WO2010047369A1 - Agent destiné au traitement de la néphropathie diabétique - Google Patents

Agent destiné au traitement de la néphropathie diabétique Download PDF

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WO2010047369A1
WO2010047369A1 PCT/JP2009/068187 JP2009068187W WO2010047369A1 WO 2010047369 A1 WO2010047369 A1 WO 2010047369A1 JP 2009068187 W JP2009068187 W JP 2009068187W WO 2010047369 A1 WO2010047369 A1 WO 2010047369A1
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substituent
optionally substituted
lower alkyl
optionally
hydrogen atom
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Japanese (ja)
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晃規 ▲濱▼口
雅子 内井
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協和発酵キリン株式会社
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Priority to JP2010534841A priority patent/JP5559696B2/ja
Publication of WO2010047369A1 publication Critical patent/WO2010047369A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Diabetic nephropathy is the main cause of introduction of dialysis, and the life prognosis of diabetic patients who have reached dialysis therapy is poor. Therefore, treatment that prevents the development of diabetic nephropathy and suppresses its development is important.
  • Nephropathy in diabetes is caused by the appearance of albuminuria (early nephropathy). If not treated, albuminuria increases by 10 to 20% annually, and proteinuria becomes positive after 10 to 15 years (apparent) Nephropathy). When the stage progresses to the stage of overt nephropathy, more than half of cases are thought to fall into end stage renal failure within 10 years (Scientific-based Diabetes Practice Guidelines, Japan Diabetes Society, 2007).
  • Strict blood glucose and blood pressure control is important for the suppression of the progression of such diabetic nephropathy.
  • blood glucose and blood pressure control is thought to suppress the development of diabetic nephropathy.
  • blood pressure management with antihypertensive drugs may be useful in treatment in the stage of overt nephropathy, especially blood pressure control with ACE inhibitors and angiotensin II receptor antagonists suppresses progression to overt nephropathy It is considered to be.
  • Angiotensin II receptor antagonist specifically inhibits angiotensin II type 1 (AT1) receptor on the cell membrane surface.
  • Angiotensin II receptor antagonist dilates glomerular export arterioles, lowers glomerular hypertension, and inhibits the action of angiotensin II, which causes glomerular fibrosis and hypertrophy, leading to the development and progression of glomerular sclerosis It is thought to suppress.
  • Peroxisome proliferator activated receptor (PPAR) gamma agonists improve hyperglycemia in type 2 diabetic patients by improving insulin resistance. Blood glucose control is important for the suppression of the onset and progression of diabetic nephropathy, and PPAR ⁇ agonists are thought to correct hyperglycemia and suppress the onset and progression of diabetic nephropathy.
  • PPAR ⁇ agonists have lipid lowering action, antioxidant action, anti-inflammatory action and blood pressure lowering action in addition to the insulin resistance improving action, and these actions also contribute to the urinary albumin lowering action. (Kidney International Int. 2001; 60: 14-30).
  • Chronic heart failure is a condition in which the heart's pumping function is reduced due to chronic myocardial injury, and it is not possible to pump blood volume absolutely or relatively to meet the oxygen demand of the major peripheral organs. It is defined as “a pathological condition that caused congestion in the system and impaired life function” (Chronic Heart Failure Treatment Guidelines (revised 2005)).
  • Basic diseases of heart failure are classified into those based on mechanical disorders such as valvular disease and hypertension, myocardial disorders such as ischemic heart disease and dilated cardiomyopathy, and transmission disorders such as atrial fibrillation.
  • the renin-angiotensin system activated by a decrease in renal blood flow due to decreased cardiac output and an increase in sympathetic nerve activity via baroreceptor reflex is thought to play a central role in pathogenesis Yes.
  • Angiotensin II receptor antagonists specifically inhibit the angiotensin II type 1 (AT1) receptor on the cell membrane surface and suppress the activation of the renin-angiotensin system.
  • Suppressing renin-angiotensin system activation in heart failure is an increase in cardiac output due to a decrease in afterload accompanying a decrease in peripheral vascular resistance, a diuretic effect due to an increase in renal blood flow and a suppression of renal Na reabsorption, and a sympathetic nerve It is thought to bring about an improvement effect on hemodynamics such as reduction of pulmonary congestion due to reduction of preload such as reduction of circulating plasma volume, venous return volume, left ventricular end-diastolic volume, etc. by suppressing activation enhancement.
  • Angiotensin II has been reported to induce cardiovascular remodeling such as cardiomyocyte hypertrophy, increase in extracellular matrix, and proliferation of vascular smooth muscle and fibroblasts.
