EP3066096A1 - Substituierte uracile als chymase inhibitoren - Google Patents

Substituierte uracile als chymase inhibitoren

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Publication number
EP3066096A1
EP3066096A1 EP14799368.7A EP14799368A EP3066096A1 EP 3066096 A1 EP3066096 A1 EP 3066096A1 EP 14799368 A EP14799368 A EP 14799368A EP 3066096 A1 EP3066096 A1 EP 3066096A1
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European Patent Office
Prior art keywords
hydrogen
alkyl
formula
compound
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP14799368.7A
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German (de)
English (en)
French (fr)
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 EP14799368.7A priority Critical patent/EP3066096A1/de
Publication of EP3066096A1 publication Critical patent/EP3066096A1/de
Withdrawn legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
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    • 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
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
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    • C07D417/14—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 three or more hetero 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).
  • a collection Chymase-positive mast cells have been found in biopsies from patients with atopic dermatitis, Crohn's disease, chronic hepatitis and cirrhosis, as well as 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.
  • 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.
  • JP10195063 describes uracil derivatives as leukotriene antagonists, WO 2013/074633 uracil derivatives as inhibitors of tyrosine kinases AXL and c-MET.
  • 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 cyano, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein 5- to 7-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of oxo, (Ci-C alkyl and Halogen may be substituted, and wherein 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group (Ci-C alkyl, hydroxy and halogen may be substituted, or
  • R 1 is a group of the formula
  • * represents the point of attachment to the uracil group, m is 0 or 1,
  • L 1A is a bond or (Ci-C alkanediyl, wherein (Ci-C alkanediyl having 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl, (Ci-C alkyl, (C3-C7) - cycloalkyl , Hydroxy and (C 1 -C 4 -alkoxy may be substituted, is hydrogen or (C 1 -C 4 ) -alkyl, is hydrogen or (C 1 -C 4 -alkyl in which (C 1 -C 4 -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, C alkyl, hydroxy and (Ci-C4) alkoxy may be substituted, or
  • R 7 is hydrogen, cyano, (C 3 -C 7 ) -cycloalkyl, hydroxycarbonyl or (C 1 -C 4) -alkoxycarbonyl, or
  • R 1 is a group of the formula
  • ** is the point of attachment to the uracil nitrogen, is -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 - ## or oxygen.
  • ## is the point of attachment to the phenyl ring, n is a number 0, 1 or 2,
  • R 10 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 ) -alkoxy,
  • R 11A is hydrogen or deuterium
  • R 11B is hydrogen, deuterium or (C 1 -C 4 ) -alkyl
  • R 12 is hydrogen, halogen, (C 1 -C 4 ) -alkyl, difluoromethyl or trifluoromethyl,
  • R 13 is halogen, (C 1 -C 4) -alkyl, difluoromethyl or trifluoromethyl,
  • R 14 is hydrogen or halogen
  • R 15 is hydrogen or halogen, for
  • R 17 is hydrogen, halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy,
  • R 18 is C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl or -N (R 21 R 22 ), in which (C 1 -C 4 ) -alkoxy having a substituent independently of one another selected from the group consisting of hydroxyl, (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 and di- (C 1 -C 4) -alkylaminocarbonyl, in which
  • R 21 is (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxycarbonyl or (C 1 -C 4 ) -
  • Alkylaminocarbonyl in which (C 1 -C 4) -alkylaminocarbonyl may be substituted by hydroxy or (C 1 -C 4) -alkoxy,
  • R 22 is hydrogen or (C 1 -C 4 ) -alkyl
  • the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein 5- to 7-membered heterocyclyl having 1 to 4 substituents independently selected from 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 (C 1 -C 4) -cycloalkyl; C 4 ) -alkylsulfonyl may be substituted, wherein 5- or 6-membered heteroaryl having 1 to 2 substituents independently of one another selected from the group (Ci-C6) alkyl, (C3-C 7 ) -cycloalkyl, hydroxy, (Ci-C6) substituents independently of one another selected from
  • the present invention relates to compounds of the general formula (I) in which
