EP2552450A1 - Use of novel pan-cdk inhibitors for treating tumors - Google Patents

Abstract

The invention relates to the use of selected sulfoximine-substituted anilinopyrimidine derivates of the formula (I) for treating tumors.

Description

 Use of new 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.

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.

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.

Compounds containing a phenylsulfonamide group are inhibitors of human

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

Carboanhydrase-2 and thereby block their enzymatic function (A. Casini, F. Abbate, A. Scozzafava, CT Supuran, Bioorganic, Med. Chem. Lett., 2003, 1, 2759). The clinical use of 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.

Examples of sulfoximine active substances 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.

Starting from this prior art, the object of the present invention is to provide compounds which not only inhibit CDK potently, but which also effectively inhibit tumor growth. Although potent CDK inhibition is a necessary but not sufficient prerequisite for effective tumor inhibition. For this purpose, further properties of the structures are necessary, such as the penetration properties into the tumor cell.

It has now been found that compounds of the general formula (I)

in the

 X is -O- or -NH-, and

R ^{1 is} a methyl, ethyl, propyl or isopropyl group, and

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,

and their physiologically acceptable salts, diastereomers and enantiomers, not only inhibit CDK potent, but also inhibit tumor growth particularly effective.

Compounds in which X is -O- are summarized by the formula (Ia).

Compounds in which X is -NH- are summarized by the formula (Ib).

The application is based on the following definitions: d-Q-alkyl

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.

Cvcv-Cycloalkyl

Under a _C3-C7 cycloalkyl ring, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a cycloheptyl ring is understood. In the general formula (I), X may be -O- or -NH-. Preferably, X is -0-.

In the general formula (I), R ^{1 may} represent a methyl, ethyl, propyl or isopropyl group. Preferably, R ^{1 is} a methyl group.

In the general formula (I), R ² and R ^{3 may} independently represent hydrogen, a methyl or ethyl group.

Preferably, 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. In the general formula (I), 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, and

R ^{2 is} a methyl group, and

R ^{3 is} hydrogen or a methyl group, and

R ^{4 is} a methyl or ethyl group or a cyclopropyl ring, and their physiologically acceptable salts, diastereomers and enantiomers. The use according to the invention of the following individual compounds, as well as their enantiomers, diastereomers and physiologically acceptable salts, is extremely preferred:

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

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

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

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

(RS) -S-ethyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide, - (RS) -S-ethyl-S- (4- {[4- {[(R) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrimidine-2- yl] amino} phenyl) sulfoximide,

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

- (RS) -S- (4- {[4- {[(IR) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) -S -methylsulfoximid.

Also to be considered as encompassed by the present invention is the use of the physiologically acceptable salts of the compounds.

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,

Dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Another object of the present invention are pharmaceutical 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. For this purpose, 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.

For these routes of administration, the compounds of the invention can be used in suitable

Administration forms are administered.

For oral administration are according to the prior art functioning quickly and / or modified compounds of the invention donating application forms that the

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.

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

intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with involvement of a resorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For other routes of administration are, for example, 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. These adjuvants 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), synthetic and natural polymers

(e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and flavor and / or odoriferous agents.

Another object of the present invention are pharmaceutical compositions containing at least one

Compound of the invention, usually together with one or more inert,

non-toxic, pharmaceutically suitable excipients and their use for the purposes mentioned above. 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.

As excipients, for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, adsorbents and adsorbents, diluents, solvents,

Cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used.

Attention is directed 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 compounds according to the formulas (I) for the prophylaxis and therapy of tumor diseases.

The compounds according to the formula (I) can be used in particular to the

Inhibit or reduce cell proliferation and / or cell division and / or induce apoptosis.

The compounds of the invention are particularly suitable for the treatment of hyper-proliferative diseases such as

Psoriasis,

 Keloids and other skin-related hyperplasias

 benign prostatic hyperplasia (BPH),

 solid tumors and

- hematological tumors. As solid tumors according to the invention, for example, 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.

For example, treatable as breast tumors are:

 Breast cancer with positive hormone receptor status

 Breast cancer with negative hormone receptor status

- Her-2 positive breast cancers

 Hormone receptor and Her-2 negative breast cancers

 BRCA-associated breast cancer

 inflammatory breast cancer.

For example, tumors of the respiratory tract are treatable

 non-small cell lung cancers and

 small cell bronchial carcinomas.

