CZ20001312A3 - MYTl kinase inhibitors - Google Patents

Description

Technical field

The present invention relates to inhibitors of membrane tyrosine threonine kinases (myti kinas), pharmaceutical compositions containing the compounds and methods for identifying the compounds and methods of using the compounds for the treatment of various forms of cancer and hyperproliferative diseases.

BACKGROUND OF THE INVENTION

The entry into mitosis is initiated by M-phase inducing factors (MPF), a complex containing cdc2 protein kinase and cyclin B. Proper MPF regulation ensures that mitosis occurs only after completion of earlier phases of the cell cycle. Phosphorylation of cdc2 on Tyr-15 and Thr-14 suppresses this activity during interphase (GI,

S and G2). In the G2-M transition, cdc2 is dephosphorylated to Tyr-15 and Thr-14, allowing MPF to phosphorylate its mitotic substrates. It is known that another family of cdc-regulatory kinases (Weel) is responsible for the phosphorylation of Tyr-15 cdc. A new member of this family, Myti, has recently been described as Thr-14 and Tyr-15 specific cdc2-kinase and has been shown to be an important regulator of cdc2 / cyclin B kinase activity (Science 270: 86-90, 1995; Mol. Cell Biol 17: 571 (1997). Inhibition of cdc2 phosphorylation is important for the timing of entry into mitosis. Experiments have shown that premature activation of cdc2 leads to the breakdown of mitosis and cell death. It is believed that inhibition of Myti causes premature activation of cdc2 and so that it can kill rapidly proliferating cells. In addition, inhibition of Myti is believed to reduce resistance to conventional DNA damaging chemotherapeutic agents since the cellular resistance mechanism contains a G2 phase cell cycle arrest and repair of damaged DNA prior to cell division. This lock can be prevented by blocking e · 6 ··

Washing inhibitory phosphorylation of cdc2. This causes premature cell entry into mitosis.

Wash kinase is an important regulator of the cell cycle, especially in the G2 / M phase. Inhibitors of this kinase will therefore be attractive for the treatment of cancer. Current treatments for tumors, including surgery, radiation and chemotherapy, are often unsuccessful in the treatment of diseases. The patient population is large. For example, only colon cancer is diagnosed with 160000 new cases and 60000 deaths per year in the United States. Worldwide, 600,000 new cases of colon cancer are diagnosed annually. The number of lung cancer is twice that of colon cancer. A major drawback of chemotherapy for most solid tumors is that most patients do not respond to this treatment. This is due to cell cycle regulation and subsequent repair of DNA damage or mitotic apparatus, which are targets for the most potent chemotherapeutic agents. Wash kinase offers a site of intervention at the level of the mechanisms by which the tumor cell becomes resistant. Inhibition of kinase washing can be therapeutically beneficial in that it can reduce tumor cell proliferation itself, and can be used together with conventional chemotherapeutic agents to overcome drug resistance.

For the reasons mentioned above, it is necessary to identify an effective inhibitor of the enzyme Myti kinase for the treatment of various diseases, including cancer, associated with said receptor.

SUMMARY OF THE INVENTION

The present invention includes compounds of formula (I), pharmaceutical compositions comprising said compounds, and methods for antagonizing the Myti kinase receptor using such compounds.

.:

· **

The present invention includes compounds of formula (I) x

wherein A represents a covalent bond or 1,2,2,3 or

1,4-disubstituted arylamino ring selected from the group consisting of:

where

R is independently selected from: H, OMe, Cl, Br, F, NO ₂ and CN; n is an integer from 1 to 4;

each X is independently selected from: H, Br, CH ₃ , NO ₂ , CN and NR R;

each Ar is independently an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S; and R and R ₂ are independently hydrogen or C _i4 alkyl, branched or cyclic, optionally containing 0 or N.

