RU2641001C1 - Salts of 4-((2-(6-(4-methylpiperazine-1-carbonyl)-naphthalen-2-yl)ethyl) amino)quinazoline-6-carbonitrile and pharmaceutical composition - Google Patents

Abstract

FIELD: pharmacology.SUBSTANCE: invention relates to the salts of 4-((2-(6-(4-methylpiperazine-1-carbonyl)naphthalen-2-yl)ethyl)amino)quinazoline-6-carbonitrile, which have the properties of a cyclin-dependent CDK8/CDK19 kinase inhibitor, and to pharmaceutical compositions comprising these salts, and to the use of such salts or such compositions for treatment of diseases or disorders mediated by the cyclin-dependent CDK8/19 kinase.EFFECT: new salts are obtained, which have improved solubility compared to the free base.13 cl, 5 tbl, 23 ex, 5 dwg

Description

Technical field

The present invention relates to 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salts, methods for their preparation, pharmaceutical compositions comprising these salts, and the use of such salts or such compositions for the treatment of diseases or disorders.

State of the art

CDK8, along with the closely related isoform CDK19, is an oncogenic kinase that regulates transcription (Xu, W. & L, JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439-452; Galbraith , MD, et al. (2010) CDK8: a positive regulator of transcription, Transcription. 1, 4-12; Firestein, R. & Hahn, WC (2009) Revving the Throttle on an oncogene: CDK8 takes the driver seat, Cancer Res 69, 7899-7901). In contrast to the more well-known members of the CDK family (such as CDK1, CDK2 and CDK4 / 6), CDK8 does not play a role in the development of the cell cycle. CDK8 gene knockout in embryonic stem cells leads to arrest of embryo development (Adler, AS, et al. (2012) CDK8 maintains tumor de - differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139) due to its important role in the phenotype of pluripotent stem cells (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551), but blocking CDK8 does not inhibit normal cell growth (Adler, AS , et al. (2012) CDK8 maintains tumor differentiation and embryonic stem cell pluripotency, Cancer Res. 72, 2129-2139, Kapoor, A., et al. (2010) The histone variant macro H2A suppresses melanoma progression through regulation of CDK8 , Nature 468, 1105-1109). The role of CDK8 in cancer is associated with its unique function as a regulator of several transcription factors involved in carcinogenesis (Xu, W. & L, JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis, J. Genet. Genomics 38, 439- 452). CDK8 has been found to play a role in melanoma (Firestein, R., et al. (2010) CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival, Int. J. Cancer 126, 2863 -2873), with colon cancer (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109), while CDK8 expression is increased by ~ 50% in a case of the latter types of cancer; and in breast cancer (E. Broude, et al. (2015) Expression of CDK8 and CDK8-interacting genes as potential biomarkers in breast cancer, Curr. Cancer Drug Targets, 15 (8), 739-749). Increased expression of CDK8 in colon cancer is associated with poor prognosis for colon cancer (Gyorffy, B., et al. (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients Breast Cancer Res. Treat. 123, 725-731).

Known mechanisms associated with CDK8 in cancer include upregulation of the Wnt / [beta] catenin pathway (Kapoor, A., et al. (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8, Nature 468, 1105-1109; Alarcon, C, et al. (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways, Cell 139, 757-769), growth factor-induced transcription (DiDonato, JA, et al. (2012) NF-kappaB and the link between inflammation and cancer, Immunol. Rev. 246, 379-400) and the TGF-beta signaling pathway (Acharyya, S., et al. (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis, Cell 150, 165-178). It has also been shown that CDK8 can support the pluripotent phenotype of embryonic stem cells and that it can be associated with the cancer stem cell phenotype (Firestein, R., et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity, Nature 455, 547-551). Chemotherapeutic drugs that cause DNA damage induce TNF-a, an activator of the transcription factor NFKB (Fabian et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol. 23, 329-336), in endothelial cells and in other stromal elements of the tumor microenvironment. Stromal TNF-a acts on tumor cells, where it induces NFkB-mediated production of the cytokines CXCL1 and CXCL2, which contribute to the survival and growth of tumor cells. CXCL 1/2 attracts myeloid cells to the tumor by binding to the CXCR2 receptor on the surface of myeloid cells. Myeloid cells then secrete small calcium-binding proteins S 100A8 and A9, which are associated with the processes of chronic inflammation and tumor growth. S 100A8 / 9 acts on tumor cells, promoting both their metastasis and survival against chemotherapy (Huang, et al. (2012) MED12 Controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling, Cell 151, 937 -950).

The publication of international patent application WO / 2013/116786 discloses derivatives of 4 - (((naphthalene-2-yl) alkyl) amino) quinosaline-6-carbonitriles, which are selective inhibitors of the cyclin-dependent kinase CDK8 / CDK19 and may be useful for the prevention and treating cyclin-dependent kinase-mediated diseases such as cancer.