For example, tumors of the brain are treatable

- glioma,

 glioblastomas,

 astrocytomas,

 Meningiomas and

 Medulloblastomas.

For example, tumors of the male reproductive organs are treatable:

 prostate cancers,

 Malignant testicular tumors and

Penis cancer. Treatable as tumors of the female reproductive organs, for example: endometrial carcinomas

 cervical cancer

 ovarian cancer

- vaginal carcinomas

 Vulvarkarzinome

For example, tumors of the gastrointestinal tract are treatable:

 Colorectal carcinomas

- Anal carcinomas

 gastric cancers

 pancreatic cancer

 Ösophagukarzinome

 Gallbladder carcinomas

- Small intestinal carcinomas

 Salivary gland carcinomas

 Neuroendocrine tumors

 Gastrointestinal stromal tumors As tumors of the urogenital tract, for example, are treatable:

 bladder cancer

 Renal cell carcinoma

 Carcinomas of the renal pelvis and the urinary tract As tumors of the eye, for example, are treatable:

 retinoblastoma

 Intraocular melanomas

Treatable as tumors of the liver, for example:

- Hepatocellular carcinomas

Cholangiocellular carcinomas For example, tumors of the skin are treatable:

 Malignant melanomas

 Basal cell carcinomas

 squamous

- Kaposi's sarcoma

 Merkel cell carcinoma

Tumors of the head and neck, for example, are treatable:

 laryngeal cancer

- Carcinoma of the pharynx and oral cavity

For example, sarcomas are treatable:

 Soft tissue sarcomas

 osteosarcomas

For example, lymphomas are treatable:

 Non-Hodgkin's lymphoma

 Hodgkin's lymphoma

 Cutaneous lymphoma

- mantle cell lymphoma

 Lymphomas of the central nervous system

 AIDS-associated lymphomas

Treatable as leukemias, for example:

- Acute myeloid leukemias

 Chronic myeloid leukemias

 Acute lymphocytic leukemia

 Chronic lymphocytic leukemia

Hairy cell leukemia Advantageously, 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

Bronchial carcinoma, colorectal carcinoma, ovarian carcinoma, cervical carcinoma,

Prostate carcinomas, leukemias or lymphomas.

 Particularly advantageously, 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,

colorectal carcinoma, small cell lung carcinoma or

 Cervical carcinomas, especially multidrug-resistant cervical carcinomas.

 These diseases are well characterized in humans, but also exist in other mammals.

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

Combination does not lead to unwanted 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, 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:

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, cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunoxone, decadron, decadron phosphate, delestrogen, denileukin diftitox , Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxo-rubicin, Dronabinol, DW-166HC, Eligard, Elitek, Ellence, Emend, Epirubicin, Epoetin-alfa, Epogen, Eptaplatin, Ergamisol, Estrace, Estradiol, Estramustine Sodium phosphate, ethinylestradiol, ethylol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestan, Fosteabin, Fotemustin, 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-αα, interleukin-2, intron A, Iressa, irinotecan, 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, 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,

 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, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexall, Trimethylmelamine, Trimetrexate, Triptorelin Acetate, Triptorelin Pamoate, UFT, Uridine, Valrubicin, Vesnarinone, Vinblastine, Vincristine, Vindesine, Vinorelbine, Virulizine, Zinecard, Zinostatin Stimalamer, 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, dSLIM, 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, 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,

Tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid, and combinations thereof.

In a preferred embodiment, 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, hydroxyurea, hydroxyprogesterone Caproate, idadirubin, ifosfamide, interferon, irinotecan, leucovorin, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl L-aspartate (PALA), plicamycin, prednisolone, prednisone, procarbazine, raloxifene, semustin, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguani n, thiotepa, topotecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine and vinorelbine.

In a promising manner, 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. 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

Side effects profile particularly suitable.

In general, the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims:

• improved efficacy in slowing down the growth of a tumor in which

 Reduction in size or even total elimination 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

 Single dose; · The ability to treat a wider range of tumors;

• achieving a higher response rate to therapy;

• longer patient survival compared to today's standard therapy.

In addition, 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 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. The main features of the production:

Preparation of the compounds of the formula (Ia) (4-Q derivatives)

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).

 Direct imination of the sulfoxide of the formula (IVc) into a protected sulfoximine of the formula

(I

or t> 2) Imination of the sulfoxide of the formula (IVc) to give an unprotected sulfoximine of the formula (IVb)

 Reduction of the compound of the formula (IVa) to give a compound of the formula (IV)

 Functionalization of the 4-position of 2,4-dichloro-5-iodopyrimidine (VII) by reaction with a mono-protected (PG = protective group) diol of the formula (VI) to give a

 Intermediates of formula (Va).

