EP2010507A2 - Nouveaux derives d'isooxazol et leurs utilisations - Google Patents

Nouveaux derives d'isooxazol et leurs utilisations

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Publication number
EP2010507A2
EP2010507A2 EP07722158A EP07722158A EP2010507A2 EP 2010507 A2 EP2010507 A2 EP 2010507A2 EP 07722158 A EP07722158 A EP 07722158A EP 07722158 A EP07722158 A EP 07722158A EP 2010507 A2 EP2010507 A2 EP 2010507A2
Authority
EP
European Patent Office
Prior art keywords
group
trifluoromethyl
phenoxy
cyano
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07722158A
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German (de)
English (en)
Inventor
Hans Scheefers
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ScheBo Biotech AG
Original Assignee
ScheBo Biotech AG
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Filing date
Publication date
Application filed by ScheBo Biotech AG filed Critical ScheBo Biotech AG
Publication of EP2010507A2 publication Critical patent/EP2010507A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • 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
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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

Definitions

  • the invention relates to novel isooxazole derivatives, to pharmaceutical compositions comprising such compounds, to uses of such compounds, and to processes for preparing such compounds.
  • the invention teaches a compound according to formula I.
  • N- [[3-chloro-5- (trifluoromethyl) -2-pyridinyl] oxy] -3,5-dimethyl-4-isoxazolecarboxamide is excluded from the invention.
  • R2 is substituted with the radical R3 in the 5-position and / or 3-position.
  • R3 may (except -H) a (C ⁇ -Cio) alkyl group or an optionally partially or fully halogenated, especially fluorinated, (C 1 -CiO) alkyl group, in particular -CH 3 , CF 3 , isopropyl, isobutyl, (C 3 -C 7) cycloalkyl, in particular cyclopropyl, for example, 1- to 4-fold substituted by methyl, cyclohexyl, (C2-C10) alkenyl, (C 2 -C 0) alkynyl group, (Ci-C 8) - Alkyl (C 3 -
  • R3 is preferably a (C 1 -C 4) alkyl group, an optionally partially or fully halogenated, especially fluorinated, (Ci-C 4) alkyl, (C 3 -C 5) - cycloalkyl, (C 2 -C ⁇ ) Alkenyl group, or (C 2 -C 8) alkynyl group.
  • a metabolite of a compound according to formula I is characterized in that 4-isooxazolyl or 5-substituted-4-isooxazolyl is converted in a cell or in an organism to a radical according to formula II.
  • the metabolite then has the structure
  • R 1 can also be arbitrary with such a metabolite as long as R 1 is physiologically tolerated.
  • R3 and R1 in formulas II and IIa have the same Meanings as explained for the formula I.
  • R 1 can be an aromatic ring (for example phenyl or benzyl) attached directly or indirectly via (C 1 -C 5) -alkyl, optionally substituted, for example with (C 1 -C 3) -alkyl, optionally one or more of the C atoms of the ring one or more different heteroatoms from the group consisting of S, O and N may be replaced, wherein the aromatic ring may be mono- or polysubstituted, identical or different, with R4.
  • aromatic ring for example phenyl or benzyl
  • R 1 can be an aromatic ring (for example phenyl or benzyl) attached directly or indirectly via (C 1 -C 5) -alkyl, optionally substituted, for example with (C 1 -C 3) -alkyl, optionally one or more of the C atoms of the ring one or more different heteroatoms from the group consisting of S, O and N may be replaced, wherein the aromatic ring may be mono- or polysub
  • R4 can be -H, -F, -Cl, -Br, -I, -CN, COOH, -OH, -NO2, NR41R42, with R41 and R42, same or different, (C1-C10) alkyl, optionally with -F , -Cl, -Br, or -I monosubstituted or polysubstituted, -O-O-R41, a (Ci-Ci 0 ) alkyl group, an optionally partially or fully halogenated, in particular fluorinated, (Ci-Ci 0 ) alkyl group , (Ci-Cio) alkoxy, (C 3 -C 7) cycloalkyl, (C 2 -C 10) alkenyl, (C 2 -C 0) alkynyl group, (Ci-C 8) - alkyl ( C 3 -C 7) cycloalkyl, (C 2 -C
  • Rl may also be for example a (Ci-Ci 0) alkyl group, an optionally partially or fully halogenated, especially fluorinated, or -COOH or -CN substituted (Ci-Ci 0) alkyl, (C 1 -C 1 0) - alkoxy, (C 3 -C 7) cycloalkyl, (C 2 -C 0) alkenyl, (C 2 -C 0) alkynyl, (Ci-C 8) -
  • Rl is phenyl, mono- or poly-halogenated phenyl, substituted by -CN or -COOH, phenyl, or (Ci-Ci 0) alkoxy substituted phenyl.
