Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
  • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • 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
  • 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
  • A61P9/04—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
  • C07D403/02—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
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • 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
  • C07D417/10—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 linked by a carbon chain containing aromatic rings

Definitions

• the present application relates to novel substituted uracil 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., Aller -gy 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 2008/103277 discloses various nitrogen heterocycles for the treatment of cancer.
• WO 2009/156182 describes uracil derivatives for the suppression or reduction of resistance formation in the treatment of cytostatics.
• 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)
• R 1 is hydrogen or (C 1 -C 4 ) -alkyl
• R 2 is a group of the formula
• 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 stands,
• R 8 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 -alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 -alkoxy),
• R 9A is hydrogen or deuterium
• R 9B is hydrogen, deuterium or (C 1 -C 4 ) -alkyl
• R i of ur is hydrogen, halogen, (C 1 -C 4 -alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 ) -alkylthio
• R 11 represents hydrogen, halogen, (C 1 -C 4 ) -alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 ) -alkylthio
• R 12 is hydrogen or halogen
• R 13 is hydrogen or halogen
• R 3 is hydrogen
• R 4 is hydrogen, halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy,
• R 5 is (Ci-C 4) alkyl, (Ci-C 4) alkoxy, (Ci-C 4) alkylthio, (Ci-C 4) alkylsulfinyl, (Ci-C4) - alkylsulfonyl or -N (R 14 R 15 ), where (C 1 -C 4 ) -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy, 4- to 7-membered heterocyclyl, (C 1 -C 4 ) -alkoxy,
• R 14 is (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxycarbonyl or (C 1 -C 4 ) -alkylaminocarbonyl, in which (C 1 -C 4 ) -alkyl is substituted by hydroxyl or (C 1 -C 4 ) -alkoxy can, and wherein (Ci-C 4 ) -alkylaminocarbonyl may be substituted by hydroxy or (Ci-C 4 ) alkoxy, is hydrogen or (Ci-C 4 ) alkyl, or R 5 represents 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, where 4- to 7-membered heterocyclyl having 1 to 3 substituents independently of one another selected from the group halogen, trifluoromethyl, (C 1 -C 4 ) - Alkyl, hydroxy, oxo, amino and (Ci-C 4 ) alkoxycarbonyl may be
• R 7 represents hydrogen, halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy, and also their salts, solvates and solvates of the salts.
• the present invention relates to compounds of the general formula (I) in which R 1 is hydrogen or (C 1 -C 4 ) -alkyl, R 2 is a group of the formula stands, where
• 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 stands,
• R 8 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 ) -alkoxy,
• R 9A is hydrogen or deuterium
• R 9B is hydrogen, deuterium or (C 1 -C 4 ) -alkyl
• R 10 represents hydrogen, halogen, (C 1 -C 4 ) -alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 ) -alkylthio,
• R 11 is hydrogen, halogen, (C 1 -C 4 ) -alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 ) -alkylthio,
• R 12 is hydrogen or halogen
• R 13 is hydrogen or halogen
• R 3 is hydrogen
• R 4 is hydrogen, halogen, (Ci-C 4) -alkyl or (Ci-C 4) -alkoxy, is (Ci-C 4) -alkyl, (GC 4) alkoxy, (Ci-C 4) - Alkylthio, (C 1 -C 4 ) -alkylsulfinyl, (C 1 -C 4 ) -alkylsulfonyl or -N (R 14 R 15 ), where (C 1 -C 4 ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of halogen , Hydroxy, 4- to 7-membered heterocyclyl, (C 1 -C 4 ) -alkoxy, Hydroxycarbonyl, (C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, mono- (C 1 -C 4) -alkylaminocarbonyl and di- (C 1 -C 4) -al
• R 15 is hydrogen or (Ci-C 4 ) -alkyl, or
• R 5 is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein 4- to 7-membered heterocyclyl having 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, (Ci-C4) alkyl , Hydroxy, oxo, amino and (Ci-C4) alkoxycarbonyl, wherein (Ci-C4) alkyl having 1 or 2 substituents independently selected from the group halogen, hydroxy or -N (R 16 R 17 ) substituted in which R 16 is hydrogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkylcarbonyl, in which R 17 is hydrogen or (C 1 -C 4 ) -alkyl, where 5 to 6 heteroaryl having 1 or 2 substituents independently selected from the group halogen, trifluoromethyl, (Ci-C4) alkyl, hydroxy, amino and (Ci-C4) alkoxy
• 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 depending on their structure, 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.
