EP1996586A1 - Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine - Google Patents

Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine

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Publication number
EP1996586A1
EP1996586A1 EP07703534A EP07703534A EP1996586A1 EP 1996586 A1 EP1996586 A1 EP 1996586A1 EP 07703534 A EP07703534 A EP 07703534A EP 07703534 A EP07703534 A EP 07703534A EP 1996586 A1 EP1996586 A1 EP 1996586A1
Authority
EP
European Patent Office
Prior art keywords
atoms
salts
solvates
formula
het
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Withdrawn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
EP07703534A
Other languages
German (de)
English (en)
Inventor
Dieter Dorsch
Christian Sirrenberg
Thomas J. J. Mueller
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1996586A1 publication Critical patent/EP1996586A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • 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

Definitions

  • the invention relates to compounds of the formula I.
  • R 5 is H, A, - [C (R 6 ) 2 ] n Ar, - [C (R 6 ) 2 ] n Het or
  • R is H or alkyl having 1-6 C atoms
  • R 7 is H, A, - [C (R 6 ) 2 ] n Ar, - [C (R 6 ) 2 l n Het or
  • A, A 1 are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which one or two
  • Ar is an unsubstituted one, two, three, four or five times by OH, OA, SH, SA, SOA, SO 2 A 1 Hal, NO 2 , NH 2 , NHA, NAA 1 , A, SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONH 2 , CONHA, CONAA 1 , NACOA 1 , NASO 2 A 1 , COOH 1 COOA, COA, CHO or CN substituted saturated, unsaturated or aromatic carbocycle having 5-14 C atoms,
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
  • Compounds may therefore be used to combat and / or treat Tumors, tumor growth and / or tumor metastases.
  • the antiproliferative effect may be demonstrated in a proliferation assay /
  • amino-pyridine derivatives bearing a 2,2,6,6-tetramethyl-piperidin-4-yl- * c residue are useful in the treatment of inflammatory and
  • the compounds of the present invention or a pharmaceutically acceptable salt thereof are used for the treatment of cancer
  • Tumors also include monocytic leukemia, brain,
  • Genitourinary, lymphatic, gastric, laryngeal and lung carcinomas including lung adenocarcinoma and small cell lung carcinoma, pancreatic and / or mammary carcinoma.
  • the compounds are also useful in the treatment of HIV-1
  • cancerous hyperproliferative diseases are brain cancer
  • Lung cancer squamous cell cancer, bladder cancer, stomach cancer,
  • cancerous cell growth is a disease that is an object of the present invention.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said
  • 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 / vitality is achieved by administration of the compounds of the invention prior to the development of the apparent disease, e.g. Prevention of Tumor Growth Alternatively, the compounds are used to treat persistent disease
  • the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs,
  • 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 incubated 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 to inhibit cell proliferation, cell vitality or migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The amount of cells remaining after treatment are then determined.
  • 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 unwanted cell population in the target tissue while maintaining patient viability. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • the compounds of the invention are useful in the treatment of apoptosis
  • 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.
  • the invention also relates to the optically active forms (stereoisomers), salts, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g.
  • 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 that elicits a biological or medical response in a tissue, system, animal, or human, such as is sought or sought by a researcher or physician.
  • therapeutically effective amount means an amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of a disease, a disease, a disease state, a disease Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder. 10
  • therapeutically effective amount also includes the
  • the invention also relates to the use of mixtures of the compounds of the formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • 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 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that
  • R2 wherein R 2 represents an indole protecting group
  • R 3 , R 4 and R 5 have the meanings given in claim 1, and A is alkyl having 1, 2, 3 or 4 C atoms,
  • R 1 has the meaning given in claim 1,
  • R 2 , R 3 , R 4 and R 5 have the meanings given in claim 1,
  • A, A 1 each independently of one another, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-
  • A is also 2-methoxy-ethyl.
  • Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a saturated, unsaturated or aromatic carbocycle having 5-14 C-g atoms preferably means cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, biphenyl or tetrahydronaphthyl.
  • 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.- 0
  • Ar is particularly preferably unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl, substituted by OH, OA, Hal and / or A, phenyl or naphthyl.
  • the heterocyclic radicals may also be partially or completely hydrogenated.
  • Unsubstituted Het can thus z.
  • B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - Or 3- furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1, -2-, -3-, -4- or -5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2, 3-dihydro-1-, -
  • Het is preferably an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N, O and / or S atoms. Het very particularly preferably denotes pyridyl, pyrimidinyl, thienyl, furyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, 1,3-benzodioxol-yl, 1,4-benzodioxan-yl, 2,1,3-benzothiadiazole yl or 2,1,3-benzoxadiazol-yl, very particularly preferred is quinolyl.
  • R 1 is preferably A, - [C (R 6) 2] n Ar, - [C (R 6) 2] n Het, COR 7, CON (R 7) 2 or SO 2 R 7, wherein Het ⁇ 2 , 2,6 > 6-tetramethyl-piperidin-4-yl, and wherein R 6 is preferably H, and wherein R 7 is preferably H or alkyl having 1, 2, 3 or 4 C-atoms.
  • R 3 is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.
  • R 4 is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.
  • R 5 is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.
  • R 6 is preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.
  • R 7 is preferably H or A, more preferably H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms.
  • Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.
  • the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
