Use of pyrimidylaminobenzamide derivatives for treating systemic mastocytosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to the use of pyrimidylaminobenzamide derivatives, particularly 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula

, or its pharmaceutically acceptable salt for preparing drugs applicable for treating and preventing systemic mastocytosis. The invention refers to a drug, a method of treating or preventing systemic mastocytosis. The invention also refers to a combination to be used for treating systemic mastocytosis containing the compound of formula (II) and imanitib taken in a therapeutically efficient amount.

EFFECT: compound (II) and combination are applicable in treating systemic mastocytosis which is characterised by resistance to imanitib and preferentially bound with FIPlLl-PDGFRa hybrid gene.

12 cl, 1 ex

 

Summary of the invention

The present invention relates to the use of derivatives pyrimidinediamine for obtaining a medicinal product intended for the treatment of systemic mastocytosis. The present invention also relates to a method of treatment system mastocytosis.

The background to the present invention

Systemic mastocytosis (SM) is divided into indolent SM (minor violation or no violation of the functions of the authority), aggressive SM (a violation of the functions of the authority), SM associated with hematological diseases nematoctonus type (SM-AHNMD), and basophilic leukemia. Clinical manifestations of SM in adults are heterogeneous and include skin diseases (usually pigmented urticaria), symptoms associated with release of mediators of mast cells (headache, flushing, dizziness, syncope, anaphylaxis etc), direct and indirect damage to organs (pain in the bone tissue due to lytic lesions in bones, osteoporosis or fracture, hepatosplenomegaly, cytopenia due to irregularities in the bone marrow). In addition, approximately 20% of patients with a diagnosis of SM is observed severe eosinophilia, and sometimes isolated eosinophilia (Tefferi and Pardanani (2004)).

In most cases, basophilic leukemia is a malignant Soboleva who eat when the patient's life span is a few months. Currently there is no effective therapy basophilic leukemia. In the natural development of indolent SM, sometimes passing into an aggressive form of SM and SM-AHNMD, the disease is characterized by a more favorable prognosis and life expectancy is ten years. The development of mastocytosis SM-AHNMD, i.e. associated with AHNMD, going with a less favourable prognosis compared with SM without AHNMD. As with indolent and aggressive form SM without AHNMD, high concentrations of mast cells and eosinophils in the bone marrow, increased serum level of alkaline phosphatase in serum, anemia and hepatosplenomegaly associated with poor prognosis (Tefferi and Pardanani (2004)). Full histological and clinical remission was observed in patients with a diagnosis of SM associated with a hybrid gene FIP1L1-PDGFRα, after treatment with Glivec (Gleevec®, Pardanani 2003a, Pardanani 2003b).

It is now established that derived pyrimidinediamine effective in the treatment of SM, primarily in the treatment of SM associated with a hybrid gene FIP1L1-PDGFRα.

The purpose of the present invention is carried out with the use of derivatives pyrimidinediamine to ensure, first of all, the system mastocytosis, especially SM, linked hybrid gene FIP1L1-PDGFRα.

Brief present the giving essence of the present invention

The present invention relates to the use of compounds pyrimidinediamine formula (I) in this context: "derivatives pyrimidinediamine"):

where R1means hydrogen, (ness.)alkyl, (ness.)alkoxy(ness.)alkyl, acyloxy(ness.)alkyl, carboxy(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl or phenyl(ness.)alkyl,

R2means hydrogen, (ness.)alkyl, optionally substituted by one or more identical or different substituents R3cycloalkyl, bascically, heterocyclyl, aryl group, or a mono - or bicyclic heteroaryl group, not containing or containing one, two or three nitrogen atom in the cycle, and not containing or containing one oxygen atom, and contains zero or one sulfur atom, and these groups in each case are unsubstituted or mono - or polyamidine,

and R3means hydroxy, (ness.)alkoxy, acyloxy, carboxy, (ness.)alkoxycarbonyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amino, mono - or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or a mono - or bicyclic heteroaryl group, not containing or containing one, two or three nitrogen atom in the cycle, and not containing or containing one oxygen atom, and contains zero or one sulfur atom, being the m these groups in each case are unsubstituted, mono - or polyamidine,

or where R1and R2together mean alkylene containing four, five or six carbon atoms, optionally mono - or disubstituted by groups: (NISS.)alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, (ness.)alkoxy, amine, mono - or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; mean benzaclin containing four or five carbon atoms, oxyalkylene containing one oxygen atom and three or four carbon atoms, or Isaakyan containing one atom of nitrogen and three or four carbon atoms, where the nitrogen is unsubstituted or substituted groups: (NISS.)alkyl, phenyl(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl, carboxy(ness.)alkyl, carbarnoyl(ness.)alkyl, N-mono - or N,N-disubstituted carbarnoyl(ness.)alkyl, cycloalkyl, (ness.)alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl,

R4means hydrogen, (ness.)alkyl or halogen,

and to the use of N-oxide or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions intended for the treatment of systemic mastocytosis, and SM associated with a hybrid gene FIP1L1-PDGFRα. In addition, the present invention relates to the use of compounds of formula I for the treatment or prevention system mastocytosis.

Key terms use the bathrooms in this context, have the following meanings, unless otherwise indicated.

The term "(ness.)" means the Deputy containing and including a maximum of 7, especially up to 7, and with a maximum of 4 carbon atoms, and specified the Deputy is a linear or branched with one or more branches.