• 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of chlorinated water.
• 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, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• 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
• 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 that coordinate with water. 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 are converted during their residence time in the body into compounds according to 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 represents a linear or branched alkoxy radical of 1 to 4 carbon atoms.
• Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
• Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. Examples which may be mentioned by way of example include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert. Butoxycarbonyl.
• Alkoxycarbonylamino 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 nitrogen atom. Examples which may be mentioned by preference include: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, "-butoxycarbonylamino,” o-butoxycarbonylamino and tert-butoxycarbonylamino.
• Alkylthio in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a sulfur atom.
• methylthio ethylthio, propylthio, isopropylthio, 1-methylpropylthio, n-butylthio, o-butylthio and tert-butylthio.
• Alkylsulfinyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a sulfoxide group.
• 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 is in the context of the invention an amino group having two identical or different linear or branched alkyl substituents, each 1 to 4 Have 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 has in each case 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-methylaminocarbonylamino N-methyl-N- ⁇ -propylaminocarbonylamino
• N- ⁇ -butyl-N-methylaminocarbonylamino N-teri.-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.
• 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 N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
• heterocycle 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 N, 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.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
• An oxo group is in the context of the invention for a Sauerers toffatom, which is bound 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 each other for all radicals which occur repeatedly. 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, methyl or ethyl
• R 2 is a group of the formula stands, where
• A is -CH 2 -, -CH 2 -CH 2 - or oxygen
• R 8a is hydrogen, fluorine, chlorine, trifluoromethyl or methyl
• R 8b is hydrogen, fluorine, chlorine, trifluoromethyl or methyl
• R 9A is hydrogen
• R 9B is hydrogen, methyl or ethyl
• R i of ur is hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl
• R 11 is hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl
• R 12 is hydrogen
• R 13 is hydrogen
• R 3 is hydrogen .
• R 4 is hydrogen, fluorine, chlorine or methoxy
• R 5 is (C 1 -C 4 -alkoxy, 5- or 6-membered heterocyclyl or 5-membered heteroaryl, where 5- to 6-membered heterocyclyl having 1 or 2 substituents independently selected from the group trifluoromethyl, methyl, ethyl, hydroxy , Oxo and (Ci-C-alkoxycarbonyl may be substituted, wherein methyl and ethyl may be substituted with -N (R 16 R 17 ), wherein R 16 is (Ci-C alkylcarbonyl, wherein R 17 is hydrogen, where 5-membered heteroaryl can be substituted by fluorine, chlorine, trifluoromethyl, methyl, hydroxyl, amino or (C 1 -C 4) -alkoxycarbonyl,
• R 6 is hydrogen, fluorine, chlorine, or methyl
• R 7 is hydrogen, fluorine, chlorine or methyl
• R 2 is a group of the formula
• A is -CH 2 - or -CH 2 -CH 2 -
• R 8a is hydrogen, chlorine, trifluoromethyl or methyl
• R 8b is hydrogen
• R 9A is hydrogen
• R 9B is hydrogen, methyl or ethyl
• R 10 is hydrogen, chlorine, trifluoromethyl or methyl
• R 11 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl
• R 12 is hydrogen
• R 13 is hydrogen
• R 3 is hydrogen
• R 4 is hydrogen, fluorine, chlorine or methoxy
• R 5 is 5- or 6-membered heterocyclyl or 5-membered heteroaryl wherein 5- to 6-membered heterocyclyl may be substituted with 1 or 2 substituents methyl, ethyl or oxo wherein 5-membered heteroaryl may be substituted with methyl or amino in which methyl may be substituted by hydroxy
• R 6 is hydrogen, fluorine, chlorine, or methyl
• R 7 is hydrogen, fluorine or methyl, and their salts, solvates and solvates of the salts.
