EP3066095A1 - 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase - Google Patents

1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase

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Publication number
EP3066095A1
EP3066095A1 EP14793181.0A EP14793181A EP3066095A1 EP 3066095 A1 EP3066095 A1 EP 3066095A1 EP 14793181 A EP14793181 A EP 14793181A EP 3066095 A1 EP3066095 A1 EP 3066095A1
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Prior art keywords
alkyl
compound
formula
hydrogen
group
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EP14793181.0A
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German (de)
English (en)
Inventor
Chantal FÜRSTNER
Jens Ackerstaff
Alexander Straub
Heinrich Meier
Hanna Tinel
Katja Zimmermann
Dmitry Zubov
Jens Schamberger
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Bayer Pharma AG
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Bayer Pharma AG
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Priority to EP14793181.0A priority Critical patent/EP3066095A1/fr
Publication of EP3066095A1 publication Critical patent/EP3066095A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • C07D413/02—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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to novel substituted l, 2,4-triazine-3,5-dione derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases.
  • Chymase is a chymotrypsin-like serine protease that is stored as a macromolecular complex with heparin proteoglycans in secretory vesicles of mast cells. After activation of the mast cells, chymase is released into the extracellular matrix and activated.
  • mast cells play an important role in wound healing and inflammatory processes, e.g. Fibrosis of wounds, angiogenesis and cardiac remodeling (Miyazaki et al., Pharmacol. Ther. 112 (2006), 668-676; Shiota et al., Hypertens. 21 (2003), 1823-1825).
  • An increase in the number of mast cells has been observed in heart failure, myocardial infarction and ischemia, in human atherosclerotic plaques and in the abdominal aortic aneurysm (Kovanen et al., Circulation 92 (1995), 1084-1088, Libby and Shi, Circulation 115 (2007), 2555) Bacani and Frishman, Cardiol. Rev.
  • Chymase-positive mast cells may also play an important role in respiratory vascular remodeling in asthma and chronic obstructive pulmonary disease. An increased number of mast cells has been found in endobronchial biopsies of asthmatic patients (Zanini et al., Allergy Clin Immunol 120 (2007), 329-333). In addition, chymase is suspected of contributing to the development of many renal diseases such as diabetic nephropathy and polycystic kidney disease (Huang et al., Am Soc. Nephrol 14 (7) (2003), 1738-1747, McPherson et al., Am. Soc. Nephrol. 15 (2) (2004), 493-500).
  • Chymase is involved predominantly in the production of angiotensin II in the heart, in the wall of the arteries and in the lungs, whereas the angiotensin converting enzyme is responsible for the formation of the peptide in the circulatory system (Fleming I., Circ.Res 98 (2006 ), 887-896).
  • chymase cleaves a number of other substrates of pathological importance. Chymase degrades extracellular matrix proteins, such as fibronectin, procollagen, and vitronectin, and tears off focal adhesions. It causes activation and release of TGF ⁇ from its latent form, which plays an important role in the development of cardiac hypertrophy and cardiac fibrosis.
  • the enzyme acts atherogenously by breaking down apolipoproteins and preventing the absorption of cholesterol by HDL.
  • the action of chymase leads to release and activation of the cytokine interleukin 1 with its pro-inflammatory properties. In addition, it contributes to the production of endothelin 1 (Bacani and Frishman, Cardiol. Rev. 14 (4) (2006), 187-193).
  • An accumulation of chymase-positive mast cells has been reported in biopsies from patients with atopic dermatitis, Crohn's disease, chronic hepatitis and liver cirrhosis, and idiopathic interstitial pneumonia (Dogrell SA, Expert Opin. Ther. Patents 18 (2008), 485-499).
  • chymase inhibitors for the treatment of various diseases has been demonstrated in numerous animal studies. Inhibition of chymase may be useful for the treatment of myocardial infarction. Jin et al. (Pharmacol. Exp. Ther. 309 (2004), 409-417) showed that ligation of the coronary artery in the dog has resulted in ventricular arrhythmias as well as increased production of angiotensin II and chymase activity in the heart. Intravenous administration of the chymase inhibitor TY-501076 reduced plasma chymase activity and angiotensin II concentration and suppressed the occurrence of arrhythmias.
  • chymase inhibition with SUN-C82257 has led to a reduction in the number of mast cells and fibrosis in the heart.
  • the diastolic function of the heart after treatment was improved (Matsumoto et al., Circulation 107 (2003), 2555-2558). Inhibition of chymase thus represents an effective principle in the treatment of cardiovascular diseases, inflammatory and allergic as well as different fibrotic diseases.