  • the C 1 -C 10 or C 1 -C 5 -alkyl groups for the radicals described, in particular R 3, may be straight-chain or branched and may be, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or n-pentyl, 2, 2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl and their random branched derivatives.
  • a methyl or ethyl group is preferred.
  • the alkyl groups mentioned may optionally be substituted by 1-5 halogen atoms.
  • the following partially or completely fluorinated groups are, for example: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1, 2-difluoroethyl, 1 , 1, 1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl.
  • trifluoromethyl or the pentafluoroethyl group wherein the fully fluorinated group is also called perfluoroalkyl.
  • Ci-Cio or Ci-Cs-Alkoxy phenomenon can straight-chained or branched and for example for a Methoxy, Ethoxy, n-propoxy, iso-Propoxy, n-Butoxy, iso-Butoxy, tert. Butoxy- or n-pentoxy-, 2, 2-dimethylpropoxy-, 2- Methylbutoxy or 3-methylbutoxy group.
  • C 1 -C 5 alkoxy groups are preferred.
  • a methoxy or ethoxy group is particularly preferred.
  • the cycloalkyl group means an optionally substituted by one or more halogen atoms, (Ci-C 5 ) alkyl groups, (Ci-C 5 ) - alkoxy, NR 10 R 1: L groups, COOR 12 groups, CHO, cyano, substituted saturated cyclic Group having 3 to 7 ring carbon atoms, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,
  • a (C 1 -C 8 ) -alkyl (C 3 -C 7 ) -cycloalkyl group is to be understood as meaning a cycloalkyl group which is linked to the ring system via a straight-chain or branched (C 1 -C 5) -alkyl moiety.
  • a (C 2 -C 8 ) alkenyl (C 3 -C 7 ) cycloalkyl group is to be understood as meaning a cycloalkyl group which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkenyl unit.
  • the heterocyclyl group is not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Perhydroquinoline and perhydroisoquinoline are also included in the heterocyclyl groups.
  • Aryl groups in the context of the invention are aromatic or partially aromatic carbocyclic groups having 6 to 14 carbon atoms which contain one ring, such as, for example, phenyl or phenylene or several condensed rings, such as, for example, naphthyl or anthranyl. Examples include phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl.
  • the aryl groups may be substituted at any convenient position resulting in a stable stereoisomer by one or more of hydroxy or halogen.
  • the optionally substituted phenyl group and the naphthyl group are preferred.
  • a (Ci-Cs) alkylaryl group is an aryl group, as described above, which is linked via a straight-chain or branched (Ci-C 8 ) -Alkyliata with the ring system.
  • a (C 2 -Ce) alkenylaryl group is an aryl group as • already described above, via a linear or branched (C 2 -Cs) alkenyl moiety is linked to the ring system.
  • a (C 2 -Cs) alkynylaryl group is an aryl group as already described above which is linked to the ring system via a straight-chain or branched (C 2 -Cs) -alkynyl unit.
  • Monocyclic heteroaryl groups can be, for example, pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, IH- and 4H-pyrazole, IH- and 2H-pyrrole, oxazole, Thiazole, furazane, IH and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.