A specific compound of this class is 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile:

4 - ((2- (6- (4-Methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile shows low water solubility.

Description of the invention

The following are definitions of terms that are used in the description of this invention.

As used in this application, the term "approximately", when used in connection with the doses, amounts or weight percent of the ingredients of the composition or dosage form, means the dose, amount or weight percent that are recognized by a person skilled in the art as having a pharmacological effect equivalent to the effect obtained when using the specified dose, quantity or weight percent. Specifically, the term “approximately” means the margin of error for a particular value, as determined by a person skilled in the art, which in part depends on how the value is measured or determined. In some embodiments, the term “approximately” means within the range of 0.05% to 30% of a given value or range.

“Solvate” means the molecular complex of a salt of the present invention, including pharmaceutically acceptable salts thereof, with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceuticals that are known to be harmless to the recipient, for example, water, ethanol, ethylene glycol and the like. Other solvents can be used as intermediate solvates in the preparation of more desirable solvates such as methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S) -propylene glycol, (R) -propylene glycol, 1,4-butane-diol and the like.

The term "hydrate" refers to a complex in which the solvent molecule is water.

Solvates and / or hydrates preferably exist in crystalline form.

The term “excipient” is used herein to describe any ingredient other than the 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt this invention.

"Pharmaceutical composition" means a composition comprising a salt according to the invention and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents deliveries such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials flax agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature, mode of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin, as well as agents that promote the formation of matrices, which in turn control the rate and place of release of the active substance, for example, hydroxypropyl methylcellulose, a mixture of polyvinyl acetate and povidone and others. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, cellulose and its derivatives, starch and its derivatives, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and dispensers are starch, alginic acid and its salts, silicates and the like. Examples of lubricants are magnesium stearate, calcium stearate, sodium lauryl sulfate, talc, sodium stearyl fumarate, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., Pharmaceutical Salts J. Pharm. Sci. 1977, 66: 1-19). As amino acids, amino acids can be used - lysine, ornithine and arginine.

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.

“Treat,” “treatment,” and “therapy” refer to a method of reducing the severity or elimination of a biological disorder and / or at least one of its accompanying symptoms. As used herein to “alleviate” a disease, disease, or condition, it means reducing the severity and / or frequency of symptoms of the disease, disorder, or condition. In addition, references to “treatment” contained herein include references to therapeutic, palliative, and prophylactic therapy.

In one aspect, the subject of treatment or the patient is a mammal, preferably a human subject. The above subject may be male or female of any age.

The term "violation" means any condition that can be improved as a result of treatment of the present invention. The definition of this term includes chronic and acute disorders or diseases, including pathological conditions that cause a mammal's predisposition to the occurrence of this violation. Non-limiting examples of diseases to be treated include benign and malignant tumors, in particular cancer of the breast, ovary, stomach, endometrium, salivary gland, lung, kidney, colon, thyroid gland, pancreas, prostate or bladder, melanoma, colorectal cancer; leukemia and lymphoid malignancies; neural, glial, astrocytal, hypothalamic and other glandular, macrophage, epithelial, stromal and blastocellular disorders; inflammatory, angiogenic and immunological disorders. The preferred disorder to be treated according to the invention are chronic lymphoproliferative diseases, cancer, autoimmune diseases.

A “therapeutically effective amount” is the amount of a therapeutic agent administered during treatment that will relieve to some extent one or more of the symptoms of the disease being treated.

In the present description and in the following claims, unless the context provides otherwise, the words “have”, “include” and “contain” or their variations, such as “has”, “having”, “includes”, “including”, “ contains "or" containing ", it should be understood as including the indicated whole or group of whole, but not the exclusion of any other whole or group of whole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salts. In some embodiments of the present invention, the 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile salts of the present invention have significantly higher solubility compared to with reason.

The present invention relates to a salt of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, wherein the salt is selected from dihydrochloride, dimaleate, disulfate.

In one embodiment, the present invention relates to a 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt, wherein the salt is dihydrochloride.

In yet another embodiment, the present invention relates to a salt of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile, wherein the salt is dihydrochloride monohydrate .

In yet another embodiment, the present invention relates to a salt of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile, which is a dihydrochloride, where the salt is in crystalline form, characterized by a powder X-ray diffraction pattern, having peaks at values around: 4.87 ± 0.2, 7.58 ± 0.2, 8.69 ± 0.2, 9.79 ± 0.2, 12.16 ± 0.2, 14.87 ± 0.2, 23.06 ± 0.2, 24.56 ± 0.2, 24.85 ± 0.2, 26.64 ± 0.2, 27.31 ± 0.2, 28.28 ± 0.2 degrees 2Θ.