  • WO 2007/150011 and WO 2009/049112 disclose a process for the preparation of pyrimidine trinions having glycine substituents.
  • WO 2008/056257 describes triazinediones as GABA-B receptor modulators for the treatment of CNS diseases
  • WO 2004/058270 triazinediones as P2X7 antagonists
  • WO 2012/002096 describes triazine dione derivatives as herbicides.
  • WO 2008/103277 discloses various nitrogen heterocycles for the treatment of cancer.
  • the object of the present invention was to provide novel substances which act as inhibitors of chymase and are suitable as such for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases.
  • the present invention relates to compounds of the general formula (I) in which
  • R 1 is hydrogen or (GC 4 ) alkyl, a group of the formula
  • attachment site is the triazinedione nitrogen atom
  • A is -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 - ** or oxygen, where ** is the point of attachment to the phenyl ring, m is a number 0, 1 or 2,
  • R 4 is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 -alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4) -alkoxy,
  • # represents the point of attachment to the triazinedione nitrogen atom, is hydrogen, is hydrogen, halogen, (Ci-C 4) -alkyl or (Ci-C 4) -alkoxy, represents (Ci-C 4) alkyl, (Ci-C 4) -alkoxy, or -N ( R 14 R 15 ) in which (C 1 -C 4 ) -alkyl may be substituted up to three times by halogen, wherein (C 1 -C 4 ) -alkoxy having a substituent hydroxy, (C 1 -C 4 ) -alkoxycarbonyl, amino, mono (C 1 -C 4 ) -alkylamino, di- (C 1 -C 4 ) -alkylamino, aminocarbonyl, mono- (C 1 -C 4 ) -alkylaminocarbonyl or di (C 1 -C 4 ) -alkylaminocarbonyl may be substituted, where
  • R 14 is (Ci-C 4) alkyl, (Ci-C 4) -alkoxycarbonyl or (C 1 -C 4) -
  • Alkylaminocarbonyl wherein (Ci-C4) alkylaminocarbonyl may be substituted with hydroxy or (Ci-C 4) alkoxy,
  • R 15 is hydrogen or (C 1 -C 4 ) -alkyl
  • attachment site is the triazinedione nitrogen atom
  • Ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl having 1 to 4 substituents independently selected from the group consisting of halogen, difluoromethyl , Trifluoromethyl, trideuteromethyl, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, oxo, hydroxy, (C 1 -C 4 ) -alkylcarbonyl, (C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and (Ci (C 1 -C 6) -alkyl and (C 3 -C 7) -cycloalkyl, in turn, having 1 to 3 substituents selected independently from the group halogen, cyano, trifluoromethyl, (C 3 -C 7) - Cycloalkyl, hydroxy, (C1-C4) -
  • R 16 is halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy, n is a number 0, 1, 2 or 3, and their salts, solvates and solvates of the salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas listed below and their salts, solvates and solvates of the salts and those of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which the coordination with water takes place. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms.
  • alkyl radical having 1 to 4 carbon atoms.
  • alkylcarbonyloxy is a linear or branched alkylcarbonyl radical which is bonded via a nitrogen atom and carries 1 to 4 carbon atoms in the alkyl chain.
  • alkylcarbonyloxy is a linear or branched alkylcarbonyl radical which is bonded via a nitrogen atom and carries 1 to 4 carbon atoms in the alkyl chain.
  • Alkoxy in the context of the invention represents a linear or branched alkoxy radical of 1 to 4 carbon atoms.
  • alkoxy radical of 1 to 4 carbon atoms.
  • Aikoxycarbonyl stand in the context of the invention for a linear or branched alkoxy radical having 1 to 4 carbon atoms and a carbonyl group attached to the oxygen.
  • Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group.
  • Aikoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the N-atom.
  • Alkylsulfonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfonyl group.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms.
  • Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N methylamino.
  • Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • Di-alkylaminocarbonyl is in the context of the invention an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms.
  • Mono-alkylaminocarbonylamino in the context of the invention represents an amino group which carries a linear or branched alkylaminocarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group.
  • Di-alkylaminocarbonylamino in the context of the invention represents an amino group which carries a linear or branched di-alkylaminocarbonyl substituent, which in each case has 1 to 4 carbon atoms in the alkyl chain, which may be identical or different, and linked via the carbonyl group is.
