KR20010109917A - Myt1 Kinase Inhibitors - Google Patents

Abstract

Novel myt1 kinase receptor antagonists and methods of use thereof are provided.

Description

Ｙｙ kinase inhibitor {Myt1 Kinase Inhibitors}

The present invention relates to a tyrosine and threonine kinase (“myt1 kinase”) enzyme inhibitor associated with a membrane, a pharmaceutical composition comprising the compound and a method of identifying the compound and a method of using the compound in the treatment of various forms of cancer and hyperproliferative diseases. It is about.

Entry into somatic cell division is initiated by the M phase promoting factor (MPF), a complex consisting of cdc2 protein kinase and cyclin B. By proper regulation of MPF, somatic division does not occur until after the preceding phases of the cell cycle are completed. Phosphorylation of Tyr-15 and Thr-14 of cdc2 inhibits this activity during interphase (G1, S and G2). Upon transition from the G2 phase to the M phase, Tyr-15 and Thr-14 of cdc2 dephosphorylate so that MPF phosphorylates the somatic cell division substrate. Certain cdc-regulated kinase groups (Weel) are known to phosphorylate Tyr-15 of cdc. Recently, new members of this group have been described as Myt1 as Thr-14 and Tyr-15-specific cdc2 kinases and have been found to be important regulators of cdc2 / cycline B kinase activity (Science 270: 86-90, 1995; Mol. Cell. Biol. Vol 17: 571, 1997). This inhibitory phosphorylation of cdc2 is important for determining when to enter somatic cell division. Studies have shown that early activation of cdc2 leads to failure of somatic cell division and cell death. Inhibiting Myt1 will result in premature activation of cdc2, thus rapidly proliferating and necrotic cells. In addition, inhibition of Myt1 is expected to reduce resistance to conventional DNA damage chemotherapy, as the mechanism for preventing cell death involves repair of DNA damage prior to stagnation and division of G2 phase in the cell cycle. This congestion can be prevented by blocking the inhibitory phosphorylation of Myt1 on cdc2. This allows the cells to enter the somatic division early.

Myt1 kinase is an important cell cycle regulator, particularly of the G2 / M phase. Thus, these inhibitors are of interest in the treatment of cancer. Conventional cancer therapies, including surgery, radiation and chemotherapy, often do not cure the disease. The number of cancer patients is large. For example, if you look at just one colon cancer, 160,000 new cases and 60,000 deaths occur each year in the United States. Lung cancer patients are twice the number of colon cancer patients. The biggest disadvantage of chemotherapy for major solid tumors is that most patients do not respond. This is because repair of cell cycle regulation and thereby damage to DNA or somatic cell division machinery (which is the target of the most effective chemotherapeutic agents) is repaired. Myt1 kinase intervenes at a lower stage in this mechanism by which cancer cells become resistant. Inhibition of Myt1 inherently has therapeutic advantages in reducing tumor proliferation by itself and can also be used with conventional chemotherapy to overcome drug resistance.

Based on this fact, there is a need for potent myt1 kinase enzyme inhibitors in the treatment of various diseases, including cancer, associated with this receptor.

The present invention includes a compound of formula 1, a pharmaceutical composition comprising the compound, and a method of antagonizing the myt1 kinase receptor using the compound.

The present invention provides a compound of Formula 1 below.

Wherein A is a covalent bond, or , And Wherein R is independently selected from the group consisting of H, OMe, Cl, Br, F, NO ₂ and CN, n is an integer from 1 to 4, 1,2-, 1, 3- or 1,4-disubstituted aryl amine ring, each X is H, Br, CH ₃ , NO ₂ , CN and NR ₁ R ₂ (R ₁ and R ₂ are independently hydrogen or O or N optionally Branched or cyclic C _1-4 alkyl), each Ar is independently optionally substituted phenyl or optionally substituted 5 comprising one or more hetero atoms selected from N, O and S Or a 6 membered heterocyclic ring.

Preferred compounds of the invention

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-thiazolyl) 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.

More preferred compounds of the present invention

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) thiazolyl)] amine.

Most preferred compounds of the present invention

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 and

1,4-bis (4- (4'-biphenyl) -2-thiazolylamino) benzene hydrobromide.