In one embodiment, the present invention relates to a 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt, wherein the salt is dimaleate. In yet another embodiment, the present invention relates to a salt of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile, which is dimaleate, where the salt is in crystalline form, characterized by a powder X-ray diffraction pattern, having peaks at values around: 7.6 ± 0.2, 8.1 ± 0.2, 10.0 ± 0.2, 15.3 ± 0.2, 15.8 ± 0.2, 16.1 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 23.5 ± 0.2, 27.1 ± 0.2, 29.1 ± 0.2 degrees 2Θ. In yet another embodiment, the present invention relates to a salt of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile, which is dimaleate, where the salt is in crystalline form, characterized by a powder X-ray diffraction pattern, having peaks at values around: 7.6 ± 0.2, 8.1 ± 0.2, 10.0 ± 0.2, 15.3 ± 0.2, 15.8 ± 0.2, 16.1 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 23.5 ± 0.2, 27.1 ± 0.2, 29.1 ± 0.2 degrees 2Θ; and additionally including at least one peak with a value selected from: 6.6 ± 0.2, 7.1 ± 0.2, 11.9 ± 0.2, 16.4 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 25.0 ± 0.2, or 26.5 ± 0.2 degrees 2Θ.

In one embodiment, the present invention relates to a 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt, wherein the salt is a disulfate.

The salts of the present invention may be in the form of solvates, including hydrates, and may exhibit polymorphism.

The salts of the present invention can be obtained from the free base by conventional chemical methods. These salts can be obtained by reacting the free base of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile with a suitable acid in water or in organic solvent, or mixtures thereof. In many cases, a non-aqueous medium may be used, for example ethyl acetate, ethanol, isopropanol, dioxane or ethers. 4 - ((2- (6- (4-Methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile and acid are combined in the required stoichiometric ratio, for example 1: 1 or 1: 2. Then the salt can crystallize, or initiate its crystallization, or it forms an amorphous solid, optionally before crystallization. After that, the solid salt can be dried, for example, by heating under reduced pressure. For purposes of illustration, without any limitation, various salt forms of the present invention can be obtained in accordance with the methods presented in the examples.

In one embodiment, the present invention relates to a pharmaceutical composition comprising in a therapeutically effective amount of at least one of the salts 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalene-2-yl) ethyl) amino) quinazoline-6-carbonitrile described herein and one or more pharmaceutically acceptable excipients. In yet another embodiment, the present invention relates to a pharmaceutical composition comprising in a therapeutically effective amount of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dihydrochloride and one or more pharmaceutically acceptable excipients. In yet another embodiment, the present invention relates to a pharmaceutical composition comprising in a therapeutically effective amount of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dimaleate and one or more pharmaceutically acceptable excipients. In yet another embodiment, the present invention relates to a pharmaceutical composition comprising in a therapeutically effective amount of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile disulfate and one or more pharmaceutically acceptable excipients.

In yet another embodiment of the invention, the pharmaceutical composition of this invention is for the prevention or treatment of a disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19. In yet another embodiment of the invention, the pharmaceutical composition of this invention is for the prevention or treatment of cancer. In some embodiments, a pharmaceutical composition of the invention is intended for the prophylaxis or treatment of colorectal cancer, melanoma, breast cancer, and prostate cancer.

The pharmaceutical composition of the present invention may contain from about 1% to about 99% of the active ingredients. In some embodiments, the pharmaceutical composition of the present invention may contain from about 1% to about 60% of the active ingredients. It is understood that the content of the active ingredient or ingredients in an individual dose of each dosage form is not necessarily an effective amount, since the required effective amount can be achieved with the introduction of several standard dosage forms.

The concentration of the therapeutic agent in the pharmaceutical composition is a certain value, for example, equal to the therapeutically effective amount, which depends on the rate of absorption, inactivation and excretion of the drug from the body, as well as other factors known to specialists in this field of technology. In addition, it should be understood that the magnitude of the dose varies significantly depending on the severity of the condition to be treated.

It should also be understood that for any particular recipient, the appropriate course of treatment should be selected for a certain time, taking into account the individual needs and opinions of the doctor who administers the pharmaceutical composition to the patient or prescribes the administration of pharmaceutical compositions.

The therapeutic agent can be administered once or repeatedly in divided doses, which are administered over different periods of time. Thus, the required amount, for example, the necessary therapeutically effective amount, determines the specialist in this field of medicine.

The pharmaceutical compositions may also include the solvates and hydrates of the salts of the present invention, or a stabilized salt form (for example, a complex with a cyclodextrin derivative or other known complexing agent).