  • N N-dimethylaminocarbonylamino
  • N N-diethylaminocarbonylamino
  • N-ethyl-N-methylamino carbonylamino N-methyl-N - "- propylaminocarbonylamino
  • N -" butyl-N-methylaminocarbonylamino
  • N-tert-butyl-N-methylaminocarbonylamino examples which may be mentioned by way of example are: N, N-dimethylaminocarbonylamino, N, N-diethylaminocarbonylamino, N-ethyl-N-methylamino carbonylamino, N-methyl-N - "- propylaminocarbonylamino, N -" - butyl-N-methylaminocarbonylamino and N-tert-butyl-N-methylaminocarbonylamino.
  • Heterocyclyl or heterocycle is in the context of the invention for a saturated or partially unsaturated heterocycle having a total of 4 to 7 ring atoms containing 1 to 3 ring heteroatoms from the series ⁇ , O and / or S and via a ring carbon atom or optionally a Ring nitrogen is linked.
  • Examples which may be mentioned are: azetidinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydrotriazolyl, oxazolidinyl, dihydrooxazolyl, thiazolidinyl, dihydrooxadiazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, oxazinanyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl and azepanyl.
  • 5- or 6-membered heterocyclyl radicals having 1 to 3 ring heteroatoms.
  • exemplary and preferred are: imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydrotriazolyl, oxazolidinyl, dihydrooxazolyl, piperazinyl and morpholinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series ⁇ , O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • monocyclic 5-membered heteroaryl radicals having two or three ring heteroatoms from the series ⁇ , O and / or S such as, for example, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of all radicals which occur repeatedly from each other. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 1 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 2 is a group of the formula stands, where
  • A is -CH 2 - or -CH 2 -CH 2 -
  • n is a number 0, 1 or 2
  • R 4 is hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl, R 3 is
  • R 9 is hydrogen
  • R 10 is hydrogen, halogen or (C 1 -C 4 ) -alkoxy
  • R 11 is (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy or -N (R 14 R 15 ),
  • R 14 is (C 1 -C 4 ) -alkyl
  • R 15 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 11 is 5- or 6-membered heterocyclyl, in which 5- or 6-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, (C 1 -C 4 -alkyl and oxo,
  • R 12 is hydrogen
  • R 13 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 3 is a group of the formula
  • G 2 is CR 21A R 21B , NR 22 , O or S wherein
  • R represents hydrogen, fluorine, (Ci-C 4) -alkyl or hydroxy
  • R2 is hydrogen, fluorine, chlorine, (Ci-C 4) -alkyl or trifluoromethyl
  • R 21A and R 21B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle
  • R 22 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, R 19 is fluorine or methyl, n is a number 0 or 1,
  • R 20 is hydrogen, (G -C 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, and their salts, solvates and solvates of the salts.
  • attachment site is the triazinedione nitrogen atom
  • A is -CH 2 - or -CH 2 -CH 2 -, is chlorine or trifluoromethyl
  • R 9 is hydrogen
  • R 11 is methoxy or ethoxy
  • R 12 is hydrogen
  • R 2 is a group of the formula
  • A is -CH 2 - or -CH 2 -CH 2 -
  • R 4 is chlorine or trifluoromethyl, and their salts, solvates and solvates of the salts.
  • compounds of the formula (I) which are preferred are also preferred
  • R 9 is hydrogen
  • R 10 is hydrogen
  • R 11 is a group of the formula
  • R 12 is hydrogen
  • R 13 is hydrogen
  • R 3 is a group of the formula
  • # represents the point of attachment to the triazinedione nitrogen atom, and their salts, solvates and solvates of the salts.