As used herein, the term "alkyl" refers to an optionally substituted hydrocarbon group linked together by a carbon-carbon single bond. Alkyl hydrocarbon groups may be linear, branched or cyclic and may be saturated or unsaturated. Preferably, this group is saturated linear or cyclic.

The compounds of the present invention may comprise one or more asymmetric carbon atoms and may exist in racemic and optically active forms. Both the compounds and diastereomers are believed to be within the scope of the present invention.

In addition, the compounds may be formulated as pharmaceutically acceptable salts or complexes thereof. Pharmaceutically acceptable salts are salts which are nontoxic in the amounts and concentrations in which they are administered.

Pharmaceutically acceptable salts include acid addition salts such as sulfates, hydrochlorides, fumarates, maleates, phosphates, sulfamate, acetates, citrate, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfos Salts, including nitrate, p-toluenesulfonate, cyclohexylsulfate and quinate. Pharmaceutically acceptable salts include 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, p-toluenesulfonic acid, cyclohexylsulfonic acid, fumaric acid, Obtained from acids such as quinic acid.

Alternatively, when a pharmaceutically acceptable salt is present with an acidic functional group such as a carboxylic acid or phenol, base addition salts such as benzatin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, Salts include procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc.

Preferred salts include hydrobromide, dihydrobromide and bistrifluoroacetate.

This compound is easily prepared by the following scheme.

The corresponding bisthiazolyl compound is dithiobiuret (as in formula 1) or any other bisthiourea, for example 1,3-phenyldithiourea (as in formula 2) in ethanol or acetone or any other suitable solvent. ) And an appropriately substituted bromoketone, such as 2-bromo-1-phenylpropan-1-one 2 equivalents, via a condensation reaction. The reaction mixture is heated to 70-90 ° C. for several hours (4-12 hours). The reaction product is cooled to give the desired product, such as the bis-hydrobromide salt. Monobromination of bisthiazole compounds is described by Oberhauser, T. J. Org. Chem. , 1997, 62, 4504-4506, via an N-bromosuccinimide reaction 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. Can be achieved. Bis-bromination is achieved by any known bromination reaction, for example by reacting bis-thiazole with N-brosuccinimide or acetic acid in refluxing DMSO or acetonitrile or with any other method known to those skilled in the art. Can be.

By appropriately manipulating and protecting any chemical functionality, the remaining compounds of Formula 1 can be synthesized by methods similar to those described above.

In order to use a compound of formula (1) or a pharmaceutically acceptable salt thereof in the treatment of humans and other mammals, it is generally formulated according to pharmaceutically standard practice in pharmaceutical compositions.

The ligands of the invention can be administered by several routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal or transmucosal administration. As systemic administration, oral administration is preferable. Oral administration can, for example, formulate the compound in conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.

Alternatively, for example, injection methods (parenteral administration) such as intramuscular administration, intravenous administration, intraperitoneal administration, and subcutaneous administration may be used. As an injection, the compounds of the invention are formulated in liquid solutions, preferably in physiologically suitable buffers or solutions such as saline, Hank's solution or Ringer's solution. In addition, the compounds may be formulated to solid form and redissolved or suspended immediately prior to use. It can also be prepared in lyophilized form.

Systemic administration may also be transmucosal or transdermal. For transmucosal or transdermal administration, appropriate penetrants for the barrier to penetrate are used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives in transmucosal administration. Detergents may also be used to promote permeation. Transmucosal administration, for example, may be by nasal sprays, rectal suppositories, or vaginal suppositories.

In topical administration, the compounds of the invention may be formulated in general as ointments, plasters, gels or creams known in the art. Dosages of various compounds can be determined by standard methods, taking into account such factors as the IC ₅₀ , EC ₅₀ of the compound, the biological half-life of the compound, the age, body size and weight of the patient, and the disease or condition associated with the patient. The importance of these and other factors to be considered is known to those skilled in the art.

Dosage also depends on the route of administration and oral bioavailability. For example, with a compound having low oral bioavailability, relatively high amounts will be required.

The composition is preferably in a single dosage form. For oral administration, for example, tablets or capsules may be administered, nasal administration may be administered a metered aerosol dose, transdermal administration may be administered in topical formulations or patches, transmucosal administration Can be administered by oral patch. In each case, the dosage is that amount that a patient can administer once.

