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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
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—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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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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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
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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 invention relates to new ECE inhibitors, their production and use for the production of pharmaceutical preparations for the treatment of diseases.
• Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3.
• endothelin or "ET” means one or all isoforms of endothelin.
• Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
• endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
• endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 261, 2868 (1990), Nature 144, 114 (1990), N. Engl. J. Med. __22_, -205 (1989), N. Engl. J. Med.
• ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
• ACE angiotensin converting enzyme
• ANP angiotensin converting enzyme
• Patent application WO 9619486 describes phosphonic acid-substituted tetrazole derivatives as mixed ECE and NEP inhibitors. From applications FR 9602672 and 9602674, dipeptide-derived thiols are known as ECE inhibitors.
• the object was therefore to provide new inhibitors of the endothelin conversion enzyme (ECE) which have a more advantageous profile of properties than those known from the prior art.
• R 1 substituted or unsubstituted, branched or unbranched Ci-Cs-alkyl-, -C-C 4 -haloalkyl-, C 3 -Cs-cycloalkyl-, -C-C 8 -alkyl-C 3 -C 8 -cycloalkyl-, wherein all alkyl radicals can be substituted one or more times with halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl,
• R 4 H one or more substituents which independently of one another come from the group halogen, CN, CF 3 or N0 2 ,
• R 5 is H, substituted or unsubstituted, branched or unbranched C ⁇ -C 8 alkyl, C ⁇ -C4 haloalkyl, C ⁇ ⁇ C 8 -Al- alkyl-C 3 -C 8 cycloalkyl, C ⁇ -C 8 - Alkylaryl or Ci-Cg-alkylhetaryl, substituted or unsubstituted aryl or hetaryl, where all aryl and hetaryl radicals can be substituted one or more times with one of the following radicals:
• Halogen nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C4 alkylthio, amino, NH (C ⁇ -C 4 alkyl ), N (-C 4 alkyl) 2 , -COOH, -COO -C -C ⁇ C 3 alkyl
• R 6 substituted or unsubstituted, branched or unbranched Ci-Cg-alkyl, C 3 -C 8 cycloalkyl, Ci-Cg-alkyl-C 3 -C 8 cycloalkyl, -C-C 8 alkylaryl or C 1 -C 8 -alkyl heta- ryl, substituted or unsubstituted aryl or hetaryl,
• aryl and hetaryl radicals can be substituted with one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 alkoxy, Mercapto, C 1 -C 4 -alkylthio-, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2
• R 7 and R 8 are independently H, substituted or unsubstituted, branched or unbranched C ⁇ -C 8 alkyl, C ⁇ -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C; jC 8 alkyl- C 3 -C 8 cycloalkyl-, C 3 -C 8 -alkynyl-, -C-C 8 -alkylaryl- or C ⁇ -C 8 -alkylhetaryl-, substituted or unsubstituted aryl- or hetaryl-, all aryl- and hetaryl- Residues can be substituted with one or more of the following residues:
• Halogen nitro, cyano, C 1 -C 4 -alkyl, C ⁇ -C-haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy-, mercapto, C ⁇ -C 4 -alkylthio-, amino, NH (C ⁇ -C 4 -alkyl) , N (-C-C-alkyl) 2nd
• R 9 H substituted or unsubstituted, branched or unbranched C ⁇ -C, 8 alkyl, C ⁇ -C4-haloalkyl, C ⁇ -C 8 -Al- alkyl-C 3 -C 8 cycloalkyl, where all alkyl radicals in each case mono- nitro, cyano, C 4 -alkyl, C may be substituted one or more times with halogen, 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C4 alkylthio, amino, H ( -C-C 4 alkyl), N (-C-C 4 alkyl) 2 , -COOH, -COO-C ⁇ -C 3 alkyl.
• ECE endothelin conversion enzyme
• CC 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
• -C-C 4 haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
• Dichlorofluoromethyl trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
• C 1 -C 4 -Alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
• C 1 -C 4 -alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
• C 1 -C 4 -Alkylthio can be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio,
• C ⁇ -C 8 alkyl can be linear or branched such as -CC 4 alkyl, pentyl, hexyl, heptyl or octyl;
• Halogen is e.g. Fluorine, chlorine, bromine, iodine.
• C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
• the compounds according to the invention can be prepared analogously to processes known to the skilled worker.
• the chloromethylisoxazoles used can be synthesized, for example, from the corresponding oximes by reaction with propargyl chloride (reaction scheme 1), as described by Lee in Synthesis 1982, 508-509.
• the thiouracils are prepared by the method described by Lamon (J. Heterocycl. Chem. 1968, 5, 837-844), which is based on the reaction of an enamine with ethoxycarbonyl isothiocyanate.
