Acyloxyalkylcarbamate prodrugs, methods of synthesis and application

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid, to based pharmaceutical compositions and to their application, for treating spasticity or a spasticity symptom, gastroesophageal reflux disease (GERD), drug addiction, alcohol addiction or alcohol abuse, or cough, or vomiting. Acyloxyalkylcarbamate prodrugs represent a compound of formula (V) or its pharmaceutically acceptable salt where R1 is selected from C1-C6alkyl substituted by C1-C6alkyl, C3-C6cycloalkyl, phenyl, phenyl C1-C6alkyl substituted by phenyl C1-C6alkyl, phenylC2-C6alkenyl, C5-C6heteroaryl containing 1 nitrogen, oxygen or sulphur atom as a heteroatom; R2 and R3 are independently selected from hydrogen, C1-C6alkyl and C3-C6cycloalkyl; R4 is selected from: hydrogen, phenyl, phenyl C1-C6alkyl and C1-C6alkyl and where "substituted" means a group wherein one or two hydrogen atoms are substitute by a substitute which represent C1-C6alkoxy. Also, the invention refers to an intermediate compound of formula (VII) and its pharmaceutically acceptable salt where X represents: fluorine, chlorine, bromine or iodine; R2 and R3 are independently selected from hydrogen and C1-C6alkyl; R4 is selected from: hydrogen, C1-C6alkyl, phenyl and phenyl C1-C6alkyl.

EFFECT: preparation of the acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid which are applicable for the oral introduction and oral introduction with using prolonged release dosage forms.

23 cl, 3 tbl, 89 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (V):

or its pharmaceutically acceptable salt,
where R1selected from C1-C6of alkyl, substituted C1-C6of alkyl, C3-C6cycloalkyl, phenyl, panels1-C6of alkyl, substituted phenyls1-C6of alkyl, panels2-C6alkenyl,5-C6heteroaryl containing as heteroatoms 1 atom of nitrogen, oxygen, or sulfur;
R2and R3independently selected from hydrogen, C1-C6the alkyl and C3-C6cycloalkyl;
R4selected from hydrogen, phenyl, panels1-C6the alkyl and C1-C6the alkyl and
where "substituted" means a group in which one or two hydrogen atoms replaced by the Deputy, which represent the a C 1-C6alkoxy.

2. The compound according to claim 1 of formula (VI):

where R1, R2, R3and R4as specified in claim 1, or its pharmaceutically acceptable salt.

3. The compound according to any one of claims 1 or 2, where R1selected from methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentile, out-pentile, second-pentile, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl, benzyl, Venetia, 2-pyridyl, 3-pyridyl or 4-pyridyl.

4. The compound according to any one of claims 1 to 3, where R2selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and R3represents hydrogen.

5. The compound according to any one of claims 1 to 4, where R4represents hydrogen.

6. The compound according to any one of claims 1 to 2,
where R1represents isopropyl;
R2represents isopropyl;
R3represents hydrogen; and
R4represents hydrogen.

7. The compound according to claim 1 of the formula:

or its pharmaceutically acceptable salt.

8. The compound according to claim 1 of the formula:

or its pharmaceutically acceptable salt.

9. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, where R1 are selected from methyl, propyl, butyl, isobutyl, 2,2-dimethylpropyl, penttila, hexyl, cyclohexyl, cyclopentyl, benzyl, pyridyl, furil, teinila, phenylpropanal, phenylpropyl;
R2and R3independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclohexyl;
R4selected from hydrogen and benzyl.

10. The compound according to any one of claims 1 to 7 and 9, which is a predominantly single diastereoisomer.

11. The compound according to any one of claims 1 to 7 and 9, where the stereochemistry of the carbon atom that is attached to R2and R3represents the S-configuration.

12. The compound according to any one of claims 1 to 7 and 9, where the stereochemistry of the carbon atom that is attached to R2and R3represents the R-configuration.

