EP1023282A1 - Novel pharmaceutically active compounds, their preparation and use as ece-inhibitors - Google Patents

Novel pharmaceutically active compounds, their preparation and use as ece-inhibitors

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Publication number
EP1023282A1
EP1023282A1 EP98952597A EP98952597A EP1023282A1 EP 1023282 A1 EP1023282 A1 EP 1023282A1 EP 98952597 A EP98952597 A EP 98952597A EP 98952597 A EP98952597 A EP 98952597A EP 1023282 A1 EP1023282 A1 EP 1023282A1
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Prior art keywords
compounds
general formula
combination
pharmaceutical preparations
alkyl
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EP98952597A
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German (de)
French (fr)
Inventor
Michael Puhl
Johann-Christian Zechel
Klaus Ditrich
Heinz Hillen
Tanja Kohl
Melanie Erhardt
Stefan Hergenröder
Claus Otto Markert
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Abbott GmbH and Co KG
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BASF SE
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the invention relates to new pharmaceutically active compounds, 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. In the following, "endothelin” or “ET” denotes one or all iso-
  • 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.
  • 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 ed. Biology 2, 207 (1990), J. Am. Med. As- 0 sociation _______ 2868 (1990), Nature 3_M, 114 (1990), N. Engl. J.
  • 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.
  • R 1 and R 2 independently substituted or unsubstituted, branched or unbranched Ci-C ⁇ -alkyl-, Ci-Ca-alkylaryl- or -CC 8 -alkylhetaryl-, substituted or unsubstituted aryl- or hetaryl-
  • R 3 is a group of formula a, b or c
  • R 4 substituted or unsubstituted C 4 -C 4 aryl, C 4 -C 4 heteroaryl, with one or more rings containing one or more heteroatoms selected from the group 0, S and N,
  • R 5 Ci-C ⁇ -alkyl, -CC 8 alkylaryl, aryl or hetaryl, dissolved.
  • the invention further relates to a process for the preparation of the above-mentioned compounds of general formula I, characterized in that compounds of general formula II
  • ECE endothelin conversion enzyme
  • R 1 and R 2 are independently substituted or unsubstituted, branched or unbranched Ci-Cs-alkyl,
  • Ci-C ⁇ -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2 -Dirnethylpropyl, 1 -Ethylpropyl, n-hexyl, 1, 1 -Dimethylpropyl, 1, 2 -Dirne hylpropyl, 1-Methylpentyl, 2 -Methylpentyl, 3 -Methylpentyl, -Methylpentyl, 1, 1 -Dimethylbutyl, 1, 2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -di
  • Alkylaryl branched or unbranched chain -C 8 alkyl aryl such as C 8 alkyl phenyl or C 8 alkyl naphthyl, such as methylphenyl, ethylphenyl, propylphenyl, 1-methylphenyl, butylphenyl , 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl , Octylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl, 1-methylethylnaphthyl, butylnaph
  • C 1 -C 8 -alkylhetaryl radicals the simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or O;
  • Aryl such as phenyl, naphthyl, anthranyl or phenanthryl
  • R 1 and R 2 are substituted or unsubstituted, branched or unbranched C 1 -C 4 -alkyl-, C ⁇ -C -alkylaryl- or C 1 -C 4 -alkylhetaryl-, substituted or unsubstituted aryl- or hetaryl- , -C-C -alkylaryl- is particularly preferred.
  • radicals R 1 or R 2 can also mean hydrogen in a less preferred form.
  • compounds with these residues show no or only very little biological activity.
  • R 3 is a group of formula a, b or c
  • R 4 substituted or unsubstituted C -C ⁇ -aryl-, C -C ⁇ -heetaryl-, with one or more rings containing one or more heteroatoms selected from the group 0, S and N, where
  • C 4 -C 4 aryl such as phenyl, naphthyl, anthranyl or phenanthryl
  • R 5 Ci-C ⁇ -alkyl, -C-C 8 alkylaryl, aryl or hetaryl,
  • alkyl branched or unbranched C 8 alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 - Methyl butyl, 2-methyl butyl, 3-methyl butyl, 2, 2-dimethyl propyl, 1-ethyl propyl, n-hexyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 1-methyl pentyl, 2-methyl pentyl, 3-methyl pentyl, 4 -methylpentyl, 1, 1 -dimethylbutyl, 1,2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1-ethylbutyl, 2-ethy
  • Alkylaryl branched or unbranched chain C ⁇ -C kylaryl- 8 -Al-, as Ci-C8 alkyl, phenyl - C 8 alkyl or C ⁇ --naphthylre- ste such as methylphenyl, ethylphenyl, propylphenyl, 1-methyl ethyl thylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl, Octylphenyl, methylnaphthyl, ethylnaphthyl, propynaph
  • Aryl such as phenyl, naphthyl, anthranyl or phenanthryl
  • the radical R5 can optionally carry further substituents.
  • 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 also include the enantiomerically pure or diastereomerically pure compounds, their salts or their mixtures.
  • 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 are prepared by a process known to the person skilled in the art, for example from Hruby et al. (J. Med. Chem 1995, 38, 3462), Coy et al. (J. Med. Chem. 1987, 30, 1162) or Coy et al. (Tetrahedrcn, 44, 1988, 835) is known and therefore requires no further explanation.
  • An amino acid derivative of the formula II which is suitably protected on the carboxylic acid function is advantageously condensed with an aminoaldehyde of the formula III to give the imine and this is then reduced in situ with, for example, NaBH 3 CN with the addition of acid to the amine of the formula IV (see reaction scheme I).
  • the protective group SGi includes all protective groups known to those skilled in protein synthesis, such as t-butyl, benzyl, trityl, methyl or polymer-bonded protective groups in the form of the commercially available polystyrene resins, such as 2-chlorotrityl chloride resin or Wang resin (Bachern, Nobvabiochem) are suitable.
  • Preferred protective groups are t-butyl and 2-chlorotrityl resins.
  • the conversion of IV to I is preferably carried out in a mixture of pyridine and methylene chloride (of about 1: 1) at temperatures between 0 and 100 ° C., preferably at 20 to 60 ° C. with a 2 to 10-fold excess of the acid chloride.
  • the compounds of the formula I are purified after completion of the synthesis by customary chromatographic methods, for example by means of preparative FPLC or HPLC chromatography which is customary in protein / peptide purification.
  • the compounds according to the invention are very similar to real peptides. They are therefore to be regarded as synthetic stable analogs of natural substrates, since this small change in the molecules does not change the conformation of the substances, or only to an insignificant extent.
  • the compounds according to the invention very selectively inhibit the endothelin conversion enzyme with activities in the im range and can be used for this.
  • MMP matrix metalloproteases
  • 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 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-related kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and tumor growth, mesenchymal
  • the compounds according to the invention are preferably administered in the form of pharmaceutical preparations in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
  • 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 the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, 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 used in the usual galenical application forms in solid or liquid form, 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 application forms thus obtained 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, renal and myocardial ischemia, acute and chronic renal insufficiency.
  • the combinations according to the invention are generally administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.
  • the active ingredient can be administered in the form of preparations that contain both active ingredients together, such as 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 its salts can be used as such excipients for tablets, coated tablets 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. Water, alcohols, polyols, glycerin and vegetable oils are suitable excipients for injection solutions. 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, lot mediators, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
  • Example 2 ECE inhibitor tests, IC 50 determinations
  • ECE endothelin conversion enzyme
  • the enzyme preparations used were further purified by mono-Q chromatography and WGA lectin chromatography.
  • the preparations thus obtained contained no interfering foreign protease activities and had specific activities in the range of 1-20 mU / mg.
  • 5 ⁇ l of this enzyme solution were mixed with 495 ⁇ l test buffer (100 mM Pi, 500 mM NaCl, 0.1 mg / ml BSA pH 7.2) and each with 5 ⁇ l correspondingly concentrated solutions (10 " 3 M, 10" 4 M , 10 " 5 Musw.) Of the inhibitors in the test buffer for 10 minutes.

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  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
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Abstract

Novel pharmaceutically active compounds of general formula (I), their preparation and use for producing pharmaceutical compositions for the treatment of diseases are disclosed. (Endothelin conversion enzyme inhibitors (=ECE)).

