Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms

Definitions

• pan-CDK inhibitors for the treatment of tumors
• the present invention relates to the use of novel pan-CDK inhibitors for the treatment of tumors.
• the new pan-CDK inhibitors are selected sulfoximine-substituted anilino-pyrimidine derivatives.
• pan-CDK inhibitors and processes for their preparation are described in PCT Application PCT / EP2009 / 007247, the disclosures of which are incorporated herein by reference, and which is incorporated herein by reference.
• CDK cyclin-dependent kinases
• Pyrimidines and analogues have already been described as active substances, for example the 2-anilino-pyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for the treatment of neurological or neurodegenerative diseases (WO 99/19305).
• CDK inhibitors a wide variety of pyrimidine derivatives are described, for example 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00 / 12486) and 2-hydroxy-3-N, N-dimethylaminopropoxy-pyrimidines (WO 00/39101).
• WO 02/096888 and WO 03/076437 have disclosed pyrimidine derivatives which have inhibitory effects on CDKs.
• Carboanhydrases (esp. Carboanhydrase-2) known and are used as diuretics, inter alia, for the treatment of glaucoma.
• the nitrogen atom and the oxygen atoms of the sulfonamide bind by hydrogen bonding with the zinc 2+ ion and the amino acid Thr 199 in the active center of the
• CDK inhibitors containing a phenylsulfonamide group could be limited by the potential for inhibition of carbonic anhydrases and a resulting spectrum of side effects be.
• sulfoximine active substances are sulfonimidoyl-modified triazoles as fungicides (H.
• WO 2005/037800 discloses open sulfoximine-substituted anilino-pyrimidine derivatives as inhibitors of cyclin-dependent kinases. Exemplified are structures which are either not substituted in the 5-position of the pyrimidine or substituted with halogen, in particular with bromine. A 5-trifluoromethyl substituent does not have any of the specifically disclosed structures.
• the object of the present invention is to provide compounds which not only inhibit CDK potently, but which also effectively inhibit tumor growth.
• potent CDK inhibition is a necessary but not sufficient prerequisite for effective tumor inhibition.
• further properties of the structures are necessary, such as the penetration properties into the tumor cell.
• X is -O- or -NH-
• R 1 is a methyl, ethyl, propyl or isopropyl group
• R 2 and R 3 independently of one another are hydrogen, a methyl or ethyl group, and R 4 is a C 1 -C 6 -alkyl group or a C 3 -C 7 -cycloalkyl ring,
• a C 1 -C 6 -alkyl group is to be understood as meaning in each case a straight-chain or branched alkyl radical, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl or a hexyl radical.
• a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a cycloheptyl ring is understood.
• X may be -O- or -NH-.
• X is -0-.
• R 1 may represent a methyl, ethyl, propyl or isopropyl group.
• R 1 is a methyl group.
• R 2 and R 3 may independently represent hydrogen, a methyl or ethyl group.
• R 2 and R 3 independently represent hydrogen or a methyl group. Particularly preferably, R 2 is a methyl group and R 3 is hydrogen or a methyl group.
• R 4 may be a C 1 -C 6 -alkyl radical or a C 3 -C 7 -cycloalkyl ring. Preferably, R 4 is a methyl or ethyl group or a cyclopropyl ring.
• a preferred subgroup of the compounds of general formula (I) are compounds in which X is -O- or -NH-, and
• R 1 is a methyl group
• R 2 is a methyl group
• R 3 is hydrogen or a methyl group
• R 4 is a methyl or ethyl group or a cyclopropyl ring, and their physiologically acceptable salts, diastereomers and enantiomers.
• Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine,
• compositions containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of tumor diseases.
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds of the invention can be used in suitable forms.
• Administration forms are administered.
• compounds of the invention in crystalline and / or amorphised and / or dissolved form, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
• capsules for example hard or soft gelatin capsules
• Parenteral administration can be done by bypassing a resorption step (e.g.
• suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• inhalant medicines including powder inhalers, nebulizers
• nasal drops solutions, sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (such as patches)
• milk Pastes, foams, scattering powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients include, among others. Excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols),
• Emulsifiers and dispersing or wetting agents for example sodium dodecylsulfate, polyoxysorbitan oleate
• binders for example polyvinylpyrrolidone
• antioxidants such as ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• flavor and / or odoriferous agents e.g., albumin
• stabilizers e.g., antioxidants such as ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• flavor and / or odoriferous agents e.g., inorganic pigments such as iron oxides
• Another object of the present invention are pharmaceutical compositions containing at least one
• the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
• excipients for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, adsorbents and adsorbents, diluents, solvents,
• Cosolvents for changing the osmotic pressure or buffers are used.
• auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
• the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
• the present invention relates to the use of the compounds according to the formulas (I) for the prophylaxis and therapy of tumor diseases.
• the compounds of the invention are particularly suitable for the treatment of hyper-proliferative diseases such as asthma, diabetes, neurological disorders, neurological disorders, and cardiovascular diseases.
• BPH benign prostatic hyperplasia
• tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue, and metastases of these tumors.
• Hematological logical tumors according to the invention are, for example, treatable multiple myelomas, lymphomas or leukemias.