  • R 1 is cyano, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein 5- to 7-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of oxo, (Ci-C4) alkyl and halogen may be substituted, and wherein 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group (Ci-C alkyl, hydroxy and halogen may be substituted, or for a group of formula
  • * represents the point of attachment to the uracil group, m is 0 or 1,
  • L 1A is a bond or (C 1 -C 4 -alkanediyl, in which (C 1 -C 3 -alkanediyl having 1 to 3 substituents selected independently of one another from the group of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, (C 3 -C 7) -cycloalkyl, hydroxy and (C 1 -C 4) -alkoxy may be substituted,
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 6 represents hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, hydroxy and (C 1 -C 4 ) Alkoxy may be substituted, or
  • R 7 is hydrogen, cyano, (C 3 -C 7 ) -cycloalkyl, hydroxycarbonyl or (C 1 -C 4) -alkoxycarbonyl, a group of the formula
  • ** is the point of attachment to the uracil nitrogen
  • A is -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 -## or oxygen, where ## is the point of attachment to the phenyl ring, n is a number 0, 1 or 2 stands,
  • R i of ur is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 -alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 -alkoxy),
  • R 11A is hydrogen or deuterium
  • R represents hydrogen, deuterium or (C 1 -C 4) -alkyl
  • R is halogen, (C 1 -C 4) -alkyl, difluoromethyl or trifluoromethyl,
  • R is hydrogen or halogen, is hydrogen or halogen, for
  • R 16 is hydrogen
  • R 17 is hydrogen, halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy,
  • R 18 is C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl or -N (R 21 R 22 ) in which (C 1 -C 4) -alkoxy having one substituent independently of one another selected from the group consisting of hydroxyl, (C 1 -C 4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino, and di ( C 1 -C 4) -alkylamino, aminocarbonyl, mono- (C 1 -C 4 ) -alkylaminocarbonyl and di- (C 1 -C 4 ) -alkylaminocarbonyl, in which (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) - Al
  • Alkylaminocarbonyl in which (C 1 -C 4) -alkylaminocarbonyl may be substituted by hydroxy or (C 1 -C 4) -alkoxy, R 22 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 18 is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, in which 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,
  • the 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 with 1 to 4 substituents independently of one another 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 (C 1 -C 4 -alkylsulfonyl may be substituted, in which 5- or 6-membered heteroaryl having 1 to 2 substituents independently of one another selected from the group (C 1 -C 6) -alkyl, ( C3-C7) cycl
  • R 25 is halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkoxy, p is a number 0, 1, 2 or 3, is hydrogen or (C 1 -C 4 ) -alkyl, and their salts, solvates and solvates of 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 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.
  • 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.
  • 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 which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • alkyl is a linear or branched 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.
  • Alkoxy in the context of the invention 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.
  • alkoxycarbonylamino 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.
  • methoxycarbonylamino, ethoxycarbonylamino, propoxy carbonylamino, "-butoxycarbonylamino,” o-butoxycarbonylamino and teri.-butoxycarbonylamino methoxycarbonylamino, ethoxycarbonylamino, propoxy carbonylamino, "-butoxycarbonylamino,” o-butoxycarbonylamino and teri.-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. Examples which may be mentioned are 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. By way of example and by way of preference: methylamino, ethylamino, propylamino, isopropylamino and tert. Butylamino.
  • 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. Examples which may be mentioned by way of example: N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl N-methylaminocarbonyl, N-methyl-N - "- propylaminocarbonyl, N -" - butyl-N-methylaminocarbonyl and N-tertiary-butyl-N-methylaminocarbonyl.
  • 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.
  • 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 groups Heteroatoms from the series N, O and / or S such as 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.