 R

(VII) (Va)

e) Preparation of the 5-CF ₃ Intermediate (V).

(Va) (V) Coupling of the compounds of the formula (IV) and (V) to the intermediate of the formula (III).

G)

 (III) (II)

h) Cleavage of the protecting group on the sulfoximine to form (Ia).

 (Ii) (la)

wherein the substituents R ¹ , R ² , R ³ and R ^{4 have} the meaning given in the general formula (I). Preparation of the compounds of general formula (Ib) (4-N derivatives)

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 formula (IVd) to the sulfoxide of the formula (IVc). b) Direct imination of the sulfoxide of the formula (IVc) into a protected sulfoxime of the formula (IVa).

or

b2) Imination of the sulfoxide of the formula (IVc) to give an unprotected sulfoxime of the formula (IVb) and subsequent introduction of the protective group to a compound of the formula (IVa).

c) reduction of the compound of the formula (IV)

(IV)

 Functionalization of the 4-position of 2,4-dichloro-5-trifluoromethyl-pyrimidine (VIIb) by reaction with an amine of the formula (Via) to give an intermediate of the formula (Vb).

e) coupling of the compounds of the formula (Vb) and (IV) to the intermediate of the formula (IIb).

f) Cleavage of the formation of (Ib).

where the substituents R ¹ , R ² , R ³ and R ^{4 have} the meanings given in the general formula (I). example 1

(A ₁ S) -5'-Cyclopropyl- ₁ S '- (4 - {[4 - {[(L, 2 A) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyridinidine-2 yl] ainino} phenyl) sulfoxiinid

The preparation of Example 1 is carried out according to Example 1 of PCT / EP2009 / 007247.

The diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:

Column: Chiralpak IA 5μ 250x30 mm

 Eluent: hexane / ethanol 8: 2

 Flow: 40.0 mL / min

 Detector: UV 254 nm

 Temperature: room temperature

 Retention time: 10.8-13.4 min; Stereoisomer 1 (= Example 1-SI-1)

 13.6-18.5 min; Stereoisomer 2 (= Example I-SI-2) Example 2

(Λ ₁ S) -5 '- (4 - {[4 - {[(L, 2α) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino-phenyl-1-yl methylsulphoximide

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:

Column: Chiralpak IC 5μ 250x20 mm

 Eluent: hexane / ethanol 8: 2

 Buffer: hexane / 0.1% DEA

 Flow: 25.0 mL / min

 Detector: UV 280 nm

 Temperature: room temperature

 Retention time: 9.5-12.1 min; Stereoisomer 1 (= example 2-SI-1)

 13.1-16.0 min; Stereoisomer 2 (= Example 2-SI-2)

Example 3

(A5) -5 '- (4 - {[4 - {[(A) -2-Hydroxy-1,2-dimethylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino-phenyl-A-methylsulfoximide

The preparation of Example 3 is carried out according to Example 3 of PCT / EP2009 / 007247.

The residue was purified by HPLC. 31 mg (0.07 mmol, yield: 14%) of the product were obtained.

Example 4

(A ₁ S) -5'-Cyclopropyl- ₁ S '- (4 - {[4 - {[(L, 2 A) -2-hydroxy-1-methylpropyl] amino} -5- (trifluoromethyl) pyrimidine-2 yl] amino} phenyl) sulfoximide

The preparation of Example 4 is carried out according to Example 4 of PCT / EP2009 / 007247.

The diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:

Column: Chiralpak IA 5μ 250x20 mm

 Eluent: hexane / 2-propanol 50:50

 Buffer: hexane / 0.1% DEA

 Flow: 15 mL / min

 Detector: UV 254 nm

 Temperature: room temperature

 Retention time: 5.9-6.6 min; Stereoisomer 1 (= Example 4-SI-1)

 7.1-8.8 min; Stereoisomer 2 (= Example 4-SI-2)

 Example 5

(A ₁ S) -5'-Cyclopropyl-5 ^, - (4 - {[4 - {[(A) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl ] amino} phenyl) sulfoximide

The preparation of Example 5 is carried out according to Example 5 of PCT / EP2009 / 007247.