Description

NEUE PHARMAZEUTISCHE WIRKSAME VERBINDUNGEN, IHRE HERSTELLUNG UND VERWENDUG ALS ECE-INHIBITORENNEW PHARMACEUTICAL EFFECTIVE COMPOUNDS, THEIR PRODUCTION AND USE AS ECE INHIBITORS
5 Beschreibung5 Description
Die Erfindung betrifft neue pharmazeutisch wirksame Verbindungen, ihre Herstellung und Verwendung zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten.The invention relates to new pharmaceutically active compounds, their production and use for the production of pharmaceutical preparations for the treatment of diseases.
1010
Endothelin ist ein aus 21 Aminosäuren aufgebautes Peptid, das von vaskulärem Endothel synthetisiert und freigesetzt wird. Endothelin existiert in drei Isoformen, ET-1, ET-2 und ET-3. Im Folgenden bezeichnet "Endothelin" oder "ET" eine oder alle Iso-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. In the following, "endothelin" or "ET" denotes one or all iso-
15 formen von Endothelin. Endothelin ist ein potenter Vasokonstrik- tor und hat einen starken Effekt auf den Gefäßtonus. Es ist bekannt, daß diese Vasokonstriktion von der Bindung von Endothelin an seinen Rezeptor verursacht wird (Nature, 332. 411-415, 1988; FEBS Letters, 231. 440-444, 1988 und Biochem. Biophys. Res.15 forms 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.
20 Commun., 15_4, 868-875, 1988).20 Commun., 15_4, 868-875, 1988).
Erhöhte oder abnormale Freisetzung von Endothelin verursacht eine anhaltende Gefäßkontraktion in peripheren, renalen und zerebralen Blutgefäßen, die zu Krankheiten führen kann. Wie in der Literatur 5 berichtet, ist Endothelin in einer Reihe von Krankheiten invol- viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonäre Hypertonie, Raynaud-Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostata-hypertrophie, Atherosklerose, Asthma und Prostatakrebs (J. Vascular ed. Biology 2 , 207 (1990), J. Am. Med. As- 0 sociation _______ 2868 (1990), Nature 3_M, 114 (1990), N. Engl . J.Increased or abnormal release of endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As reported in literature 5, 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 ed. Biology 2, 207 (1990), J. Am. Med. As- 0 sociation _______ 2868 (1990), Nature 3_M, 114 (1990), N. Engl. J.
Med. 322. 205 (1989), N. Engl. J. Med. ____&, 1732 (1993), NephronMed. 322, 205 (1989), N. Engl. J. Med. ____ &, 1732 (1993), Nephron
££., 373 (1994), Stroke 25., 904 (1994), Nature _____., 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research __&, 663 (1996), Nature Medicine 1, 944,(1995)). 5££., 373 (1994), Stroke 25, 904 (1994), Nature _____., 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research __ &, 663 (1996), Nature Medicine 1, 944, (1995)). 5
Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB-Rezeptor, werden zur Zeit in der Literatur beschrieben (Nature 348. 730 (1990) , Nature 348. 732 (1990) ) . Demnach sollten Substanzen, die die Bindung von Endothelin an einen oder an beide Rezeptoren in- 0 hibieren, physiologische Effekte von Endothelin antagonisieren und daher wertvolle Pharmaka darstellen.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.
Nachteil bei diesen Rezeptorantagonisten ist jedoch, daß sich Endothelin schon gebildet hat und die Wirkung des Endothelins nach 5 Entstehung antagonisiert werden muß. Substanzen, die eine Bildung des Endothelins aus seinem Vorläufer, dem sogenannten "Big-Endo- thelin" verhindern, greifen auf einer früheren Stufe der Endothe- linwirkung an und stellen damit eine gesuchte Alternative zu den Endothelinrezeptorantagonisten dar, da sie eine direktere bessere Wirkung haben müßten, wie Inhibitoren des ACE (ACE = "angiotensin converting enzyme" , Szelke et al. Nature, 299, 555) oder des ANP (ANP = ,Sybertz et al., J. Pharmacol. Exp.Ther. 1989, 250, 624) beispielsweise zeigen.However, a disadvantage of these receptor antagonists is that endothelin has already formed and the action of the endothelin must be antagonized after it has arisen. Substances that prevent the formation of endothelin from its predecessor, the so-called "big endothelin", take effect at an earlier stage of endothelin and thus represent a sought-after alternative to the endothelin receptor antagonists, since they should have a more direct, better effect, such as inhibitors of ACE (ACE = "angiotensin converting enzyme", Szelke et al. Nature, 299, 555) or of the ANP (ANP =, Sybertz et al., J. Pharmacol. Exp. Ther. 1989, 250, 624), for example.
Es bestand deshalb die Aufgabe, Inhibitoren des Endothelin-KOn- versionsenzym (= ECE) bereitzustellen.The task was therefore to provide inhibitors of the endothelin conversion version enzyme (= ECE).
Diese Aufgabe wurde durch Verbindungen der allgemeinen Formel I;This object was achieved by compounds of the general formula I;
ihre physiologisch wirksamen Salzen oder deren Kombination, in der die Substituenten folgende Bedeutung haben:their physiologically active salts or a combination thereof, in which the substituents have the following meaning:
R1 und R2 unabhängig voneinander substituiertes oder unsubsti- tuiertes, verzweigtes oder unverzweigtes Ci-Cβ-Alkyl-, Ci-Ca-Alkylaryl- oder Cι-C8-Alkylhetaryl-, substituiertes oder unsubstituiertes Aryl- oder Hetaryl-R 1 and R 2 independently substituted or unsubstituted, branched or unbranched Ci-Cβ-alkyl-, Ci-Ca-alkylaryl- or -CC 8 -alkylhetaryl-, substituted or unsubstituted aryl- or hetaryl-
R3 eine Gruppe der Formel a, b oder cR 3 is a group of formula a, b or c
R4 substituiertes oder unsubstituiertes C4-Cι4-Aryl-, C4-Cι4-He- taryl-, mit einem oder mehreren Ringen enthaltend ein oder mehrere Heteroatome ausgewählt aus der Gruppe 0, S und N,R 4 substituted or unsubstituted C 4 -C 4 aryl, C 4 -C 4 heteroaryl, with one or more rings containing one or more heteroatoms selected from the group 0, S and N,
R5 Ci-Cβ-Alkyl-, Cι-C8-Alkylaryl-, Aryl- oder Hetaryl-, gelöst.R 5 Ci-Cβ-alkyl, -CC 8 alkylaryl, aryl or hetaryl, dissolved.
Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der oben genannten Verbindungen der allgemeinen Formel I, dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel II The invention further relates to a process for the preparation of the above-mentioned compounds of general formula I, characterized in that compounds of general formula II
mit Verbindungen der allgemeinen Formel IIIwith compounds of the general formula III
kondensiert und mit einem Reduktionsmittel zu Verbindungen der allgemeinen Formel IVcondensed and with a reducing agent to give compounds of general formula IV
reduziert und mit einem Acylierungsmittel RC0C1 (V) und Abspal - tung der Schutzgruppe SGI zu den oben genannten Verbindungen der Formel I umsetzt, wobei die Substituenten R1, R2, R3 und R4 , die oben genannte Bedeutung haben und SGi eine Schutzgruppe bedeutet.reduced and reacted with an acylating agent RC0C1 (V) and cleavage of the protective group SGI to give the above-mentioned compounds of the formula I, the substituents R 1 , R 2 , R 3 and R 4 having the abovementioned meaning and SGi being a protective group means.
Weiterhin betrifft die Erfindung die Verwendung von Verbindungen der allgemeinen Formel I zur Hemmung des Endothelin-Konversions- enzyms (= ECE) , zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten sowie die Verwendung dieser pharmazeutischen Zubereitungen in Kombination mit mindestens einem weiteren blutdrucksenkenden Wirkstoff bzw. Arzneimittel.The invention further relates to the use of compounds of the general formula I for inhibiting the endothelin conversion enzyme (= ECE), for the production of pharmaceutical preparations for the treatment of diseases and the use of these pharmaceutical preparations in combination with at least one further antihypertensive active ingredient or Drug.
