Method for melt granulation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to a method for preparing solid pharmaceutical dosage forms containing a quinolone compound. E.g. the method under the invention involves using an extruder, particularly a turn-screw extruder designed for granulation from the quinolone compound mixed with a granulation excipient.

EFFECT: developing the method for preparing the solid pharmaceutical dosage forms containing the quinolone compound.

6 cl, 2 ex

 

The scope to which the invention relates.

The present invention relates to a method for producing solid dosage forms for oral administration containing as a drug compound quinoline. The characteristic of this method is the use of granulation of the melt in the extruder. Such solid dosage forms for oral administration can be used for the treatment and prevention of proliferative diseases, including cancer.

Background of invention

Summary of the invention

The present invention relates to pharmaceutical granulation technique that allows you to turn unwanted polymorphic modification or a mixture of different physical forms of the active pharmaceutical ingredient in the desired form and to ensure that only the required form in the medicinal product. In the case of lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-she in obtaining clinically desired anhydrous form is observed the formation of monohydrate as an impurity, which is characterized by a lower solubility. However, the monohydrate can completely and irreversibly transformed in anhydrous form at temperatures above 140C. In the present invention using the granulation of the melt at high temperature is re, which allows to obtain granules in pure anhydrous form, regardless of the composition of the source material, including the monohydrate, or a mixture of the monohydrate and anhydrous forms.

Detailed description of the invention

The present invention relates to a process for the preparation of pharmaceutical compositions, especially solid dosage forms for oral administration based on the quinoline compounds, primarily lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-she. A feature of the method according to the invention is the granulation of the melt in the extruder.

The term "pharmaceutical composition"used in this context, refers to a mixture containing a medicinal compound that is intended for administration to a mammal, e.g. a human, for the prevention, treatment and control of specific diseases or conditions in a mammal.

The term "pharmaceutically acceptable"as used in this context, refers to such compounds, materials, compositions and/or dosage forms which are, in accordance with the opinion of the medical staff, are suitable for contact with the tissues of mammals, especially humans, in the absence of excessive toxicity, irritation, allergic reactions and other complications in accordance with mimim ratio of benefit/risk.

The term "medicinal compound"used in this context, refers to any compound, substance, drug; drug or active ingredient having therapeutic or pharmacological effect, such as inhibition of the receptor tyrosinekinase, and which is suitable for administration to mammals, such as man, in the composition, which is primarily suitable for oral administration. The term "medicinal compound"used in this context, includes quinoline compounds described in US 6774237 and WO 2006/127926. The preferred compound is 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-he of the formula (I):

A more preferred compound is a compound of formula (I) as a salt of lactic acid, i.e. lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it.

In WO 2006/127926 provides information about polymorphic forms and solvate of 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it.

The present invention also relates to a method of treatment of a disease that is sensitive to inhibition of receptor tyrosinekinase described in US 6774237 and WO 2006/127926. These methods include, but are not limited to, inhibition of active the STI VEGFR2 and FGFR3, and include the stage of introduction to a subject that is in need of such treatment, a therapeutically effective amount of drug compounds.

The term "excipient for granulation"used in this context, refers to any pharmaceutically acceptable material or compound, which can be subjected to granulation of the melt mixed with a medicinal compound, as described below. For example, excipients for granulation may be a polymer or polimerny material.

The term "polymer"used in this context, refers to a polymer or mixture of polymers, the glass transition temperature, softening temperature or melting which, alone or in combination does not exceed the melting point (or interval of the melting temperature) medicinal compounds. The glass transition temperature (Tarticle") represents the temperature at which there is a change of the characteristics of such a polymer, for example, from the mass of high viscosity is formed mass of relatively low viscosity. Types of polymers include, but are not limited to, vodorastvorimye, similar to swollen, water-insoluble polymers, and combinations of these types.

Examples of polymers include, but are not limited to,

the homopolymers and copolymers of N-vinylation, for example, homopolymer and copolymers of N-vinylpyrrolidone(e.g., polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinylacetate or finalproject,

simple and complex cellulose ethers (e.g., methylcellulose and ethylcellulose), hydroxyethylcellulose (e.g., hydroxypropylcellulose), hydroxyethylmethylcellulose (e.g. hypromellose), phthalates, cellulose (for example, phthalate-cellulose acetate and phthalate of hydroxypropylmethylcellulose) and succinate cellulose (e.g., succinate of hydroxypropylmethylcellulose or succinate-acetate hydroxypropylmethylcellulose),

high polyalkylene, such as polyethylene oxide and polypropyleneoxide and copolymers of ethylene oxide and propylene oxide,

the polyacrylates and polymethacrylates (for example, the copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methylmethacrylate, copolymers of butyl methacrylate and 2-dimethylaminoethylmethacrylate, poly(hydroxyethylacrylate), poly(hydroxyethylmethacrylate)),

polyacrylamides,

polymers of vinyl acetate, such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate,

polyvinyl alcohol, and

oligo - and polysaccharides, such as carrageenan, galactomannans and xanthan gum, or mixtures of one or more of these polymers.