• A is -CH 2 - or -CH 2 -CH 2 -
• R 8a is chlorine or trifluoromethyl
• R 8b is hydrogen
• R 9A is hydrogen
• R 9B is hydrogen
• R 10 is chlorine, trifluoromethyl or methyl
• R 11 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl
• R 12 is hydrogen
• R 13 is hydrogen
• R 3 is hydrogen
• R 4 is hydrogen, fluorine or chlorine
• R 5 is a group of the formula
• R 6 is hydrogen, fluorine, chlorine or methyl
• R 7 is hydrogen, fluorine or methyl, and their salts, solvates and solvates of the salts.
• R 1 is hydrogen, methyl or ethyl
• R 2 is a group of the formula
• A is -CH 2 - or -CH 2 -CH 2 -
• R 8 is chlorine or trifluoromethyl
• R 8b is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is a group of the formula
• (d-1) stands, R 6 is hydrogen, R 7 is hydrogen, and their salts, solvates and solvates of the salts.
• R 2 is a group of the formula
• A is -CH 2 - or -CH 2 -CH 2 -
• R 8a is chlorine or trifluoromethyl
• R 8b is hydrogen
• their salts, solvates and solvates of the salts are examples of the salts.
• R 5 is a group of the formula
• (d-1) stands, and their salts, solvates and solvates of the salts.
• the invention further provides a process for preparing compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)
• T 3 is (C 1 -C 4 ) -alkyl, in an inert solvent or else without solvent with a compound of formula (III) in a compound of formula (VII)
• T 5 is (C 1 -C 4 ) -alkyl
• T 6 is hydrogen, (Ci-C-alkyl or both radicals T 6 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 - converts to a compound of formula (II), or
• R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each as defined above, and
• R 1B is hydrogen, hydrolyzed, optionally splits off any protecting groups and / or the compounds of formulas (II) and (1-2) optionally with the corresponding () solvents and / or (ii) bases or acids in their solvates, salts and / or solvates of the salts.
• Inert solvents for process steps (II) + (III) - »(IV), (VI) + (III) -» (VII) and (VIII) + (IX) -> (X) are, for example, ethers, such as diethyl ether, dioxane , Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, 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 (
• Suitable bases for process steps (II) + (III) - »(IV) and (VIII) + (IX) -» (X) are alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert .-Butoxide, 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 triethylamine, diisopropylethylamine, l, 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 l- [N-tert.
• the base is in this case generally used in an amount of 1 to 5 mol, preferably in an amount of 1.2 to 3 mol, based on 1 mol of the compound of formula (II) or (IX).
• the reactions (II) + (III) - »(IV), (VI) + (III) -» (VII) and (VIII) + (IX) - »(X) are generally carried out in a temperature range of 0 ° C. to + 150 ° C, preferably at + 20 ° C to + 120 ° C, optionally in a microwave.
• 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.
• DPPE 2-bis (diphenylphosphino) ethane
• Ph 2 P-Py diphenyl (2-pyridyl) phosphine
• DAP-DP p-dimethylaminophenyl) diphenylphosphine
• tris-DAP tris (4-dimethylaminophenyl) phosphine
• a suitable dialkyl azodicarboxylate such as, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl-azodicarboxylate, ⁇ , ⁇ , ⁇ ' ⁇ '-tetramethyl azodicarboxamide (TMAD), 1,1'-azodicarbonyl-dipiperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD).