  • a Qxo 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 cyano, 5-membered heterocyclyl or 5-membered heteroaryl, wherein 5-membered heterocyclyl may be substituted with oxo, and wherein 5-membered heteroaryl may be substituted with hydroxy, or a group of the formula
  • L 1A is a bond or (C 1 -C 4 ) -alkanediyl
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 6 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 ) -alkyl, hydroxy and ( Ci-C 4 ) -alkoxy may be substituted, or
  • R 7 is hydrogen, (C 1 -C 4 ) -alkyl, cyano, (C 3 -C 6) -cycloalkyl, hydroxycarbonyl or (C 1 -C 4 ) -alkoxycarbonyl, or a group of the formula
  • ** represents the point of attachment to the uracil nitrogen atom
  • A is -CH 2 - or -CH 2 -CH 2 -
  • n is a number 0, 1 or 2
  • R 10 is hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl
  • R 11A is hydrogen or deuterium
  • R 11B is hydrogen or deuterium
  • R 12 is fluorine, chlorine, methyl or trifluoromethyl
  • R 13 is fluorine, chlorine, methyl or trifluoromethyl
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 16 is hydrogen
  • R 17 is hydrogen, halogen, methoxy or ethoxy
  • R 18 is (C 1 -C 4 ) -alkyl, methoxy or ethoxy,
  • R 18 is 5- or 6-membered heterocyclyl, wherein 5- or 6-membered heterocyclyl may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, methyl and oxo,
  • R 19 is hydrogen, R 20 is hydrogen, or
  • R 3 is a group of the formula
  • G 2 is CR 27A R 27B , NR, O or S. wherein is hydrogen, fluorine, (Ci-C alkyl or hydroxy stands for hydrogen, fluorine, chlorine, (Ci-C-alkyl or trifluoromethyl, or
  • R 27A and R 27B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle which is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • R 25 is fluorine or methyl, p is a number 0 or 1,
  • R 26 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, R 4 is hydrogen or methyl, and their salts, solvates and solvates of the salts.
  • R 1 is cyano, 5-membered heterocyclyl or 5-membered heteroaryl, where 5-membered heterocyclyl may be substituted by oxo, and where 5-membered heteroaryl having Hydroxy may be substituted, or
  • R 1 is a group of the formula
  • * represents the point of attachment to the uracil group, m is 0 or 1,
  • L 1A is a bond or (C 1 -C 4 -alkanediyl
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 6 represents hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, hydroxy and (C 1 -C 4 ) Alkoxy may be substituted, or R 5 and R 6 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocycle,
  • R 7 is hydrogen, (C 1 -C 4 -alkyl, cyano, (C 3 -C 6) -cycloalkyl, hydroxycarbonyl or (C 1 -C 4 -alkoxycarbonyl), a group of the formula
  • ** is the point of attachment to the uracil nitrogen
  • A is -CH 2 - or -CH 2 -CH 2 -
  • n is a number 0, 1 or 2
  • R i of ur is hydrogen, fluorine, chlorine, difluoromethyl Is trifluoromethyl or methyl
  • R 11A is hydrogen or deuterium
  • R 11B is hydrogen or deuterium
  • R 12 is fluorine, chlorine, methyl or trifluoromethyl
  • R 13 is fluorine, chlorine, methyl or trifluoromethyl
  • R 14 is Hydrogen
  • R 15 is hydrogen, for stands in which
  • R 16 is hydrogen
  • R 17 is hydrogen, halogen, methoxy or ethoxy
  • R 18 is (C 1 -C 4 ) -alkyl, methoxy or ethoxy, or
  • R 18 is 5- or 6-membered heterocyclyl, where 5- or 6-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, methyl and oxo,
  • R 19 is hydrogen
  • R 20 is hydrogen, or
  • G 2 is CR 27A R 27B , NR 28 , O or S wherein
  • R 27A is hydrogen, fluorine, (C 1 -C 4 ) -alkyl or hydroxyl
  • R 27B is hydrogen, fluorine, chlorine, (C 1 -C 4 ) -alkyl or trifluoromethyl, or
  • R 27A and R 27B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle
  • R 28 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • R 25 is fluorine or methyl, p is a number 0 or 1,
  • R 26 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, R 4 is hydrogen or methyl, and their salts, solvates and solvates of the salts.
