WO2014173815A1 - Use of (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-methylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide for the treatment of specific tumours - Google Patents
Use of (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-methylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide for the treatment of specific tumours Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- (RS)-S-cvclopropyl-S-(4- ⁇ r4- ⁇ rqR, 2R)-2-hydroxy-l-methylpropylloxy ⁇ -5- (trifluoromethyl)pyrimidin-2-yl1amino ⁇ phenyl)sulphoximide for the treatment of specific tumours
- the present invention relates to the use of (RS)-S-cyclopropyl-S-(4- ⁇ [4- ⁇ [(1R, 2R)-2-hydroxy-l- methylpropyl]oxy ⁇ -5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)sulphoximide, in particular (R)- S-cyclopropyl-S-(4- ⁇ [4- ⁇ [(lR, 2R)-2 -hydroxy- l-methylpropyl]oxy ⁇ -5-(trifluoromethyl)pyrimidin-2- yl]amino ⁇ phenyl)sulphoximide, for the treatment of specific tumours.
- CDKs The cyclin-dependent kinases
- the cyclin-dependent kinases (CDKs) are an enzyme family which plays an important role in the regulation of the cell cycle and therefore represents a particularly interesting target for the design of small inhibitory molecules.
- Selective inhibitors of CDKs can be used for treating cancer or other disorders caused by impaired cell proliferation.
- Pyrimidines and analogues have already been described as active compounds, for example the 2- anilinopyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for the treatment of neurological or neurodegenerative disorders (WO 99/19305).
- CDK inhibitors for example 2-amino-4-substituted pyrimidines (WO 01/ 14375), purines (WO 99/02162), 5-cyanopyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N,N-dimethylaminopropoxypyrimidines (WO 00/39101).
- WO 02/096888 and WO 03/076437 disclose in particular pyrimidine derivatives having CDK- inhibitory activity.
- active sulphoximine compounds are sulphonimidoyl-modified triazoles as fungicides (H. Kawanishi, H. Morimoto, T. Nakano, T. Watanabe, K. Oda, K. Tsujihara, Heterocycles 1998, 49, 181) or arylalkylsulphoximines as herbicides and pesticides (Shell International Research, Ger. P. 2 129 678).
- WO 2005/037800 discloses open sulphoximine-substituted anilinopyrimidine derivatives as inhibitors of cyclin-dependent kinases. Examples are given of structures which, in the 5-position of the pyrimidine, are either unsubstituted or substituted by halogen, in particular bromine. None of the specific structures disclosed has a 5-trifluoromethyl substituent.
- the novel pan-CDK inhibitors and processes for their preparation are described in the PCT application PCT/EP2009/007247, the disclosure of which is referred to by the present application and which is incorporated into the present application by this reference.
- PCT/EP2011/054733 relates to the use of a group of pan-CDK inhibitors for various tumour disorders.
- (RS)-S-Cyclopropyl-S-(4- ⁇ [4- ⁇ [( 1R, 2R)-2-hydroxy- l-methylpropyl]oxy ⁇ -5- (trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)sulphoximide is Exemplary compound 1.
- DEI 02010014427 relates to the combination of the abovementioned group of pan-CDK inhibitors with other tumour therapeutics for various tumour disorders.
- (RS)-S-Cyclopropyl-S-(4- ⁇ [4- ⁇ [(lR, 2R)-2- hydroxy- 1 -methylpropyl] oxy ⁇ -5 -(trifluoromethy l)pyrimidin-2-y 1] amino ⁇ phenyl) sulphoximide is Exemplary compound 1.
- Compound A (RS)-S-Cyclopropyl-S-(4- ⁇ [4- ⁇ [( 1R, 2R)-2-hydroxy- l-methylpropyl]oxy ⁇ -5- (trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)sulphoximide
- Compound A is a selected sulphoximine-substituted anilinopyrimidine derivative which can be separated into two stereoisomers, namely:
- Compound A' is preferred and is, as BAY1000394, undergoing clinical trials.
