MXPA00005309A - Myt1 kinase inhibitors. - Google Patents

Abstract

The present invention provides novel receptor antagonists of myt1 kinase and methods for using them.

Description

INHIBITORS OF MYT1 CINASA FIELD OF THE INVENTION The present invention relates to inhibitors of tyrosine and threonine kinase ("myt1 kinase") enzyme associated with membrane, to pharmaceutical compositions comprising these compounds and methods for identifying these compounds and to methods for using these compounds to treat various forms of cancer and diseases. proliferative BACKGROUND OF THE INVENTION Entry into mitosis is initiated by the phase-promoting factor (MPF), a complex that contains the cdc2 protein kinase and cyclin B. Proper regulation of MPF ensures that mitosis occurs only after earlier phases of the cycle. cell are complete. The phosphorylation of cdc2 in Tyr-15 and Thr-14 suppresses this activity during the phase (G1, S and G2). In the G2-M transition, cdc2 is dephosphorylated in Tyr-15 and Thr-14 allowing MPF to phosphorylate its fungal substrates. It is known that a different family of cdc regulatory kinases (Wee1) is responsible for the phosphorylation of cdc Tyr-15. A new member of this family, Myt1 was recently described as the cdc2 kinase Thr-14 and Tyr15-specific, and showed to be an important regulator of the activity of cdc2 / cyclin B kinase (Science 270: 86-90, 1995; Mol. Cell, Biol. Vol 17: 571, 1997). The inhibitory phosphorylation of cdc2 is important for the regulation of the time of entry into mitosis. Studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. It is predicted that the inhibition of Myt1 causes the premature activation of cdc2, and in this way would kill the cells that proliferate rapidly. In addition, Myt1 inhibition is predicted to reduce resistance to chemotherapeutics to conventional DNA damage, because the mechanisms by which cells prevent death include disruption in the G2 phase of the cell cycle, and repair or damage to cells. DNA before the division. This interruption should be avoided by blocking the inhibitory Myt1 phosphorylation of cdc2. In this way, the cell is forced to enter mitosis prematurely. Myt1 kinase is an important regulator of the cell cycle, particularly in the G2 / M phase. Therefore, inhibitors would be attractive for the treatment of cancer. Current therapies against cancer, including surgery, radiation and chemotherapy, are commonly unsuccessful in curing the disease. The patient populations are large. For example, only of colon cancer there are 160,000 new cases each year in the United States, and 60,000 deaths. There are 60,000 new cases of colon cancer each year worldwide. The figure for lung cancer is double that of colon cancer. The greatest deficiency of chemotherapies for large solid tumors is that most patients can not respond to them. This is due to the regulation of the cell cycle and the subsequent repair of damage to DNA or fungal apparatus, the targets of the most effective chemotherapeutic agents. Myt1 kinase offers a downstream point of intervention from these mechanisms by which tumor cells develop resistance. The inhibition of Myt1 could have therapeutic benefit to reduce the proliferation of tumors, and in addition, it could be used in conjunction with conventional chemotherapies to overcome drug resistance. Based on the foregoing, there is a need to identify a potent inhibitor of mytl kinase enzyme for the treatment of various indications, including cancer, associated with the present receptor.