If the compounds, salts, etc. specified in the plural, this form also includes the compound, salt or the like in the singular.

Any asymmetric carbon atoms are in (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. Thus, these compounds are present as mixtures of isomers or as pure isomers, preferably enantiomerically pure diastereomers.

The present invention also relates to the possible tautomers of the compounds of formula I.

(Ness.)alkyl preferably denotes a linear or branched alkyl comprising from 1 to 7 carbon atoms, preferably containing from 1 to 4 carbon atoms, preferred (ness.)alkyl means butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferred (ness.)alkyl means methyl, propyl or tert-butyl.

(Ness.)acyl means preferably formyl or (ness.)alkylsulphonyl, especially acetyl.

The aryl group means aromaticus is the first Deputy, which is attached to the base molecule through a carbon atom in the aromatic ring. In a preferred embodiment, the aryl means aromatic Deputy containing from 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrene, and means unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, which are primarily chosen from the group comprising amino, mono - or disubstituted amino, halogen, (ness.)alkyl, substituted (ness.)alkyl, (ness.)alkenyl, (ness.)quinil, phenyl, hydroxy, hydroxy in the form of simple or complex ester, nitro, cyano, carboxy, esterified carboxy in the form of ester, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenylthio, phenyl(ness.)alkylthio, (ness.)alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, (ness.)alkylresorcinol, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, (ness.)alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, such as primarily trifloromethyl, dihydroxybis (-B(OH)2), heterocyclyl, mono - or bicyclic heteroaryl group, and (ness.)alkylenedioxy attached to the adjacent atom is m carbon cycle, such as methylenedioxy. Aryl preferably denotes phenyl, naphthyl or tetrahydronaphthyl, which in each case is unsubstituted or independently substituted by one or two substituents which are selected from the group including halogen, especially fluorine, chlorine or bromine; hydroxy, hydroxy, esterified (ness.)the alkyl (simple ether), for example, methyl groups, halogen(ness.)alkyl, for example trifluoromethyl, or phenyl; means (ness.)alkylenedioxy, prisoedinenii to the two adjacent carbon atoms, for example, methylenedioxy, (ness.)alkyl, for example methyl or propyl; halogen(ness.)alkyl, for example trifluoromethyl; hydroxy(ness.)alkyl, for example hydroxymethyl or 2-hydroxy-2-propyl; (ness.)alkoxy(ness.)alkyl, for example, methoxymethyl or 2-methoxyethyl; (ness.)alkoxycarbonyl(ness.)alkyl, for example, methoxycarbonylmethyl; (ness.)quinil, such as 1-PROPYNYL, esterified carboxy (ester), primarily (ness.)alkoxycarbonyl, for example, methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-mono-substituted carbarnoyl, first of all, carbarnoyl, monosubstituted groups (ness.)alkyl, for example methyl, n-propyl or ISO-propyl; amino; (ness.)alkylamino, for example, methylamino, di(ness.)alkylamino, for example, dimethylamino or diethylamino, (ness.)alkylamino, for example, pyrrolidino or piperidino, (the bottom is.)oxyalkylene, for example, morpholino, (ness.)analcreampie, for example, piperazine derivatives, acylamino, for example, acetylamino or benzoylamine, (ness.)alkylsulfonyl, for example, methylsulphonyl, sulfamoyl, or phenylsulfonyl.

Cycloalkyl group preferably means cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl and is unsubstituted or substituted by one or more, especially one or two, substituents which are selected from the above group of substituents for aryl, more preferably comprising (ness.)alkyl, such as methyl, (ness.)alkoxy, such as methoxy or ethoxy, or hydroxy, and also oxo, or a condensed benzene ring, such as benzocyclobutene or bassilekin.

Substituted alkyl means the above-mentioned alkyl, especially (ness.)alkyl, preferably methyl, containing one or more, especially up to three, substituents, which are primarily chosen from the group comprising halogen, especially fluorine, amino, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, N-(ness.)alkanolamine, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl and phenyl(ness.)alkoxycarbonyl. First of all, preferred is trifluoromethyl.

Mono - or disubstituted amino means primarily the amino group, substituted by one or two substituents that are independently from each other selected from the GRU is dust: (NISS.)alkyl, such as methyl, hydroxy(ness.)alkyl, such as 2-hydroxyethyl, (ness.)alkoxy(ness.)alkyl, such as methoxyethyl, phenyl(ness.)alkyl, such as benzyl or 2-phenylethyl, (ness.)alkanoyl, such as acetyl, benzoyl, substituted benzoyl where the phenyl substituent is primarily substituted by one or more, preferably one or two, substituents which are selected from groups: nitro, amino, halogen, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, and carbarnoyl, and phenyl(ness.)alkoxycarbonyl, where the phenyl substituent is unsubstituted or primarily substituted by one or more, preferably one or two, substituents which are selected from groups: nitro, amino, halogen, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, and carbarnoyl, and preferably denotes N-(ness.)alkylamino, such as N-methylamino, hydroxy(ness.)alkylamino, such as 2-hydroxyethylamino or 2-hydroxypropyl, (ness.)alkoxy(ness.)alkyl, such as methoxyethyl, phenyl(ness.)alkylamino, such as benzylamino, N,N-di(ness.)alkylamino, N-phenyl(ness.)alkyl-N-(ness.)alkylamino, N,N-di(ness.)alkylenediamine, (ness.)alkanolamine, such as acetylamino, or Deputy, who is chosen from the group comprising benzoylamine and Anil(ness.)alkoxycarbonyl, where the phenyl substituent in each case is unsubstituted or primarily substituted by substituents: nitro, or amino, or halogen, amino, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, carbarnoyl or aminocarbonyl. Disubstituted amino means (ness.)alkylamino, for example, pyrrolidino, 2-oxopyrrolidin or piperidino, (ness.)oxyalkylene, for example, morpholino, or (ness.)analcreampie, for example, the piperazine derivatives or N-substituted, piperazine derivatives, such as N-methylpiperazine or N-ethoxycarbonylpyrimidine.