13. Pharmaceutical composition for the treatment of spasticity or symptom of spasticity, gastroesophageal reflux disease (GERD), drug dependence, alcohol dependence or alcohol abuse, or cough, or vomiting containing compound according to one of claims 1 to 12 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to item 13, containing dosage forms with delayed release for oral use.

15. The compound according to any one of claims 1 to 12 for use in the treatment or prevention of spasticity, a symptom of spasticity, gastroesophageal reflux bol is FDI (GERD), drug dependence, alcohol dependence or alcohol abuse, addiction to nicotine or abuse of nicotine, or cough, or vomiting.

16. The connection indicated in paragraph 15, where the symptom of spasticity choose from: involuntary movements and pain associated with spasticity.

17. The use of compounds according to any one of claims 1 to 12 for the manufacture of a medicinal product for the treatment or prevention of spasticity, a symptom of spasticity, gastroesophageal reflux disease (GERD), drug dependence, alcohol dependence or alcohol abuse, or cough, or vomiting.

18. The application 17, where the symptom of spasticity choose from involuntary movements and/or pain associated with spasticity.

19. The compound of formula (VII):

and its pharmaceutically acceptable salt, where X represents fluorine, chlorine, bromine or iodine;
R2and R3independently selected from hydrogen and C1-C6of alkyl;
R4selected from hydrogen, C1-C6of alkyl, phenyl and panels1-C6the alkyl.

20. The connection according to claim 19, where X represents chlorine;
R2and R3represent methyl; and
R4represents benzyl.

21. The connection according to claim 19 of the formula (VIII):

and its pharmaceutically acceptable salt.

22. The connection on either the from PP and 21, where R2selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; and R3represents hydrogen.

23. The compound according to any one of p and 21, where R4represents hydrogen.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is 2-alkyl-cycloalk(en)yl-carboxamides of formula

, in which X, s, R1 , L, R2 and A assume values given in the formula of invention, a method of producing said compounds, an agent and use of said compounds against unwanted microorganisms.

EFFECT: higher activity compared to existing compounds, low toxicity and high toleration by plants.

6 cl, 8 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to hot or sweet flavourants in form of a synthetic amide compound or edible salt thereof in amount ranging from approximately 0.001 parts per million to approximately 100 parts per million. The amide compound has formula

where A is a phenyl or a 5- or 6-member heteroaryl ring selected from a group comprising pyridine, pyrazine, pyrazole, thiazole, furan, thiophene, benzofuran and benzothiophene; m equals 1, 2 or 3, each R1 is independently selected from hydroxyl, fluorine, chlorine, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy and isopropoxy, or alternatively two R1 are bonded to form a saturated C1-C3 alkylenedioxy ring on the phenyl; and R2 is a C3-C10 branched alkyl. The amide compound also has formula

in which substitutes A, B, R50, R60, R70, R80, n and m assume values given in the formula of invention. The amide compound is also a specific chemical compound.

EFFECT: obtaining hot and sweet taste modifiers and boosters for food and medicinal products.

39 cl, 7 tbl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or salts thereof, (1), where R1 denotes a hydrogen atom or a C1-6alkyl group; R2 denotes a hydrogen atom, R3 denotes a hydrogen atom or a C1-6alkyl group when R4 and R5 denote hydrogen atoms, R6 denotes a hydrogen atom or a cyano group, or in >C(R6) C(R5)(R4) - denotes a double bond, R4 and R6 are absent, and R5 denotes a hydrogen atom; or R4 denotes a hydrogen atom and R5 denotes a hydroxy group or a halogen atom, R6 denotes a hydrogen atom or a cyano group, R7 denotes one or two substitutes selected from a group comprising a hydrogen atom, a halogen atom, a nitro group and C1-6alkoxy group, A denotes a 5-member or a 6-member non-aromatic heterocyclic ring which contains one sulphur atom (the sulphur atom can form an oxide), W denotes an oxo group, two hydrogen atoms, two fluorine atoms or a combination of a hydrogen atom and a hydroxy group, and X denotes an oxygen atom or a sulphur atom.