The diastereomer mixture was separated by preparative HPLC into the pure stereoisomers: Chiralpak AD-H 5μ 250x20 mm

 Hexane / 2-propanol 60:40

 Hexane / 0.1% DEA

 20.0 mL / min

 UV 280 nm

 room temperature

 5.1-6.3 min; Stereoisomer 1 (= Example 5-SI-1)

 8.0-10.8 min; Stereoisomer 2 (= Example 5-SI-2)

Example ö

(A5) -5'-Ethyl- ₁ S '- (4 - {[4 - {[(L, 2A) -2-hydroxy-1-methylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) sulfoximide

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:

Chiralpak AD-H 5μ 250x20 mm

 Hexane / 2-propanol 60:40

 Hexane / 0.1% DEA

 20.0 mL / min

 UV 280 nm

 room temperature

 6.2-6.8 min; Stereoisomer 1 (= Example 6-SI-1)

7.2-8.9 min; Stereoisomer 2 (= Example 6-SI-2) Example 7

(A5) -5'-ethyl- ₁ S '- (4 - {[4 - {[(A) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl)

pyrimidin-2-yl] amino} phenyl) sulfoximide

The preparation of Example 7 is carried out according to Example 7 of PCT / EP2009 / 007247.

The diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:

Column: Chiralpak AD-H 5μ 250x20 mm

 Eluent: A: hexane B: 2-propanol

 Buffer: hexane / 0.1% DEA

Gradient: 20-> 40% B (20 ') + 40% B (5')

 Flow: 10.0 mL / min

 Detector: UV 280 nm

 Temperature: room temperature

 Retention time: 17.5-19.8 min; Stereoisomer 1 (= example 7-SI-1)

 20.1-22.0 min; Stereoisomer 2 (= Example 7-SI-2)

Example 8

(A5) -5 '- (4 - {[4 - {[(L, 2A) -2-hydroxy-1-methylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl] amino-phenyl-A-methylsulfoximide

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:

Chiralpak IC 5μ 250x20 mm

 Hexane / ethanol 50:50

 Hexane / 0.1% DEA

 20.0 mL / min

 UV 254 nm

 room temperature

 5.1-5.8 min; Stereoisomer 1 (= Example 8-SI-1)

 6.1-6.7 min; Stereoisomer 2 (= Example 8-SI-2)

Example 9

(A5) -5 '- (4 - {[4 - {[(IA) -2-Hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrimidin-2-yl-amino-phenyl-A-methylsulfoximide

The preparation of Example 9 is carried out according to Example 9 of PCT / EP2009 / 007247.

The diastereomer mixture was separated by preparative HPLC into the pure stereoisomers:

Chiralpak IC 5μ 250x20 mm

 Hexane / ethanol 80:20

 30.0 mL / min

 UV 254 nm

 room temperature

6.0-6.7 min; Stereoisomer 1 (Example ^9: SI l)

7.1-8.9 min; Stereoisomer 2 ^(Example 9-SI-2) Example 10

10.1 Assay 1: CDK1 / CycB Kinase Assay

Recombinant CDK1 and CycB GST fusion proteins purified from baculovirus-infected

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

Concentrations of test substances (0 μΜ, as well as within the range 0.01 - 100 μΜ) in

Assay buffer [50mM Tris / HCl pH8.0, 10mM MgCl ₂ , 0.1mM Na ortho-vanadate, 1.0mM

Dithiothreitol, 0.5 μΜ adenosine trisphosphate (ATP), 10 μg / measuring point histone IIIS, 0.2 μΟί / εε88ρυη1ίί 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 μΙ / measuring point).

15 μΐ 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. After drying the filter strips for 1 hour at 70 ° C, the filter strips were covered with scintillator strips (MeltiLex ™ A, Wallac) and baked at 90 ° C for 1 hour. The amount of incorporated ³³ P (substrate phosphorylation) was determined by

Scintillation measurement in a gamma radiation meter (Wallac) determined. The measurement data were normalized to 0%> inhibition (enzyme reaction without inhibitor) and 100%> inhibition (all

Assay components except enzyme). The determination of the IC ₅ o values was carried out using a 4-parameter fit using the proprietary software.