  • the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned
  • R 5 is H or A
  • A is unbranched or branched alkyl having 1-6 C atoms, wherein one or two CH 2 groups may be replaced by O or S atoms and / or also 1-7 H atoms by F, means;
  • R 3 is H or A
  • R 4 is H or A
  • R 5 is H or A 1
  • R 7 is H or A
  • A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH 2 groups may be replaced by O or S atoms and / or also 1-7 H atoms by F,
  • Ar is phenyl or naphthyl which is unsubstituted or mono-, di-, tri-, tetra- or quintuple OH, OA, Hal and / or A,
  • R 2 is H or A
  • R 3 is H or alkyl with 1 -6 C atoms
  • R 4 is H or alkyl having 1-6 C atoms
  • R 5 is H or alkyl having 1-6 C atoms
  • R 7 is H or alkyl having 1-6 C atoms
  • A is unbranched or branched alkyl having 1-6 C atoms, in which one or two CH 2 groups are substituted by O- or S-
  • Atoms and / or 1-7 H atoms can be replaced by F,
  • Ar is unsubstituted or monosubstituted, disubstituted, trisubstituted, trisubstituted or pentane-substituted by OH, OA, Hal and / or A.
  • Phenyl or naphthyl Het an unsubstituted mono- or binuclear aromatic heterocycle having 1 to 4 N-, O- and / or
  • the compounds of the formula II and of the formula III are generally known. If they are new, they can be produced by methods known per se.
  • reaction takes place in an inert solvent and is carried out in the 3 Q rule 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.
  • Alkali or alkaline earth metals preferably potassium, sodium,
  • the 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), ethyl glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylform
  • Carboxylic acids such as formic acid or acetic acid; Nitro compounds like
  • glycol ethers particularly preferred are glycol ethers, THF, dichloromethane and / or DMF.
  • Preferred indole protecting groups are e.g. Sulfonyl protecting groups such as tosyl or mesyl, further protecting groups such as e.g. BOC.
  • Compounds of the formula I can furthermore be obtained by reacting compounds of the formula III with compounds of the formula IV.
  • the compounds of formula IV are known in the rule. If they are new, they can be produced by methods known per se.
  • the reaction takes place in an inert solvent and takes place in the
  • an acid-binding agent preferably one organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or
  • Alkali or alkaline earth metals preferably potassium, sodium,
  • the reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about -15 ° and 150 °, usually between 40 ° and 120 °, particularly preferably between 60 ° and 11O 0 C.
  • Suitable inert solvents are the mentioned above.
  • a standard method for ether cleavage e.g. a methyl ether, is the use of boron tribromide.
  • Hydrogenolytically removable groups e.g. the cleavage of a benzyl ether, z. B. by treatment with hydrogen in the presence of a
  • Catalyst eg., A noble metal catalyst such as palladium, expediently on a support such as coal
  • Suitable solvents are those given above, in particular z.
  • alcohols such as methanol or ethanol or amides such as DMF.
  • Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
  • Esters can e.g. with acetic acid or with NaOH or KOH in water,
  • Water THF or water dioxane be saponified at temperatures between 0 and 100 °.
  • Alkylations on the nitrogen are carried out under standard conditions, as known to those skilled in the art.
  • the compounds of formula I can be further obtained by solubilizing them from their functional derivatives, in particular
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxyl groups, corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom which is substituted by an N- Atom, carry an amino protecting group, z.
  • acyl groups derived from cyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • alkanoyl such as acetyl, propionyl, butyryl
  • Aralkanoyl such as phenylacetyl
  • Aroyl such as benzoyl or toluyl
  • Aryloxyalkanoyl such as POA
  • Alkoxycarbonyl as
  • hydroxy-protecting groups include i.a. tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • the COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg, Asp (OBut)).
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as Tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 °, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
  • the trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine.
  • the cleavage takes place, depending on the desired end product, with TFA / 10% thiophenol, the trityl group is split off from all the above amino acids, when using TFA / anisole or TFA / thioanisole only the trityl group of His, Asn and GIn is cleaved, whereas they remains on the Cys side chain.
  • the Pbf (pentamethylbenzofuranyl) group is used to protect Arg. The cleavage takes place e.g. with TFA in dichloromethane.
  • Hydrogenolytically removable protecting groups may e.g. By cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon).
  • a catalyst e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon.
  • Suitable solvents are those given above, in particular z.
  • alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds z.
  • 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.
  • 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, benzoate, salicylate, ascorbate and the like.
  • pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate,
  • Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones
  • Arginine betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
  • Ci 8 alkyl halides, eg decyl, dodecyl, lauryl, myristyl and
  • 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 prepared by contacting the salt form with a base and isolating the free base to standard
  • the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
  • Preferred metals are sodium, potassium, magnesium and calcium.
  • Suitable 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 solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
  • Invention also multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine,
  • compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • a moiety 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 of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be in the form of dosage units containing a predetermined amount of active ingredient per
  • dosage unit included, to be presented.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
  • such 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) Ways, adapt.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal Ways, adapt.
  • Starch or mannitol is mixed.
  • a flavor, preservative, dispersant and dye may also be present.
  • a powder mixture is prepared, granulated or dry pressed, a lubricant and disintegrant are added and the whole is compressed into tablets.