  • R 1 is cyano, or
  • R is a group of the formula
  • R 1 is a group of the formula
  • * represents the point of attachment to the uracil group, m is 0 or 1,
  • L 1A is a bond, methanediyl or ethanediyl
  • R 5 represents hydrogen
  • R 6 is hydrogen or methyl, where methyl may be substituted with hydroxy, or
  • R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle
  • R 7 is hydrogen, cyano, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, is a group of the formula
  • ** represents the point of attachment to the uracil nitrogen atom
  • A is -CH 2 - or -CH 2 -CH 2 -
  • R 10 is chlorine or trifluoromethyl
  • R 11A is hydrogen
  • RI IB stands for hydrogen
  • R 12 is chlorine or methyl
  • R 13 is chlorine or trifluoromethyl
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 17 is hydrogen or methoxy
  • R 18 is methoxy or ethoxy
  • R 18 is a group of the formula stands in which
  • R 19 is hydrogen
  • R 20 is hydrogen, or a group of the formula
  • R 4 is hydrogen, and their salts, solvates and solvates of the salts.
  • R 1 is cyano, and their salts, solvates and solvates of the salts.
  • R 1 is a group of the formula
  • R 1 is a group of the formula
  • L 1A is a bond, methanediyl or ethanediyl
  • R 5 represents hydrogen
  • R 6 is hydrogen or methyl, wherein methyl may be substituted with hydroxy, or
  • R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle
  • R 7 is hydrogen, cyano, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, and their salts, solvates and solvates of the salts.
  • R 2 is a group of the formula
  • ** is the point of attachment to the uracil nitrogen atom
  • A is -CH 2 - or -CH 2 -CH 2 -
  • R 10 is chlorine or trifluoromethyl, and their salts, solvates and solvates of the salts.
  • R 16 is hydrogen
  • R 17 is hydrogen
  • R 18 is methoxy or ethoxy, or
  • R 18 is a group of the formula
  • R 19 is hydrogen
  • R 20 is hydrogen
  • R 3 is a group of the formula
  • 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 2 is (C 1 -C 4 ) -alkyl
  • T 3 is (C 1 -C 4 ) -alkyl, in an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (III)
  • R 2 has the abovementioned meaning, and represents hydroxyl or a suitable leaving group, in particular chlorine, bromine or iodine,
  • T 1A , R 2 and R 3 each have the meanings given above,
  • T 2 is (C 1 -C 4 ) -alkyl
  • T 3 is (C 1 -C 4 ) -alkyl
  • R 4 has the abovementioned meaning, in an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (III) to give a compound of the formula (XII)
  • Q * represents oxygen or sulfur, reacts, any protecting groups present and / or the compounds of formulas (1-1), (1-2), (1-3) and (1-4) optionally with the corresponding () solvents and / or (ii) bases or acids converted into their solvates, salts and / or solvates of the salts.
  • Inert solvents for process steps (II) + (III) - »(IV), (IX) + (III) -» (X) and (XI) + ( ⁇ ) -> (XII) 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 (XI) + (III) -» (XII) 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] oct
  • alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium
  • 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 (XI).
  • a base is not required in all cases.
  • the reactions (II) + (III) - »(IV), (IX) + (III) -» (X) and (XI) + (III) - »(XII) are generally carried out in a temperature range of 0 ° C. to + 200 ° 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.
  • triphenylphosphine or tri-n-butylphosphine, 1, 2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine (Ph 2 P-Py), (-dimethylaminophenyl) diphenylphosphine (DAP-DP), tris ( 4-dimethylaminophenyl) phosphine (tris-DAP) and a suitable dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, NNN'N'-tetramethyl azodicarboxamide (TMAD), 1, l '- (azodicarbonyl) dipiperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l,
  • DPPE 1, 2-bis
  • Inert solvents for the Mitsunobu reactions (IV) + (V) - »(VI) and ( ⁇ ) + (V) -» (1-2) 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.
  • THF or a mixture of THF and DMF is used.
  • the Mitsunobu reactions (IV) + (V) - »(VI) and ( ⁇ ) + (V) -» (1-2) 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).
  • Inert solvents for process steps (IV) + (V) -> (VI) and ( ⁇ ) + (V) -> (1-2) 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, dimethylsulfoxide, N, N'-dimethylpropyleneurea
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzen
  • Suitable bases for the process steps (IV) + (V) - »(VI) and ( ⁇ ) + (V) -» (1-2) 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 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.