Die Substituenten R1 und R2 in den oben genannten Formeln I, II, III und IV haben folgende Bedeutung:The substituents R 1 and R 2 in the above formulas I, II, III and IV have the following meaning:
R1 und R2 unabhängig voneinander substituiertes oder unsubsti- tuiertes, verzweigtes oder unverzweigtes Ci-Cs-Alkyl-,R 1 and R 2 are independently substituted or unsubstituted, branched or unbranched Ci-Cs-alkyl,
Ci-Ca-Alkylaryl- oder Cι-C8-Alkylhetaryl-, substituiertes oder unsubstituiertes Aryl- oder Hetaryl-, wobeiCi-Ca-alkylaryl- or -CC 8 -alkylhetaryl, substituted or unsubstituted aryl or hetaryl, wherein
Alkyl verzweigte oder unverzweigte Ci-Cβ-Alkylketten wie beispielsweise Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1 -Methylpropyl- , 2 -Methylpropyl, 1, 1-Dimethylethyl, n-Pentyl, 1 -Methylbutyl, 2-Methylbutyl, 3 -Methylbutyl, 2 , 2 -Dirnethylpropyl , 1 -Ethylpropyl, n-Hexyl, 1, 1 -Dimethyl- propyl, 1, 2 -Dirne hylpropyl, 1-Methylpentyl, 2 -Methylpentyl, 3 -Methylpentyl, -Methylpentyl, 1 , 1 -Dimethylbutyl, 1, 2-Dimethylbutyl, 1, 3 -Dimethylbutyl, 2 , 2 -Dimethylbutyl, 2, 3 -Dimethylbutyl, 3 , 3 -Dimethylbutyl, 1 -Ethylbutyl,Alkyl branched or unbranched Ci-Cβ-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2 -Dirnethylpropyl, 1 -Ethylpropyl, n-hexyl, 1, 1 -Dimethylpropyl, 1, 2 -Dirne hylpropyl, 1-Methylpentyl, 2 -Methylpentyl, 3 -Methylpentyl, -Methylpentyl, 1, 1 -Dimethylbutyl, 1, 2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl,
2-Ethylbutyl, 1 , 1 , 2 -Trimethylpropyl , 1, 2 , 2 -Tri ethylpropyl, 1-Ethyl-l -methylpropyl, 1 -Ethyl- 2 -methylpropyl , n-Heptyl oder n-Octyl;2-ethylbutyl, 1, 1, 2 -trimethylpropyl, 1, 2, 2 -triethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl;
• Alkylaryl verzweigtkettiges oder unverzweigtkettiges Cι-C8-Al- kylaryl-, wie Cι-C8-Alkyl-phenyl- oder Cι-C8-Alkyl-naphthylre- ste wie Methylphenyl , Ethylphenyl, Propylphenyl , 1-Methyle- thylphenyl, Butylphenyl , 1-Methylpropylphenyl, 2-Methylpro- pylphenyl, 1, 1-Dimethylethylphenyl, Pentylphenyl , 1-Methylbu- tylphenyl, 2 -Methylbutylphenyl, 3 -Methylbutylphenyl, 2,2-Di- methylpropylphenyl , 1 -Ethylpropylphenyl, Hexylphenyl, Heptyl- phenyl , Octylphenyl, Methylnaphthyl , Ethylnaphthyl , Propy- naphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1 -Methyl - propylnaphthyl, 2 -Methylpropylnaphthyl, 1 , 1-Dimethylethyl- naphthyl, Pentylnaphthyl , 1 -Methylbutylnaphthyl, 2-Methylbu- tylnaphthyl, 3 -Methylbutylnaphthyl, 2 , 2 -Dimethylpropylnaph- thyl, 1 -Ethylpropylnaphthyl Hexylnaphthyl , Heptylnaphthyl oder Octylnaphthyl; • Alkylaryl branched or unbranched chain -C 8 alkyl aryl, such as C 8 alkyl phenyl or C 8 alkyl naphthyl, such as methylphenyl, ethylphenyl, propylphenyl, 1-methylphenyl, butylphenyl , 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl , Octylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl, 1-methylethylnaphthyl, butylnaphthyl, 1-methyl-propylnaphthyl, 2-methylpropylnaphthyl, 1, 1-dimethylethyl-naphthyl, pentylnaphthyl, 1-methylbutylnaphthylnaphthyl, 2-methylnaphthyl, 2-methyl , 2, 2 -dimethylpropylnaphthyl, 1 -ethylpropylnaphthyl hexylnaphthyl, heptylnaphthyl or octylnaphthyl;
• Alkylhetaryl verzweigtkettige oder unverzweigtkettige• Alkylhetaryl branched or unbranched
Cι-C8-Alkylhetarylreste, die einfache oder kondensierte aromatische Ringsysteme mit einem oder mehreren heteroaromatischen 3- bis 8-gliedrigen Ringen, die ggf. ein oder mehrer Heteroa- tome wie S, N oder O enthalten können;C 1 -C 8 -alkylhetaryl radicals, the simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or O;
Aryl wie Phenyl, Naphthyl, Anthranyl oder Phenanthryl;Aryl such as phenyl, naphthyl, anthranyl or phenanthryl;
Hetaryl einfache oder kondensierte aromatische Ringsysteme mit einem oder mehreren heteroaromatischen 5- bis 8-gliedri- gen Ringen, die ggf. ein oder mehrer Heteroatome wie S, N oder 0 enthalten können, wie Thienyl-, Pyridyl- oder Indoyl-.Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 5- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or 0, such as thienyl, pyridyl or indoyl.
Alle genannten Reste R1 oder R2 können gegebenenfalls mit einem oder mehreren der Reste -NHp(Cι-C8-Alkyl) 2_p, -QHn(Cι-C8-Alkyl)ι-n, -SS-t-Butyl, -CN, -N02 oder Halogen wie Fluor, Chlor, Brom oder Iod substituiert sein, wobei p = 0, 1 oder 2, Q = Schwefel oder Sauerstoff, n = 0 oder 1 bedeutet und C_-C8-Alkyl die obenen genannte Bedeutung hat .All of the radicals R 1 or R 2 mentioned can, if appropriate, be reacted with one or more of the radicals -NH p (-C 8 -alkyl) 2 _ p , -QH n (-C 8 -alkyl) ι- n , -SS-t -Butyl, -CN, -N0 2 or halogen such as fluorine, chlorine, bromine or iodine may be substituted, where p = 0, 1 or 2, Q = sulfur or oxygen, n = 0 or 1 and C_-C 8 alkyl has the meaning given above.
Bevorzugt werden für R1 und R2 Reste, die sich von natürlichen oder unnatürlichen Aminosäuren ableiten, wobei funktionelle Gruppen dieser Reste geschützt oder ungeschützt sein können. Da sich die Reste R1 und R2 vorteilhafterweise von natürlichen oder unnatürlichen Aminosäuren ableiten, können die den Resten benachbarten Stereozentren sowohl in der D- als auch in der L-Konfigura- tion (= R- oder S-Form) vorliegen. Weitere bevorzugte Reste für R1 und R2 sind substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Cι-C4-Alkyl-, Cχ-C -Alkylaryl- oder Cι-C4-Alkylheta- ryl-, substituiertes oder unsubstituiertes Aryl- oder Hetaryl-, besonders bevorzugt ist Cι-C -Alkylaryl- .R 1 and R 2 are preferably residues derived from natural or unnatural amino acids, functional groups of these residues being able to be protected or unprotected. That I the residues R 1 and R 2 advantageously derive from natural or unnatural amino acids, the stereo centers adjacent to the residues can be present both in the D and in the L configuration (= R or S form). Further preferred radicals for R 1 and R 2 are substituted or unsubstituted, branched or unbranched C 1 -C 4 -alkyl-, Cχ-C -alkylaryl- or C 1 -C 4 -alkylhetaryl-, substituted or unsubstituted aryl- or hetaryl- , -C-C -alkylaryl- is particularly preferred.
Prinzipiell können die Reste R1 oder R2 in einer wenig bevorzugten Form auch Wasserstoff bedeuten. Verbindungen mit diesen Resten zeigen jedoch keine oder nur eine sehr geringe biologische Wirkung.In principle, the radicals R 1 or R 2 can also mean hydrogen in a less preferred form. However, compounds with these residues show no or only very little biological activity.
