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EP1389201A1 - Derives de n-oxyde anthranylamide et leur utilisation en tant que produits pharmaceutiques - Google Patents

Derives de n-oxyde anthranylamide et leur utilisation en tant que produits pharmaceutiques

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Publication number
EP1389201A1
EP1389201A1 EP02740563A EP02740563A EP1389201A1 EP 1389201 A1 EP1389201 A1 EP 1389201A1 EP 02740563 A EP02740563 A EP 02740563A EP 02740563 A EP02740563 A EP 02740563A EP 1389201 A1 EP1389201 A1 EP 1389201A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
halogen
substituted
cyano
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Withdrawn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
EP02740563A
Other languages
German (de)
English (en)
Inventor
Alexander Ernst
Andreas Huth
Martin Krüger
Karl-Heinz Thierauch
Andreas Menrad
Martin Haberey
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.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE2001123573 external-priority patent/DE10123573B4/de
Priority claimed from DE2001125293 external-priority patent/DE10125293A1/de
Application filed by Schering AG filed Critical Schering AG
Publication of EP1389201A1 publication Critical patent/EP1389201A1/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Withdrawn legal-status Critical Current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
    • C07D213/89—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
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to substituted N-oxidanthranylamide derivatives, their preparation and use as medicaments for the treatment of diseases which are triggered by persistent angiogenesis.
  • Persistent angiogenesis can be the cause of various diseases such as psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombogenic microangiopathic syndrome, transplant rejections and glomerulopathy, fibrotic Diseases such as cirrhosis of the liver, mesangial cell proliferative diseases and atherosclerosis or lead to an exacerbation of these diseases.
  • arthritis such as rheumatoid arthritis, hemangioma, angiofibroma
  • eye diseases such as diabetic retinopathy, neovascular glaucoma
  • renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombogenic
  • Persistent angiogenesis is induced by the factor VEGF via its receptor.
  • VEGF binds to the receptor and tyrosine phosphorylation is caused.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • anthranylic acid amides are known, which are used as medicaments for the treatment of psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephroprobiotic, malignant nephropatombia, malignant nephropatombia Syndromes, transplant rejection and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative diseases, atherosclerosis, Injuries to the nerve tissue and to inhibit the reocciusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices to keep vessels open, such as. B. stents are used.
  • the known compounds are generally effective in the indicated indications, but their activity is generally associated with an inhibitory potential for metabolizing enzymes of the liver (cytochrome P 450 isoenzymes). This harbors the risk of undesirable drug interactions and therefore poorer tolerability of the drug.
  • A stands for the group -N (R 7 ) -
  • W represents oxygen, sulfur, two hydrogen atoms or the group -N (R 8 ) -,
  • Rf independently of one another represent hydrogen, fluorine, C 1 -C 4 -alkyl or the group -N (R 11 ) - and / or R a and / or R b with R c and / or R or R c with R e and / or R f can form a bond, or up to two of the radicals Ra-R f can bridge each having up to 3 C atoms to R 1 or to R 7 , represents d-Ce-alkyl,
  • R 1 for optionally one or more, identical or different with halogen, hydroxy, cyano, C1-C 6 -alkyloxy, aralkyloxy, Ci-C ⁇ -alkyl and / or with the group -NR 12 R 13 substituted or unbranched C ⁇ - C ⁇ 2 alkyl or C 2 -C-
  • R 2 for unsubstituted or optionally one or more, the same or different with cyano, halogen, -CC 6 alkyl, halo -CC 6 alkyl, -C 6 alkoxy, amino, hydroxy and / or with Group -OR 18 or -R 19 substituted hetaryl, which has at least one N-oxide
  • D represents a nitrogen atom or the group CR 3 ,
  • E represents a nitrogen atom or the group CR 4
  • F represents a nitrogen atom or the group CR 5
  • G represents a nitrogen atom or the group CR 6 , where R 3 , R 4 , R 5 and R 6 represent hydrogen, halogen or unsubstituted or optionally mono- or polysubstituted by halogen -CC 6 alkoxy, -C-C 6 -Alkyl or dC 6 -
  • R 7 is hydrogen or -CC 6 alkyl or forms a bridge with up to 3 ring members with R a -R f from Z or to R 1 , R 8 , R 9 R 10 and R 11 for Are hydrogen or dC 6 -alkyl, R 2 and R 13 are hydrogen, d-C ⁇ -alkyl or form a ring which may contain a further heteroatom, R 4 for the group (CH 2 -CH 2 -O) u (CH 2 ) v -R 15 stands,
  • Group NR 16 R 17 , R 16 and R 7 are hydrogen, d-Ce-alkyl, -CC 6 -acyl or one
  • R 18 represents the group (CH 2 -CH 2 -O) w (CH 2 ) p -R 15 ,
  • Group NR 16 R 17 and u, v, w and p are 0-5, and their isomers and
  • the compounds according to the invention prevent tyrosine phosphorylation or stop persistent angiogenesis and thus the growth and spread of tumors, in particular being characterized by less inhibition of isoforms of the cytochrome P 450 (2C9 and 2C19).