The term "plasticizer"is used in this Contex is e, indicates material that can be included in the pharmaceutical composition for the purpose of lowering the glass transition temperature and melt viscosity of the polymer by increasing the free volume between polymer chains. The plasticizers include, but are not limited to, water, sorbitol, esters of citric acid (for example, triethylcitrate, triacetin), low-molecular polyalkylene (for example, glycols, polypropylenglycol, polyethylene/propylene glycols, glycerol, pentaerythritol, monoacetate, diacetate or triacetate of glycerol, propylene glycol, diethylsulfoxide sodium, and the active pharmaceutical ingredient. The plasticizer may be present in a concentration of about 0-15%, for example 0.5 to 5% based on the weight of the pharmaceutical composition. Examples of the plasticizers described in the Handbook The Handbook of Pharmaceutical Additives, Ash and others, Gower Publishing (2000).

Polimernymi the excipients for granulation are, but not limited to, esters, hydrogenated oils, oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides and mixtures thereof.

Examples of esters, such as esters of glycerol include, but are not limited to, glycerol monostearate, for example, CAPMUL GMS (firm Abitec Corp., Columbus, OH), palmitostearate glits is Rina, acetylated glycerol monostearate, sorbitol monostearate, e.g., ARLACEL 60 (the company Uniqema, New Castle, Germany, cetylpalmitate, for example, CUTINA CF (company Cognis Corp, Dusseldorf, Germany), magnesium stearate and calcium stearate.

Examples of hydrogenated oils include, but are not limited to, gidrirovannoe castor oil, gidrirovannoe cottonseed oil, gidrirovannoe soybean oil, gidrirovannoe palm oil. Example oils include sesame oil.

Examples of waxes include, but are not limited to, Carnauba wax, beeswax and spermaceti wax. Examples of hydrocarbons include, but are not limited to, microcrystalline wax and paraffin wax, Examples of fatty alcohols, i.e. high molecular weight non-volatile alcohols containing from about 14 to about 31 carbon atoms include, but are not limited to, cetyl alcohol, for example, CRODACOL C-70 (firm Corp Croda, Edison, NJ), stearyl alcohol, for example, CRODACOL S-95 (firm Croda Corp), lauric alcohol, ministerului alcohol.

Examples of fatty acids which may contain from about 10 to about 22 carbon atoms include, but are not limited to, stearic acid, for example, HYSTRENE 5016 (firm Crompton Corp., Middlebury, CT), dekanovu acid, palmitic acid, lauric acid and myristic acid.

The term "granulate is from the melt", used in this context, refers to the processing method, which comprises the following stages:

(a) obtaining a mixture of medicinal substance with at least one excipient for the granulation

(b) granulating the mixture using an extruder while heating the mixture to a temperature lower than or approximately equal to the melting temperature (interval melting point) medicinal compounds, and

(C) cooling the extrudate to room temperature, for example, at a controlled rate.

Heating and mixing the drug compound with excipients for granulation with the formation of the internal phase in the form of granules (i.e., from the extrudate) is carried out in the extruder. For example, excipients for granulation may be present in an amount of from about 1 to about 50% based on the weight of the composition, In one embodiment, excipients for granulation may be present in an amount of from about 3 to about 25% based on the weight of the composition. In contrast, granules obtained by wet granulation, in the process of granulation of the melt according to the present invention does not require the presence during the granulation fluid, such as water, methanol, ethanol, isopropanol or acetone.

The obtained granules are, for example, particles of drug substances is a, fully or substantially coated from excipients for granulation, or, in another embodiment, the particles of drug substance completely or largely in the composition of the particles excipients for granulation or mixed with it.