BRIEF DESCRIPTION OF THE INVENTION The present invention includes compounds represented by the formula (I) below, pharmaceutical compositions comprising said compounds and methods of antagonizing the mytl kinase receptor using these compounds.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I), below: Formula (I) wherein A represents a covalent bond, or a 1, 2, 1, 3, or 1, 4-disubstituted aryl amine ring selected from group consisting of: wherein: R is independently selected from the group consisting of H, Ome, Cl, Br, F, NO2 and CN; N is an integer from 1 to 4; each X is independently selected from the group consisting of H, Br, CH3, NO2, CN and NR ^; each Ar is independently optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring comprising one or more heteroatoms selected from N, O and S; and Ri and R 2 are, independently, hydrogen or C 1-4 alkyl, branched or cyclic, optionally containing O or N. The compounds of the present invention that are preferred are selected from the group consisting of: bis [2-] (4-phenyl-5-methyl) thiazolyl] amine, bis [2- (4- (2-pyridyl) thiazoyl] amine, bis [2- (4- (3-pyridyl) thiazolyl] amine, N , N-bis (5- (3,4-dichlorophenyl) -2-thiazolyl) amine, N, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine, 1,4-bis (4 - (4'-biphenyl) -2-tiazolyl) benzene, 1,3-bis (4- (3-pyridyl) -2-thiazolylamino) benzene, 1,4-bis [4-fluorophenyl-2-thiazolylamino] benzene and 1,4-bis (4- (4-methoxy-phenyl) -2-thiazolylamino) benzene The most preferred compounds of the present invention are selected from the group consisting of: bis [2- (4-phenyl) -5-methyl) thiazolyl] amine, 1,4-bis (4- (4-methoxyphenyl) -2-thiazolylamino) benzene, N, Nb, (4- (4'-biphenyl) -2-thiazole) amine, 1,4-bis (4- (4-biphenyl) -2-thiazolylamino) benzene, 1,4-bis [4-fluorophenyl-2-thiazolylamino) benzene, bis [2- (4- (2-pyridyl ) t iazolyl] amine and bis [2- (4- (3-pyridyl) thiazole] amine. The compounds of the present invention that are still more preferred are selected from the group consisting of: bis [2- (4-phenyl-5-methyl) thiazoyl] amine, 1,4-bis (4- (4-methoxyphenyl) - 2-thiazolylamino) benzene, N, N-bis (4- (4'-biphenol) -2-thiazole) amine and 1,4-bis (4- (4'-biphenyl) hydrobromide - 2-thiazolylamino) benzene. As used herein, "alkyl" refers to an optionally substituted hydrocarbon group linked together by individual carbon-carbon bonds. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Preferably, the group is linear or cyclic saturated. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated as being within the scope of the present invention. The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. The pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.

Pharmaceutically acceptable salts include the acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate and quinate. The pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid. Pharmaceutically acceptable salts also include the basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc, when present acidic functional groups, such as carboxylic acid or phenol. Preferred salts include hydrobromide, dibromhydrate and bistrifluoroacetate. The present compounds are easily prepared by means of the schemes represented below: SCHEME 1 SCHEME 2 NBS, HBF4 The corresponding bistiazolyl compounds are synthesized by means of the condensation of dithiobiuret (as in eq.1) or any other bistiourea such as 1,3-phenyldithiourea (as in eq.2) with two equivalents of an appropriately substituted bromoketone such as 2 -bromo-1-phenylpropan-1-one in a solvent such as ethanol or acetone or any other suitable solvent. The reaction mixture is heated at 70-90 ° C for several hours (4-12h). cooling the reaction gives the desired product as bis-hydrobromide salts.

