Polymorphous form of 2-aminothiazole compounds as kinase inhibitor and method of its obtaining

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

 

The present invention relates to an industrial method for the synthesis of pharmaceutical compounds having the formula I:

which are useful as specific inhibitors tyrosinekinase and, more specifically, as inhibitors of c-kit and bcr-abl. Group R1and R2identical or different, represent each a hydrogen atom, halogen, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, solubilizers group; m indicates 0 to 5, and n means 0 to 4; R3represents an aryl or heteroaryl group as described in the claims.

PRIOR art

Tyrosine kinase represents a protein receptor type or precepting type that carry the terminal phosphate from ATP to the tyrosine residues of proteins, thus activating or inactivating the transmission path signals. These proteins, known to be involved in many cellular mechanisms, which in the case of violations lead to disorders such as abnormal cell proliferation and migration, and inflammation.

Today, there are approximately 58 known receptor tyrosinekinase. These include well-known VEGF receptors (Kim et al., Nature 362, pp.841-844, 1993), PDGF receptor, c-kit, Flt-3 / FLK family. These receptors can transmit signals to other tyrosinekinase is, including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack, and so on

Among tyrosinekinase receptors of particular interest is c-kit. Indeed, c-kit is a key receptor that activates mast cells, which are proven directly or indirectly involved in numerous pathologies, in respect of which the applicant filed WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, WO 03/0720090, WO 03/072106, WO 04/076693 and WO 2005/016323.

The inventors have discovered that fat cells present in the tissues of patients involved in, or contribute to the Genesis of diseases such as autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease (IBD)) allergic diseases, bone loss, such cancers, solid tumors, leukemia and GIST (gastrointestinal stromal tumor), tumor angiogenesis, inflammatory diseases, interstitial cystitis, mastocytosis, a disease graft versus host disease, infectious diseases, metabolic disorders, fibrosis, diabetes, and diseases of the Central nervous system. In these diseases it has been shown that mast cells participate in the destruction of tissues by releasing a cocktail of different proteases and mediators, such as histamine, neutral proteases, lipid mediators (prostaglandins, thromboxanes and leukotr the ENES), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MIP-1a, MIP-1b, MIP-2 and IFN-γ).

The receptor c-kit can also be constitutively activated by mutations that lead to abnormal cell proliferation and the development of diseases such as mastocytosis (mutation D816V) and various types of cancer, such as GIST (c-kitA27, colomina deletion).

In addition, 60%-70% of patients with AML (acute myeloblastic leukemia) have blast cells, which Express c-kit, the receptor for stem cell factor (SCF) (Broudy, 1997). SCF stimulates the growth of hematopoietic precursors and acts as a survival factor for AML blasts. In some cases (1-2%) AML has been described mutation in the conservative remnant of the kinase domain (Kit816), leading to constitutive activation of c-kit (Beghini et al., 2000; Longley et al., 2001). This strengthening of the functional mutation (replacement of Asp Val/Tyr) identified in technoclone leukemic cell lines and in samples obtained from patients with mastocytosis (Longley et al., 1996).

In addition, the inventors have investigated about 300 patients suffering from systemic mastocytosis, and showed that the mutation Kit816 is expressed in approximately 60% of cases. In this regard, the inventors filed WO 04/076693, which refers to the specialized treatment of various forms of mastocytosis depending on the presence or absence of mutations Kit816.

Thus, the authors invented the I recently suggested to affect c-kit for the depletion of fat cells, responsible for these disorders. The inventors have discovered in this regard, a new potent and selective inhibitors of c-kit, which are 2-(3-aminoaryl)amino-4-Aristotle described in their PCT publication WO 2004/014903.

Synthesis of substituted 2-aminothiazole known from the literature. The following publications relative to the total synthesis of these compounds are usually obtained using a two-stage scheme, including bromination source of ketones (A) (G. Crank and R. Kahn, Austr. J. Chem, 38 (3), 447-458 (1985)) with subsequent cyclocondensation intermediate α-bromoketones (C) with thiourea by heating under reflux in ethanol or methanol (M. Maziere et al, Bull. Soc. Chim. France, 1000-1003 (1963); J.D. Spivack, U.S. patent 3299087).

However, when R represents such electron-withdrawing group as a functional group, nitro, output cycloaddition does not exceed 65% (S.P. Singh et al, Indian j. Chem. Sect. B, 29 (6), 533-538, (1990)). This deficiency is probably a consequence of the instability of nitroacetophenone, which leads to the formation as impurities and highly reactive by-product of the interaction in the presence of a base.

From the above it is evident that this methodology applied to nitroacetophenone has shortcomings synthesis related to one or more of these characteristics: output scalable to mnogogruppovogo synthesis and purification. The purpose of the invention was to improve used in industry is the way in which good the outputs obtained using the simple industrial operations.