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- Waldenstrom Waldenstrom
- mastocytosis/mastocytoma medulloblastoma, melanoma
- meningeal carcinomatosis meningioma
- metastases multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
- the present application furthermore provides (RS)-S-cyclopropyl-S-(4- ⁇ [4- ⁇ [(1R, 2R)-2-hydroxy-l- methylpropyl]oxy ⁇ -5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)sulphoximide
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- Waldenstrom Waldenstrom
- mastocytosis/mastocytoma medulloblastoma, melanoma
- meningeal carcinomatosis meningioma
- metastases multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
- Both in monotherapy and in combination therapy there are preferably 3 days of treatment and 4 days of non-treatment.
- the treatment protocol is, if required, adapted to the individual disease situation of the patient and/or in the combination therapy with the substance or the substances employed in the combination therapy.
- the present application furthermore provides combinations of
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- Waldenstrom Waldenstrom
- mastocytosis/mastocytoma medulloblastoma, melanoma
- meningeal carcinomatosis meningioma
- metastases multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
- the present invention also embraces the use of the physiologically acceptable salts of Compound A.
- Physiologically acceptable salts of Compound A include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
- hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic
- Physiologically acceptable salts of Compound A also include salts of customary bases such as, by way of example and preferably, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- alkali metal salts for example sodium salts and potassium salts
- alkaline earth metal salts for example calcium salts and magnesium salts
- the present invention furthermore provides medicaments comprising compound A and at least one or more further active compounds for the treatment and/or prophylaxis of
- myelodysplastic-myeloproliferative diseases adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macro
- Waldenstrom Waldenstrom
- mastocytosis/mastocytoma medulloblastoma, melanoma
- meningeal carcinomatosis meningioma
- metastases multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
- Compound A according to the invention can act systemically and/or locally. To this end, it can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.
- Compound A can be administered in suitable administration forms.
- Suitable administration forms for oral administration are those which function according to the prior art and deliver the compounds according to the invention rapidly and/or in modified fashion, and which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention), films/lyophilizates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
- solubilisers are macrogols, in particular macrogol 400.
- Suitable surfactants are polysorbates, in particular polysorbate 20.
- Suitable flavourings are essential oils, in particular menthol.
- the concentration of the pharmaceutical may be from 0.1 mg/ml to 10 mg/ml, preferably from 0.2 mg/ml to 8 mg/ml, particularly preferably from 0.3 mg/ml to 6 mg/ml and most preferably from 0.4 mg/ml to 4 mg/ml. Examples given are the concentrations 0.2 mg/ml and 4.8 mg/ml. Tablets comprising or consisting of fillers, disintegrants and/or one or more additives for pressing have also been found to be advantageous for Compound A.
- Suitable fillers are polyols such as mannitol, in particular in granulated form, or else cellulose derivatives such as microcrystalline cellulose.
- Suitable additives for pressing are stearates, in particular magnesium stearate.
- Suitable disintegrants are cellulose derivatives, in particular croscarmellose.
- the concentration of the pharmaceutical may be from 0.1 mg/tablet to 10 mg/tablet, preferably from 0.3 mg/tablet to 8 mg/tablet, particularly preferably from 0.4 mg/tablet to 6 mg/tablet and most preferably from 0.5 mg/tablet to 5 mg/tablet.
- Compound A Prior to and for formulation into the form of a medicament, Compound A is preferably present in micronized form.
- Parenteral administration can bypass an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
- Suitable administration forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- suitable examples are inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants or stents.
- inhalation medicaments including powder inhalers, nebulizers
- nasal drops solutions or sprays
- tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants
- Compound A can be converted to the administration forms mentioned.
- auxiliaries include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g.
- the present invention further provides medicaments which comprise compound A, typically together with one or more inert, nontoxic, pharmaceutically suitable auxiliaries, and for the use thereof for the aforementioned purposes.