* 4

Preferred compounds of the present invention are 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-thiazolyl) amine;

N, N-bis (5- (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 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, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine; l, 4-bis (4- (4 ^1-biphenyl) -2-thiazolylamino) benzene;

1,4-bis (4-fluorophenyl-2-thiazolylamino) benzene; bis [2- (4- (2-pyridyl)) thiazolyl] amine; a. bis [2- (4- (3-pyridyl)) thiazolyl] amine.

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, N-bis (4- (4'-biphenyl) -2-thiazolyl) amine;

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

As used herein, the term alkyl refers to an optionally substituted hydrocarbon group bound by one carbon-carbon bond. The alkyl group may be linear, branched or cyclic, saturated or unsaturated. Preferably this group is · · · ·

4>

‘4

J- · · · · · · · · ««

• · i

Saturated linear or cyclic.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic or optically active forms. All of these compounds and diastereomers are within the scope of the present invention.

The compounds of the present invention may be prepared in the form of pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they can be administered.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleainate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained using acids such as sulfuric, hydrochloric, maleic, phosphoric, sulfamic, acetic, citric, lactic, tartaric, malic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexyl sulfamic, fumaric and quinic.

Pharmaceutically acceptable salts also include base addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonia, alkylamine and zinc, if present. an acidic functional group such as a carboxylic acid or phenol.

Preferred salts are hydrobromide, dihydrobromide and bistrifluoroacetate.

The compounds of the present invention are as follows:

can be prepared

Scheme l

Scheme 2

NBS.H8F,

-20 ° C

CNCH »

Appropriate bisthiazolyl compounds are synthesized by condensation of dithiobiuret (as shown in Equation 1) or any other bisthiourea such as 1,3-phenyldithiourea (as shown in Equation 2) with two equivalents of a suitably substituted bromoketone such as 2-bromo-1- phenylpropan-1-one, in a solvent such as ethanol or acetone or in any other suitable solvent. The reaction mixture is heated at 70-90 ° C for several hours (4-12 hours). Cooling the reaction mixture yields the desired material as the bis-hydrobromide salt.

The monobromination of the bisthiazole compounds can be carried out, for example, by reacting 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 the like.

A »A • A

A A

Any other suitable solvent, according to procedures described in the literature (Oberhauser, T., J. Org. Chem. 1997, 62: 4504-4506). Bis-bromination can be carried out by any known bromination reaction, such as the reaction of bis-thiazole with

N-bromosuccinimide using refluxing DMSO or acetonitrile or bromine in acetic acid or any other method known to those skilled in the art.

With appropriate modifications and protection of any chemical function, the synthesis of other compounds of formula (I) may be carried out in a manner analogous to the above.

When a compound of Formula I or a pharmaceutically acceptable salt thereof is used for the treatment of humans or other mammals, the compound is usually prepared by standard pharmaceutical techniques in the form of a pharmaceutical composition.

The ligands of the present invention can be administered by a variety of routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or mucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds may be prepared as conventional oral dosage forms such as capsules, tablets, and liquid compositions such as syrups, elixirs and concentrated drops.

Alternatively, injectable compositions (for parenteral administration) may be used, for example, for intravenous, intraperitoneal, subcutaneous and intramuscular administration. For injection, the compounds of the present invention are formulated in liquid solutions, preferably in physiologically acceptable buffers or solutions, such as saline, Hank's solution or Ringer's solution. Further, the compounds of the present invention

99 ···· 9 · 9 9 9 9 9 «. 9 · • · 9 • * 9 • 9 • 9 9 9 • 9 9 9 9 9 9 * 8 e. 9 • · • 9 9

The invention may be prepared in solid form and may be dissolved or suspended immediately prior to use. Lyophilized forms may also be prepared.

Systemic administration can also be accomplished by mucosal or transdermal routes. For trans-mucosal or transdermal administration, agents permitting barrier penetration are used in the compositions. Such agents are known in the art and include, but are not limited to, for transgucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate penetration. Transmucosal administration may, for example, be performed using nasal sprays, rectal suppositories or vaginal suppositories.

