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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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