- composition of Compound A into pharmaceutical preparations is carried out in a manner known per se by converting the active compound(s) into the desired administration form using auxiliaries customary in the art of pharmaceutical formulation.
- auxiliaries are, for example, carrier substances, fillers, disintegrants, binders, moisturizers, glidants, absorbants and adsorbants, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavour correctants, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffer.
- the pharmaceutical formulations may be present.
- liquid form for example as solutions, tinctures, suspensions or emulsions.
- auxiliaries for the purpose of the invention can, for example, be salts, saccharides (mono-, di-, tri-, oligo- and/or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, where the auxiliaries may be of natural origin or can be obtained synthetically or by partial synthesis.
- Suitable for oral or peroral administration are in particular tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.
- Suitable for parenteral administration are in particular suspensions, emulsions and especially solutions.
- Dosage and treatment protocol can and must be varied depending on the type of carcinoma and the treatment target.
- the daily dose is from 0.5 mg to 20 mg and may be divided into a plurality of identical or different dosage units, preferably 2.
- the preferred daily dose is from 1.0 mg to 15 mg and may be divided into a plurality of identical or different dosage units, preferably 2.
- Treatment may be carried out over 2 to 60 days, where the treatment is preferably followed by 2 to 30 days of non-treatment. Treatment is successful if there is at least disease stabilization and the side-effects occur to an extent which is easily treatable, but at least easily acceptable.
- Compound A may be employed alone or, if required, in combination with one or more other pharmacologically active substances, provided this combination does not lead to unwanted and unacceptable side-effects. Accordingly, the present invention furthermore provides medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and/or prevention of the disorders mentioned above.
- Compound A may be combined with known antihyperproliferative, cytostatic or cytotoxic substances for the treatment of cancerous disorders.
- the combination of the compounds according to the invention with other substances customary for cancer therapy or else with radiotherapy is particularly indicated.
- active compounds suitable for combinations there may be mentioned:
- the compound A can be combined with antihyperproliferative agents, which can be, by way of example - without this list being conclusive:
- compound A can also be combined with biological therapeutics such as antibodies (for example Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
- biological therapeutics such as antibodies (for example Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
- compound A in combination with other therapies directed against angiogenesis such as, for example, with Avastin, axitinib, regorafenib, Recentin, sorafenib or sunitinib.
- therapies directed against angiogenesis such as, for example, with Avastin, axitinib, regorafenib, Recentin, sorafenib or sunitinib.
- antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favourable profile of side effects.
- the following aims can be pursued with the combination of compound A with other cytostatically or cytotoxically active agents:
- the compounds according to the invention can also be used in conjunction with radiotherapy and/or surgical intervention.
- PCT/EP2011/066295 discloses a preparation which is developed further.
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)sulphoximide and/or (S)-S-cyclopropyl-S-(4-{[4-{[(1R, 2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin- 2-yl]amino}phenyl)sulphoximide for the treatment of specific tumours.
Description
Use of (RS)-S-cvclopropyl-S-(4-{r4-{rqR, 2R)-2-hydroxy-l-methylpropylloxy}-5- (trifluoromethyl)pyrimidin-2-yl1amino}phenyl)sulphoximide for the treatment of specific tumours The present invention relates to the use of (RS)-S-cyclopropyl-S-(4-{ [4-{ [(1R, 2R)-2-hydroxy-l- methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide, in particular (R)- S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2 -hydroxy- l-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)sulphoximide, for the treatment of specific tumours. The cyclin-dependent kinases (CDKs) are an enzyme family which plays an important role in the regulation of the cell cycle and therefore represents a particularly interesting target for the design of small inhibitory molecules. Selective inhibitors of CDKs can be used for treating cancer or other disorders caused by impaired cell proliferation. Pyrimidines and analogues have already been described as active compounds, for example the 2- anilinopyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for the treatment of neurological or neurodegenerative disorders (WO 99/19305). Most diverse pyrimidine derivatives are described as CDK inhibitors, for example 2-amino-4-substituted pyrimidines (WO 01/ 14375), purines (WO 99/02162), 5-cyanopyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N,N-dimethylaminopropoxypyrimidines (WO 00/39101).