  • cyclic heteroaryl groups may include phthalidyl, thiophthalidyl, indolyl, isoindolyl, Dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl, quinolinyl, isoquinolinyl, Quinolonyl, isoquinolone, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7- or 1,8-naph
  • a (C 1 -C 5) -alkyl heteroaryl group is a heteroaryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 1 -C 8 ) -alkyl unit.
  • a (C 2 -Cs) alkenyl heteroaryl group is one
  • Heteroaryl group as described above, which is linked via a straight-chain or branched (C 2 -C 8 ) alkenyl unit with the ring system.
  • a (C 2 -C 8 ) alkynyl heteroaryl group is one
  • Heteroaryl group as described above, which is linked via a straight-chain or branched (C 2 -C 8 ) - alkynyl moiety with the ring system.
  • a (C 1 -C 8 ) alkylheterocyclyl group is a heterocyclyl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 1 -C 8 ) -alkyl moiety.
  • a (C 2 -C 8 ) alkenyl heterocyclyl group is one
  • Heterocyclyl group as already described above, which is linked via a straight-chain or branched (C 2 -C 8 ) -Alkenyliata with the ring system.
  • R 10 to R 12 may independently of one another and the same or different be all groups according to the radicals R 3 or R 1,
  • compounds of the invention may be combined with other drugs known per se.
  • drugs known per se.
  • the compound according to the invention can be mixed with the active substance in the context of a single galenic preparation.
  • the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound according to the invention and in a second preparation of the active ingredient are included. In the context of the first preparation, it is also possible to set up a substance which is different from the active ingredient of the second preparation.
  • Compounds of the invention can be prepared, for example, by optionally first a compound of formula III
  • R 1 is as defined in any one of the preceding claims and wherein the compound of formula III and its sulfinyl halide may be substituted in position 3.
  • an aminooxy compound of the formula IV is not available, it can be prepared by reacting a compound of the formula V
  • R 20 and R 21 can, in principle, be -H radicals according to R 1 or R 3, where R 20 is preferably -H and / or R 21 is preferably -H or Cl-8 alkoxy, in particular ethyloxy,
  • the invention further teaches a pharmaceutical composition containing a compound of the invention.
  • a pharmaceutical composition containing a compound of the invention.
  • Compounds are, for example, Ca ++ , CaCl + , Na + , K + , Li + or cyclohexylammonium, or Cl " , Br " , acetate, trifluoroacetate, propionate, lactate, oxalate, malonate, maleinate, citrate, benzoate, salicylate etc. in question.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulisation
  • Sweeteners and solubilizers find use.
  • adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile Water and mono- or polyhydric alcohols, such as glycerol, called.
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, Sodium bicarbonate, or sodium carbonate.
  • N, N'-dibenzylethylenediamine diethanolamine
  • ethylenediamine N-methylglucamine
  • N-benzylphenethylamine diethylamine
  • phosphate Sodium bicarbonate
  • sodium carbonate sodium bicarbonate
  • Physiologically acceptable salts are salts with inorganic or organic acids, such as hydrochloric acid,
  • inorganic or organic bases such as NaOH, KOH, Mg (OH) 2 , diethanolamine, ethylenediamine, or with amino acids, such as arginine, lysine, glutamic acid, etc.
  • inorganic salts such as CaCl 2 , NaCl or their free ions, such as Ca 2+ , Na + , Cl " , S ⁇ 4 2 - or combinations thereof, are prepared by
  • the invention is based on the finding that, in addition to the classic metabolic diseases, such as diabetes mellitus, obesity, other diseases, such as cancer, autoimmune diseases and rheumatism are ultimately at least caused by metabolic imbalances.
  • Compounds according to the invention presumably inhibit dihydroorotate dehydrogenase, which is particularly effective in
  • Mitochondria finds and serves Pyrimidinnukleotidsynthese. Ultimately, inter alia, the proliferation of activated lymphocytes is inhibited.
