EP2032537A1 - Nouveaux dérivés d'urée et leurs utilisations - Google Patents

Nouveaux dérivés d'urée et leurs utilisations

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Publication number
EP2032537A1
EP2032537A1 EP07764419A EP07764419A EP2032537A1 EP 2032537 A1 EP2032537 A1 EP 2032537A1 EP 07764419 A EP07764419 A EP 07764419A EP 07764419 A EP07764419 A EP 07764419A EP 2032537 A1 EP2032537 A1 EP 2032537A1
Authority
EP
European Patent Office
Prior art keywords
cancer
group
chloro
amino
phenyl
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Withdrawn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
EP07764419A
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German (de)
English (en)
Inventor
Hans Scheefers
Ursula Scheefers-Borchel
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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Publication date
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Publication of EP2032537A1 publication Critical patent/EP2032537A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • 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
    • A61P17/06—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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the invention relates to novel urea derivatives, pharmaceutical compositions comprising such compounds, uses of such compounds as an active substance or as a prodrug, and to processes for preparing such compounds (active substances and produgs).
  • the invention teaches a compound according to formula I:
  • X and Y may be the same or different and are either a bond or -O- or -S-, where at least one of the groups X or Y is -O- or -S-,
  • R 1 is selected from the group consisting of "2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2 - or 3-pyrazinyl, 2- or 4-pyrimidinyl, 3- or 4-pyridazinyl, 3-, 4- or 5-isoxazolyl, 3-furazanyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 4-, 5-, 6- or 7-indolyl, mono- or polysubstituted or unsubstituted, 4-, 5-, 6- or 7-isoindolyl, 1, 8-naphthyridin-2 ⁇ or -3- or 4-yl, and phenyl ", monosubstituted or polysubstituted or unsubstituted,
  • R 2 is 4-, 5-, 6- or 7-indolyl, mono- or polysubstituted or unsubstituted, 4-, 5-, 6- or 7-isoindolyl, monosubstituted or polysubstituted or unsubstituted, 4-, 5-, 6 or 7-benzoxazolyl, monosubstituted or polysubstituted or unsubstituted, or a radical according to formula II,
  • V and W independently of one another represent a bond or -NH-
  • left-hand ring in formula II may be monosubstituted, disubstituted, trisubstituted or trisubstituted, identically or differently, with halogen atoms, in particular fluorine, chlorine or bromine,
  • the metabolites include in particular glucuronates of the above compound and N-pyridine oxide.
  • R 1 can be mono-, di- or tri-halogenated with -F, -Cl, -Br, - I, (C 1 -C 8 ) -alkyl, optionally mono- or polysubstituted with -F, -Cl, -br, or -I, or (Ci-C 8 ) -oxyalkyl, wherein the substituents may be the same or different.
  • R 1 is preferably phenyl, quinolyl, or 1, 8-naphthyridin-4-yl, in particular with -F, -Cl-, Br-, -I, and / or (C 1 -C 8 ) -alkyl, optionally mono- or polysubstituted with -F, -Cl, -Br, or - I, halogenated, substituted.
  • R 1 is more preferably 4-bromo-, 4-chloro-, or 4-fluoro-3- (C 1 -C 3 ) -alkylphenyl, where (C 1 -C 3 ) -alkyl is monosubstituted, disubstituted or trisubstituted Particularly preferred is halogenated methyl or ethyl, -F, -Cl, or -Br.
  • R 2 can be mono-, di- or trihydric with -F, -Cl, -Br, -X 1 (C 1 -C 8 ) -alkyl, optionally mono- or polysubstituted with -F, -Cl, -Br, or -I, halogenated, or substituted (C 1 -C 8 ) -oxyalkyl, wherein the substituents may be the same or different. It may in particular be an N-substituent, for example N-methyl. In the case of benzoxazolyl, it may be a 2-substituent.