  • a powder mixture is prepared by mixing the appropriately comminuted compound with
  • Granulation can run the powder mixture through a tabletting machine, resulting in irregularly shaped lumps, which are broken up into granules.
  • the granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil
  • 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.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient can be used with either a paraffinic or water miscible cream base.
  • the active ingredient can be formulated into a cream 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.
  • 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.
  • Nasal drops containing a liquid carrier include drug solutions in water or oil.
  • Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
  • Formulations may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • 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
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Given day can be so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative 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 set contains suitable containers, such as boxes or boxes, 5 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 derivatives, solvates and stereoisomers, including mixtures thereof in Q of all ratios, and an effective amount of another drug substance is dissolved or in lyophilized form.
  • the instant compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment and control of cancers.
  • the present invention comprises the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer.
  • 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
  • a pharmaceutical composition for the treatment and / or control of a tumorigenic disease in a mammal which process comprises administering to a diseased mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.
  • Illness where the disease is a solid tumor.
  • the solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.
  • 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 myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
  • the invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, wherein the bone pathology from the group osteosarcoma, osteoarthritis and
  • the compounds of formula I may also be coadministered with other well-known therapeutics selected for their particular suitability for the condition being treated.
  • the present compounds are also useful for combination with known anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors.
  • the present compounds are particularly suitable for co-administration with radiotherapy.
  • Estrogen receptor modulators refers to compounds that have the
  • estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but no
  • Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Cytotoxic agents refers to compounds which cause cell death primarily by direct action on cell function or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis
  • the cytotoxic agents include, for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine,
  • Temozolomide Heptaplatin, Estramustine, Improsulfan-tosylate, Trofosfamide, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100,
  • MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin see WO 00/50032, but this is not intended to be limiting.
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '''-dideshyrmM'-deoxy- ⁇ '-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin , 2,3,4, 5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N 1 N-dimethyl-L-valyl-L-valyl-N-methyl-L-valy lL -prolyl-L-proline t-butylamide, TDX258 and BMS188797.
  • paclitaxel vindesine sulfate
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
  • Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and
  • antiproliferative agents also include other monoclonal antibodies against growth factors than those already listed under the “angiogenesis inhibitors”, such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).
  • Tumor cell proliferation / tumor cell vitality described by drugs The cells are seeded in suitable cell density in microtiter plates (96-well format). On the following day, the test substances are added in the form of a concentration series. After two more days of culture in serum-containing medium, the cell density is determined photometrically by staining the cells with crystal violet.
  • the cells are cultured in medium. At intervals of 3-4 days ⁇ 5, the cells are detached from the culture dishes using trypsin solution and seeded in fresh medium at a suitable dilution. The cells are cultured at 37 ° C and 10% CO 2 .
  • test substances are dissolved, for example, in DMSO and then in appropriate concentration (if necessary).
  • Dilution series in the cell culture medium.
  • the dilution steps can be adjusted depending on the efficiency of the active ingredients and the desired spread of the concentrations.
  • the test substances are mixed in appropriate concentrations with cell culture medium.
  • Test compound dilutions are added to the cells (at the desired concentrations in the cell culture medium). The cells are incubated for a further 48 hours at 37 ° C and 10% CO 2 .
  • the medium is removed from the cells and the cells are washed with PBS. After removing the PBS wash solution, 100 ⁇ l / well of Crystal Violet is added and allowed to stand for 15 minutes, for example
  • the crystal violet is dissolved by adding 200 ⁇ l_ of methanol (per well).
  • An absorption measurement is carried out at a suitable wavelength, for example 550 nm, in the microtiter plate reader (for example TECAN
  • the absorbance value of the medium control (no use of cells and test substances) is subtracted from all other extinction values.
  • the controls (cells without test substance) with the solvent DMSO are set equal to 100 percent and all other extinction values related thereto (expressed as% of control, for example):
  • Chromolith Performance RP-18e Merck KGaA, Cat 1.02129.0001
  • reaction mixture is stirred in the autoclave apparatus for 48 hours under a pressure of 1 atm of carbon monoxide.
  • the reaction mixture is washed with saturated sodium chloride solution and the aqueous phase extracted with dichloromethane.
  • the combined organic phases are dried over sodium sulfate and evaporated.
  • the residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate as eluent: tert-butyl 3-hex-2-ynylpyrrolo [2,3-b] pyridine-1-carboxylate as colorless oil; ESI 313.
  • 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 bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.
  • a solution of 1 g of an active ingredient of the formula I 1 938 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 is in the usual
  • 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