The monobromination of the bistiazole compounds can be achieved for example by the reaction of N-bromosuccinimide in the presence of an acid such as fluoroboric acid, or any other suitable protic acid, in a solvent such as acetonitrile or any other suitable solvent, following a procedure described in the literature (Oberhauser, TJ Org. Chem., 1997, 62, 4504-4506). The bis-bromination can be achieved by any known bromination reaction, such as a reaction of the bis-thiazole with N-bromosuccinimide using refluxing DMSO or acetonitrile or bromine in acetic acid, any other method known to chemists skilled in the art. With the proper manipulation and protection of any chemical functionality, the synthesis of the remaining compounds of the formula (I) is achieved by methods analogous to those above. To use a compound in the formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with normal pharmaceutical practice as a pharmaceutical composition. The present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal or transmucosal administration. For oral administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated in conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops. Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal and subcutaneous, may be used. For injection, the compounds of the invention are formulated in liquid solutions, preferably in pH regulators or physiologically compatible solutions such as saline solution, Hank's solution or Ringer's solution. In addition, the compounds can be formulated in solid form and redissolved or suspended immediately before use. Freeze-dried forms can also be produced. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, suitable penetrants are used in the formulation for the barrier to be crossed. Such penetrants are generally known in the art, including, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate the transfer. Transmucosal administration, for example, can be by means of nasal sprays, rectal suppositories or vaginal suppositories. For topical administration, the compounds of the invention can be formulated in ointments, ointments, gels or creams, as is generally known in the art. The amounts of various compounds that will be administered can be determined by standard procedures taking into account such factors as the IC50, Ec5o of the compound, the biological half-life of the compound, the age, size and weight of the patient, and the disease disorder associated with the patient . The importance of these and other factors that will have to be considered are known to those skilled in the art. The amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Preferably, the composition is in unit dosage form. For oral application, for example, a tablet or capsule may be administered, for nasal application, a metered dose may be administered, for transdermal application a topical formulation or patch may be administered, and for the transmucosal delivery a patch may be administered oral. In each case, the dosage is such that the patient can administer a single dose. Each dosage unit for oral administration suitably contains 0.01 to 500 mg / Kg and preferably 0.1 to 50 mg / Kg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dose for parenteral, nasal, oral, transmucosal or transdermal inhalation routes suitably contains from 0.01 mg to 100 mg / Kg, of a compound of the formula (I). A topical formulation suitably contains 0.01 to 5.0% of a compound of the formula (I). The active ingredient can be administered from 1 to 6 times a day, preferably one, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art. As used herein, the "treatment" of a disease includes, but is not limited to, prevention, retardation and prophylaxis of the disease. As used herein, treatable "diseases" using the present compounds include, but are not limited to, leukemias, solid tumor cancers, metastases, soft tissue cancers, brain cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, cancer of the head and cancer of the neck, proliferative diseases chronic inflammatory diseases such as psoriasis and rheumatoid arthritis; proliferative cardiovascular diseases such as restenosis; proliferative ocular disorders such as diabetic retinopathy and benign hyperproliferative diseases such as hemangiomas. The composition of formula (I) and its pharmaceutically acceptable salts that are active when administered orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical carrier normally used to prepare solid formulations can be used. Examples of such vehicles include magnesium stearate, pipe soil, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any encapsulation routine is suitable, for example using the above mentioned vehicles in a hard gelatin capsule shell. When the composition is in the form of a capsule with a soft gelatin shell, any pharmaceutical carrier normally used to prepare dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, can be considered and incorporated into a soft gelatin capsule shell. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous vehicle optionally containing a parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion which can be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this manner, with a binder and / or lubricant, for example, polymeric glycols, gelatins, shortening of cocoa or other low melting vegetable waxes or fats or their synthetic analogues. Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste, or are in the form of a medicated plaster, patch or membrane. Preferably, the composition is in unit dosage form, eg, a tablet, capsule or measured aerosol dose, so that the patient can administer a single dose. No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance therewith. The biological activity of the compounds of the formula (I) is demonstrated by the tests indicated hereinafter.

In vitro tests Compounds capable of inhibiting mytl kinase can be identified with in vitro tests and cellular tests as described below. Variations of these tests would be obvious to those skilled in the art.

Expression of GST-Myt1 A GST-Myt1 expression construct having the glutathione-S-transferase gene fused to the amino terminus of Mytl kinase was constructed by means of a linker containing a thrombin cleavage site. This clone has been truncated at amino acid 362 of Mytl, just before the transmembrane domain. This construct was cloned into the Baculovirus expression vector, pFASTBAC, and this was used to make the viral concentrate for subsequent infection. Spodoptera frugiperda (Sf21) cells were infected with the virus expressing GST-Myt1 and the cells were cultured for 3 days, then harvested and frozen.

Purification of GST-Mvt1 The GST-Myt1 protein was purified as follows: a Sf21 cell pellet expressing GST-Myt1 was resuspended on ice in 10 ml of pH lysis buffer (50mM Tris-CI, pH 7.5, 250mM NaCl2, 1 mM dithiothreitol (DTT), 0.1% NP-40, 5% (w / w) of protease inhibitor cocktail, 1 mM sodium orthovanadate), the cells were lysed by sonification and centrifuged at 100,000xg for 30 minutes. The supernatant was added to 5 mis (packed volume) of Glutathione Sepharose 4B, and equilibrated in wash buffer (20mM Tris-CI, pH 7.0, 10mM MgCl 2, 100mM NaCl 2, 1mM DTT, 0.5% ( p / p) of protease inhibitor cocktail, 1 mM sodium orthovanadate). The mixture was rocked for 30 minutes. The resin with bound GST-Myt1 was centrifuged at 500xg for 5 minutes and washed with 14 ml of washing buffer. The pellets were centrifuged as indicated above and resuspended in another 14 ml of washing buffer. The suspension was transferred to a column and allowed to pack, and then the wash buffer was allowed to flow therethrough by gravity. GST-Mytl was eluted from the column with 10 ml of 10mM glutathione in 50 mM Tris-CI, pH 8.0 in 500ul fractions. The protein concentrations in the fractions were determined using the Bio-Rad protein test kit as indicated in the instructions. The fractions containing GST-Mytl were mixed and diluted to a concentration of -0.5 mg / ml and dialysed for 4 hours at 4 ° C in dialysis buffer (20 mM HEPES, pH 7.0, 1 mM manganese acetate, 100 mM NaCl2. , 0.05% Brij-35, 10% glycerol, 1 mM DTT, 0.2% protease inhibitor cocktail (v / v), 1 mM sodium orthovanadate). Aliquots of protein were taken and stored at -80 °.