• Inert solvents for the Mitsunobu reaction (IV) + (V) -> (1-1) 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 reaction (IV) + (V) -> (1-1) is generally carried out in a temperature range from -78 ° C to + 180 ° C, preferably at 0 ° C to + 50 ° C, optionally in a microwave , The reactions may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
• Inert solvents for process step (IV) + (V) -> (1-1) are then, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as Dichloromethane, trichloromethane, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ ), pyridine, acetone, 2-butanone or
• ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene
• Suitable bases for process step (IV) + (V) -> (1-1) are customary inorganic bases. These include in particular alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, optionally with the addition of an alkali metal iodide such as potassium iodide, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert.-butylate, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide. Preference is given to using potassium carbonate with potassium iodide or sodium hydride.
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
• an alkali metal iodide such as potassium iodide
• alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert.-buty
• the base is in this case generally used in an amount of 1 to 5 mol, preferably in an amount of 1.2 to 3 mol, based on 1 mol of the compound of formula (IV).
• the reaction (IV) + (V) -> (1-1) is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably at + 20 ° C to + 80 ° C, optionally in a microwave.
• 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.
• Inert solvents for process step (VII) -> (IV) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or others Solvents such as chlorobenzene, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ ), pyridine, acetone, 2-butanone or acetonitrile.
• ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
• hydrocarbons such as benzene, toluene, xylene, hexane,
• reaction (VII) -> (IV) is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 120 ° C, optionally in a microwave.
• 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.
• Process step (X) + (XI) -> (1-1) is similar to a reaction referred to in the literature as Chan-Lam coupling.
• Inert solvents for process step (X) + (XI) -> (1-1) are ethers, such as 1,4-dioxane or tetrahydrofuran, halogenated hydrocarbons, such as dichloromethane, trichloromethane, 1,2-dichloroethane, or other solvents, such as dimethylformamide (DMF). , N-methylpyrrolidone (NMP), acetonitrile or dimethyl sulfoxide (DMSO). It is likewise possible to use mixtures of the solvents mentioned.
• the addition of molecular sieve is advantageous.
• Suitable bases for process step (X) + (XI) -> (1-1) are pyridine, pyridine derivatives such as. B. DMAP or organic tertiary amines such. For example, diisopropylethylamine or triethylamine. Triethylamine is preferred when (XI) corresponds to a boronic ester or a trifluoroborate salt, or pyridine when (XI) is a boronic acid.
• Suitable catalysts for process step (X) + (XI) -> (1-1) are copper (II) salts, such as, for example, copper (II) acetate or copper (II) triflate; copper (II )-Acetate.
• the process step (X) + (XI) -> (1-1) is carried out in air or under an oxygen-containing atmosphere.
• the reaction (X) + (XI) -> (1-1) is generally carried out in a temperature range of 0 ° C to + 150 ° C, preferably at + 20 ° C to + 80 ° C.
• the hydrolysis of the ester group R 1A of the compound (1-1) to compounds of the formula (1-2) is carried out by treating the esters in inert solvents with acids or bases, wherein the latter salts by treatment with acid in the free carboxylic acids are transferred.
• 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.
• Suitable acids for ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, if appropriate 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, pre-eclampsia, inflammatory cardiovascular diseases, peripheral and cardiac vascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasms 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
• cardiac failure also encompasses more specific or related forms of disease such as acutely decompensated heart failure, right heart failure, left ventricular failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvulopathy, heart insufficiency in valvular heart failure, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, Tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac disease, diastolic heart failure, and systolic heart failure.
• ischemic cardiomyopathy dilated cardiomyopathy
• congenital heart defects valvulopathy
• the compounds according to the invention are also suitable for the prophylaxis and / or treatment of polycystic kidney disease (PCKD) and of the syndrome of inadequate ADH secretion (SIADH). Furthermore, 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.
• PCKD polycystic kidney disease
• SIADH syndrome of inadequate ADH secretion
• 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 Increased pressure with malignant hypertension, urinary 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 emphysema), cystic fibrosis (CF), acute coronary syndrome (ACS), heart muscle inflammation (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 induced or dust-induced asthma), of various forms of 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.
