WO2010078905A1 - Benzothiazolonderivate - Google Patents
Benzothiazolonderivate Download PDFInfo
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- WO2010078905A1 WO2010078905A1 PCT/EP2009/008756 EP2009008756W WO2010078905A1 WO 2010078905 A1 WO2010078905 A1 WO 2010078905A1 EP 2009008756 W EP2009008756 W EP 2009008756W WO 2010078905 A1 WO2010078905 A1 WO 2010078905A1
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- het
- stereoisomers
- tautomers
- pharmaceutically acceptable
- acceptable salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the invention was based on the object, new compounds with valuable
- the present invention relates to compounds and the use of
- the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and / or modulation of Met-kinase signal transduction play a role.
- Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, ultimately resulting in a cellular response.
- Compound PHA-665752 an indole derivative, is active against the HGF receptor c-
- HGF and Met directed. It is also reported there that HGF and Met significantly contribute to the malignant process of various types of cancers, e.g. multiple myeloma.
- the present invention relates to compounds of formula I which inhibit, regulate and / or modulate Met-kinase signal transduction, compositions containing these compounds, and methods for their use in the treatment of met-kinase-related diseases and conditions, such as angiogenesis, Cancer, tumorigenesis,
- Atherosclerosis eye diseases such as age-related macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis,
- Wound healing, graft rejection, metabolic and immune system disorders including autoimmune diseases, cirrhosis, diabetes and blood vessel diseases, as well as instability and permeability
- Solid tumors can be treated with Met kinase inhibitors.
- These solid tumors include monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma.
- the present invention is directed to methods for the regulation, modulation or inhibition of Met kinase for the prevention and / or
- the compounds of the formula I can also be used in the treatment of certain forms of cancer.
- the compounds of Formula I can be used to be additive or synergistic in certain existing cancer chemotherapies
- Met kinase Examination of the activity or expression of Met kinase can be used. In addition, they are particularly suitable for use in diagnostic procedures for diseases associated with unregulated or disturbed met kinase activity.
- the compounds according to the invention have an in vivo antiproliferative action in a xenograft tumor model.
- the compounds of the invention are administered to a patient with a hyperproliferative disorder, e.g. To inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to
- Tissue repair etc.
- present compounds are useful for prophylactic or therapeutic purposes.
- the present compounds are useful for prophylactic or therapeutic purposes.
- the present compounds are useful for prophylactic or therapeutic purposes.
- treating is used to refer to both the prevention of disease and the treatment of pre-existing conditions.
- Prevention of proliferation by administration of the compounds of the present invention prevents development of the apparent disease, e.g., to prevent tumor growth, prevent metastatic growth which achieves reduction of cardiovascular surgery-associated restenosis, etc.
- the compounds are used to treat persistent diseases by stabilizing or ameliorating the clinical symptoms of the patient.
- the host or patient may be of any mammalian species, e.g. B. one
- Rats and hamsters Rats and hamsters; Rabbits; Horses, cattle, dogs, cats etc.
- Animal models are of interest for experimental studies, wherein they provide a model for treating a human disease.
- the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted. The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the undesirable cell population in the target tissue while increasing the viability of the patient
- Treatment is generally continued until there is a significant reduction, e.g. At least about 50%
- interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., et al.
- kinase activity is a technique well known to those skilled in the art.
- Generic Assay Systems for Determining Kinase Activity with Substrates e.g. Histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pp. 333-338) or the myelin basic protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).
- Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
- Phospho-AK binds only the phosphorylated substrate. This binding is detectable with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence
- the ailments of interest include, but are not limited to, the following conditions.
- the compounds of the invention are useful in the treatment of a variety of conditions involving proliferation and / or migration smooth muscle cells and / or inflammatory cells in the intimal layer of a vessel is present, resulting in limited blood flow to this vessel, z.
- Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.
- 4,5-dihydropyrazoles for combating cancer are known from WO 03/079973 A2.
- met kinase inhibitors are known from WO 2005/004607, WO 2005/030140, WO 2006/014325, WO 2006/021881 and WO 2006/021881.