  • R 3 can be -H, -F, -Cl, -Br, -I, a (C 1 -C 10 ) -alkyl group or (C 1 -C 6 ) -oxyalkyl, a (C 1 -C 10 ) -alkyl group or an optionally partially or completely halogenated, in particular fluorinated, (C 1 -C 10 ) -alkyl group, (C 3 -C 7 ) -cycloalkyl group, (C 2 -C 10 ) -alkenyl group,
  • alkylaryl (C 2 -C 8) -Alkenylarylrios, or (C 2 -C 8) - Alkynylaryl group, or an optionally substituted by 1-2 keto groups, 1-2 (C 1 -C 5 ) -alkyl groups, 1-2 (C 1 -C 5 ) -alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, 3 mono- or bicyclic heteroaryl group containing nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms, a (C 1 -C 8 ) -alkylheteroaryl group, or a (C 2 -C 8 ) -alkenyl heteroaryl group, a (C 2 -C 8 ) alkynyl heteroaryl group, these groups being attached via any position with formula II may be linked and may optionally be hydrogenated at one or more sites.
  • R 3 may be - (CO) -NH-alkyl, or - (CO) -O-NH-alkyl or - (CO) -NH-oxyalkyl.
  • the alkyl groups for the radicals described can be straight-chain or branched and are, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl radical, 2, 2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, as well as 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.
  • alkoxy groups may be straight-chain or branched and, for example, for a methoxy,
  • the cycloalkyl group means an optionally substituted by one or more halogen atoms, (Ci-C 5 ) alkyl groups, (Ci-C 5 ) - alkoxy groups, NR 10 R 11 groups, COOR 12 groups, CHO, cyano, substituted saturated cyclic group 3 to 7 ring carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.
  • 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 8 ) -alkyl moiety.
  • a (C 2 -C 8 ) alkenyl (C 3 -C 7 ) cycloalkyl group is meant a cycloalkyl group which has a straight-chain. or branched (C 2 -C 8 ) alkenyl moiety is linked to the ring system.
  • 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 have a ring, such as phenyl or phenylene or more condensed rings such as 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.
  • a (C! -C 8) alkylaryl group is an aryl group as already described above, which is attached via a linear or branched (Ci-C 8) alkyl moiety with the ring system.
  • a (C 2 -C 8 ) alkenylaryl group is an aryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkenyl unit.
  • a (C 2 -C 8 ) 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 -C 8 ) -alkynyl unit.
  • Examples of monocyclic heteroaryl groups include pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran,
  • bicyclic heteroaryl groups include phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindlylyl, 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-nap
  • a (C 1 -C 8) alkylheteroaryl group is a heteroaryl group as already described above which is attached via a linear or branched (Ci-C 8) alkyl moiety with the ring system.
  • a (C 2 -C 8 ) alkenyl heteroaryl group is a heteroaryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) alkenyl unit.
  • a (C 2 -C 8 ) alkynylheteroaryl group is a heteroaryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkynyl unit.
  • a (C 1 -C 8 ) alkylheterocyclyl group is one
  • Heterocyclyl group as already described above, which is linked via a straight-chain or branched (C 1 -C 8 ) - alkyl unit with the ring system.
  • a (C 2 -C 8 ) alkenyl heterocyclyl group is a heterocyclyl group, as already described above, which is linked via a straight-chain or branched (C 2 -C 8 ) alkenyl unit to the ring system.
  • V may be linked to Y such that V is ortho, meta, or para to Y.
  • R 2 The structural element -V-O-W- (see formula II) optionally contained in R 2 can have one of the following meanings:
  • the structural element -V-O-W- is preferably -O-, -NH-O-, or -O-NH-. Most preferably, the structural element -V-O-W- is -O-.
  • the invention further teaches a pharmaceutical composition containing a compound of the invention.