In General, the extruder consists of a rotating auger (screw)that is installed in a stationary cylinder, one end of which is optional installed the profiling head. Uniform mixing of materials along the entire length of the screw (e.g., drug substance, component, slowing the rate of release, and any other desired excipients) is provided by rotation of the screw inside the cylinder. Accordingly, the extruder can be divided at least into three zones: the zone diet, zone heating, the batching area. In the area of food raw materials fed into the extruder, for example, from a bunker. In the heating zone of the source material is heated to a temperature below the melting temperature of medicinal substance. For the heating zone is a zone metering, in which the mixed material is extruded through an optional major head, you get a product of a certain shape, for example, in the form of granules or tape. Types of extruders, which primarily can be used in the present invention include one -, two - and mnogochasovye extruders, that may not necessarily equipped with mixing blades.

The resulting granules can be processed into forms for oral administration, for example, solid oral dosage forms such as tablets, pills, lozenges, microtablets, capsules or sachets, adding standard excipients, which constitute the external phase of the pharmaceutical composition. The external phase of the pharmaceutical composition may also contain additional drug compound. These solid dosage forms are, for example, the standard oral dosage forms. Examples of these excipients include, but are not limited to, the release retarders, plasticizers, dezintegriruetsja agents, binding agents, lubricants, slipping agents, stabilizing agents, fillers and diluents. Specialist in the art can select one or more of these excipients depending on the particular desired properties of the solid oral dosage form using simple standard experiments without additional costs. The quantity of each excipient can be modified in a known interval. Techniques and excipients, which are used when receiving oral dosage forms are described in the following the x publications included in the description of the application as references (see The Handbook of Pharmaceutical Excipients, 4th ed. Ed. Rowe, American Pharmaceuticals Association (2003), Remington, the Science and Practice of Pharmacy, 20th ed., edit Gennaro, Lippincott Williams & Wilkins (2003).

The term "retarder release"used in this context, refers to any material or compound that slows the release of drugs from the pharmaceutical composition when administered orally. Using a component that slows the release, you can get a variety of systems with a slow release, known in the art, for example, a diffusion system, a system based on the dissolution and/or osmotic system. Retarder release may be a polymer or polimernoe substance. Pharmaceutical composition with delayed release of the present invention may contain, for example, at least 5% of the inhibitor of the release based on the weight of the composition.

Examples of pharmaceutically acceptable dezintegriruetsja agents include, but are not limited to, starches, cellulose, sodium salt glycolate, cross-linked polymers, such as crosslinked polyvinylpyrrolidone or crosspovidone, e.g., POLYPLASDONE XL (company International Specialty Products, Wayne, NJ), crosslinked sodium carboxymethyl cellulose or sodium salt croscarmellose,such as AC-DI-SOL, FMC), stitched calcium salt of carboxymethylcellulose and guar gum. Disintegrity agent may be present in amounts from about 0% to about 10% based on the weight of the composition. In one embodiment, disintegrity agent is present in amount from about 0.1% to about 8% based on the weight of the composition.

Examples of pharmaceutically acceptable binding agents include, but are not limited to, starches, cellulose and derivatives thereof, for example, microcrystalline cellulose, such as AVICEL PH (firm FMC, Philadelphia, PA), povidone, copolyvidone, hydroxypropylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose METHOCEL (Dow Chemical Corp., Midland, MI) and gelatin. The binding agent may be present in amounts from about 0% to about 50% based on the weight of the composition, for example 10-40% based on the weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable moving substances include, but are not limited to, starches, talc, trehzameshchenny calcium phosphate, calcium stearate, stearic acid, sodium fumarate, hydrogenated oils, Capitol, polyethylene glycol. The lubricating substance can be present in amounts from about 0% to about 10% based on the weight of the composition. what one embodiment, the lubricating substance may be present in an amount from about 0.1% to about 1.5% based on the weight of the composition. Moving the substance may be present in an amount from about 0.1% to about 10% based on the weight of the composition.

Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include, but are not limited to, sugar, dextrine, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, for example, may be present in amount from about 15% to about 40% based on the weight of the composition.

To obtain pharmaceutical compositions of the present invention medicinal compound and excipient for granulation is mixed in a ratio in the range from 99:1 to 1:1 (calculated on dry weight) before or after you add in the hopper of the extruder. In one embodiment, the ratio of drug compounds and excipients for granulation is in the range of from 97:3 to 40:60 (per dry weight). In another embodiment, the ratio of the components may be in the range of from 97:3 to 75:25 (based on dry weight). Optional internal phase, you can add a plasticizer.

The mixture is heated to a temperature below the melting temperature of medicinal compounds. When heated mixture, it is stirred by a screw (screw) extruder. The mixture is maintained at a value which temperature and stir over time, sufficient to obtain a granulated product. After passing the mixture along the entire length of the cylinder of the extruder, formed granulated product (which is an extrudate), and the granulated mixture is cooled.