WO 02/096888 and WO 03/076437 disclose in particular pyrimidine derivatives having CDK- inhibitory activity.
Examples of active sulphoximine compounds are sulphonimidoyl-modified triazoles as fungicides (H. Kawanishi, H. Morimoto, T. Nakano, T. Watanabe, K. Oda, K. Tsujihara, Heterocycles 1998, 49, 181) or arylalkylsulphoximines as herbicides and pesticides (Shell International Research, Ger. P. 2 129 678).
WO 2005/037800 discloses open sulphoximine-substituted anilinopyrimidine derivatives as inhibitors of cyclin-dependent kinases. Examples are given of structures which, in the 5-position of the pyrimidine, are either unsubstituted or substituted by halogen, in particular bromine. None of the specific structures disclosed has a 5-trifluoromethyl substituent.
The novel pan-CDK inhibitors and processes for their preparation are described in the PCT application PCT/EP2009/007247, the disclosure of which is referred to by the present application and which is incorporated into the present application by this reference. (RS)-S-(4-{ [4-{ [(lR, 2R)-2 -Hydroxy- 1 - methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino }phenyl)-lS'-methylsulphoximide is Exemplary compound 1.
PCT/EP2011/054733 relates to the use of a group of pan-CDK inhibitors for various tumour disorders. (RS)-S-Cyclopropyl-S-(4- { [4- { [( 1R, 2R)-2-hydroxy- l-methylpropyl]oxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino }phenyl)sulphoximide is Exemplary compound 1.
DEI 02010014427 relates to the combination of the abovementioned group of pan-CDK inhibitors with other tumour therapeutics for various tumour disorders. (RS)-S-Cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2- hydroxy- 1 -methylpropyl] oxy } -5 -(trifluoromethy l)pyrimidin-2-y 1] amino } phenyl) sulphoximide is Exemplary compound 1.
Based on this prior art, it was the object of the present invention to provide compounds for patients suffering from specific tumours.
This is foreseeable only to a limited extent.
It has now been found that the compound (RS)-S-cyclopropyl-S-(4-{ [4-{ [(1R, 2R)-2-hydroxy-l- methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino }phenyl)sulphoximide (Compound A), in particular (R)-S-cyclopropyl-S-(4-{ [4-{ [(1R, 2R) -2-hydroxy-l -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino }phenyl)sulphoximide (Compound A'), in specific tumour types in humans, indeed leads to stabilization, where side-effects occur to an extent which is easily treatable.
- (R)-S-cyclopropyl-S-(4- { [4- { [( 1R, 2R)-2-hydroxy- 1 -methylpropyljoxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide (Compound A') and
- (S)-S-cyclopropyl-S-(4-{ [4-{ [(1R, 2R)-2-hydroxy-l -methylpropyljoxy }-5- (trifluoromethyl)pyrimidin-2-yl]amino } phenyl) sulphoximide (Compound A").
Compound A' is preferred and is, as BAY1000394, undergoing clinical trials.
If Compound A is referred to herein below, this is understood to mean both the pure stereoisomers A' and A" and any mixture of these two compounds.