  • one or more physiologically compatible excipients and / or excipients may be mixed with the compound and the mixture galenically for local or systemic administration, in particular orally, parenterally, for infusion or infusion into a target organ, for injection (zBiV, im, intracapsular or intralumbar ), for application in tooth pockets (space between tooth root and gums) and / or prepared for inhalation.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention can be carried out in the usual way. Examples of counterions for ionic compounds are Ca ++ , CaCl + , Na + , K + , Li + or
  • Suitable solid or liquid galenic 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 aerosols, dry powder inhalation preparations, transdermal systems, and
  • Preparations with protracted release of active ingredient in the production of which customary auxiliaries such as carriers, disintegrants, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. It is also possible to encapsulate the active ingredient in preferably biodegradable nanocapsules, for example for the preparation of a preparation for inhalation.
  • 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.
  • a diluent it is also possible to work without a diluent.
  • Physiologically acceptable salts are salts with inorganic or organic acids, such as lactic acid, hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg (OH) 2 , diethanolamine, Ethylenediamine, or with amino acids such as arginine, lysine, glutamic acid, etc. or with inorganic salts, such as
  • CaCl 2 , NaCl or their free ions such as Ca 2+ , Na + , Cl " , SO 4 2" or combinations thereof. They are manufactured according to standard methods.
  • the invention is based on the finding that by introducing at least one -O- for one of the groups X or Y, an improved efficacy is obtained since compounds with
  • Substances according to the invention additionally act or inhibit two kinase classes. This includes on the one hand the inhibition of signal transmission to blood vessel cells (antiangiogenic), in which receptor tyrosine kinases, such as VEGFR, PDGFR, KIT and FLT-3. On the other hand, this includes the inhibition of tumor profiliferation involving serine / threonine kinases, such as RAF / MEK / ERK signaling pathway, for example c-Raf, B-Raf or A-Raf.
  • receptor tyrosine kinases such as VEGFR, PDGFR, KIT and FLT-3.
  • tumor profiliferation involving serine / threonine kinases such as RAF / MEK / ERK signaling pathway, for example c-Raf, B-Raf or A-Raf.
  • the invention further teaches the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases selected from the group consisting of "cancer, e.g. Lung cancer (NSCLC), head and neck cancer (HNSCC), kidney cancer (RCC, NPC), leukemia, ovarian cancer, liver cancer, sarcoma, meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, chronic inflammation, asthma , Allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic
  • diseases selected from the group consisting of "cancer, e.g. Lung cancer (NSCLC), head and neck cancer (HNSCC), kidney cancer (RCC, NPC), leukemia, ovarian cancer, liver cancer, sarcoma, meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer
  • a pharmaceutical composition according to the invention may contain several different compounds covered by formula I above. Furthermore, a pharmaceutical according to the invention
  • Composition additionally contain an agent other than the compound of formula I. 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 of the invention with a pharmaceutically suitable and physiologically acceptable carrier and optionally other suitable active ingredients, additives or excipients and mixed into a suitable
  • 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 metabolisms in small or large tumors.
  • a pharmaceutical composition according to the invention may additionally contain an active substance other than the compound according to the invention, in particular selected from the group consisting of "aldesleukin, amifostine, atrasentan, bevacizumab, bexarotene, bortezomib,
  • Capecitabine carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytamide, dacarbazine, docetaxel, droloxifene, edrecolomab, epothilone, erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fuorouracil, formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, ixabepilone, Lonafarnib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Pemetrexed, Porfimer, Rituximab, Tegafur, Temozolomide, Tipifarnib, T ⁇ potecan, Trimetrexate, Vorozole, Vinblastine, and mixtures of two or more such agents.
