EP2964259A1 - Use of (rs)-s-cyclopropyl-s-(4-{[4-{[(1r,2r)-2-hydroxy-1-methylpropyl]- oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide for treatment of specific tumours - Google Patents

Abstract

The invention relates to the use of (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2- hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}- phenyl)sulfoximide and/or (S)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2- hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}- phenyl)sulfoximide for treatment of specific tumors.

Description

 Use of (RS) -S-C-cyclopropyl-S- (4- {r4- {ILR, 2R) -2-hydroxy-1-methylpropyl-oxy} -5- (trifluoromethyl) -pyrimidin-2-ylamino} -phenyl) -sulfoximide for the treatment of specific tumors

The present invention relates to the use of (RS) -S-cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidine 2-yl] amino} phenyl) sulfoximide, especially (R) -S-cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide for the treatment of specific tumors.

The cyclin-dependent kinases (CDK) are an enzyme family that plays an important role in the regulation of the cell cycle and thus represents a particularly interesting target for the development of small inhibitory molecules. Selective inhibitors of CDKs can be used to treat cancers or other diseases that cause cell proliferation disorders. 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). As 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).

In particular, WO 02/096888 and WO 03/076437 have disclosed pyrimidine derivatives which have inhibitory effects on CDKs.

Examples of sulfoximine drugs are sulfonimidoyl-modified triazoles as fungicides (H. Kawanishi, H. Morimoto, T. Nakano, T. Watanabe, K. Oda, K. Tsujihara, Heterocycles 1998, 49, 181) or arylalkyl sulfoximines as herbicides and pesticides (Shell International Research, Ger. P. 2,129,678).

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 novel 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. (RS) -S- (4- {[4- {[(lR, 2R) -2-hydroxy-l-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) - _l S '- methylsulfoximide is example compound 1.

The use of a group of pan CDK inhibitors in various tumor diseases is the subject of PCT / EP2011 / 054733. (RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide

Example compound 1.

The combination of the aforementioned group of pan-CDK inhibitors with other tumor therapeutics in various tumor diseases is the subject of DE102010014427. (RS) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide is example compound 1.

Based on this prior art, the object of the present invention is to provide compounds for patients with lymphomas, in particular diffuse large B-cell lymphomas, with rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas, in particular the lungs, the head and neck or the cervix.

The oncological efficacy of a compound in a specific indication can not be foreseen for oncological efficacy in other specific indications.

Among other things, tumors differ in their degree of differentiation, in their vascularization, in the formation of hypoxic or necrotic areas and in their metabolic adaptation. In summary, there is a picture of great heterogeneity, which can be reflected in the response to drug treatment.

This heterogeneity can also be seen at the tumor cell level, which is attributed not only to the tissue of origin, but also to the type and number of accumulated genomic changes, such as mutations and amplifications. The strong variation of the response to oncological drugs even at the cellular level, for example, impressively demonstrates the analysis of the US Food and Drug Administration of NCI 60 panel data from human tumor cell lines (Holbeck, SL, Collins, JM, Doroshow, JH, Analysis of Food and Drug Administration-Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines. Mol Cancer Ther; 9 (5); 1451-1460, 2010). It has now been found that the compound is (RS) -S-cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidine -2-yl] amino} phenyl) sulfoximide (Compound A), in particular (R) -S-cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy } -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide (Compound A ') in previously unrecognized specific tumor types, namely in lymphomas, especially in diffuse large B-cell lymphoma or mantle cell Lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas, especially the lungs, the head and neck or the cervix.

Connection A

(RS) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide (Compound A) is a selected sulfoximine-substituted anilino-pyrimidine derivative which can be resolved into two stereoisomers, namely:

- (R) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide (Compound A ') and

 - (S) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide (Compound A ").

Compound A 'is preferred and as BAY 1000394 in clinical development.

In the following, compound A refers to both the pure stereoisomers A 'and A "and any mixture of these two.

An object of the present application is the use of

(RS) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide, especially

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

for the treatment of lymphomas, in particular diffuse large B-cell lymphomas or mantle cell lymphomas, of rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas, in particular of the lungs, the head and neck or the cervix.