The inventors have found that the interaction of acetylated nitroacetophenone with α-broketail at room temperature in methanol and in the presence of a base such as potassium carbonate, gives the desired thiazole 3-6 h with excellent output (90-97%).

In addition, net thiazole received by simple filtration after adding water to the reaction mixture.

Therefore, the present invention proposes a new industrial method for the synthesis of 2-amino(nitroil)thiazole with a good yield by reacting a stable acetylated nitroacetophenone with α-broketail under mild conditions.

Disclosure of inventions

The invention relates to a method for obtaining compounds of formula (I):

or its salts or MES, where

R1and R2selected independently from hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifloromethyl, alkoxy, cyano, dialkylamino and solubilizers group,

m means 0-5, and n means 0-4,

R3is one of the following:

(1) aryl group such as phenyl or his Deputy is on option bearing any combination, at any position in the ring one or more substituents, such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(2) heteroaryl group, such as 2-, 3 - or 4-Peregrina group, which may additionally bear any combination of one or more substituents, such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(3) five-membered ring aromatic heterocyclic group such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents, such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

includes the stages consisting of:

a) cyclization at room temperature, the compound (IV):

with intermediate connection Int4 formula:

where Ra may represent a methyl, trifluoromethyl, isopropyl or phenyl, possibly substituted, and R2, R3and n are as described above, to obtain the compound (III):

where R2, R3and n are as described above;

b) nitrogroup reduction of the compounds (III) Poluchenie the compounds of formula II:

where R2, R3and n are as described above;

C) joining in an aprotic solvent and the compound (II):

to the compound of formula Int5:

where Rb represents a hydroxyl, or alkoxy, or halogen group, and R1and m are as described above, to obtain the compound (I).

In one preferred embodiment at a stage in) the compound (II) is treated with 3.0 equivalents of Lewis acid and added to a solution of 1.0 equivalent of ester (Int5). In addition, the Lewis acid is a trimethylaluminum.

In another preferred embodiment at a stage in) a solution of 1.0 equivalent of acid chloride (Int5) are added to a solution of 0.8 equivalent of the compounds of formula II. Here the reaction is carried out in basic conditions, and may represent, for example, triethylamine.

In another preferred embodiment at a stage in) 1.0 equivalent of the compounds of formula II are combined with 1.1 equivalent of benzoic acid (Int5). This reaction is performed with the use of an activating agent, such as a reagent of Mukaiyama (2-chloro-1-methylpyridine iodide).

At the stage a), the reaction mixture was diluted with water and the precipitated product emit filtering.

At the stage b) of the method described above, the compound (II) p is obtain by restoring the corresponding nitro compounds, carried out by hydrogenation. The hydrogenation can be carried out with a catalyst, such as Raney Nickel, and the reaction is carried out in a polar proton solvent such as methanol or ethanol.

At the stage b), the reaction mixture was diluted with water and the precipitated product emit filtering.

In yet another preferred embodiment of stage (a) the cyclization is carried out in basic conditions at a temperature of from 20 to 30°C. the Base may be potassium carbonate, and the reaction is carried out in a polar proton solvent such as methanol or ethanol.

The above-described method may further include a step for the compound (IV), including the interaction of the intermediate Int1 formula:

with Int2 formula:

and Int3 formula NH4SCN,

where Ra, R2and n are as defined above.

Preferably, this reaction is carried out in an aprotic solvent such as acetone. Also, the reaction mixture is preferably diluted with water and the precipitated product emit filtering.

If not stated otherwise, when used herein, the terms determined in the following way:

Used herein, the term "aryl group" means a monocyclic or polycyclic aromatic radical containing acomplete and hydrogen. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracene, fluorene, indenyl, azulene and naphthyl, as well as benzododecinium carbocyclic groups, such as 5,6,7,8-tetrahydronaphthyl. The aryl group may be substituted or substituted by one or more substituents. In one of the embodiments of the aryl group is a monocyclic ring, where the specified ring contains 6 carbon atoms, designated here as "(6)aryl."

Used herein, the term "alkyl group" means a saturated remotemachine or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Typical saturated alkali with direct chain include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkali include isopropyl, fluorine-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-etylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2.5-dimethylpentyl, 2,2-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 2-ethylphenyl, 3-ethylphenyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-atilde the Tyl, 2-methyl-3-ethylphenyl, 2-methyl-4-ethylphenol 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylbutyl, 3,3 is di-ethylhexyl, 2,2 is di-ethylhexyl, 3,3 is di-ethylhexyl and the like. Alkyl groups included in compounds according to this invention, can be possibly substituted by one or more substituents.

Used herein, the term "alkoxy" refers to an alkyl group that is attached to another group by an oxygen atom. Examples of alkoxygroup include methoxy, isopropoxy, ethoxy, tert-butoxy and the like. Alkoxygroup can be possibly substituted by one or more substituents.