• bronchitis chronic bronchitis, infectious bronchitis, eosinophilic bronchitis
• 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 result 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.
• the compounds according to the invention can also be used cosmetically on aging and keratinizing 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 lymphoprohferative system such as Hodgkin's and Non-Hodgkin's Lymphoma), diseases of the gastrointestinal tract and the Abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis
• 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 more other active ingredients, in particular for the treatment and / or prophylaxis of the above mentioned diseases.
• suitable combination active ingredients which may be mentioned are those which inhibit signal transduction cascade, by way of example and preferably from the group of kinase inhibitors, in particular from the group of 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);
• 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 blockers, 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.
• the 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.
• 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).
• 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, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• an ACAT inhibitor such as, for 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.
• 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.
• 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.
• a lipase inhibitor such as, for example and preferably, orlistat.
• the compounds according to 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.
• ASBT IBAT
• the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
• 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.
• Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
• tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
• capsules e.g. Soft gelatin capsules
• dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• 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 medicaments including powder inhalers, nebulizers, aerosols
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• transdermal therapeutic systems eg plasters
• 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 conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients include 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) and flavor and / or odoriferous.
• excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl
• 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: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50mm x 1mm; Eluent A: 1 l water + 0.5 mL 50% formic acid, eluent B: 1 l acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A - »0.1 min 90% A -» 1.5 min 10% A - »2.2 min 10% A; Flow: 0.33 mL / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 2 Instrument: Waters (Micromass) Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; 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 100% A - »3.0 min 10% A -» 4.0 min 10% A - »4.01 min 100% A (flow 2.5 mL / min) -» 5.00 min 100% A; Oven: 50 ° C; Flow: 2 mL / min; UV detection: 210 nm.
• Method 3 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 4 Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 ⁇ 20 mm x 4 mm; Eluent A: 1 l water + 0.5 mL 50% formic acid, eluent B: 1 l acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 100% A -> 3.0 min 10% A -> 4.0 min 10% A -> 4.1 min 100% flow: 2.5 mL / min, oven: 55 ° C; Flow 2 / ml; UV detection: 210 nm.
• Method 5a (preparative HPLC): column: Reprosil C18 ⁇ , 250x30; Flow 50 mL / min; Runtime: 18 minutes; Detection at 210nm; Injection after 3 min runtime; Eluent: water + 0.1% formic acid (A), methanol (B); Gradient: up to 4.25 min 40% B, 4.50 min 60% B, 11.50 min 80% B, 12.00-14.50 min 100% B, 14.75-18.00 min 40% B.
• Method 5b (preparative HPLC): Same as method 5a but with the following Eluent: water (A), methanol (B); Gradient: until 4.25 min 50% B, 4.50 min 70% B, 11.50 min 90% B, 12.00-14.50 min 100% B, 14.75-18.00 min 50% B.
• Method 6a (preparative HPLC): column: Reprosil C18 ⁇ , 250 ⁇ 30, flow 50 ml / min, runtime: 38 min, detection at 210 nm, eluent acetonitrile (A), water (B); Gradient: 3 minutes 10% A, 27 minutes 95% A, 34 minutes 95% A, 34-38 minutes 10% A.
• Method 6b (preparative HPLC): as method 6a but eluent B is 0.1% formic acid in water.
• Method 7a (preparative HPLC): column: Reprosil C18, 10 ⁇ m, 250 mm ⁇ 30 mm.
• Eluent A formic acid 0.1% in water
• eluent B methanol
• Flow 50 ml / min;
• Program 0 to 4.25 min: 60% A / 40% B; 4.25 to 4.50 min: gradient to 60% B; 4.50 min to 17 min gradient to 100% B; 17 min to 19.50 min 100% B; 19.50 min to 19.75 min gradient to 40% B; 19.75 to 22 minutes (end): 60% A / 40% B.