  • Angiotensin II receptor antagonists have been reported to inhibit the action of these angiotensin II, suppress cardiac hypertrophy and cardiovascular remodeling, which are the previous stages of heart failure, and improve the pathology of heart failure (circulation ( Circulation) 2006; 114: 2850-70).
  • PPAR ⁇ agonist has lipid lowering action, antioxidant action, anti-inflammatory action, blood pressure lowering action in addition to insulin resistance improving action, left ventricular diastolic dysfunction in diabetic model rats, left ventricle after myocardial infarction It has been reported to suppress cardiac hypertrophy due to remodeling and pressure load (J Cardiovasc Pharmacol. 2001; 38: 868-74, Circulation 2002; 106: 3126- 32, Circulation 2002; 105: 1240-46).
  • a drug containing a compound used in the present invention as an active ingredient and having PPAR ⁇ agonist activity, preferably further an angiotensin II receptor antagonistic activity is known (see Patent Document 1).
  • An object of the present invention is to provide a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to the following (1) to (26).
  • R 1 has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent.
  • R 2 and R 3 are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl.
  • R 1 has the same meaning as defined above, and R 6 and R 7 are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR 9 R 10 (wherein R 9 and R 10 are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R 9 and R 0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - CONR 11 R 12 (wherein, R 11 and R 12 are the same Or, differently
  • R 11 and R 12 together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent.
  • R 8 represents a hydrogen atom or a substituent
  • Represents lower alkyl optionally having R 4 and R 5 are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl
  • Q 1 -Q 2 -Q 3 represents CH ⁇ CH—CH ⁇ CH, S—CH ⁇ CH, or CH ⁇ CH—S
  • Z 1 -Z 2 represents C ⁇ CR 13 (wherein R 13 represents a hydrogen atom or
  • a therapeutic and / or prophylactic agent for diabetic nephropathy comprising a tricyclic compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the tricyclic compound represented by the formula (I) is represented by the formula (IA)
  • R 1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent.
  • R 2A and R 3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl.
  • R 1A has the same meaning as described above, and R 6A and R 7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted.
  • R 9A and R 10A are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - CONR 11A R 12A (wherein, R 11A and R 12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted.
  • R 8A represents a lower alkyl which may have a hydrogen atom or a substituent]
  • R 4A and R 5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl
  • Y A represents a single bond, CH 2 , CH 2 CH 2 , CH ⁇ CH, O, S, CH 2 O, OCH 2
  • R 18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
  • Z 1A -Z 2A is C ⁇ CR 13AB (wherein R 13AB represents a hydrogen atom), CH—CR 14AB R 15AB (wherein R 14AB and R 15AB both represent a hydrogen atom), or When N-CR 16AB R 17AB (wherein R 16AB and R 17AB both represent a hydrogen atom)
  • a A represents a group selected from the group consisting of the following formulas (B3) to (B6)
  • the therapeutic and / or prophylactic agent for diabetic nephropathy according to (1) which is a tricyclic compound represented by the formula: (3) Group in formula (IA)
  • the therapeutic and / or prophylactic agent for diabetic nephropathy according to (2) wherein is a group selected from the group consisting of the formulas (A1) to (A20). (4) in formula (IA)
  • Z 1A -Z 2A is C ⁇ CR 13AA (wherein R 13AA is as defined above), CH—CHR 15AA (wherein R 15AA is as defined above), or N—CR
  • a A is the following formula (B3)
  • R 1 has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent.
  • R 2 and R 3 are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl.
  • R 1 has the same meaning as defined above, and R 6 and R 7 are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR 9 R 10 (wherein R 9 and R 10 are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R 9 and R 0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - CONR 11 R 12 (wherein, R 11 and R 12 are the same Or, differently
  • R 11 and R 12 together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent.
  • R 8 represents a hydrogen atom or a substituent
  • Represents lower alkyl optionally having R 4 and R 5 are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl
  • Q 1 -Q 2 -Q 3 represents CH ⁇ CH—CH ⁇ CH, S—CH ⁇ CH, or CH ⁇ CH—S
  • Z 1 -Z 2 represents C ⁇ CR 13 (wherein R 13 represents a hydrogen atom or
  • a therapeutic and / or prophylactic agent for heart failure comprising a tricyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • the tricyclic compound represented by the formula (I) is represented by the formula (IA)
  • R 1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent.
  • R 2A and R 3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl.
  • R 1A has the same meaning as described above, and R 6A and R 7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted.
  • R 9A and R 10A are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - CONR 11A R 12A (wherein, R 11A and R 12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted.