Der Substituent R3 hat in den oben genannten Formeln I, III und IV folgende Bedeutung:The substituent R 3 in the above formulas I, III and IV has the following meaning:
R3 eine Gruppe der Formel a, b oder cR 3 is a group of formula a, b or c
Die Formeln a, b und c können gegebenenfalls weitere Substituenten tragen. R5 in der Formel b hat die unten genannte Bedeutung.The formulas a, b and c can optionally carry further substituents. R 5 in formula b has the meaning given below.
Der Substituent R4 hat in den oben genannten Formeln I und V folgende Bedeutung:The substituent R 4 in the above formulas I and V has the following meaning:
R4 substituiertes oder unsubstituiertes C -Cχ -Aryl-, C -Cχ -He- taryl-, mit einem oder mehreren Ringen enthaltend ein oder mehrere Heteroatome ausgewählt aus der Gruppe 0, S und N, wobeiR 4 substituted or unsubstituted C -Cχ -aryl-, C -Cχ -heetaryl-, with one or more rings containing one or more heteroatoms selected from the group 0, S and N, where
C4-Cι4-Aryl wie Phenyl, Naphthyl, Anthranyl oder Phenanthryl;C 4 -C 4 aryl such as phenyl, naphthyl, anthranyl or phenanthryl;
C -Cι -Hetaryl einfache oder kondensierte aromatische Ringsysteme mit einem oder mehreren heteroaromatischen 5- bis 8-gliedrigen Ringen, die ggf. ein oder mehrer Heteroatome wie S, N oder O enthalten können, wie beispielsweise Thienyl-, Pyridyl- oder Indoyl-. Alle genannten Reste R4 können gegebenenfalls mit einem oder mehreren der folgenden Reste: verzweigtkettiges oder unverzweigtket - tiges Cι-C4-Alkyl-, C6-Cι4-Aryl- , -COOR6 , -NHp (Cι-C8-Alkyl) 2_p, -QH- n(Cι-C8-Alkyl)ι-n, -SS-t-Butyl, -CN, ~N0 oder Halogen wie Fluor, Chlor, Brom oder Iod substituiert sein, wobei R6 = H oderC -C -Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 5- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or O, such as thienyl, pyridyl or indoyl. All of the radicals R 4 mentioned can optionally be substituted with one or more of the following radicals: branched or unbranched - C 1 -C 4 -alkyl-, C 6 -C 4 -Aryl-, -COOR 6 , -NH p (Cι-C 8 - Alkyl) 2 _ p , -QH- n (-CC 8 -alkyl) ι- n , -SS-t-butyl, -CN, ~ N0 or halogen such as fluorine, chlorine, bromine or iodine, where R 6 = H or
Cι-C8_Alkyl, p = 0, 1 oder 2, Q = Schwefel oder Sauerstoff, n = 0 oder 1 bedeutet und Cχ-C8-Alkyl-, Cι-C -Alkyl- oder C6-Cι -Aryl- die obenen genannte Bedeutung haben.C 1 -C 8 alkyl, p = 0, 1 or 2, Q = sulfur or oxygen, n = 0 or 1 and Cχ-C 8 alkyl, C 1 -C 4 alkyl or C 6 -C 5 aryl which have the meaning given above.
Der Substituent R5 in der oben genannten Formeln b hat folgende Bedeutung :The substituent R 5 in the above formula b has the following meaning:
R5 Ci-Cβ-Alkyl-, Cι-C8-Alkylaryl-, Aryl- oder Hetaryl-,R 5 Ci-Cβ-alkyl, -C-C 8 alkylaryl, aryl or hetaryl,
- Alkyl verzweigte oder unverzweigte Cι-C8-Alkylketten wie beispielsweise Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1 -Methylpropyl - , 2 -Methylpropyl , 1, 1 -Dimethylethyl, n-Pentyl, 1 -Methylbutyl, 2 -Methylbutyl, 3 -Methylbutyl, 2 , 2 -Dimethylpropyl, 1 -Ethylpropyl , n-Hexyl, 1, 1-Dimethyl- propyl, 1, 2 -Dimethylpropyl, 1 -Methylpentyl, 2 -Methylpentyl, 3 -Methylpentyl, 4 -Methylpentyl, 1, 1 -Dimethylbutyl, 1,2 -Dimethylbutyl, 1, 3 -Dimethylbutyl , 2 , 2 -Dimethylbutyl, 2, 3 -Dimethylbutyl, 3 , 3 -Dimethylbutyl, 1-Ethylbutyl, 2-Ethylbutyl, 1, 1, 2 -Trimethylpropyl, 1, 2, 2 -Trimethylpropyl, 1- Ethyl -1 -methylpropyl, 1 -Ethyl -2 -methylpropyl, n-Heptyl oder n-Octyl ;- Alkyl branched or unbranched C 8 alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 - Methyl butyl, 2-methyl butyl, 3-methyl butyl, 2, 2-dimethyl propyl, 1-ethyl propyl, n-hexyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 1-methyl pentyl, 2-methyl pentyl, 3-methyl pentyl, 4 -methylpentyl, 1, 1 -dimethylbutyl, 1,2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl;
Alkylaryl verzweigtkettiges oder unverzweigtkettiges Cι-C8-Al- kylaryl-, wie Ci -C8 -Alkyl -phenyl - oder Cι-C8 -Alkyl -naphthylre- ste wie Methylphenyl, Ethylphenyl, Propylphenyl , 1-Methyle- thylphenyl, Butylphenyl, 1-Methylpropylphenyl, 2-Methylpro- pylphenyl, 1, 1-Dimethylethylphenyl, Pentylphenyl , 1-Methylbu- tylphenyl, 2 -Methylbutylphenyl, 3 -Methylbutylphenyl, 2,2-Di- methylpropylphenyl, 1-Ethylpropylphenyl, Hexylphenyl, Heptyl- phenyl, Octylphenyl, Methylnaphthyl, Ethylnaphthyl, Propy- naphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1 -Methyl - propylnaphthyl , 2 -Methylpropylnaphthyl, 1, 1 -Dimethylethyl - naphthyl, Pentylnaphthyl , 1 -Methylbutylnaphthyl, 2 -Methylbutylnaphthyl, 3 -Methylbutylnaphthyl, 2 , 2 -Dimethylpropylnaph- thyl, 1-Ethylpropylnaphthyl Hexylnaphthyl , Heptylnaphthyl oder Octylnaphthyl;Alkylaryl branched or unbranched chain Cι-C kylaryl- 8 -Al-, as Ci-C8 alkyl, phenyl - C 8 alkyl or Cι--naphthylre- ste such as methylphenyl, ethylphenyl, propylphenyl, 1-methyl ethyl thylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl, Octylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl, 1-methylethylnaphthyl, butylnaphthyl, 1-methyl-propylnaphthyl, 2-methylpropylnaphthyl, 1, 1-dimethylethyl-naphthyl, pentylnaphthyl, 1-methylbutylnaphthyl-2-methyl-naphthyl-2-methyl-naphthyl-2-methyl-naphthyl, 2-dimethylpropylnaphthyl, 1-ethylpropylnaphthyl hexylnaphthyl, heptylnaphthyl or octylnaphthyl;
Aryl wie Phenyl, Naphthyl, Anthranyl oder Phenanthryl;Aryl such as phenyl, naphthyl, anthranyl or phenanthryl;
- Hetaryl einfache oder kondensierte aromatische Ringsysteme mit einem oder mehreren heteroaromatischen 5- bis 8-gliedri- gen Ringen, die ggf. ein oder mehrer Heteroatome wie S, N oder 0 enthalten können, wie Thienyl-, Pyridyl- oder Indoyl-;- Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 5- to 8-membered rings, which may contain one or more heteroatoms such as S, N or may contain 0, such as thienyl, pyridyl or indoyl;
Der Rest R5 kann gegebenenfalls weitere Substituenten tragen.The radical R5 can optionally carry further substituents.
Die erfindungsgemäßen Verbindungen können als freie Verbindungen vorliegen, oder in Form ihrer physiologisch wirksamen Salze, deren tautomeren und isomeren Formen oder in Form der Kombination aus den freien Verbindungen und den verschiedenen Salzen. Unter den erfindungsgemäßen Verbindungen sind auch die enantiomerenrei - nen oder diastereomerenreinen Verbindungen, deren Salze oder deren Mischungen zu verstehen.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 also include the enantiomerically pure or diastereomerically pure compounds, their salts or their mixtures.