- the invention relates to compounds of the formula I. wherein
- E, E ', E ", E” 1 each independently of one another C or N,
- R 1 , R 2 are each independently H or A, R 1 and R 2 together also (CH 2 ) P , where 1 or 2 CH 2 group (s) may be replaced by O and / or NH,
- R 4 is Het 1 , NHCOOR 5 , NHCONHR 5 , NHCOCONHR 5 , NO 2 or
- R 4 ' is H or Hal
- Ar is unsubstituted or mono-, di- or trisubstituted by Hal, A, OH,
- Hal is F, Cl, Br or I
- m is 1, 2, 3 or 4
- n is 0, 1, 2, 3 or 4
- p is 1, 2, 3, 4 or 5
- q is 1, 2, 3, 4 or 5 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios,
- Solvates are e.g. Mono- or dihydrate or
- compositions are understood as meaning, for example, the salts of the compounds according to the invention and also what are known as prodrug compounds.
- biodegradable polymer derivatives of the compounds of the invention include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
- the term "effective amount” means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
- terapéuticaally effective amount means one
- terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
- the invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, e.g. in the
- the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1-11 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a) a Compound of formula II
- R 1 , R 2 , R 4 and R 4 have the meanings given in claim 1 and Q is Cl, Br, I or a free or reactively functionally modified OH group,
- A, A ' each independently, alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,
- Cyclic alkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylamino) -pheny
- Methylaminocarbonyl -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-
- Ar is particularly preferably mono-, di- or trisubstituted by Hal and / or CN substituted phenyl.
- the heterocyclic radicals may also be partially or completely hydrogenated.
- Het can thus z. B. also represent 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl,
- Het 1 means, notwithstanding further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or
- Pyrimidinyl furthermore preferably 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-triazole
- Het 1 particularly preferably denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-triazole-1, -3 - or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4 Thiadiazole-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or
- Hal preferably denotes F, Cl or Br 1 but also I, particularly preferably F or Cl.
- the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above.
- Some preferred groups of compounds may be through the following
- Partial formulas Ia to Ig are expressed which correspond to the formula I and wherein the unspecified radicals corresponding to those given in the formula I.
- a ' are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and / or Cl;
- Ib Het a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 3 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by A and / or COOR 6 may be substituted; in Ic Het piperidinyl, pyrrolidin-yl, morpholin-4-yl, piperazin-yl, 1, 3
- Oxazolidin-3-yl imidazolidinyl, oxazolyl, oxadiazolyl, thiazolyl, thienyl, furanyl or pyridyl, wherein the radicals are also one or two times by A and / or
- COOR 6 can be substituted means
- Ih R 4 is Het 1 , NHCOOR 5 or NO 2 ;
- Ik R 6 is H, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl;
- R 3 A COA, (CH 2 ) n Het, Hal, O (CH 2 ) m NAA 'or O (CH 2 ) m Het,
- R 4 is Het 1 , NHCOOR 5 or NO 2 ,
- Oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3 or 4-pyidazinyl or pyrazinyl which is unsubstituted or monosubstituted or disubstituted by A, O (CH 2 ViNH 2 , O (CH 2 ) m NHA, O (CH 2 ) m NAA ⁇ Het, OHet, N CH-NAA 1 .
- N CH-NHA
- N CH-NH 2 and / or O (CH 2 ) m Het are substituted
- R 6 is H, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl,
- a 1 A 1 are each independently of one another unbranched or branched alkyl having 1-10 C atoms, wherein 1-7 H atoms by F and / or Cl can be replaced, Hal denotes F, Cl, Br or I, m is 1, 2, 3 or 4;
- the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known and suitable for the reactions mentioned.
- the starting compounds of the formulas II and III are generally known. If they are new, they can be produced by methods known per se. Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.
- L preferably denotes Cl, Br, 1 1 or a free or reactively modified OH group such as an activated ester, an imidazolide or Alky ⁇ sulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or aryl sulfonyloxy having 6-10 C atoms (preferably phenyl or p-Tolylsulfonyloxy).
