thereof, and use of the compound or the pharmaceutical composition in preparing a medicament,
- the medicine is used for treating, preventing or reducing patients with aldosterone excess, diabetic nephropathy, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, kidney failure and stroke and other diseases.
- the invention relates to a compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate of a compound represented by formula (I) Substances, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- Each of R 1 , R 2 , R 3 and R 4 is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, carboxyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, aminoacyl, aminosulfonyl, C 3-8 cycloalkyl , C 6-10 aryl, 3-8 atom heterocyclic group or 5-10 atom heteroaryl group;
- R 6 is H, D, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkane Group, C 6-10 aryl group, 3-8 atom heterocyclic group or 5-10 atom heteroaryl group;
- Each R 7 and R x is independently H, D, halogen, cyano, C 1-6 alkoxyacyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, aminoacyl or aminosulfonyl;
- Each R a and R b is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl;
- R c is H, D, OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 6-10 aryl or 5-6 Atomic heteroaryl
- Y is O or S
- R 8 is C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 atom heterocyclic group, 5-6 atom heteroaryl, C 3-8 cycloalkyl C 1- 6 alkyl, (3-8 atom heterocyclic group) C 1-6 alkyl, (5-6 atom heteroaryl) C 1-6 alkyl, phenyl or phenyl C 1- 6 alkyl; wherein R 8 is unsubstituted or substituted with 1, 2, 3 or 4 R z ;
- the compound represented by formula (I) according to the present invention is a compound represented by formula (Ia) or formula (Ib) or a stereoisomer of a compound represented by formula (Ia) or formula (Ib) Isomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and Y have the meanings described in the present invention.
- each of R 1 , R 2 , R 3 and R 4 is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy group, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, carboxy, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, aminoacyl, aminosulfonyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-6 atom heterocyclic group or 5-6 atom heteroaryl group;
- R 6 is H, D, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkane Group, C 6-10 aryl group, 3-6 atom heterocyclic group or 5-6 atom heteroaryl group;
- Each R 7 and R x is independently H, D, halogen, cyano, C 1-4 alkoxyacyl, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl;
- Each R a and R b is independently H, D, C 1-4 alkyl or C 1-4 haloalkyl.
- each of R 1 , R 2 , R 3 and R 4 is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoro Ethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methyl Acyl, ethylacyl, methylsulfonyl, aminoacyl or aminosulfonyl;
- Each R a and R b is independently H, D, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1 2,2-difluoroethyl or trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl);
- R 6 is H, D, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy , Monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, epoxyethyl, pyrrolidinyl, piperidinyl, Piperazinyl, morpholinyl, pyridyl, pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl;
- R 7 is H, D, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, propoxyacyl, carboxyl, methyl, ethyl, propyl, butyl , Methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, Trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino or dimethylamino.
- the compound of the present invention may be a compound represented by formula (IIIa) or formula (IIIb), or stereoisomers, geometric isomers of a compound represented by formula (IIIa) or formula (IIIb), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R x is H, D, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, propoxyacyl, carboxyl, methyl, ethyl , Propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2 -Difluoroethyl, trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino or di Methylamino.
- R 8 is C 3-6 cycloalkyl, heterocycle consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms, C 3-6 cycloalkyl C 1-4 Alkyl, (3-6 atom heterocyclyl) C 1-4 alkyl or (5-6 atom heteroaryl) C 1-4 alkyl; wherein R 8 is unsubstituted or substituted 1, 2, 3, or 4 Rz substitutions; Rz has the meaning as described herein.
- R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, Tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furyl, thienyl, Thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl Methyl, cyclo
- the invention in another aspect, relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the invention; optionally, it further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
- a pharmaceutically acceptable carrier optionally, it further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
- the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from the group consisting of an ACE inhibitor, a renin inhibitor, an angiotensin II receptor antagonist, Beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.
- active ingredients selected from the group consisting of an ACE inhibitor, a renin inhibitor, an angiotensin II receptor antagonist, Beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and antithrombotic agents.
- the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used to treat, prevent or reduce the following diseases in patients: diabetic nephropathy, aldosterone Hyperemia, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, kidney failure or stroke.
- the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used as a mineralocorticoid receptor antagonist.
- the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for the treatment, prevention or alleviation of the following diseases in a patient: diabetic nephropathy, aldosteronism, hypertension, heart failure, myocardial infarction Sequelae, cirrhosis, kidney failure or stroke.
- the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for antagonizing a mineralocorticoid receptor.
- the present invention relates to a method for treating, preventing or reducing the following diseases in a patient using a compound of the present invention or a pharmaceutical composition of the present invention: diabetic nephropathy, aldosteronism, hypertension, heart failure, myocardium Sequelae of infarction, cirrhosis, kidney failure or stroke.
- the invention relates to a method for antagonizing a mineralocorticoid receptor using a compound of the invention or a pharmaceutical composition of the invention.
- a component means one or more components, i.e., more than one component may be considered for adoption or use in an embodiment of the described embodiment.
- patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
- Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotomers), geometric isomers (cis / trans) isomers, atropisomers, etc. .
- Enantiomers refer to two isomers of a compound that cannot overlap but mirror image each other.
- Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
- any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R, S) -configuration presence.
- each asymmetric atom has at least a 50% enantiomeric excess in the (R)-or (S) -configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
- the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, based on differences in the physicochemical properties of the components. And / or fractional crystallization.
- tautomers or “tautomeric forms” refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerization is possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
- protontautomers also known as prototropic tautomers
- Valence tautomers include interconversions through the reorganization of some bonding electrons.
- keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerism is phenol-keto tautomerism.
- a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
- substituents such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
- a class of compounds such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
- C 1 -C 6 alkyl or “C 1-6 alkyl” specifically refer to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl
- C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl) and C 4 alkyl (ie, butyl, including N-butyl, isobutyl, sec-butyl and tert-butyl).
- linking substituents are described.
- the Markush variables listed for that group should be understood as the linking group.
- the “alkyl” or “aryl” represents a linked An alkylene group or an arylene group.
- alkyl or "alkyl group” as used in the present invention means a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be any It is optionally substituted with one or more substituents described herein.
- the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, that is, C 1-6 alkyl; in still other implementations
- the alkyl group contains 1-4 carbon atoms, that is, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-3 carbon atoms, that is, C 1-3 alkyl.
- the C 1-6 alkyl described in the present invention includes C 1-4 alkyl; in other embodiments, the C 1-6 alkyl described in the present invention includes C 1-3 alkyl.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl ), N-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl 1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- Methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl Base, etc.
- alkoxy means that an alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (including n-butoxy, Isobutoxy, sec-butoxy, t-butoxy) and the like.
- haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms, and such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy , Chloroethyl (for example, 2-chloroethyl), trifluoroethyl (including but not limited to, 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1 -Methyl ethyl and the like.
- amino denotes the group -NH 2.
- carboxy refers to the group -COOH.
- hydroxy refers to the group -cyano, “nitro”, “mercapto group” refer to the group -OH, -CN, -NO 2, -SH .
- alkylamino or “alkylamino” denotes the group -NH 2 is substituted with one or two alkyl groups, i.e., the alkyl amino or alkylamino include monoalkylamino and dialkylamino; wherein The alkyl group has the meaning as described in the present invention.
- alkylamino group include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, and the like.
- cycloalkyl means a saturated monocyclic, bicyclic or tricyclic system containing 3-12 ring carbon atoms.
- cycloalkyl contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, cycloalkyl contains 3-8 ring carbon atoms, such as C 3- 8 cycloalkyl; in still other embodiments, cycloalkyl contains 3-6 ring carbon atoms, such as C 3-6 cycloalkyl.
- cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
- C 3-8 cycloalkyl includes C 3-6 cycloalkyl; and C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl .
- the cycloalkyl group may be optionally substituted with one or more substituents described herein.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein, said Heterocyclic groups are non-aromatic and do not contain any aromatic rings.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- a ring nitrogen atom can be optionally oxidized to an N-oxide.