For topical administration, the compounds of the present invention may be prepared in the form of ointments, balms, gels or creams as known in the art.

'’·. 5. ‘...

The amount of different compounds administered can be determined in a standard manner, taking into account factors such as IC, EC ₅₀ , half-life of the compound, age, size and weight of the patient, and paceint disease. The importance of these and other factors taken into account is known in the art.

The amount administered also depends on the route of administration and oral bioavailability. For example, for compounds with lower oral bioavailability, relatively higher doses of the compound will be administered.

Preferably, the composition is in unit dosage form. For oral administration, it may be used, for example a tablet or capsule, for nasal administration may use a predetermined dose aerosol, transdermal administration may be used in a transdermal patch or composition for transmucosal administration and may be used buccal · ··· · ^h patch. In any case, the dosage is such that a single dose may be administered to the patient.

Each dosage unit for oral administration preferably contains from 0.01 to 500 mg / kg, more preferably 0.1 to 50 mg / kg, of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dose for parenteral, nasal oral inhalation, mucosal and transdermal routes of administration preferably contains from 0.01 mg to 100 mg / kg of the compound of formula I. The topical compositions preferably contain from 0.01 to 5.0% of the compound of formula I. be administered 1 to 6 times daily, preferably administered once daily in such a way as to achieve the desired activity, as is clear to those skilled in the art.

As used herein, the term treatment of a disease means preventing, alleviating and prophylaxis of the disease. The term treatable using the compounds of the present invention as used includes, without limitation, leukemia, solid tumors, metastasis, soft tissue tumors, brain tumors, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, cancer bladder cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer; chronic inflammatory proliferative diseases such as psoriasis and rheumatoid arthritis; proliferative cardiovascular diseases such as restenosis; proliferative eye diseases such as diabetic retinopathy; and benign hyperproliferative diseases such as hemangiomas.

The compounds of formula I and their pharmaceutically acceptable salts, which are active when administered orally, can be formulated as syrups, tablets, capsules, and medical wafers. The syrup composition typically comprises a suspension or solution of the compound or a compound thereof

salts in a liquid carrier such as ethanol, peanut oil, olive oil, glycerin or water, coloring or flavoring. When the composition is in the form of tablets, any pharmaceutical carrier commonly used in the preparation of solid compositions may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any capsule preparation technique may be used, for example using the above carriers in a solid gelatin capsule. When the composition is in the form of soft gelatin capsules, any pharmaceutical carrier commonly used in the preparation of dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, which are incorporated into the soft gelatin capsule can be used.

Typical parenteral compositions consist of a solution or suspension of the compound or a salt thereof in a sterile aqueous or non-aqueous carrier which optionally contains a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil.

Typical formulations for inhalation are in the form of a solution, suspension or emulsion, which can be administered as dry powders or in the form of an aerosol using conventional propellants such as dichlorofluoromethane or trichlorofluoromethane.

Typical suppository formulations comprise a compound of formula I or a pharmaceutically acceptable salt thereof, which is active in this mode of administration, with a binding and / or glidant such as polymeric glycols, gelatin, cocoa butter or other vegetable waxes or fats or synthetic analogues thereof with low melting point.

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, bandage or membrane.

Preferably, the composition is in unit dosage form, for example, in the form of a tablet, capsule, or metered-dose aerosol, so that a single dose can be administered to the patient.

When administered by the method of the present invention, no unacceptable toxicological effects of the compounds of the present invention are expected.

The biological activity of the compounds of formula I is demonstrated in the following tests.

In vitro tests

Compounds capable of binding the kinase kinase can be identified in in vitro assays and cell assays as described below. Variations of these assays will be apparent to those skilled in the art.