• Method 7b (preparative HPLC): same as Method 7a but with the following gradient: 0 to 7.25 min: 60% A / 40% B; 7.25 to 7.50 min: gradient to 60% B; 7.50 min to 20 min gradient to 100% B; 20 minutes to 32.50 minutes 100% B; 32.50 min to 32.75 min gradient to 40% B; 32.75 to 35 min (end): 60% A / 40% B.
• Method 7c (preparative HPLC): similar to Method 7a but with pure water as eluent A.
• Method 8 (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 9 (preparative HPLC): column: Grom-Sil 120 ODS-4HE, 10 ⁇ , SNr. 3331, 250 mm x 30 mm.
• Eluent A TFA 0.1% in water
• eluent B acetonitrile
• Flow 50 ml / min program: 0-1 min: 10% B; 1-25 min: gradient to 95% B; 25-39 minutes: 95% B; 39-45 minutes: 10% B.
• Method 10 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Met: 250 ° C; Gradient: 70 ° C, 30 ° C / min 310 ° C (hold for 3 min).
• Method 11 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 30 x 2 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 -> 1.2 min 5% A 2.0 min 5% A Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.
• Method 13 (preparative HPLC): column: Kromasil C18 5 ⁇ , 250x20mm, eluent: methanol (B) / water + 0.1% TFA (A), gradient: 0 to 4.25 min 60% A, 4.5 min 40% A, 11.5 min 20% A, 12 min 0% A, 14.5 min 0% A, 14.75 min 60% A, 18 min 60% A, flow: 25mL / min, detection: 210 nm.
• Method 14 (preparative HPLC ): As method 8 but with column Chromatorex C18 5 ⁇ , 250x20mm.
• Example 1A (2-chloroethyl) -3- (2-fluoro-4-nitrophenyl) urea
• Example 15A In analogy to Example 15A, the following substances were prepared from the respectively mentioned anilines. In some cases, to improve the reaction after addition of potassium tert. b tylate the reaction mixture gently heated for a few hours (50 ° C). In some cases, the product was obtained by extraction of the acidified mixture with ethyl acetate, drying of the organic phases over sodium sulfate and concentration in vacuo.
• Example 15A The preparation and purification were carried out analogously to Example 15A from 4 g (20.5 mmol) of 1- (4-amino-2-fluorophenyl) imidazolidin-2-one (Example 9A). Yield: 3.96 g (53% of theory).
• Example 25A Ethyl 2,4-dioxo-3- [3- (trifluoromethyl) benzyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate
• the mixture was concentrated under reduced pressure, admixed with 305 ml of water and 305 g of ice, adjusted to pH 1 with hydrochloric acid and extracted with ethyl acetate.
• the organic phase was dried with sodium sulfate, concentrated in vacuo and dried under high vacuum.
• the residue was stirred ten times with diethyl ether and the liquid was decanted off. After drying the residue in a high vacuum, 47.8 g (39% of theory, purity 84%) of the target compound were obtained
• Example 28A Ethyl 1- [4- (2-amino-2-oxoethoxy) phenyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 14A The preparation and purification were carried out analogously to Example 29A from 4.41 g (17 mmol) of tert-butyl-3- (4-aminophenyl) -1H-pyrazole-1-carboxylate (Example 14A). Yield: 1.97 g (13% of theory, purity: 48%).
• Example 12A The preparation and purification were carried out analogously to Example 29A from 1.11 g (3.54 mmol) of tert-butyl-5- (4-aminophenyl) -1,2,5-thiadiazolidine-2-carboxylate-1,1-dioxide (Example 12A ). Yield: 0.72 g (33% of theory, purity: 79%).
• Example 11A The preparation and purification were carried out in analogy to Example 29A from 3.37 g (12.2 mmol) of tert-butyl 4- (4-aminophenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazole 1-carboxylate (Example 11A). Yield: 1.66 g (40% of theory, purity: 72%).