• treatable as breast tumors are:
• tumors of the respiratory tract are treatable.
• tumors of the brain are treatable.
• tumors of the male reproductive organs are treatable:
• Penis cancer Treatable as tumors of the female reproductive organs, for example: endometrial carcinomas
• tumors of the gastrointestinal tract are treatable:
• Gastrointestinal stromal tumors As tumors of the urogenital tract, for example, are treatable:
• Intraocular melanomas Intraocular melanomas
• Treatable as tumors of the liver for example:
• tumors of the skin are treatable:
• Tumors of the head and neck are treatable:
• sarcomas are treatable:
• lymphomas are treatable:
• Treatable as leukemias for example:
• the compounds according to formula (I) can be used for the treatment of breast cancers, in particular hormone receptor negative, hormone receptor positives or BRCA-associated breast carcinomas, as well as pancreatic carcinomas, renal cell carcinomas, malignant melanomas and other skin tumors, small cell lung carcinomas, non-small cell
• Prostate carcinomas leukemias or lymphomas.
• the compounds of the formula (I) can be used for the treatment of breast cancers, in particular estrogen receptor negative breast carcinomas,
• Ovarian carcinoma especially cisplatin-resistant ovarian carcinoma
• Cervical carcinomas especially multidrug-resistant cervical carcinomas.
• An object of the invention is the use of the compounds of general formula (I) according to the invention as medicaments for the treatment of tumors.
• Another object of the invention is the use of the compounds of general formula (I) according to the invention for the preparation of a medicament for the treatment of tumors.
• Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.
• the compounds of the invention may be used alone or as needed in combination with one or more other pharmacologically active substances, as long as they are
• Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
• the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers.
• the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated. Examples of suitable combination active ingredients are:
• Methotrexate Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotan, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Nolvadex, NSC-631570, OCT-43, Octreotide, Ondansetron hydrochloride, Orapred, Oxaliplatin, Paclitaxel , Pediapred, Pegaspargase, Pegasys, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium,
• Tamoxifen Tamsulosin, Tasonermin, Tastolactone, Taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan,
• Ibandronic acid interferon-gamma, intron-PEG, ixabepilone, keyhole limpet-hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifen, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, Neovastat, Nolatrexed, Oblimersen, Onko-TCS, Osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, Quazepam, R-1549, raloxifene, ranpirnas, 13-d-retinoic acid, satrap latin, seocalcitol, T - 138067, Tarceva, taxoprexin, thymosin-alpha-1,
• the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:
• Abraxan aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodetoxycytidine, Docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyure
• the compounds according to the invention can also be combined with biological therapeutics such as antibodies (eg Avastin, Rituxan, Erbitux, Herceptin, cetuximab) and recombinant proteins.
• biological therapeutics such as antibodies (eg Avastin, Rituxan, Erbitux, Herceptin, cetuximab) and recombinant proteins.
• the compounds according to the invention can also achieve positive effects in combination with other anti-angiogenic therapies, for example with avastin, axitinib, regorafenib, recentin, sorafenib or sunitinib.
• Combinations with inhibitors of the proteasome and mTOR as well as antihormones and steroidal metabolic enzyme inhibitors are beneficial because of their favorable
• the compounds according to the invention can also be used in conjunction with a radiation therapy and / or a surgical intervention. Preparation of the compounds of the invention
• the compounds according to the invention can be prepared by a process which is characterized by the following steps: a) oxidation of a compound of the formula (IVd) to give the sulfoxide of the formula (IVc).
• Example 1 The preparation of Example 1 is carried out according to Example 1 of PCT / EP2009 / 007247.
• Example 2 The preparation of Example 2 is carried out according to Example 2 of PCT / EP2009 / 007247.
• the diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:
• Example 3 The preparation of Example 3 is carried out according to Example 3 of PCT / EP2009 / 007247.
• Example 4 The preparation of Example 4 is carried out according to Example 4 of PCT / EP2009 / 007247.
• Example 5 The preparation of Example 5 is carried out according to Example 5 of PCT / EP2009 / 007247.
• Example 6 The preparation of Example 6 is carried out according to Example 6 of PCT / EP2009 / 007247.
• the diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:
• Example 7 The preparation of Example 7 is carried out according to Example 7 of PCT / EP2009 / 007247.
• Example 8 The preparation of Example 8 is carried out according to Example 8 of PCT / EP2009 / 007247.
• the diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:
• Example 9 The preparation of Example 9 is carried out according to Example 9 of PCT / EP2009 / 007247.
• Insect cells (Sf9) were purchased from ProQinase GmbH, Freiburg.
• the histone IIIS used as kinase substrate is commercially available from Sigma.
• CDKl / CycB (200 ng / measuring point) was incubated for 10 min at 22 ° C in the presence of various
• Assay buffer [50mM Tris / HCl pH8.0, 10mM MgCl 2 , 0.1mM Na ortho-vanadate, 1.0mM
• Dithiothreitol 0.5 ⁇ adenosine trisphosphate (ATP), 10 ⁇ g / measuring point histone IIIS, 0.2 ⁇ / ⁇ 88 ⁇ 1 ⁇ 33 P-gamma ATP, 0.05% NP40, 1, 25% dimethyl sulfoxide].