  • the medication with the compounds according to the invention can therefore be carried out without risk, regardless of the medicinal products which are administered and which are broken down via these isoforms. If R 7 forms a bridge to R 1 , heterocycles are formed to which R 1 is fused. Examples include:
  • R a , R b , Rc, Rd, Re, Rf independently represent hydrogen or dC 4 alkyl, Z forms an alkyl chain.
  • R a and / or Rb form a bond with R c and / or R d or R c and / or R d with R e and / or Rf, then Z represents an alkenyl or alkynyl chain.
  • Z represents a cycloalkyl or cycloalkenyl group.
  • R a -R f form a bridge with up to 3 C atoms to R 1 , then Z together with R 1 is a benzo or hetaryl-fused (Ar) cycloalkyl. Examples include:
  • Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. To understand butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
  • alkoxy is in each case a straight-chain or branched alkoxy radical, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec.
  • alkoxy pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy.
  • Cycloalkyl means monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings such as, for example, adamantanyl.
  • Cycloalkenyl is to be understood in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycioheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, it being possible for the linkage to take place both on the double bond and on the single bonds.
  • Halogen is to be understood as fluorine, chlorine, bromine or iodine.
  • Alkenyl is in each case to be understood as a straight-chain or branched alkenyl radical which contains 2-6, preferably 2-4, carbon atoms. The following radicals may be mentioned, for example: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl , But-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but -3-en-1-yl, allyl.
  • the aryl radical has 6 to 12 carbon atoms such as naphthyl, biphenyl and especially phenyl.
  • the hetaryl radical each comprises 3-16 ring atoms and can contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, instead of carbon, and can be mono-, bi- or tricyclic, and can additionally be benzo-fused in each case ,
  • Examples include:
  • the aryl and hetaryl radicals can each be 1-; Be substituted twice or three times, identically or differently, with hydroxy, halogen, CrC alkoxy, with dC 4 alkyl, one or more halogen-substituted C 1 -C 4 alkyl, the hetaryl radical R 2 containing at least one nitrile group got to.
  • N-oxides of aromatic hetarylene are understood to mean N-oxides which have at least one nitrogen atom in the ring or rings which is oxidized If several nitrogen atoms are contained in the ring or in the rings, then one nitrogen atom contained in the ring or in the rings, several nitrogen atoms contained in the ring or in the rings or all in the ring or in the rings Rings contained nitrogen atoms to be oxidized to N-oxides.
  • N-oxides may be mentioned, for example:
  • the physiologically tolerable salts of organic and inorganic bases are suitable as salts, for example those which are good soluble alkali and alkaline earth salts as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1, 6-hexadiamine, ethanoiamine, giucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak- Base, 1-amino-2,3,4-butanetriol.
  • physiologically compatible salts of organic and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid and others are suitable.
  • the compounds of general formula I according to the invention also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers.
  • A stands for the group -N (R 7 ) -
  • C is C 2 alkyl
  • X is d-Ce alkyl
  • R 1 for optionally one or more, identical or different with halogen, cyano, hydroxy, C C ⁇ -alkyloxy, aralkyloxy, C 1 -C 6 -alkyl and / or branched or unbranched C 1 -C 2 substituted with the group -NR R 13 -Alkyl or C 2 -C 2 -alkenyl; or for C 3 -C 10 cycloalkyl or C 3 which is optionally substituted one or more times, identically or differently, with halogen, cyano, hydroxy, CrC ⁇ alkyloxy, C 1 -C 6 alkyl and / or with the group -NR 12 R 13 -C 10 - cycloalkenyl; or for optionally one or more, identical or different, with halogen, cyano, cyano-dC 6 -alkyl, hydroxy, Ci-Ce-alkyloxy, aralkyloxy, dC 6 -alkyl, halo
  • Has group D stands for group CR 3 ,
  • E represents the group CR 4 .