GST-Myth expression:

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

GST-Mytl cleaning:

The GST-Myt1 protein was purified as follows: A pellet of Sf21 cells expressing GST-Myt1 was resuspended on ice in ml of lysis buffer (50 mM Tris-Cl, pH 7.5, 250 mM NaCl, 1 mM

L. ² dithiothreitol (DTT), 0.1% NP-40, 5% (v / v) protease inhibitor mixture, 1 mM sodium orthovanadate), cells were lysed by sonication and centrifuged at 100,000 xg for 30 minutes. The supernatant was added to 5 ml (packed volume) of Glutathion Sepharose 4B equilibrated in wash buffer (20 mM Tris-Cl, pH 7.0, mM MgCl ₂ , 100 mM NaCl ₂ , 1 mM DTT, 5% v / v). (mixture of protease inhibitors, 1 mM sodium orthovanadate). The mixture was shaken for 30 minutes. GST-Myt1-bound resin was centrifuged at 500 xg for 5 minutes and washed with 14 ml wash buffer. The beads were centrifuged as above and resuspended in another 14 ml wash buffer. The suspension was transferred to the column and allowed to stand, and then the wash buffer was drained. GST-Myt1 was eluted from the column using 10 ml of 10 mM glutathione in 50 mM Tris-Cl, pH 8 in 500 L fractions. Protein concentrations were determined in fractions using the Protein assay kit (Bio-Rad) according to the manufacturer's instructions. Fractions containing GST-Myt1 were collected and diluted to a concentration of approximately 0.5 mg / ml and dialyzed for 4 hours at 4 ° C in dialysis buffer (20 mM HEPES, pH 7.0, 1 mM manganese acetate, 100 ml). mM NaCl ₂ , 0.05% Brij-35, 10% glycerol, 1 mM DTT, 0.2% (v / v) protease inhibitor mixture, 1 mM sodium orthovanadate). The protein was aliquoted and stored at -80 ° C.

Enzyme tests

GST-Mytl'autophosphorylation-DELFIA test

Delayed fluorescence immunoassays (DELFIA) were performed in 96-well NUNC maxisorp plates, at 50 g / well with 0.25 g GST-Myt1, in buffer A (50 mM HEPES, pH 7.4, 2 mM Mn (0Ac)). _2, 5 ATP Μ, L mM DTT). To determine the pH optimum, use of divalent cations and K _m ATP, some components varied as shown in the figures. Autophosphorylation reactions were initiated by the addition of GST-Mat1 in buffer and run at ambient temperature with shaking for 20 minutes. Reactions were terminated by adding EDTA to a final concentration of 20 mM and the protein was allowed to further bind to the wells for an additional 40 minutes. The wells were washed three times with 300 L TBS / Tween (50 mM Tris, pH 7.4, 150 mM NaCl ₂ , 0.2% Tween-20). After washing, the plates were blocked with Pierce Superblock in TBS at a concentration of 100

1 / well ,. This was immediately decanted and the blocking was repeated two more times. The plate was then washed again three times with 300 L / well TBS-Tween. 100 µl of Eu-labeled anti-phosphotyrosine antibody diluted to 0.125 g / ml in TBS / Tween containing 0.15 mg / ml BSA was added to the wells and allowed to incubate for 30 minutes with shaking at ambient temperature. The wells were then washed three times with 300 L of TBS / Tween, 200 were added to each well

Enhancement of the solution and incubation with shaking for 10 minutes. Plate as determined on a 1420 VICTOR plate reader from Wallac, Inc. Identical conditions are used for inhibition assays except that ATP is used in an amount of 1 M and that inhibitors are added at a final concentration of 1% in dimethylsulfoxide (DMSO). Typical concentration ranges at which test compounds are expected to inhibit washing by autophosphorylation are 0.001 to 10 M.