Another object of the present application is the use of

 (RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide,

especially

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

for the manufacture of a medicament for the treatment of lymphoma, in particular diffuse large B-cell lymphoma or mantle cell lymphoma, of rhabdomyosarcomas,

 Neuroblastomas or squamous cell carcinomas, especially the lungs, the head and neck or the cervix.

A further subject of the present application is (RS) -S-cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidine 2-yl] amino} phenyl) sulfoximide, in particular

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

for the treatment of lymphomas, in particular diffuse large B-cell lymphomas or mantle cell lymphomas, of rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas, in particular of the lungs, the head and neck or the cervix.

Further objects of the present application are pharmaceuticals and pharmaceuticals

Containing formulations

(RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

especially

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

for the treatment of lymphomas, in particular diffuse large B-cell lymphomas or mantle cell lymphomas, of rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas, especially the lungs, the head and neck or the cervix.

Further objects of the present application are combinations of

 (RS) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide,

especially

 (R) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

with at least one further active ingredient for the treatment of lymphomas, in particular diffuse large B-cell lymphomas or mantle cell lymphomas, of rhabdomyosarcomas,

Neuroblastomas or squamous cell carcinomas, especially the lungs, the head and neck or the cervix.

Also to be regarded as covered by the present invention is the use of the physiologically acceptable salts of the compound A.

Physiologically acceptable salts of compound A include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. 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 compound A also include salts of conventional 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 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine,

 Triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine. The present invention further relates to medicaments comprising compound A and at least one or more further active compounds for the treatment of lymphomas, in particular diffuse large B-cell lymphomas or mantle cell lymphomas, of rhabdomyosarcomas,

Neuroblastomas or squamous cell carcinomas, especially the lungs, the head and neck or the cervix. The compound A according to the invention can act systemically and / or locally. For this purpose, it may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent. For these routes of administration, the compound A can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. 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, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, Aerosols or solutions.

Solutions which are shown to be advantageous for compound A are solutions comprising or consisting of solubilizers, surface-active substances and / or one or more

Flavorings.

Suitable solubilizers are macrogols, in particular macrogol 400.

Polysorbates, in particular polysorbate 20, are suitable as surface-active substances. Suitable flavoring substances are essential oils, in particular menthol.

The drug concentration may be 0.1 mg / ml to 10 mg / ml, preferably 0.2 mg / ml to 8 mg / ml, more preferably 0.3 mg / ml to 6 mg / ml, and most preferably 0.4 mg / ml to 4 mg / ml. By way of example, the concentrations are 0.2 mg / ml and 4.8 mg / ml.

Also shown to be advantageous for compound A are tablets containing or consisting of fillers, disintegrants and / or one or more pressing additives.

Suitable fillers are polyols such as mannitol, in particular in granulated form or cellulose derivatives such as microcrystalline cellulose. Suitable pressing additives are stearates, in particular magnesium stearate.

Suitable disintegrants are cellulose derivatives, in particular croscarmellose.

The drug concentration may be 0.1 mg / tablet to 10 mg / tablet, preferably 0.37 mg / tablet to 8 mg / tablet, more preferably 0.4 mg / tablet to 6 mg / tablet, and most preferably 0.5 mg / tablet to 5 mg / tablet.

By way of example, the concentration is 5 mg / tablet.

The compound A is preferably present before and for the formulation in a dosage form in micronized form.

 Parenteral administration can be done by bypassing a resorption step (e.g.

intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with the involvement of resorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and

 Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations,

Vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powdered powders, implants or stents.

Compound A can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecylsulfate, polyoxysorbitanoleate), excipients

(For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous. Another object of the present invention are pharmaceutical compositions containing the compound A, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above. The formulation of compound A 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.

Examples of excipients which may be used are excipients, fillers, disintegrants, binders, humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants,

Preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used. Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

The pharmaceutical formulations can

in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or

in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, tinctures, suspensions or emulsions.

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.

For oral or oral administration, in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.