- an activated ester an imidazolide or Alky ⁇ sulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or aryl sulfonyloxy having 6-10 C atoms (preferably phenyl or p-Tolylsulfonyloxy).
- the reaction is generally carried out in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.
- an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.
- an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid of the alkali or alkaline earth metals preferably of potassium, sodium, calcium or cesium may be beneficial.
- reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about
- Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, 1-methyl-pyrroli
- Dimethylformamide (DMF); Nitrites such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents. Particularly preferred is acetonitrile, dichloromethane, NMP and / or DMF.
- the abovementioned compounds according to the invention can be used in their final non-salt form.
- the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
- Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
- bases are for example
- Alkali metal hydroxides including potassium hydroxide, sodium hydroxide and
- Formula I acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate , Succinate, citrate,
- organic and inorganic acids e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate,
- pharmaceutically acceptable acid addition salts include Compounds of the formula I which are: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,
- Metaphosphate methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
- base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III) -,
- Salts of compounds of formula I 1 derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, Caffeine, chloroprocaine, choline, N.N'-dibenzylethylenediamine (benzathine),
- Lidocaine Lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine,
- Piperidine polyamine resins, procaine, purines, theobromine, triethanolamine, Triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) - methylamine (tromethamine), but this is not intended to be limiting.
- Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (Cr C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (Ci 0 - Ci 8 ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl- (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.
- agents such as (C 1 -C 4
- Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
- hydrochloride dihydrochloride, hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.
- the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
- the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
- the free base forms differ, in a sense, from their corresponding salt forms with respect to certain physical ones
- the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
- metals are sodium, potassium, magnesium and calcium.
- Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
- the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
- the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
- the free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar
- a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
- Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
- An active ingredient is to be understood, which contains a compound of formula I in the form of one of its salts, especially if this salt form the Drug provides improved pharmacokinetic properties compared to the free form of the drug or any other salt form of the drug previously used.
- the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
- the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
- compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
- a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
- dosage units containing a predetermined amount of active ingredient per unit dose.
- Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient.
- pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
- compositions may be administered by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes.
- Such formulations may be prepared by any method known in the pharmaceutical art, such as by including the active ingredient with the carrier (s) or
- compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
- Tablet or capsule the active component with an oral, non-toxic and pharmaceutically acceptable inert carrier, such.
- Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
- a pharmaceutical excipient e.g. an edible carbohydrate such as starch or mannitol.
- a flavor, preservative, dispersant and dye may also be present.
- Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
- Lubricants and lubricants such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
- a disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
- suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
- Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
- the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
- the tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing , a lubricant and a disintegrant are added and the whole is compressed into tablets.
- a powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a
- Binders such as e.g. Carboxymethylcellulose, an alginate, gelatin or
- Polyvinylpyrrolidone a dissolution reducer, such as e.g. Paraffin, one
- Absorption enhancer e.g. a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed.
- the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
- a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
- the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules.
- the granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
- the compounds of the invention can also be used with a
- a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
- Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
- Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
- Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
- Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
- the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
- the formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.
- the compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol,
- Stearylamine or phosphatidylcholines are formed.
- the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds can also be coupled with soluble polymers as targeted drug carriers.
- Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
- the compounds may be coupled to a class of biodegradable polymers suitable for controlled release of a drug, eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
- a drug eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
- Formulations can be used as separate patches for longer, narrow
- the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
- Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
- the formulations are preferably applied as a topical ointment or cream.
- the active ingredient may be either paraffinic or water-miscible
- Cream base can be used.
- the active ingredient can become a cream be formulated with an oil-in-water cream base or a water-in-oil base.
- the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
- Formulations include lozenges, lozenges and mouthwashes.
- compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
- compositions adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
- Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
- Fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
- compositions adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes, foams or
- compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile
- Suspensions which may contain suspending agents and thickeners.
- the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
- sterile carrier liquid e.g. Water for injections
- Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
- formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
- a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
- an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per
- the actual amount per day would usually be between 70 and 700 mg, with this amount may be given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per day so that the total daily dose is the same.