Halogen means primarily fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

Esterified hydroxy in the form of simple ether means primarily With8-C20alkyloxy, such as n-decyloxy, (ness.)alkoxy (preferred), such as methoxy, ethoxy, isopropoxy or tert-Butylochka, phenyl(ness.)alkoxy, such as benzyloxy, phenyloxy, halogen(ness.)alkoxy, such as triptoreline, 2,2,2-triptoreline or 1,1,2,2-tetrafluoroethoxy, or (ness.)alkoxy, substituted mono - or bicyclic-heteroaryl containing one or two nitrogen atom, preferably (ness.)alkoxy, substituted imidazolium, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, before ever the 2-, 3 - or 4-pyridyl, pyrimidinyl, primarily 2-pyrimidinyl, pyrazinyl, ethenolysis, primarily 3-ethenolysis, chinoline, indolyl or thiazolyl.

Esterified hydroxy in the form of ester means first of all (ness.)alkanoyloxy, benzoyloxy, (ness.)alkoxycarbonyl, such as tert-butoxycarbonylamino, or phenyl(ness.)alkoxycarbonyl, such as benzyloxycarbonyloxy.

Esterified carboxy in the form of ester means first of all (ness.)alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or etoxycarbonyl, phenyl(ness.)alkoxycarbonyl or phenoxycarbonyl.

Alkanoyl means primarily alkylsulphonyl primarily (ness.)alkanoyl, for example, acetyl.

N-Mono - or N,N-disubstituted carbarnoyl primarily substituted by one or two substituents that are independently chosen from the group: (NISS.)alkyl, phenyl(ness.)alkyl and hydroxy(ness.)alkyl, or (ness.)alkylene, oxa(ness.)alkylen, or Aza(ness.)alkylene, optionally substituted at the terminal nitrogen atom.

Mono - or bicyclic heteroaryl group, not containing or containing one, two or three nitrogen atom, and contains zero or one oxygen atom, and contains zero or one sulfur atom, and these groups in each case are unsubstituted or mono - and polyamidine, means heterocyclic residue containing unsaturated cycle linking heteroaryl balance with the main part of the molecule of formula I and preferably means the cycle, and in the spanning cycle, but not necessarily in any condensed cycle, at least one carbon atom is replaced by a heteroatom chosen from the group comprising nitrogen, oxygen and sulfur; and connecting the loop preferably comprises from 5 to 12, more preferably 5 or 6 atoms in the cycle and which is unsubstituted or substituted by one or more, especially one or two, substituents which are selected from the above substituents for aryl, more preferably from the group of: (NISS.)alkyl, such as methyl, (ness.)alkoxy, such as methoxy or ethoxy, or hydroxy. Preferred mono - or bicyclic heteroaryl group selected from groups: 2N-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazoles, purinol, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-hemolysins, ethanolic, hinely, phthalazine, naphthyridine, Minoxidil, hintline, indolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, tetrazolyl, furutani, benzo[d]pyrazolyl, thienyl and furanyl. Preferred mono - or bicyclic heteroaryl GRU the PU is chosen from the group including pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazoles, primarily 5-indazoles, pyridyl, especially 2-, 3 - or 4-pyridyl, pyrimidinyl, primarily 2-pyrimidinyl, pyrazinyl, ethenolysis, primarily 3-ethenolysis, chinoline, especially 4 - or 8-chinoline, indolyl, especially 3-indolyl, thiazolyl, benzo[C1]pyrazolyl, thienyl and furanyl. In one preferred embodiment of the present invention pyridyl substituted by hydroxyl in the ortho-position to the nitrogen atom and, therefore, there are at least partly in the form of a corresponding tautomer, pyridine-(1H)2-she. In another preferred embodiment, pyrimidinyl substituted by hydroxyl in position 2 and position 4 and, therefore, exist in several tautomeric forms, for example, in the form of pyrimidine-(1H, 3H)2,4-dione.

Heterocyclyl means first of all five-, six - or semicolony heterocyclic system containing one or two heteroatoms, which are selected from the group comprising nitrogen, oxygen and sulfur, and this system is unsaturated or fully or partially saturated and unsubstituted or substituted primarily groups: (NISS.)alkyl, such as methyl, phenyl(ness.)alkyl, such as benzyl, oxo or heteroaryl, such as 2-piperazinil, heterocyclyl oznachaet the first 2 - or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-(ness.)alkyl-4-piperidinyl, N-(ness.)alkylpiperazine, morpholine, for example 2 - or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl or 2-methyl-1,3-dioxolane-2-yl.

Salt means above all pharmaceutically acceptable salts of compounds of formula I.