EFFECT: medicinal agent based on these compounds have inhibitory action on production of prostaglandin E2 and can be used in medicine to treat urological diseases.

5 cl, 7 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing dimethyl ether of 2,5-thiophene dicarboxylic acid by reacting thiophene with carbon tetrachloride in the presence of methanol and a tris(2,4-pentanedionato)iron catalyst Fe(acac)3 which is activated by a nitrogen-containing ligand - quinoline or pyridine, at temperature 150°C for 6 hours in molar ratio 0.04:0.4:4:45:30. Dimethyl ether of 2,5-thiophene dicarboxylic acid is used in production of electroconductive polymers, electrodes, sensors, capacitors, displays, optical brighteners, gel electrolytes and ion-exchange membranes.

EFFECT: high output of product.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing dimethyl ether of 2,5-thiophene dicarboxylic acid, , which involves reaction of 2-thiophene carboxylic acid with methanol and CCl4 in the presence of a catalyst tris(2,4-pentanedionato)iron Fe(acac)3, activated with a nitrogen-containing ligand - pyridine with molar ratio [Fe(acac)3] : [C5H5N] : [2-thiophene carboxylic acid] : [methanol] : [CCl4]=0.01:0.05-0.1:1:45-135:30, at temperature of 140-160°C for 3-6 hours.

EFFECT: high output of dimethyl ether of 2,5-thiophene dicarboxylic acid which is the base material for production of electroconductive polymers, electrodes, sensors, capacitors, displays, gel electrolytes, ion-exchange membranes and optical bleaching agents.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel biologically active compounds of formula , where substitutes R, R1, R2 and R3 are defined in the formula of invention, and can be obtained using a method which involves reaction of corresponding chloroacetamides with a prepared solution of elementary sulphur with morpholine or piperidine, passing the obtained solution of monothiooxamides through a layer of sorbent and then reaction of monothiooxamides with hydrazine-hydrate, reaction of the obtained compound with aldehydes in dimethyl formamide at room temperature and precipitation with methanol which gives good output of the end product.

EFFECT: obtained compounds are highly effective against pathogenic bacteria, are characterised by selectivity and can be used to inhibit type III secretion in pathogenic bacteria.

3 cl, 8 dwg, 1 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted derivatives of oxamic acid thiohydrazides of general formula: , where R and R1 denote H, unsubstituted or substituted Het, phenyl, Alk, wherein substitutes can be Alk, Hal, CF3, COOR3, SR3, or R+R1=C2H4OC2H4; R2 denotes H, Alk, OR3, Hal, where R3=Alk; Het denotes a 5- or 6-member ring which contains one or two heteroatoms selected from N and S. The invention also relates to a method for synthesis of said compounds.

EFFECT: obtaining novel compounds which exhibit antibacterial activity and can be used as antibacterial agents for inhibiting pathogenic bacteria, including Chlamydia.

4 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new biologically active substances and specifically to 4-(methylphenyl)-4-oxo-2-[3-ethoxycarbonyl-4,5-R2,R1-thiophen-2-ylamino]but-2-enoic acid of general formula: R1,R2=CH3 R1+R2=(CH2)3.

EFFECT: obtaining new compounds having anti-inflammatory and analgesic activity, as well as low toxicity, which can be used as medicinal agents.

1 cl, 1 tbl, 4 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to compounds of general formula (II) and pharmaceutically acceptable salts thereof, and to use and a pharmaceutical composition based on the said compounds. In formula (II) compounds, A is a heteroaromatic 5-member cyclic system containing one group X selected from a group consisting of S and O; Z1 and Z2 independently represent O; R2 is OR6; R6 is H; R8 is hydrogen or (C1-C6)alkyl; E is phenyl which is optionally substituted with 1-4 substitutes in form of halogen; Y is phenyl which is optionally substituted with 1-2 substitutes selected from halogen, (C1-C6)alkoxy or halogen((C1-C6))alkyloxy; m equals 0; n equals 0; q equals 0; t equals 0; or pharmaceutically acceptable salts thereof.