  • a measurable biochemical parameter for these metabolic lapses is, for example, the increase in pyruvate kinase type M2 (M2-PK), which increases in the blood of patients of all the above and the following diseases.
  • M2-PK pyruvate kinase type M2
  • the M2-PK detectable in the blood of the patient comes from different cells: cancer from tumor cells, sepsis from immune cells, rheumatism from immune and / or sinovial cells.
  • the tetrameric form of M2-PK is highly ordered cytosolic complex, the glycolysis enzyme complex.
  • PGM phosphoglyceromutase
  • the invention intervenes here and inhibits disease-related metabolic lapses by competitive binding to suitable target molecules, in particular of the glycolysis enzyme complex, such as pyruvate kinase, asparaginase, serine dehydratases, transaminases, deaminases, and / or glutaminases.
  • suitable target molecules in particular of the glycolysis enzyme complex, such as pyruvate kinase, asparaginase, serine dehydratases, transaminases, deaminases, and / or glutaminases.
  • the transamination, the oxidative deamination, the hydrolytic deamination, the eliminating deamination and the reductive are blocked
  • Substances according to the invention can furthermore be used for the treatment of heart failure or Chronic Cardiac Failure (CCF).
  • CCF Chronic Cardiac Failure
  • These include the NYHA I to NYHA IV variants or grades defined in the New York Heart Association (NYHA) Classification. All of these diseases are acute and / or chronic inability of the heart muscle, during exercise or at rest to apply the necessary for the metabolism of the organism blood ejection or the required delivery rate.
  • causes are u.a. in complex coronary inflammatory processes (activation of cells of the immune system as well as complement).
  • the administration of anti-inflammatory substances according to the invention avoids the imminent life-threatening acidosis (by lactate formation) become.
  • the substances according to the invention intervene directly in the energy metabolism and improve it. Side effects are therefore comparatively low.
  • the invention therefore further provides the use of a compound of the invention for the preparation of a pharmaceutical composition for treating one or more diseases selected from the group consisting of "cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, Prostate cancer, skin cancer, chronic inflammation, asthma, allergy, rhinitis,
  • cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, Prostate cancer, skin cancer, chronic inflammation, asthma, allergy, rhinitis,
  • Uveitis urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowl disease, degenerative joint diseases, diseases of the rheumatic type with cartilage degradation, sepsis, autoimmune diseases, type I diabetes, hashimosis
  • Thyroiditis autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, chronic inflammatory bowel disease, Crohn's disease, uveitis, psoriasis, atypical dermatitis, collagenosis, goodpasture syndrome, disorders with impaired leukocyte adhesion, cachexia, diseases due to increased TNFalpha concentration, diabetes, obesity, bacterial Infections, especially with resistant bacteria, heart failure and Chronic Cardiac Failure (CCF).
  • treatment also includes prophylaxis.
  • a pharmaceutical composition according to the invention may comprise a plurality of different compounds covered by formula I above. Furthermore, a pharmaceutical composition according to the invention may additionally comprise one of the compound of the
  • Formula I contain different active ingredient. Then it is a combination preparation.
  • the various active ingredients used can be prepared in a single dosage form, ie. the active ingredients are mixed in the dosage form.
  • the invention also relates to a process for the preparation of a pharmaceutical composition, wherein at least one compound according to the invention is mixed with a pharmaceutically suitable and physiologically acceptable carrier and optionally other suitable active ingredients, additives or excipients and brought into a suitable dosage form.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • this dose may be 0.1 to 1000 mg, preferably 1 to 300 mg, and in the case of injection solutions in ampoule form 0.01 to 1000 mg, preferably 1 to 100 mg.
  • daily doses of 0.1 to 1000 mg of active ingredient, preferably 1 to 500 mg are indicated for the treatment of an adult patient weighing 50 to 100 kg, for example 70 kg.
  • higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
  • AOA aminooxyacetate
  • NH 2 -O-CH 2 -COOH or its salts or esters, for example Cl-ClO alkyl or hydroxyalkyl esters.
  • AOA is particularly effective for small tumors ( ⁇ 0.1 to 1 cm 3 ) or prevents their formation, in particular the formation of metastases, while compounds of the invention is particularly effective against the large tumors. This is due to the different metabolic processes in small and large tumors.
  • the above statements on combinations apply analogously.
  • Ethyl acetohydroxamate (9.2 g, 89.22 mmol) is dissolved in 100 ml absolute DMF dissolved and added at 0 0 C KO 11 Bu (11.05 g, 98.5 mmol). After 30 min. Stirring at 20 0 C is added 2,5-Dibromophenylflourid (1.25 g, 98.5 mmol) and then stirred at 8O 0 C for a further 1.5 h. While cooling with ice, 600 ml of water are added, the mixture is extracted twice with 400 ml of ethyl acetate each time, washed with 400 ml of saturated NaCl solution, dried on sodium sulfate and concentrated in vacuo. Overnight, a crystalline mass is obtained, which is filtered off with suction and washed with a small amount of EA. Yield: 8.92 g, 27%.
  • the product from 1.1 (8.92 g, 26.5 mmol) is dissolved in dioxane (32 ml) and cooled to 0 ° C. with an ice-bath. Using a syringe, add 60% perchloric acid (22.3 ml) slowly. The ice bath is removed and after stirring for 1 h at 20 0 C, the reaction mixture is added to 500 ml of ice water and neutralized with a 40% sodium hydroxide solution. The aqueous phase is extracted twice with 600 ml of ethyl acetate, washed with 400 ml of saturated NaCl solution, dried over sodium sulfate and concentrated in vacuo. Yield: 7 g, quantitative.
  • step 1.2 The intermediate from step 1.2 (4.98 g, 18.66 mmol) is dissolved under argon atmosphere in 100 mL of anhydrous pyridine.
  • the product from stage 1.3 (2.7 g, 18.65 mmol), dissolved in 10 ml of absolute dichloromethane, is then added dropwise slowly. After 16 h stirring, the reaction mixture is concentrated at 70 0 C in vacuo and coevaporated once with toluene.
  • the residue obtained is drawn onto silica gel and, after purification over bottle silica gel (Tol / EE 3: 1), the end product is obtained, which can be recrystallised from isopropanol.
  • Chloroacetic acid sodium salt (175.3 g, 1.51 mol) is dissolved in 300 ml of water and acetoxime (100 g, 1.37 mol) dissolved in 310 ml of water was added. Furthermore, 137 g of a 40% aqueous NaOH are added and the reaction mixture is heated to boiling for one hour. After cooling to 20 0 C, the reaction solution is extracted four times with 200 ml of ether and discarded the organic phase. The aqueous phase is brought to pH 3-4 with HCl, saturated with NaCl and extracted 6 times with 300 ml of ether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The intermediate product is obtained as a yellowish solid. Yield: 65 g.
  • step 5.1 The product from step 5.1 (26 g, 198.3 mmol) is placed in a wide-mouth Erlenmeyer flask and mixed with 260 ml of water. To the resulting solution is added dropwise 16 ml of conc. HCl and heated with stirring to 90 0 C. After 3.5 h stirring at 90 0 C, the concentrated solution (50 ml) is cooled and with 390 ml of isopropanol / ether (1: 3). After 2 days in the refrigerator, the resulting precipitate is filtered off, washed and dried under high vacuum. This gives colorless crystals. Yield: 6 g.
  • 5-Methylisoxazole-4-carboxylic acid (2.37 g, 18.65 mmol) is placed under argon atom and treated with thionyl chloride (23.83 ml, 326.5 mmol). The mixture is then stirred for 1 h at 90 0 C, cooled and the thionyl chloride removed in vacuo. The product is used without further purification.