These compounds can form, for example, acid additive salts, preferably with organic or inorganic acids and compounds of the formula I, comprising basic nitrogen atom, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, Caprylic acid, capric acid, dodekanisa acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, Emelyanova acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, cyclohexanecarbonyl acid, hell is mantanona acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane - or econsultancy acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonate acid, benzolsulfonat acid, 2-naphthalenesulfonate acid, 1,5-naphthalenedisulfonic acid, 2-, 3 - or 4-methylbenzenesulfonic acid, mmelserna acid, atisara acid, modellerna acid, N-cyclohexylsulfamic acid, N-methyl, N-ethyl - or N-propylsulfonyl acid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged substituents such as carboxy or sulfo, these compounds also comprise the salts of bases, for example, metal salts or ammonium, such as salts of alkali metals or alkaline earth metals, for example salts of sodium, potassium, magnesium or calcium, or ammonium salts or suitable organic amines, such as tertiary monoamines, for example triethylamine or three(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethylpiperidine or N,N'-dimethylpiperazine.

If the same molecule is the basic group and an acid group, the compound of formula I forms an internal salt.

For isolation or purification it is also possible to use the with pharmaceutically unacceptable salts, for example, the picrate or perchlorate. For treatment use only pharmaceutically acceptable salts or free compounds (which are suitable in the form of pharmaceutical preparations) and, therefore, are preferred.

Due to the close structure of the new compounds in free form and compounds in the form of their salts, including those salts that are used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds in this context means a reference to the corresponding salt.

Compounds included within the scope of formula I, and the retrieval method described in the application WO 04/005281, published January 15, 2004, which is incorporated into this description by reference. Preferred is 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide and its pharmaceutically acceptable salts of formula (II):

In each case, if in the present description provides links to applications and scientific publications, primarily in the description of pyrimidinediamine, in the present description also includes the final products, the pharmaceutical preparations and the claims.

The structure of the active agents, the corresponding code numbers, nonproprietary or tor the new names can be found in the current edition of the Handbook "The Merck Index" or in a database, e.g. Patents International (e.g. IMS World Publications). Relevant content is included in the present description by reference.

Now unexpectedly found that derivatives pyrimidinediamine possess therapeutic properties that manifest primarily in the application as an inhibitor of PDGFRα (platelet-derived growth factor α, PDGFRα) and, above all, for the treatment and prevention of diseases associated with hybrid gene FIP1L1-PDGFRα, such as systemic mastocytosis.

Reduction of FIP1L1-PDGFRα used in this context, means a hybrid product FIP1L1 genes (FIP1 like 1) and PDGFRα.

The present invention thus relates to the use of derivatives pyrimidinediamine for obtaining a medicinal product intended for the treatment of systemic mastocytosis, called hybrid gene FIP1L1-PDGFRα, or other diseases associated with FIPL1-PDGFRα or similar mutations that activate PDGFRα.

Systemic mastocytosis (SM) includes indolent SM, aggressive SM and SM associated with hematologic disease nematoctonus type and basophilic leukemia.

In another embodiment, the present invention relates to the use of derivatives pyrimidinediamine to obtain a pharmaceutical to the notizie, designed for use in the treatment of allergic rhinitis, allergic dermatitis, drug Allergy or food Allergy, disease Quincke, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis primarily for the treatment of allergic rhinitis, allergic dermatitis, drug Allergy or food Allergy, disease Quincke, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis that is resistant to imatinib.

The term "allergic rhinitis", which is used in this context, means any allergic reaction of the nasal mucosa. This allergic reaction can occur, for example, continuously, for example, vernal conjunctivitis, or at certain times of the year, for example, hay fever.

The term "atopic dermatitis", which is used in this context, means, first of all, atopic dermatitis, allergic contact dermatitis and eczematous dermatitis, but also means, for example, seborrheic dermatitis, lichen Wilson, hives and acne. Atopic dermatitis defined above in this context, means a chronic inflammatory skin disease in patients with hereditary predisposition to bonigen the th threshold sensitivity of skin itching. Atopic dermatitis is characterized by severe itching, leading to scratching and rubbing, which in turn causes the typical eczema. Allergic contact dermatitis defined above in this context, refers to a form of dermatitis due to allergic sensitivity to various substances, which causes an inflammatory reaction in the skin of patients who have a hypersensitivity to allergens in the result of prior exposure to these substances.

The term "drug Allergy or food Allergy", which is used in this context, refers to allergic reactions caused by drug or food antigens, such as, for example, strawberries, milk or eggs.

The term bronchopulmonary aspergillosis refers to infection of the lungs by the fungi Aspergillus.

The term "mastocytosis", which is used in this context, refers to systemic mastocytosis, for example, to mastocytoma, and mastocytosis neoplasms in dogs. Mastocytosis means myeloproliferative violation, virtually untreatable and mostly with poor prognosis. The pathogenesis of mastocytosis is associated with constitutive activation of the receptor tyrosine kinase KIT. The vast majority of patients with mastocytosis rosregulirovanie tyrosine kinase activity PR is owing to the mutation of codon 816 in the protein (D816V), which also confers resistance in vitro and in vivo to imatinib or of imatinib mesilate, which later received the trade name Gleevec® in the United States or Glivec® in other countries.

Mast cells play an important role as the primary effector cells in allergic diseases mentioned in this context. Antigen-specific IgE mediated degranulation of mast cells leads to the subsequent release of chemical mediators, many cytokines and leukotriene synthesis. In addition, mast cells participate in pathogeneses multiple sclerosis.