  • Another object of the invention is a process for the preparation of compounds of the formula (I) according to the invention, characterized in that
  • R 3 has the abovementioned meaning, in an inert solvent with sodium nitrite and a suitable acid to give a compound of the formula (II-1) in which
  • R 3 has the abovementioned meaning, diazotized, and the diazonium salt optionally in the presence of a suitable base with a compound of formula (III)
  • R 3 and T 1 in each case have the meanings given above, then reacting these in an inert solvent, if appropriate in the presence of a suitable base, into a compound of the formula (V)
  • R 3 has the abovementioned meaning, then under Mitsunobu conditions with an activating reagent, for example diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and a phosphine reagent, for example triphenylphosphine or tributylphosphine in an inert solvent, with a compound of the formula (VI)
  • an activating reagent for example diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)
  • a phosphine reagent for example triphenylphosphine or tributylphosphine in an inert solvent
  • A, m, R 3 and R 4 have the meanings given above, and these are subsequently reacted in an inert solvent in the presence of a suitable acid or base to give a compound of the formula (I-1)
  • R 1A is hydrogen, hydrolyzed, or
  • R 1A is hydrogen
  • R 3 has the abovementioned meaning, hydrolyzed, then the acid function esterified to give a compound of formula (IX)
  • R 3 has the abovementioned meanings, and R 1B is (C 1 -C 4 ) -alkyl, and these are then analogously to process [A] under Mitsunobu conditions with an activating reagent, for example diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and a phosphine reagent, for example triphenylphosphine or tributylphosphine in an inert solvent, with a compound of the formula (VI) in which
  • an activating reagent for example diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)
  • a phosphine reagent for example triphenylphosphine or tributylphosphine in an inert solvent
  • R 1B stands for (Ci-C 4 ) -alkyl, converted, or
  • any protecting groups which may be present are split off and / or the compounds of the formulas (1-1) and (1-2), if appropriate, with the corresponding () solvents and / or (ii) bases or acids in their solvates, Salts and / or solvates of the salts converted.
  • Inert solvents for process step (II) -> (II-1) and (II-1) + (III) -> (IV) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol or n-butanol, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ ), pyridine, acetone, 2-butanone; Sulfolane, sulfolene, water or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, water is used.
  • Suitable acids for process step (II) -> (II-1) are e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid. Hydrochloric acid is preferably used.
  • Suitable bases for process steps (II-1) + (III) - »(IV) and (IV) -» (V) are alkali metal alcoholates, such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium tert. butoxide, alkali metal carboxylates such as sodium or potassium acetate, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic bases such as pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo 4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO ®), or phosphazene base such as for example, 1- [N-tert-
  • reaction (II) -> (II-l) is generally carried out in a temperature range from 0 ° C to + 30 ° C, preferably at 0 ° C. Generally, one works at normal pressure.
  • the reaction (II-l) + (III) -> (IV) is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 120 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the reactions (V) + (VI) -> (VII) and (IX) + (VI) - »(1-1) are carried out under Mitsunobu conditions [see: a) Hughes, DL" The Mitsunobu Reaction "Organic Reactions; John Wiley & Sons, Ltd., vol. 42, pp. 335.
  • Inert solvents for the Mitsunobu reactions are, for example, ethers, such as tetrahydrofuran, diethyl ether, hydrocarbons, such as benzene, toluene, xylene, Halogenated hydrocarbons such as dichloromethane, dichloroethane or other solvents such as acetonitrile or dimethylformamide (DMF). It is likewise possible to use mixtures of the solvents mentioned. Preferably, THF or a mixture of THF and DMF is used.
  • the Mitsunobu reactions (V) + (VI) - »(VII) and (IX) + (VI) -» (1-1) are generally carried out in a temperature range from -78 ° C to + 180 ° C, preferably at 0 ° C to + 50 ° C, if necessary in a microwave.
  • the reactions may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • the hydrolysis of the nitrile group of the compounds (V) and (VII) to give compounds of the formula (VIII) or (1-1) is carried out by treating the nitriles in inert solvents with suitable acids.
  • suitable acids for the hydrolysis of the nitrile group are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid or acetic acid or mixtures thereof, optionally with the addition of water. Preference is given to hydrogen chloride.
  • Suitable inert solvents for these reactions are water, diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetonitrile, acetic acid, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetic acid.
  • the hydrolysis of the nitrile group is generally carried out in a temperature range from 0 ° C to 180 ° C, preferably at + 80 ° C to 120 ° C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • the esterification of the acid group R 1A of the compound (VIII) to compounds of the formula (IX) is carried out by treating the acid in a suitable solvent with an alcohol, for example methanol or ethanol, in the presence of thionyl chloride.
  • Suitable solvents for this reaction are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetonitrile, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • the preferred solvent is the alcohol which initiates the reaction, for example methanol or ethanol.
  • the acid may first be converted to the acid chloride with thionyl chloride, which may then be reacted with an alcohol of the formula R 1B OH.
  • esterification of the acid group R 1A of compound (VIII) to compounds of formula (IX) may be effected by heating the compound of formula (VIII) with an alcohol of formula R 1B OH in the presence of an inorganic acid such as hydrogen chloride. Sulfuric acid or phosphoric acid, take place.
  • the esterification is generally carried out in a temperature range from 0 ° C to 180 ° C, preferably at + 20 ° C to 120 ° C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • the hydrolysis of the ester group R 1A of the compound (1-2) to compounds of the formula (1-1) is carried out by treating the esters in acids or bases with inert solvents, with the latter salts being formed by treatment with acid be converted into the free carboxylic acids.