Pharmaceutically acceptable excipients may include, for example, pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, delivery vehicles, such as, for example, buffers, preservatives, antioxidants, stabilizing agents, fillers, grinders, wetting agents, surface-active agents. active substances, glidants, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, colorants, dusting agents, matting agents , lubricating agents, antibacterial agents, fungicides, lubricants, disintegrating agents, delayed delivery regulators, film formers, flavoring agents, antioxidants, binders, adhesive substances, scaffolds (structure-forming), plasticizers [Handbook of Pharmaceutical Excipients, ed. 6th ed. Raymond C. Rowe, Paul J. Sheskey, Marian E. Quinn, Pharmaceutical Press and American Pharmacists Association, 2009].

Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include, but are not limited to, glucose, powdered sugar, pressed sugar, dextrates, dextrins, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, starch and its derivatives, calcium hydrogen phosphate, calcium carbonate, magnesium carbonate, sucrose and others. The filler may be present in a concentration of from about 0% to about 99% based on the total weight of the composition.

Examples of pharmaceutically acceptable disintegrating agents include, but are not limited to, starches, for example sodium starch glycolate, modified starch, clays, cellulose and its derivatives, for example methyl cellulose, alginic acid and its salts, resins, crosslinked polymers, for example crosslinked polyvinylpyrrolidone or crospovid crosslinked sodium salt of carboxymethyl cellulose or sodium carmellose, crosslinked calcium salt of carboxymethyl cellulose or croscarmellose, soy polysaccharides and guar gum, gas-forming disintegrants: solid s organic acids in combination with carbonates or bicarbonates and wetting - surfactants. The disintegrant may be present in a concentration of from about 0% to about 99% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable binding agents include, but are not limited to, starch paste, gelatin, sucrose, sodium alginate, alginic acid gels, natural gums, macrogol, cellulose derivatives, for example, hydroxypropylmethyl cellulose or hypromellose, povidones, povidone-vinyl acetate or copovidone. Pure solvents can also be used as a binder solution, examples of which include, but are not limited to, purified water, alcohols and their solutions or suspensions with the active substance. The binding agent may be present in a concentration of from about 0% to about 99% based on the total weight of the pharmaceutical composition and can be used as a dry binder or as a binder in the form of a solution or suspension.

Examples of pharmaceutically acceptable lubricating and gliding agents include, but are not limited to, talc, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, magnesium carbonate, polyethylene glycol, glyceryl behenate, hydrogenated castoril, glycerol palmitrite, glycerol palmitrite sodium stearyl fumarate, mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, poloxamer, paint small, kaolin, macrogol, polysorbate or a mixture thereof. A lubricant may be present in a concentration of from about 0% to about 20% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable adhesive agents include, but are not limited to, sugar syrup, magnesium oxide, polyvinylpyrrolidone, polyethylene glycol, cellulose and its derivatives, for example, carboxymethyl cellulose, methyl cellulose. The adhesive agent may be present in a concentration of from about 0% to about 15% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable surfactants include, but are not limited to, twins, lanolin, lecithin, gum arabic, gelatin, fatty acid esters, stearic or oleic acid sodium salts, sucrose monopalmitate, sodium laurisulfate. A surfactant may be present in a concentration of from about 0% to about 15% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable structure-forming agents include, but are not limited to, sugar, magnesium oxide, calcium oxide, talc, basic magnesium carbonate. The structure-forming agent may be present in a concentration of from about 0% to about 15% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable film formers include, but are not limited to, cellulose derivatives, for example methyl cellulose, hypromellose, ethyl cellulose; polyvinylpyrrolidone, polyvinyl alcohol, shellac, finished coatings Eudragit, Kollikoat, Sepifilm, Opadray, Acrylic-Iz. The film former may be present in a concentration of from about 0% to about 15% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable plasticizers include, but are not limited to, glycerin, tween-80, PEG, propylene glycol, glycerol triacetate, dibutyl phthalate, citric acid esters, waxes, urethane, castor oil, petroleum jelly, oleic acid. The plasticizer may be present in a concentration of from about 0% to about 15% based on the total weight of the pharmaceutical composition.

Examples of pharmaceutically acceptable prolonging agents include, but are not limited to, cellulose derivatives, for example methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose; polyvinylpyrrolidone, polyvinyl alcohol, shellac, finished coatings Eudragit, Kollikoat, Sepifilm, Opadray, Acrylic-Iz. A prolonging agent may be present in a concentration of from about 0% to about 99% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention may be in the form of a powder, granules or dosage form, for example, in the form of a tablet or capsule.

In one embodiment of the present invention, the pharmaceutical composition may be encapsulated in a capsule shell for oral administration, in particular in a shell of a hard gelatin capsule.

In yet another embodiment of the present invention, the pharmaceutical composition may be compressed into tablets. Tablets may optionally be coated or coated.

The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract and / or buccally, lingually or sublingually enters the bloodstream directly from the oral cavity.