Mastocytosis neoplasm occur both in humans and in animals. Mastocytosis neoplasma dogs are called mastocytoma and generally ranges from 7% to 21% of all tumors in dogs. Mastocytosis person differs temporary or indolent character, while neoplasma dogs are characterized by unpredictability, in most cases, aggressiveness and metastasis. For example, individual mastocytoma people rarely metastasize, unlike dogs, which are approximately 50% mastocytoma are malignant, as described in the book Hottendorf & Nielsen (1969), including 46 publications that describe tumors in 938 dogs.

Cancer in populations of domestic animals is a spontaneous disease. Pet owners who are a hundred who are stated to extend the life of their Pets, in most cases, seek advice on the care and treatment of animals to the veterinary oncologists in private veterinary hospitals and veterinary training centers across the country. The issues of medical treatment for cancer patients in veterinary similar to the treatment of the person, which include surgery, chemotherapy, radiation therapy, and biotherapy. In the United States, registered 42 million dogs and about 20 million cats. Estimated cases of cancer each year registered about 4 million new cases of the disease in dogs and similar size in cats.

Skin mastocytosis tumors in dogs are a common problem. Most mastocytoma tumors are benign and can be cured by simple resection, however, if the tumor is characterized by recurrent or extensive metastases to distant parts of the body, in this case, the disease is virtually impossible to treat. Therapeutic effect on recurrent tumors includes external radiation therapy. In the treatment of distant metastases or diffuse tumors favorable effect lomustin and vinblastine (Lomustine®, vinblastine) in combination with chemotherapy. Departments metastasis mastocytoma tumors include the skin, regional lymph nodes, with whom lesenko, liver and bone marrow.

Part of the receptor tyrosine kinase KIT in the pathological process mastocytosis confirmed by the fact that some mutations that lead to constitutive activation of the tyrosine kinase KIT, identified in many lines of fat cells. For example, a point mutation of C-KPH person in the replacement of Val by Asp816 domain phosphotransferase and autoactivate receptor is observed in the line of fat cells obtained from malignant tumors with long basophilic leukemia person (NMS-1), and in the corresponding codon in two lines in the fat cells of rodents. In addition, this activating mutation identified in situ in some cases mastocytosis person. Two other activating mutations identified in the intracellular kolomanbrunnen fragment KIT, i.e. replacement Val560Gly in the line of mast cells HMC-1, and deletion of seven amino acid residues (Thr573-His579) in line fat cells of rodents, the so-called FMA3.

The present invention primarily relates to the use of derivatives pyrimidinediamine for obtaining a medicinal product intended for the treatment of systemic mastocytosis.

In another embodiment, the present invention proposes a method of treatment system mastocytosis, including the introduction of a mammal in need of such treatment, therapeutic the ski effective amount of derivatives pyrimidinediamine, or their pharmaceutically acceptable salts, or prodrugs.

In the present invention preferably features a method of treating mammals, especially humans, suffering from systemic mastocytosis, including the introduction of a mammal in need of such treatment, inhibition hybrid gene PIP1L1-PDGFRα number 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide (compound (II)or its pharmaceutically acceptable salt.

In the present description, the term "treatment" includes both prophylactic or preventive treatment and treatment or the vast development of the disease action, including treatment of patients at risk of developing the disease or patients, disease-prone and emerging disease. This term also includes treatment to slow the progression of the disease.

The term "therapeutic effect", which is used in this context, means the effectiveness of the treatment of developing episodes of diseases, including systemic mastocytosis.

The term "prophylactic" means the prevention of primary manifestations of the disease or recurrence of disease, including systemic mastocytosis.

The term "slow progression", which is used in this context, means the introduction of active is soedineniya patients at the stage, the earlier the disease, or at an early stage of the disease, for example, patients on the diagnosis of the respective disease, or patients undergoing medical treatment, or in patients after an accident, which may result in the development of related diseases.

Such a wide range of properties means that the use of derivatives pyrimidinediamine is of interest primarily for the manufacture of a medicinal product intended for the treatment of systemic mastocytosis.

The effectiveness of this drug, first of all, has implications for treatment in the clinic of patients with systemic mastocytosis.

To assess the suitability of derivative pyrimidinediamine primarily for the treatment of systemic mastocytosis with high therapeutic index and other advantages of conducting clinical trials known standard methods.

The exact dose derived pyrimidinediamine used to suppress system mastocytosis depends on several factors including the host body, the nature and severity of the disease, the route of administration. The compound of formula I is administered by any standard means, including oral, parenteral, for example, intraperitoneal, intravenous, intramuscular, subcutaneous, wew is opuholevogo or rectal, or enteral administration. The compound of formula I is preferably administered orally, preferably the daily dose is from 1 to 300 mg/kg body weight or, for larger primates, a daily dose of from 50 to 5000 mg, preferably from 500 to 3,000 mg. Preferred oral daily dose is from 1 to 75 mg/kg body weight or, for larger primates, a daily dose of from 10 to 2000 mg, which is administered as a single dose or divided multiple doses, for example, twice a day.

Usually at the beginning of treatment prescribed a low dose and then the dose is gradually increased until the optimal dose required for treatment of a particular subject. The upper limit of the dose is limited by side effects and is determined when tested in the treatment of the subject.