10.2 Assay 2: CDK2 / CycE Kinase Assay

Recombinant CDK2 and CycE GST fusion proteins purified from baculovirus-infected

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

Concentrations of test substances (0 μΜ, as well as within the range 0.01 - 100 μΜ) in

Assay buffer [50mM Tris / HCl pH8.0, 10mM MgCl ₂ , 0.1mM Na ortho-vanadate, 1.0mM

Dithiothreitol, 0.5 μΜ adenosine trisphosphate (ATP), 10 μg / measuring point histone IIIS, 0.2 μΟί / εε88ρυη1ίί 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 μΙ / measuring point). 15 μΐ 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. After drying the filter strips for 1 hour at 70 ° C, the filter strips were covered with scintillator strips (MeltiLex ™ A, Wallac) and baked at 90 ° C for 1 hour. The amount of incorporated ³³ P (substrate phosphorylation) was determined by

 Scintillation measurement in a gamma radiation meter (Wallac). The data were normalized to 0% inhibition (enzyme reaction without inhibitor) and 100% inhibition (all

Assay components except enzyme). The determination of the IC ₅ o values was carried out using a 4-parameter fit using the proprietary software.

10.3 Assay 3: VEGF receptor-2 kinase assay

Recombinant VEGF receptor tyrosine kinase-2 was purified as a GST fusion protein from baculovirus-infected insect cells (Sf9). Poly (Glu4Tyr), which was used as a kinase substrate, was purchased from Sigma. 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 μΜ, and within the range 0.001-30 μΜ) in 30 μΐ assay buffer [40 mM Tris / HCl pH 5.5, 10 mM MgCl ₂ , 1 mM MnCl ₂ , 3 μM Na ortho-vanadate, 1.0 mM dithiothreitol, 8 μM adenosine trisphosphate (ATP), 0.96 μg / assay point poly (Glu ₄ Tyr), 0.2 μΟί / εε88ρυη 1ίί ³³ P-gamma ATP, 1.4% dimethylsulfoxide]. The reaction was stopped by addition of EDTA solution (250 mM, pH 8.0, 15 μΙ / measuring point).

15 μΐ 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. After drying the filter strips for 1 hour at 70 ° C, the filter strips were covered with scintillator strips (MeltiLex ™ A, Wallac) and baked at 90 ° C for 1 hour. The amount of incorporated ³³ P (substrate phosphorylation) was determined by

 Scintillation measurement in a gamma radiation meter (Wallac). The measurement data were normalized to 0%> inhibition (enzyme reaction without inhibitor) and 100%) inhibition (all

Assay components except enzyme). The determination of the IC ₅ o values was carried out using a 4-parameter fit using the proprietary software. 10.4 Assay 4: Proliferation Assay Example 1: Proliferation Assay

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 μΐ growth medium (DMEM / HAMS Fl 2, 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 below), while the medium of the other plates by fresh culture medium (200 μΐ), the test substances in various concentrations (0 μΜ, and in the range - 30 μΜ, 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 μl / 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. The cells were stained by adding 100 μΙ / measuring point of a 0.1% crystal violet solution (pH adjusted to pH 3 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 addition of 100 μΙ / 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 extinction of the untreated (0 μΜ) cells (= 100%). The measured data were normalized to 0%> inhibition (cell proliferation without inhibitor) and 100%) inhibition (zero plate). The determination of the IC ₅ o values was carried out using a 4-parameter fit using the proprietary software.

The substances were investigated in the following cell lines, which exemplify the indicated indications:

Tab. L

10.5 in vivo models

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)

Treatment Groups: Specified under 10.8.

The studies were designed to determine the initial response of the human tumor model to the therapies with the exemplary compound 2-SI-2. Percent tumor growth inhibition (TWH) was calculated either at the end of studies from the tumor weights (TWH _TG ) according to the formula 100 x [1- (tumor weight of treatment group / tumor weight of vehicle group)] or on the day the vehicle group had to be stopped from the tumor areas (TWH _TF ) according to the formula 100 x [1 - (tumor area of the treatment group on the day of the measurement - tumor area of the treatment group before the start of the treatment) / (tumor area of the vehicle group on the day of the measurement - tumor area of the vehicle group before the beginning of the treatment) ]. At a

Tumor growth inhibition greater than 50%, the treatment was considered effective.