Enzymatic tests DELFIA autophosphorylation test for GST-Mvtl Delayed fluorescent immunological assays (DELFIA) were performed on 96-cavity NUNC maxisorp plates at 50ul / cavity with 0.25 ug of GST-Mytl in buffer solution A (50 mM HEPES, pH 7.4, Mn (OAc) 2 2mM, 5uM ATP, 1mM DTT). (DELETE) For the determination of the optimum pH, use of divalent cation and Km of ATP, the appropriate component was varied as indicated in the figures. (DELETE) The autophosphorylation reactions were initiated by adding GST-Myt1 in buffer and allowed to proceed at room temperature with stirring for 20 minutes. The reactions were stopped by adding EDTA to a final concentration of 20mM, and the protein was allowed to continue to join in the cavities for an additional 40 minutes. The wells were washed 3 times with 300ul TBS / Tween (50mM Tris, pH 7.4, 150mM NaCl2, 0.2% Tween-20). After washing, the plate was blocked using Pierce's Superblock in TBS at 100ul / well. This was immediately decided and the blockade was repeated twice more. Then the plate was washed again with three washes of 300ul / cavity of TBS-Tween. Then 100ul of Eu-labeled antiphosphotyrosine antibody diluted to 0.125ug / ml in TBS / Tween containing 0.15mg / ml of BSA was added to the wells and allowed to incubate for 30 minutes with shaking at room temperature. After, the cavities were washed three times with 300ul of TBS / Tween, 200ul of intensifying solution was added per cavity and incubated with agitation for 10 minutes. The plate w is then read on the VICTOR 1420 plate counter from Wallac, Inc. Identical conditions are used for inhibitor studies except that ATP is at 1uM and the inhibitors are added in dimethyl sulfoxide (DMSO) to a concentration end of 1%. Typical ranges of concentration at which the test compounds are expected to inhibit mytl autophosphorylation are 0.001 to 10uM.

Biological studies Cell cycle studies Pharmacological studies were carried out that considered cellular effects in the adherent Hela S3 cell line. The cells were plated at a sufficiently low concentration so that 24 hours later they were at 10-20% confluence (typically 2x105 cells / 15cm e3). The cells were then synchronized in S phase by a repeated thymidine block. Briefly, cells were treated with 2mM thymidine for 18 hours, freed for 8 hours by 3 washes, and then treated again with thymidine. After the second release of thymidine, 95% of the cells were in S-phase. The synchronized cells were then returned to a complete medium containing a drug that causes DNA damage such as 50nM topotecan (one dose found is sufficient to stop cells in the initial G2 phase without inducing apoptosis) alone and in combination with the test compounds for up to 18 hours. The cell cycle profiles were then performed cytometrically using a procedure for staining the nuclei with propidium iodide. (Vindelov et al, Cytometry Vol. 3, No. 5, 1983, pp. 333-327). It would be expected that the Mytl inhibitors would reverse the G2 arrest caused by the agent causing DNA damage. Typical concentration ranges for such an activity would be 0.001 to 10 uM.