- Derivatives thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
- the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
- the invention is also a set (kit), consisting of separate packages of
- the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
- suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
- the set may e.g. containing separate ampoules, in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable
- the present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of tyrosine kinase-related diseases.
- diseases include proliferation of tumor cells, pathological neovascularization (or angiogenesis) that promotes solid tumor growth, neovascularization in the eye (diabetic retinopathy, age-related macular degeneration, and the like), and inflammation (psoriasis, rheumatoid arthritis, and the like ).
- the present invention includes the use of the compounds of
- Preferred carcinomas for the treatment are from the group of brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma.
- Another group of preferred forms of cancer are monocytic leukemia,
- Eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
- Inflammatory diseases include, for example, rheumatoid arthritis, Psoriasis, contact dermatitis, late-type hypersensitivity reaction, and the like.
- the present invention also encompasses the use of compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment or prevention of retinal vascularization.
- Methods for the treatment or prevention of ocular diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
- the use for treating or preventing inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reactions, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets, is also within the scope of the present invention.
- tyrosine kinase-related diseases or conditions refers to pathological conditions that are dependent on the activity of one or more tyrosine kinases.
- the tyrosine kinases are involved either directly or indirectly in the signal transduction pathways of various cellular activities, including proliferation, adhesion and migration as well as differentiation
- Diseases associated with tyrosine kinase activity include proliferation of tumor cells, pathological vascular remodeling that promotes solid tumor growth, neovascularization in the eye
- the compounds of formula I can be administered to patients for the treatment of cancer, especially fast growing tumors.
- the invention thus relates to the use of compounds of the formula I 1 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the Signal transduction of kinases plays a role.
- Particularly preferred is the use for the manufacture of a medicament for the treatment of diseases which are affected by inhibition of Met kinase by the compounds of claim 1. Especially preferred is the use for treating a disease wherein the disease is a solid tumor.
- the solid tumor is preferably selected from the group of tumors of the lung, the squamous epithelium, the bladder, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach and / or larynx.
- the solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
- a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
- anticancer agent refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
- the anticancer treatment as defined herein may be used as a sole therapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compound of the present invention.
- Such chemotherapy may include one or more of the following categories of antitumour agents: (i) antiproliferative / antineoplastic / DNA damaging agents and combinations thereof, as used in medical oncology, such as alkylating agents (for example, cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan , Chlorambucil, busulphan and nitrosoureas);
- Antimetabolites e.g., antifolates, such as fluoropyrimidines, such as
- Anti-tumor antibiotics eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, Mitomycin C, dactinomycin and mithramycin
- antimitotic agents for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere
- Topoisomerase inhibitors for example, epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan, and camptothecin
- cell-differentiating agents for example, all-trans-retinoic acid, 13-cis-retinoic acid, and fenretinide
- cytostatic agents such as anti-estrogens (eg tamoxifen, torem
- Bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists for example goserelin, leuprorelin and buserelin
- progesterone for example megestrol acetate
- aromatase inhibitors for example anastrozole, letrozole, vorazole and exemestane
- inhibitors of 5 ⁇ -reductase such as finasteride
- agents that inhibit the invasion of cancer cells for example metalloproteinase inhibitors, such as marimastat and inhibitors of urokinase.
- inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example, the anti-erbb2 antibody trastuzumab [Herceptin TM] and the anti-erbb1 antibody cetuximab [C225]), Famesyltransferase inhibitors, tyrosine kinase inhibitors and serine / threonine
- Kinase inhibitors for example, epidermal growth factor family inhibitors (for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline).
- epidermal growth factor family inhibitors for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline.
- vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
- antisense therapies for example, those directed against the targets listed above, such as ISIS 2503, an anti-Ras
- immunotherapy approaches including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to reduction T cell anergy, batches using transfected immune cells such as cytokine-transfected dendritic cells, batches using cytokine-transfected tumor cell lines, and anti-idiotypic antibody approaches.
- cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
- T cell anergy batches using transfected immune cells such as cytokine-transfected dendritic cells
- batches using cytokine-transfected tumor cell lines and anti-idiotypic antibody approaches.