Dosage forms suitable for oral administration include solid, semi-solid and liquid systems, such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids or powders; lozenges (including those filled with liquid); chewing forms; gels; rapidly soluble dosage forms; films; suppositories; Sprays and buccal / mucoadhesive adhesives.

Liquid dosage forms include suspensions, solutions, syrups and elixirs. Such dosage forms can be used as fillers in soft or hard capsules (for example, gelatin or hydroxypropyl methyl cellulose) and usually contain a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifiers and / or suspending agents . Liquid dosage forms can also be made by reconstituting a solid, for example, from a sachet.

The salts of the present invention may also be administered parenterally. Parenteral administration includes, but is not limited to, administering the pharmaceutical composition by injecting the composition, administering the composition through a surgical incision, applying the composition using a non-surgical wound penetrating the tissue, and the like. In particular, it is contemplated that parenteral administration includes, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intraarticular injection or infusion; and renal dialysis infusion techniques. Intratumoral delivery, for example, intratumoral injection, may also be useful. Regional perfusion is also provided.

Dosage forms of pharmaceutical compositions suitable for parenteral administration usually contain the active ingredient in combination with a pharmaceutically acceptable carrier, for example, sterile water or a sterile isotonic solution. Such dosage forms can be manufactured, packaged or sold in a form suitable for bolus administration or for continuous administration. Injectable dosage forms can be manufactured, packaged, or sold in unit dosage form, for example, in ampoules, or in multi-dose containers containing a preservative. Dosage forms for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous bases, pastes, and the like.

The salts of the present invention can also be administered intranasally or inhaled, usually in the form of a dry powder (alone, as a mixture or in the form of particles with mixed components, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, such as an aerosol container pressure, pump, spray, atomizer (preferably an atomizer that uses the principle of electrohydrodynamics to produce fine mist) or a nebulizer that uses or not and It uses a suitable propellant, or as nasal drops.

A pressurized container, pump, spray, nebulizer or nebulizer typically contains a salt solution or suspension of the invention, including, for example, a suitable substance for dispersing, dissolving or prolonging the release of the active substance, a propellant as a solvent.

Prior to use as a dry powder or suspension, the drug is usually micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable grinding method, such as grinding in a spiral jet mill, grinding in a fluidized bed jet mill, supercritical cleaning of a liquid to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters or cartridges for use in an inhaler or insufflator may be configured to contain a powder mixture of the salt of this invention, a suitable powder base, and an activity modifier.

A suitable solution formula for use in a nebulizer using the principle of electrohydrodynamics to produce fine mist may contain a suitable dose of the salt of the present invention with one press, and the volume per press may vary, for example, from 1 μl to 100 μl.

Suitable flavoring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to the dosage forms of this invention for inhalation / intranasal administration.

In the case of powder inhalers and aerosols, the dosage unit is set by means of a valve that delivers a metered amount. Units in accordance with this invention are usually set for the introduction of a measured dose or "injection" of a binding molecule according to this invention. The total daily dose will usually be administered as a single dose or more often as divided doses throughout the day.

Dosage forms can be performed for immediate and / or modified release. Modified release dosage forms include delayed, delayed, pulsating, controlled, targeted and programmed release.

A typical composition is prepared by mixing, moistening, granulating, drying, calibrating, mixing with extragranular components, dusting, tabletting, coating, encapsulating the salt of the present invention and the excipient and / or mixture thereof [Handbook of Pharmaceutical Granulation Technology, 3rd ed. ed. Dilip M / Parikh, Informa Healthcare USA, Inc., T. 198, 2010; Pharmaceutical Dosage Forms: Tablets: Unit Operations and Mechanical Properties, 3rd ed., Ed. Larry L. Augsburger et al., Informa Healthcare USA, Inc., vol. 1, 2008]. Suitable carriers, diluents and other functional excipients are known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The particular carrier, diluent or other functional excipient used will depend on the means and purpose for which the salt of the present invention is used. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.

In one embodiment, the present invention relates to the use of the 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt of the present invention or a pharmaceutical composition of the present the invention for the treatment of a disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19, in a subject in need of such treatment.

In yet another embodiment, the present invention relates to the use of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride for the treatment of a disease or disorder mediated CDK8 / 19 cyclin-dependent tyrosine kinase in a subject in need of such treatment.

In yet another embodiment, the present invention relates to the use of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dimaleate for treating a disease or disorder mediated CDK8 / 19 cyclin-dependent tyrosine kinase in a subject in need of such treatment.

In yet another embodiment, the present invention relates to the use of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile disulfate for the treatment of a disease or disorder mediated CDK8 / 19 cyclin-dependent tyrosine kinase in a subject in need of such treatment.