Die enantiomeren bzw. diastereomeren Formen der erfindungsgemäßen Verbindungen lassen sich in bekannter Weise beispielsweise über die Bildung diastereomerer Salze, über chirale Chromatographie - verfahren oder über stereoselektive Synthesen reinigen bzw. herstellen.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.
Die Herstellung der erfindungsgemäßen Verbindungen erfolgt nach einem dem Fachmann bekannten Verfahren wie es beispielsweise aus Hruby et al. (J. Med. Chem 1995, 38, 3462), Coy et al. (J. Med. Chem. 1987, 30, 1162) oder Coy et al . (Tetrahedrcn, 44 ,1988, 835) bekannt ist und bedarf deshalb keiner näheren Erläuterung. Dabei wird vorteilhafterweise ein an der Carbonsaurefunktion geeignet geschütztes Aminosäurederivat der Formel II mit einem Ami- noaldehyd der Formel III zum Imin kondensiert und dieses dann in situ mit beispielsweise NaBH3CN unter Säurezusatz zum Amin der Formel IV reduziert (siehe Reaktionsschema I) .The compounds according to the invention are prepared by a process known to the person skilled in the art, for example from Hruby et al. (J. Med. Chem 1995, 38, 3462), Coy et al. (J. Med. Chem. 1987, 30, 1162) or Coy et al. (Tetrahedrcn, 44, 1988, 835) is known and therefore requires no further explanation. An amino acid derivative of the formula II which is suitably protected on the carboxylic acid function is advantageously condensed with an aminoaldehyde of the formula III to give the imine and this is then reduced in situ with, for example, NaBH 3 CN with the addition of acid to the amine of the formula IV (see reaction scheme I).
Reaktionsschema I: Synthese der Verbindungen der Formel I Reaction Scheme I: Synthesis of the Compounds of Formula I
(II) (IV)(II) (IV)
R4COCI (V) Entfernen von SGiR 4 COCI (V) Remove SGi
I)I)
Als Schutzgruppe SGi sind alle dem Fachmann in der Proteinsynthese bekannten Schutzgruppen wie t-Butyl, Benzyl, Trityl, Methyl oder auch polymer gebundene Schutzgruppen in Form der handelsüblichen Poylstyrol-Harze wie z.B. 2-Chlortritylchloridharz oder Wang-Harz (Fa. Bachern, Fa. Nobvabiochem) geeignet. Bevorzugt werden als Schutzgruppen t-butyl und 2-Chlortritylharze.The protective group SGi includes all protective groups known to those skilled in protein synthesis, such as t-butyl, benzyl, trityl, methyl or polymer-bonded protective groups in the form of the commercially available polystyrene resins, such as 2-chlorotrityl chloride resin or Wang resin (Bachern, Nobvabiochem) are suitable. Preferred protective groups are t-butyl and 2-chlorotrityl resins.
Die Umsetzung zum Imin und die in situ Reduktion erfolgen wie in der Literatur (V.J. Hruby et al . J. Med. Chem. 1995, 38, 3462, D. H. Coy et al. J. Med. Chem., 1987, 30, 1162 und D. H. Coy et al .Tetrahedron 44 1988 835) beschrieben, wobei zur Iminbildung - wie von Gallop et al. (J. Am. Chem. Soc. 1995, 117, 7029) beschrieben vorteilhafterweise Trimethylorthoformiat zugesetzt wer- den kann.The conversion to the imine and the in situ reduction take place as in the literature (VJ Hruby et al. J. Med. Chem. 1995, 38, 3462, DH Coy et al. J. Med. Chem., 1987, 30, 1162 and DH Coy et al. Tetrahedron 44 1988 835), wherein for imine formation - as described by Gallop et al. (J. Am. Chem. Soc. 1995, 117, 7029), trimethyl orthoformate can advantageously be added.
Die weitere Derivatisierung von den Verbindungen der Formel IV zu Verbindungen der Formel I erfolgt vorzugsweise mit einem Säure- Chlorid unter Basenzusatz; auch dieser Reaktionsschritt bedarf keiner näherer Erläuterung und ist dem Fachmann bekannt. The further derivatization of the compounds of the formula IV to give the compounds of the formula I is preferably carried out using an acid chloride with addition of base; this reaction step also requires no further explanation and is known to the person skilled in the art.
(IV)(IV)
Die Umsetzung von IV zu I wird bevorzugt in einem Gemisch von Pyridin und Methylenchlorid (von ca 1:1) bei Temperaturen zwischen 0 und 100 °C bevorzugt bei 20 bis 60 °C mit einem 2 bis 10 fachen Überschuß des Säurechlorids durchgeführt.The conversion of IV to I is preferably carried out in a mixture of pyridine and methylene chloride (of about 1: 1) at temperatures between 0 and 100 ° C., preferably at 20 to 60 ° C. with a 2 to 10-fold excess of the acid chloride.
Falls erforderlich werden die Verbindungen der Formel I nach Abschluß der Synthese nach üblichen chromatographischen Methoden gereinigt, beispielsweise über eine präparative in der Pro- tein-/Peptidreinigung übliche FPLC- oder HPLC-Chromatographie.If necessary, the compounds of the formula I are purified after completion of the synthesis by customary chromatographic methods, for example by means of preparative FPLC or HPLC chromatography which is customary in protein / peptide purification.
Der Ersatz einer Peptidbindung durch eine CH2NH-Gruppe in den erfindungsgemäßen Verbindungen führt dazu, daß diese Verbindungen eine erhöhte Stabilität gegenüber peptidspaltenden Enzymen aufweisen und damit eine längere biologische Wirksamkeit zeigen.The replacement of a peptide bond by a CH 2 NH group in the compounds according to the invention leads to the fact that these compounds have an increased stability towards peptide-cleaving enzymes and thus show a longer biological activity.
Da die Seitenketten von dieser Modifikation nicht betroffen sind, ähneln die erfindungsgemäßen Verbindungen echten Peptiden sehr. Sie sind damit als synthetische stabile Analoge der natürlichen Substrate anzusehen, da durch diese geringe Änderung in den Molekülen sich die Konformation der Substanzen nicht oder nur unwe- sentlich ändert.Since the side chains are not affected by this modification, the compounds according to the invention are very similar to real peptides. They are therefore to be regarded as synthetic stable analogs of natural substrates, since this small change in the molecules does not change the conformation of the substances, or only to an insignificant extent.
Die erfindungsgemäßen Verbindungen hemmen sehr selektiv das Endothelin-Konversionsenzym mit Aktivitäten im ιm-Bereich und können dafür verwandt werden. Bei anderen Metalloproteasen wie ACE (= "angiotensin converting enzyme" ) , NEP 24.11 (= neutrale Endopeptidase 24.11) oder die Matrixmetalloproteasen (= MMP) MMP-1, MMP-3 oder MMP-9 konnte eine Hemmung in diesem Bereich nicht beobachtet werden; auch Thermolysin, Papain und Thrombin akzeptieren diese Verbindungen nicht als Substrate bzw, werden durch sie auch nicht inhibiert. Der Vorteil einer solchen selektiven Klasse von Inhibitoren liegt auf der Hand: zum einen wird nicht in andere enzymatische Prozesse eingegriffen, so daß auch nicht mit unerwünschten Nebeneffekten zu rechnen ist, zum anderen sind diese Verbindungen dann auch gegenüber einem enzymatischen Abbau sehr stabil, da sie nicht durch andere Proteasen in einer unspezifischen Reaktion abgebaut werden können. Sie können deshalb mit hoher Wahrscheinlichkeit in sehr niedrige Dosen verab- reicht werden, wodurch die Wahrscheinlichkeit von Nebenwirkungen durch beispielsweise Abbauprodukte der Verbindungen weiter reduziert werden kann.The compounds according to the invention very selectively inhibit the endothelin conversion enzyme with activities in the im range and can be used for this. With other metalloproteases such as ACE (= "angiotensin converting enzyme"), NEP 24.11 (= neutral endopeptidase 24.11) or the matrix metalloproteases (= MMP) MMP-1, MMP-3 or MMP-9, an inhibition in this area could not be observed; Thermolysin, papain and thrombin also do not accept these compounds as substrates or are not inhibited by them. The advantage of such a selective class of inhibitors is obvious: on the one hand, there is no intervention in other enzymatic processes, so that undesirable side effects are also not to be expected, on the other hand, these compounds are also very stable to enzymatic degradation because they cannot be degraded by other proteases in an unspecific reaction. You are therefore very likely to be given very low doses. enough, which can further reduce the likelihood of side effects from, for example, degradation products of the compounds.