- heterocyclyl may be used interchangeably with the term “heterocyclic”.
- heterocyclic groups include, but are not limited to, ethylene oxide, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, Oxazolyl, imidazolidyl, isoxazolyl, piperidinyl, piperazinyl or morpholinyl, and the like.
- the heterocyclic group may be composed of 3-8 atoms or 3-6 atoms, the atom is C, N, O or S and at least one atom is N, O or S;
- the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms;
- the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms;
- the heterocyclic group consisting of 3-6 atoms includes, but is not limited to, ethylene oxide Aziridine Azetidinyl Oxetanyl Pyrrolidinyl Tetrahydrofuranyl Tetrahydrothienyl Thiazolidinyl Pyrazolidinyl Pyrazolinyl Oxazolidinyl Imidazolidinyl Piperidinyl Piperazinyl Morpholinyl Wait.
- the heterocyclyl group may be optionally substituted with one or more substituents described herein.
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
- aryl means a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic And has one or more attachment points connected to the rest of the molecule.
- aryl may be used interchangeably with the term “aromatic ring” or "aromatic ring”. Examples of the aryl group may include phenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl.
- the aryl group may be optionally substituted with one or more substituents described herein.
- the group "C 6-10 aryl” means an aryl group containing 6 to 10 ring carbon atoms.
- heteroaryl can be connected to the rest of the molecule (such as the main structure in the general formula) through any reasonable site (which can be C in CH or N in NH).
- heteroaryl may be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”.
- heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl , Thiazolyl, triazolyl, tetrazolyl, and the like.
- heteroaryl may be optionally substituted with one or more substituents described herein.
- heteroaryl is a heteroaryl group consisting of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 are selected from O , S and N ring heteroatoms
- examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like.
- jk atoms (j and k are each independently any non-zero natural number, and k> j)" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms And / or heteroatoms such as O, N, S, P; the "jk” includes j, k, and any natural number between the two.
- “composed of 3-8 atoms”, “composed of 5-10 atoms” or “composed of 5-6 atoms” means that the cyclic group is composed of 3-8, 5-10, or 5-6 It is composed of ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P.
- heteroaryl group consisting of 5-10 atoms and “heteroaryl group consisting of 5-6 atoms” in the present invention refer to a heteroaryl group containing 5-10 ring atoms and containing 5-6 rings Atom heteroaryl, wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S.
- pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to a human and generally do not produce an allergic or similar inappropriate response, such as gastrointestinal upset, dizziness, and the like.
- pharmaceutically acceptable refers to use in animals, particularly in humans, as approved by a federal regulatory agency or national government or as enumerated in the United States Pharmacopeia or other generally recognized pharmacopoeia.
- carrier refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered.
- These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
- Water and aqueous solutions e.g. saline solution, glucose solution, glycerol solution
- Suitable pharmaceutical carriers are described in "Remington's Pharmaceuticals” by E.W. Martin.
- prodrug used in the present invention means that a compound is converted into a compound represented by formula (I) in vivo. Such transformations are influenced by the prodrug's hydrolysis in the blood or the enzyme's conversion into the parent structure in the blood or tissues.
- the prodrug compound of the present invention may be an ester.
- esters can be used as prodrugs of phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates. , Carbamates and amino acid esters.
- a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
- prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylation of the hydroxy group on the parent.
- phosphate esters such as these phosphate ester compounds are obtained by phosphorylation of the hydroxy group on the parent.
- Methodabolite refers to a product obtained by metabolizing a specific compound or a salt thereof in the body.
- the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention.
- Such a product can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidolation, deamidation, esterification, degreasing, enzymatic cleavage and the like.
- the invention includes metabolites of a compound, including metabolites produced by sufficient contact of a compound of the invention with a mammal for a period of time.
- “Pharmaceutically acceptable salt” as used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
- Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., Describe acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
- Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as ethyl Acid salts, oxalate salts, maleate salts, tartrate salts, citrate salts, succinate salts, malonate salts; or other methods described in the literature of books such as ion exchange methods to obtain these salts.
- inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate
- organic acid salts such as ethyl Acid salts, oxalate salts, maleate salts, tartrate salts, citrate salts, succinate salts, malonate salts
- ion exchange methods to obtain these salts.
- salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, cyclopentyl propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , Malate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pipate, pectate, persulfate, 3-phenylpropane Acid salt, picrate
- Salts obtained by reaction with a suitable base include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 .
- the present invention also contemplates the formation of quaternary ammonium salts of any compound containing a N group.
- Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- the pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by anti- counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
- solvate of the present invention means an association formed by one or more solvent molecules and a compound of the present invention.
- Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association formed by the solvent molecules being water.
- esters in the present invention refers to an in vivo hydrolyzable ester formed from a compound containing a hydroxyl group or a carboxyl group.
- esters are, for example, pharmaceutically acceptable esters which are hydrolyzed in the human or animal body to produce the parent alcohol or acid.
- the compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with an appropriate group.
- groups include, but are not limited to, alkyl, arylalkyl, and the like.
- N-oxide means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
- N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
- the corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages).
- oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages).
- oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages).
- oxidants
- the "compounds of the present invention”, “compounds of the present invention”, “compounds of the present invention” or similar expressions used in the present invention refer to compounds represented by any one of the general structure described in the present invention .
- the compound of the present invention may refer to formula (I) or formula (Ia) or formula (Ib) or formula (II) or formula (IIa) or formula (IIb) or formula (III) or formula (IIIa) in the present invention.
- a compound represented by formula (IIIb) The compounds of the present invention also include specific compounds in any one of the examples.
- any disease or disorder as used herein in some embodiments refers to ameliorating the disease or disorder (ie, slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., parameters that stabilize the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
- any structural formula given in the present invention is also intended to represent the isotopically enriched form of these compounds and the isotopically enriched form.
- Isotopically enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
- isotopes especially deuterium (ie, 2 H or D)
- deuterium in the present invention is considered as a substituent of the compound of formula (I).
- Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, especially deuterium.
- isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.
- the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation) for each specified deuterium atom, At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factors.
- the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
- the present invention provides a phenyl-substituted dihydronaphthyridine compound and a pharmaceutical composition thereof that can competitively antagonize an aldosterone receptor (MR), and the compound or the pharmaceutical composition in the preparation of a medicament.
- the medicament is used for treating, preventing or reducing patients with diabetic nephropathy, aldosterone hyperemia, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, liver cirrhosis, kidney failure and stroke and other diseases.
- the invention relates to a compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate of a compound represented by formula (I) Substances, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and Y have the meanings described in the present invention.
- the compound of the present invention is a compound represented by formula (Ia) or formula (Ib) or a stereoisomer or geometric isomer of compound represented by formula (Ia) or formula (Ib) Isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and Y have the meanings described in the present invention.
- each of R a and R b described in the present invention is independently H, D, C 1-6 alkyl or C 1-6 haloalkyl.
- each of R a and R b described herein is independently H, D, C 1-4 alkyl or C 1-4 haloalkyl.
- each of the R a and R b are the present invention are independently H, D, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, monofluoromethyl , 2,2-difluoroethyl, 1,2-difluoroethyl or trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl).
- R c described in the present invention is H, D, OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 6-10 aryl or 5-6 atom heteroaryl.
- R c according to the present invention is H, D, OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, butyl, trifluoromethoxy, Difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, furyl, pyridyl, pyrimidinyl, or oxazolyl.
- each of R 1 , R 2 , R 3 and R 4 described in the present invention is independently H, D, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, carboxyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, aminoacyl, Aminosulfonyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-8 atom heterocyclic group or 5-10 atom heteroaryl.
- each of R 1 , R 2 , R 3 and R 4 is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy group, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, carboxy, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, aminoacyl, aminosulfonyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-6 atom heterocyclic group or 5-6 atom heteroaryl.
- each of R 1 , R 2 , R 3 and R 4 is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoro Ethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methyl Acyl, ethylacyl, methylsulfonyl, aminoacyl or aminosulfonyl.
- R 6 is H, D, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkylamino, C 3-8 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl consisting of 5-10 atoms.