In yet another embodiment, the present invention relates to the use of the 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt of the present invention or a pharmaceutical composition of the present invention for treating a disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19 in a subject in need of such treatment; where the disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19 is cancer. In some embodiments, the present invention relates to the use of the 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile salt of the present invention or a pharmaceutical composition of the present invention for the treatment of colorectal cancer, melanoma, breast cancer, prostate cancer, in a subject in need of such treatment.

Description of figures

In FIG. 1. presents a powder x-ray of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate.

In FIG. 2. presents a powder x-ray of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dimaleate.

In FIG. 3. The dissolution profile of formulations 1, dry. mixed; 1, ow gr .; 2, dry. mixed; 2, ow. gr .; 3, dry. mixed

In FIG. 4. The dissolution profile of formulations 4, 5, 6, 7, 8, 9 is presented.

In FIG. 5. The dissolution profile of formulations 10, 11, 12, 15, 16 is presented.

For a better understanding of the invention, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any form.

All publications, patents and patent applications referred to in this specification are incorporated herein by reference. Although the aforementioned invention has been described in some detail by way of illustration and example in order to avoid ambiguous interpretation, it will be readily understood by those skilled in the art that certain changes and modifications may be made without departing from the spirit and scope of the enclosed embodiments. the implementation of the invention.

Examples

Example 1. A method for producing 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile.

4 - ((2- (6- (4-Methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile was prepared according to the following scheme:

4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalene-2-yl) ethyl) amino) quinazoline-6-carbonitrile: ¹ H NMR (400 MHz, DMSO-d ₆ ), δ, ppm : 8.82 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.05 (dd, J 8.6, 1.7 Hz, 1H), 7.95-7.88 (m, 3H), 7.82 (s, 1H) , 7.77 (d, J 8.6 Hz, 1H), 7.52 (d, J 8.4 Hz, 1H), 7.45 (d, J 8.4 Hz, 1H), 3.89 (q, J 6.7 Hz, 2H), 3.8-3.4 (br s, 4H), 3.16 (t, J 7.3 Hz, 2H), 2.32 (br s, 4H), 2.19 (s, 3H). IR spectrum (KBr), cm ^-1 : 3361, 2935, 2786, 1625.

Example 2. A method for producing 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dihydrochloride monohydrate.

61 g of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile are charged to 800 ml of 2-propanol and 800 ml of water. To the resulting suspension add 23 ml of concentrated hydrochloric acid. The mixture is heated to a boil and incubated for 30 minutes. The resulting suspension is cooled with stirring to 20-25 ° C and incubated for 2 hours. The suspension is filtered, the filter cake washed with pre-chilled 2-propanol 2 times 500 ml. The product was collected from the filter and dried for 10 hours at 50 ° C. Obtain 65 g (yield 93%).

NMR ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm: 11.45 (s, 1H), 11.15 (s, 1H), 9.38 (s, 1H), 8.95 (s, 1H), 8.35 (d, J 8.7 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.95 (t, J 8.4 Hz, 2H), 7.89 (s, 1H), 7.58-7.52 (m, 2H), 4.09-4.01 (k, J 6.7 Hz, 2H), 3.70-3.31 (br s, 4H), 3.25 (t, J 7.3 Hz, 2H), 3.11 (s, 4H), 2.77 (s, 3H).

IR (KBr), cm ^-1 : 3021, 2942, 2697, 2236, 1625.

X-ray powder diffraction pattern of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate is shown in FIG. 1, characteristic peaks are given below:

Example 3. Determination of chloride content in 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate.

The chloride content in 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate was determined by potentiometric titration.

48.9 mg of sample 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dihydrochloride monohydrate was dissolved in 50 ml of purified water. The resulting solution was titrated using an automatic titrator (serial number 17147, 848 Titrino plus, Metrohm, Switzerland) with a 0.014 M silver nitrate solution. At the end of the titration, we obtained the volume that went to the titration until the equivalence point was reached.

The chloride content in the sample 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate was calculated based on the ratio: 1 ml A 0.014 M silver nitrate solution corresponds to 0.5 mg Cl ^- . The chloride content was:

Below is a theoretical calculation of the chloride content in sample 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate:

the molar mass of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dihydrochloride monohydrate is 541.5 g / mol;

the molar mass of chlorine is 35.5 g / mol;

The error of the method is ± 2%.

Example 4. A method for producing 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dimaleate.

144 g of maleic acid are added to 6 L of ethanol. 259 g of 4 - ((2- (b- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile are added at 40 ° C. The resulting suspension is heated to boiling and incubated for 30 minutes. The resulting solution is cooled with stirring to 20-25 ° C and incubated for 3 hours. The suspension is filtered, the filter cake washed with precooled ethanol 2 times 1 liter. The product was collected from the filter and dried for 10 hours at 40 ° C. 360 g are obtained (90% yield).