  • the ester hydrolysis is preferably carried out with acids.
  • Suitable inert solvents for these reactions are water, diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetonitrile, acetic acid, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran or acetonitrile.
  • Suitable bases are the alkali metal or alkaline earth metal bicarbonates, such as sodium or potassium bicarbonate. Preference is given to sodium bicarbonate.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid in the case of the tert-butyl ester and hydrochloric acid in admixture with acetic acid, and sulfuric acid in admixture with acetic acid and water in the case of methyl esters and ethyl esters are preferred.
  • the ester cleavage is generally carried out in a temperature range from 0 ° C to 180 ° C, preferably at + 20 ° C to 120 ° C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention are inhibitors of chymase and are therefore suitable for the treatment and / or prophylaxis of cardiovascular, inflammatory, allergic and / or fibrotic disorders.
  • diseases of the cardiovascular system or cardiovascular diseases are to be understood as meaning, for example, the following diseases: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, atherosclerosis, Cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiac vascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasm of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders, edema formation such as Pulmonary edema, cerebral edema, renal edema or heart failure-related edema, as well as restenoses such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations,
  • PTA percutaneous trans
  • cardiac insufficiency also encompasses more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, Tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • the term acute renal insufficiency includes acute manifestations of kidney disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, volume depletion (eg dehydration, blood loss), shock, acute glomerulonephritis, hemolytic uremic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence Jones kidney in plasmocytoma, acute supravesical or subvesical drainage obstruction, immunological kidney disease such as renal transplant rejection, immune complex-induced kidney disease , tubular dilatation, hyperphosphatemia and / or acute kidney disease, which may be characterized by the need for dialysis, as well as in partial resections of the kidney, dehydration by forced diuresis, uncontrolled Blu hypertension, malignant hypertension, urinary tract obstruction and infection and amyloidosis and systemic disorders with glomerular glomerular graft
  • chronic renal insufficiency includes chronic manifestations of kidney disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerular and tubular proteinuria, Renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection, immune complex-induced kidney disease, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • the compounds of the invention are also suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), the acute Lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced pulmonary emphysema), cystic fibrosis (CF), acute coronary syndrome (ACS), myocarditis, and others autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, UC) , Pancreatitis, peritonitis, rheumatoid diseases
  • the compounds according to the invention can furthermore be used for the treatment and / or prophylaxis of asthmatic disorders of varying degrees of severity with intermittent or persistent course (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma)
  • bronchitis chronic bronchitis, infectious bronchitis, eosinophilic bronchitis
  • bronchiolitis obliterans bronchiectasis
  • pneumonia idiopathic interstitial pneumonia
  • farmer's lung and related diseases cough and cold diseases (chronic inflammatory cough, iatrogenic cough), Nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and polyps.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, Hypertrophic scarring (also after surgical procedures), nevi, diabetic retinopathy and proliferative vitroretinopathy.
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery. Furthermore, the compounds according to the invention can also be used cosmetically on aging and keratinous skin.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of dyslipidemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias), nephropathy and neuropathy), cancers (skin cancer, brain tumors, breast cancer, bone marrow tumors , Leukemia, liposarcoma, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, as well as malignant tumors of the lymphoproliferative system such as Hodgkin's and Non-Hodgkin's Lymphoma), diseases of the gastrointestinal tract and the Abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis
  • the compounds of the formula (I) according to the invention are furthermore suitable for the treatment and / or prophylaxis of ophthalmological diseases such as, for example, glaucoma, normotensive glaucoma, ocular hypertension and combinations thereof, age-related macular degeneration (AMD), dry or non-exudative AMD, moist or exudative or neovascular AMD, choroidal neovascularization (CNV), retinal detachment, diabetic retinopathy, atrophic retinal pigment epithelium (RPE), hypertrophic retinal pigment epithelium (RPE), diabetic macular edema, retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, angiogenesis at the Anterior to the eye such as corneal angiogenesis for example after keratitis, corneal transplantation or keratoplasty, corneal angiogenesis due to
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal insufficiency, nephropathies, fibrotic disorders of the internal organs and dermatological fibroses.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or several other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients which may be mentioned are those which inhibit the signal transduction cascade, by way of example and preferably from the group of the kinase inhibitors, in particular from the group of the tyrosine kinase and / or serine / threonine kinase inhibitors;
  • MMPs matrix metalloproteases
  • stromelysin in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (here in particular of MMP-1, MMP-3, MMP-8), inhibit the degradation and remodeling of the extracellular matrix , MMP-9, MMP-10, MMP-11 and MMP-13) as well as the metallo-elastase (MMP-12);
  • NO-independent, but heme-dependent, stimulators of soluble guanylate cyclase in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Prostacyclin analogs such as by way of example and preferably iloprost, beraprost, treprostinil or epoprostenol;
  • phodiesterases 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil; antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists, Rho kinase inhibitors and diuretics;
  • PDE phodiesterases
  • antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances
  • antihypertensive agents by way of example and preferably from the
  • Vasopressin receptor antagonists such as, and preferably, conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050; bronchodilatory agents, by way of example and preferably from the group of beta-adrenergic receptor agonists, in particular albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or from the group of anticholinergics, in particular ipratropium bromide; anti-inflammatory agents, by way of example and with preference from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone; and / or lipid metabolism-alter
  • the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, sorafenib, Regorafenib, sunitinib, tandutinib, tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.
