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WO2009036753A2 - Nouveaux produits pharmaceutiques, procédés de fabrication de ceux-ci et utilisation de ceux-ci en thérapie médicale - Google Patents

Nouveaux produits pharmaceutiques, procédés de fabrication de ceux-ci et utilisation de ceux-ci en thérapie médicale Download PDF

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Publication number
WO2009036753A2
WO2009036753A2 PCT/DE2008/001566 DE2008001566W WO2009036753A2 WO 2009036753 A2 WO2009036753 A2 WO 2009036753A2 DE 2008001566 W DE2008001566 W DE 2008001566W WO 2009036753 A2 WO2009036753 A2 WO 2009036753A2
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unbranched
branched
optionally
group
compounds
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PCT/DE2008/001566
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German (de)
English (en)
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WO2009036753A3 (fr
Inventor
Hans Scheefers
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Schebo Biotech Ag
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Publication date
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Publication of WO2009036753A2 publication Critical patent/WO2009036753A2/fr
Publication of WO2009036753A3 publication Critical patent/WO2009036753A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present patent application relates to novel pharmaceuticals, for example based on novel substituted 4-pyridin-3yl-pyrimidines, processes for their preparation and their use in therapy, for example in the therapy of cancer.
  • the application claims priority from the German prior application DE 102007046266 (filing date: 20.9.07).
  • known drugs for the treatment of cancer there are a number of tumors that do not respond to therapeutics.
  • the known therapies are characterized by a variety of side effects.
  • R 1 and R 2 independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a CF 3 group or a C 1 -C 4 alkyl group, which may be unbranched or branched
  • R 3 is an optionally 1-3-fold hydroxy, halogen or Ci-C 5 alkoxy substituted (Ci-C-io) alkyl group, the one or more times by
  • Oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and optionally also one or more times can be unsaturated,
  • Sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
  • Ring-containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and may optionally also be mono- or polyunsaturated,
  • L 1 and L 2 are independently of one another -N (R 4 ) - -O-
  • R 4 is hydrogen or a branched or unbranched CrC 4 -
  • Alkyl group means
  • This finding is based on the compounds described in this document.
  • the compounds of general formula I according to the invention are novel substituted 4-pyridin-3yl-pyrimidines.
  • the optional radicals R 1 and R 2 are preferably hydrogen, fluorine or CH 3 or CF 3 groups.
  • the radical R 3 is a chain which may contain cyclic moieties.
  • the chains in R 3 may contain in particular terminal N-containing aliphatic rings, such as piperidine or morpholine.
  • the chain in R 3 can also heterocycles, such as pyrrole, furan, thiophene, pyridine, pyrimidine, quinoline, isoquinoline, pyrazine, Containing quinazoline, quinoxaline.
  • R 3 is a phenyl radical which in turn is monosubstituted or polysubstituted with F, CF 3 , Me, Het, O-Het, - (CH 2 ) X -Het, - (CH 2 ) X -O-Het, wherein X is 0, 1, 2, 3 or 4 and wherein Het is a saturated or unsaturated heterocycle (such as piperidine, pyridine, thiazole, oxazo, pyrrole, imidazole, piperazine) which in turn has one or more substituents (such as methyl , Methoxy, ethyl, ethoxy). Particularly preferred radicals R 3 are shown in FIGS. 1 and 2.
  • the linkers L 1 and L 2 are an ether, ester, amine, amide, carbonyl or
  • At least one of the groups L 1 and L 2 stands for
  • the radical R 4 optionally present in the linker groups is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group, preferably for
  • R 4 is hydrogen.
  • the compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form.
  • stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the invention may be present, which are also subject of the invention.
  • Particularly preferred radicals R 3 are shown in FIGS. 1 and 2.
  • Most preferred is compound 1862 and the connection 34 and the compound 1862-791
  • the compounds of the general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They are particularly useful for the treatment of hematological or solid tumors, e.g. non-Hodgkin's tumors, or of T-cell lymphomas.
  • the effect of the compounds according to the invention as cancer therapeutics may possibly be due to their suitability for the inhibition of tyrosine kinase.
  • the compounds of the general formula I lead to a dose-dependent inhibition of colony formation in the colony assay of the company Oncotest (Freiburg).
  • IC 50 values in 25 different cell culture lines were generally between 4 and 40 ⁇ M.
  • Outstanding selectivity was found in small cell lung carcinoma (LXFS650), followed by renal carcinoma (RXF 1393).
  • the invention therefore teaches the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases selected from the group consisting of cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colorectal cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer .
  • cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colorectal cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer .
  • Skin cancer gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, asthma, allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowel disease, degenerative joint disease, rheumatic diseases Formennikes with cartilage degradation, sepsis, autoimmune diseases, type I
  • Treatment also includes prophylaxis.
  • the present invention teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way.
  • Free carboxylic acid groups may also be present in the form of their salts with physiologically acceptable counterions such as Mg ++ , Ca ++ , Na + , K + , Li + or ammonium derivatives such as cyclohexylammonium.
  • Amino-containing compounds may also be present in the form of an ammonium salt, for example as chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate or tartrate.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), preparation forms forzelpulverinhalation, transdermal systems and preparations with sustained release drug, in the preparation of conventional auxiliaries such as carriers, blasting, binding, coating, swelling, lubricants or lubricants, flavorings, sweeteners and Solvent finder use.
  • auxiliaries such as carriers, blasting, binding, coating, swelling, lubricants or lubricants, flavorings, sweeteners and Solvent finder use