  • Ethylacetohydroxamat (EH-671.2-2, 3.85 g, 37.3 mmol) is dissolved in 40 ml of absolute DMF and, at 0 0 CK 11 OBu (EH-671.2- 2, 4.61 g, 41.1 mmol) was added , After 30 min. Stirring at RT is added 2-bromo-5-fluorotrifluoromethylbenzene (10 g, 41.2 mmol) and then stirred at 80 0 C for a further 2h. While cooling with ice, 300 ml of water are added, and the mixture is extracted twice with 200 ml of ethyl acetate (EH-86.7-28) each, with 200 ml of sat. NaCl, dried over sodium sulfate (EH-93.8-10) and concentrated in vacuo. After purification on flash silica gel (Tol / PE 2: 1), 1377.13-1 (12.08 g, 90%) are obtained.
  • Ethyl 4-bromo- (3-trifluoromethyl) phenoxy-acetohydroxamate (1377.13, 12.08 g, 37 mmol) is dissolved in dioxane (60 ml) and cooled to 0 ° C. with an ice-bath. Using a syringe, add 60% perchloric acid (15 mL) slowly. The ice bath is removed and, after stirring at RT, the reaction mixture is added to 1200 ml of ice water and neutralized with a 40% sodium hydroxide solution. The aqueous phase is extracted twice with 1000 ml of ethyl acetate, with 800 ml of sat. NaCl solution, dried over sodium sulfate and concentrated in vacuo. This gives 1377.13-1 (8.7g, 92%) as a dark brown liquid.
  • the analytical data are as follows:
  • Ethyl 2,4-dinitrophenoxy-acetohydroxamate (3 g, 11.14 mmol) is dissolved in dioxane (12 mL) and cooled to 0 ° C. with an ice-bath. With the aid of a syringe, a 60% perchloric acid (9 ml) is slowly added. The ice bath is removed and after 2 h stirring at 2O 0 C, the reaction mixture is added to 240 ml of ice water and neutralized with a 50% sodium hydroxide solution. The aqueous phase is extracted twice with 240 ml of ethyl acetate, with 240 ml of sat. NaCl solution, dried over sodium sulfate and concentrated in vacuo. A dark brown solid is obtained as product (2 g, 91%).
  • Tetrazolium salt XTT sodium 3 "- [1- (phenylaminocarbonyl) - 3, 4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid
  • XTT sodium 3 "- [1- (phenylaminocarbonyl) - 3, 4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid
  • PMS electrose coupling phenazine methosulfate
  • the staining intensity correlates with the mitochondrial dehydrogenase activities and the number of living cells.
  • the quantification of the color intensity is carried out spectrophotometrically with the aid of an ELISA reader.
  • Cell lines determines the optimal output count per well for an ideal optical density measurement. In addition, correlation curves between the OD and the underlying cell number were generated for each cell line. Furthermore, for each cell line the optimal time of the substance addition and the culture time was determined.
  • SO 779 stands for the synthesis product of Example 1, SO 779 I for the synthesis product of Example 2 and SO 779 I (s) for the tosylate salt of the synthesis product of Example 2.
  • MCF-7 and MDA-MB-453 are human breast cancer Cell lines
  • HT 29 is a human colon carcinoma cell line
  • BxPC-3 is a human pancreatic tumor cell line
  • Novikoff is a rat hepatoma cell line
  • KB Vl is a multidrug-resistant derivative of HELA cells
  • WI 38 is a fetal lung fibroblast cell line.
  • Example 2 The synthesis product of Example 2 (free form) 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.
  • the bars represent the IC50 / IC70 concentrations in relation to the mean of all IC50 / IC70 values.
  • the IC50 / IC70 value is lower than the mean of all IC50 / IC70 values, ie these models are more sensitive compared to the average of all models.
  • a bar to the right indicates higher IC50 / 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 non-small cell adenocarcinoma of the lung
  • LXFE squamous cell carcinoma of the lung
  • FXFL large cell
  • LXFS small cell lung carcinoma
  • MAXF breast tumor
  • MEXF melanoma
  • OVXF ovarian carcinoma
  • PAXF pancreatic carcinoma
  • RXF renal carcinoma
  • IC50 and IC70 values were relatively close in almost all models.