For parenteral administration in particular suspensions, emulsions and above all solutions in question. The present invention relates to the use of the compound A, in particular the compound A 'for the treatment of lymphoma, in particular diffuse large B-cell lymphoma or mantle cell lymphoma, rhabdomyosarcoma, neuroblastoma or squamous cell carcinoma, in particular the lung, the head and neck or the cervix.

Dosage and treatment scheme:

The dosage and the treatment regimen can and must vary depending on the type of carcinoma and

Treatment goal can be varied.

The daily dose is usually between 0.5 mg and 20 mg and can be divided into several identical or different dosage units, preferably 2.

The preferred daily dose is between 1.0 mg and 15 mg and may be divided into several equal or different dosage units, preferably 2.

This applies both to monotherapy and to combination therapy with other anti-hyperproliferative, cytostatic or cytotoxic substances, wherein a dose reduction may be necessary in the combination therapy.

The treatment may be carried out for 2 to 60 days, with the treatment preferably followed by a break of 2 to 30 days.

A successful treatment is when at least one disease stabilization occurs and the side effects occur in a treatable, but at least well tolerated extent.

Compound A may be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. 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. For example, compound A can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers. The

Combination of the compounds according to the invention with other substances commonly used for cancer therapy or else with radiotherapy is particularly indicated.

Examples of suitable combination active ingredients are:

 Abraxan, afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabine, arsenic trioxide, aromasine, 5-azacytidine, azathioprine, BCG or tice- BCG, bestatin, beta-methasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefeson,

Celmoleukin, Cerubidin, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, Decadron, Decadron phosphate, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxorubicin, Dronabinol , DW-166HC, Eligard, Elitek, Ellence, Emend, Epirubicin, Epoetin-alfa, Epogen, Eptaplatin, Ergamisole, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid, Etopophos, Etoposide, Fadrozole, Farston, Filgrastim, Finasteride , Fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabin, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron Hydrochloride, histrelin,

Hycamtin, hydrocorton, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2a, interferon-alpha-2β, interferon-alpha-nl, interferon-alpha-n3 , Interferon-beta, interferon-gamma-la, interleukin-2, intron A, Iressa, mnotecan, Kytril, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl, lomustine,

Lonidamine, Marinol, Mechlorethamine, Mecobalamin, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Menest, 6-Mercaptopurine, Mesna, Methotrexate, Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotane, 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, Prednimustin, Prednisolone, Prednisone, Premarin, Procarbazine, Procrit, Raltitrexed, RDEA119, Rebif, Rhenium 186 etidronate, Rituximab, Roferon-A, Romurtide, Salagen, Sandostatin, Sargramostim, Semustin, Sizofiran, Sobuzoxan, Solu-Medrol , Streptozocin, Strontium-89-chloride, Synthroid, Tamoxifen, Tamsulosin, Tasonermin, Tastolactone, Taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, T ositumomab, tastuzumab, teosulfan, tretinoin, Trexal, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizine, zinecard, zinostatin stalinamer, zofran; ABI-007, Acolbifen, Actimmun, Affinitak, Aminopterin, Arzoxifen, Asoprisnil, Atamestan, Atrasentan, BAY 43-9006 (Sorafenib), Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin MTC, dSLEM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium 166-DOTMP, 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, neovastate, nolatrexed, oblimersen, onco-TCS, osmidem, paclitaxel Polyglutamate, pamidronate disodium, PN-401, QS-21, Quazepam, R-1549,

Raloxifene, Ranpirnas, 13-cw Retinoic Acid, Satraplatin, Seocalcitol, T-138067, Tarceva, Taxoprexin, Thymosin-alpha-1, Tiazofurin, Tipifarnib, Tirapazamine, TLK-286, Toremifene, TransMID-107R, Valspodar, Vapreotide, Vatalanib, Verteporfin, vinflunine, Z-100, zoledronic acid, as well as combinations thereof.