- the medicaments of Table 1 below are combined with the compounds of the formula I.
- Topotecan Elsamitrucin (Spectrum) Dexrazoxanet (TopoTarget) J-107088 (Merck & Co)
- Rhizoxin (Fujisawa) D 24851 (ASTA Medica)
- Epothilone B Novartis
- ZD 6126 AstraZeneca
- Auristatin PE (Teikoku NeuroPharma)
- Taxoprexin (Protarga) CA-4 (OXiGENE)
- CapCell TM CYP450- (Reducing Agent, Zambon)
- GCS-IOO gal3 antagonist, inhibitor, Encore
- Efaproxiral oxygenator, receptor agonist, Leo
- PI-88 heparanase inhibitor antagonist
- Tiazofurin IMPDH inhibitor, indisulam (p53 stimulant,
- SR-31747 (IL-1 antagonist, rituximab (CD20 Antikörpe ⁇
- PBI-1402 PMN stimulant, (immunotoxin, KS Biomedix
- PCK-3145 apoptosis
- SRL-172 T-cell stimulant, promoter, PoIa
- TLK-286 (glutathione-S agent, Leo)
- PT-100 growth factor (differentiator, NIH)
- Bryostatin-1 (PKC stimulant; ILEX Oncology)
- CDA-II Apoptosis promoter, Bioniche
- Rhizoxin (Fujisawa) D 24851 (ASTA Medica)
- Epothilone B Novartis
- ZD 6126 AstraZeneca
- Auristatin PE (Teikoku NeuroPharma)
- Taxoprexin (Protarga) CA-4 (OXiGENE)
- Histone acetyltransfer tacedinalin Pfizer
- pivaloyloxymethyl butyrate ase- SAHA Aton Pharma
- TNF-alpha-virulizine (Lorus Therapeutics Revimid (Celgene)
- Tocladesin cyclic ranitimase (ribonuclease)
- CapCell TM CYP450- (Reducing Agent, Zambon)
- GCS-IOO gal3 antagonist, inhibitor, Encore
- Efaproxiral oxygenator, receptor agonist, Leo
- PI-88 Heparanase Inhibitor Antagonist, TransMolecular
- SR-31747 (IL-1 antagonist, Genentech)
- SRL-172 T cell stimulant, CHS-828 (cytotoxic
- TLK-286 glutthione-S-trans-retinoic acid
- PT-100 growth factor MX6 (apoptosis promoter
- CDA-II apoptosis promoter Ro-31-7453 (apoptosis
- SDX-101 apoptosis-brostallicin (apoptosis)
- Such joint treatment can be achieved by simultaneously, sequentially or separately dosing the individual components of the treatment.
- Such combination products employ the compounds of the invention.
- the Met kinase is recombinantly human as "N-terminally 6His tagged" for the purpose of protein production in insect cells (Sf21, S. frugiperda) and subsequent affinity chromatographic purification Protein expressed in a baculovirus expression vector.
- To measure the kinase activity can be made of various available measuring systems. In scintillation proximity (Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19), the FlashPlate method or the filter binding assay, the radioactive phosphorylation of a protein or peptide as a substrate with radioactively labeled ATP ( 32 P-ATP, 33 P-ATP).
- HTR-FRET Homogeneous Time-resolved Fluorescence Resonance Energy Transfer
- FP Fluorescence Polarization
- Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
- Phospho-AK specific phospho-antibodies
- the phospho-antibody binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated antibody (Ross et al., 2002, Biochem. J.).
- test plates are 96-well Flashplate R microtiter plates from Perkin Elmer (Cat. No. SMP200).
- the components of the kinase reaction described below are pipetted into the assay plate.
- “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization.
- APCI-MS atmospheric pressure chemical ionization - mass spectrometry
- Chromolith Performance RP18e 100 mm long, inner diameter 3 mm, wavelength: 220 nm
- Step 1
- a suspension of 88.0 g (366 mmol) of 3- (5-hydroxypyrimidin-2-yl) -benzoic acid in 1.4 l of methanol is treated with 32.7 ml (445 mmol) of thionyl chloride and heated to 80 ° C. for 2 hours. Then 20 ml (276 mmol) of thionyl chloride and after 2 hours another 10 ml (138 mmol) of thionyl chloride are added. After each addition, the reaction mixture is stirred for 2 hours at 80 ° C. The reaction mixture is concentrated in vacuo to a volume of about 300 ml.