  • 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 methoxide, sodium or potassium ethoxide
  • 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) or (XII).
  • the reactions (IV) + (V) -> (VI) and (XII) + (V) -> (1-2) are generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably at + 20 ° C to + 80 ° C, if necessary in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the hydrolysis of the compounds of the formula (VI) to give compounds of the formula (VII) is carried out by treating the esters in acids or bases with inert solvents, with the latter converting the initially formed salts into the free carboxylic acids by treatment with acid.
  • 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 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.
  • Inert solvents for process step (VII) + (VIII) -> (1-1) 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 , Trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-di
  • Suitable condensing agents for the amide formation for process step (VII) + (VIII) -> (1-1) are, for example, carbodiimides such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl- , N, N'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N, N'-carbonyldiimidazole (CDI), 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert.-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2 dihydroquinoline, or isobut
  • TBTU is used in conjunction with ⁇ -methylmorpholine, HATU in conjunction with N, N-diisopropylethylamine or l-chloro-N, N, 2-trimethylprop-l-en-lam.
  • the condensations (VII) + (VIII) -> (1-1) are generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Azide sources for step (1-2) -> (1-3) are, for example, trimethylsilyl azide and sodium azide.
  • trimethylsilyl azide is used.
  • the azide source especially in the case of trimethylsilyl azide, in excess, for example in an amount of 1.3 moles to 100 moles, based on 1 mole of the compound of formula (1-2), is used
  • Inert solvents for process step (1-2) -> (1-3) using trimethylsilyl azide 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 other solvents such as chlorobenzene, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone ( ⁇ ). It is likewise possible to use mixtures of the solvents mentioned.
  • DMPU N, N'-dimethylpropyleneurea
  • ⁇ N-methylpyrrolidinone
  • Suitable catalysts for the reaction (1-2) -> (1-3) when using trimethylsilyl azide are organotin oxides, preferably di- ("- butyl) tin oxide.
  • Lewis acid such as zinc bromide, zinc chloride, copper (II) sulfate, aluminum trichloride or tributyltin chloride are also suitable.
  • the catalyst is generally used in an amount of 0.01 to 0.3 mol, preferably in an amount of 0.05 to 0.2 mol, based on 1 mol of the compound of formula (1-2).
  • the reaction (1-2) -> (1-3) is generally carried out in a temperature range from 20 ° C to + 180 ° C, preferably at + 80 ° C to + 120 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (1-2) ⁇ (XIII) 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, trichloromethane , 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ ) or pyridine. It is also possible Use mixtures of these solvents.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or di
  • the reaction (1-2) -> (XIII) is generally carried out in a temperature range from 20 ° C to + 180 ° C, preferably at + 50 ° C to + 110 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Carbonyl donors for the reaction (XIII) ⁇ (1-4) are, for example, carbonyldiimidazole, esters of chloroformic acid, e.g. Isobutyl chloroformate or phosgene derivatives such as diphosgene and triphosgene. Preference is given to using isobutyl chloroformate.
  • Thiocarbonyldiimidazole is preferably used as the thiocarbonyl donor.
  • Inert solvents for the reaction of the compound of the formula (XIII) with a carbonyl donor or a thiocarbonyl donor 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, trichloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ ), acetonitrile or pyridine.
  • ethers such as diethyl ether, dioxane, tetrahydro
  • Suitable bases include, for example, pyridine and organic bases such as triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU ).
  • pyridine Preference is given to pyridine.
  • the reaction of the compound of the formula (XIII) with a carbonyl donor or a thiocarbonyl donor to give the corresponding intermediate is generally carried out in a temperature range from 0 ° C to 80 ° C, preferably at RT.
  • the cyclization of the intermediate from the reaction with a carbonyl donor to the oxadiazolone is usually carried out at higher temperatures, for example from RT to 200 ° C, optionally in a microwave. In some cases, the use of a base such as potassium or sodium teri. butylate advantageous.