In a preferred embodiment, compound A of the present invention may be combined with the following active ingredients:

1311-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide , Bisantres, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide , Cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin-alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin-diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin , Enocitabine, Epirubicin, Epitiostanol, Epoetin-alfa, Epoetin-beta, Eptaplatin, Eribul in, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestan, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxime, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125- Seeds, ibandronic acid, ibritumomab-tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab, mnotecan, ipabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, Letrozole, Leuprorelin, Levamisole, Lisuride, Lobaplatin, Lomustine, Lonidamine, Masoprocol, Medroxyprogesterone, Megestrol, Melphalan, Mepitiostan, Mercaptopurine, Methotrexate, Methoxsalen, Methylaminolevulinate, Methyltestosterone, Mifamurtide, Miltefosine, Miriplatin, Mitobronitol, Mitoguazon, Mitolactol, Mitomycin, Mitotan, Mitoxantrone, Nedaplatin, Nelarabine, Nilotinib, Nilutamide, Nimotuzumab, Nimustine, Nitracrin, Ofatumumab, Omeprazole, Oprelvekin, Oxaliplatin, p53 Gene Therapy, Paclitaxel, Palifermin, Palladium 103-seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin-beta (methoxy-PEG-epoetin-beta), pegfilgrastim, peg-interferon-alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin , Plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, radium-223 chloride, raloxifene, raltitrexed, ranimustine, racoxan, refametinib, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim , Sargramostim, Sipuleucel-T, Sizofiran, Sobuzoxan, Sodium glycididazole, Sorafenib, Streptozocin, Sunitinib, Talaporfin, Tamibaroten, Tamoxifen, Tasonermin, Teceleukin, Tegafur, Tegafur + Gimer acyl + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, toositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex Valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zostatin statinamer, zoledronic acid, zorubicin.

Promisingly, compound A can also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin, cetuximab) and recombinant proteins.

Compound A may also provide positive effects in combination with other angiogenic therapies, such as Avastin, axitinib, regorafenib, recentin, sorafenib, or sunitinib. Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.

In general, the following objectives can be pursued with the combination of compound A with other cytostatic or cytotoxic agents:

 • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;

• the possibility of using the chemotherapeutic agents used in lower doses than in monotherapy; • the possibility of a more tolerable therapy with fewer side effects compared to a single dose;

 • the ability to treat a wider range of tumors;

 • achieving a higher response rate to therapy;

· A longer survival time of the patients compared to today's standard therapy.

 In addition, the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.

Examples

1. Preparation of the compounds of the invention

 The preparation of the compounds according to the invention is comprehensively described in

PCT / EP2009 / 007247, to the disclosure of which the present application refers and which is to become part of this application by reference.

 A further developed production is disclosed in PCT / EP2011 / 066295, to the disclosure of which the present application also refers and which is to become part of this application by reference. 2. proliferation assay

 Human tumor cells were originally obtained from the American Type Culture Collection (ATCC), the German Collection of Microorganisms and Cell Cultures (DSMZ) Braunschweig, CLS Cell Lines Service GmbH Eppelheim, the Institute Gustave Roussy (Villejuif, France), or the Charite Berlin (Tab 2).

Adherent growing cells (A-673, RD, Rh30, Rh41, SK-N-AS, NCI-H2286, HCC-366, FaDu, CAL-33, RPMI-2650, SiHa) were grown at a density of 3000-4000 cells / Measuring point, depending on

Growth rate of the cell line, in a 96-well multititer plate in 200 microL

Growth medium (DMEM / HAMS F12, 2 mM L-glutamine, 10 fetal calf serum) plated. After 24 hours, the cells of one plate (zero point plate) were stained with crystal violet (see above), while the medium of the other plates was replaced with fresh culture medium (200 microL) to which the

Test substances in different concentrations (0 microM, as well as in the range 0.001-3 microM, the final concentration of the solvent dimethyl sulfoxide was 0.5%) were added replaced. The cells were incubated for 4 days in the presence of the test substances. Cell proliferation was determined by staining the cells with crystal violet. The cells were fixed by adding 20 microL / measuring point of a 1 L% glutaraldehyde solution for 15 minutes at room temperature. To Washing the fixed cells three times with water, the plates were dried at room temperature. The cells were supplemented by adding 100 microL / measuring point of a 0, l