Oral administration includes 0.01 to 500 mg / Kg and preferably 0.1 to 50 mg / Kg of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein each dosage unit is suitably weighed as the free base. For parenteral, nasal, oral inhalation, transmucosal or transdermal routes, the daily dosage of the compound of formula 1 is suitably 0.01 mg to 100 mg / Kg. Topical formulations suitably comprise from 0.01 to 5.0% of the compound of formula (1). The active ingredient may be administered 1 to 6 times daily, preferably once enough to exhibit the desired activity, as will be apparent to those skilled in the art.

As used herein, the term "treatment" of a disease includes, but is not limited to, preventing, delaying, and preventing a disease. As used herein, the term "disease" treatable using a compound of the present invention refers to leukemia, solid tumor, cancer metastasis, soft tissue tumor, brain tumor, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone tumor, Prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, head and neck cancer, chronic inflammatory proliferative diseases, including restenosis and rheumatoid arthritis, and proliferative cardiovascular diseases such as stenosis And proliferative eye diseases, such as diabetic retinopathy, and include but are not limited to benign hyperproliferative diseases, such as hemangiomas.

Compositions of compounds of Formula 1 and their pharmaceutically acceptable salts, when administered orally, exhibit activity and may be formulated into syrups, tablets, capsules, and lozenges. Syrup formulations usually consist of a suspension or solution of the compound or salt with a flavourant and colorant in a liquid carrier such as ethanol, peanut oil, olive oil, glycerin or water. If the composition is in tablet form, any of the pharmaceutical carriers commonly used in the manufacture of solid dosage forms can be used. Examples of such carriers are magnesium stearate, terra alba, talc, gelatin, acacia gum, stearic acid, starch, lactose and sucrose. If the composition is in capsule form, any conventional encapsulation using the carriers mentioned above, for example in a hard gelatin capsule shell, is suitable. If the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier commonly used in the preparation of dispersions or suspensions, such as aqueous gums, celluloses, silicates or oils, may be contemplated and incorporated into the soft gelatin capsule shell.

Typical parenteral compositions are solutions or suspensions of compounds or salts optionally comprising parenterally acceptable oils, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or cesium oil, in sterile aqueous or non-aqueous carriers. consist of.

Typical compositions for inhalants are solutions, suspensions or emulsions which are administered in the form of dry powders or aerosols using conventional propellants, for example dichlorodifluoromethane or trichlorofluoromethane.

Typical suppository formulations include a compound of formula (1) or a pharmaceutically acceptable salt thereof that is active when administered in this manner, and includes binders and / or lubricants, for example polymeric glycols, gelatin, cocoa butter or other low melting vegetable Waxes or fats or synthetic analogs thereof.

Typical dermal or transdermal formulations include conventional liquid or non-liquid excipients, such as creams, ointments, lotions or pastes, or in the form of economics, patches or membranes with the addition of drugs.

Preferably the composition is a single dosage form, such as a tablet, capsule or metered aerosol dosage form, so that a patient can administer a single dosage.

Administration of a compound of the present invention in accordance with the present invention does not anticipate acceptable toxic effects.

The test described below demonstrated the biological activity of the compound of formula 1.

In vitro analysis

Compounds capable of inhibiting Myt1 kinase can be identified by the in vitro assays and cellular assays described below. The parameters of this analysis are obvious to those skilled in the art.

Expression of GST-Myt1

A GST-Myt1 expression construct was constructed having a glutathione-S-transferase gene fused to the amino terminus of Myt1 kinase via a thrombin cleavage site containing linker. This clone is cut at amino acid 362 of Myt1, just before the transmembrane domain. This construct was cloned into the baculovirus expression vector pFASTBAC and used to create virus colonies for later infection. Spodoptera frugiperda cells (Sf21) were infected with a virus expressing GST-Myt1 and the cells were cultured for 3 days, followed by harvesting and freezing.