  • the cyclization of the intermediate from the reaction with a thiocarbonyl donor to thiadiazolone is carried out using boron trifluoride-diethyl ether complex. Suitable solvents are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. Preferred is THF.
  • the reaction takes place in a temperature range from 0 ° C. to 70 ° C., preferably at RT.
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, starting from the compounds of the formula (I) obtained by the above processes.
  • transformations are carried out by conventional methods known to those skilled in the art, as described in this experimental section, and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage Etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
  • 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, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders, edema 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, as well as micro- and
  • cardiac insufficiency also encompasses more specific or related forms of disease such as acutely decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve failure, heart failure in cardiac valve defects, 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 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 polycys
  • 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 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 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 sores
  • cough and cold sores chronic inflammatory cough, iatrogenic cough
  • nasal irritation including rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever
  • 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 according to the invention are suitable for combating postoperative scar formation, for example as a consequence of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically on aging and keratinizing skin.
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of dyslipidemias (hypercholesterolemia, hypertriglyceridemia, elevated concentrations of the 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 and malignant tumors of the lymphoproliferative system such as Hodgkin's and Non-Hodgkin's Lymphoma) of 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 on the front of 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 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; Exemplary and preferably inhibitors of the matrix metalloproteases (MMPs), 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); Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT 2b receptor; organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate,
  • NO-independent, but heme-dependent stimulators of soluble guanylate cyclase such as, in particular, the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • soluble guanylate cyclase in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; Prostacyclin analogs, such as by way of example and preferably iloprost, beraprost, treprostinil or epoprostenol;
  • 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 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.
  • 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.
  • 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.
  • 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 preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • 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.
  • 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.
  • 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 of the invention are used in combination with a rho-kinase inhibitor, as exemplified 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 as exemplified 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 alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile
  • 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, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as, for 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.
  • 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.
  • 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: 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 2 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 90% A -> 0.1 min 90% A -> 1.5 min 10% A -> 2.2 min 10% A Furnace: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
  • Method 3 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.
  • Method 4 Device Type MS: Waters (Micromass) Quattro Micro; Device type HPLC: Agilent 1100 series; Column: Thermo Hypersil GOLD 3 ⁇ 20 x 4 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 100% A -> 3.0 min 10% A -> 4.0 min 10% A; Oven: 50 ° C; Flow: 2 ml / min; UV detection: 210 nm.
  • Method 5 (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; Gradient: 0 to 6 min: 90% A / 10% B; 6 min to 27 min: gradient to 95% B; 27 minutes to 38 minutes 95% B; 38 min to 39 min gradient to 10% B; 39 min to 43 min (end): 60% A / 40% B. Small deviations of the gradient are possible.
  • Method 6 (preparative HPLC): As method 4 but with Chromatorex column C18 5 ⁇ , 250x20mm.
  • Method 7 (Preparative HPLC): Column: Reprosil C18 ⁇ mol, 250 ⁇ 30, flow 50 ml / 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 8 (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;
  • Method 9 (preparative HPLC): Column: Reprosil C18, 10 ⁇ m, 250 mm ⁇ 30 mm. Eluent A: water, eluent B: methanol; Flow: 50 ml / min; Program: 0 to 4.25 min: 50% A / 50% B; 4.25 to 4.50 min: gradient to 70% B; 4.50 min to 11.5 min gradient to 90% B; 12.00 min to 14.50 min 100% B; 14.50 min to 18.00 min gradient to 50% B (end). Slight deviations of the gradient are possible.
  • Method 10 (Preparative HPLC): Column: Reprosil C18, 10 ⁇ m, 250 mm ⁇ 30 mm. Eluent A: water, eluent B: methanol; Flow: 50 ml / min; Program: 0 to 4.25 min: 70% A / 30% B; 4.25 to 4.50 min: gradient to 50% B; 4.50 min to 11.5 min gradient to 70% B; 12.00 min to 14.50 min 100% B; 14.50 min to 18.00 min Gradient to 30% B (end). Slight deviations of the gradient are possible. Method 11 (preparative HPLC): Column: Reprosil C18, 10 ⁇ m, 250 mm ⁇ 30 mm.