- Step 10 Preparation of 4- ⁇ 2- [2- (3-chloromethyl-phenyl) -pyrimidin-5-yloxy] -ethyl ⁇ -morpholine hydrochloride:
- Tripotassium phosphate trihydrate and 9 mg (0.01 mmol) of bis (triphenylphosphine) - palladium chloride added and stirred at 80 ° C for 18 hours.
- 9 mg (0.01 mmol) of bis (triphenylphosphine) -palladium chloride are added twice more and the mixture is stirred at 80 ° C. for 24 hours.
- the reaction mixture is diluted with water, extracted with ethyl acetate, dried and evaporated.
- the crude product is purified by preparative HPLC. The product is present as trifluoroacetate.
- reaction mixture is stirred into water, the precipitate is filtered off with suction and the residue is dried in vacuo.
- Stage b 9.83 g (51.7 mmol) of [3- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanol are dissolved in 150 ml of toluene; heated to 35 ° C and then 4.91 mol (52 mmol) of phosphorus tribromide, dissolved in toluene, added dropwise. The mixture is stirred for 1 h at 35 ° C and 2 h at RT. The batch is stirred into ice-water. It is extracted three times with ethyl acetate. The organic phase is dried and concentrated. The crude product is purified by column chromatography on silica gel (PE / EA, 9: 1).
- the product "A13" is present as trifluoroacetate.
- Example A Injection glasses
- a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of twice-distilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and closed under sterile conditions , Each injection jar contains 5 mg of active ingredient.
- a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool.
- Each suppository contains 20 mg of active ingredient.
- a solution of 1 g of an active compound of the formula I, 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g of Na 2 HPO 4 • 12H 2 O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
- a mixture of 1 kg of active ingredient of the formula I 1 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate in the usual manner
- Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
- a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.
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Abstract
Description
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JP2011544794A JP5653933B2 (ja) | 2009-01-07 | 2009-12-08 | ベンゾチアゾロン誘導体 |
CA2748908A CA2748908C (en) | 2009-01-07 | 2009-12-08 | Benzothiazolone derivatives |
MX2011007232A MX2011007232A (es) | 2009-01-07 | 2009-12-08 | Derivados de benzotiazolona. |
BRPI0923602A BRPI0923602A2 (pt) | 2009-01-07 | 2009-12-08 | derivados de benzotiazolona |
AU2009336847A AU2009336847B2 (en) | 2009-01-07 | 2009-12-08 | Benzothiazolone derivative |
US13/143,467 US8877751B2 (en) | 2009-01-07 | 2009-12-08 | Benzothiazolone derivatives |
EA201101042A EA021067B1 (ru) | 2009-01-07 | 2009-12-08 | Производные бензотиазолона |
EP09768335A EP2373635A1 (de) | 2009-01-07 | 2009-12-08 | Benzothiazolonderivate |
SG2011047552A SG172424A1 (en) | 2009-01-07 | 2009-12-08 | Benzothiazolone derivative |
CN200980153630XA CN102272112A (zh) | 2009-01-07 | 2009-12-08 | 苯并噻唑酮衍生物 |
IL213827A IL213827A (en) | 2009-01-07 | 2011-06-28 | Derivatives of benzothiazolone |
ZA2011/05779A ZA201105779B (en) | 2009-01-07 | 2011-08-05 | Benzothiazolone derivative |
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US (1) | US8877751B2 (de) |
EP (1) | EP2373635A1 (de) |
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AR (1) | AR074989A1 (de) |
AU (1) | AU2009336847B2 (de) |