Biological studies

Cell cycle studies

Drug tests studying their effects on cells were performed on

HeLa S3 adherent cell line. Cells were plated at a low enough concentration to 24 hours later were 10-20% confluent (typically 2 x 10 ^cells / 15 cm ^3). Then the cells were synchronized in S phase using repeated thymidine blocking. Briefly, 2 mM thymidine was added to the cells for 18 hours, which was removed over 8 hours with 3 washes, and then thymidine was added to the cells again. After the second thymidine removal, 95% of the cells were in the S phase. The synchronized cells were then returned to complete media containing a DNA damaging drug, for example 50 nM topotecan (a dose that was found to be sufficient to cause cell arrest in the early G2 phase without inducing apoptosis), alone and in combination with test compounds for a period of time. 18 hours. The cell cycle profile was obtained cytometrically using the procedure described for propidium iodide staining of adolescents (Vindelov et al., Cytometry, Volume 3, No. 5, 1983, 323-327). It was assumed that the Myti inhibitor should abolish the G2 arrest caused by the DNA damaging agent. A typical concentration range for such activity should be up to 0.001 to 10 M.

Proliferation / apoptosis tests

Prliferation assays were performed on various adherent and non-adherent cell lines including HeLa S3, HT29 and Jurkat (deleted ***). The proliferation assay utilized colorimetric changes resulting from the reduction of tetrazolium XTT to formazan product by metabolically active cells (Scudiero et al., Cancer Research, 48: 1981, 4827-4833). Cells were plated in 100 L in 96-well plates at approximately 10% confluency (cell concentration varied for each cell line) and cultured for 24 hours. Compounds were then added with or without sufficient vehicle-containing media to give a final volume of 200 L containing chemical reagents in 0.2% DMSO. Different concentrations of DNA-damaging antiproliferative drugs such as topotecan, test compounds and combinations were added to the cells at 37 ° C and 5% CO ₂ 72 hours later, 50 L of the mixture was added to each well.

XTT / phenazine methosulfate and cells were incubated for 90 minutes. Plates were read at 450 nm and the antiproliferative effects were compared to vehicle-treated cells. It was expected that Myti inhibitors would inhibit the proliferation of such tumor cell lines and / or increase the cytotoxicity of DNA damaging chemotherapeutic agents. Typical concentration ranges for such activity should be up to 0.001 to 10 M. Other cell proliferation or cytotoxicity assays known to those skilled in the art may also be used for test compounds.

The present invention includes, but is not limited to, the assays set forth below. The nuclear nuclear resonance spectrum was recorded at 300 MHz using a Bruker AM300 spectrometer. CDCl 3 is deuteriochloroform, DMSO-d is hexadeuteriodimethylsulfoxide, and CD ₃ OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million ()) down relative to the tetramethylsilane internal standard. The abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = triplet doublet, app = apparent, br = broad. J is the NMR coupling constant measured in Hertz. The continuous infrared (IR) spectrum was detected on a Perkin Elmer 683 infrared spectrometer and the Fourier transformed infrared (FTIR) spectrum was detected on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were detected in transmission mode and line positions are reported as inverse wavelength values (οπΓ ^χ ).

Mass spectra were determined on either VG70 FE, PE Syx API III or VG ZAB HF instruments, using rapid bombardment.

1 * 6 **

atoms (FAB) or electrospray (ES) ionization. Elemental analyzes were obtained using a Perkin Elmer 240C elemental analyzer. Melting points were determined on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gradient chromatography were performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were performed on Rainin or Beckman chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatography support. Apex-ODS refers to an octadecylsilyl derivatized silica gel chromatography carrier having a nominal particle size of 5 manufactured by Jones.

Chromatography, Littleton, Colorado. YMC ODS-AQ ^R is an ODS chromatography support that is registered under the trademark (YMC Co. Ltd., Kyoto, Japan). PRP-1 ^R is a polymeric (styrene-divinylbenzene) chromatographic support and is registered under the trademark (Hamilton Co., Reno, Nevada). Celite ^R is a filtering agent composed of acid-washed diatomaceous silica and is registered under trademark (Manville Corp., Denver, Colorado).

DETAILED DESCRIPTION OF THE INVENTION

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) δ 7.74 (d, J = 10 Hz, 4H), 7.52 (t, J = 6 Hz, 4H), 7.39 (t, J = 11 Hz, 2H). Example 2: bis [2- (4- (2-pyridyl) thiazolyl] amine, dihydrobromide).