  • F represents the group CR 5
  • G represents the group CR 6
  • R 3 , R 4 , R 5 and R 6 represent hydrogen
  • R 7 represents hydrogen or Ci-Ce-alkyl
  • R 9 represents hydrogen or Ci-Ce-alkyl
  • R 12 and R 13 represent hydrogen, -CC 6 -alkyl or form a ring which may contain a further heteroatom
  • R 14 represents the group (CH 2 -CH 2 -O) u (CH 2 ) v -R 15 ,
  • Group NR 16 R 17 , R 16 and R 17 represent hydrogen, Ci-Ce-alkyl, dC 6 -acyl or form a ring which may contain a further hetero atom,
  • R 18 represents the group (CH 2 -CH 2 -O) w (CH 2 ) p -R 15 ,
  • Group NR 16 R 17 and u, v, w and p are 0-5, and their isomers and salts.
  • A stands for the group -N (R 7 ) -
  • X represents -C 6 alkyl
  • R 1 for optionally one or more, identical or different with halogen, cyano, hydroxy, CrC 6 - alkyloxy, aralkyloxy, -C-C 6 alkyl and / or with the group -NR 12 R 13 substituted or unbranched C ⁇ -d 2 alkyl or C2 -C 2 alkenyl; or for C 3 -C 10 cycloalkyl or C3- which is substituted one or more times, identically or differently, with halogen, cyano, hydroxy, dC 6 -alkyloxy, d-Ce-alkyl and / or with the group -NR 12 R 13 C1 0 - cycloalkenyl; or for optionally one or more, the same or different, with halogen, cyano, cyano-d-Ce-alkyl, hydroxy, -C-C 6 alkyloxy aralkyloxy, Ci-
  • D represents the group CR 3 .
  • E represents the group CR 4 .
  • F represents the group CR 5 .
  • G represents the group CR 6 , where R 3 , R 4 , R 5 and R 6 represent hydrogen,
  • R 7 represents hydrogen or Ci-Ce-alkyl
  • R 9 represents hydrogen or Ci-Ce-alkyl
  • R 12 and R 13 represent hydrogen, C 1 -C 6 -alkyl or form a ring which may contain a further heteroatom
  • R 14 represents the group (CH 2 -CH 2 -O) u (CH 2 ) vR 15 ,
  • R 16 and R 17 represent hydrogen, Ci-Ce-alkyl, dC 6 -acyl or one
  • Ring forming another hetero atom can contain R 18 represents the group (CH 2 -CH 2 -O) w (CH 2 ) p -R 15 ,
  • Group NR 16 R 17 and u, v, w and p are 0-5, and their isomers and salts.
  • A stands for the group -N (R 7 ) -
  • C 1 -C 2 alkyl X represents C 1 -C 6 -alkyl
  • R 1 represents optionally one or more times, identical or different, with halogen, cyano, hydroxy, C 1 -C 6 - alkyloxy, aralkyloxy, C 1 -C 6 - Alkyl and / or with the group -NR 12 R 13 substituted branched or unbranched C 1 -C 2 alkyl or C 2 -d 2 alkenyl; or for optionally one or more, the same or different, halogen, cyano, hydroxy, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyl and / or C 3 -C ⁇ o-cycloalkyl or C substituted by the group -NR 12 R 13 3 -C ⁇ o-cycloalkenyl; or for optionally one or more, the same or different, with halogen, cyano, cyano -CC 6 alkyl,
  • R 2 is unsubstituted or optionally one or more, identical or different with halogen, -CC 6 alkyl, halo-Ci-Ce-alky], C -C alkoxy, amino, hydroxy and / or with the group -OR 18 or -R 19 substituted
  • Hetaryl which has at least one N-oxide group
  • D stands for the group CR 3
  • E stands for the group CR 4 .
  • F represents the group CR 5 .