<Refining of GST-Myt1>

GST-Myt1 protein was purified as follows. Lysis buffer on ice (50 mM Tris-Cl, pH 7.5, 250 mM NaCl ₂ , 1 mM dithiothreitol (DDT), 0.1% NP-40,5% (v / v) protease inhibitor mixture, 1 mM sodium orthovana) Date) Sf21 cell pellets expressing GST-Myt1 in 10 ml were resuspended, cells were lysed by sonication and centrifuged at 100,000 × g for 30 minutes. This supernatant was added to 5 ml (packed volume) of glutathione sepharose 4B and washed buffer (20 mM Tris-Cl, pH 7.0, 100 mM MgCl ₂ , 100 mM NaCl ₂ , 1 mM DDT, 0.5% (v / v)). Equilibrium was reached in the protease inhibitor mixture, 1 mM sodium orthovanadate. This mixture was shaken for 30 minutes. The GST-Myt1 bound resin was centrifuged at 500 × g for 5 minutes and then washed with 14 ml of wash buffer. Beads were centrifuged as above and resuspended with 14 ml of other wash buffer. After the suspension was transferred to a column and packed, the wash buffer was allowed to flow through by gravity. GST-Myt1 was eluted from the column using 10 ml of 10 mM glutathione (pH 8.0) in a 500 ml fraction of 50 ml Tris-Cl. Bio-Rad's protein analysis kit was used as a guide to determine protein concentration in fractions. Fractions containing GST-Myt1 were collected and diluted to a concentration of about 0.5 mg / ml and dialyzed buffer (20 mM HEPES, pH 7.0, 1 mM manganese acetate, 100 mM NaCl ₂ , 0.05% Brij-35) at 4 ° C. for 4 hours. , 10% glycerol, 1 mM DDT, 0.2% (v / v) protease inhibitor mixture, 1 mM sodium orthovanatate). This protein was divided and stored at -80 ° C.

Enzyme Analysis

GST-Myt1 Autophosphorylation-Delpia (DELFIA) Assay

96 well NUNC maxisorp plates at 50 μl / well with 0.25 μg GST-Myt1 in Buffer A (50 mM HEPES, pH 7.4, 2 mM Mn (OAc) ₂ , 5 uM ATP, 1 mM DDT). Delayed fluorescence immunoassay (DELFIA) was performed. GST-Myt1 was added to the buffer to initiate autophosphorylation and the reaction proceeded while shaking at room temperature for 20 minutes. EDTA was added to terminate the reaction to a final concentration of 20 mM and allow protein to bind to the wells for an additional 40 minutes. This well was washed three times with 300 μl TBS / Tween (50 mM Tris, pH 7.4, 150 mM NaCl ₂ , 0.2% Tween-20). After washing, plates were shielded with 100 μl / well of Pierce's Superblock in TBS. This was followed immediately and the shield repeated twice or more. Thereafter, the plates were washed three more times with 300 ul / well TBS-twin. Then 100 μl of Eu-labeled anti-phosphotyrosine antibody diluted to 0.125 ug / ml in TBS / Twin containing 0.15 mg / ml BSA was added to the wells and incubated for 30 minutes with shaking at room temperature. Thereafter, the wells were washed three times with 300 μl TBS / Twin, and 200 μl of the enrichment solution was added per well and incubated with shaking for 10 minutes. Subsequently, the plates were measured with a 1420 VICTOR plate measuring instrument sold by Wallac, Inc. The same conditions were used for inhibitor studies except that ATP was 1 μM and the inhibitor was added at a final concentration of 1% in dimethyl sulfoxide (DMSO). Typical concentration ranges in which test compounds are expected to inhibit myt1 autophosphorylation are 0.001-10 μM.

<Biological research>

Cell cycle research

Drug studies were performed with Hela S3 adherent cell lines in consideration of cellular action. Cells were plated at sufficiently low concentrations and 10-20% joined after 24 hours (typically 2 × 10 ⁵ cells / 15 cm e3). Thereafter, thymidine shielding was repeated to tune to the cell S phase. In short, cells were treated with 2 mM thymidine for 18 hours, washed three times for 8 hours to separate the cells, and then again with thymidine. After the second separation from thymidine, 95% of the cells were in S phase. The tuned cells were then added to complete medium containing DNA-damaging drugs such as 50 nM Topotecan alone and in combination with the test mixture for 18 hours. The nuclei were then subjected to cell cycle profiles in the cytoplasm using the propidium iodide staining method (Vindelov et al., Cytometry vol. 3, No. 5, 1983, 323-327). Myt1 inhibitors will reverse G2 identity caused by DNA damaging agents. Typical concentration ranges for this activity are 0.001-10 μΜ.