  • a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib,
  • the compounds according to the invention are used in combination with a serotonin receptor antagonist, such as by way of example and preferably PRX-08066.
  • a serotonin receptor antagonist such as by way of example and preferably PRX-08066.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, mLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, mLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor B-relaxer, mineralocorticoid receptor Antagonists, Rho-kinase inhibitors and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.
  • a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol,
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are used in combination with a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • a PPAR delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound according to the invention), rapidly disintegrate in the oral cavity.
  • Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • absorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers, aerosols
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures ), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Method 1 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8 ⁇ 50 x 1mm; Eluent A: 1 l of water + 0.25 mL of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 mL of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 mL / min; UV detection: 210 - 400 nm.
  • Method 3 Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 2.1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 0.3 min 90% A -> 1.7 min 5% A -> 3.0 min 5% A Furnace: 50 ° C; Flow: 1.20 ml / min; UV detection: 205-305 nm.
  • Method 4 (preparative HPLC): column: Reprosil C18, 10 ⁇ m, 250 mm ⁇ 30 mm.
  • Eluent A formic acid 0.1% in water
  • eluent B acetonitrile
  • Flow 50 ml / min;
  • Method 5 (preparative HPLC): As Method 4 but with column Chromatorex C18 5 ⁇ , 250x20mm.
  • Method 6 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A -> 0.5 min 97% A -> 3.2 min 5% A -> 4.0 min 5% A Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm.
  • the cold solution 2 was stirred into the solution 1 and the mixture was stirred at RT overnight, during which a solid precipitated.
  • 40 ml of 6N aqueous hydrochloric acid were added, the suspension was stirred for a further 30 minutes and the solid was filtered off under suction.
  • the solid was washed with 25 ml of water, stirred with 50 ml of 2-propanol and filtered again. It was then suspended in 80 ml of glacial acetic acid. To this suspension was added 1.15 g (14.0 mmol) of sodium acetate. The mixture was heated at reflux temperature overnight. After cooling to RT, the resulting solution was poured into ice-water and the mixture was stirred for 10 minutes. The resulting product was filtered off with suction and dried under HV. This gave 1.57 g (55% of theory) of the title compound.
  • Example 3A Analogously to Example 3A, from 500 mg (2.82 mmol) of 1- (4-aminophenyl) -imidazolidin-2-one (preparation see: P. Stabile et al., Tetrahedron Letters 2010, 51 (24), 3232-3235) and 441 mg (2.82 mmol) of ethyl (cyanoacetyl) carbamate the title compound, with the difference that the glacial acetic acid solution of the crude product has been completely separated by preparative HPLC (Method 4). 173 mg (16% of theory, purity 80%) of the title compound were obtained.
  • Example 6A The combined residues from Example 6A (1.58 g) were taken up in 100 ml of methanol and the suspension was added dropwise with 1.81 ml of thionyl chloride. Subsequently, the reaction mixture was heated at reflux overnight. After cooling to RT, 100 ml of diethyl ether were added. The resulting solid was filtered off with suction and dried in HV. 418 mg (25% of theory over two steps) of the title compound were obtained.
  • Example 8A Analogously to Example 8A, 50.0 mg (0.194 mmol) of 2- (4-methoxy-2-methylphenyl) -3,5-dioxo-2,3,4,5-tetrahydro-l, 2,4-triazine-6-carbonitrile from Example 2A with 50.2 mg (0.23 mmol) of 5- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-l-ol (racemate). 20 mg (23% of theory) of the title compound were obtained.