The present application provides the use of
(RS)-S-cyclopropyl-S-(4-{ [4- { [(1R, 2R)-2-hydroxy- 1 -methylpropyljoxy } -5- (trifluoromethyl)pyrimidin-2-yl] amino } phenyl) sulphoximide
in particular
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l -methylpropyljoxy }-5-(trifluoromethyl)pyrimidin- 2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
The present application furthermore provides the use of
(RS)-S-cyclopropyl-S-(4-{ [4- { [(1R, 2R)-2-hydroxy- 1 -methylpropyljoxy } -5- (trifluoromethyl)pyrimidin-2-yl] amino } phenyl) sulphoximide
in particular
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l -methylpropyljoxy }-5-(trifluoromethyl)pyrimidin- 2-yl] amino }phenyl)sulphoximide for preparing a medicament for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum. The present application furthermore provides (RS)-S-cyclopropyl-S-(4-{ [4-{ [(1R, 2R)-2-hydroxy-l- methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide
in particular
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l -methylpropyljoxy }-5-(trifluoromethyl)pyrimidin- 2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
The present application furthermore provides medicaments and pharmaceutical formulations comprising
(RS)-S-cyclopropyl-S-(4-{ [4- { [(1R, 2R)-2-hydroxy- 1 -methylpropyljoxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino } phenyl) sulphoximide
in particular
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l -methylpropyljoxy }-5-(trifluoromethyl)pyrimidin- 2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Both in monotherapy and in combination therapy, there are preferably 3 days of treatment and 4 days of non-treatment.
However, the treatment protocol is, if required, adapted to the individual disease situation of the patient and/or in the combination therapy with the substance or the substances employed in the combination therapy.
The present application furthermore provides combinations of
(RS)-S-cyclopropyl-S-(4-{ [4- { [(1R, 2R)-2-hydroxy- 1 -methylpropyljoxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino } phenyl) sulphoximide
in particular
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l -methylpropyljoxy }-5-(trifluoromethyl)pyrimidin- 2-yl] amino }phenyl)sulphoximide
with at least one further active compound for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma,
anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
The present invention also embraces the use of the physiologically acceptable salts of Compound A.
Physiologically acceptable salts of Compound A include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic 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 customary bases such as, by way of example and preferably, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
The present invention furthermore provides medicaments comprising compound A and at least one or more further active compounds for the treatment and/or prophylaxis of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma, ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M.
Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Compound A according to the invention can act systemically and/or locally. To this end, it can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.
For these administration routes, Compound A can be administered in suitable administration forms.
Suitable administration forms for oral administration are those which function according to the prior art and deliver the compounds according to the invention rapidly and/or in modified fashion, and which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention), films/lyophilizates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
Solutions comprising or consisting of solubilisers, surfactants and/or one or more flavourings have been found to be advantageous for Compound A. Suitable solubilisers are macrogols, in particular macrogol 400.
Suitable surfactants are polysorbates, in particular polysorbate 20.
Suitable flavourings are essential oils, in particular menthol.
The concentration of the pharmaceutical may be from 0.1 mg/ml to 10 mg/ml, preferably from 0.2 mg/ml to 8 mg/ml, particularly preferably from 0.3 mg/ml to 6 mg/ml and most preferably from 0.4 mg/ml to 4 mg/ml. Examples given are the concentrations 0.2 mg/ml and 4.8 mg/ml.
Tablets comprising or consisting of fillers, disintegrants and/or one or more additives for pressing have also been found to be advantageous for Compound A.
Suitable fillers are polyols such as mannitol, in particular in granulated form, or else cellulose derivatives such as microcrystalline cellulose.
Suitable additives for pressing are stearates, in particular magnesium stearate.
Suitable disintegrants are cellulose derivatives, in particular croscarmellose.
The concentration of the pharmaceutical may be from 0.1 mg/tablet to 10 mg/tablet, preferably from 0.3 mg/tablet to 8 mg/tablet, particularly preferably from 0.4 mg/tablet to 6 mg/tablet and most preferably from 0.5 mg/tablet to 5 mg/tablet.
An example given is the concentration 5 mg/tablet.
Prior to and for formulation into the form of a medicament, Compound A is preferably present in micronized form.
Parenteral administration can bypass an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Suitable administration forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For the other administration routes, suitable examples are inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants or stents.
Compound A can be converted to the administration forms mentioned.