• the reaction was stopped by addition of EDTA solution (250 mM, pH 8.0, 15 ⁇ / measuring point).
• Insect cells (Sf9) were purchased from ProQinase GmbH, Freiburg. Histone IIIS, which was used as a kinase substrate, was purchased from Sigma. CDK2 / CycE (50 ng / measuring point) was incubated for 10 min at 22 ° C in the presence of various
• Assay buffer [50mM Tris / HCl pH8.0, 10mM MgCl 2 , 0.1mM Na ortho-vanadate, 1.0mM
• Dithiothreitol 0.5 ⁇ adenosine trisphosphate (ATP), 10 ⁇ g / measuring point histone IIIS, 0.2 ⁇ / ⁇ 88 ⁇ 1 ⁇ 33 P-gamma ATP, 0.05% NP40, 1.25% dimethyl sulfoxide].
• the reaction was stopped by addition of EDTA solution (250 mM, pH 8.0, 15 ⁇ / measuring point). 15 ⁇ of each reaction batch was applied to P30 filter strips (Wallac) and unincorporated 33 P-ATP was removed by washing the filter strips three times each for 10 minutes in 0.5% phosphoric acid.
• Recombinant VEGF receptor tyrosine kinase-2 was purified as a GST fusion protein from baculovirus-infected insect cells (Sf9).
• VEGF receptor tyrosine kinase (90 ng / measuring point) was incubated for 10 min at 22 ° C in the presence of various concentrations of test substances (0 ⁇ , and within the range 0.001-30 ⁇ ) in 30 ⁇ assay buffer [40 mM Tris / HCl pH 5.5, 10 mM MgCl 2 , 1 mM MnCl 2 , 3 ⁇ M Na ortho-vanadate, 1.0 mM dithiothreitol, 8 ⁇ M adenosine trisphosphate (ATP), 0.96 ⁇ g / assay point poly (Glu 4 Tyr), 0.2 ⁇ / ⁇ 88 ⁇ 1 ⁇ 33 P-gamma ATP, 1.4% dimethylsulfoxide]. The reaction was stopped by addition of EDTA solution (250 mM, pH 8.0, 15 ⁇ / measuring point).
• Cultured human tumor cells (originally purchased from the ATCC, HeLa-MaTu and HeLa-MaTu-ADR, originally obtained from Epo GmbH, Berlin) were in a density of 1000 to 5000 cells / measurement point, depending on the growth rate of the cell line in a 96 -Loch multititer plate in 200 ⁇ growth medium (DMEM / HAMS Fl 2, 2 mM L-glutamine, 10% fetal calf serum) plated.
• DMEM / HAMS Fl 2 mM L-glutamine, 10% fetal calf serum 200 ⁇ growth medium
• the cells of one plate were stained with crystal violet (see below), while the medium of the other plates by fresh culture medium (200 ⁇ ), the test substances in various concentrations (0 ⁇ , and in the range - 30 ⁇ , the final concentration of the solvent dimethylsulfoxide was 0.5%) were added replaced.
• the cells were incubated for 4 days in the presence of the test substances.
• the cell proliferation was determined by staining the cells with crystal violet.
• the cells were fixed by the addition of 20 ⁇ l / measuring point of a 1% strength glutaraldehyde solution for 15 minutes at room temperature. After washing the fixed cells three times with water, the plates were dried at room temperature.
• Tumor cells cultured in cell culture were implanted subcutaneously into the flank of female or male NMRI nude mice. Treatment was started as soon as the tumors had grown to a size of about 20 mm 2 . The studies were terminated as soon as the tumors in one of the groups exceeded a size of approx. 150 mm 2 .
• the following experimental groups were used:
• Vehicle group Solubilizer treatment (40% PEG400 / 60% water)
• TWH Percent tumor growth inhibition
• the exemplary compound 2-SI-2 was investigated in the following in vivo tumor models, which exemplify the indicated indications:
• MOLM-13 14 9 The results of the proliferation assays demonstrate the efficacy of the exemplary compounds in a variety of different human tumor cells with a pronounced uniform profile. These data suggest a wide application of the exemplary compounds for treating solid, such as hematological tumors, of different histological types.
• Example 2-SI-2 in 40% (v / v) PEG 400 in water b) 0.15 mg / ml, 0.2 mg / ml , 0.25 mg / ml
• TWH TF (measured on the day the vehicle group was stopped): 99% at 2.0 mg / kg. b) TWH TF : 110% at 2.5 mg / kg
• MDA-MB231 human breast tumor cells implanted on female NMRI nude mice.
• TWH TF (measured on the day the vehicle group was stopped): 92% at 2.0 mg / kg. b) TWH TF : 76% at 2.5 mg / kg.
• the example compound shows its effectiveness in various application schemes, which include once daily and several times daily application, as well as contain treatment-free intervals or manage without treatment-free intervals. Surprisingly, the compound is also in
• Tumor models that are not or only poorly responsive to treatment with cytotoxic agents approved for clinical use.

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