Used herein, the term "heteroaryl" or similar terms mean a monocyclic or polycyclic heteroaromatic ring containing carbon atoms in a ring and one or more heteroatoms in the ring (such as, for example, oxygen, sulfur or nitrogen). Typically, the heteroaryl group has from 1 to about 5 heteroatoms in the ring and from 1 to about 14 carbon atoms in the ring. Typical heteroaryl groups include pyridyl, 1-oxopyridine, furanyl, benzo[1,3]dioxole, benzo[1,4]dioxines, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, chinoline, pyrazolyl, isothiazolin, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, ethenolysis, indazoles, b is isoxazolyl, benzofuran, indolizinyl, imidazopyridine, tetrazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, indolyl, tetrahydroindole, isoindolyl, imidazopyridine, hintline, purinol, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, benzo(b)thienyl. The heteroatom may be substituted by a protective group known to specialists in this field, for example, the hydrogen on the nitrogen may be substituted by tert-butoxycarbonyl group. Heteroaryl groups can be substituted by one or more substituents. In addition, the ring heteroatoms nitrogen or sulfur can be oxidized. In one of the embodiments of the heteroaromatic ring selected from a 5-8-membered monocyclic heteroaryl rings. The attachment point heteroaromatic or heteroaryl ring to the other group may be either a carbon atom or heteroatom heteroaromatic or heteroaryl rings.

Used herein, the term "heterocycle" refers collectively to heteroseksualnymi groups and heteroaryl groups.

Used herein, the term "heteroseksualci" means a monocyclic or polycyclic group, having at least one heteroatom selected from O, N or S, and having 2-11 carbon atoms, which may be saturated or unsaturated, but is not the flavor is achieved. Examples geterotsiklicheskikh groups include (but are not limited to): piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 4-piperidinyl, pyrrolidinyl, hydantoinyl, valerolactam, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyridine, tetrahydropyrimidines, tetrahydrothiopyrano, tetrahydropyranyloxy, morpholinyl, thiomorpholine, dimorpholinyldiethyl, thiomorpholine, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuran-2-it, tetrahydrothieno and tetrahydro-1,1-DIOXOLANYL. Typically, monocyclic heterocytolysine groups have from 3 to 7 members. Preferred 3-7-membered monocyclic heterocytolysine groups are groups having 5 or 6 ring atoms. The heteroatom may be substituted by a protective group known to specialists in this field, for example, the hydrogen on the nitrogen may be substituted by tert-butoxycarbonyl group. In addition, heterocytolysine group may be substituted by one or more substituents. In addition, the connection point of the heterocyclic ring to the other group may be either a carbon atom or heteroatom of the heterocyclic ring. Only stable isomers of such substituted heterocyclic groups will be considered in this is the definition.

Used herein, the term "Deputy" or "substituted" means that a hydrogen radical on a compound or group is replaced with any desired group, which is essentially stable in the reaction conditions in unprotected form or when protected by a protective group. Examples of preferred substituents are the substituents found in the exemplary compounds and embodiments disclosed here, as well as halogen (chloro, iodide, bromo or fluorescent); alkyl; alkenyl; quinil; hydroxy; alkoxy; nitro; thiol; thioether; Imin; cyano; amido; phosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); halogenated (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or condensed or unfused floor and cyclic (for example, cyclopropyl cyclobutyl, cyclopentyl or cyclohexyl), or heteroseksualci, kotorye may be monocyclic or condensed or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinil, morpholinyl or triazinyl), monocyclic or condensed or unfused floor and cyclic and aryl or heteroaryl (for example, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, p is Rasool, pyridyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene or benzofuran); amino (primary, secondary, or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such groups can also be substituted condensed ring structure or bridge, for example-OCH2O-. These substituents may be further substituted by the Deputy selected from such groups. In some embodiments, the term "Deputy" or the adjective "substituted" refers to the Deputy selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, geterotsiklicheskie, aryl, heteroaryl, aralkyl, heteroalkyl, halogenoalkane, -C(O)NR11R12, -NR13C(O)R14halogen, -OR13, cyano, nitro, halogenoalkane, -C(O)R13, -NR11R12, -SR13, -C(O)OR13, -OC(O)R13, -NR13C(O)NR11R12, -OC(O)NR11R12, -NR13C(O)OR14, -S(O)rR13, -NR13S(O)rR14, -OS(O)rR14, S(O)rNR11R12, -O, -S, and-N-R13where r is 1 or 2; R11and R12at each occurrence are independently H, possibly substituted alkyl, possibly substituted alkenyl, possibly substituted quinil, Forex is substituted cycloalkyl, possibly substituted cycloalkenyl, possibly substituted heteroseksualci, possibly substituted aryl, possibly substituted heteroaryl, possibly substituted aralkyl or possibly substituted heteroalkyl; or R1and R12taken together with the nitrogen atom to which they are attached, represents a possibly substituted heteroseksualci or possibly substituted heteroaryl; and R13and R14at each occurrence are independently H, possibly substituted alkyl, possibly substituted alkenyl, possibly substituted quinil, possibly substituted cycloalkyl, possibly substituted cycloalkenyl, possibly substituted heteroseksualci, possibly substituted aryl, possibly substituted heteroaryl, possibly substituted aralkyl or possibly substituted heteroalkyl. In some embodiments, the term "Deputy" or the adjective "substituted" refers to solubilisers group.