  • Example 8A Analogously to Example 8A, 50.0 mg (0.194 mmol) of 2- (4-methoxy-2-methylphenyl) -3,5-dioxo-2,3,4,5-tetrahydro-l, 2,4-triazine-6-carbonitrile from Example 2A with 42.4 mg (0.23 mmol) of 5-chloro-1,2,3,4-tetrahydronaphthalene-l-ol (racemate). 38 mg (36% of theory, purity 77%) of the title compound were obtained.
  • Example 8A Analogously to Example 8A, 50.0 mg (0.194 mmol) of 2- (4-methoxy-2-methylphenyl) -3,5-dioxo-2,3,4,5-tetrahydro-l, 2,4-triazine-6-carbonitrile from Example 2A with 52.2 mg (0.23 mmol, purity 90%) (S) -4- (trifluoromethyl) indan-1-ol (S-enantiomer). 38 mg (40% of theory, purity 90%) of the title compound were obtained.
  • Example 8A Analogously to Example 8A, 60.0 mg (0.20 mmol) of the compound from Example 3A were reacted with 48.6 mg (0.24 mmol) of (iS) -4- (tri-methyl) indan-1-ol (S enantiomer). 35 mg (36% of theory) of the title compound were obtained.
  • Example 17A Analogously to Example 17A, 1.86 g (5.86 mmol) of the compound from Example 19A in 75 ml of methanol were reacted with 2.13 ml (29.1 mmol) of thionyl chloride. 2.0 g (94% of theory) of the title compound were obtained.
  • Example 1 Exemplary embodiments: Example 1
  • Example 1 The following compounds in Table 1 (Examples 2 to 8) were prepared analogously to Example 1 from the corresponding precursors, wherein the reaction time has been determined by reaction control by HPLC or LC-MS. All LC-MS data given in Table 1 were measured by Method 1. Table 1:
  • Example 11 Analogously to Example 11, 150 mg (0.45 mmol) of the compound from Example 7A were reacted under conditions of Mitsunobu with 90.9 mg (0.54 mmol) of 5-chloro-1,2,3,4-tetrahydronaphthalene-1-ol. 140 mg (62% of theory) of the title compound were obtained.
  • Example 11 Analogously to Example 11 were 150 mg (0.47 mmol) of the compound from Example 17A, 210 mg (801 ⁇ ) triphenylphosphine and 148 ⁇ (754 ⁇ ) DIAD with 103.3 mg (570 ⁇ ) 5-chloro-1,2,3,4 Tetrahydronaphthalen-l-ol (racemate) reacted. 140 mg (62% of theory) of the title compound were obtained.
  • Example 11 Analogously to Example 11 were 150 mg (0.47 mmol) of the compound from Example 17A, 210 mg (801 ⁇ ) triphenylphosphine and 148 ⁇ (754 ⁇ ) DIAD with 122.3 mg (570 ⁇ ) 5- (trifluoromethyl) -l, 2.3 , 4-tetrahydronaphthalene-l-ol (racemate) reacted. 135 mg (55% of theory) of the title compound were obtained.
  • the enzyme source used is recombinant human chymase (expressed in HEK293 cells) or chymase purified from hamster tongues.
  • the substrate for chymase is Abz-HPFHL-Lys (Dnp) -NÜ 2 .
  • assay 1 ⁇ of a 50-fold concentrated solution of test substance in DMSO, 24 ⁇ enzyme solution (dilution 1: 80,000 human or 1: 4,000 hamsters) and 25 ⁇ substrate solution (final concentration 10 ⁇ ) in assay buffer (Tris 50 mM (pH 7.5), sodium chloride 150 mM, BSA 0.10%, chaps 0.10%, glutathione 1 mM, EDTA 1 mM) in a white 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). The reaction is incubated for 60 min at 32 degrees and the fluorescence emission at 465 nm after excitation at 340 nm is measured in a fluorescence reader eg Tecan Ultra (Tecan, Switzerland).
  • fluorescence reader eg Tecan Ultra (Tecan, Switzerland).
  • test compound is tested on the same microtiter plate in 10 different concentrations from 30 ⁇ to 1 nM in duplicate.