NMR ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm: 8.82 (s, 1H), 8.79 (s, 1H), 8.57 (s, 1H), 8.06 (d, J 8.6 Hz, 1H), 7.99 (s, 1H), 7.95-7.92 (m, J 8.5, 4.7 Hz, 2H), 7.85 (s, 1H), 7.78 (d, J 8.6 Hz, 2H), 7.57-7.50 (m, J 15.3, 8.6 Hz , 1H), 6.13 (s, 4H), 3.94-3.89 (q, J 6.8 Hz, 2H), 3.89-3.42 (br.s, 4H), 3.26 (s, 4H), 3.18 (t, J 7.2 Hz, 2H), 2.84 (s, 3H).

IR (KBr), cm ^-1 : 3034, 2951, 2614, 2234, 1707, 1626.

An X-ray powder diffraction pattern of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazoline-6-carbonitrile dimaleate is shown in FIG. 2, characteristic peaks are given below:

Example 5. A method for producing 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile disulfate.

10 g of 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile are charged to 100 ml of ethanol and 100 ml of water. To the resulting suspension was added 3.5 ml of concentrated sulfuric acid. The mixture is heated to a boil. The resulting suspension is cooled with stirring to 20-25 ° C and incubated for 1 hour. The suspension is filtered, the filter cake washed with previously chilled 50% 2-propanol 2 times 50 ml. The product was collected from the filter and dried for 10 hours at 50 ° C. Obtain 13 g (yield 92%).

NMR ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm: 9.79 (br s, 1H), 9.50 (s, 1H), 8.20 (d, J 8.9 Hz, 1H), 8.02 (s, 1H) , 7.95 (t, J 8.2 Hz, 2Н), 7.87 (s, 1Н), 7.84 (d, 8.1 Hz, 1Н), 7.58-7.52 (m, 2Н), 4.00-3.95 (q, J 6.7 Hz, 2Н) ), 3.90-3.23 (br s, 8H), 3.20 (t, J 7.3 Hz, 2H), 2.85 (s, 3H).

Example 6. The study of solubility.

The solubility of various salts is determined according to the United States Pharmacopeia "General notices and requirements" article 5.30., And the data obtained are shown in table 1.

Example 7. A method of obtaining a pharmaceutical composition.

Tablets according to the composition of composition 1 are prepared according to the following procedure:

A) 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalene-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate is mixed with microcrystalline cellulose, povidone and croscarmellose sodium in a mixer, with this gives a powdery mixture. Next, magnesium stearate is added to the resulting mixture and mixed to obtain a tabletting mixture of composition 1. By compression on a tablet press, tablets are obtained from the tabletting mixture.

B) 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalene-2-yl) ethyl) amino) quinazoline-6-carbonitrile dihydrochloride monohydrate is mixed with microcrystalline cellulose and croscarmellose sodium in a granulator mixer, with this gives a powdery mixture. Povidone is dissolved in purified water and then the resulting solution is added to a powdery mixture of components in a mixer-granulator. Wet granulation and wet granulate calibration are carried out. The calibrated wet granulate is dried in a dryer, and dry granulate is obtained. Next, dry granulate is calibrated on a calibrator. The obtained calibrated dry granulate is dusted with magnesium stearate, having previously sieved it, in a mixer, to obtain a mixture for tabletting the composition 1. By pressing on a tablet press, tablets are obtained from the tablet mixture.

Example 8

Tablets according to the composition of composition 2 are prepared according to the following procedure:

A) 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dimaleate is mixed with microcrystalline cellulose, povidone and croscarmellose sodium in a mixer, while get a powder mixture. Next, magnesium stearate is added to the resulting mixture and mixed. By compression on a tablet press, tablets are obtained from the tablet mixture.

B) 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile dimaleate is mixed with microcrystalline cellulose and croscarmellose sodium in a granulator mixer, while get a powder mixture. Povidone is dissolved in purified water and then the resulting solution is added to a powdery mixture of components in a mixer-granulator. Wet granulation and wet granulate calibration are carried out. The calibrated wet granulate is dried in a dryer, and dry granulate is obtained. Next, dry granulate is calibrated on a calibrator. The resulting calibrated dry granulate is dusted with magnesium stearate, after having sieved it, in a mixer. By compression on a tablet press, tablets are obtained from the tablet mixture.

Example 9

The pharmaceutical composition is prepared in a similar manner to that described in Example 8, Method A, except that crospovidone is added instead of croscarmellose sodium.

Example 10

The pharmaceutical composition is obtained in a manner analogous to the method described in example 8, method B. After that, the coating on the tablets is carried out in a coator.

Example 11

The pharmaceutical composition is obtained in a manner analogous to the method described in example 8, method B.

Example 12

The pharmaceutical composition is prepared in a similar manner to that described in method B, except that sodium stearyl fumarate is added in place of magnesium stearate.

Example 13

The pharmaceutical composition is obtained in a manner analogous to the method described in example 12.