Proliferation / proliferation studies Proliferation studies were performed on a variety of adherent and non-adherent cell lines Hela S3, HT29, and Jurkat (DELETE ***). The proliferation test used a colorimetric change resulting from the reduction of the tetrazolium reagent XTT to a formazan product by metabolically active cells (Scudiero et al, Cancer Research, 48, 1981, 4827-4833). Cells were seeded in 100uis in 96-well plates to almost 10% confluence (cell concentration varied with cell lines) and developed for 24 hours. The compounds were then added with or without sufficient medium containing vehicle to carry the cells to a final volume of 200ul containing chemical reagents in 0.2% DMSO. The cells received multiple concentrations of antiproliferative drugs that damage DNA such as topotecan, the test compounds and the combination treatment at 37 ° C, 5% C02. 72 hours later, 50ul of an XTT / phenazine methosulfate mixture was added to each well and the cells allowed to incubate for 90 minutes. The plate was read at 450nm, and the antiproliferative effects were compared in relation to the cells treated with vehicle. It was expected that inhibitors of Mytl inhibit the proliferation of such cancer cell lines and / or increase the cytotoxicity of chemotherapeutic drugs that damage DNA. Typical concentration ranges for such activity would be 0.001 to 10uM. Other tests for cell proliferation or cytotoxicity could also be used with the test compounds, and these tests are known to those skilled in the art. The present invention includes but is not limited to the following examples. Nuclear magnetic resonance spectra were recorded at 300 MHz using a Bruker AM 300 spectrometer. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethyl sulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts were reported in parts per million (?) To the field from the internal standard tetramethylsilane. The abbreviations for the NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad . J indicates the NMR coupling constant measured in Hertz. The continuous-wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer and the Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. The IR and FTIR spectra they registered in transmission mode, and the positions of the bands were reported as the inverse of the wave number (cm "1) .The mass spectra were performed on any of the instruments VG 70 FE, PE Syx API III, or VG ZAB HF, using ionization by accelerated atom bombardment (FAB) or electrospray (ES) The elemental analyzes were obtained using a Perkin-Elmer 240C elemental analyzer.The melting points were performed on a Thomas-Hoover melting point apparatus and are not corrected. All temperatures were recorded in degrees Celsius, Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin-film plates were used for thin-layer chromatography, both gravity and flash chromatography were performed on silica gel. E. Merck Kieselgel 60 (230-400 mesh) Analytical and preparative HPLC was performed on Rainin or Beckman chromatographs ODS refers to a silica gel chromatographic support obtained from octadecylsilyl or 5 μ Apex-ODS indicates a silica gel chromatographic support obtained with octadecylsilyl having a nominal particle size of 5 μ, manufactured by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric chromatographic support (styrene-divinylbenzene), and is a registered trademark of Hamilton Co., Reno, Nevada). Celite® is a filter aid composed of diatomaceous silica washed with acid, and is a registered trademark of Manville Corp., Denver, Colorado.

EXAMPLE 1 Bisr2- (4-phenyl-5-metH) thiazolyl-1amine bromide MS (ES) m / e 363.7 [M + H] + 1 H NMR (300MHz, DMSO-d) δ 7.74 (d, J = 10Hz, 4H), 7.52 (t, J = 6Hz, 4H), 7.39 (t , J = 11 Hz, 2H).

EXAMPLE 2 bisF2- (4- (2-pyridyl) thiazolipamine bromohydrate MS (ES) m / e 337.7 [M + H] + 1 H NMR (300MHz, DMSO-d) δ 8.71 (d, J = 3Hz, 2H), 8.23 (m, 4H), 8.05 (s, 2H), 7.59 (t, J = 6Hz, 2H) EXAMPLE 3 bisr2-r4- (3-pyridyl) t-azolillamna bistrifluoroacetate MS (ES) m / e 337.7 [M + Hf 1 H NMR (300MHz, DMSO-d) δ 9.33 (s, 2H), 9.04 (d, J = 10Hz, 2H), 8.75 (d, J = 5Hz, 2H ), 8.08 (t, J = 11 Hz, 2H), 7.88 (s, 2H) EXAMPLE 4 N, N-Bis (5- (3,4-dichlorophenyl) -2-thiazolyl) amine bromide 1 H NMR (300MHz, DMSO-d) δ 8.33 (s, 1 H), 8.18 (s, 2H), 7.94 (d, J = 8.2Hz, 2H), 7.82 (s, 2H), 7.73 (d, J = 8.2Hz, 2H).

EXAMPLE 5 1,3-Bisr4- (3-pyridyl) -2-thiazolylaminolylbenzene Bromhydrate MS (ES) m / e 428.8 [M + H] + 1 H NMR (300MHz, DMSO-d) δ 10.44 (s, 2H), 9.17 (d, J = 1.7Hz, 2H), 8.47 (dd, J = 1.7, 4.7Hz, 2H), 8.23-8.29 (m, 4H), 7.56 (s, 2H), 7.39 (dd, J = 5.0, 8.0 Hz), 7.32 (s, 2H). Formulations for pharmaceutical use incorporating the compounds of the present invention can be prepared in various forms and with numerous excipients. Following are examples of such formulations: EXAMPLE 6 Formulation for inhalation A compound of the formula (I), (1 mg to 100 mg) is converted into an aerosol from a metered dose inhaler to deliver the desired amount of drug each time it is used.