The exemplary compound 2-SI-2 was investigated in the following in vivo tumor models, which exemplify the indicated indications:

Table 2

 Tumor indication in vivo Tumor model

 Estrogen receptor negative breast carcinoma MDA-MB 231

 Ovarian carcinoma A2780Cis

 Colon / rectum carcinoma HCT116

 Small cell bronchial carcinoma NCI-H69

 NCI-H146

 NCI-H526

 NCI-H82

 Cervical Carcinoma HeLa-MaTu

HeLa MaTu ADR 10.6 Results from the enzyme assays

Table 3

 CDK1 / CycB CDK2 / CycE VEGF-R2

Enzyme (Assay 1) (Assay 2) (Assay 3)

 Concentration of loaf-maximal inhibition of enzyme activity

Ex. Or cell proliferation, IC ₅ o [nM]

 1-SI-1 9 7 114 1-SI-2 7 9 163

2-SI-1 5 6 84

2-SI-2 4 5 281

3 13 10

 4-SI-1 6 6 46

4-SI-2

 5-SI-1 25 8 70

5-SI-2 9 8 82

6-SI-l 10 5 73

6-SI-2 5 5 71

7-SI-l 24 4 143

7-SI-2 7 5 136

8-SI-11 11 6 116

8-SI-2 3 4 81

9-SI-1 4 5 158

9-SI-2 17 3 154

10.7 Results from the proliferation assays

Table 4

 IC50 nM]

 Ex. 1 2 3 4 5 6 7 8 9

Cell line SI-1 SI-2 SI-1 SI-2 SI-1 SI-1 SI-2 SI-1 SI-2 SI-1 SI-2 SI-1 SI-2 SI-1 SI-2

SK-BR-3 13 21 33

 MDA-MB

 18 16

231

 MDA-MB

 15 16 11

453

 MCF7 48 15 39 11 70 34 33 34 59 26 106 39 44 23 89 271

OVCAR-8 12 14

 NCI

33 29 37

 ADR-Res

 A2780 3

 A2780-

10

cis

 HT29 29 28 12

 Caco-2 80 16 80 24 98 35 112 42 120 26 196 67 32 41 61 200

SW480 15 19 22 45 31

 HCT116 18 16 20 28 24 17 17

 DU145 45 8 28 9 76 31 107 26 100 197 152 42 64 30 34 185

PC3 25 27 <10

 NCI-H460 48 12 68 16 113 16 70 33 50 24 119 51 30 28 34 112

A549 20 23 <10

 H1975 11 14 16

 NCI-H69 37 37

 Caki2 26 24 <10

 786-0 20 22 30

 MIA

 21 19 14

PaCa 2

 HeLa 12 13 33 50 32 33 25

 HeLa

13 11 12 8 70 10 22 10 16 10 27 10 14 10 20 21 MaTu

 HeLa MaTu 35 8 32 7 63 16 63 24 35 18 112 36 30 24 19 114 ADR

 A431 14 17 20

 A375 14 15

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.

10.8 Results from the in vivo tumor models

10.8.1 Cervical Carcinoma Model

Study:

 Effectiveness in HeLa-MaTu human cervical carcinoma xenograft model

Test System:

 HeLa-MaTu human cervical carcinoma cells implanted on female NMRI nude mice

 Application Form:

 Oral (stomach tube)

 formulation

a) 0.05 mg / ml, 0.10 mg / ml, 0.15 mg / ml, 0.2 mg / ml 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 Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 0.5 to 2.0 mg / kg (1.5 to 6.0 mg / m ² ) once daily

b) 1.5 to 2.5 mg / kg (4.5 to 7.5 mg / m ² ) twice a day for 2 consecutive days, followed by 5 treatment-free days

 Essential results

a) TWH _TG : 97% at 2.0 mg / kg

b) TWH _TG : 98% o at 2.5 mg / kg, signs of tumor regression 10.8.2 multi-drug resistant cervical carcinoma model

Study:

 Effectiveness in the HeLa-MaTu-ADR Res. Xenograft Model

Test System:

HeLa-MaTu-ADR multidrug-resistant human cervical carcinoma cells implanted on female NMRI nude mice.

 Application Form:

 Oral (stomach tube)

formulation

a) 0.15 mg / ml, 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.20 mg / ml, 0.25 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 1.5 and 2.0 mg / kg (4.5 and 6.0 mg / m ² ), lx daily

b) 2.0 and 2.5 mg / kg (6.0 and 7.5 mg / m ² ), twice daily for 2 consecutive days, followed by 5 treatment-free days

 Essential results

a) TWH _TG : 97% at 2.0 mg / kg

b) TWH _TG : 90% at 2.5 mg / kg, signs of tumor regression

10.8.3 Colon carcinoma model

Study:

 Effectiveness in the HCTl 16 human colorectal xenograft model.