L'invention concerne des composés de formule I, dans laquelle R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP> et R<SUP>5</SUP> ont les significations données dans la revendication 1, lesdits composés étant des inhibiteurs de la prolifération cellulaire et de la vitalité cellulaire et pouvant être utilisés pour le traitement de tumeurs.
EP07703534A 2006-03-20 2007-02-21 Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine Withdrawn EP1996586A1 (fr)

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DE102006012617A DE102006012617A1 (de) 2006-03-20 2006-03-20 4-(Pyrrolopyridinyl)-pyrimidinyl-2-amin-derivate
PCT/EP2007/001494 WO2007107221A1 (fr) 2006-03-20 2007-02-21 Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine

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US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
DE102007028515A1 (de) 2007-06-21 2008-12-24 Merck Patent Gmbh 6-(Pyrrolopyridinyl)-pyrimidinyl-2-amin-derivate
DE102008005493A1 (de) * 2008-01-22 2009-07-23 Merck Patent Gmbh 4-(Pyrrolo[2,3-c] pyridine-3-yl)-pyrimidin-2-yl-amin-derivate
DE102008031517A1 (de) 2008-07-03 2010-01-07 Merck Patent Gmbh Pyrrolopyridinyl-pyrimidin-2-yl-amin-derivate
CN101723936B (zh) * 2008-10-27 2014-01-15 上海睿星基因技术有限公司 激酶抑制剂及其在药学中的用途
CN104940202B (zh) 2009-06-17 2018-10-16 沃泰克斯药物股份有限公司 流感病毒复制抑制剂
MX2012000709A (es) 2009-07-15 2012-03-16 Abbott Lab Inhibidores de pirrolopiridina de cinasas.
CN102471345A (zh) 2009-07-15 2012-05-23 雅培制药有限公司 激酶的吡咯并吡嗪抑制剂
DE102009060175A1 (de) * 2009-12-23 2011-06-30 Merck Patent GmbH, 64293 Pyrrolo[2,3-d] pyrazin-7-yl-pyrimidin-Verbindungen
DE102010050558A1 (de) * 2010-11-05 2012-05-10 Merck Patent Gmbh 1H-Pyrrolo[2,3-b]pyridinderivate
CN103492381A (zh) 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 流感病毒复制的抑制剂
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UA118010C2 (uk) 2011-08-01 2018-11-12 Вертекс Фармасьютікалз Інкорпорейтед Інгібітори реплікації вірусів грипу
PL3068782T3 (pl) 2013-11-13 2018-12-31 Vertex Pharmaceuticals Incorporated Sposoby wytwarzania inhibitorów replikacji wirusów grypy
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MA42422A (fr) 2015-05-13 2018-05-23 Vertex Pharma Inhibiteurs de la réplication des virus de la grippe
JP6704416B2 (ja) 2015-05-13 2020-06-03 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ インフルエンザウイルスの複製の阻害剤を調製する方法
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CN115785134B (zh) * 2022-10-28 2023-08-29 浙大城市学院 一种含氮杂环的硼酸化合物及制备方法和应用

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JP2009530321A (ja) 2009-08-27
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