• Example 29A The preparation and purification were carried out analogously to Example 29A from 2.16 g (11.24 mmol) of 3- (4-aminophenyl) -1,3-oxazinan-2-one (WO 2009/064835, p. 85). Yield: 2.06 g (41% of theory, purity: 80%).
• Example 43A 1- (4-Azidophenyl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Example 46A 1- [4- (Methylsulfanyl) phenyl] -2,4-dioxo-3- [3- (trifluoromethyl) benzyl] -1,3,3,4-tetrahydropyrimidine-5-carboxylic acid
• reaction mixture was concentrated on a rotary evaporator to a residual volume of about 100 ml and then poured onto 600 ml of an ice / water mixture.
• the resulting solid was isolated by filtration, washed twice with water and twice with diethyl ether and then dried under high vacuum. 3.91 g (79% of theory) of the title compound were obtained.
• Example 50A Ethyl 3- [2-chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 52A Ethyl 3- (2,3-dichlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 55A Ethyl 1- [4- (teri-butoxycarbonyl) phenyl] -3- (2,3-dichlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 56A Analogously to Example 56A, 220 mg (0.31 mmol) of the compound from Example 54A were treated with trifluoroacetic acid in dichloromethane. The solid formed by the addition of ether was filtered off, washed with ether and dried under high vacuum. 153 mg (78% of theory) of the title compound were obtained.
• Example 56A Analogously to Example 56A, from 232 mg (0.45 mmol) of the compound from Example 55A, 202 mg (97% of theory) of the title compound were obtained.
• Example 60A Ethyl 3- [2-methyl-3- (trifluoromethyl) benzyl] -1- [4- (hydrazinocarbonyl) phenyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 59 A Analogously to Example 59 A, 200 mg (0.43 mmol) of the compound from Example 58 A and 25 ⁇ (0.51 mmol) of hydrazine hydrate gave 127 mg (60% of theory) of the title compound.
• the cooled reaction mixture was acidified with 1 N aqueous hydrochloric acid and diluted with water. The mixture was concentrated on a rotary evaporator and the remaining suspension was filtered. The solid was washed with water and ethyl acetate and dried in vacuo at 50 ° C. 692.6 mg (41% of theory, purity 70%) of the title compound were obtained.
• Example 67A The title compound was prepared and purified analogously to Example 67A with a reaction time of 3 h. Starting from 1.25 g (4.13 mmol) of 1- (4-amino-2,6-dichlorophenyl) -3-tert-butylimidazolidin-2-one from Example 70A, 759 mg (74% of theory) of the title compound were obtained.
• Example 90A Preparation and purification of the title compound were carried out analogously to Example 90A. Starting from 1.42 g (6.42 mmol) of 4-methyl-1- (4-nitrophenyl) imidazolidin-2-one from Example 94A, 1.13 g (92% of theory) of the title compound were obtained.
• Example 90A Preparation and purification of the title compound were carried out analogously to Example 90A. Starting from 1.11 g (5.28 mmol) of methylmethyl (4-nitrophenyl) carbamate from Example 99A and after additional purification by flash chromatography (cyclohexane / ethyl acetate 5: 1), 726 mg (76% of theory) of the title compound were obtained.
• Example 102A Ethyl 1- (4-nitrophenyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Example 106A Preparation and purification of the title compound were carried out analogously to Example 106A and a reaction time of 2.5 h. Starting from 526 mg (3.95 mmol) of indan-1-amine (racemate) and 949 mg (15.79 mmol) of urea, 563 mg (80% of theory) of the title compound were obtained.
• Example 117A Preparation and purification of the title compound were carried out analogously to Example 117A. Starting from 1.15 g (5.24 mmol) of 1- (2-chloro-3,6-difluorobenzyl) urea from Example 118A and 1.59 ml (7.86 mmol) of diethyl ethoxymethylenemalonate, 851 mg (45% of theory) of the title compound were obtained.
• Example 1 Exemplary embodiments: Example 1

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• 2014
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