• the subsequent alkylation of the thiouracil derivatives z. B. with chloromethylisoxazoles is then carried out by standard methods by alkylation with the addition of a base, as described, for example, in Houben-Weyl: Methods of Organic Chemistry, Volume IX, pp.
• reaction Scheme II If the group N-Rl is derived from an amino acid, the synthesis can be carried out particularly efficiently on a solid phase by using the carboxylic acid function as an anchor group for the attachment to a solid support (reaction scheme III). Methods of solid phase synthesis are described in detail, for example, by Bunin in "The combinatorial index" (Academic Press, 1998).
• R 1 is substituted or unsubstituted, branched or unbranched C ⁇ -C 8 alkyl, C ⁇ -C 4 haloalkyl, C 3 -C 8 -cycloalkyl alkyl, C ⁇ -C 8 alkyl-C 3 -C 8 cycloalkyl -, where all alkyl radicals in each case can be mono- or polysubstituted by halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C 4 - Alkylthio, amino,
• R 4 H one or more substituents which independently of one another come from the group halogen, CN, CF 3 or N0, R 5 H, substituted or unsubstituted, branched or unbranched C 1 -C 8 -alkyl, C 1 -C 4 -haloalkyl -, C ⁇ -C 8 -Alkyl-C 3 -C 8 -cycloalkyl-, -C-C 8 -alkylaryl- or C ⁇ -C 8 -alkylhetary-, substituted or unsubstituted aryl or hetaryl-, all aryl - and hetaryl radicals can be mono- or polysubstituted by one of the following radicals: halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl,
• R 6 is substituted or unsubstituted, branched or unbranched C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 8 -Al- alkyl-C 3 -C 8 cycloalkyl, C ⁇ -C8 alkylaryl - or C 1 -C 8 alkylhetaryl, substituted or unsubstituted aryl or hetaryl, it being possible for all aryl and hetaryl radicals to be substituted with one or more of the following radicals: halogen, nitro, cyano, C ⁇ - C 4 -alkyl, C 4 haloalkyl, hydroxyl, C!
• R 7 and R 8 are independently H, substituted or unsubstituted, branched or unbranched C ⁇ ⁇ C 8 alkyl, C ⁇ -C haloalkyl, C 3 -C 8 cycloalkyl, Cx-Cs-Al yl-Cs-Cs - Cycloalkyl-, C 3 -C 8 -alkynyl, -C-C 8 -alkylaryl- or -C-C 8 -alkylhetaryl-, substituted or unsubstituted aryl or hetaryl, all aryl and hetaryl radicals being simple or can be substituted several times with one of the following radicals:
• Halogen nitro, cyano, ⁇ C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C4-alkylthio, amino, NH (C ⁇ -C4 alkyl) , N (-C-C-alkyl) 2nd
• R 9 H substituted or unsubstituted, branched or unbranched C ⁇ -C, 8 alkyl, C ⁇ -C4-haloalkyl, C ⁇ -C 8 -Al- alkyl-C 3 -C 8 cycloalkyl, where all alkyl radicals in each case mono- or more nitro, cyano, C ⁇ -C-C may be substituted with halogen, 4 alkyl, 4 haloalkyl, hydroxy, C ⁇ ⁇ C 4 -alk- oxy, mercapto, C ⁇ -C-alkylthio, amino, NH (-CC alkyl), N (-C 4 alkyl) 2 , -COOH, -COO -C -C 3 alkyl.
• the compounds according to the invention can be present as free compounds, or in the form of their physiologically active salts, their tautomeric and isomeric forms or in the form of the combination of the free compounds and the various salts.
• the compounds according to the invention are also to be understood as meaning the enantiomerically pure or diastereomerically pure compounds, their salts or mixtures thereof.
• the enantiomeric or diastereomeric forms of the compounds according to the invention can be purified or prepared in a known manner, for example via the formation of diastereomeric salts, via chiral chromatography processes or via stereoselective syntheses.
• the compounds according to the invention very selectively inhibit the endothelin conversion enzyme with activities in the ⁇ m range.
• NEP 24.11 neutral endopeptidase 24.11
• MMP Matrix metalloproteases
• selectivities ECE / NEP 24.11 of> 10 are obtained.
• Thermolysin, papain and thrombin also do not accept these compounds as substrates or are not inhibited by them.
• the compounds according to the invention are suitable for the production of pharmaceutical preparations for the treatment of diseases, preferably for the production of medicaments for the treatment of diseases associated with a vasoconstriction or other biological effects of endothelin.
• the enantiomerically pure or diastereomerically pure compounds are preferably used as the active ingredient.