- R 6 is H, D, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 6-10 aryl, 3-6 atom heterocyclic group or 5-6 atom heteroaryl.
- R 6 is H, D, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl , Monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy , Difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, epoxyethyl, pyrrolidine Methyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, thiazolyl, pyrazolyl, or pyrimidinyl.
- the compound of formula (I) according to the present invention may be a compound represented by formula (II) or formula (IIa) or formula (IIb) or formula (II) or formula (IIa) or formula (IIb) ) Stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs of the compounds shown,
- R 7 , R 8 , X and Y have the meanings described in the present invention.
- X in the present invention is CR x or N, wherein R x has the meaning described in the present invention.
- R 7 according to the present invention is H, D, halogen, cyano, C 1-6 alkoxyacyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, aminoacyl or aminosulfonyl.
- R 7 according to the present invention is H, D, halogen, cyano, C 1-4 alkoxyacyl, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl.
- R 7 according to the present invention is H, D, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, propoxyacyl, carboxyl, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl Group, 1,2-difluoroethyl, trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Methylamino or dimethylamino.
- Y according to the present invention is O or S.
- the compound of the present invention may be a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound represented by formula (III) , Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 8 and R x have the meanings described in the present invention.
- the compound of the present invention may be a compound represented by formula (IIIa) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound represented by formula (IIIa) , Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 8 and R x have the meanings described in the present invention.
- the compound of the present invention may be a compound represented by formula (IIIb) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound represented by formula (IIIb) , Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
- R 8 and R x have the meanings described in the present invention.
- R x described in the present invention is H, D, halogen, cyano, C 1-6 alkoxyacyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, aminoacyl or aminosulfonyl.
- R x described in the present invention is H, D, halogen, cyano, C 1-4 alkoxyacyl, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl.
- R x described in the present invention is H, D, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, propoxyacyl, carboxyl, Methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl Group, 1,2-difluoroethyl, trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Methylamino or dimethylamino.
- R 8 is a C 3-8 cycloalkyl group, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of 5-6 atoms, and a C 3-8 cycloalkane C 1-6 alkyl, (3-8 atom heterocyclic group) C 1-6 alkyl, (5-6 atom heteroaryl) C 1-6 alkyl, phenyl or benzene C 1-6 alkyl; wherein R 8 is unsubstituted or substituted with 1, 2, 3 or 4 R z ; wherein R z has the meaning described in the present invention.
- R 8 is C 3-6 cycloalkyl, heterocycle consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms, C 3-6 cycloalkyl C 1-4 Alkyl, (3-6 atom heterocyclyl) C 1-4 alkyl or (5-6 atom heteroaryl) C 1-4 alkyl; wherein R 8 is unsubstituted or substituted 1, 2, 3, or 4 R z substitutions; wherein R z has the meaning described in the present invention.
- R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetra Hydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furyl, thienyl, thiazole Methyl, pyrazolyl, pyridyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl , Cyclohe
- R 8 according to the present invention may be, but is not limited to, one of the following groups:
- the compound of the present invention has a structure of one of the following or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolism Product, ester, pharmaceutically acceptable salt or prodrug:
- the invention in another aspect, relates to a pharmaceutical composition comprising a compound according to the invention.
- the pharmaceutical composition of the present invention optionally further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.
- the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from the group consisting of an ACE inhibitor, a renin inhibitor, and an angiotensin II receptor.
- the present invention relates to the use of a compound or a pharmaceutical composition according to the present invention in the preparation of a medicament, wherein the medicament is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, aldosteronism, high Blood pressure, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, kidney failure or stroke.
- the present invention also relates to the use of a compound or a pharmaceutical composition according to the present invention in the preparation of a medicament, wherein the medicament is used as a mineralocorticoid receptor antagonist.
- the compound or pharmaceutical composition of the present invention is used to treat, prevent or reduce the following diseases in patients: diabetic nephropathy, aldosterone hyperemia, hypertension, heart failure (including chronic heart failure, etc.), myocardial infarction Sequelae, liver cirrhosis, kidney failure or stroke.
- the compound or pharmaceutical composition of the present invention can be used to antagonize the mineralocorticoid receptor.
- the present invention relates to a method for treating, preventing or alleviating the following diseases in a patient using a compound or a pharmaceutical composition of the present invention: diabetic nephropathy, aldosteronism, hypertension, heart failure (including chronic heart failure Etc.), the sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke, the method comprises treating the patient with a therapeutically effective dose of a compound or a pharmaceutical composition of the present invention.
- the present invention also relates to a method for antagonizing the mineralocorticoid receptor using the compound or the pharmaceutical composition according to the present invention, which method comprises using an effective dose of the compound or the pharmaceutical composition according to the present invention with a biological agent.
- Body including in vivo or in vitro contact.
- the compounds or pharmaceutical compositions of the present invention competitively antagonize aldosterone receptors (MR), and therefore they can be useful agents for treating and preventing conditions associated with increased aldosterone levels.
- MR aldosterone receptors
- the compounds or pharmaceutical compositions of the present invention can be used to treat or prevent aldosterone receptor-mediated diseases.
- the invention also encompasses methods of treating or alleviating or susceptible patients with aldosterone receptor-mediated diseases, which methods comprise treating the patient with a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
- the invention comprises the use of a compound of the invention and a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for the treatment of diseases related to mineralocorticoid receptors or aldosterone in patients, including those described in the invention.
- the present invention includes a pharmaceutical composition comprising a compound represented by formula (I) and at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle for effective treatment required in combination the amount.
- the salt is a pharmaceutically acceptable salt.
- pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically relevant in relation to the other components making up the formulation and the mammal used for the treatment.
- the salts of the compounds of the present invention also include those used to prepare or purify formula (I) or formula (Ia) or formula (Ib) or formula (II) or formula (IIa) or formula (IIb) or formula (III) or formula ( IIIa) or an intermediate of a compound represented by formula (IIIb) or formula (I) or formula (Ia) or formula (Ib) or formula (II) or formula (IIa) or formula (IIb) or formula (III) or formula (IIIa) or a salt of an isolated enantiomer of a compound represented by formula (IIIb), but not necessarily a pharmaceutically acceptable salt.
- the salts of the compounds of the present invention can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvate, oxalic acid, glycolic acid and salicylic acid; pyranoic acids such as glucuronic acid and galactose Alkyd acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
- the biological activity of the compounds of the invention can be assessed by using any conventionally known method. Appropriate detection methods are well known in the art.
- the compounds of the present invention can be tested for MR antagonistic activity, pharmacokinetic activity, and / or liver microsomal stability and the like by appropriate conventional methods.
- the detection method provided by the present invention is only presented as an example and does not limit the present invention.
- the compounds of the invention are active in at least one of the detection methods provided by the invention.
- the compounds of the present invention have good antagonistic activity on aldosterone receptors, and have good in vivo pharmacokinetic properties, such as better absorption and exposure, and higher bioavailability; for example, the compounds of the present invention Has lower toxicity.
- the pharmaceutical composition of the present invention is characterized by formula (I) or formula (Ia) or formula (Ib) or formula (II) or formula (IIa) or formula (IIb) or formula (III) or formula ( IIIa) or a phenyl substituted dihydronaphthyridine compound represented by the formula (IIIb), the compound listed in the present invention or the compound of Example 1-10, and a pharmaceutically acceptable carrier, adjuvant, or ⁇ ⁇ Shape agent.
- the amount of the compound in the composition of the present invention is effective for treating or alleviating diseases related to mineralocorticoid receptor or aldosterone in a patient.
- the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or excipient.
- a pharmaceutically acceptable carrier include any solvent, diluent, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form.
- a pharmaceutically acceptable carrier include any solvent, diluent, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
- Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; auxiliary materials such as cocoa
- the pharmaceutical composition of the present invention can be administered directly or in a pharmaceutical composition or pharmaceutical form with a suitable carrier or excipient, which is well known in the art.
- the method of treatment of the invention may comprise administering an effective compound of the invention to an individual in need.