  • excipients examples include magnesium carbonate, titanium dioxide, lactose, manidine and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in defined doses with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate.
  • N, N-dibenzylethylenediamine, diethanolamine ethylenediamine, N-methylglucamine
  • N-benzylphenethylamine diethylamine
  • phosphate sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • this dose may be from 0.1 to 1000 mg, preferably from 10 to 50 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 10 to 40 mg.
  • the preparation of infusion solutions is another preferred embodiment.
  • daily doses for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active ingredient, preferably 10 -50 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be achieved by single administration in the form of a single dose Dosi ⁇ rungseinh ⁇ it or several smaller dosage units as well as by multiple subdivided doses at intervals.
  • the preparations according to the invention can be prepared, for example, as follows:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone,
  • the coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax. Dragee weight: 245 mg.
  • Composition 1 tablet contains: • Active substance 100.0 mg
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet mass (2.0 mm mesh size) and drying in a rack oven at 50 0 C is sieved again (1, 5 mm mesh size) and admixed with the lubricant. The ready-to-use mixture is processed into tablets.
  • 1 tablet contains:
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve of 1.5 mm mesh size.
  • Hard gelatine capsules (with 150 mg active substance)
  • 1 capsule contains:
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
  • Suppositories (with 150 mg active substance) 1 suppository contains:
  • the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
  • Suspension (with 50 mg active substance) 100 ml suspension contain:
  • Dest. Water is heated to 7O 0 C.
  • p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After adding and loosening the
  • the suspension is evacuated to vent with stirring.
  • 5 ml of suspension contain 50 mg of active ingredient.
  • the active substance is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.
  • compositions can be prepared for the compounds mentioned below of the alternative embodiments mentioned in this document.
  • compounds of the invention may be combined with other drugs known per se.
  • drugs known per se.
  • Exemestane Flavopiridol, Fludarabine, Fluorouracil, Formestane, Fulvestrant, Gefitinib, Gemcitabine, Idarubicin, Irinotecan, Ixabepilone, Lonafamib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Pemetrexed, Porfimer, Rituximab, Tegafur, Temozolomide, Tipifamib, Topotecan, Trimimetrexate, Vorozole, Vinblastine, and mixtures of two or more such agents.
  • the compound according to the invention can be mixed with the active substance in the context of a single galenic preparation.
  • the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound according to the invention and in a second preparation of the active ingredient are included.
  • first preparation it is also possible to set up a substance which is different from the active ingredient of the second preparation.
  • the further compounds of the general formula I according to the invention are prepared by the methods of organic chemistry known to those skilled in the art, the introduction of the C-O-N-C group preferably (but not exclusively) by reaction with tert-butyl-dimethylsilylhydroxylamine (or its analogs).
  • Human tumor cells for example, hormone-independent human mammary carcinoma cells, MCF7, human non-small cell lung carcinoma cells, e.g. DIM 45, hormone independent human prostate carcinoma cells, e.g. ATCC HTB-81 or MaTu-MDR, can in one
  • Density of about 5,000 cells per measurement point in 96-l_och multi-well plates in 200 .mu.l of the appropriate growth medium are prepared. After 24 hours, the cells of one plate can be stained with crystal violet while replacing the medium of the other plates with fresh culture medium to which the test substances are added at various concentrations (0 ⁇ mol and in the range 0.01-30 ⁇ mol). The cells can then be incubated for four days in the presence of the test substances. Cell proliferation can be determined by staining the cells with crystal violet.
  • the yellow tetrazolium salt XTT sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid
  • XTT sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid
  • the bioreduction of XTT becomes potential by the addition of PMS (electron coupling phenazine methosulfate).
  • the color intensity correlates with the mitochondrial dehydrogenase activities and the number of living cells.
  • the quantification of the color intensity is carried out spectrophotometrically with the aid of an ELISA reader.
  • the optimal starting cell count per well for each cell line was determined for an ideal measurement of the optical density.
  • correlation curves between the OD and the underlying cell number were generated for each cell line.
  • the optimal time of substance addition and culture time was determined for each cell line (see implementation).
  • the OD in the ELISA reader (620 nm reference wavelength) was measured at a wavelength of 450 nm.
  • MCF-7 human breast cancer cell line
  • MDA-MB-453 human breast cancer cell line
  • HT 29 human colon carcinoma cell line
  • BxPC-3 human pancreatic tumor cell line
  • KB-V1 multidrug-resistant derivative of HeLa cells
  • KBV600 internal name: KB-V1, cultured with 600 ng / ml vinblastine KBVO: internal name; KB-V1, without Virnblastin
  • Wl 38 human, fetal fibroblast-like cell line of the lung
  • NK Novikoff rat hepatoma cell line
  • R 6 is hydrogen or a branched or unbranched C 1 -C 4 - alkyl group
  • R 7 represents a halogen atom, a cyano group, a nitro group, a CF 3 or a -C 2 F 5 group
  • R 8 represents a halogen atom (preferably fluorine or chlorine), a cyano group, a hydroxy group, a C 1 -C 4 -alkoxy group, a nitro group, a CF 3 or a C 2 F 5 group,
  • R 9 represents a hydroxy group, a C 1 -C 4 alkoxy group, a
  • Z is independently a direct bond or an oxygen atom, with the proviso that at least one Z is an oxygen atom, preferably exactly one Z is an oxygen atom L stands for
  • R 6 has the abovementioned meaning
  • n stands for integers from zero to four, eg for zero, one, two, three or four
  • the compounds of the alternative embodiments are effective in the production of inhibitors of specific proteins - and thus in the therapy of associated diseases -:
  • kinase inhibitor e.g., EGFR tyrosine kinase
  • Kinase inhibitor e.g., bcr-abl or c-kit or PDGF-R V tyrosine kinase