  • R 8A represents a lower alkyl which may have a hydrogen atom or a substituent]
  • R 4A and R 5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl
  • Y A represents a single bond, CH 2 , CH 2 CH 2 , CH ⁇ CH, O, S, CH 2 O, OCH 2
  • R 18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
  • Z 1A -Z 2A is C ⁇ CR 13AB (wherein R 13AB represents a hydrogen atom), CH—CR 14AB R 15AB (wherein R 14AB and R 15AB both represent a hydrogen atom), or When N-CR 16AB R 17AB (wherein R 16AB and R 17AB both represent a hydrogen atom)
  • a A represents a group selected from the group consisting of the following formulas (B3) to (B6)
  • a A is the following formula (B3)
  • the therapeutic and / or prophylactic agent for heart failure according to any one of (15) to (20).
  • a method for preventing and / or treating heart failure comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to any one of (14) to (23).
  • the present invention provides a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FIG. 1 shows the amount of protein excreted in urine 12 weeks after administration of Compound 95 in Zucker Fatty rats.
  • FIG. 1 (right) shows the amount of urinary albumin excreted 12 weeks after administration of Compound 95 in Zucker Fatty rats.
  • the unit of the vertical axis in FIG. 1 represents mg / kg / day.
  • Each column in FIG. 1 represents the results in the Lean group, the Control group, and the compound 95 (10 mg / kg) administration group from the left (see the meanings of the Lean group and the Control group later).
  • FIG. 2 shows the amount of protein excreted in urine 12 weeks after administration of Compound 95 in Zucker diabetic Fatty rats.
  • FIG. 2 shows the relative weight of the heart 8 weeks after administration of Compound 95 in stroke-prone spontaneously hypertensive rats (SHRSP).
  • SHRSP stroke-prone spontaneously hypertensive rats
  • FIG. 4 shows the relative weight of the heart 8 weeks after administration of Compound 95 in salt-loaded Dahl-S (salt-sensitive hypertensive) rats.
  • the unit of the vertical axis in FIG. 4 represents g / 100 gB.W.
  • Lower alkyl and lower alkyl, lower alkylsulfanyl, lower alkanoyloxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylcarbamoyl and lower alkyl moiety of di-lower alkylcarbamoyl include, for example, linear or branched alkyl having 1 to 10 carbon atoms.
  • methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like can be mentioned.
  • the two lower alkyl moieties of the di-lower alkylcarbamoyl may be the same or different.
  • lower alkenyl examples include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically, vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. Can be given.
  • Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aralkyl examples include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl, naphthyl.
  • Examples thereof include methyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.
  • aryl examples include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, azulenyl, anthryl and the like.
  • aliphatic heterocyclic group and the aliphatic heterocyclic group part of the aliphatic heterocyclic carbonyl include, for example, a 5-membered or 6-membered monocyclic fatty acid containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a heterocyclic heterocyclic group a bicyclic or tricyclic condensed 3- to 8-membered ring, and a condensed aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom More specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl 5,6-dihydro-2H-pyranyl, oxazolidinyl, mole Lino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl
  • aromatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is condensed.
  • Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , Which may contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3- to 8-membered rings and containing at least one nitrogen atom ( Examples of the condensed heterocyclic group may include other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl,
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • Lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkoxy optionally having substituent, lower alkylsulfanyl optionally having substituent, substituted Lower alkanoyloxy which may have a group, lower alkanoyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, lower alkylcarbamoyl which may have a substituent, and Examples of the substituent in the di-lower alkylcarbamoyl which may have a substituent are the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl, C 3-8 cycloalkyl having 1 to 3 substituents.
  • the substituents in the aryl which may have a substituent, the aralkyl which may have a substituent, and the aromatic heterocyclic group which may have a substituent may be the same or different. 1 to 3, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl, C 1-10 alkyl, trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group , C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR during X R Y (wherein, R X and R Y are the same or different, a hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl Represents C 6-14 aryl, an aromatic
  • Cycloalkyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, aliphatic heterocyclic carbonyl which may have a substituent and may have a substituent
  • substituent in the nitrogen-containing heterocyclic group formed together with a good adjacent nitrogen atom are the same or different, for example, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl having 1 to 3 substituents.
  • Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl.
  • the two C 1-10 alkyls in the diC 1-10 alkylcarbamoyl may be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • the C 7-16 aralkyl moiety of the C 7-16 aralkyl and C 7-16 aralkyloxy and C 7-16 aralkyloxycarbonyl, for example groups mentioned for illustrative said aralkyl is exemplified.
  • Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen include the groups exemplified in the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen.