Example 14

The pharmaceutical composition is prepared in a similar manner to that described in Example 8, Method B, except that sodium starch glycolate is added instead of croscarmellose sodium.

Example 15

The pharmaceutical composition is obtained in a manner analogous to the method described in example 14.

Example 16

The pharmaceutical composition is prepared in a similar manner to that described in Example 8, Method B, except that lactose monohydrate is used instead of microcrystalline cellulose.

Example 17

The pharmaceutical composition is obtained in a manner analogous to the method described in example 16.

Example 18

The pharmaceutical composition is prepared in a similar manner to that described in Example 8, Method B, except that lactose monohydrate is added instead of microcrystalline cellulose and sodium stearyl fumarate is added instead of magnesium stearate.

Example 19

The pharmaceutical composition is obtained in a manner analogous to the method described in example 18.

Example 20

The pharmaceutical composition is prepared in a similar manner to that described in Example 8, Method B, except that lactose monohydrate is added instead of microcrystalline cellulose and sodium starch glycolate is added instead of croscarmellose sodium. Then carry out the coating on the tablets in the coator.

Example 21

The pharmaceutical composition is prepared in a similar manner to that described in Example 10 for a dosage of 50 mg.

Example 22

The pharmaceutical composition is prepared in a similar manner to that described in Example 10 for a dosage of 5 mg.

Example 23. The dissolution profile.

The dissolution of the tablets was carried out as described in the US Pharmacopoeia <711> "Dissolution", using the apparatus "Paddle mixer", under the following conditions: dissolution medium - 0.1 M solution of hydrochloric acid; the volume of the dissolution medium is 900 ml; the temperature of the dissolution medium is (37.0 ± 0.5) ° C; stirrer rotation speed - 50 rpm. The amount of dissolved drug substance (%) was determined by UV spectrophotometry. The optical densities of the standard and test solution were measured on a spectrophotometer at a wavelength of 324 nm in a cuvette with a layer thickness of 10 mm. As a comparison solution, a dissolution medium was used. The specified method is characterized by selectivity, accuracy and linearity. According to the specification, the limits of the permissible absolute error of the spectrophotometer for measuring spectral directional transmittance coefficients are ± 1% for the device. The error in sample preparation is acceptable about 5%. The dissolution profiles of the tablets are shown in table 2.1-2.4.

Claims (13)

1. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, which is a dihydrochloride. 2. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile according to claim 1, which is dihydrochloride monohydrate. 3. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, which is dihydrochloride, where this salt is in crystalline form, characterized by X-ray powder diffraction pattern having peaks at values around: 4.87 ± 0.2, 7.58 ± 0.2, 8.69 ± 0.2, 9.79 ± 0.2, 12.16 ± 0.2, 14.87 ± 0.2, 23.06 ± 0.2, 24.56 ± 0.2, 24.85 ± 0.2, 26.64 ± 0.2, 27.31 ± 0.2, 28.28 ± 0.2 degrees 2Θ. 4. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, which is a dimaleate. 5. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, which is a dimaleate, where this salt is in crystalline form, characterized by X-ray powder diffraction pattern having peaks at values: 7.6 ± 0.2, 8.1 ± 0.2, 10.0 ± 0.2, 15.3 ± 0.2, 15.8 ± 0.2, 16.1 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 23.5 ± 0.2, 27.1 ± 0.2, 29.1 ± 0.2 degrees 2Θ. 6. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile according to claim 5, wherein the x-ray powder diffraction pattern further comprises at least , one peak with a value selected from: 6.6 ± 0.2, 7.1 ± 0.2, 11.9 ± 0.2, 16.4 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 25.0 ± 0.2, or 26.5 ± 0.2 degrees 2Θ. 7. Salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile, which is a disulfate. 8. A pharmaceutical composition comprising a therapeutically effective amount of a salt according to any one of claims. 1-7 and one or more pharmaceutically acceptable excipients and intended for the prevention or treatment of a disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19. 9. The pharmaceutical composition according to claim 8, wherein the disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19 is cancer. 10. The pharmaceutical composition of claim 9, wherein the cancer is selected from the group consisting of colorectal cancer, melanoma, breast cancer, and prostate cancer. 11. The use of the salt 4 - ((2- (6- (4-methylpiperazin-1-carbonyl) naphthalen-2-yl) ethyl) amino) quinazolin-6-carbonitrile according to any one of claims. 1-7 or the pharmaceutical composition of claim 8 for treating a disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19 in a subject in need of such treatment. 12. The use of claim 11, wherein the disease or disorder mediated by the cyclin-dependent tyrosine kinase CDK8 / 19 is cancer. 13. The use of claim 12, wherein the cancer is selected from the group consisting of colorectal cancer, melanoma, breast cancer, and prostate cancer.

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