This can be accomplished in a manner known per se by mixing with inert nontoxic pharmaceutically suitable auxiliaries. These auxiliaries include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g.
antioxidants, for example ascorbic acid), dyes (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants. The present invention further provides medicaments which comprise compound A, typically together with one or more inert, nontoxic, pharmaceutically suitable auxiliaries, and for the use thereof for the aforementioned purposes.
The formulation of Compound A into pharmaceutical preparations is carried out in a manner known per se by converting the active compound(s) into the desired administration form using auxiliaries customary in the art of pharmaceutical formulation.
Here, suitable auxiliaries are, for example, carrier substances, fillers, disintegrants, binders, moisturizers, glidants, absorbants and adsorbants, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavour correctants, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffer.
Reference should be made to Remington's Pharmaceutical Science, 15th ed.
Mack Publishing Company, East Pennsylvania (1980).
The pharmaceutical formulations may be present
in solid form, for example as tablets, coated tablets, pills, suppositories, capsules, transdermal systems or
in semisolid form, for example as ointments, creams, gels, suppositories, emulsions or
in liquid form, for example as solutions, tinctures, suspensions or emulsions.
Auxiliaries for the purpose of the invention can, for example, be salts, saccharides (mono-, di-, tri-, oligo- and/or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, where the auxiliaries may be of natural origin or can be obtained synthetically or by partial synthesis.
Suitable for oral or peroral administration are in particular tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions. Suitable for parenteral administration are in particular suspensions, emulsions and especially solutions.
Dosage and treatment protocol:
Dosage and treatment protocol can and must be varied depending on the type of carcinoma and the treatment target.
In general, the daily dose is from 0.5 mg to 20 mg and may be divided into a plurality of identical or different dosage units, preferably 2. The preferred daily dose is from 1.0 mg to 15 mg and may be divided into a plurality of identical or different dosage units, preferably 2.
This applies to monotherapy as well as combination therapy with other antihyperproliferative, cytostatic or cytotoxic substances, where in the case of combination therapy it may be necessary to reduce the dose.
Treatment may be carried out over 2 to 60 days, where the treatment is preferably followed by 2 to 30 days of non-treatment. Treatment is successful if there is at least disease stabilization and the side-effects occur to an extent which is easily treatable, but at least easily acceptable.
Compound A may be employed alone or, if required, in combination with one or more other pharmacologically active substances, provided this combination does not lead to unwanted and unacceptable side-effects. Accordingly, the present invention furthermore provides medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and/or prevention of the disorders mentioned above.
For example, Compound A may be combined with known antihyperproliferative, cytostatic or cytotoxic substances for the treatment of cancerous disorders. The combination of the compounds according to the invention with other substances customary for cancer therapy or else with radiotherapy is particularly indicated.
As examples of active compounds suitable for combinations, there may be mentioned:
Abraxane, afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulphate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidin, chlorambucil, cisplatin, cladribin, 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, ergamisol, estrace, estradiol, estramustine sodium phosphate, ethinylestradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farstone, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabin, 5-fluorodeoxyuridine monophosphate, 5- fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocortone, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2a, interferon-alpha-2 , interferon-alpha-nl, interferon-alpha-n3, interferon-beta, interferon-gamma-la, interleukin-2, intron A, iressa, irinotecan, kytril, lapatinib, lentinan sulphate, 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, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, RDEA119, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxoter, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifen, tositumomab, tastuzumab, teosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin-stimalamer, zofran; ABI-007, acolbifen, actimmune, affinitak, aminopterin, arzoxifen, asoprisnil, atamestane, 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 hemocyanine, L-651582, lanreotide, lasofoxifen, 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, raloxifen, ranpirnas, 13-cis-retic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin-alpha-1, tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifen, transMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunin, Z-100, zoledronic acid and combinations of these.
In a preferred embodiment, the compound A can be combined with antihyperproliferative agents, which can be, by way of example - without this list being conclusive:
Abraxane, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinylestradiol, etoposide, fludarabin phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, 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, raloxifen, semustine, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine and vinorelbine.