Die erfindungsgemäßen Verbindungen, ihre stereoisomeren Formen und/oder physiologisch wirksamen Salze, sowie deren tautomeren oder isomeren Formen eignen sich für die Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten bevorzugt zur Herstellung von Medikamenten, die zur Behandlung von Krank- heiten, die mit einer Vasokonstriktion oder anderen biologischen Wirkungen von Endothelin assoziiert sind. Bevorzugt werden die enantiomerenreinen oder diastereomerenreinen Verbindungen als Wirkstoff benutzt.The compounds according to the invention, their stereoisomeric forms and / or physiologically active salts, and their tautomeric or isomeric forms are suitable for the production of pharmaceutical preparations for the treatment of diseases, preferably for the production of medicaments for the treatment of diseases with a vasoconstriction or other biological effects of endothelin. The enantiomerically pure or diastereomerically pure compounds are preferably used as the active ingredient.
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pulmo- nalem Hochdruck, Myokardinfarkt, chronischer Herzinsuffizienz, Angina Pectoris, akutem/chronischem Nierenversagen, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Sub- arachnoidalblutungen, Migräne, Asthma, Atherosklerose, endo- toxischem Schock, Endotoxin- induziertem Organversagen, intravas- kul rer Koagulation, Restenose nach Angioplastie, benigne Prosta- ta-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Cyclosporininduziertes Nieren- versagen, Metastasierung und Wachstum mesenchymaler Tumoren,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-related kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and tumor growth, mesenchymal
Krebs, Prostatakrebs, Kontrastmittel-induziertes Nierenversagen, Pankreatitis oder gastrointestinale Ulcera.Cancer, prostate cancer, contrast-induced kidney failure, pancreatitis or gastrointestinal ulcers.
Die erfindungsgemäßen Verbindungen werden bevorzugt in Form sol- eher pharmazeutischen Zubereitungen verabreicht, bei denen die Freisetzung unter solchen Bedingungen abläuft, wie sie in bestimmten Körperkomparti enten, z.B. im Magen, Darm, Blutkreislauf, Leber, vorherrschen.The compounds according to the invention are preferably administered in the form of pharmaceutical preparations in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
Ein weiterer Gegenstand der Erfindung sind Kombinationspräparate aus erfindungsgemäßen Inhibitoren der Formel I und Inhibitoren des Renin-Angiotensin Systems. Inhibitoren des Renin-Angiotensin- Systems sind Reninhemmer, Angiotensin-II-Antagonisten und vor allem Angiotensin-Converting-Enzyme (ACE) -Hemmer .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 the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
Die Kombinationen können in einer gemeinsamen galenischen Form oder zeitlich und räumlich getrennt appliziert werden.The combinations can be applied in a common galenical form or separately in time and space.
Bezüglich Dosierung und Applikationsart sind die gleichen Fakto- ren zu berücksichtigen wie für die entsprechenden Einzel - Substanzen. Diese Kombinationspräparate eignen sich vor allem zur Behandlung und Verhütung von Hypertension und deren Folgeerkrankungen, sowie zur Behandlung von Herzinsuffizienz.With regard to dosage and type of application, the same factors must be taken into account as for the corresponding individual substances. These combination products are particularly suitable for the treatment and prevention of hypertension and its complications, as well as for the treatment of heart failure.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, intrapero- toneal) verabfolgt werden. Die Applikation kann auch mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.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.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab.The dosage depends on the age, condition and weight of the patient and on the type of application.
Die neuen Verbindungen der Erfindung können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet wer- den, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tabletten- Sprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungs- mitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Ver- lag, Stuttgart, 1991) . Die so erhaltenen Applikationsformen ent- halten den Wirkstoff normalerweise in einer Menge von 0,1 bis 90 Gew. -% .The new compounds of the invention can be used in the usual galenical application forms in solid or liquid form, 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 application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 90% by weight.
Die Kombination eines Calciumantagonisten mit den erfindungsgemäßen Hemmstoffen können als Mittel zur Behandlung von Erkrankungen verwendet werden, die auf einer Vasokonstriktion beruhen oder mit einer pathologischen Vasokonstriktion einhergehen. Beispiele sind: Sämtliche Formen des Bluthochdrucks (einschließlich pulmo- nale Hypertonie), Koronare Herzerkrankungen, Herzinsuffizienz, renale und myokardiale Ischämie, akute und chronische Nieren- Insuffizienz.The combination of 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. Examples are: All forms of high blood pressure (including pulmonary hypertension), coronary heart disease, heart failure, renal and myocardial ischemia, acute and chronic renal insufficiency.
Aufgrund der Potenzierung der Wirkung der Einzelkomponenten ist die Kombination beider Wirkstoffklassen eine ideale Ergänzung. Ein weiterer Vorteil ist, daß durch die Dosisreduktion uner- wünschte Nebenwirkungen seltener auftreten.Due to the potentiation of the effect of the individual components, the combination of both classes of active ingredients is an ideal addition. Another advantage is that undesirable side effects occur less frequently due to the dose reduction.
Die erfindungsgemässen Kombinationen werden im allgemeinen oral, z.B. in Form von Tabletten, Lacktabletten, Dragees, Hart- und Weichgelatinekapseln, Lösungen, Emulsionen oder Suspensionen ver- abreicht. Die Verabreichung kann aber auch rektal, z.B. in Form von Suppositorien, oder parenteral, z.B. in Form von Injektions- lösungen, erfolgen. Die Verabreichung der Wirkstoff kann in Form von Präparaten erfolgen, die beide Wirkstoffe zusammen, wie Tabletten oder Kapseln enthalten, oder getrennt als ad-hoc-Kombina- tion von Einzelsubstanzen, die gleichzeitig oder zeitlich abgestuft appliziert werden können.The combinations according to the invention are generally administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. The active ingredient can be administered in the form of preparations that contain both active ingredients together, such as tablets or capsules, or separately as an ad hoc combination of individual substances that can be applied simultaneously or at different times.
Zur Herstellung von Tabletten, Lacktabletten, Dragees und Hartgelatinekapseln kann eine erfindungsgemäße Kombination mit pharmazeutisch inerten, anorganischen oder organischen Excipientien verarbeitet werden. Als solche Excipientien kann man für Tablet- ten, Dragees und Hartgelatinekapseln Lactose, Maisstärke oder Derivate davon, Talk, Stearinsäure oder deren Salze verwenden. Für Weichgelatinekapseln eignen sich als Excipientien pflanzliche Öle, Wachse, Fette, halbfeste und flüssige Polyole.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 its salts can be used as such excipients for tablets, coated tablets and hard gelatin capsules. Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
Zur Herstellung von Losungen und Sirupen eignen sich als Excipientien z.B. Wasser, Polyole, Saccharose, Invertzucker, Glukose und dergleichen. Für Injektionslosungen eignen sich als Excipientien Wasser, Alkohole, Polyole, Glyzerin, vegetabile Öle. Für Suppositorien eignen sich als Excipientien natürliche oder gehär- tete Öle, Wachse, Fette, halbflüssige oder flüssige Polyole und dergleichen.Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like. Water, alcohols, polyols, glycerin and vegetable oils are suitable excipients for injection solutions. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
Die pharmazeutischen Zubereitungen können daneben noch Konservierungsmittel, Losevermittler, Stabilisierungsmittel. Netzmittel, Emulgiermittel, Süssmittel, Färbemittel, Aromatisierungsmittel. Salze zur Veränderung des osmotischen Druckes, Puffer, Überzugs - mittel und/oder Antioxidantien enthalten.The pharmaceutical preparations can also contain preservatives, lot mediators, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
Beispiele:Examples:
Beispiel 1: Synthese der Verbindungen la bis lkExample 1: Synthesis of compounds la to lk
a. 0.4 mMol Phenylalanin, das C-terminal mit dem 2C1-Tritylharz geschützt wurde (2a), wurden in 9 ml DMF /HOAc 99:1 mit 0.75 mMol N-Fmoc-phenylalaninal (3a) (R = CH2PH, R3 = Fmoc) versetzt und 0,5 h geschüttelt. Dann wurde solange portionsweise NaBH3CN zugesetzt, bis der Ninhydrintest keine freie, primäre Aminogruppe mehr anzeigte. Anschließend wurde abgesaugt, der Feststoff (4a) mit DMF, Isopropanol und Methylenchlorid gewaschen und im Vakuum getrocknet.a. 0.4 mmol phenylalanine, which was protected at the C-terminal with the 2C1-trityl resin (2a), was mixed in 9 ml DMF / HOAc 99: 1 with 0.75 mmol N-Fmoc-phenylalaninal (3a) (R = CH 2 PH, R 3 = Fmoc) and shaken for 0.5 h. Then NaBH 3 CN was added in portions until the ninhydrin test no longer indicated any free, primary amino group. The mixture was then filtered off, the solid (4a) washed with DMF, isopropanol and methylene chloride and dried in vacuo.