The compounds of formula I can be mixed with one or more pharmaceutically acceptable carriers and, optionally, one or more other standard pharmaceutical adjuvants and enter enterline, for example, orally in the form of tablets, capsules, microtablets, etc. or parenterally, for example, intraperitoneally or intravenously, in the form of sterile solutions or suspensions for injection. Compositions for enteral and parenteral receive standard methods.

Derivatives pyrimidinemethanol alone or in combination with at least one pharmaceutically active compound, used to treat these diseases. These active compounds are mixed in a single pharmaceutical preparation or in the form of combination products in the form of a "set of components, the components of the combination is administered in independent dose or in the form of different fixed combinations with certain quantities of the components of the combination, i.e. simultaneously or at certain periods of time. Thus, the components of the kit, for example, is administered simultaneously or sequentially, i.e. in different periods of time and with the same or different intervals for any component in the set. Examples of compounds that can be used in combination with derivative pyrimidinediamine include, without limitation, cytotoxic khimioterapevticheskie drugs, such as cytosine arabinoside, daunorubicin, doxorubicin, cyclophosphamide, VP-16, or imatinib, etc. in Addition, derivatives pyrimidinediamine can be combined with other inhibitors of signal transmission or other submitted to oncogene drugs with expected significant synergistic effect.

In addition, the present invention relates to combinations derived pyrimidinediamine, as described in this context, with imatinib for the treatment of diseases of the States, described in this context. This combination shows the effect of simultaneous introduction of, for example, in the form of a fixed combination pharmaceutical composition or drug, or if a serial or sequential administration. Currently preferred is recommended to introduce derivatives pyrimidinediamine in the dosage form, as described in this context, and commercial drug imatinib (GLEEVEC® in the United States or GLIVEC® in Europe) in the dose.

The treatment system mastocytosis the above combination is the primary treatment, i.e. treatment was first diagnosed disease without any prior chemotherapy or similar treatment, or is secondary, i.e. the treatment of the disease after prior treatment with imatinib or derived pyrimidinediamine, depending on the severity or stage of disease, as well as the General condition of the patient, etc.

The effectiveness of treatment derived pyrimidinediamine system mastocytosis illustrated by the results obtained in the following examples. These examples are presented only to illustrate the present invention and do not limit its scope.

The analysis is independent of IL-3 proliferatio cells

The effect of compounds on viability and proliferation of cells received ivali using the ATPLite kit™ for luminescent detection of ATP firms Perkin Elmer Life Sciences (catalog No. 6016947) according to the attached instructions. This system of analysis based on detection of fluorescent radiation in the reaction of ATP with luciferase and D-luciferine.

Cell line Ba/F3 FIP-PDGFRα, Ba/F3 kit D-816-V, Ba/F3 kit D-816-Y, Ba/F3 kit delVV, Ba/F3 kit R-634-W were cultured in medium RPMI 1640 (firm Invitromex, catalog No. L0501)containing 10% fetal calf serum (ETS firms Amimed, catalog No. 2-01F86-I), 2 mm L-glutamine (Gibco)in 96-well tablets black for tissue cultures (Packard company) to a density of 10,000 cells per well in 50 μl complete medium and were immediately added to 50 μl of the hole in the serial twofold dilution of the concentrated solution of compounds (in the double repeat). As control was used cells in the absence of the above compounds. For subtracting the baseline signal used the environment in the absence of cells. After 70 h of incubation (37°C, 5% CO2cells were literally adding 50 µl of well solution for lysis of animal cells (included in the kit) and were shaken in a shaker for 5 min at 700 rpm Then added 50 μl of substrate solution (luciferase and D-luciferin) and after shaking for 5 min and keeping the tablet in the dark for 10 min, measured the emission of light on the instrument Packard TopCount.

The activity of compounds was determined in the form of a General suppression of the growth of cell cultures (TGI) and the specified value was calculated after the ith follows: after subtracting the baseline signal, obtained from control cells was taken as equal to 100%. The action of the compounds were expressed as percent reduction of the control signal. Values TGI5O was determined by curve response/dose method graphical extrapolation.

Line GIST882 is a line of cells stromal tumors of the gastrointestinal tract of man (GIST)expressing an activating mutation of KIT exon 13-642-E) (article D.A. Tuveson, Willis N.A., Jacks T., Griffin J.D., Singer, S., Fletcher C.D., J.A. Fletcher, G.D. Demetri, STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications, Oncogene, 20(36), 5054-8 (16 August 2001)). The GIST882 cell line was cultured in RPMI medium 1640 (firm Invitromex, catalog No. L0501)containing 15% ETS, and 2 mm glutamine (Gibco). To enhance adhesion and cell growth before cultivation flasks with cell culture and 96-well plates to tissue cultures were treated with 1.5% gelatin solution in purified water (nanorover) within 30 to 60 min at 37°C. Before use gelatin (BIORAD, purity EIA, No. 170-6537) were sterilized under heat (autoclaving).

GIST882 cells were cultured in 96-well tablets for tissue cultures (Packard company) to a density of 10,000 cells per well in 50 μl complete medium and incubated for 1 day for adhesion of cells. In the wells was added a serial twofold dilution of the solution vysheukazannoe the th connection (50 ál in a hole) in the two repeats (final volume: 100 μl in the hole). As control was used cells in the absence of the above compounds. As a base line signal used the environment in the absence of cells. After incubation (37°C, 5% CO2) for 70 h, the cells were literally adding 50 μl of well solution for lysis of animal cells (included in the kit) and was shaken for 5 min on a shaker at 700 rpm Then added 50 μl of substrate solution (luciferase and D-luciferin) and after shaking for 5 min and incubation in the dark for 10 min measured the emission of light on the instrument Packard TopCount.