  • the compounds described in the above (1) to (20) are more preferable. More specifically, the compounds represented by the general formula (IA-A) or (IA-B),
  • R 1X represents C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy
  • R 6X represents a hydrogen atom, halogen, trifluoromethyl, or C 1 1-6 alkyl represents
  • R 7X represents a hydrogen atom, halogen, or C 1-6 alkyl
  • Y X represents CH 2 CH 2 , CH 2 O, or OCH 2
  • R 13X represents a hydrogen atom or C 1 -6 alkyl
  • a X represents the following formula (b2) or (b3).
  • D is CH or N;
  • R 1X is preferably, for example, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, and more preferably ethyl, propyl, cyclopropyl, ethoxy and the like.
  • R 6X is, for example, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl and the like, more preferably a hydrogen atom, chlorine atom, methyl and the like, and even more preferably a chlorine atom, methyl and the like.
  • R 7X is, for example, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, or isopropyl, and more preferably a hydrogen atom or methyl.
  • Y X is more preferably, for example, CH 2 CH 2 or CH 2 O.
  • R 13X for example, C 1-6 alkyl is preferable, methyl, ethyl, propyl and the like are more preferable, and methyl is more preferable.
  • a X for example the formula (b3) are preferable.
  • the pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Pharmaceutically acceptable acid addition salts of compounds (I) and (IA) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalic acid Organic salts such as salts, maleates, fumarate, citrates, benzoates, methanesulfonates, and the like.
  • Examples of pharmaceutically acceptable metal salts include sodium salts and potassium salts.
  • Alkaline earth metal salts such as alkali salts, magnesium salts, calcium salts, aluminum salts, zinc salts and the like.
  • pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium.
  • pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and pharmaceutically acceptable amino acid addition salts. Is, for example lysine, glycine, phenylalanine, aspartic acid, addition salts, such as glutamic acid.
  • the pharmaceutically acceptable salts of compounds (I) and (IA) may exist in the form of adducts with water or various solvents, and these adducts are also present in the diabetic nephropathy of the present invention. Or it can be used for therapeutic and / or prophylactic agents such as heart failure.
  • Diabetic nephropathy refers to diabetic nephropathy in renal failure such as nephrosis, early nephropathy, overt nephropathy or end stage renal failure.
  • Heart failure means heart failure selected from left heart failure, right heart failure, acute heart failure or chronic heart failure.
  • Specific diseases that cause heart failure include cardiomyopathy, valvular disease, ischemic heart disease, hypertensive heart disease, atrial fibrillation, pulmonary heart, congenital heart disease, pericardial disease, myocarditis, etc.
  • cardiomyopathy CAD
  • valvular disease CAD
  • ischemic heart disease hypertensive heart disease
  • atrial fibrillation CAD
  • pulmonary heart congenital heart disease
  • pericardial disease myocarditis, etc.
  • compounds (I) and (IA) there may exist stereoisomers such as geometric isomers and optical isomers, tautomers, etc., but diabetic nephropathy or heart failure of the present invention, etc. All possible isomers and mixtures thereof can be used for the therapeutic and / or prophylactic agent.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method described in WO2008 / 096829. Specific examples of the compounds used in the present invention are shown in Tables 1 to 34, but the scope of the compounds used in the present invention is not limited thereto.
  • the compounds (I) and (IA) may be purified as they are when they are obtained in the salt form.
  • (I) and (IA) may be isolated or purified by dissolving or suspending them in a suitable solvent and adding an acid or base to form a salt.
  • the example number, reference example number and compound number are the example number, reference example number and compound number in WO2008 / 096829.
  • Test Example 1 Action on Diabetic Nephropathy In order to investigate the inhibitory effect of the onset of diabetic nephropathy, male Zucker Fatty (Crlj: ZUC-Lepr fa : genotype Lepr fa / Lepr fa ) Rats were used. In addition, male Zucker Lean as a control normal rats were used (Crlj:: ZUC-Lepr fa Lepr fa / + or + / +) rats. Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL.
  • MC methylcellulose
  • the control group showed increased urinary protein excretion and urinary albumin excretion compared to the Lean group.
  • Compound 95 (10 mg / kg) significantly suppressed increases in urinary protein excretion and urinary albumin excretion. From the above results, it was revealed that Compound 95 suppresses the onset of diabetic nephropathy in Zucker Fatty rats.
  • male Zucker diabetic Fatty (ZDF, ZDF / CrlCrlj-Lepr fa ) rats of 11 weeks of age already presenting with diabetic nephropathy were used in the study.
  • male Lean (ZDF / CrlCrlj-?