- the individual is a mammalian individual, and in some preferred embodiments, the individual is a human individual.
- the effective amount of the compound, pharmaceutical composition or medicament of the present invention can be easily determined through routine experimentation, and the most effective and convenient route of administration and the most appropriate preparation can also be determined through routine experimentation.
- the pharmaceutical dosage form of the compound of the present invention may be provided in the form of an immediate release, controlled release, sustained release, or target drug release system.
- common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powders, aerosols and lyophilized preparations.
- special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special bottles.
- Pharmaceutical dosage forms often consist of drugs, excipients, and container / sealing systems.
- excipients also known as inactive ingredients
- excipients can be added to the compounds of the present invention to improve or promote the manufacture, stability, administration, and safety of the drug, and can provide the desired drug release Curve method. Therefore, the type of excipients added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the steps of preparation. Pharmaceutical excipients exist in this field and include those listed in various pharmacopeias.
- compositions of the present invention can be manufactured by any method well known in the art, such as by conventional mixing, sieving, dissolving, melting, granulating, manufacturing sugar-coated pills, tabletting, suspension, extrusion, spray drying, Grinding, emulsifying, (nano / micron) encapsulation, packing or lyophilization processes.
- the composition of the present invention may include one or more physiologically acceptable inactive ingredients that promote the processing of the active molecule into a formulation for medical use.
- the composition can be formulated in an aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphates, histidines or citrates for adjusting the pH of the formulation, and such as chlorine A tonicity agent for sodium or dextrose.
- physiologically compatible buffers including, for example, phosphates, histidines or citrates for adjusting the pH of the formulation, and such as chlorine A tonicity agent for sodium or dextrose.
- semi-solid, liquid formulations or patches may be preferred, and may contain penetration enhancers; such penetration agents are generally known in the art.
- the compounds can be formulated as liquid or solid dosage forms and used as immediate or controlled / sustained release formulations.
- Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, creams, suspensions and emulsions.
- the compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds of the invention may act systemically and / or locally. They can be administered in a suitable manner, for example, by oral administration, gastrointestinal administration, pulmonary administration, nasal administration, sublingual administration, translingual administration, buccal administration, rectal administration, dermal administration Drug, transdermal, conjunctival, ear canal, or as a graft or stent.
- the compounds of the invention are preferably administered orally or parenterally.
- Suitable modes of administration for oral administration are as follows: Modes of administration in which the compounds of the present invention are released rapidly and / or in a modified manner according to the manner in which the prior art works, which include crystalline and / or amorphous and / or dissolved
- a compound of the invention such as tablets (uncoated tablets or tablets coated with a coating that is tolerated or delayed by dissolution or insolubility of the gastric juice that releases the compound of the invention), in the oral cavity Rapidly disintegrating tablets or films / flakes, films / lyophilized bodies, capsules (such as hard or soft capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
- suitable examples are inhaled pharmaceutical forms (including powder inhalers, sprayers), nasal drops, solutions or sprays, tablets for tongue, sublingual or buccal administration, films / Tablets or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, concussions), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (Milch ), Pastes, foams, sprays, implants or stents.
- inhaled pharmaceutical forms including powder inhalers, sprayers), nasal drops, solutions or sprays, tablets for tongue, sublingual or buccal administration, films / Tablets or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, concussions), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (Milch
- a therapeutically effective amount of a compound of the present invention should be present in the aforementioned pharmaceutical formulation at a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight of the entire mixture.
- a therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. A suitable dosage range for a human individual can be determined using, for example, data obtained from animal studies and cell culture assays.
- a compound of the invention can be prepared as a medicament for oral administration.
- An exemplary dose of a compound of the invention in a medicament for oral administration is from about 0.01 to about 100 mg / kg (where kg represents the weight of the subject).
- the medicament comprises from about 0.01 to about 20 mg / kg (where kg represents the weight of the subject), or optionally from about 0.01 to about 10 mg / kg (where kg represents the weight of the subject), Or optionally from about 0.01 to about 5.0 mg / kg (where kg represents the weight of the subject).
- the compounds of the present invention are administered parenterally at an effective dosage of about 0.001-1 mg / kg, preferably about 0.01-0.5 mg / kg body weight.
- the dosing regimen for agents commonly used for oral administration is three times per week, twice per week, once per week, three times per day, twice per day, or once per day.
- the compound of the present invention is administered as an active ingredient in a total amount of about 0.001 to about 50, preferably 0.001 to 10 mg / kg body weight per 24 hours, and in order to obtain a desired result, a plurality of It is administered in a single dose.
- a single dose may preferably contain the compound of the invention in an amount of about 0.001 to about 30, especially 0.001 to 3 mg / kg body weight.
- an effective amount or a therapeutically effective amount or dose of an agent refers to the amount of the agent or compound that causes improvement in symptoms or prolonged survival in an individual.
- Toxicity and therapeutic efficacy of the molecule can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by measuring LD 50 (lethal to 50% of the dose groups) and the ED 50 (50% of the population a therapeutically effective The dose).
- the dose ratio of toxicity and therapeutic effects is the therapeutic index and can be expressed as LD 50 / ED 50. Agents that exhibit high therapeutic indices are preferred.
- An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response from a tissue, system, animal, or human being sought by a researcher, veterinarian, doctor, or other clinician. Dosages preferably fall within a range of circulating concentrations that include the ED 50 of minimal toxicity or no toxicity. The dosage can vary within this range, depending on the dosage form used and / or the route of administration used. The correct formulation, route of administration, dose, and interval of administration should be selected in accordance with methods known in the art, taking into account the particularity of the individual's condition.
- the dose and interval can be individually adjusted to provide the plasma level of the active moiety sufficient to achieve the desired effect; that is, the minimum effective concentration (MEC).
- MEC minimum effective concentration
- the MEC of each compound will vary, but can be estimated, for example, from in vitro data and animal experiments.
- the dose necessary to obtain MEC will depend on the characteristics of the individual and the route of administration. In the case of topical administration or selective ingestion, the effective local concentration of the drug may be independent of plasma concentration.
- the amount of the medicament or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the pain, the mode of administration, and the judgment of the prescribing physician.
- composition of the invention may be provided in a packaging or dispensing device containing one or more unit dosage forms (containing the active ingredient).
- the package or device may include metal or plastic foil (such as a blister pack) or glass and rubber stoppers.
- the packaging or dispensing device may be accompanied by instructions for medicine.
- Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for the treatment of a given condition.
- the compounds of the present invention are suitable for the prevention and / or treatment of conditions related to various disorders and diseases, and are particularly characterized by conditions in which the plasma aldosterone concentration increases or the plasma aldosterone concentration changes relative to the plasma renin concentration, or with these changes Related disorders. Examples that can be mentioned are: spontaneous primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal cancer, aldosterone hyperactivity related to cirrhosis, Hyperaldosterone related to heart failure, (relative) hyperaldosterone related to essential hypertension, and the like.
- the compounds of the invention are also suitable for preventing sudden cardiac death in patients with an increased risk of sudden cardiac death.
- patients are especially those with one of the following conditions: primary and secondary hypertension, hypertension heart disease with or without congestive heart failure, refractory hypertension, acute and chronic heart failure Failure, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy (such as Bmgada syndrome), cardiomyopathy due to Chagas disease, shock, Arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, strokes, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricle Dysfunction, myocarditis, cardiac hypertrophy, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders, and vascu
- the compounds of the invention may additionally be used for the prevention and / or treatment of edema formation, such as pulmonary edema, nephrogenic edema, or floating lung associated with heart failure, and for example in thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and Restenosis after coronary angioplasty (PTCA), heart transplant and bypass surgery.
- edema formation such as pulmonary edema, nephrogenic edema, or floating lung associated with heart failure
- thrombolytic therapy percutaneous transluminal angioplasty (PTA) and Restenosis after coronary angioplasty (PTCA), heart transplant and bypass surgery.
- PTA percutaneous transluminal angioplasty
- PTCA Restenosis after coronary angioplasty
- the compounds of the present invention are also suitable for use as potassium-sparing diuretics and for treating electrolyte disorders such as hypercalcemia, hypernatremia, or hypokalemia.