The activity of compounds was determined in the form of a General suppression of the growth of cell cultures (TGI) and the specified value was calculated as follows: after subtracting the baseline signal obtained from control cells is equal to 100%. The action of the compounds were expressed as percent reduction of the control signal. Values TGI50 was determined by curve response/dose method graphical extrapolation.

The compound (II) inhibits cell proliferation GIST882, the average IC50 value is <200 nm.

Analysis of the effect on autophosphorylation Kit in cells

The degree of phosphorylation of target cells was determined using raw or processed by the above connection of cell lysates by ELISA. Adhered the s cells were cultured in 96-well tablets for tissue cultures with a flat bottom to the stage of merging. Suspension-growing cells were added to wells at a density of 100,000 to 150,000 cells per well. After processing the serial dilutions of the compounds, the cells were washed once with buffer FSB, then the cells were literally adding buffer solution for lysis volume from 100 to 150 μl (50 mm Tris/HCl, pH 7.4, 150 mm sodium chloride, 5 mm EDTA, 1 mm EGTA, 1% NP-40, 2 mm orthovanadate sodium, 1 mm PMSF, 50 μg/ml Aprotinin and 80 µg/ml leupeptin). Cell lysates were used immediately or stored at -20°C. 50 μl of lysate was transferred into a tablet black (NUNC-Maxisorp, catalog No. 437111), pre-coated with a monoclonal antibody anti-CD 117 received at the company Diaclone (No. 854510000). The coating antibody was diluted in the FSB, and incubated the plates overnight at 4°C (50 ál/well). Phosphorylation associated Kit were detected using commercial antibodies anti-P-Tyr, labeled with alkaline phosphatase (AP), PY20 AR firm Zymed in the range of final concentrations from 1:3000 to 1:10000 (from 0.1 to 0.33 µg/ml). Secondary antibodies were added after removal of cell lysates. At the final stage was added fluorescent substrate AR 90 ál in the hole (CDPStar RTU, dye Emerald II company Applied Biosystems (catalog No. TS) and incubated for 45 min at RT in the dark. The tablets covered with a film TopSealTM-A Packard company (No. katal is the 6005185) and measured the intensity of the luminescence in the form of pulses per second on scintillation counter Packard Top Count (Top Count).

Calculated the difference between the ELISA signal (pulse/s)measured for lysates of untreated cells, and the signal baseline (all components in the absence of cell lysate) and the obtained value was taken as 100%, which means the presence of constitutively phosphorylated protein Kit in these cells. The effect of compounds on the activity of the kinase Kit was expressed as percent reduction of the rate of phosphorylation. The values of IC50 and IC90 were determined by curve based response/dose.

Example I

Clinical trials with open-label phase II to assess the safety and efficacy of compounds (II), which is administered orally at 400 mg twice a day. For the treatment of selected patients with a diagnosis of SM on specific criteria of the disease and on the appropriate indications for treatment. The results are based on preliminary data for the first 23 patients. Results: the median age was 49 years (range from 33 to 78 years) and the average time since diagnosis of SM was 27 months (range from 1 to 292 months). For these groups of patients according to the available data in 13/17 patients identified mutation of c-kit D816V in bone marrow cells. The average duration of effect of the compound (II) was 144 days. 18 (78%) patients completed the full course of treatment; 5 (22%) patients interrupted treatment, 3 patients (13%) patients observed the negative the positive side effects, and 2 (9%) patient refused treatment. Registered 3 cases (13%) (2 incomplete remission and 1 minor response), according to analysis of serum tryptase, the number of fat cells in the bone marrow and improve clinical symptoms. In 2 of 3 patients detected background level mutations and identified a mutation in the kinase c-kit D816V. The obtained data demonstrate the clinical activity of compound (II) with an acceptable safety and tolerability in the treatment of patients with SM.

1. The use of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula (II)

or its pharmaceutically acceptable salt for a medicinal product intended for the treatment or prevention system mastocytosis.

2. The use according to claim 1, in which systemic mastocytosis is resistant to imatinib.

3. The use according to claim 1 or 2, in which systemic mastocytosis associated with a hybrid gene FIP1L1-PDGFRα.

4. The use of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula (II)

or its pharmaceutically acceptable salts for the treatment or prevention system mastocytosis.

5. The use according to claim 4 for the treatment of systemic mastocytosis associated with hybrid g is nom FIP1L1-PDGFRα.

6. Drug for the treatment of systemic mastocytosis associated with hybrid gene FIP1L1-PDGFRα, comprising the compound of formula (II)

or its pharmaceutically acceptable salt in a therapeutically effective amount.

7. A method of treating mammals, including humans, suffering from systemic mastocytosis, namely, that mammal in need of such treatment, introducing a compound of the formula (II)

or its pharmaceutically acceptable salt in a therapeutically effective amount.

8. Combination for use in the treatment of systemic mastocytosis, including (a) 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide formula (II)

or its pharmaceutically acceptable salt in a therapeutically effective amount and
b) imatinib taken in therapeutically effective amounts.

9. The use of combinations, including
a) 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide formula (II)

or its pharmaceutically acceptable salt and
b) imatinib taken in therapeutically effective amounts for the treatment of systemic mastocytosis.