  • Rats were used as control normal rats. Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL. Eleven week old ZDF rats were orally administered Compound 95 (10 mg / kg) or vehicle (0.5% MC, control group) once a day for 12 weeks in a volume of 5 mL / kg. Solan (0.5% MC, Lean group) was similarly administered to 11-week-old Lean rats. Twelve weeks after the start of administration, urine was collected for 24 hours using a metabolic cage, and urinary protein excretion was measured as an indicator of renal damage. The results are shown in FIG.
  • MC methylcellulose
  • Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL.
  • Solvents (0.5% MC, WKY group) were administered to WKY rats. Eight weeks after the start of administration, the animals were dissected under anesthesia and the heart weight was measured. The results are shown in FIG. A significant increase in relative heart weight (heart weight relative to body weight of 100 g) was observed in the Control group compared to the WKY group.
  • Compound 95 exhibited an antihypertensive action and significantly suppressed an increase in cardiac hypertrophy compared to the control group. From the above results, it was revealed that Compound 95 suppresses cardiac hypertrophy in SHRSP.
  • Test Example 3 Salt-sensitive hypertensive (Dahl-S) rats were used in an action test for heart disease .
  • Compound (I) or a pharmaceutically acceptable salt is useful for the treatment and / or prevention of heart failure and the like.
  • Compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof can be administered alone as they are, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention comprises compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof alone or as an active ingredient for any other therapeutic and / or prophylactic agent as active ingredients. It can contain as a mixture of these.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). Manufactured by any method.
  • oral administration and parenteral administration such as intravenous administration.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof are the dosage form, patient age, body weight, nature or severity of symptoms to be treated and / or prevented, etc.
  • the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day.
  • parenteral administration such as intravenous administration
  • parenteral administration such as intravenous administration
  • parenteral administration such as intravenous administration
  • parenteral administration such as intravenous administration
  • 0.001 to 1000 mg preferably 0.01 to 100 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Production Example 1 Tablet A tablet having the following composition is prepared by a conventional method.
  • Compound 29, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
  • the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
  • Magnesium stearate 0.6 mg 200 mg
  • Formulation Example 2 Injection An injection having the following composition is prepared by a conventional method. Compound 29, 1 g is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial). Formulation Compound 29 2 mg Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
  • Production Example 3 Tablets Tablets having the following composition are prepared by a conventional method.
  • Compound 95, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
  • the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
  • Formulation Compound 95 20 mg Lactose 143.4 mg
  • Magnesium stearate 0.6 mg 200 mg
  • Formulation Example 4 Injection An injection having the following composition is prepared by a conventional method. Compound 95, 1 g is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial). Formula Compound 95 2 mg Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
  • the present invention can provide a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing, for example, a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

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Abstract

La présente invention concerne un agent destiné au traitement et/ou à la prévention d’une néphropathie diabétique, d’une insuffisance cardiaque ou analogues, qui contient un composé tricyclique représenté par la formule générale (I) ou l’un de ses sels pharmaceutiquement acceptables en tant que principe actif. (Dans la formule, R1 représente un alkyle inférieur éventuellement substitué ou analogues ; R2 et R3 peuvent être identiques ou différents et chacun représente un atome d’hydrogène ou analogues ; R4 et R5 peuvent être identiques ou différents et chacun représente un atome d’hydrogène ou analogues ; Q1-Q2-Q3 représente CH=CH-CH=CH ou analogues ; Y représente une liaison simple ou analogues ; Z1-Z2 représente C=CR13 (où R13 représente un atome d’hydrogène ou analogues) ; et A représente un groupe choisi dans le groupe constitué par des groupes représentés par les formules (b1) à (b6) (où R18 représente un alkyle inférieur éventuellement substitué ou analogues).)
PCT/JP2009/068187 2008-10-22 2009-10-22 Agent destiné au traitement de la néphropathie diabétique WO2010047369A1 (fr)

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WO2013018899A1 (fr) * 2011-08-03 2013-02-07 協和発酵キリン株式会社 Dérivé de dibenzooxépine

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Publication number Priority date Publication date Assignee Title
WO2013018899A1 (fr) * 2011-08-03 2013-02-07 協和発酵キリン株式会社 Dérivé de dibenzooxépine
CN103874697A (zh) * 2011-08-03 2014-06-18 协和发酵麒麟株式会社 二苯并氧杂*衍生物
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JPWO2013018899A1 (ja) * 2011-08-03 2015-03-05 協和発酵キリン株式会社 ジベンゾオキセピン誘導体

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JPWO2010047369A1 (ja) 2012-03-22

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