Crystal violet solution (pH adjusted to pH3 by addition of acetic acid). After washing the stained cells three times with water, the plates were dried at room temperature. The dye was dissolved by adding 100 microL / measuring point of a 10% acetic acid solution. The extinction was determined photometrically at a wavelength of 595 nm. The percentage change in cell growth was calculated by normalizing the measurements to the absorbance values of the zero plate (= 0%) and the absorbance of the untreated (0 microM) cells (= 100%). The measurement data were normalized to 0% inhibition (cell proliferation without inhibitor) and 100% inhibition (zero plate). The IC ₅₀ values were determined by means of a 4-parameter fit.

Cells growing in suspension (HBL-1, TMD-8, GRANTA-519, Jeko-1) were grown in a 96-well clear bottom multititer plate at a cell density of 2000-4000 cells / measurement point, depending on cell line growth rate 100 microL growth medium (DMEM / HAMS F12, 2 mM L-glutamine, 10% fetal calf serum) plated. After 24 hours, the cell density in a plate (zero point plate) was shaken by addition of 60 microL / measuring point CTG solution (Promega Cell Titer Glo Solution (catalog # G755B and G756B)) followed by incubation for 2 min followed by 10 min (im darken) and measurement of luminescence (VICTOR V, Perkin Elmer).

 For the test plates, the test substances were prepared in different concentrations (0 microM, as well as in the range 0.001-3 microM, the final concentration of the solvent dimethylsulfoxide was 0.5%) as 3-fold concentrated solutions in fresh growth medium. Aliquots a 50 microL were added to the cell suspensions and the cells were incubated for 4 days in the presence of the test substances. Subsequently, the cell density was determined by CTG solution as described above and IC50 values were calculated by means of a 4-parameter fit.

The cytotoxic effect of BAY 1000394 on Jeko-1 and UPN-1 cells was also determined after 24 hours of substance incubation. For this purpose, 50,000 cells per measurement point were plated in 96-well plates and incubated with BAY 1000394 in various concentrations in the range of 0.001 to 1.0 microM. After 24 hours, the viability of the cells was determined by the WST-1 method (Roche Diagnostics # 11644807001). The substances were investigated in the following cell lines, which exemplify the indicated indications (Table 1).

Tab. 1 List of investigated cell lines and results of proliferation assays.

 * after 24-hour substance incubation

The results of the proliferation assays demonstrate the efficacy of BAY1000394 in the human tumor cells examined. These data suggest an application of BAY1000394 in the tumor types studied.

Claims

claims

use of

 (RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

use of

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

use of

 (RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl sulfoximide for the manufacture of a medicament for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or

 Squamous cell carcinoma of the lung, head and neck or cervix.

use of

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl sulfoximide for the manufacture of a medicament for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or

 Squamous cell carcinoma of the lung, head and neck or cervix.

Use according to one of claims 1 to 4, characterized in that a lymphoma is treated.

Use according to one of claims 1 to 5, characterized in that a diffuse large B-cell lymphoma or a mantle cell lymphoma is treated.

7. Use according to one of claims 1 to 4 characterized

that a neuroblastoma is being treated. (RS) -S-Cyclopropyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoxirnide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

(R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

Containing pharmaceutical or pharmaceutical formulation

(RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

Containing pharmaceutical or pharmaceutical formulation

(R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.

A compound according to any one of claims 8 or 9 or a pharmaceutical or pharmaceutical formulation according to any one of claims 10 or 11, characterized in that a lymphoma is treated.

A compound according to any one of claims 8 or 9 or a pharmaceutical or pharmaceutical formulation according to any one of claims 10 or 11, characterized in that a neuroblastoma is treated.

combination of

(RS) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulfoximide with at least one further active ingredient for the treatment of lymphomas, rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lungs, the head and neck or the cervix.

15. combination of

 (R) -S-Cyclopropyl-S- (4- {[4- {[(IR, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl ) sulphoximide

 with at least one further active ingredient for the treatment of lymphomas, of

 Rhabdomyosarcomas, neuroblastomas or squamous cell carcinomas of the lung, head and neck or cervix.