EP2827871A1 - Utilisation de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide pour traiter des tumeurs spécifiques - Google Patents

Utilisation de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide pour traiter des tumeurs spécifiques

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Publication number
EP2827871A1
EP2827871A1 EP13709923.0A EP13709923A EP2827871A1 EP 2827871 A1 EP2827871 A1 EP 2827871A1 EP 13709923 A EP13709923 A EP 13709923A EP 2827871 A1 EP2827871 A1 EP 2827871A1
Authority
EP
European Patent Office
Prior art keywords
trifluoromethyl
hydroxy
methylpropyl
cyclopropyl
oxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13709923.0A
Other languages
German (de)
English (en)
Inventor
Martin KORNACKER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Intellectual Property GmbH
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Filing date
Publication date
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Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Publication of EP2827871A1 publication Critical patent/EP2827871A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of (RS) -S-cyclopropyl-S- (4- ⁇ [4- ⁇ [(IR, 2R) -2-hydroxy-1-methylpropyl] oxy ⁇ -5- (trifluoromethyl especially (R ) -S-Cyclopropyl-S- (4- ⁇ [4- ⁇ [(IR, 2R) -2-hydroxy-1-methylpropyl] oxy ⁇ -5- (trifluoromethyl) pyrimidin-2-yl] amino ⁇ phenyl) sulfoximide for the treatment of specific tumors.
  • CDK cyclin-dependent kinases
  • CDK inhibitors a wide variety of pyrimidine derivatives are described, for example 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00 / 12486) and 2-hydroxy-3-N, N-dimethylaminopropoxy-pyrimidines (WO 00/39101).
  • WO 02/096888 and WO 03/076437 have disclosed pyrimidine derivatives which have inhibitory effects on CDKs.
  • sulfoximine active substances are sulfonimidoyl-modified triazoles as fungicides (H.
  • WO 2005/037800 discloses open sulfoxime-substituted anilino-pyrimidine derivatives as inhibitors of cyclin-dependent kinases. Exemplified are structures which are either not substituted in the 5-position of the pyrimidine or substituted with halogen, in particular with bromine. A 5-trifluoromethyl substituent does not have any of the specifically disclosed structures.
  • the novel pan-CDK inhibitors and processes for their preparation are described in PCT Application PCT / EP2009 / 007247, the disclosures of which are incorporated herein by reference, and which is incorporated herein by reference.
  • pan-CDK inhibitors in various tumor diseases is the subject of PCT / EP201 1/054733.
  • the object of the present invention is to provide compounds for patients with thyroid carcinomas, mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinomas, which lead in these patients at least to a stabilization of the tumor disease, without the side effects to a termination of the Force therapy.
  • Compound A is a selected sulfoximine-substituted anilino-pyrimidine derivative which can be resolved into two stereoisomers, namely:
  • Compound A is preferred and as BAY1000394 in clinical development.
  • compound A refers to both the pure stereoisomers A 'and A "and any mixture of these two.
  • An object of the present application is the use of
  • Another object of the present application is the use of
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma
  • Another object of the present application is the use of
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma
  • Another object of the present application is the use of
  • Another object of the present application is the use of
  • Another object of the present application is the use of
  • a further subject of the present application is (RS) -S-cyclopropyl-S- (4- ⁇ [4- ⁇ [(1R, 2R) -2-hydroxy-1-methylpropyl] oxy ⁇ -5- (trifluoromethyl) pyrimidine 2-yl] amino ⁇ phenyl) sulfoximide,
  • a further subject of the present application is (RS) -S-cyclopropyl-S- (4- ⁇ [4- ⁇ [(1R, 2R) -2-hydroxy-1-methylpropyl] oxy ⁇ -5- (trifluoromethyl) pyrimidine 2-yl] amino ⁇ phenyl) sulfoximide,
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma, treated for 3 days and paused for 4 days.
  • a further subject of the present application is (RS) -S-cyclopropyl-S- (4- ⁇ [4- ⁇ [(1R, 2R) -2-hydroxy-1-methylpropyl] oxy ⁇ -5- (trifluoromethyl) pyrimidine 2-yl] amino ⁇ phenyl) sulfoximide,
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma, treated for 3 days and paused for 4 days.
  • thyroid carcinomas mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinoma
  • a dose reduction may be necessary. Both in monotherapy and in combination therapy is preferably treated for 3 days and paused for 4 days.
  • the treatment scheme is coordinated, for example, with the individual disease situation of the patient and / or in the combination therapy with the substance or the substances which are used in the combination therapy. Further objects of the present application are combinations of
  • Physiologically acceptable salts of compound A include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid,
  • Physiologically acceptable salts of compound A also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (e.g., sodium and potassium salts), alkaline earth salts (e.g., calcium and potassium salts)
  • alkali metal salts e.g., sodium and potassium salts
  • alkaline earth salts e.g., calcium and potassium salts
  • Magnesium salts and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, by way of example and by way of limitation, 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 compound A and at least one or more further active ingredients for the treatment and / or prophylaxis of
  • Thyroid carcinoma mesothelioma, squamous cell carcinoma of the esophagus or
  • the compound A according to the invention can act systemically and / or locally.
  • it may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compound A can be administered in suitable administration forms.
  • 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, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, Suspensions, aerosols or solutions.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, Suspensions, aerosols or solutions.
  • Solubilizers surface-active substances and / or one or more flavoring agents.
  • Suitable solubilizers are macrogols, in particular macrogol 400.
  • Polysorbates in particular polysorbate 20, are suitable as surface-active substances.
  • Suitable flavoring substances are essential oils, in particular menthol.
  • the drug concentration may be 0.1 mg / ml to 10 mg / ml, preferably 0.2 mg / ml to 8 mg / ml, more preferably 0.3 mg / ml to 6 mg / ml, and most preferably 0.4 mg / ml to 4 mg / ml.
  • the concentrations are 0.2 mg / ml and 4.8 mg / ml.
  • Suitable fillers are polyols such as mannitol, in particular in granulated form or else
  • Cellulose derivatives such as microcrystalline cellulose.
  • Suitable pressing additives are stearates, in particular magnesium stearate.