10. The use according to claim 9, where specified the system exclusive mastocytosis associated with a hybrid gene FIP1L1-PDGFRα.

11. The use of combinations, including
a) 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide formula (II)

or its pharmaceutically acceptable salt and
b) imatinib taken in therapeutically effective amounts in the manufacture of drugs for the treatment of systemic mastocytosis.

12. The application of claim 11, where the specified systemic mastocytosis associated with a hybrid gene FIP1L1-PDGFRα.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (XVIII): which can be used for monitoring and studying the metabolism in clinical and preclinical examinations. The invention also concerns a method for preparing the specified compound.

EFFECT: development of the effective method for preparing the compound.

2 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: medicine.

SUBSTANCE: there are presented versions of antibodies specific to claudin 18A2 produced by immunisation by a related amino acid sequence or a nucleic acid or a host cell expressing said peptide. The antibodies possess an ability to mediate elimination of cancer cells expressing claudin 18A2. There are disclosed versions of antibody-producing hybridomas. What is described is a conjugate or a pharmaceutical composition on the basis of antibodies or conjugates for elimination and/or inhibition of a cancer cell expressing claudin 18A2. There are disclosed versions of the method for growth inhibition and/or elimination of the cancer cell, as well as for treating or preventing a disease or a disorder involving cancer cells expressing claudin 18A2 with using the antibodies, conjugate and pharmaceutical composition under the invention.

EFFECT: use of the invention can find further application in medicine for treating cancer cells expressing claudin 18A2.

39 cl, 33 dwg, 5 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: what is offered is an antibody or its antigen-binding fragment which specifically coupling hlL-4R with KD less than 200-pM measured with using surface plasmon resonance. What is described is a recovered nucleic acid molecule coding the antibody, and a based vector for producing the antibody. There are disclosed a host-vector system for producing the antibody or its antigen-binding fragment, and a method for producing the substances stated above with using such system. What is disclosed is using the antibody or antigen-binding fragment for preparing a drug for relieving (inhibiting) hlL-4R mediated diseases. What is disclosed is a composition on the basis of the antibody or antigen-binding fragment to be used in a method for treating a hlL-4R mediated disease or disorder in humans.

EFFECT: inventions can find application in therapy of the hlL-4R mediated diseases.

15 cl, 3 dwg, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemical compound and specifically to N-ethylpiperazylamide of betulinic acid of formula (I): which can be used in medicine as a medicinal agent with antitumour activity.

EFFECT: high efficiency of the compounds.

1 cl, 6 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which: X8 denotes N, and X5 and X6 denote CH; R7 denotes phenyl or C5-6-heteroaryl group which is optionally substituted with one or more groups selected from halogen, hydroxy group, nitro group, cyano group, carboxy group and thiol, or phenyl or a methoxy group -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)N(CH2CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH2CH3)2 or C1-4-alkyl, optionally substituted with a hydroxy group; RN3 and RN4, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperidinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; R2 denotes NRN5RN6, where RN5 and RN6, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperdinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; or a pharmaceutically acceptable salt thereof, and where "C5-6-heteroaryl" denotes a heteroaryl group selected from furan, thiophene, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, octatriazole, isoxazine, pyridine, pyridazine, pyrimidine, pyrazine and triazine; and where "C3-5-heterocyclyl", as used here, relates to a univalent structure obtained by removing a hydrogen atom from the ring of the heterocyclic compound, where that structure contains 5 or 6 ring atoms, 1-4 of which are ring heteroatoms selected from oxygen, nitrogen and sulphur; and under the condition that when R2 denotes an unsubstituted morpholine group, RN3 and RN4, together with the nitrogen atom with which they are bonded, form a morpholine group, R7 does not denote an unsubstituted phenyl, and when R2 denotes an unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom with which they are bonded, form an unsubstituted piperidinyl, R7 does not denote unsubstituted phenyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having mTOR inhibiting activity.

EFFECT: novel compound which can be suitable for treating malignant growths is obtained and described.

10 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing (-)-beta-elemenal, use of (-)-beta-elemenal as an antitumour agent, as well as to a pharmaceutical composition and a medicinal agent based on said compound. The method involves reaction of a mixture of isomeric beta-elemenols (2:1) with c MnO2, activated in a vacuum at 150°C as a catalyst. The initial mixture of isomeric beta-elemenols (2:1) is obtained by reacting a mixture of diastereomeric epoxides (2:1) with diisopropylamine in the presence of n-BuLi.

EFFECT: higher efficiency.

4 cl, 21 tbl, 9 dwg, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: preparation shows high bactericidal and antimetastatic activity that is ensured by the presence of a water extract of shelf fungus and birch bark taken in weight proportions 1:4.

EFFECT: preparation shows bactericidal and antimetastatic activity.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is offered is an agent for treating cancer in the form of a solution for injections in the following ratio (wt %): 5-fluorouracil - 0.087, metronidazole - 0.5, water for injections - 1.841, low-molecular polyethylene - 66.527, emulsifier T-2 - 16.778, Lutrol F-127 - 1.677, Cremophore RH 40 - 2.520, olive oil - 10.070.

EFFECT: invention provides preparing the agent for treating female genital cancer showing anticancer and antimicrobial activity, uniformly distributed in tissues, having manifested prolonged action and being accessible.

2 dwg, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

Up!