- the compounds of the present invention are also suitable for the treatment of renal diseases such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), renal sclerosis, chronic renal failure, and cystic kidney disease for the prevention of kidney injury (E.g. kidney damage caused by immunosuppressants related to organ transplantation (e.g., cyclosporin A)) and for renal cancer.
- renal diseases such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), renal sclerosis, chronic renal failure, and cystic kidney disease for the prevention of kidney injury (E.g. kidney damage caused by immunosuppressants related to organ transplantation (e.g., cyclosporin A)) and for renal cancer.
- the compounds of the invention may additionally be used for the prevention and / or treatment of diabetes and sequelae of diabetes, such as neuropathy and kidney disease.
- the compounds of the invention can be further used in the prevention and / or treatment of microalbuminuria, for example caused by diabetes or hypertension, and proteinuria.
- the compounds of the invention are also suitable for the prevention and / or treatment of disorders associated with increased plasma glucocorticoid concentrations or with local increases in glucocorticoid concentrations in tissues, such as the heart.
- disorders associated with increased plasma glucocorticoid concentrations or with local increases in glucocorticoid concentrations in tissues, such as the heart are: adrenal dysfunction that causes excessive production of glucocorticoids (Cushing's syndrome), adrenal tumors that cause excessive production of glucocorticoids, and pituitary tumors that autonomously produce ACTH (promoting (Adrenocortical hormone), which leads to adrenal hyperplasia and Cushing's disease.
- the compounds of the invention may additionally be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.
- the compounds of the present invention may be further used for the prevention and / or treatment of inflammatory conditions such as those caused by viruses, Borrelia, fungi, bacteria or mycobacteria, and inflammatory conditions of unknown etiology, such as multiple arthritis, lupus erythematosus, joints Peripheral or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
- inflammatory conditions such as those caused by viruses, Borrelia, fungi, bacteria or mycobacteria
- inflammatory conditions of unknown etiology such as multiple arthritis, lupus erythematosus, joints Peripheral or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
- the compounds of the invention can be further used to treat central nervous disorders such as depression, anxiety and chronic pain, especially migraines, and neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
- the compounds of the invention are also suitable for preventing and / or treating vascular damage, such as in percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, reocclusion or restenosis after bypass surgery. Later vascular injury, and endothelial dysfunction, Raynaud's disease, thromboocclusive vasculitis (Buerger's syndrome), and tinnitus syndrome.
- PTCA percutaneous transluminal coronary angioplasty
- stent implantation coronary angioscopy
- reocclusion or restenosis after bypass surgery.
- Later vascular injury, and endothelial dysfunction Raynaud's disease, thromboocclusive vasculitis (Buerger's syndrome), and tinnitus syndrome.
- the compound of the present invention may be used alone or in combination with other active ingredients if necessary.
- the invention further relates to a medicament comprising at least one compound of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the abovementioned conditions, and in particular for the treatment and / or prevention of the invention Combination of drugs for diseases.
- Suitable active ingredients for combination include, but are not limited to, active ingredients that lower blood pressure, such as and preferably selected from calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin Inhibitors, ⁇ -receptor blockers, ⁇ -receptor blockers and Rho kinase inhibitors; diuretics, especially pupa diuretics, and thiazide and thiazide diuretics; antithrombotic effect Agents, such as and preferably selected from platelet aggregation inhibitors, anticoagulants or or fibrinolytic substances; active ingredients that alter lipid metabolism, such as and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors such as And preferably HMG-CoA reductase inhibitor or squalene synthesis inhibitor, ACAT inhibitor, CETP inhibitor, bile acid reuptake inhibitor and lipoprotein (a) antagonist; organic nitrate and NO donor, For example, sodium nitroprusside, nitroglycer
- HNE human neutrophil elastase
- compounds that inhibit the signal transduction cascade such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib, and erlotinib
- cardiac energy metabolism such as ermoxe, dichloroacetate, ranolazine or trimetazidine.
- the compound of the present invention can also be administered in combination with other active ingredients than the above-mentioned active ingredients.
- the compounds of the present invention are combined with diuretics such as aspartate, bumetanide, tosemide, benzfluthiazide, diarrhea, dihydrochlorothiazide, hydrofluoromethazine, Chlorothiazide, polithiazide, trichlorothiazide, chlorothione, indapamide, metoprazine, quinethylzine, acetazolamide, dichlorobenzamide, acetazolamide, glycerol, isosorbide Alcohol, mannitol, amiloride, or ampicillin are administered in combination.
- diuretics such as aspartate, bumetanide, tosemide, benzfluthiazide, diarrhea, dihydrochlorothiazide, hydrofluoromethazine, Chlorothiazide, polithiazide, trichlor
- the compounds of the present invention can be prepared by the methods described in the present invention, unless further specified, wherein the definition of the substituent is as shown in formula (I).
- the following reaction schemes and examples are provided to further illustrate the content of the present invention.
- Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were obtained by refluxing and drying the sodium metal.
- Anhydrous dichloromethane and chloroform were obtained by refluxing drying with calcium hydride.
- Ethyl acetate, petroleum ether, n-hexane, N, N-dimethylacetamide and N, N-dimethylformamide are dried before using anhydrous sodium sulfate.
- the following reactions are generally carried out under a positive pressure of nitrogen or argon or a dry tube over an anhydrous solvent (unless otherwise indicated).
- the reaction bottle is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
- the glassware is dried.
- the column was a silica gel column.
- Silica gel 300-400 mesh
- Silica gel 300-400 mesh
- NMR spectral data were measured with a Bruker Avance400 nuclear magnetic resonance spectrometer or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer with CDC1 3 , DMSO-d 6 , CD 3 OD or Acetone-d 6 as solvents (reported in ppm)
- Use TMS (0ppm) or chloroform (7.25ppm) as the reference standard.
- MS mass spectrometry
- MS mass spectrometry
- the above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specifications are 2.1 ⁇ 30mm, 5 ⁇ m.
- the injection volume was determined by sample concentration; the flow rate was 0.6 mL / min; and the peak value of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm.
- the mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure aqueous solution (phase B).
- the gradient elution conditions are shown in Table 1:
- DMSO-d 6 deuterated dimethyl sulfoxide; g g; mg mg; mol mol; mmol mmol; mL ml; ⁇ L microliter
- R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R x all have the meanings as described in the present invention
- L is Cl, Br, I, methanesulfonyl , P-toluenesulfonyl and other leaving groups
- R 0 is unsubstituted or substituted C 1-6 alkyl (such as methyl, ethyl, t-butyl, benzyl (ie, benzyl), cyanoethyl Group, trimethylsilyl, etc.).
- each reaction step in each reaction scheme described in the present invention is reacted in a solvent inert to the reaction, and the solvent inert to the reaction includes, but is not limited to, the solvent or an alternative thereof in the examples of the present invention. Thing.
- the compound represented by Formula IA can be prepared according to the method described in Reaction Scheme 1. Wherein, a compound of formula I-1 and a compound of formula I-2 undergo an aldol condensation reaction under appropriate conditions to obtain a compound represented by formula I-3, and then form a ring with a compound of formula I-4 under appropriate conditions to obtain formula I- Compound shown in 5.
- the reaction of the compound of the formula I-5 with the compound LR 8 under basic conditions gives the compound of the formula I-6.
- the compound of the formula I-6 is subjected to deprotection (hydrolysis or palladium hydrocarbon reduction, etc.) to obtain the compound of the formula I-7, and then a condensation reaction is performed to obtain the compound of the formula IA.
- the compound represented by Formula IA can also be prepared according to the method described in Reaction Scheme 2. Wherein, a compound of formula I-1 and a compound of formula I-8 undergo an aldol condensation reaction under appropriate conditions to obtain a compound of formula I-9, and then form a ring with a compound of formula I-4 under appropriate conditions to obtain a formula Compound shown by I-10. The compound of formula I-10 and compound LR 8 are reacted under basic conditions (for example, in the presence of cesium carbonate, potassium carbonate, silver carbonate or sodium cyanide) to obtain a compound represented by formula IA.