  • Suitable disintegrants are cellulose derivatives, in particular croscarmellose.
  • the drug concentration may be 0.1 mg / tablet to 10 mg / tablet, preferably 0.3 mg / tablet to 8 mg / tablet, more preferably 0.4 mg / tablet to 6 mg / tablet, and most preferably 0.5 mg / tablet to 5 mg / tablet. By way of example, the concentration is 5 mg / tablet.
  • the compound A is preferably present before and for the formulation in a dosage form in micronized form.
  • Parenteral administration can be done by bypassing a resorption step (e.g.
  • Absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • Tablets films / wafers or capsules, suppositories, ear or eye preparations,
  • Vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powdered powders, implants or stents.
  • Compound A can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • adjuvants include, among others.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers eg antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odor remedies include, among others.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dode
  • compositions containing the compound A are pharmaceutical compositions containing the compound A, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the formulation of the compound A to give pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • excipients for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, adsorbents and adsorbents, diluents, solvents,
  • Cosolventien, emulsifiers, solubilizers, proposed solutions for changing the osmotic pressure or buffers are used.
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • the present invention relates to the use of compound A, in particular compound A 'for the therapy of thyroid carcinomas, mesotheliomas, squamous cell carcinoma of the esophagus or cholangiocellular carcinomas.
  • Dosage and treatment scheme :
  • the dosage and the treatment regimen can and must vary depending on the type of carcinoma and
  • Treatment goal can be varied.
  • the daily dose is usually between 0.5 mg and 20 mg and can be divided into several identical or different dosage units, preferably 2.
  • the preferred daily dose is between 1.0 mg and 15 mg and may be divided into several equal or different dosage units, preferably 2.
  • the treatment may be carried out for 2 to 60 days, with the treatment preferably followed by a break of 2 to 30 days.
  • Successful treatment regimens were 28 days of treatment followed by a 14-day break, and especially 3 days of treatment, followed by a 4-day break.
  • a successful treatment is when at least one disease stabilization occurs and the side effects occur in a well treatable, but at least well tolerated extent.
  • Disease stabilization in mesothelioma patients was achieved with a daily dose of 2.4 mg, 9.6 mg, and 19.2 mg divided into two equal dose units.
  • Disease stabilization in thyroid carcinoma patients was also achieved with a daily dose of 15 mg divided into two dose units (5 mg in the morning, 10 mg in the evening). It was treated for 3 days and paused for 4 days.
  • Disease stabilization in a patient with squamous cell carcinoma of the esophagus could be achieved with a daily dose of 1 mg divided into two equal units of dose. It was treated for 28 days and paused for 14 days.
  • Compound A may be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects.
  • the present invention therefore further relates to 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 abovementioned disorders.
  • compound A can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers.
  • the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.
  • Suitable combination active ingredients are:
  • Methotrexate Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotan, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Nolvadex, NSC-631570, OCT-43, Octreotide, Ondansetron hydrochloride, Orapred, Oxaliplatin, Paclitaxel , Pediapred, Pegaspargase, Pegasys, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium,
  • Tamoxifen Tamsulosin, Tasonermin, Tastolactone, Taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexall, Trimethylmelamine, Trimimetrex, Triptorelin Acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizine, zinecard, zinitrate-stimalamer, zofran; ABI-007, Acolbifen, Actimmun, Affinitak, Aminopterin, Arzoxifen, Asopris
  • 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,
  • compound A of the present invention may be combined with anti-hyperproliferative agents which may be by way of example, without being exhaustive:
  • compound A can also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin, cetuximab) and recombinant proteins.
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin, cetuximab) and recombinant proteins.
  • Compound A may also provide positive effects in combination with other angiogenic therapies, such as Avastin, axitinib, regorafenib, recentin, sorafenib, or sunitinib.
  • angiogenic therapies such as Avastin, axitinib, regorafenib, recentin, sorafenib, or sunitinib.
  • Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.
  • 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
  • Patient 1010 age 66 years, male, epitheloid mesothelioma, progressive onset of disease, systemic prior therapy with Alimta and cisplatin, gemcitabine, doxorubicin, decabins
  • Patient 1010 achieved disease stabilization according to RECIST 1.1 and was treated for approximately 4 months
  • Patient 1016 achieved disease stabilization according to RECIST 1.1 and was treated for more than 3 months
  • Patient 1023 achieved disease stabilization according to RECIST 1.1 and was treated for about 2 months
  • Patient 1024 achieved RECIST 1.1 disease stabilization and was treated for approximately 2 months
  • Patient 2006 oral solution, ingredients micronized BAY 1000394 (0.2 mg / ml), levomenthol (synonym: 1-menthol, flavoring) Macrogol (400) (synonym: polyethylene glycol (400), solubilizer), polysorbate 20 (surfactant)
  • Patient 1030 tablet, ingredients BAY 1000394, micronised, 5 mg / tablet, granulated mannitol (filler), microcrystalline cellulose (filler), croscarmellose (disintegrant), magnesium stearate (additive), red varnish (coating)
  • Dosage and treatment scheme :
  • Patient 2006 dose 2 times a day 0.3 mg, application regimen 28 days treatment and 14 days rest, duration of treatment until progression of the disease
  • Patient 1030 dose 5 mg in the morning, 10 mg in the evening, application regimen 3 days of treatment and 4-day break, duration of treatment until disease progression
  • Patient 2006 The patient achieved disease stabilization according to RECIST 1.1 and was treated for approximately 2 months
  • Patient 1030 The patient achieved disease stabilization according to RECIST 1.1 and has been treated for more than 3 months
  • the patient achieved disease stabilization according to RECIST 1.1 and has been treated for more than 4 months