  • G represents the group CR 6 , where
  • R 3 , R 4 , R 5 and R 6 represent hydrogen
  • R 7 represents hydrogen or Ci-Ce-alkyl
  • R 9 represents hydrogen or Ci-Ce-alkyl
  • R 12 and R 13 represent hydrogen, dC 6 -alkyl or form a ring which may contain a further heteroatom
  • R 14 represents the group (CH 2 -CH 2 -O) u (CH 2 ) v -R 15 ,
  • R 5 represents aryl, hetaryl, dC 6 alkyl, aralkyl, -CH 2 CN or the group NR 16 R 17 ,
  • R 16 and R 17 represent hydrogen, d-Ce-alkyl, dC 6 -acyl or one
  • R 18 represents the group (CH 2 -CH 2 -O) w (CH 2 ) p -R 15 ,
  • R 19 stands for aryl, hetaryl, Ci-Ce-alkyl, aralkyl, -CH 2 CN or for the group NR 16 R 17 and u, v, w and p stand for 0-5, and their isomers and
  • A stands for the group -N (R 7 ) -
  • Z represents a bond
  • X represents d-Ce-alkyl
  • R 2 represents unsubstituted or optionally mono- or polysubstituted with halogen pyridyl, which has at least one N-oxide group;
  • D represents the group CR 3 .
  • E represents the group CR 4 .
  • F represents the group CR 5
  • G represents the group CR 6
  • R 3 , R 4 , R 5 and R 6 represent hydrogen
  • R 7 represents hydrogen
  • R 9 represents hydrogen, and their isomers and salts.
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments on account of their inhibitory activity with regard to phosphorylation of the VEGF receptor.
  • the compounds according to the invention are suitable for the treatment of diseases which are caused or promoted by persistent angiogenesis.
  • the compounds of the formula I are identified as inhibitors of tyrosine kinase KDR and FLT, they are particularly suitable for the treatment of diseases which are persistent due to the VEGF receptor Angiogenesis or an increase in vascular permeability can be caused or promoted.
  • the present invention also relates to the use of the compounds according to the invention as inhibitors of the tyrosine kinase KDR and FLT.
  • the present invention thus also relates to medicaments for the treatment of tumors and their use.
  • the compounds of the invention can be used either alone or in
  • vessels open e.g. B. stents, as immunosuppressive agents to support scar-free wound healing, age spots and contact dermatitis.
  • the ascites formation in patients can also be suppressed with the compounds according to the invention.
  • VEGF-related edema can also be suppressed.
  • Lymphangiogenesis plays an important role in lymphogenic metastasis (Karpanen, T. et al., Cancere Res. 2001 Mar 1, 61 (5): 1786-90, Veikkola T. et al., EMBO J. 2001, Mar 15; 20 (6): 1223-31).
  • the compounds according to the invention now also show excellent activity as VEGFR kinase 3 inhibitors and are therefore also suitable as effective inhibitors of lymphangiogenesis.
  • Treatment with the compounds according to the invention not only reduces the size of metastases, but also reduces the number of metastases.
  • the invention thus further relates to the use of the compounds of the general formula I for the manufacture of a medicament for use as or for the treatment of psoriasis, kaposis sarcoma, restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, such as rheumatoid arthritis, Hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplant rejection and glomerulopathy, dermatotic diseases, despherent diseases, despherotic diseases, despherent diseases, like liver disease, like fibrotic diseases, despherent diseases, such as liver fibrotic diseases, desensitizing diseases, such as liver fibrotic diseases, such as liver fibrotic diseases, desensitizing
  • VEGF-related edema can also be suppressed.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, milk sugar , Starch, magnesium stearate, talc, vegetable oils,
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener or, if necessary, one or more flavorings is added.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • A represents the group OR 13 , where R 13 represents hydrogen, or C ⁇ . 6 -acyl, first alkylates the amine group and then converts COA to an amide; or converting the NH 2 group into halogen, converting A into an amide and converting halogen into the corresponding amine, and optionally splitting off a protective group and converting it into an N-oxide, or b) a compound of the general formula III
  • the amide formation takes place according to methods known from the literature.
  • An appropriate ester can be used to form the amide.
  • the ester is, according to J. Org. Chem. 1995, 8414, with aluminum trimethyl or according to Tetr. Lett. 38, 2685, (1997) with dimethylammonium chloride or solvents such as methylene chloride, preferably at room temperature, or according to Synlett, 1997, 277, with methylammoxane (MAO) in solvents such as methylene chloride or toluene or mixtures thereof at room temperature to boiling temperature and the corresponding amine in Solvents implemented. If the molecule contains two ester groups, both are converted into the same amide.
  • an acid amine can also be prepared according to J. Org. Chem. 61, 4196 (1996), with catalytic amounts of 3,4,5-trifluoro implement phenylboronic acid in solvents such as toluene or mesitylene, with elimination of water.