- basic conditions for example, in the presence of cesium carbonate, potassium carbonate, silver carbonate or sodium cyanide
- Step 2) 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine Benzyl-3-carboxylate
- Step 3 4- (4-cyano-2-methoxyphenyl) -5- (cyclopropylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxylic acid benzyl ester
- Step 4) 4- (4-cyano-2-methoxyphenyl) -5- (cyclopropylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxylic acid
- Step 5 4- (4-cyano-2-methoxyphenyl) -5- (cyclopropylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxamide
- Step 2) 4- (4-cyano-2-methoxyphenyl) -5-((3,3-difluorocyclobutyl) methoxy) -2,8-dimethyl-1,4 -Benzyl dihydro-1,6-naphthyridin-3-carboxylate
- Step 3 4- (4-cyano-2-methoxyphenyl) -5-((3,3-difluorocyclobutyl) methoxy) -2,8-dimethyl-1,4 -Dihydro-1,6-naphthyridine-3-carboxylic acid
- Step 4) 4- (4-cyano-2-methoxyphenyl) -5-((3,3-difluorocyclobutyl) methoxy) -2,8-dimethyl-1,4 -Dihydro-1,6-naphthyridine-3-carboxamide
- Step 2) 4- (4-cyano-2-methoxyphenyl) -5- (cyclopentylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxylic acid benzyl ester
- Step 3 4- (4-cyano-2-methoxyphenyl) -5- (cyclopentylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxylic acid
- Step 4) 4- (4-cyano-2-methoxyphenyl) -5- (cyclopentylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6- Naphthyridine-3-carboxamide
- a saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2).
- the organic phases were combined, washed with an aqueous sodium bicarbonate solution (5 mL) and a saturated saline solution (10 mL), and dried over anhydrous sodium sulfate. Filter and evaporate the solvent under reduced pressure.
- Step 1) 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5- (oxetan-3-yloxy) -1,4-dihydro Benzyl-1,6-naphthyridin-3-carboxylic acid
- Step 2) 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5- (oxetan-3-yloxy) -1,4-dihydro -1,6-naphthyridin-3-carboxylic acid
- Step 3 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5- (oxetan-3-yloxy) -1,4-dihydro -1,6-naphthyridine-3-carboxamide
- Step 1) 4- (4-cyano-2-methoxyphenyl) -5- (cyclobutylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6-naphthyridine Benzyl-3-carboxylate
- Step 2) 4- (4-cyano-2-methoxyphenyl) -5- (cyclobutylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid
- Step 3 4- (4-cyano-2-methoxyphenyl) -5- (cyclobutylmethoxy) -2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-formamide
- Step 2) 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine -3-formamide
- Step 3 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5- (oxetan-3-ylmethoxy) -1,4-di Hydrogen-1,6-naphthyridine-3-carboxamide
- Step 1) 4- (4-cyano-2-methoxyphenyl) -5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- Benzyl 3-formate
- Step 2) 4- (4-cyano-2-methoxyphenyl) -5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-formic acid
- Step 3 4- (4-cyano-2-methoxyphenyl) -5-cyclobutyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-formamide
- ammonium chloride 60 mg, 1.12 mmol
- 4- (4-cyano-2-methoxyphenyl) -5-cyclobutyloxy-2,8-dimethyl-1, 4-dihydro-1,6-naphthyridine-3-carboxylic acid 150 mg, 0.37 mmol
- 2- (7-azobenzotriazole) -N, N, N ', N'-tetramethylurea Hexafluorophosphate 270mg, 0.71mmol
- N, N-diisopropylethylamine 0.5mL, 3mmol
- Step 2) (1-methylcyclobutyl) methyl mesylate
- Step 3 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-((1-methylcyclobutyl) methoxy) -1,4-di Benzyl hydrogen-1,6-naphthyridin-3-carboxylate
- Step 4) 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-((1-methylcyclobutyl) methoxy) -1,4-di Hydrogen-1,6-naphthyridine-3-carboxylic acid
- Step 5 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-((1-methylcyclobutyl) methoxy) -1,4-di Hydrogen-1,6-naphthyridine-3-carboxamide
- ammonium chloride (30 mg, 0.56 mmol), 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-((1-methylcyclobutane Yl) methoxy) -1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.12 mmol), 2- (7-azobenzotriazole) -N, N, N ', N'-Tetramethylurea hexafluorophosphate (90 mg, 0.24 mmol) and N, N-diisopropylethylamine (0.2 mL, 1 mmol) were dissolved in N, N-dimethylformamide (20 mL) The temperature was raised to 50 ° C.
- Step 2) 4- (4-cyano-2-methoxyphenyl) -5-((1-cyanocyclopropyl) methoxy) -2,8-dimethyl-1,4-di Benzyl hydrogen-1,6-naphthyridin-3-carboxylate
- Step 3 4- (4-cyano-2-methoxyphenyl) -5-((1-cyanocyclopropyl) methoxy) -2,8-dimethyl-1,4-di Hydrogen-1,6-naphthyridine-3-carboxylic acid
- Step 4) 4- (4-cyano-2-methoxyphenyl) -5-((1-cyanocyclopropyl) methoxy) -2,8-dimethyl-1,4-di Hydrogen-1,6-naphthyridine-3-carboxamide
- ammonium chloride 50mg, 0.93mmol
- 4- (4-cyano-2-methoxyphenyl) -5-((1-cyanocyclopropyl) methoxy) -2 , 8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 80 mg, 0.19 mmol
- 2- (7-azobenzotriazole) -N, N, N ', N'-Tetramethylurea hexafluorophosphate 140 mg, 0.39 mmol
- N, N-diisopropylethylamine 0.2 mL, 1 mmol
- the temperature was raised to 50 ° C.
- the plasmid containing Gal4 DNA binding domain (DBD) containing mineralocorticoid receptor (MR) ligand binding domain (LBD) was fused and Gal4UAS (upstream activation sequence) )
- the firefly luciferase reporter plasmid under control was transfected into human embryonic kidney cells (HEK293). According to the level of firefly luciferase activity, the changes of mineralocorticoid receptor activity before or after stimulation or the effects of different stimuli on mineralocorticoid receptor activity were judged.
- the plasmid carrying the Renilla luciferase gene was used as a control plasmid to transfect the cells to provide an internal control of transcriptional activity so that the test results are not disturbed by changes in experimental conditions. .
- the Renilla luciferase signal is used for correction, that is, the subsequent inhibition rate calculation is performed using the F / R value;
- Example 1 19.45 Example 3 28.71 Example 5 17.78 Example 7 3.44 Example 8 7.74
- the compound of the present invention has good mineralocorticoid receptor (MR) antagonistic activity, and can be used as an effective mineralocorticoid receptor antagonist.
- MR mineralocorticoid receptor
- test compound solution The test compound is prepared into a solution with 5% dimethyl sulfoxide, 5% Solutol HS 15 and 90% physiological saline for oral and intravenous administration.
- 190-250g male SD rats were randomly divided into two groups, three in each group.
- One group was intravenously injected with the test compound at a dose of 1.0 mg / kg, and the other group was orally administered with the test compound at a dose of 2.5 or 5.0 mg
- blood was collected at time points 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0 and 24 hours.
- Establish a standard curve of a suitable range according to the sample concentration and use the ABSCICI API4000 LC-MS / MS to determine the concentration of the test compound in the plasma sample in the MRM mode.
- WinNonLin 6.3 software non-compartment model method was used to calculate the pharmacokinetic parameters.
- the compound of the present invention has good pharmacokinetic properties in vivo.