Test System:

HCT 116 human colorectal tumor cells implanted on female NMRI nude mice.

Application Form:

Oral (stomach tube).

formulation

a) 0.15 mg / ml, 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.20 mg / ml, 0.25 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

c) 0.40 mg / ml, 0.50 mg / ml, 0.60 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 1.5 and 2.0 mg / kg (4.5 and 6.0 mg / m ² ), lx daily.

b) 2.0 and 2.5 mg / kg (6.0 and 7.5 mg / m ² ), twice daily for 2 consecutive days, followed by 5 treatment-free days.

c) 4.0 to 6.0 mg / kg (12 to 18 mg / m ² ), once a day for 2 consecutive days, followed by 5 treatment-free days.

 Essential results

a) TWH _TG : 67% at 2.0 mg / kg.

b) TWH _TG : 57% at 2.5 mg / kg, signs of tumor regression,

c) TWH _TG : 83% at 5.0 mg / kg. 10.8.4 Small cell lung carcinoma model

Study:

 Effectiveness in NCI-H69 human small cell lung tumor model.

Test System:

NCI-H69 human small cell lung tumor cells implanted on female NMRI nude mice. Application Form:

Oral (stomach tube).

formulation

a) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.25 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 2.0 mg / kg (6.0 mg / m ² ), once daily.

b) 2.5 mg / kg (7.5 mg / m ² ), twice a day for 2 consecutive days, followed by 5

 treatment-free days.

Essential results

a) 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

10.8.5 Small cell lung carcinoma model

Study:

 Effectiveness in the NCI-H146 human small cell lung tumor model.

Test System:

NCI-H146 human small cell lung tumor cells implanted on female NMRI nude mice. Application Form:

Oral (stomach tube).

formulation

a) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 2.0 mg / kg (6.0 mg / m ² ), once daily.

b) 2.0 mg / kg (6.0 mg / m ² ), twice a day for 2 consecutive days, followed by 5

 treatment-free days.

Essential results

a) TWH _TG : 95% at 2.0 mg / kg.

b) TWH _TG : 82% at 2.0 mg / kg

10.8.6 Small cell lung carcinoma model

Study:

 Effectiveness in NCI-H82 human small cell lung tumor model.

Test System:

NCI-H82 human small cell lung tumor cells implanted on female NMRI nude mice. Application Form:

Oral (stomach tube).

formulation

a) 0.17 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 1.7 mg / kg (5.1 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

 Essential results

a) TWH _TG : 86% at 1.7 mg / kg.

10.8.7 Small cell lung carcinoma model

Study:

 Effectiveness in the NCI-H526 human small cell lung tumor model.

Test System:

NCI-H526 human small cell lung tumor cells implanted on female NMRI nude mice. Application Form:

Oral (stomach tube).

formulation

a) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

c) 0.15 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

d) 0.17 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 2.0 mg / kg (6.0 mg / m ² ), once daily.

b) 2.0 mg / kg (6.0 mg / m ² ), twice a day for 2 consecutive days, followed by 5

 treatment-free days.

c) 1.5 mg / kg (4.5 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

d) 1.7 mg / kg (5.1 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

 Essential results

a) TWH _TG : 98% at 2.0 mg / kg.

b) TWH _TG : 72% at 2.0 mg / kg.

c) TWH _TG : 79% at 1.5 mg / kg.

d) TWH _TG : 88% at 1.7 mg / kg. 10.8.8 Breast Cancer Model

Study:

 Effectiveness in the MDA-MB231 human breast tumor model MDA-MB231.

Test System:

MDA-MB231 human breast tumor cells implanted on female NMRI nude mice.

Application Form:

Oral (stomach tube).

formulation

a) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.25 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

c) 0.15 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

d) 0.17 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 2.0 mg / kg (6.0 mg / m ² ), once daily.

b) 2.5 mg / kg (7.5 mg / m ² ), twice a day for 2 consecutive days, followed by 5

 treatment-free days.

c) 1.5 mg / kg (4.5 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

d) 1.7 mg / kg (5.1 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

 Essential results

a) 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.

c) TWH _TF : 70% at 1.5 mg / kg.

d) TWH _TF : 70% at 1.7 mg / kg. 10.8.9 Ovarian carcinoma model

Study:

 Effectiveness in the A2780-Cis human ovarian tumor model.

Test System:

Effectiveness in the A2780-Cis human ovarian tumor model A2780-Cis Cisplatin-resistant human ovarian tumor cells implanted on female NMRI nude mice.