<Proliferation / Apoptosis Study>

Proliferation studies were performed with a variety of adherent and non-adherent cell lines including Hela S3, HT29 and Jurkat. Proliferation assays utilize chromatic changes that result from the reduction of the tetrazolium reagent XTT to the formazan product by metabolically active cells (Scudiero et al., Cancer Research, 48, 1981, 4827-4833). ]. Cells were seeded and propagated for 24 hours so that about 10% confluence (cell concentration varies with cell line) in 100 μl of 96 well plates. Thereafter, the compound was added to the chemical reagent containing solution in a final volume of 200 μL of 0.2% DMSO with or without sufficient excipient-containing medium to culture the cells. Cells were treated with various concentrations of DNA damaging antiproliferative drugs such as topotecan, test compound and combination treatment at 37 ° C. under 5% CO ₂ . After 72 hours, 50 μl of XTT / phenazine methosulfate mixture was added to each well and the cells were left to incubate for 90 minutes. Plates were read at 450 nm and antiproliferative effects were compared with respect to cells treated with excipients. Myt1 inhibitors inhibited the proliferation of this cancer cell line and / or increased the cytotoxicity of DNA damaging chemotherapeutic drugs. Typical concentration ranges for this activity will be 0.001-10 μΜ. Other assays for cell proliferation or cell injury can also be used with test compounds, which assays are known to those skilled in the art.

The 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. CDCl ₃ is deuterochloroform, DMSO-d ₆ is hexadeuteriodimethylsulfoxide and CD ₃ OD is tetradeuteriomethanol. Chemical shifts were recorded in ppm downfield from standard tetramethylsilane. Abbreviations for NMR data are as follows. s = singlet, d = doublet, q = quarter, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J represents the NMR binding constant measured in hertz. Continuous wave infrared (IR) spectra were recorded with a PerkinElmer 683 infrared spectrometer, and Fourier transformed infrared (FTIR) spectra were recorded with a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode and band positions were recorded in inverse wavelengths (cm ⁻¹ ). Mass spectra were measured with a VG 70 FE, PE Syx API III or VG ZAB HF device using high speed electron bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analysis results were obtained using a Perkin-Elmer 240C elemental analyzer. The melting point was measured and not calibrated using the Thomas-Hover Melting Point apparatus. All temperatures are reported in degrees Celsius.

Thin layer chromatography on Analtech Silica Gel GF and E. coli. E. Merck Silica Gel 60 F-254 thin layer plates were used. Both flash and gravity chromatography. It was performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analysis and preparative HPLC were performed with Rainin or Beckman chromatography. ODS is an octadecylsilyl derivatized silica gel chromatography support. 5 μApex-ODS represents an octadecylyl derivatized silica gel chromatography support having a nominal particle size of 5 μ prepared by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatography support and is based on YMC Co., Kyoto, Japan. Ltd is a registered trademark. PRP-1® is a polymer (styrene-divinylbenzene) chromatography support and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter aid consisting of acid-washed diatomaceous earth silica and is a registered trademark of Manville Corp., Denver, Colorado.

<Example 1>

Bis [2- (4-phenyl-5-methyl) thiazolyl] amine hydrobromide

MS (ES) m / e 363.7 [M + H] ^{+ 1} H NMR (300 MHz, DMSO-d) ?? 7.74 (d, J = 10 Hz, 4H), 7.52 (t, J = 6 Hz, 4H), 7.39 (t, J = 11Hz, 2H)

<Example 2>

Bis [2-4- (2-pyridyl) thiazolyl] amine hydrobromide

MS (ES) m / e 337.7 [M + H] ^{+ 1} H NMR (300 MHz, DMSO-d) ?? 8.71 (d, J = 3 Hz, 2H), 8.23 (m, 4H), 8.05 (s, 2H ), 7.59 (t, J = 6 Hz, 2H)

<Example 3>

Bis [2-4- (3-pyridyl) thiazolyl] amine bistrifluoroacetate

MS (ES) m / e 337.7 [M + H] ^{+ 1} H NMR (300 MHz, DMSO-d) ?? 9.33 (s, 2H), 9.04 (d, J = 10 Hz, 2H), 8.75 (d, J = 5 Hz, 2H), 8.08 (t, J = 11 Hz, 2H), 7.88 (s, 2H)

<Example 4>

N, N-bis (5 (3,4-dichlorophenyl) -2-thiazolyl) amine dihydrobromide

H NMR (300MHz, DMSO-d) ?? 8.33 (s, 1H), 8.18 (s, 2H), 7.94 (d, J = 8.2Hz, 2H), 7.82 (s, 2H), 7.73 (d, J = 8.2 Hz, 2H).