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Abstract
Description
时间(min) | A(CH 3CN,0.1%HCOOH) | B(H 2O,0.1%HCOOH) |
0-3 | 5-100 | 95-0 |
3-6 | 100 | 0 |
6-6.1 | 100-5 | 0-95 |
6.1-8 | 5 | 95 |
实施例编号 | MR IC 50(nM) |
实施例1 | 19.45 |
实施例3 | 28.71 |
实施例5 | 17.78 |
实施例7 | 3.44 |
实施例8 | 7.74 |
Claims (19)
- 一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药,其中,X为CR x或N;各R 1、R 2、R 3和R 4独立地为H、D、氨基、羟基、巯基、氰基、硝基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、羧基、C 1-6烷酰基、C 1-6烷基磺酰基、氨基酰基、氨基磺酰基、C 3-8环烷基、C 6-10芳基、3-8个原子组成的杂环基或5-10个原子组成的杂芳基;R 5为氰基、-C(=O)R c或-C(=O)NR aR b;R 6为H、D、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基、C 6-10芳基、3-8个原子组成的杂环基或5-10个原子组成的杂芳基;各R 7和R x独立地为H、D、卤素、氰基、C 1-6烷氧基酰基、羧基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷酰基、C 1-6烷基磺酰基、氨基酰基或氨基磺酰基;各R a和R b独立地为H、D、C 1-6烷基或C 1-6卤代烷基;R c为H、D、OH、C 1-6烷氧基、C 1-6烷基、C 1-6卤代烷氧基、C 1-6卤代烷基、C 6-10芳基或5-6个原子组成的杂芳基;Y为O或S;R 8为C 3-8环烷基、3-8个原子组成的杂环基、5-6个原子组成的杂芳基、C 3-8环烷基C 1-6烷基、(3-8个原子组成的杂环基)C 1-6烷基、(5-6个原子组成的杂芳基)C 1-6烷基、苯基或苯基C 1-6烷基;其中,R 8未被取代或被1、2、3或4个R z取代;各R z独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6卤代烷基、C 1-6烷氨基、C 1-6烷基磺酰基、C 1-6烷基酰基、C 3-8环烷基、3-8个原子组成的杂环基、5-6个原子组成的杂芳基或C 6-10芳基;其中,各R z独立地未被取代或被1、2、3或4个R w取代;各R w独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷基磺酰基、C 1-6烷基酰基、C 3-8环烷基、3-8个原子组成的杂环基、5-6个原子组成的杂芳基或C 6-10芳基。
- 根据权利要求1-2任意一项所述的化合物,其中,各R 1、R 2、R 3和R 4独立地为H、D、氨基、羟基、巯基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、羧基、C 1-4烷酰基、C 1-4烷基磺酰基、氨基酰基、氨基磺酰基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基;R 6为H、D、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基、C 6-10芳基、3-6个原子组成的杂环基或5-6个原子组成的杂芳基;各R 7和R x独立地为H、D、卤素、氰基、C 1-4烷氧基酰基、羧基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷酰基、C 1-4烷基磺酰基、氨基酰基或氨基磺酰基;各R a和R b独立地为H、D、C 1-4烷基或C 1-4卤代烷基。
- 根据权利要求1-3任意一项所述的化合物,其中,各R 1、R 2、R 3和R 4独立地为H、D、氨基、羟基、巯基、氰基、硝基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基、二甲基氨基、羧基、甲基酰基、乙基酰基、甲基磺酰基、氨基酰基或氨基磺酰基;各R a和R b独立地为H、D、甲基、乙基、丙基、丁基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基或三氟乙基;R 6为H、D、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基、二甲基氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、噻唑基、吡唑基或嘧啶基;R 7为H、D、氰基、甲基酰基、乙基酰基、丙基酰基、甲氧基酰基、乙氧基酰基、丙氧基酰基、羧基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基或二甲基氨基。
- 根据权利要求1-5任意一项所述的化合物,其中,R x为H、D、氟、氯、溴、碘、氰基、甲基酰基、乙基酰基、丙基酰基、甲氧基酰基、乙氧基酰基、丙氧基酰基、羧基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基或二甲基氨基。
- 根据权利要求1-6任意一项所述的化合物,其中,R 8为C 3-6环烷基、3-6个原子组成的杂环基、5-6个原子组成的杂芳基、C 3-6环烷基C 1-4烷基、(3-6个原子组成的杂环基)C 1-4烷基或(5-6个原子组成的杂芳基)C 1-4烷基;其中,R 8未被取代或被1、2、3或4个R z取代。
- 根据权利要求1-7任意一项所述的化合物,其中,R 8为环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基、吗啉基、吡咯基、呋喃基、噻吩基、噻唑基、吡唑基、吡啶基、嘧啶基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、氮杂环丁基甲基、氮杂环丁基乙基、氧杂环丁基甲基、氧杂环丁基乙基、吡咯烷基甲基、吡咯烷基乙基、四氢呋喃基甲基、四氢呋喃基乙基、四氢噻吩基甲基、四氢噻吩基乙基、哌啶基甲基、哌啶基乙基、哌嗪基甲基、哌嗪基乙基、吗啉基甲基、吗啉基乙基、吡咯基甲基、吡咯基乙基、呋喃基甲基、呋喃基乙基、噻吩基甲基、噻吩基乙基、噻唑基甲基、噻唑基乙基、吡唑基甲基、吡唑基乙基、咪唑基甲基、咪唑基乙基、三唑基甲基、三唑基乙基、四唑基甲基、四唑基乙基、吡啶基甲基、吡啶基乙基、嘧啶基甲基或嘧啶基乙基;其中,R 8未被取代或被1、2、3或4个R z取代。
- 根据权利要求1-8任意一项所述的化合物,其中,各R z独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4卤代烷基、C 1-4烷氨基、C 1-4烷基磺酰基、C 1-4烷基酰基、C 3-6环烷基、3-6个原子组成的杂环基、5-6个原子组成的杂芳基或C 6-10芳基;其中,各R z独立地未被取代或被1、2、3或4个R w取代;各R w独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷基磺酰基、C 1-4烷基酰基、C 3-6环烷基、3-6个原子组成的杂环基、5-6个原子组成的杂芳基或C 6-10芳基。
- 根据权利要求1-9任意一项所述的化合物,其中,各R z独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、三氟甲氧基、一氟甲氧基、二氟甲氧基、三氟甲基、二氟甲基、一氟甲基、甲氨基、乙氨基、二甲氨基、甲基乙基氨基、二乙基氨基、甲基磺酰基、乙基磺酰基、甲基酰基、乙基酰基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基、吗啉基、吡咯基、呋喃基、噻吩基、噻唑基、吡唑基、吡啶基、嘧啶基或苯基;其中,各R z独立地未被取代或被1、2、3或4个R w取代;各R w独立地为=O、氘、氟、氯、溴、碘、羟基、氰基、NH 2、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、三氟甲氧基、一氟甲氧基、二氟甲氧基、三氟甲基、二氟甲基、一氟甲基、甲氨基、乙氨基、二甲氨基、甲基乙基氨基、二乙基氨基、甲基磺酰基、乙基磺酰基、甲基酰基、乙基酰基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、吡唑烷基、恶唑烷基、咪唑烷基、异恶唑烷基、哌啶基、哌嗪基、吗啉基、吡咯基、呋喃基、噻吩基、噻唑基、吡唑基、吡啶基、嘧啶基或苯基。
- 一种药物组合物,其包含权利要求1-11任意一项所述的化合物;任选地,其进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
- 根据权利要求12所述的药物组合物,其进一步包含一种或多种其他活性成分,所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
- 根据权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物在制备药物中的用途,其中,所述药物用于治疗、预防或减轻患者如下疾病:糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风。
- 根据权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物在制备药物中的用途,其中,所述药物用作盐皮质激素受体拮抗剂。
- 权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物用于治疗、预防或减轻患者如下疾病:糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风。
- 权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物用于拮抗盐皮质激素受体。
- 一种使用权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物治疗、预防或减轻患者如下疾病的方法:糖尿病肾病、醛甾酮过多症、高血压、心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭或中风。
- 一种使用权利要求1-11任意一项所述的化合物或权利要求12-13任意一项所述的药物组合物拮抗盐皮质激素受体的方法。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113549067A (zh) * | 2020-04-24 | 2021-10-26 | 广东东阳光药业有限公司 | 二氢萘啶类化合物的晶型及其用途 |
WO2023041004A1 (zh) | 2021-09-18 | 2023-03-23 | 上海拓界生物医药科技有限公司 | 取代的1,4-二氢-1,6-萘啶酰胺及其用途 |
WO2024022481A1 (zh) * | 2022-07-29 | 2024-02-01 | 苏中药业集团股份有限公司 | 苯基取代的二氢萘啶类化合物及其制备与用途 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113549066B (zh) * | 2020-04-24 | 2023-07-21 | 年衍药业(珠海)有限公司 | 二氢萘啶类化合物的晶型及其用途 |
CN113214248B (zh) * | 2021-04-13 | 2022-04-26 | 湖南南新制药股份有限公司 | 一种1,4-二氢-1,6-萘啶衍生物、药物组合物及其用途 |
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WO2024022262A1 (zh) * | 2022-07-25 | 2024-02-01 | 深圳信立泰药业股份有限公司 | 一种内皮素a(eta)受体拮抗剂化合物的盐及其制备方法和医药用途 |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000006568A1 (de) | 1998-07-29 | 2000-02-10 | Bayer Aktiengesellschaft | Substituierte pyrazolderivate |
WO2000006569A1 (de) | 1998-07-29 | 2000-02-10 | Bayer Aktiengesellschaft | Mit sechsgliedrigen heterocyclischen ringen kondensierte substituierte pyrazolderivate |