  • Step 5.2 The intermediate from Step 5.2 (8.3 g, 76 mmol) is dissolved in 50 mL of water and neutralized with 38.3 mL of 2N NaOH (76.6 mmol). Then, after cooling to 0 ° C., the product from stage 5.3 (11.45 g, 76 mmol), dissolved in 42 ml of absolute diethyl ether, is slowly added dropwise. Within 50 min. 37.5 ml of a 2 N NaOH solution are added dropwise and the reaction solution is brought to pH 3 with a 5 N HCl. Then it is stripped off via ether and the aqueous phase extracted four times with 50 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. A white solid is obtained. Yield: 5.2 g, 34%.
  • Example 6.1 The structure of Example 6.1 was tested in a colony assay.
  • tumor stem cells from various human tumor entities were cultured in soft agar and the formation of tumor colonies in and in the absence of the test substance was counted.
  • a total of 25 different tumor models were tested. These included colon, pancreatic and gastric carcinomas, small cell and non-small cell lung tumors, breast, ovarian and renal carcinomas as well as melanomas.
  • the use of these different types of tumors allows an assessment of whether the tested substance is only selective for certain tumor entities, or for a multitude or even a plurality of tumor entities.
  • FIG. 1 shows the effect of the structure of example 6.1. In all 25 models, this substance resulted in a dose-dependent inhibition of
  • the IC50 value (substance concentration at which a 50% reduction in colony count was observed compared to the control) was 160 ⁇ M; the IC70 value (70% reduction) was 220 ⁇ M.
  • the bars represent the IC70 concentrations in relation to the mean of all IC70 values Bar to the left, the IC70 value is lower than the mean of all IC70 values, ie these models are more sensitive compared to the average of all models. A bar to the right indicates higher IC70 values than the average of the models and indicates a lower sensitivity than the average.
  • the abbreviations stand for the following tumor models.
  • CXF Colon carcinoma
  • GXF Gastric carcinoma
  • LXFA Lung non-small cell adenocarcinoma
  • LXFE Lung squamous cell carcinoma
  • FXFL Large cell
  • LXFS small cell lung carcinoma
  • MAXF breast tumor
  • MEXF melanoma
  • OVXF ovarian carcinoma
  • PAXF pancreatic carcinoma
  • RXF renal carcinoma
  • tumor cell lines were used (a human colon carcinoma cell line, two human breast cancer cell lines, a human pancreatic tumor cell line, a multidrug resistant descendent of a human cervical carcinoma cell line, as well as a rat hepatoma cell line) and tested under different nutrient conditions (with and without pyruvate in the nutrient medium).
  • the mean IC50 in these cell culture assays was 150 ⁇ M and included a range of 30 to 280 ⁇ M.
  • IC50 was at 60 ⁇ M and IC70 at 100 ⁇ M.
  • the highest IC50 and IC70 values were 240 ⁇ M and 400 ⁇ M, respectively, and were determined for a renal tumor model.
  • Examples 6.2, 6.3 and 6.4 were obtained in cell culture experiments analogous to the above studies as mean IC50 values: 80 uM, 340 uM and 180 uM.

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Abstract

L'invention concerne de nouveaux dérivés d'isooxazol, pouvant être utilisés pour la fabrication de compositions pharmaceutiques.
EP07722158A 2006-03-24 2007-03-26 Nouveaux derives d'isooxazol et leurs utilisations Withdrawn EP2010507A2 (fr)

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DE102006014165A DE102006014165A1 (de) 2006-03-24 2006-03-24 Neue Isooxazol-Derivate und deren Verwendungen
PCT/DE2007/000600 WO2007110068A2 (fr) 2006-03-24 2007-03-26 Nouveaux derives d'isooxazol et leurs utilisations

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ES2102367T3 (es) * 1990-05-18 1997-08-01 Hoechst Ag Amidas de acidos isoxazol-4-carboxilicos y amidas de acidos hidroxialquiliden-cianoaceticos, medicamentos que contienen estos compuestos y su utilizacion.
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