The term "solubilizers group" means any group which can be essentially ionized and which allows the compound to be dissolved in the desired solvent, such as, for example, water or water-containing solvent. In addition, solubilizers group may be a group that increases the lipophilicity of the compound or complex. Typically, solubilizers group selected from and Kilroy group, substituted by one or more heteroatoms, such as N, O, S, each of which may substituted alkyl group, a substituted independently alkoxy, amino, alkylamino, dialkylamino, carboxyla, cyano, or substituted cyclogeraniol or heteroaryl, or phosphate, or sulfate, or carboxylic acid.

For example, under "solubilizers group" here mean one of the following:

alkyl, cycloalkyl, aryl, heteroaryl group, containing either at least one heteroatom nitrogen or oxygen, or substituted by at least one amino group or exography.

the amino group, which may be a saturated cyclic amino group which may be substituted by the group consisting of alkyl, alkoxycarbonyl, halogen, halogenoalkane, hydroxyalkyl, amino, monoalkylamines, dialkylamines, carbamoyl, monoalkylphenol and dialkylamino.

one of the structures (a) and)shown below, where the wavy line and arrow correspond to the place of connection to the core structure of formula I.

The term C is cloaker" means a saturated cyclic alkyl radical, having 3 to 10 carbon atoms. Typical cycloalkyl include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii and cyclodecyl. Cycloalkyl group may be substituted by one or more substituents.

The term "halogen" means-F, -Cl, -Br or-I.

In one of specific embodiments of the invention, a method of synthesis may substituted 2-(3-aminoaryl)amino-4-aryldiazonium having formula I.

where:

R1and R2selected independently from hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifloromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizers group.

m means 0-5, and n means 0-4.

R3is one of the following:

(1) aryl group such as phenyl or a substituted variant bearing any combination, at any position in the ring one or more substituents, such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(2) heteroaryl group, such as 2-, 3 - or 4-Peregrina group, which may additionally bear any combination of one or more substituents, such as halogen, alkyl groups containing from 1 to 10 at the MOU carbon trifluoromethyl and alkoxy;

(3) five-membered ring aromatic heterocyclic group such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents, such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

One aspect of the invention relates to a method for obtaining 2-(3-aminoaryl)amino-4-aryldiazonium (I) or pharmaceutically acceptable salts, is shown in Scheme II, including:

a) Interaction nitroaniline (Int1), acylchlorides (Int2) and ammonium thiocyanate (Int3) in a suitable solvent to obtain (IV)

where:

Ra may represent a methyl, trifluoromethyl, isopropyl or phenyl, possibly substituted.

R2selected independently from hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifloromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizers group.

n means 0-4.

b) Interaction of brometea (Int4) - protected thiourea (IV) in a suitable solvent and using appropriate bases.

Deputy R3in (Int4) and the compounds (III), (II), and (I), shown in Scheme II below, is one of the following:

(1) aryl group such as phenyl or zames the config option bearing any combination, at any position in the ring one or more substituents, such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(2) heteroaryl group, such as 2-, 3 - or 4-Peregrina group, which may additionally bear any combination of one or more substituents, such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(3) five-membered ring aromatic heterocyclic group such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents, such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

C) the Restoration of the nitro group of compound (III) to the corresponding amine (II) in a suitable solvent.

g) the Interaction of aniline (II) with (Int5) using suitable methods of joining in a suitable solvent.

Rb can represent a hydroxyl, or alkoxy, or halogen group.

R1selected independently from hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifloromethyl, alkoxy, amino, alkylamino, dialkyl is but solubilizers group.

m means 0-5.

In yet another specific embodiment of the method, shown in Scheme II, used for the synthesis of compounds of formula V or pharmaceutically acceptable salt,

where:

R1selected independently from hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifloromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizers group.

m means 0-5.

The compound (VIII) can be obtained by adding nitroaniline (Int1a) to a solution of ammonium thiocyanate and acetylchloride in an aprotic solvent, preferably acetone.

The compound (VII) is obtained by cyclization of compound (VIII) with bromoethanol (Int4a) in basic conditions, preferably potassium carbonate, in a polar proton solvent such as methanol.