  • amidines are obtained under analogous conditions.
  • aprotic polar solvents such as dimethylformamide
  • an activated acid derivative for example obtainable with hydroxybenzotriazole and a carbodiimide such as diisopropylcarbodiimide or with pre-formed reagents such as HATU (Chem. Comm. 1994, 201) or BTU
  • HATU Hex. Comm. 1994, 201
  • BTU BTU
  • the process via the mixed acid anhydride, the acid chloride, the imidazolide or the azide can also be used for the amide formation.
  • dimethylacetamide is preferred as solvent at temperatures from room temperature to the boiling point of the solvent, preferably at 80-100 ° C.
  • the second ester group must be introduced into the molecule after the first amide group has been generated and then amidated, or one has a molecule in which one group is an ester and the other is an acid and amidates the two groups successively according to different methods.
  • Thioamides are derived from the anthranilamides by reaction with diphosphadithians according to Bull Soc.Chim.Belg. 87, 229, 1978 or by reaction with phosphorus pentasulfide in solvents such as pyridine or even completely without solvents at temperatures from 0 ° C. to 200 ° C.
  • the reduction of the nitro group is carried out in polar solvents at room temperature or elevated temperature.
  • Suitable catalysts for the reduction are metals such as Raney nickel or noble metal catalysts such as palladium or platinum or also palladium hydroxide, optionally on supports.
  • metals such as Raney nickel or noble metal catalysts such as palladium or platinum or also palladium hydroxide, optionally on supports.
  • hydrogen for example, ammonium formate, cyclohexene or hydrazine can also be used in a known manner.
  • Reducing agents such as tin-II-chloride or titanium (III) -chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts. Iron can also be used as a reducing agent.
  • the reaction is then carried out in the presence of an acid such as acetic acid or
  • Ammonium chloride optionally carried out with the addition of a solvent such as water, methanol, iron / ammonia etc. With an extended reaction time, acylation of the amino group can occur in this variant.
  • the amine can be subjected to reductive alkylation with aldehydes or ketones, in the presence of a reducing agent such as sodium cyanoborohydride in a suitable inert solvent such as ethanol at temperatures from 0 ° C. to the boiling point of the solvent implements.
  • a reducing agent such as sodium cyanoborohydride
  • a suitable inert solvent such as ethanol
  • one starts from a primary amino group one can optionally react in succession with two different carbonyl compounds, whereby mixed derivatives are obtained [literature e.g. Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043].
  • An alkylation can also be achieved by reacting the Mitsonubo variant with an alcohol in the presence of, for example, triphenylphosphine and azodicarboxylic acid ester.
  • the amino group can also be alkylated by alkylating agents such as halides, tosylates, mesylates or triflates.
  • suitable solvents are polar solvents such as ethanol, tetrahydrofuran, acetonitrile or dimethylformamide.
  • an auxiliary base such as triethylamine, DABCO pyridine or potassium carbonate can be advantageous.
  • isatoic anhydride can advantageously be used.
  • bases like sodium hydride, however cesium carbonate in solvents such as tetrahydrofuran or dimethylformamide at temperatures between room temperature and the boiling point of the solvent, preferably at 60 ° C., can also be converted into the anion, which is then reacted further with the alkylating agent.
  • Ether cleavages are carried out according to methods customary in the literature. Selective cleavage can also be achieved with several groups present in the molecule.
  • the ether is treated, for example, with boron tribromide in solvents such as dichloromethane at temperatures between -100 ° C to the boiling point of the solvent, preferably at -78 ° C.
  • solvents such as dichloromethane
  • the temperature can preferably be between 150 ° C. and between room temperature and the boiling point of the solvent.
  • benzyl ether cleavage is also possible with strong acids such as trifluoroacetic acid at temperatures from room temperature to the boiling point.
  • a hydroxyl group which is ortho or para to a nitrogen of a 6-ring hetaryl
  • halogen can be accomplished, for example, by reaction with inorganic acid halides such as, for example, phosphorus oxychloride, optionally in an inert solvent
  • Sodium t-butoxide is preferably used as the base and a biphenylphosphine as the auxiliary ligand.
  • the introduction of the halogens chlorine, bromine or iodine via an amino group can also be carried out, for example, according to Sandmeyer, by mixing the diazonium salts formed intermediately with nitrites with copper (I) chloride or copper (I) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid or with Potassium iodide converts.
  • the halogens can e.g. by adding methylene iodide or tetrabromomethane in a solvent such as dimethylformamide.