Abstract

L'invention concerne l'utilisation de (R)-S-cyclopropyl-S-(4-{[4-{[(1R, 2R)-2-hydroxy-1- méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide et/ou de (S)-S-cyclopropyl-S-(4-{[4-{[(1R, 2R)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2- yl]amino}phényl)sulfoximide pour le traitement de tumeurs spécifiques.
EP13709923.0A 2012-03-21 2013-03-18 Utilisation de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide pour traiter des tumeurs spécifiques Withdrawn EP2827871A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102012204506 2012-03-21
PCT/EP2013/055561 WO2013139734A1 (fr) 2012-03-21 2013-03-18 Utilisation de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide pour traiter des tumeurs spécifiques

Publications (1)

Publication Number Publication Date
EP2827871A1 true EP2827871A1 (fr) 2015-01-28

Family

ID=47891732

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13709923.0A Withdrawn EP2827871A1 (fr) 2012-03-21 2013-03-18 Utilisation de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorméthyl)pyrimidin-2-yl]amino}phényl)sulfoximide pour traiter des tumeurs spécifiques

Country Status (20)

Country Link
US (1) US20150051232A1 (fr)
EP (1) EP2827871A1 (fr)
JP (1) JP2015510910A (fr)
KR (1) KR20140135215A (fr)
CN (1) CN104220075A (fr)
AP (1) AP2014007915A0 (fr)
AU (1) AU2013234451A1 (fr)
CA (1) CA2867746A1 (fr)
CL (1) CL2014002472A1 (fr)
EA (1) EA201491732A1 (fr)
HK (1) HK1204294A1 (fr)
MA (1) MA35943B1 (fr)
MX (1) MX2014011240A (fr)
PH (1) PH12014502075A1 (fr)
SA (1) SA113340398B1 (fr)
SG (1) SG11201405386SA (fr)
TN (1) TN2014000391A1 (fr)
TW (1) TW201338779A (fr)
WO (1) WO2013139734A1 (fr)
ZA (1) ZA201406986B (fr)

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Publication number Priority date Publication date Assignee Title
WO2015071231A1 (fr) * 2013-11-14 2015-05-21 Bayer Pharma Aktiengesellschaft Combinaisons de (rs)-s-cyclopropyl-s-(4-{[4-{[(1r,2r) -2-hydroxy-1-méthylpropyl]oxy}-5-(trifluorométhyl)pyrimidin-yl-2]amino}phenyl)sulfoximide pour le traitement de tumeurs
IL249370B (en) 2014-06-13 2022-06-01 Tufts College Fap-activated medical substances and their related uses

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Publication number Publication date
WO2013139734A1 (fr) 2013-09-26
SG11201405386SA (en) 2014-11-27
CN104220075A (zh) 2014-12-17
EA201491732A1 (ru) 2015-08-31
HK1204294A1 (en) 2015-11-13
CA2867746A1 (fr) 2013-09-26
ZA201406986B (en) 2016-08-31
TN2014000391A1 (en) 2015-12-21
PH12014502075A1 (en) 2014-12-10
AP2014007915A0 (en) 2014-09-30
KR20140135215A (ko) 2014-11-25
US20150051232A1 (en) 2015-02-19
MA35943B1 (fr) 2014-12-01
CL2014002472A1 (es) 2014-12-12
SA113340398B1 (ar) 2016-04-04
MX2014011240A (es) 2014-10-15
AU2013234451A1 (en) 2014-09-25
TW201338779A (zh) 2013-10-01
JP2015510910A (ja) 2015-04-13

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