The compound (VII) restore obtaining the compound (VI). Preferably, the reduction is performed with a catalyst, such as reactivated the Raney Nickel. The recovery may be carried out in alcoholic or polar aprotic solvent such as THF (THF). According to one embodiment the reaction is carried out in the presence of hydrogen. The reaction can also be carried out under the conditions of hydrogenation with phase transfer.

The compound (V) obtained using different conditions:

1) where Rb represents alkoxygroup, ester (Int5a) is subjected to the reactions proceed with (VI) using trimethylaluminum as the activating agent in an aprotic solvent such as dichloromethane or toluene.

2) where Rb represents halogen, such as chloride, the acid chloride (Int5a) are combined with (VI) in basic conditions using preferably triethylamine in an aprotic solvent such as dichloromethane.

3) where Rb represents a hydroxyl group, carboxylic acid (Int5a) are combined with (VI) using an activating agent, such as a reagent of Mukaiyama or HOBt/EDCI, in an aprotic solvent, preferably DMF.

The invention is explained in detail in the examples below, which are offered only as an illustration and therefore should not be construed as limiting the scope of the invention.

EXAMPLE 1

1-Acetyl-3-(2-methyl-5-nitrophenyl)thiourea

Into the reactor were introduced ammonium thiocyanate (25 kg, 328,43 mol), acetylchloride (24 kg, 337,53 mol), acetone (225 l) and 2-methyl-5-nitroaniline (Int1) (42 kg, 276,04 mol). The temperature was maintained at 25±10°C for approximately 4 hours. Was added water (413 l), and the reaction mixture was stirred for approximately 1 hour. The precipitate was filtered, the item is washed with water and diisopropyl ether. The product is then dried in tray drier at 45-50°C.

Yield=84%.

1H NMR (DMSO-d6): δ=12.37 (1H, s); 11.68 (1H, s); 8.68 (1H, d, J=2.5 Hz); 8.06 (1H, dd, J=8.4, 2.5 Hz); 7.58 (1H, d, J=8.4 Hz); 2.33 (3H, s); 2.18 (3H, s).

MS (ES+) m/z=254,1 (M+H)+; (ES-) m/z=252,3 (M-H)-.

TPL=205°C.

EXAMPLE 2

(2-Methyl-5-nitrophenyl)-(4-pyridine-3-iltiazem-2-yl)Amin

Into the reactor were introduced methanol (1120 l), potassium carbonate (287 kg, 2076,70 mol) and 1-acetyl-3-(2-methyl-5-nitrophenyl)thiourea (67 kg 264,53 mol). Then added 2-bromo-1-pyridin-3-ylatason (Int4) (52 kg, 259,96 mol) and the temperature was maintained at 25-30°C for 4 hours. To the reaction mixture were added water (692 l)and the precipitate was filtered, washed with water and diisopropyl ether. The product is then dried in tray drier at 45-50°C.

Yield=95%.

1H NMR (DMSO-d6): δ=9.83 (1H, s); 9.60 (1H, d, J=2.5 Hz); 9.18 (1H, d, J=1.9 Hz); 8.53 (1H, dd, J=4.6, 1.5 Hz); 8.27 (1H, dt, J=8.0, 1.9 Hz); 7.80 (1H, dd, J=8.2, 2.5 Hz); 7.66 (1 H, s); 7.48 (2H, m); 2.44 (3H, s).

MS (ES+) m/z=313,1 (M+H)+; (ES-) m/z=311,3 (M-H)-.

TPL=225°C.

EXAMPLE 3

4-Methyl-N3-(4-pyridine-3-iltiazem-2-yl)benzene-1,3-diamine

In the reactor a mixture of (2-methyl-5-nitrophenyl)-(4-pyridine-3-iltiazem-2-yl)amine (40 kg, 128,06 mol), Raney Nickel (2.7 kg, 46,00 mol) and methanol (600 l) was heated to 40-45°C and was first made when hydrogen pressure (5 kg/cm2within 2 hours. The reaction mixture was filtered and concentrated. To the residue was added water is under stirring. The product is then filtered and dried in a tray dryer at 45-50°C.

Yield=85%.

1H NMR (DMSO-d6): δ=9.20 (1H, s); 9.09 (1H, dd, J=2.3, 0.76 Hz); 9.48 (1H, dd, J=4.8, 1.7 Hz); 8.20 (1H, dt, J=8.0, 2.1 Hz); 7.42 (1H, ddd, J=7.8, 4.8, 0.8 Hz); 7.38 (1H, s); 7.09 (1H, d, J=2.3 Hz); 6.85 (1H, d, J=8.0 Hz); 6.29 (1H, dd, J=8.0, 2.3 Hz); 4.95 (1H, s);2.10(3H,s).

MS (ES+) m/z=283,1 (M+H)+; (ES-) m/z=281,4.

TPL=136°C.