  • a solvent such as dimethylformamide.
  • the removal of the amino group can be accomplished either by reaction with an organic nitric acid ester in tetrahydrofuran or by diazotization and reductive boiling of the diazonium salt, for example with phosphorous acid, optionally with the addition of copper (I) oxide.
  • Fluorine can be introduced, for example, by Balz-Schiemann reaction of the diazonium tetrafluoroborate or according to J. Fluor. Chem. 76, 1996, 59-62 by diazotization in the presence of HFxPyridin and subsequent boiling, if necessary in the presence of a fluoride ion source such as e.g. Tetrabutylammonium fluoride.
  • a fluoride ion source such as e.g. Tetrabutylammonium fluoride.
  • the t-butoxycarbonyl group is split off by reacting in a solvent such as tetrahydrofuran, dioxane or ethanol with an acid such as 1-acidic acid at temperatures between room temperature and the boiling point of the solvent. It is also possible to split off the t-BOC group with strong acids such as trifluoroacetic acid at temperatures between -20 ° C to the boiling point, preferably at room temperature.
  • a solvent such as methylene chloride is not essential, but can be beneficial.
  • acylation of an amine is carried out in a known manner either by the processes described under amide formation or by reaction with activated acid derivatives such as, for example, acid chloride or acid anhydride
  • Solvents such as methylene chloride, actonitrile or tetrahydrofuran optionally in the presence of bases such as triethylamine.
  • bases such as triethylamine.
  • catalytic amounts of dimethylaminopyridine can be advantageous.
  • the N-oxidation can be carried out by processes known from the literature by oxidation with oxidizing agents such as, for example, m-chloroperbenzoic acid or magnesium monoperoxyphthalate.
  • oxidizing agents such as, for example, m-chloroperbenzoic acid or magnesium monoperoxyphthalate.
  • methylene chloride can be used as the solvent at temperatures from 0 ° C. to the boiling point of the solvent.
  • Intermediate dimethyl- or methyltrifluoromethyldioxirane can also be used as a reagent in solvents such as acetonitrile at temperatures from 0 ° C to the boiling point of the solvent.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, any form of chromatography or salt formation.
  • the salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and separating off the precipitate or, usually, working up the solution.
  • Stock solution A 3mM ATP in water pH 7.0 (-70 ° C)
  • Stock solution B g-33P-ATP 1mCi / 100 ⁇ l
  • stock solution C poly- (Glu4Tyr) 10mg / ml in water
  • Substrate solvent 10mM DTT, 10mM manganese chloride, 100mM magnesium chloride
  • Enzyme solution 120mM Tris / HCl, pH 7.5, 10 ⁇ M sodium vanadium oxide
  • 10 ⁇ l substrate mix (10 ⁇ l vol ATP stock solution A + 25 ⁇ Ci g-33P-ATP (approx. 2.5 ⁇ l of stock solution B) + 30 ⁇ l poly- (Glu4Tyr) stock solution C + 1.21ml Substrate solvent), 10 ⁇ l inhibitor solution (substances corresponding to the dilutions, as a control 3% DMSO in substrate solvent) and 10 ⁇ l enzyme solution (11.25 ⁇ g enzyme stock solution (KDR or FLT-1 kinase) are diluted in 1, 25 ml enzyme solution at 4 ° C) , It is mixed thoroughly and incubated at room temperature for 10 minutes.
  • cytochrome P450 inhibition was according to the publication by Crespi et al. (Anal. Biochem., 248, 188-190 (1997)) using baculovirus / insect cell-expressed human cytochrome P 450 isoenzymes (1A2, 2C9, 2C19, 2D6, 3A4).