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux produits pharmaceutiques à base de nouvelles 4-pyridine-3yl-pyrimidines substituées, des procédés de fabrication de ceux-ci, ainsi que leur utilisation en thérapie médicale, notamment en cas de maladies cancéreuses.
PCT/DE2008/001566 2007-09-20 2008-09-19 Nouveaux produits pharmaceutiques, procédés de fabrication de ceux-ci et utilisation de ceux-ci en thérapie médicale WO2009036753A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007046266.4 2007-09-20
DE102007046266 2007-09-20

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WO2009036753A2 true WO2009036753A2 (fr) 2009-03-26
WO2009036753A3 WO2009036753A3 (fr) 2009-05-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224967A1 (en) * 2003-05-02 2004-11-11 Chen Guoqing P Phenylaminopyrimidine derivatives and methods of use
US20040248918A1 (en) * 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2005058320A1 (fr) * 2003-12-19 2005-06-30 Novartis Ag Combinaison de (a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine et (b) au moins un inhibiteur de formation de l'hypusine et son utilisation
WO2005075454A2 (fr) * 2004-02-04 2005-08-18 Novartis Ag Formes salines de 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide
WO2006021458A2 (fr) * 2004-08-27 2006-03-02 Gpc Biotech Ag Derives de pyrimidine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224967A1 (en) * 2003-05-02 2004-11-11 Chen Guoqing P Phenylaminopyrimidine derivatives and methods of use
US20040248918A1 (en) * 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2005058320A1 (fr) * 2003-12-19 2005-06-30 Novartis Ag Combinaison de (a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine et (b) au moins un inhibiteur de formation de l'hypusine et son utilisation
WO2005075454A2 (fr) * 2004-02-04 2005-08-18 Novartis Ag Formes salines de 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide
WO2006021458A2 (fr) * 2004-08-27 2006-03-02 Gpc Biotech Ag Derives de pyrimidine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung

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