EXAMPLE 4

N-[4-Methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide derivatives

Method And

In the reactor at low pressure nitrogen added 4-methyl-M3-(4-pyridine-3-iltiazem-2-yl)benzene-1,3-diamine (95 g, 336,45 mmol), dichloromethane (2 l). To this suspension is cooled to a temperature of 5°C, was added dropwise 2M/n-hexane solution of trimethylaluminum (588 ml). The reaction mixture was brought slowly to 15° and maintained for 2 h under stirring. Within 10 minutes was added 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (100 g, 402,71 mmol) in dichloromethane (200 ml). After 1 h stirring at room temperature the reaction mixture was heated to the temperature of reflux distilled for 20 h and cooled to room temperature. This solution was transferred dropwise via cannula to a reactor containing 2 N. NaOH (2.1 liters)was cooled to 5°C. After stirring for 3 h at room temperature the precipitate was filtered through celite. The solution was extracted with dichloromethane, and the organic layer PR is mawali water and a saturated solution of sodium chloride, dried over MgSO4and concentrated under vacuum. The obtained brown solid was recrystallized from i-Pr2O obtaining 130,7 g (78%) powder beige color.

Method B

Obtain acid chloride

To a mixture of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride (1.0 EQ.), dichloromethane (7 vol.) triethylamine (2.15 EQ.) added thionyl chloride (1.2 EQ.) at 18-28°Sreaction the mixture was stirred at 28-32°C for 1 hour.

The accession of the acid chloride to aminothiazolo

To a cooled (0-5°C) suspension of 4-methyl-N3-(4-pyridine-3-iltiazem-2-yl)benzene-1,3-diamine (0.8 EQ.) and diethylamine (2.2 EQ.) in dichloromethane (3 vol.) the solution of acid chloride (obtained above) maintained the temperature below 5°C. the Reaction mixture was heated to 25-30°C and stirred at the same temperature for 10 hours To the reaction mixture were added methanol (2 vol.) and water (5 vol.) and stirred. After separation of the layers the aqueous layer was added methanol (2 vol.), dichloromethane (5 vol.) and sodium hydroxide solution (aqueous, 10%, up until the pH was not 9,5-10,0) and was stirred for 10 minutes. The layers were separated. The organic layer was washed with water and saturated sodium chloride solution. The organic layer was concentrated and added ethanol (2 vol.) and stirred. The mixture was concentrated. To the residue was added ethanol and stirred. The product was filtered and dried at 5-55°C in a vacuum tray dryer.

Output=65-75%.

Method In

To a solution of 4-methyl-N3-(4-pyridine-3-iltiazem-2-yl)benzene-1,3-diamine (1.0 EQ.) in DMF (DMF) (20 vol.) were added successively triethylamine (5 EQ.), 2-chloro-1-methylpyridine iodide (2 EQ.) and 4-(4-methylpiperazin-1-ylmethyl)benzoic acid (2 EQ.). The reaction mixture was stirred for 7 h at room temperature. Then the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4and concentrated. The crude product was purified by column chromatography using elution with 100% EtOAc to obtain yellow solid.

Yield=51%.

1H NMR (CDCl3): δ=9.09 (1H, s, NH); 8.52 (1H, br s); 8.27 (1H, s); 8.13 (1H, s); 8.03 (1H, s); 7.85 (2H, d, J=8.3 Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (1H, s); 3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (Cl) m/z=499 (M+H)+

An additional aspect of the present invention refers to a specific polymorpha salt methanesulfonic acid N-[4-methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide of formula (IX).

The following describes the polymorphic form of the compound (IX), which is the most preferred properties related to the manufacture, storage and preparation of medications. For example, this form remains dry at 80% relative humidity and thermodynamically stable at temperatures below 200°C.

Polymorph this form is aracterized pattern x-ray diffraction, illustrated in figure 1, comprising characteristic peaks at approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree Θ, and characterized by differential scanning calorimetry (DSC), illustrated in figure 2, which shows a single maximum value at approximately 237,49±0,3°C.

Picture of x-ray diffraction obtained using Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) carried out using a Perking Elmer Precisely (Diamond DSC).

This polymorphic form can be obtained by treating 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide of 1.0 to 1.2 equivalents methanesulfonic acid at a suitable temperature, preferably from 20 to 80°C.

The reaction is carried out in a suitable solvent, especially a polar solvent such as methanol or ethanol, or a ketone, such as acetone, or an ether, such as diethyl ether, or dioxane, or a mixture.

This invention is illustrated in the example below, which is offered only as an illustration and therefore should not be construed as limiting the scope of the invention.

Obtaining the above-mentioned polymorphic forms of 4-(4-methylpiperazin-1-ilma who yl)-M-[4-methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide of methansulfonate.

4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide (1.0 EQ.) was dissolved in ethanol (about 4,5.) at 65-70°C. Methanesulfonyl acid (1.0 EQ.) was added slowly at the same temperature. The mixture was cooled to 25-30°C and maintained for 6 hours the Product was filtered and dried in a vacuum tray dryer at 55-60°C. Yield=85-90%. The initial melting point NPL=236°C.