  • Eluent A 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 12 (MS; DCI NH 3 ): Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas NH 3 ; Source temperature: 200 ° C; Ionization energy 70eV.
  • Method 13 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 19 Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0x50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A -> 3.0 min 5% A ⁇ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.
  • Method 20 (preparative HPLC): Column: Chromatorex C18, 10 ⁇ m, 250 mm ⁇ 30 mm. Eluent A: water, eluent B: methanol; Flow: 75 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 9.99 min: gradient to 80% B; 9.99 to 12.40 min: gradient to 100% B; 12.40 to 17.21 min: 100% B; 17:21 to 17:46 min: gradient to 40% B; 17:46 to 18:22 min (end): 60% A / 40% B.
  • Example 5A Ethyl 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrhydropyrimidine-5 carboxylate
  • reaction mixture was diluted with water, acidified with 1N aqueous hydrochloric acid and the resulting solid was filtered off. The solid was washed with water and ethyl acetate and dried in vacuo at 50 ° C overnight. 736 mg (85% of theory) of the target compound were obtained.
  • the aqueous phase was concentrated, treated with dichloromethane / methanol (1: 1) and the resulting solid was filtered off.
  • the filtrate was concentrated, treated with MTBE / ethyl acetate (1: 1), the resulting solid was filtered off, washed with ethyl acetate and then dried in vacuo at 50 ° C. 1.55 g (73% of theory) of the title compound were obtained.
  • Example 22A 3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3 - [(1R) -4- (trifluoromethyl) -2 , 3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R-enantiomer)
  • Example 23A 1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3 - [(1R) -4- (trifluoromethyl) -2 , 3-dihydro-1H-inden-1-yl] -1,3,3,4-tetrahydropyrimidine-5-carboxylic acid (R-enantiomer)
  • Example 24A 3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3 - [(1R) -4- (trifluoromethyl) -2 , 3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R-enantiomer)
  • Example 26A 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo -l, 2,3,4-tetrahydropyrimidine-5-carboxylic acid
  • Example 30A (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrhydropyrimidine-5-carbonitrile
  • Example 31A (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
  • Example 32A (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine carbonitrile
  • Example 36A 1- (1-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -N'-hydroxy-2,4-dioxo-3 - [(IR) -4-
  • Example 37A to 41A were prepared from the corresponding nitriles and 5 equivalents of hydroxylamine hydrochloride (Table 1).
  • reaction solution was diluted at RT with ethyl acetate and extracted with 1N aqueous hydrochloric acid.
  • the organic phase was washed with saturated aqueous sodium carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated.
  • the residue was stirred with 3 ml of methanol, the solid was filtered off with suction, washed with methanol and diethyl ether and dried. 160 mg (76% of theory) of the title compound were obtained.
  • reaction solution was diluted at RT with ethyl acetate and extracted with 1N aqueous hydrochloric acid.
  • the organic phase was washed with saturated aqueous sodium carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated.
  • the residue was stirred with 2 ml of methanol, the solid was filtered off with suction, washed with a little methanol and then with diethyl ether and dried. 126 mg (59% of theory) of the title compound were obtained.
  • Example 13 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -5- (1H-tetrazol-5-yl) -3 - [(1R) -4 - (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] pyrimidine-2,4 (1H, 3H) -dione (R-enantiomer)
  • Example 14 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -5- (1H-tetrazol-5-yl) -3 - [(1R) -4 - (trifluoromethyl) -2-dihydro-1H-n-en-yl] pyrimidine-2,4 (1H) -dione (R-enantiomer)
  • Example 15 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -5- (1H-tetrazol-5-yl) -3 - [(1R) -4 - (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] pyrimidine-2,4 (1H, 3H) -dione (R-enantiomer)
  • Example 6 50 mg (0.11 mmol) of 1- (1-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4 -dioxo-l, 2,3,4-tetrahydropyrimidine-5-carbonitrile (Example 6) were initially charged in 1.5 ml of toluene at RT 2.65 mg (0.011 mmol) of di-n-butyltin oxide and 36.8 mg (0.32 mmol) of trimethylsilyl azide were added and the mixture was stirred for 4 h at reflux temperature.