  • a particularly high sensitivity was determined for a non-small cell lung tumor model, a small cell lung tumor model and a breast tumor model.
  • IC50 was 60 ⁇ M
  • IC70 was 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'urée qui sont appropriés pour la production de compositions pharmaceutiques.
EP07764419A 2006-06-27 2007-06-27 Nouveaux dérivés d'urée et leurs utilisations Withdrawn EP2032537A1 (fr)

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DE102006029795A DE102006029795A1 (de) 2006-06-27 2006-06-27 Neue Harnstoff-Derivate und deren Verwendungen
PCT/DE2007/001168 WO2008000252A1 (fr) 2006-06-27 2007-06-27 Nouveaux dérivés d'urée et leurs utilisations

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DE102008021699A1 (de) 2008-04-25 2009-10-29 Schebo Biotech Ag Neue Pyrrolopyrimidin-Derivate und deren Verwendung
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung
EP2492701B1 (fr) 2011-02-28 2018-09-05 Siemens Aktiengesellschaft Procédé et dispositif destinés au test d'une éolienne
AR088729A1 (es) * 2011-03-29 2014-07-02 Actelion Pharmaceuticals Ltd Derivados de 3-ureidoisoquinolin-8-ilo y una composicion farmaceutica
CN104496896B (zh) * 2014-05-21 2017-07-14 江西科技师范大学 含磺酰脲结构的索拉非尼衍生物的制备及应用

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AU2006201959B2 (en) * 1997-12-22 2008-09-04 Bayer Healthcare Llc Inhibition of Raf Kinase using Substituted Heterocyclic Ureas
CZ299156B6 (cs) * 1997-12-22 2008-05-07 Bayer Corporation Substituované heterocyklické mocoviny, farmaceutické prípravky je obsahující a jejich použití
ES2154253T3 (es) * 1997-12-22 2012-01-27 Bayer Healthcare Llc Inhibición de la actividad de p38 cinasa usando ureas heterocíclicas sustituidas.
US7928239B2 (en) * 1999-01-13 2011-04-19 Bayer Healthcare Llc Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
US20030207914A1 (en) * 2001-04-20 2003-11-06 Bayer Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
JP4366936B2 (ja) * 2001-04-20 2009-11-18 バイエル コーポレイション キノリル、イソキノリルまたはピリジル尿素を使用するｒａｆキナーゼの阻害
CA2463272C (fr) * 2001-10-22 2009-11-17 Laura Cook Blumberg Derives de piperazine a activite antagoniste du recepteur ccr1
CA2502148A1 (fr) * 2002-10-16 2005-02-17 Board Of Regents, The University Of Texas System Procedes et compositions pour augmenter l'efficacite de substances actives d'un point de vue biologique
EP1603879A2 (fr) * 2003-02-28 2005-12-14 Bayer Pharmaceuticals Corporation Derives de pyridine substitues utilises pour traiter des cancers et d'autres troubles
JP5229853B2 (ja) * 2003-02-28 2013-07-03 ニッポネックス インコーポレイテッド 癌その他の疾患の治療に有用な新規な二環尿素誘導体
UY28213A1 (es) * 2003-02-28 2004-09-30 Bayer Pharmaceuticals Corp Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos.
ATE517885T1 (de) * 2004-04-30 2011-08-15 Bayer Healthcare Llc Substituierte pyrazolyl-harnstoff-derivate zur behandlung von krebs
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WO2007059202A2 (fr) * 2005-11-15 2007-05-24 Bayer Healthcare Ag Derives de pyrazolyluree utilisables dans le traitement du cancer
JP2009518298A (ja) * 2005-12-01 2009-05-07 バイエル ヘルスケア リミティド ライアビリティ カンパニー 癌治療に有用な尿素化合物
CN101007801A (zh) * 2006-01-27 2007-08-01 上海恒瑞医药有限公司 吡咯取代的2－二氢吲哚酮衍生物、其制法与医药上的用途

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