1. Polymorphic form of the compound (IX)

characterized by a pattern of x-ray diffraction, comprising characteristic peaks at approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees 2Θ.

2. Polymorphic form according to claim 1, characterized by differential scanning calorimetry, which shows a single maximum value at approximately 237,49±0,3°C.

3. Polymorphic form according to claim 1 or 2 for use as an inhibitor of c-kit.

4. Polymorphic form according to claim 1 or 2 for depletion of fat cells.

5. The method of obtaining polymorphic forms of the compound (IX) according to any one of claims 1 and 2, including the processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-iltiazem-2-ylamino)phenyl]benzamide methanesulfonate acid at a temperature of from 20 to 80°C in a solvent selected from the group comprising methanol, e is anal, acetone, diethyl ether, dioxane and mixtures thereof.

6. The method according to claim 5, where the reaction is carried out in ethanol.

7. The method according to claim 5 or 6, where the reaction is carried out using 1.0 equivalent methanesulfonic acid.



 

Same patents:

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention provides to a high degree a safe pharmaceutical drug which is effective for diseases caused by MMP-2 and/or MMP-9. The pharmaceutical drug contains, as an active ingredient, at least one member selected from a group which consists of thiazole derivatives of formula (1): where R1 is a phenyl group which can have 1-3 lower alkoxy groups as substitutes in the phenyl ring, and R2 is a pyridyl group which can have 1-3 carboxyl groups as substitutes in the pyridine ring, or salts thereof.

EFFECT: high activity and use when treating diseases such as fibrosis and pulmonary emphysema.

4 cl, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-S-benzylpyrimidine derivatives having CRTH2 receptor antagonist activity. In formula 1: R1 means -CO2H; R4a and R4b mean hydrogen; W means -C(O)NR7-; R2 and R3, each independently mean F; Cl; Br;-NR10R11 or (C1-C6)alkoxy, optionally substituted by 1-3 halogen atoms; R5 means hydrogen; R6 means (C1-C6)alkyl; (C6-C19)aryl or (5-15)-member heteroaryl containing nitrogen, oxygen or sulphur atoms as heteroatoms, wherein above aryl and heteroaryl are optionally substituted by one or more substitutes specified in a group consisting of halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; and (C1-C6)alkoxy optionally substituted by one, two or three halogen atoms; R7 means hydrogen; R10 and R11, each independently mean (C1-C6)alkyl; or R10 and R11, together with N, whereto attached form a 3-8- member saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms in the ring; k is equal to 0; m is equal to 1.

EFFECT: invention also refers to using the above compounds for preparing a drug for treating allergic and inflammatory diseases mediated by CRTH2 receptor activity, such as asthma, atopic dermatitis, allergic conjunctivitis, Churg-Strauss disease, sinusitits, basophilic leukaemia, and recurrent urticaria.

27 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and immunology. The preparation contains an antibody, histidine and Polysorbate 80. Besides, a method of treating a subject with using the above preparation and a method of stabilising anti-human α-interferon antibody 13H5 are described. The invention can be used in medicine.

EFFECT: what is disclosed is a stable aqueous preparation containing the antibody or fragment thereof which are specifically bound to human α-interferon.

7 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses a combination preparation for increasing the potency of vaccines containing an antigen. The preparation contains synthetic glycolipid PBS-57 and the vaccine. The ingredients of the combination preparation may be used both together, and successively. The preparation under the invention is administered intravenously, intracutaneously, subcutaneously and by any other known ways. Glyolipid PBS-57 is an adjuvant with a reduced number of side actions and in the meantime promotes the development of a durable protective immunity.

EFFECT: administered preparation promotes the humoral immune response to a vaccine antigen in an individual, particularly provides increasing the production of IgG, IgA and/or IgM antibodies, activates CD4+ T lymphocytes and CD8+ cytotoxic lymphocytes in the individual.

10 cl, 16 dwg, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a new multifunctional combined interferon drug preparation of broad spectrum of action. A preparation in the form of a suppository contains a synergistic combination of the immunomodulator interferon alpha-2b and the herbal biostimulant aloe extract; it contains vitamin E, glycine, buffer salts, tysol, lecithin and solid fat as a base in the specified proportions.

EFFECT: invention provides preparing the combined drug preparation in the form of long storage-stable suppository having the standard physical-chemical, structural and mechanical, multifunctional biological properties, higher bioavailability and synergistic therapeutic efficacy of interferon alpha-2b with the herbal biostimulant aloe extract.

1 cl, 5 tbl, 3 dwg

Novel antibodies // 2490277

FIELD: chemistry.