EXAMPLE 7 Tablet formulation Tat jelly / ingredients For each tablet 1. Active ingredient 40 mg Compound of the formula (I) 2. Corn starch 20 mg 3. Alginic acid 20 mg 4. Sodium alginate 20 mg 5. Mg stearate 1.3 mg Procedure for tablet formulation Ingredients 1, 2, 3 and 4 are mixed in an appropriate mixer / combiner. Sufficient water is added in portions to the combination with careful mixing after each addition until the dough has a consistency that allows its conversion into wet granules. The wet mass is converted to granules by passing them through an oscillating granulator using a No. 8 mesh screen (2.38 mm). The moist granules are then dried in an oven at 60 ° C until dry. The dry granules are lubricated with the ingredient No. 5 and the lubricated granules are compacted in an appropriate tabletting machine.

EXAMPLE 8 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of the formula I in polyethylene glycol with heating. This solution is then diluted with water for injection (up to 100 ml). The solution is made sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated therein for reference as if each individual publication was specific and individually indicated to be incorporated by reference as fully indicated.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound according to formula (I), below: Formula (I) wherein A represents a covalent bond, or a 1, 2, 1, 3, or 1, 4-disubstituted aryl amine ring selected from the group consisting of: wherein: R is independently selected from the group consisting of H, Ome, Cl, Br, F, NO2 and CN; n is an integer from 1 to 4; each X is independently selected from the group consisting of H, Br, CH3, N02, CN and NR? R2; each Ar is independently optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring comprising one or more heteroatoms selected from N, O and S; and Ri and R2 are, independently, hydrogen or C-, branched or cyclic alkyl, optionally containing O or N.

2. A compound according to claim 1, which is selected from the group consisting of: bis [2] - (4-phenyl-5-methyl) thiazolyl] amine, bis [2- (4- (2-pyridyl) thiazolyl] amine, bis [2- (4- (3-pyridyl) thiazolyl] amine, N, N- bis (5 (3,4-dichlorophenyl) -2-thiazoIiI) amine, N, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine, 1,4-bis (4- (4'- biphenyl) -2-thiazolylamino) benzene, 1,3-bis (4- (3-pyridyl) -2-thiazolylamino) benzene, 1,4-bis [4-fluorophenyl-2-thiazolylamino) benzene and 1,4-bis (4- (4-methoxyphenyl) -2-thiazolylamino) benzene

3. A compound according to claim 2, which is selected from the group consisting of: bis [2- (4-phenyl-5-methyl) thiazolyl) ] amine, 1,4-bis (4- (4-methoxyphenyl) -2-thiazolylamino) benzene, N, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine, 1,4-bis ( 4- (4'-biphenyl) -2-thiazolylamino) benzene, 1,4-bis [4-fluorophenyl-2-thiazolylamino) benzene, bis [2- (4- (2-pyridyl) thiazolyl] amine and bis [2- (4- (3-pyridyl) thiazole] amine.

4. A compound according to claim 2, which is selected from the group consisting of: bis [2- (4-phenyl-5-methyl) thiazoyl] amine, 1,4-bis (4- (4-methoxyphenyl) ) -2-thiazolylamino) benzene, N, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine and 1,4-bis (4- (4'-biphenyl) -2-thiazolylamide hydrobromide no) benzene.

5. The use of a compound as claimed in claim 1 for the manufacture of a medicament for antagonizing a mytl kinase receptor in a subject.

6. The use of a compound as claimed in claim 1 for manufacturing a medicament for the treatment of a disease or disorder selected from the group consisting of leukemias, cancers and solid tumor metastases, soft tissue cancers, brain cancer , cancer of the esophagus, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, cancer kidney, cancer of the head and neck cancer, proliferative chronic inflammatory diseases, proliferative cardiovascular diseases, proliferative eye disorders and benign hyperproliferative diseases.

7. The use as claimed in claim 5, wherein the disease or disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, diabetic retinopathy and hemangiomas. pcftl I FN DE > ? INVENTION Novel tagonists of mytl kinase receptor are provided and methods to use them JN / JT / sll * rcp * jtc * ald * pbg * P00 / 548