  • Representative IC 50 values for the compounds according to the invention are given in the following Table 3:
  • aorta Male Syrian hamsters (120-150 g) were euthanized with carbon dioxide. The aorta was dissected and placed in ice-cold Krebs-Henseleit buffer. (Composition in mmol / 1: sodium chloride 112, potassium chloride 5.9, calcium chloride 2.0, magnesium chloride 1.2, sodium dihydrogen phosphate 1.2, sodium bicarbonate 25, glucose 11.5). The aorta was cut into 2 mm long rings, transferred to an organ bath filled with 5 mL Krebs-Henseleit buffer and connected to a myograph (DMT, Denmark). The buffer was warmed to 37 ° C and gassed with 95% oxygen, 5% carbon dioxide. To measure the isometric muscle contraction, the aortic rings were mounted between two hooks.
  • One of the hooks was connected to a pressure transducer.
  • the second hook was flexible and allowed precise pre-load adjustment according to a protocol described by Mulvany and Halpern (Circulation Research 1977; 41: 19-26).
  • the drug's response was tested by adding potassium-containing Krebs-Henseleit solution (50 mmol / 1 KCl).
  • an artificial peptide angiotensin 1-18 With an artificial peptide angiotensin 1-18, a contraction of the aortic rings was induced. Angiotensin 1-18 is converted to angiotensin II independently of ACE. Subsequently, the aortic rings were incubated with the test substance for 20 minutes and the contraction measurement repeated. Chymase inhibition is shown to reduce the angiotensin 1-18-induced contraction.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv solution:
  • the compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic sodium chloride solution, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic sodium chloride solution, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Abstract

La présente invention concerne de nouveaux dérivés des 1,2,4-triazine-3,5-diones substitués et leur utilisation, un procédé pour leur préparation, leur utilisation seuls ou en combinaison pour le traitement et/ou la prophylaxie de maladies et leur utilisation pour la préparation de médicaments destinés au traitement et/ou à la prophylaxie de maladies.
EP14793181.0A 2013-11-08 2014-11-05 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase Withdrawn EP3066095A1 (fr)

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EP14793181.0A EP3066095A1 (fr) 2013-11-08 2014-11-05 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase

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EP13192182 2013-11-08
EP14793181.0A EP3066095A1 (fr) 2013-11-08 2014-11-05 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase
PCT/EP2014/073799 WO2015067650A1 (fr) 2013-11-08 2014-11-05 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase

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EP3338780A1 (fr) 2016-12-20 2018-06-27 Bayer Pharma Aktiengesellschaft Utilisation d'inhibiteurs de chymase pour le traitement de l'endométriose, fibrose post opératoire et maladies caractérisées par la formation de fibrose
WO2021000933A1 (fr) * 2019-07-03 2021-01-07 南京明德新药研发有限公司 Composés de pyrimidinone utilisés en tant qu'inhibiteurs de chymase et leur utilisation
CN114671878B (zh) * 2020-12-25 2023-08-04 广东东阳光药业有限公司 取代的含氮双环化合物及其用途
WO2022135514A1 (fr) * 2020-12-25 2022-06-30 广东东阳光药业有限公司 Dérivés d'uracile multi-substitués et leur utilisation
WO2023194222A1 (fr) 2022-04-05 2023-10-12 Socpra Sciences Santé Humaines S.E.C. Inhibiteurs de chymase destinés à être utilisés dans la résolution sélective de thrombus dans des troubles thrombotiques ou thromboemboliques
CN117510426B (zh) * 2024-01-04 2024-04-19 山东国邦药业有限公司 一种抗球虫类兽药三嗪环的合成方法

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RU2181360C2 (ru) * 1996-09-06 2002-04-20 Ниппон Каяку Кабусики Кайся Новые производные ацетамида, способ их получения, фармацевтический состав и ингибиторы протеаз на их основе
AU744739B2 (en) * 1998-02-17 2002-02-28 Nippon Kayaku Kabushiki Kaisha Novel acetamide derivative and use thereof
JP2003342265A (ja) * 2002-05-22 2003-12-03 Senju Pharmaceut Co Ltd トリアゾリジン誘導体およびその医薬用途
US8501749B2 (en) * 2009-01-30 2013-08-06 Boehringer Ingelheim International Gmbh Azaquinazolinediones chymase inhibitors
UA112897C2 (uk) * 2012-05-09 2016-11-10 Байєр Фарма Акцієнгезелльшафт Біциклічно заміщені урацили та їх застосування для лікування і/або профілактики захворювань

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CN105899500A (zh) 2016-08-24
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WO2015067650A1 (fr) 2015-05-14
US20160287599A1 (en) 2016-10-06

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