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Abstract

La présente invention concerne des dérivés de N-oxyde anthranylamide, leur préparation et leur utilisation en tant que produits pharmaceutiques pour le traitement de maladies résultant de l'angiogenèse persistante. Les composés de l'invention peuvent être utilisés dans le cadre du psoriasis, du sarcome de Kaposi, de la resténose, de l'endométriose, de la maladie de Crohns, de la maladie de Hodgkins, de la leucémie, de l'arthrite telle que l'arthrite rhumatoïde, de l'hémangiome, de l'angiofribrome, des maladies oculaires telles que la rétinopathie diabétique, du glaucome néovasculaire, des maladies rénales telles que la glomérulonéphrite, de la néphropathie diabétique, de la néphrosclérose maligne, des syndromes thrombiques microangiopathiques, des rejets de transplantation et de la glomérulopathie, des maladies fibrotiques telles que la cirrhose du foie, des maladies de prolifération des cellules mésangiales, de l'arthériosclérose, des lésions des tissus nerveux. Lesdits composés peuvent également être utilisés pour empêcher la réocclusion de vaisseaux après un traitement par sonde à ballonnet, dans le cadre des prothèses vasculaires ou après utilisation de dispositifs mécaniques pour maintenir des vaisseaux ouverts, tels que des tuteurs endovasculaires. Lesdits composés peuvent être utilisés comme immunosuppresseurs, pour contribuer à une cicatrisation sans cicatrice, contre les taches de vieillissement et la dermatite de contact. Les composés de l'invention peuvent également servir d'inhibiteurs de VEGFR-3 dans le cadre de la lymphangiogenèse.
EP02740563A 2001-05-08 2002-05-03 Derives de n-oxyde anthranylamide et leur utilisation en tant que produits pharmaceutiques Withdrawn EP1389201A1 (fr)

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DE2001123573 DE10123573B4 (de) 2001-05-08 2001-05-08 N-Oxidanthranylamid-Derivate und deren Verwendung als Arzneimittel
DE10123573 2001-05-08
DE2001125293 DE10125293A1 (de) 2001-05-15 2001-05-15 N-Oxidanthranylamid-Derivate und deren Verwendung als Arzneimittel (II)
DE10125293 2001-05-15
PCT/EP2002/004923 WO2002090349A1 (fr) 2001-05-08 2002-05-03 Derives de n-oxyde anthranylamide et leur utilisation en tant que produits pharmaceutiques

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US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
US7105682B2 (en) * 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US20030134836A1 (en) * 2001-01-12 2003-07-17 Amgen Inc. Substituted arylamine derivatives and methods of use
US6995162B2 (en) * 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US6878714B2 (en) * 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7307088B2 (en) * 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
US7615565B2 (en) 2002-07-31 2009-11-10 Bayer Schering Pharma Aktiengesellschaft VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines
UA89035C2 (ru) 2003-12-03 2009-12-25 Лео Фарма А/С Эфиры гидроксамовых кислот и их фармацевтическое применение
US7906533B2 (en) 2004-11-03 2011-03-15 Bayer Schering Pharma Ag Nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
EP1657241A1 (fr) * 2004-11-03 2006-05-17 Schering Aktiengesellschaft Nouveaux urées d' anthranylamide pyridine ayant une activité inhibitrice de kinase du récepteur de VEGF
EP1655295A1 (fr) * 2004-11-03 2006-05-10 Schering Aktiengesellschaft Anthranilamide pyridinurées comme inhibiteurs de kinase du récepteur VEGF
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
JP5096927B2 (ja) 2004-12-31 2012-12-12 レディ ユーエス セラピューティックス， インコーポレイテッド Ｃｅｔｐインヒビターとしての新規ベンジルアミン誘導体
US8247556B2 (en) 2005-10-21 2012-08-21 Amgen Inc. Method for preparing 6-substituted-7-aza-indoles
US8987262B2 (en) 2007-10-19 2015-03-24 Universite de Bordeaux Use of a beta blocker for the manufacture of a medicament for the treatment of hemangiomas
EP2050441A1 (fr) 2007-10-19 2009-04-22 Université Victor Segalen Bordeaux 2 Utilisation de bêtabloquants pour la fabrication d'un médicament pour le traitement d'hémangiomes
EP2346827B1 (fr) 2008-08-27 2013-11-13 Leo Pharma A/S Dérivés de pyridine comme récepteur de vegfr-2 et inhibiteurs de la protéine tyrosine kinase
JP5964965B2 (ja) 2011-08-18 2016-08-03 ドクター レディズ ラボラトリーズ リミテッド コレステリルエステル転送タンパク質（ｃｅｔｐ）インヒビターとしての置換複素環式アミン化合物
HK1197238A1 (en) 2011-09-27 2015-01-09 雷迪博士实验室有限公司 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis
KR20250152072A (ko) * 2023-02-23 2025-10-22 더 리젠트스 오브 더 유니이버시티 오브 캘리포니아 녹내장을 치료하기 위한 신규 방법

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DE10023484A1 (de) 2000-05-09 2001-11-22 Schering Ag Anthranylamide und deren Verwendung als Arzneimittel

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