 Application Form:

 Oral (stomach tube).

formulation

a) 0.20 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

b) 0.15 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

c) 0.17 mg / ml Example 2-SI-2 in 40% (v / v) PEG 400 in water

Dosage and treatment scheme:

a) 2.0 mg / kg (6.0 mg / m ² ), once daily.

b) 1.5 mg / kg (4.5 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

c) 1.7 mg / kg (5.1 mg / m ² ), twice a day for 3 consecutive days, followed by 4

 treatment-free days.

 Essential results

a) TWH _TG : 85% at 2.0 mg / kg.

b) TWH _TG : 88% at 1.5 mg / kg.

c) TWH _TG : 92% at 1.7 mg / kg. The results of the treatment study with the example compound 2-SI-2 in monotherapies

demonstrate the antitumor activity of the exemplary compound in animal models of human cervical tumors, small cell bronchial tumors, colorectal tumors, breast tumors, and ovarian tumors. 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.

Claims

claims

1. Use of a compound of the general formula (I)

in the

 X is -O- or -NH-, and

R ^{1 is} a methyl, ethyl, propyl or isopropyl group, and

R ² and R ^{3 are} independently hydrogen, methyl or ethyl, and

R ^{4 is} a C 1 -C 6 -alkyl group or a C ₃ -C ₇ -cycloalkyl ring

 stands,

 and their physiologically tolerated salts, diastereomers and enantiomers

 for the treatment of tumors.

2. Use according to claim 1 of a compound of general formula (I)

 in the

 X is -O- or -NH-, and

R ^{1 is} a methyl group, and

R ^{2 is} a methyl group, and

R ^{3 is} hydrogen or a methyl group, and

R ^{4 represents} a methyl or ethyl group or represents a cyclopropyl ring,

 and their physiologically tolerated salts, diastereomers and enantiomers

for the treatment of tumors. use of

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

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

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

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

 - (RS) -S-Cyclopropyl-S- (4- {[4- {[(R) -2-hydroxy-1,2-dimethylpropyl] amino} - 5- (trifluoromethyl) pyrirnidin-2-yl] amino} phenyl) sulfoximide

 - (RS) -S-ethyl-S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] amino} -5- (trifluoromethyl) pyrimidine

2-yl] amino} phenyl) sulfoximide

 (RS) -S-ethyl-S- (4- {[4- {[(R) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrimidine

2-yl] amino} phenyl) sulfoximide

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

 - (RS) -S- (4- {[4- {[(IR) -2-hydroxy-1,2-dimethylpropyl] amino} -5- (trifluoromethyl) pyrirnidin-2-yl] amino} phenyl) -S -methylsulfoximid

and their physiologically tolerated salts, diastereomers and enantiomers

for the treatment of tumors.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of tumors.

Use according to any one of claims 1 to 3 for the treatment of

Breast carcinoma, pancreatic carcinoma, renal cell carcinoma, malignant melanoma and other skin tumors, small cell lung carcinoma, non-small cell

Bronchial carcinoma, colorectal carcinoma, ovarian carcinoma, cervical carcinoma, prostate carcinoma, leukemia or lymphoma. Use according to claim 5 for the treatment of

 Breast cancer, ovarian carcinoma, colorectal carcinoma, small cell

 Bronchial carcinoma or cervical carcinoma.

use of

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

 and their physiologically tolerated salts, diastereomers and enantiomers for the treatment of

 multidrug-resistant cervical carcinoma, colorectal carcinoma, small cell

 Bronchial carcinoma, breast cancer and cisplatin-resistant ovarian carcinoma

Compounds of the general formula (I)

in the

 X is -O- or -NH-, and

R ^{1 is} a methyl, ethyl, propyl or isopropyl group, and

R ² and R ^{3 are} independently hydrogen, methyl or ethyl, and

R ^{4 is} a C 1 -C 6 -alkyl group or a C ₃ -C ₇ -cycloalkyl ring

 stands,

and their physiologically tolerated salts, diastereomers and enantiomers for the treatment of tumors.

9. (RS) -S- (4- {[4- {[(1R, 2R) -2-hydroxy-1-methylpropyl] oxy} -5- (trifluoromethyl) pyrimidin-2-yl] amino} phenyl) - S-methylsulfoximide, and their physiologically acceptable salts, diastereomers and enantiomers for the treatment of tumors.