• the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic kidney failure, renal failure, cerebral vasospasm, cerebral ischemia, sub-arachnoid hemorrhage, migraine, asthma, Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, ischemic and intoxication-caused kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and cancer of the mesenchymal tumor , Contrast agent-induced kidney failure, pancreatitis or gastrointestinal ulcers.
• the compounds according to the invention are preferably administered in the form of those pharmaceutical preparations in which the release takes place under conditions which prevail in certain body compartments, for example in the stomach, intestine, bloodstream, liver.
• the invention furthermore relates to combination preparations of inhibitors of the formula I according to the invention and inhibitors of the renin-angiotensin system.
• Inhibitors of renin angiotensin are preferably administered in the form of those pharmaceutical preparations in which the release takes place under conditions which prevail in certain body compartments, for example in the stomach, intestine, bloodstream, liver.
• Systems are renin inhibitors, angiotensin-II antagonists and especially angiotensin converting enzyme (ACE) inhibitors.
• ACE angiotensin converting enzyme
• the combinations can be applied in a common galenical form or separately in time and space.
• the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotonically). It can also be applied with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the new compounds of the invention can be applied in the usual galenical application forms solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (cf. H. Sucker et al.: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
• a calcium antagonist with the inhibitors according to the invention can be used as an agent for the treatment of diseases which are based on a vasoconstriction or are associated with a pathological vasoconstriction.
• diseases which are based on a vasoconstriction or are associated with a pathological vasoconstriction. Examples are: All forms of high blood pressure (including pulmonary hypertension), coronary heart disease, heart failure ciency, renal and myocardial ischemia, acute and chronic
• the combinations according to the invention are generally administered orally, e.g. in the form of tablets, coated tablets, coated tablets, hard and
• Soft gelatin capsules, solutions, emulsions or suspensions administered can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• the active ingredient can be administered in the form of preparations which like both active ingredients
• Contain tablets or capsules or separately as an ad hoc combination of individual substances that can be applied simultaneously or at different times.
• a combination according to the invention with pharmaceutically inert, inorganic or organic excipients can be processed to produce tablets, coated tablets, coated tablets and hard gelatin capsules.
• Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such excipients for tablets, dragees and hard gelatin capsules.
• Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
• Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like.
• Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
• the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
• the solid was filtered off under N 2, rinsed with diethyl ether, and under a stream of N 2 dried.
• reaction was carried out analogously to 2 with 4-amino-l-benzylpiperidine (0.8g, 4.2mmol) and 2- (N-carbethoxythiocarbamoyl) -1- (N-piperidino) propene 1 (1.0g, 3.9mmol) in 45ml ethanol.
• reaction was carried out analogously to 2 with phenylamine (0.4g, 4.29mmol) and 2- (N-carbethoxythiocarbamoyl) -1- (N-piperidino) -propene 1 (1.10g, 4.3mmol) in 40ml ethanol.
• Activity is carried out in black 96-well micro-fluorine U-bottom microtiter plates (No.011-010-7205, Dynatech). 2 ⁇ l of the inhibitor solution in 0% DMSO (DMSO diluted with lOmmolar Na-Phosphate 50mM NaCl pH 7.2) reach 40 ⁇ l test buffer, which contains ECE with a final concentration of 51 ⁇ U / ml. Incubate for 10 minutes at 20 - 25 ° C. The test is started by adding 2 ⁇ l of a 35 ⁇ g / ml substrate solution in lOmM Na-Phosphate 50mM NaCl pH7.2.
• the test is stopped by adding 200 ⁇ l of a 0.05mg / ml avidin solution in test buffer. After 15 minutes of incubation at 20-25 ° C, the fluorescence polarization of each hole is measured in a fluorescence polarization measuring device (measuring device: Polarstar, BMG). An inhibition curve was formed from the inhibition values at the different inhibitor concentrations and the half-maximal inhibition (IC 50 value) was read off as a measure of the potency of the inhibitor.
• IC 50 value half-maximal inhibition
• IC 50 Inhibitor concentration required to reduce ECE activity to 50%.

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• 1999
  • 1999-04-13 DE DE19916719A patent/DE19916719A1/de not_active Withdrawn
• 2000
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  • 2000-04-04 CN CN00807504A patent/CN1350533A/zh active Pending
  • 2000-04-04 JP JP2000610852A patent/JP2002541256A/ja active Pending
  • 2000-04-04 EP EP00922601A patent/EP1165554A1/de not_active Withdrawn
• 2001
  • 2001-10-01 ZA ZA200108035A patent/ZA200108035B/en unknown
• 2002
  • 2002-09-26 HK HK02107079.7A patent/HK1045688A1/zh unknown

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