SUBSTANCE: present invention relates to immunology. Disclosed is an anti-α5β1 antibody, which is described through amino acid sequences of six hypervariable regions and an antigen-binding moiety thereof. Described are conjugates of the disclosed antibodies with a medicinal agent or a label, a pharmaceutical composition, use of the disclosed antibodies to prepare a medicinal agent, methods and an industrial product for inhibiting angiogenesis and/or vascular permeability in a subject, and for treating cancer, an ophthalmic disease and an autoimmune disease in a subject. The invention describes an isolated nucleic acid, an expression vector, a cell and a method of producing an antibody or an antigen-binding moiety thereof, as well as a method of detecting α5β1 protein in a sample.

EFFECT: present invention can find further use in therapy and diagnosis of α5β1-mediated diseases.

52 cl, 11 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to biotechnology. What is presented is a method of treating a mammal suffering an inflammatory disease wherein the inflammatory disease is atopic dermatitis, eczema, or itch. The method comprises administering to a mammal a recovered monoclonal antibody or antigen-binding fragment thereof which is prepared by inoculating a non-human animal an adjuvant and a polypeptide (zcytor17lig) containing amino acid residues 27-164 SEQ ID NO: 2, followed by recovering said antibodies from said animal.

EFFECT: using the invention can find application in medicine for treating atopic dermatitis, eczema, or itch.

2 cl, 7 dwg, 21 tbl

FIELD: medicine.

SUBSTANCE: presented inventions refer to immunology, and concern methods and compositions for preventing or treating conjunctivitis associated with feline herpes virus-I (FHV-I). The used composition contains the strain Enterococcus faecium NCIMB 10415 (SF68) in the amount at least approximately 102-1011 CFU per one gram of the composition. The methods consist in administering such composition to an animal.

EFFECT: present invention allows modulating FHV-I immunity, enhancing the efficacy of the FHV-I vaccine, reducing morbidity associated with chronic FHV-1 infection and serving to prevent or treat conjunctivites associated with FHV-I.

12 cl, 9 dwg, 5 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to new derivatives of 4-aminopyrimidine, having antagonistic activity in respect to the receptor H4. In the formula : R1 is selected from C1-8alkyl, C3-8cycloalkyl-C0-6alkyl, aryl-C1-6alkyl, the group of the formula R2 and R3 together with the atom N, with which they are linked, creating the saturated heterocyclic group, which may be a 4-7-member monocyclic or 9-member condensed bycyclic one, where the specified heterocyclic group may contain up to two atoms N and does not contain any other heteroatoms, and may be unnecessarily substituted with one or more substitutes, independently selected from C1-4alkyl and NRaRb, provided that if the heterocyclic group either contains 2 atoms N and is not substituted with the group NRaRb, or comprises 1 atom N and is substituted with one group NRaRb; or R2 is H, and R3 is pyrrolidinyl substituted with C1-4alkyl group; where Ra is H or C1-4alkyl; Rb is H or C1-4alkyl; R4 and R5 is H; R6 is aryl group; n is equal to 1; and aryl is phenyl group, unnecessarily substituted with halogen. The invention also relates to a pharmaceutical composition containing the specified compounds, to application of compounds for production of a medicinal agent for treatment of such diseases as an allergic, immunological or inflammatory diseases or pain, and also to a method for production of the specified compounds.

EFFECT: higher efficiency of application of compounds in treatment of diseases.

34 cl, 30 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to rituximab binding to B-cell surface markers, e.g. CD20. More specifically, the invention concerns using rituximab for treating rheumatoid arthritis in a mammal with an inadequate response to a TNF-alpha inhibitor.

EFFECT: invention provides reducing a joint damage in the patients.

6 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of treating cancer in a patient, wherein the method involves administering a cancer-inhibiting amount of a compound of formula I into a patient's body. The method of treating cancer in the patient, including a human, wherein the method involves administering the cancer-inhibiting amount of a first compound of formula I or a physiologically acceptable salt thereof into the patient's body, wherein X represents CH or N, each R1 independently represents hydrogen or -CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamino; each R2 independently represents the group ZYR6; Z represents a bond or the C1-3 alkylene or oxoalkylene group optionally substituted by the group R7; Y represents a bond, an oxygen atom or the group NR6; R6 is a hydrogen atom, the group COOR8, the alkyl, alkenyl, cycloalkyl, aryl or aralalkyl group optionally substituted by one or more groups COOR8, CONR82, NR82, OR8, =NR8, =O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, the optionally alkoxylated or aminoalkyl group; R8 is a hydrogen atom or the optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically acceptable cation; R3 represents the C1-8 alkylene group, 1,2-cycloalkylene group or 1,2-arylene group, optionally substituted by R7; and each R4 independently represents hydrogen or C1-3 alkyl.

EFFECT: invention refers to a pharmaceutical composition for treating cancer in the patient, containing the compound of formula I, as well as to a kit for treating cancer.

23 cl, 3 ex, 7 dwg

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