MS (ES) m / e 337.7 [M + H] +. NMR (300 MHz, DMSO-d) δ 8.71 (d, J =

1 * 1

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] + ^X H NMR (300 MHz, DMSO-d) ?? 9.33 (s, 2H), 9.04 (d, J = 10 Hz, 2H ), 8.75 (d, J = 5Hz, 2H), 8.08 (t, J =

Hz, 2H), 7.88 (s, 2H).

Example 4: N, N-bis [5- (3,4-dichlorophenyl) -2-thiazolyl] -amine dihydrobromide ^{Χ Η} NMR (300 MHz, DMSO-d) ?? 8.33 (s, 1H), 8, 18 (s, 2 H), 7.94 (d,

J = 8.2 Hz, 2H), 7.82 (s, 2H), 7.73 (d, J = 8.2 Hz, 2H).

Example 5: 1,3-bis [4- (3-pyridyl) -2-thiazolylamino] benzene, dihydrobromide.

MS (ES) m / e 428.8 [M + H] + ^{Χ Η} NMR (300 MHz, DMSO-d) ?? 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 (s, 2H).

Pharmaceutical compositions containing the compounds of the present invention can be prepared in various forms and with various additives. Examples of such devices are given below:

Example 6: Inhalant

The compound of formula (I) (1 mg to 100 mg) is administered as an aerosol from a metered dose inhaler so that a predetermined amount of the compound is administered.

1 «8

Example 7: Tablets

Tablets / ingredients on a tablet

1. Active ingredient (compound of formula I) ... 40 mg

2. Maize starch 20 mg

3. Alginic acid ..................... 20 mg

4. Sodium alginate .............................. 20 mg

5. Magnesium steranus ............................. 1.3 mg

Tablet production process

The components 1, 2, 3 and 4 are mixed in a suitable mixer. Sufficient water is added in portions with thorough mixing after each addition until the consistency of the mass allows conversion to wet granules. The wet mass is converted to granules using an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140 ° F (60 ° C) to dryness. The dry granules are moistened with Component No. 5 and the moistened granules are compressed in a suitable tablet press.

Example 8: Parenteral composition

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I in polyethylene glycol with heating. This solution is then diluted with water for injection (100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile 14 containers.

All publications, including patents and patent applications,. referred to in the present invention are hereby incorporated by reference in their entirety.

Claims (7)

Compound of Formula I: x X (I) wherein A represents a covalent bond or 1,2, 1,3 or 1,4-disubstituted arylamino ring selected from the group consisting of: N / where R is independently selected from: H, OMe, Cl, Br, F, NO ₂ and CN; n is an integer from 1 to 4; Ř. each X is independently selected from: H, Br, CH ₃ , NO, CN i each Ar is independently an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S; and R _x and R ₂ are independently hydrogen or C _x alkyl, branched or cyclic, optionally containing O or N. Live £ · < * &% ***. i • 4 • A compound according to claim 1 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-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. A compound according to claim 2 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)) thiazolyl] amine. A compound according to claim 3 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; and 1,4-bis (4- (4'-biphenyl) -2-thiazolylamino) benzene hydrobromide. 5. A method of antagonizing a receptor for the washing of kinase comprising administering to an individual in need of such treatment an effective amount of a compound of claim 1. A method for treating diseases or disorders selected from the group consisting of leukemia, solid tumors and metastases, soft tissue tumors, brain tumors, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer; chronic inflammatory proliferative diseases; proliferative cardiovascular disease; a proliferative ocular disease and a benign hyperproliferative disorder characterized in that an individual in need of such treatment is administered an effective amount of a compound of claim 1. The method of claim 4, wherein the disease or disorder being treated is selected from the group consisting of psoriasis, rheumatoid arthritis, diabetic retinopathy, and hemangiomas.