After cooling, the extrudate can be crushed and then sift through a sieve. Then the pellets (which are the internal phase of the pharmaceutical composition) mixed with excipients for solid oral dosage forms (external phase of the pharmaceutical composition), i.e. fillers, binders, dezinfeciruyuhimi agents, lubricating agents and the like, the resulting mixture can then be stirred, for example, in the mixer, V-blender, and then extruding or forming into tablets, for example, in a monolithic tablets or mixture to fill capsules.

On tablets optional can cause functional or non-functional coating known in the art. Examples of methods of coating include, but are not limited to, sugar coating, film coating, coating by microencapsulation or pressing. Examples of coatings include, but are not limited to, intersolubility cover, cover for delayed-release coatings for controlled release.

The effectiveness of the pharmaceutical to the of mposite of the present invention can be evaluated during standard clinical trials, for example, with the introduction of known doses of drugs for known indications that provide therapeutically effective levels of drug compounds in the blood, for example, at a dose in the range of 2.5 to 1000 mg drug connections per day to a mammal weighing 75 kg, for example, an adult and a standard animal models.

In the present invention proposes a method of treatment of a subject suffering from a disease, condition or violation that is treatable drug connection, and the said method is that the subject who needs this kind of treatment is administered a therapeutically effective amount of the pharmaceutical composition of the present invention.

The invention is illustrated by the following examples without limiting its scope. Examples are provided to illustrate the method of application of the present invention in practice.

The lactate monohydrate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it
Example 1
% (based on the weight of the compositionQuantity per tablet (mg)
Ingredient
Internal phase
40,00%260,0
Hydroxypropylcellulose EXF4,00%26,0
External phase
Microcrystalline cellulose (AVICEL PH102)50,5%328,2
Sodium salt croscarmelloseto 5.00%32,5
Magnesium stearate0,50%3,3
Only100%650,0

The ingredients of the internal phase, i.e. lactate monohydrate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-she and hydroxypropylcellulose Klusel EXF (Aqualon company) were mixed and stirred in bunker mixer for about 200 turns. The mixture was sent to a loading area or into the hopper of the twin screw extruder. Suitable twin screw extruder is a pharmaceutical co-rotating twin screw extruder PRISM 16 mm (Thermo Electron Corp., Waltham, Massachusetts).

N the one end of the twin screw extruder is the main head with a hole size of approximately 3 mm, Twin screw extruder is composed of five separate zones or sections of a cylinder, which can be independently set different parameters. In the direction from the hopper to the major head, the zones in the order they were heated to the following temperatures: 145C 145C, 120C, 80C and 40C. the screw rotation Speed was set at 150 rpm, but you can use higher speed to 400 rpm

The extrudate or pellet coming out of the extruder, cooled to room temperature, soaking them for 15-20 minutes Then cooled granules were sifted through a sieve with mesh size 18 mesh. The cooled granules contain anhydrous form lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it.

To receive the external phase avicel and sodium salt croscarmellose was mixed with the obtained granules in a suitable hopper mixer, for about 200 turns. Magnesium stearate was first sieved through a sieve with a cell size of 30 mesh. Then magnesium stearate was mixed with the mixture for about 60 rpm. The final mixture was pressed into tablets in a standard rotary machine for tabletting (firm Manesty Beta Press) when pressing force in the range from 6 kN to 40 kN or in the press Claver, when pressing force in the range of 5-15 kN. Received a monolithic tablet hardness which is online is rule 100-400 N, acceptable fragility of less than 1.0 wt.% after 500 drops.

The following tablets were obtained in the same way.

Example 2
Quantity per tablet (mg)
IngredientWt.%
Internal phase
The lactate monohydrate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it90,00%765,0
Hydroxypropylcellulose (HPC-EXF)10,0%85,0
External phase
Magnesium stearateTracking number (external grease)Tracking number
Only100%850
The force pressing (kN) Hardness (H)Friability (%)Time raspadaemosti (min)
Example 173000.4~2.5
Example 2122000.3~30

It should be understood that the present invention is described in sufficient detail, and the present description is intended to illustrate and not limit the scope of invention, which is defined by the attached claims. Other objects, advantages and modifications of the invention are included in the scope of the attached claims.

1. A method of obtaining a pharmaceutical composition comprising the stage of:
(a) mixing drugs lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it is at least one excipients for granulation with the formation of the mixture,
(b) mixing the above-mentioned mixture in the extruder while heating this mixture to a temperature below the melting temperature of the specified drug connection, and
(C) extrusion of this mixture to obtain granules.