0.4 mMol (4a) wurden in ca 10 ml Pyridin / Methylenchlorid 1/1 mit einer katalytischen Menge DMAP (= 4-Dimethylaminopyridin) und 2 mMol 2-Thiophencarbonsäurechlorid versetzt und geschüttelt, bis der Ninhydrintest keine sekundäre Aminogruppe mehr anzeigte. Die Reaktion wurde abgesaugt, mit DMF und Methylenchlorid nachgewaschen und die polymere Schutzgruppe wie folgt entfernt:A catalytic amount of DMAP (= 4-dimethylaminopyridine) and 2 mmol of 2-thiophenecarboxylic acid chloride were added to 0.4 mmol (4a) in approx. 10 ml pyridine / methylene chloride 1/1 and shaken until the ninhydrin test no longer indicated a secondary amino group. The reaction was filtered off, washed with DMF and methylene chloride and the polymeric protective group removed as follows:
(4a) wurden in ca 10 ml eines Gemischs aus Essigsäure, Trifluor- ethanol und Methylenchlorid 1/1/8 für 1 h geschüttelt, die Lösung, die la enthielt, abfiltriert und eingeengt (Reaktionsschema II) .(4a) were shaken in about 10 ml of a mixture of acetic acid, trifluoroethanol and methylene chloride 1/1/8 for 1 h, the solution containing la was filtered off and concentrated (reaction scheme II).
Reaktionsschema II: Synthese der Verbindung da]Reaction Scheme II: Synthesis of the Compound da]
Die folgenden Verbindungen lb bis le und lg bis lk wurden in analoger Weise hergestellt. Die angegebenen Molmassen wurden über molekülspektroskopische Methoden ermittelt. The following compounds lb to le and lg to lk were prepared in an analogous manner. The molar masses stated were determined by means of molecular spectroscopic methods.
Beispiel 2: ECE-Inhibitor-Tests, IC50- BestimmungenExample 2: ECE inhibitor tests, IC 50 determinations
Für die Testung von Inhibitoren des Endothelin-Konversionsenzyms (ECE) wurde rekombinantes human-ECE aus CHO-Zellen, wie in Schmidt et al. (FEBS Letters 356, 1994: 238-243) beschrieben, eingesetzt.For testing inhibitors of the endothelin conversion enzyme (ECE), recombinant human ECE from CHO cells was used, as described in Schmidt et al. (FEBS Letters 356, 1994: 238-243).
Die eingesetzten Enzympräparationen wurden nach Membranisolierung, -solubilisierung durch Mono-Q-Chromatographie und WGA-Lec- tinchromatographie weiter gereinigt. Die so erhaltenen Präparationen enthielten keine störenden Fremdproteaseaktivitäten und wiesen spezifische Aktivitäten im Bereich von 1-20 mU/mg auf. 5 μl dieser Enzymlösung wurden mit 495 μl Testpuffer (100 mM Pi, 500 mM NaCl, 0,1 mg/ml BSA pH 7,2) und jeweils mit 5 μl entsprechend kon- zentrierten Lösungen (10"3 M, 10"4 M, 10"5 Musw.) der Inhibitoren im Testpuffer 10 Minuten vorinkubiert . 50 μl Aliquots wurden mit 5 μl 2.10'3 M Big-ETl Lösung (= "Big-Endothelinl) in 0,02 % Essigsäure vermischt. Die Ansätze wurden nach 1 Stunde bei 37°C durch Zugabe von 150 μl 0,5 % TFA (= Trifluoressigsäure) in Wasser ge- stoppt, 5 Minuten bei 10000 x g zentrifugiert und die Enzymreaktion durch Messung des gebildeten Endothelins mittels Rever- sed-Phase-HPLC, wie in Takada et al . (Biochem. Biophys. Res. Comm. 176. 860, 1991), K. Ohnaka et al. (Biochem. Biophys. Res. Commun. 168, 1128, 1990) beschrieben, bestimmt. Aus den Hemmwerten bei den verschiedenen Inhibitorkonzentrationen wurde eine Hemmkurve gebildet und die halbmaximale Hemmung (ICso-Wert) als Maß für die Wirkstärke des Inhibitors abgelesen. Tabelle I gibt die ICsQ-Werte der verschiedenen Substanzen gegenüber ECE, ACE und NEP 24.11 wieder.After membrane isolation and solubilization, the enzyme preparations used were further purified by mono-Q chromatography and WGA lectin chromatography. The preparations thus obtained contained no interfering foreign protease activities and had specific activities in the range of 1-20 mU / mg. 5 μl of this enzyme solution were mixed with 495 μl test buffer (100 mM Pi, 500 mM NaCl, 0.1 mg / ml BSA pH 7.2) and each with 5 μl correspondingly concentrated solutions (10 " 3 M, 10" 4 M , 10 " 5 Musw.) Of the inhibitors in the test buffer for 10 minutes. 50 ul aliquots were mixed with 5 ul 2.10 ' 3 M Big-ETl solution (=" Big-Endothelinl) in 0.02% acetic acid. After 1 hour at 37 ° C., the batches were stopped by adding 150 μl of 0.5% TFA (= trifluoroacetic acid) in water, centrifuged for 5 minutes at 10,000 × g and the enzyme reaction by measuring the endothelin formed by means of the reversed phase -HPLC as described in Takada et al. (Biochem. Biophys. Res. Comm. 176, 860, 1991), K. Ohnaka et al. (Biochem. Biophys. Res. Commun. 168, 1128, 1990). 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. Table I shows the ICsQ values of the various substances compared to ECE, ACE and NEP 24.11.
Tabelle I: ICso-Werte der verschiedenen InhibitorenTable I: IC 50 values of the various inhibitors

Claims

Patentansprüche:Claims:
1. Verbindungen der allgemeinen Formel I,1. Compounds of the general formula I,
ihre physiologisch wirksamen Salze oder deren Kombination, in der die Substituenten folgende Bedeutung haben:their physiologically active salts or their combination, in which the substituents have the following meanings:
R1 und R2 unabhängig voneinander substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Cι-C8-Alkyl-, Cι-C8-Alkylaryl- oder Cι-C8-Alkylhetaryl-, substituiertes oder unsubstituiertes Aryl- oder Hetaryl-R 1 and R 2 are independently substituted or unsubstituted, branched or unbranched C 1 -C 8 alkyl, C 1 -C 8 alkylaryl or C 1 -C 8 alkylhetaryl, substituted or unsubstituted aryl or hetaryl
R3 eine Gruppe der Formel a, b oder cR 3 is a group of formula a, b or c
R4 substituiertes oder unsubstituiertes C -Cι -Aryl-, C -Cι - Hetaryl-, mit einem oder mehreren Ringen enthaltend ein oder mehrere Heteroatome ausgewählt aus der Gruppe 0, S und N,R 4 substituted or unsubstituted C -C aryl, C -C hetaryl, with one or more rings containing one or more heteroatoms selected from the group 0, S and N,
R5 Cι-C8-Alkyl-, Cι-C8-Alkylaryl-, Aryl- oder Hetaryl-.R 5 -C 8 alkyl, -C 8 alkylaryl, aryl or hetaryl.