In a highly promising manner, compound A can also be combined with biological therapeutics such as antibodies (for example Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
It is also possible to achieve positive effects by using compound A in combination with other therapies directed against angiogenesis such as, for example, with Avastin, axitinib, regorafenib, Recentin, sorafenib or sunitinib. Combinations with inhibitors of the proteasome and of mTOR and
antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favourable profile of side effects.
Generally, the following aims can be pursued with the combination of compound A with other cytostatically or cytotoxically active agents:
• improved efficacy in slowing the growth of a tumour, in reducing its size or even in the complete elimination thereof, compared with treatment with an individual active compound;
• the possibility of using the chemotherapeutics used in a lower dosage than in the case of
monotherapy;
• the possibility of a more tolerable therapy with fewer side effects compared with individual administration;
• the possibility of treatment of a broader spectrum of tumours;
• the achievement of a higher rate of response to the therapy;
• a longer survival time of the patient compared with present-day standard therapy.
In addition, the compounds according to the invention can also be used in conjunction with radiotherapy and/or surgical intervention.
Preparation of the compounds according to the invention
The preparation of the compounds according to the invention is extensively described in
PCT/EP2009/007247, the disclosure of which is referred to by the present application and which is incorporated into the present application by this reference.
PCT/EP2011/066295, the disclosure of which is likewise referred to by the present application and which is incorporated into the present application by this reference, discloses a preparation which is developed further.
Claims
1. Use of
(RS)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l-mefhylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
2. Use of
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l-methylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Use of
(RS)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l-mefhylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for preparing a medicament for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Use of
(R)-S-cyclopropyl-S-(4-{ [4-{ [(lR, 2R)-2-hydroxy-l-methylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for preparing a medicament for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
(RS)-S-Cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
(R)-S-Cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl] amino }phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Medicament or pharmaceutical formulation comprising
(RS)-S-cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Medicament or pharmaceutical formulation comprising
(R)-S-cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Combination of
(RS)-S-cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide with at least one further active compound for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
Combination of
(R)-S-cyclopropyl-S-(4- { [4- { [( 1 R, 2R)-2-hydroxy- 1 -methylpropyl] oxy } -5- (trifluoromethy l)pyrimidin-2-y 1] amino } phenyl) sulphoximide
with at least one further active compound for the treatment of
myelodysplastic-myeloproliferative diseases, adenocarcinoma, adenoid tumor, adenoma, adenomatosis, adenomatous polyposis coli, adenomatous polyps, adenosarcoma,
ameloblastoma, anaplasia, angiofibroma, astrocytoma, cancer/carcinoma, carcinoid tumors/syndromes/neoplasias, carcinosarcoma, craniopharyngioma, cysts, glioblastoma, glioma, hamartoma, hemangioblastoma, hemangioma, hepatoblastoma, histiocytoma, hodgkin's disease, hormone secreting neoplasias, insulinoma, keratosis, leukemia, lymphoma, lymphomatoid granulomatosis, macroglobulinemia (M. Waldenstrom), mastocytosis/mastocytoma, medulloblastoma, melanoma, meningeal carcinomatosis, meningioma, metastases, multiple endocrine neoplasia, neoplasia/neoplasm, nerve sheath tumors, neurofibromatosis, neuroma, papilloma, papillomavirus infections, polyps/polyposis, precursor cell leukemia-lymphoma, pseudomyxoma peritonei, sarcoma, teratocarcinoma, teratoma, tuberous sclerosis, tumor invasion, tumor thrombus, turban tumor syndrome (cylindromatosis) and/or xeroderma pigmentosum.
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| EP13164852.9 | 2013-04-23 | ||
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015071231A1 (en) * | 2013-11-14 | 2015-05-21 | Bayer Pharma Aktiengesellschaft | Combinations of (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluormethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide for treating tumours |
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