Example 5

1,1-bis [4- (3-pyridyl) -2-thiazolylamino] benzene dihydrobromide

MS (ES) m / e 428.8 [M + H] ^{+ 1} H NMR (300 MHz, DMSO-d) ?? 10.44 (s, 2H), 9.17 (d, J = 1.7 Hz, 2H), 8.47 (dd, J = 1.7,4.7 Hz, 2H), 8.23-8.29 (m, 4H), 7.56 (s, 2H), 7.39 (dd, J = 5.0, 8.0 Hz), 7.32 (s, 2H)

Pharmaceuticals comprising the compounds of the present invention can be prepared with many excipients in various forms. Examples of this formulation are shown below.

<Example 6>

Inhalation Formulation

Compounds of Formula 1 (1 mg to 100 mg) were aerosolized from metered dose inhalers delivering a predetermined amount of drug with each use.

<Example 7>

Tablet formulation

Per tablet / component tablets

1.40 mg of active ingredient (compound of formula 1)

2. 20 mg corn starch

3. Alginic acid 20 mg

4. Sodium Alginate 20 mg

5.Mg Stearate 1.3 mg

Tablet forming process

Components 1, 2, 3 and 4 were mixed in a suitable mixer / blend. Careful mixing after the addition of each component adds sufficient water to the blend until the mixture exhibits the desired consistency to make it wet granules, making them wet granules. An eighth mesh (2.38 mm) screen was used to convert the granulation by passing the wet mixture through a vibrating granulator. The wet granules were then dried in an oven at 140 ° F. (60 ° C.) until dry. The dry granules were lubricated with component 5 and the lubricated granules were compressed with a suitable tablet press.

<Example 8>

Parenteral Formulations

A pharmaceutical composition for parenteral administration was prepared by dissolving an appropriate amount of the compound of formula 1 in polyethylene glycol while heating. Thereafter, the solution was diluted with water for injection (final 100 mL). Thereafter, the solution was sterilized by filtration through a 0.22 micron membrane filter and sealed in a sterile container.

All publications, including patents and patent applications cited herein, are hereby incorporated by reference, the same as if individually set forth herein that each individual publication is incorporated herein by reference in its entirety.

The compounds of formula 1 of the present invention are myt1 kinase inhibitors and are useful for the treatment of various forms of cancer and hyperproliferative diseases.

Claims (7)

To the compound according to formula (1). <Formula 1> Wherein A is a covalent bond, or , And Wherein R is independently selected from the group consisting of H, OMe, Cl, Br, F, NO ₂ and CN, n is an integer from 1 to 4, 1,2-, 1, 3- or 1,4-disubstituted aryl amine ring, each X is H, Br, CH ₃ , NO ₂ , CN and NR ₁ R ₂ (R ₁ and R ₂ are independently hydrogen or O or N optionally Branched or cyclic C _1-4 alkyl), each Ar is independently optionally substituted phenyl or optionally substituted 5 comprising at least one hetero atom selected from N, O and S Or a 6 membered heterocyclic ring. The method of claim 1, 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-thiazolyl) 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. The method of claim 2, 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) thiazolyl] amine. The method of claim 3, 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 and 1,4-bis (4- (4'-biphenyl) -2-thiazolylamino) benzene hydrobromide. A method for antagonizing the myt1 kinase receptor comprising administering an effective amount of a compound according to claim 1 to a patient in need of antagonism against the myt1 kinase receptor. Leukemia, solid tumor, cancer metastasis, soft tissue tumor, brain tumor, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone tumor, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, head cancer and neck cancer, Treatment of said disease or condition comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof for the treatment of a disease or condition selected from the group consisting of chronic inflammatory proliferative disease, proliferative eye disease and benign hyperproliferative disease. Way. The method of claim 4, wherein the disease or condition to be treated is selected from the group consisting of psoriasis, rheumatoid arthritis, diabetic retinopathy and angioma.