Verbindungen der allgemeinen Formel I, ihre physiologisch wirksamen Salze oder deren Kombination nach Anspruch 1, dadurch gekennzeichnet, daß die Substituenten R1 und R2 unabhängig voneinander substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Cι~C -Alkyl-, Cχ-C -Alkylaryl- oder Cι-C-Alkylhetaryl-, substituiertes oder unsubstituiertes Aryl- oder Hetaryl- bedeuten. Compounds of the general formula I, their physiologically active salts or their combination according to Claim 1, characterized in that the substituents R 1 and R 2 are independently substituted or unsubstituted, branched or unbranched C 1 -C 8 -alkyl-, Cχ-C -alkylaryl- or -CC alkylhetaryl, substituted or unsubstituted aryl or hetaryl mean.
3. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel II3. A process for the preparation of compounds of general formula I according to claim 1, characterized in that compounds of general formula II
mit Verbindungen der allgemeinen Formel IIIwith compounds of the general formula III
kondensiert und mit einem Reduktionsmittel zu Verbindungen der allgemeinen Formel IVcondensed and with a reducing agent to give compounds of general formula IV
reduziert und mit einem Acylierungsmittel RC0C1 (V) und Abspaltung der Schutzgruppe SGI zu Verbindungen der Formel I gemäß Anspruch 1 umsetzt, wobei die Substituenten R1, R2, R3 und R4, die unter Anspruch 1 genannte Bedeutung haben und SGi eine Schutzgruppe bedeutet.reduced and with an acylating agent RC0C1 (V) and splitting off the protective group SGI to give compounds of the formula I according to claim 1, where the substituents R 1 , R 2 , R 3 and R 4 have the meaning given in claim 1 and SGi is a protective group means.
4. Verwendung von Verbindungen der allgemeinen Formel I, ihrer physiologisch wirksamen Salze oder deren Kombination gemäß4. Use of compounds of general formula I, their physiologically active salts or a combination thereof
Anspruch 1 zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten.Claim 1 for the production of pharmaceutical preparations for the treatment of diseases.
5. Verwendung von Verbindungen der allgemeinen Formel I, ihrer physiologisch wirksamen Salze oder deren Kombination gemäß5. Use of compounds of general formula I, their physiologically active salts or a combination thereof
Anspruch 1 zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten, die mit einer Vasokonstriktion oder anderen biologischen Wirkungen von Endothelin assoziiert sind. Claim 1 for the manufacture of pharmaceutical preparations for the treatment of diseases associated with vasoconstriction or other biological effects of endothelin.
6. Verwendung von Verbindungen der allgemeinen Formel I, ihrer physiologisch wirksamen Salze oder deren Kombination gemäß Anspruch 1 zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten ausgewählt aus der Gruppe Hy- 5 pertonie, pulmonalem Hochdruck, Myokardinfarkt, chronischer6. Use of compounds of general formula I, their physiologically active salts or their combination according to claim 1 for the manufacture of pharmaceutical preparations for the treatment of diseases selected from the group hypertension, pulmonary high pressure, myocardial infarction, chronic
Herzinsuffizienz, Angina Pectoris, akutem/chronischem Nierenversagen, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endotoxischem Schock, Endotoxin- induziertemHeart failure, angina pectoris, acute / chronic kidney failure, kidney failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced
10 Organversagen, intravaskulärer Koagulation, Restenose nach10 organ failure, intravascular coagulation, restenosis after
Angioplastie, benigne Prostata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Cyclosporininduziertes Nierenversagen, Metastasierung und Wachstum mesenchymaler Tumoren, Krebs, Prostatakrebs,Angioplasty, benign prostatic hyperplasia, ischemic and intoxication-related kidney failure or hypertension, cyclosporin-induced kidney failure, metastasis and growth of mesenchymal tumors, cancer, prostate cancer,
15 Kontrastmittel-induziertes Nierenversagen, Pankreatitis und gastrointestinale Ulcera.15 Contrast-induced kidney failure, pancreatitis and gastrointestinal ulcers.
7. Verwendung von Verbindungen der allgemeinen Formel I gemäß Anspruch 1 zur Hemmung des Endothelin-Konversionsenzym.7. Use of compounds of general formula I according to claim 1 for inhibiting the endothelin conversion enzyme.
2020th
8. Verwendung von Verbindungen nach Anspruch 7 zur selektiven Hemmung des Endothelin-Konversionsenzym, wobei andere Proteasen ausgewählt aus der Gruppe ACE, NEP, MMP-1, MMP-3, MMP-9, Thermolysin, Papain und Thrombin nicht gehemmt werden.8. Use of compounds according to claim 7 for the selective inhibition of the endothelin conversion enzyme, wherein other proteases selected from the group ACE, NEP, MMP-1, MMP-3, MMP-9, thermolysin, papain and thrombin are not inhibited.
2525
9. Verwendung von Verbindungen der allgemeinen Formel I gemäß Anspruch 1 in Kombination mit weiteren blutdrucksenkenden Wirkstoffen zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten.9. Use of compounds of general formula I according to claim 1 in combination with other antihypertensive active substances for the production of pharmaceutical preparations for the treatment of diseases.
3030
10. Pharmazeutische Zubereitungen enthaltend Verbindungen der allgemeinen Formel I, ihre physiologisch wirksamen Salze oder deren Kombination gemäß Anspruch 1.10. Pharmaceutical preparations containing compounds of general formula I, their physiologically active salts or their combination according to claim 1.
35 11. Kombination aus einer pharmazeutischen Zubereitung nach Anspruch 10 und mindestens einem weiteren blutdrucksenkenden Wirkstoffe.35 11. Combination of a pharmaceutical preparation according to claim 10 and at least one other antihypertensive active substances.
12. Kombination nach Anspruch 11 enthaltend als blutdrucksenken- 0 den Wirkstoff ACE-Inhibitoren.12. Combination according to claim 11 containing as the blood pressure lowering the active ingredient ACE inhibitors.
5 Neue pharmazeutisch wirksame Verbindungen, ihre Herstellung und Verwendung5 New pharmaceutically active compounds, their production and use
ZusammenfassungSummary
Die Erfindung betrifft neue pharmazeutisch wirksame Verbindungen, ihre Herstellung und Verwendung zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von Krankheiten. The invention relates to new pharmaceutically active compounds, their production and use for the production of pharmaceutical preparations for the treatment of diseases.
EP98952597A 1997-10-14 1998-09-18 Novel pharmaceutically active compounds, their preparation and use as ece-inhibitors Withdrawn EP1023282A1 (en)

Applications Claiming Priority (3)

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DE19745146A DE19745146A1 (en) 1997-10-14 1997-10-14 New N-acyl N-acyl-aminoethyl alpha-amino acid derivatives
DE19745146 1997-10-14
PCT/EP1998/005945 WO1999019320A1 (en) 1997-10-14 1998-09-18 Novel pharmaceutically active compounds, their preparation and use as ece-inhibitors

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US20030176356A1 (en) * 2001-04-24 2003-09-18 University Of North Texas Health Science Center Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma
US6887877B2 (en) 2001-06-11 2005-05-03 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
US20060183753A1 (en) * 2002-12-20 2006-08-17 Bayer Healthcare Ag Use of substituted 2,5-diamidoindoles for the treatment of urological diseases

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GB9300048D0 (en) * 1993-01-04 1993-03-03 Wellcome Found Endothelin converting enzyme inhibitors
WO1994022906A1 (en) * 1993-03-26 1994-10-13 Warner-Lambert Company Inhibitors of endothelin converting enzyme
GB9313330D0 (en) * 1993-06-28 1993-08-11 Fujisawa Pharmaceutical Co New compound and its preparation
AU691201B2 (en) * 1993-11-01 1998-05-14 Japat Ltd. Endothelin receptor antagonists
US5610177A (en) * 1994-08-08 1997-03-11 Warner-Lambert Company Acylated amino acids as endothelin antagonists

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CA2305499A1 (en) 1999-04-22
IL135168A0 (en) 2001-05-20
ZA989312B (en) 2000-04-13
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