WO2001019355A2 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Dicarbonsäurederivate mit neuartigen pharmazeutischen eigenschaften |
WO2001019776A2 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2001019778A1 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2002042301A1 (de) | 2000-11-22 | 2002-05-30 | Bayer Aktiengesellschaft | Neue pyridin-substituierte pyrazolopyridinderivate |
WO2002070510A2 (de) | 2001-03-07 | 2002-09-12 | Bayer Aktiengesellschaft | Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2002070462A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Aktiengesellschaft | Substituierte aminodicarbonsäurederivate |
WO2003095451A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Healthcare Ag | Carbamat-substituierte pyrazolopyridine |
WO2007009670A1 (de) * | 2005-07-22 | 2007-01-25 | Bayer Healthcare Ag | 4-chromenonyl-1,4-dihydropyridincarbonitrile und ihre verwendung |
WO2009056934A1 (en) * | 2007-10-31 | 2009-05-07 | Pfizer Products Inc. | 1,4-dihydronaphthyridine derivatives |
CN101641352A (zh) * | 2007-02-27 | 2010-02-03 | 拜耳先灵制药股份公司 | 取代的4-芳基-1,4-二氢-1,6-萘啶酰胺和其用途 |
US20100035902A1 (en) * | 2006-06-07 | 2010-02-11 | Bayer Healthcare Ag | 5-aryl-substituted dihydropyridopyrimidines and dihydropyridazines and use thereof as mineral corticoid antagonists |
-
2019
- 2019-05-20 AU AU2019272300A patent/AU2019272300B2/en active Active
- 2019-05-20 EP EP19807918.8A patent/EP3798219A4/en active Pending
- 2019-05-20 US US17/056,466 patent/US20210206760A1/en active Pending
- 2019-05-20 JP JP2020565343A patent/JP7457658B2/ja active Active
- 2019-05-20 WO PCT/CN2019/087516 patent/WO2019223629A1/zh unknown
- 2019-05-20 CN CN201910416791.9A patent/CN110511219B/zh active Active
- 2019-05-20 CA CA3100271A patent/CA3100271A1/en active Pending
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000006568A1 (de) | 1998-07-29 | 2000-02-10 | Bayer Aktiengesellschaft | Substituierte pyrazolderivate |
WO2000006569A1 (de) | 1998-07-29 | 2000-02-10 | Bayer Aktiengesellschaft | Mit sechsgliedrigen heterocyclischen ringen kondensierte substituierte pyrazolderivate |
WO2001019355A2 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Dicarbonsäurederivate mit neuartigen pharmazeutischen eigenschaften |
WO2001019776A2 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2001019778A1 (de) | 1999-09-13 | 2001-03-22 | Bayer Aktiengesellschaft | Neuartige dicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2002042301A1 (de) | 2000-11-22 | 2002-05-30 | Bayer Aktiengesellschaft | Neue pyridin-substituierte pyrazolopyridinderivate |
WO2002070510A2 (de) | 2001-03-07 | 2002-09-12 | Bayer Aktiengesellschaft | Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften |
WO2002070462A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Aktiengesellschaft | Substituierte aminodicarbonsäurederivate |
WO2003095451A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Healthcare Ag | Carbamat-substituierte pyrazolopyridine |
WO2007009670A1 (de) * | 2005-07-22 | 2007-01-25 | Bayer Healthcare Ag | 4-chromenonyl-1,4-dihydropyridincarbonitrile und ihre verwendung |
US20100035902A1 (en) * | 2006-06-07 | 2010-02-11 | Bayer Healthcare Ag | 5-aryl-substituted dihydropyridopyrimidines and dihydropyridazines and use thereof as mineral corticoid antagonists |
CN101641352A (zh) * | 2007-02-27 | 2010-02-03 | 拜耳先灵制药股份公司 | 取代的4-芳基-1,4-二氢-1,6-萘啶酰胺和其用途 |
WO2009056934A1 (en) * | 2007-10-31 | 2009-05-07 | Pfizer Products Inc. | 1,4-dihydronaphthyridine derivatives |
Non-Patent Citations (19)
Title |
---|
"Handbook of Pharmaceutical Additives", 2002, SYNAPSE INFORMATION RESOURCES, INC. |
"Inactive Ingredient Guide", 1996, CENTER FOR DRUG EVALUATION AND RESEARCH (CEDR |
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY |
B. PITTF. ZANNADW.J. REMME, N. ENGL. J. MED. ML, 1999, pages 709 - 717 |
B. PITTW. REMMEF. ZANNAD, N. ENGL. J. MED, 2003, pages 1309 - 1321 |
BIOCHEM, vol. 11, 1972, pages 942 - 944 |
BRILLA ET AL., JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 25, no. 5, 1993, pages 563 - 75 |
CASTREN ET AL., J. OF NEUROENDOCRINOLOGY, vol. 3, 1993, pages 461 - 66 |
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC. |
J. RAUTIO ET AL.: "Prodrugs: Design and Clinical Applications", NATURE REVIEW DRUG DISCOVERY, vol. 7, 2008, pages 255 - 270, XP055227338, DOI: 10.1038/nrd2468 |
L. W. DEADY, SYN. COMM., vol. 7, 1977, pages 509 - 514 |
REMINGTON: TROY ET AL.: "Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS |
S. J. HECKER ET AL.: "Prodrugs of Phosphates and Phosphonates", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2008, pages 2328 - 2345, XP008148502, DOI: 10.1021/jm701260b |
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19 |
See also references of EP3798219A4 |
SMITH ET AL.: "March's Advanced Organic Chemistry", 2007, JOHN WILEY & SONS |
SWARBRICK ET AL.: "Encyclopedia of Pharmaceutical Technology", 1988, MARCEL DEKKER, pages: 366 - 81 |
T. HIGUCHIV. STELLA: "Bioreversible Carriers in Drug Design", vol. 14, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS, article "Pro-drugs as Novel Delivery Systems" |
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS |
Cited By (4)
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CN113549067A (zh) * | 2020-04-24 | 2021-10-26 | 广东东阳光药业有限公司 | 二氢萘啶类化合物的晶型及其用途 |
CN113549067B (zh) * | 2020-04-24 | 2023-10-03 | 年衍药业(珠海)有限公司 | 二氢萘啶类化合物的晶型及其用途 |
WO2023041004A1 (zh) | 2021-09-18 | 2023-03-23 | 上海拓界生物医药科技有限公司 | 取代的1,4-二氢-1,6-萘啶酰胺及其用途 |
WO2024022481A1 (zh) * | 2022-07-29 | 2024-02-01 | 苏中药业集团股份有限公司 | 苯基取代的二氢萘啶类化合物及其制备与用途 |
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