  • Example 29 The title compound was prepared analogously to Example 2 from 230.0 mg (0.81 mmol) of 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carbonitrile prepared from Example 31A and 162.6 (0.89 mmol) of 5-chloro-1,2,3,4-tetrahydronaphthalene-1-ol. This gave 180 mg (32% of theory, purity about 64%) of the title compound, which was used without additional purification for the preparation of Example 29.
  • HPLC control showed complete conversion to the intermediate.
  • the mixture was added with ethyl acetate and 1 N aqueous hydrochloric acid.
  • the organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum.
  • the resulting intermediate was taken up in 2 ml of xylene, mixed with 1.3 mg (0.005 mmol) of 1-ethyl-3-methyl-1H-imidazole-3-iumhexafluorophosphate and reacted for 1 h at 200 ° C in the microwave.
  • Example 33 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -5- (5- oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) pyrimidine-2,4 (lH, 3H) -dione
  • Example 36 1- (3,4-Dimethoxyphenyl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -5- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- yl) pyrimidine-2,4 (lH, 3H) -dione
  • Example 38 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -5- (5-oxo-4,5-dihydro-1,2,4-oxadiazole 3-yl) -3 (IR) -4- (tri-methyl) -2,3-dihydro-1H-inden-1-yl] pyrimidine-2,4 (1H, 3H) -dione (R-enantiomer)
  • Example 40 3- (3,4-Dimethoxyphenyl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -5- (5-oxo-4,5-dihydro-1,2,4-thiadiazole-3- yl) pyrimidine-2,4 (lH, 3H) -dione
  • Example 42 3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3 - [(1R) -4- (trifluoromethyl) -2 , 3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxamide (R-enantiomer)
  • Example 46 Example 46 was dissolved in 2 ml of acetic acid and 1 ml of conc. Hydrochloric acid for 1 hour at 120 ° C stirred. After cooling to RT, the reaction mixture was diluted with water, the resulting precipitate was filtered off, washed with a little MTBE and dried in vacuo. 145 mg (85% of theory) of the title compound were obtained.
  • reaction solution was diluted with 20 ml of dichloromethane and washed successively twice with 10 ml of 1N aqueous hydrochloric acid, then with 10 ml of water and a saturated aqueous sodium hydrogencarbonate solution.
  • the organic phase was concentrated, dissolved in acetonitrile / DMSO and separated by preparative HPLC (Method 7). 26.4 mg (25% of theory) of the title compound were obtained.
  • Example 64 3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3 - [(1R) -4- (trifluoromethyl) -2 , 3-dihydro-1H-inden-1-yl] -N- [(trifluoromethyl) sulfonyl] -1, 2,3, 4-tetrahydro-pyrimidine-5-carboxamide (R-enantiomer)
  • Example 64 Analogously to Example 64, the title compound was prepared from 160 mg (0.32 mmol) of the compound from Example 44A and 57 mg (0.38 mmol) of trifluoromethanesulfonic acid amide. 42 mg (20% of theory) 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).
  • assay buffer Tris 50 mM (pH 7.5), sodium chloride 150 mM, BSA 0.10%, chaps 0.10%, glutathione 1 mM, EDTA 1 mM
  • 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).
  • a test compound is tested on the same microtiter plate in 10 different concentrations from 30 ⁇ to 1 nM in duplicate.
  • Compounds according to the invention tested in this assay inhibited chymase activity with an IC 50 less than 10 ⁇ .
  • 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 compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of 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.

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WO2018197333A1 (en) * 2017-04-27 2018-11-01 Bayer Aktiengesellschaft Selective adrenoreceptor alpha2c receptor antagonists alone, or in combination with chymase inhibitors for use in the treatment and/or prophylaxis of peripheral artery diseases (pad)
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GB201918414D0 (en) * 2019-12-13 2020-01-29 Z Factor Ltd Compounds and their use for the treatment of Alpha1-Antitrypsin deficiency
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WO2022135534A1 (zh) * 2020-12-25 2022-06-30 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
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