BR (1) | BRPI0923602A2 (de) |
CA (1) | CA2748908C (de) |
DE (1) | DE102009003975A1 (de) |
EA (1) | EA021067B1 (de) |
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Cited By (2)
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EP2933245A1 (de) * | 2014-04-17 | 2015-10-21 | Bayer Technology Services GmbH | Oxidative Carbonylierung von Amino-Arylverbindungen durch Aryl-Formiate |
WO2017108569A1 (en) | 2015-12-22 | 2017-06-29 | Syngenta Participations Ag | Pesticidally active pyrazole derivatives |
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DK2961391T3 (en) * | 2013-02-28 | 2017-09-04 | Novartis Ag | Formulation comprising a benzothiazolone compound |
JP7214879B2 (ja) * | 2019-02-01 | 2023-01-30 | メッドシャイン ディスカバリー インコーポレイテッド | c-Met阻害剤としてのピリミジニルを含むトリシクリル系化合物 |
CN115583939A (zh) * | 2022-11-04 | 2023-01-10 | 苏州莱安医药化学技术有限公司 | 一种特泊替尼中间体的合成方法 |
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2009
- 2009-01-07 DE DE102009003975A patent/DE102009003975A1/de not_active Withdrawn
- 2009-12-08 CN CN200980153630XA patent/CN102272112A/zh active Pending
- 2009-12-08 CA CA2748908A patent/CA2748908C/en active Active
- 2009-12-08 US US13/143,467 patent/US8877751B2/en not_active Expired - Fee Related
- 2009-12-08 JP JP2011544794A patent/JP5653933B2/ja not_active Expired - Fee Related
- 2009-12-08 BR BRPI0923602A patent/BRPI0923602A2/pt not_active IP Right Cessation
- 2009-12-08 SG SG2011047552A patent/SG172424A1/en unknown
- 2009-12-08 MX MX2011007232A patent/MX2011007232A/es not_active Application Discontinuation
- 2009-12-08 KR KR1020117018354A patent/KR20110102504A/ko not_active Application Discontinuation
- 2009-12-08 EP EP09768335A patent/EP2373635A1/de not_active Withdrawn
- 2009-12-08 EA EA201101042A patent/EA021067B1/ru not_active IP Right Cessation
- 2009-12-08 AU AU2009336847A patent/AU2009336847B2/en not_active Ceased
- 2009-12-08 WO PCT/EP2009/008756 patent/WO2010078905A1/de active Application Filing
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2010
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2011
- 2011-06-28 IL IL213827A patent/IL213827A/en active IP Right Grant
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2933245A1 (de) * | 2014-04-17 | 2015-10-21 | Bayer Technology Services GmbH | Oxidative Carbonylierung von Amino-Arylverbindungen durch Aryl-Formiate |
WO2015158799A1 (en) * | 2014-04-17 | 2015-10-22 | Bayer Technology Services | Oxidative carbonylation of amino aryl compounds by alkyl formates |
WO2017108569A1 (en) | 2015-12-22 | 2017-06-29 | Syngenta Participations Ag | Pesticidally active pyrazole derivatives |
Also Published As
Publication number | Publication date |
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JP5653933B2 (ja) | 2015-01-14 |
US8877751B2 (en) | 2014-11-04 |
EP2373635A1 (de) | 2011-10-12 |
CA2748908C (en) | 2017-10-24 |
IL213827A (en) | 2015-05-31 |
JP2012514610A (ja) | 2012-06-28 |
CA2748908A1 (en) | 2010-07-15 |
DE102009003975A1 (de) | 2010-07-08 |
MX2011007232A (es) | 2011-08-03 |
CN102272112A (zh) | 2011-12-07 |
AU2009336847B2 (en) | 2015-12-10 |
US20110269756A1 (en) | 2011-11-03 |
EA021067B1 (ru) | 2015-03-31 |
AR074989A1 (es) | 2011-03-02 |
BRPI0923602A2 (pt) | 2016-01-12 |
SG172424A1 (en) | 2011-07-28 |
IL213827A0 (en) | 2011-07-31 |
KR20110102504A (ko) | 2011-09-16 |
AU2009336847A1 (en) | 2011-08-25 |
EA201101042A1 (ru) | 2012-01-30 |
ZA201105779B (en) | 2012-04-25 |
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