2. The method according to claim 1, where the decree is the principal connection is the lactate monohydrate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it.

3. The method according to claim 1 or 2, where the specified excipient for granulation is chosen from the group including:
polyvinylpyrrolidone, vinyl acetate, finalproject, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, phthalate-cellulose acetate, phthalate of hydroxypropylmethylcellulose, succinate of hydroxypropylmethylcellulose, succinate-acetate hydroxypropylmethylcellulose, polyethylene oxide, polypropyleneoxide, ethylene oxide, propylene oxide, copolymers of methacrylic acid, copolymers of acrylate, copolymers of methacrylic acid, copolymers of methyl methacrylate, copolymers of butyl methacrylate, copolymers of 2-dimethylaminoethylmethacrylate, polyacrylamides, poly(hydroxyethylacrylate), polyacrylamides, poly(hydroxyethylmethacrylate), vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, carrageenan, galactomannan, xanthan gum, water, sorbitol, triethyl citrate, triacetin, the glycols, polypropyleneglycol, glycerin, pentaerythritol, monoacetate, diacetate, triacetate of glycerol, propylene glycol, diethylsulfoxide sodium, monostearate, glycerylmonostearate, acetylated glycerylmonostearate, sorbitol monostearate, cetylpalmitate, magnesium stearate and calcium stearate, gidrirovannoe castor oil, gidrirovannoe cottonseed oil, g is kiravannie soybean oil, gidrirovannoe palm oil, Carnauba wax, beeswax, spermaceti wax, microcrystalline wax and paraffin, cetyl alcohol, stearyl alcohol, lauric alcohol, ministerului alcohol, stearic acid, dekanovu acid, palmitic acid, lauric acid and myristic acid.

4. The method according to claim 1 or 2, where the specified excipient for granulation is chosen from the group comprising sorbitol, hydroxypropylcellulose and propyleneglycol.

5. The method according to claim 1 or 2, where the temperature of heating is less than 140C.

6. The method according to claim 1 or 2, where these granules contain anhydrous lactate 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-she.



 

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3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 3,8-diaminotetrahydroquinoline derivatives of formula (1a) or to their pharmaceutically acceptable salts wherein X represents CH2, C=O or CH-OR; m is 1 or 2; Ar represents a phenyl group or a 5-merous or 6-merous aromatic heterocyclic group having one element specified in S and N, (wherein the phenyl group may be substituted by 1-2 halogen atoms); each R1 and R2 represents a hydrogen atom; R3 represents a C1-C6 alkyl group or indolyl-C1-4 alkyl group (the indolyl group is optionally substituted by a C1-C6 alkyl group or a halogen atom), n is 0; R4 and R5 which may be identical or different, each represents a hydrogen atom or a C1-C6 linear or branched alkyl group; each R6 and R7 represents a hydrogen atom; and R represents a hydrogen atom. Also, the present invention refers to a drug preparation and a pharmaceutical composition of the basis of the compound of formula (1a), to the compound of formula (F1), to a method for preparing an intermediate compound (e).

EFFECT: there are prepared new 3,8-diaminotetrahydroquinoline derivatives which possess high GHS-R antagonist activity.

10 cl, 1 tbl, 124 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to application of compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)phenyl]propionitryl (compound A) or its pharmaceutically acceptable salt for obtaining pharmaceutical preparation, intended for treatment of disease, depending on epidermal growth factor receptor (EGFR), connected with EGFR amplification, EGFR1 mutation, T790M EGFR mutation, or their combination. Invention also relates to combinations of said compound with other active compounds and to methods of treating said diseases with said compounds and pharmaceutical preparations. Pharmaceutical preparations include said compound alone or in combination with, first of all, EGFR modulator.

EFFECT: application of combinations provides synergetic effect.

16 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula where A is pyridinyl; and B is a condensed ring system consisting of: a. a phenyl ring bonded to a molecular residue, b. a second heterocyclic 5- or 6-member ring which is condensed with the phenyl ring, and has one nitrogen or oxygen atom, and to tautomeric forms thereof.

EFFECT: obtaining novel imidazole derivatives which are antagonists of adrenergic receptors.

6 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to pharmaceutics and medicine and concerns the use of compounds of formula (I) their pharmaceutically acceptable salts and solvates for treating depression and related disorders, Parkinson's disease, drug addiction, morphine tolerance and morphine dependence.

EFFECT: development of the preparation for treating depression and related disorders, Parkinson's disease, drug addiction, morphine tolerance and morphine dependence.

7 cl, 5 tbl, 33 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

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