EFFECT: obtaining aromatic compounds of formula (II) for inhibiting dehydroorotate dehydrogenase.

6 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention describes novel compounds of formula (I), where substitutes R1, R2, R3, Ar and A are described in the formula of invention, having histone deacetylase inhibiting activity, use thereof and methods for synthesis of said compounds.

EFFECT: improved composition properties.

15 cl, 72 ex, 9 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of (R)-2-arylpropionamides of general formula I, in which Ar is phenyl group, substituted in 3(meta) position by group R1, selected from: linear or branched C1-C8-alkanoyl, C3-C6- cycloalkanoyl, heteroarylcarbonyl, C1-C6-alkylaminocarbonyl, arylaminocarbonyl, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamino, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C6-aryloxycarbonyl, C1-C8-alkansulfonyl, arylsulfonyl, or 3,4-dihydro-1H-quinolyl-2-on; R is selected from: -H, OH; - heteroaryl group is selected from: pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole; - α or β carboxyl residue can consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted with other carboxyl (COOH) group; - residue with formula SO2Rd, in which Rd is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl or pyridyl, on condition that compounds of formula I are not the following compounds: (R)-2-(3-phenoxyphenyl)-propanoyl-phenylglycine; (R)-2-( phenoxyphenyl)-propanoyl-glycine; (R)-2-[(3'-acetyl)phenyl]-R-4''-pyrimidyl)propionamide. Invention also relates to method of obtaining formulaI compound and application of formula I compound for preparation of medications for treatment of diseases including C5a induced hemotaxis of human PMNs.

EFFECT: obtained are novel derivatives of (R)-2-arylpropionamide, possessing useful biological properties.

9 cl, 3 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4(5)-(2-hetaryl) and 4(5)-(2-hetaryl)-2-(2'-hetaryl)-imidazoles of general formula R=2-furyl, 2-thienyl; R'H; and R=2-furyl, 2-thienyl; R'=2-furyl is obtained using 2-bromoacetylfuran (thiophene) of general formula 2-thienyl and aldehydes in the presence of copper acetate, synthesis of a 2-bromoacetylfuran (thiophene) precursor is carried out by reacting 2-acetylfuran (thiophene) with copper (II) bromide.

EFFECT: increased safety of the process.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the method for preparation of 5-hydroxymethylfurfural by the acid-catalytic conversion of fructose in the two-phase system water-dioxane at atmospheric pressure in the presence of sodium hydrosulphate in the concentrations 200-400 g/l with additives of sulfuric acid (4.9-19.6 g/l) as catalyst and dioxane as extractant (the ratio water/dioxane is in the range 1:2-1:5). 5-hydroxymethylfurfural is used in the production of food additives, pharmaceutics, polymer materials and motor-fuel additives.

EFFECT: decrease of the process time in 2-3 times, reducing of toxity and consumption of the extractant.

1 cl, 7 ex

FIELD: chemistry of organosilicon compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds and their using in therapy. Invention describes compounds of the formula (I): wherein radical are given in the invention claim. These substances are claimed as compounds possessing antagonistic activity with respect to GnRH, and pharmaceutical composition comprising these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 7 ex

FIELD: chemistry of organosilicon compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds and their using in therapy. Invention describes compounds of the formula (I): wherein alternate values are given in the invention claim. These substances are claimed as compounds possessing antagonistic activity with respect to GnRH, and pharmaceutical composition comprising these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 5-methyl-2-propyonylfuran that is an intermediate product of the broadly known antioxidant - 2-ethyl-5-methyl-3-hydroxypyridine and its salts used in technique, agriculture and medicine (preparations "Emoxipine", "Mexidol" and others). Method of synthesis involves the acylation process that is carried out by the simultaneous mixing reagents and polyphosphoric acid as a catalyst under adiabatic conditions in the following mole ratio of components 2-methylfuran : propionic anhydride : polyphosphoric acid = 1:(1.02-1.06):(0.025-0.04), respectively; during the process the temperature increases spontaneously to the optimal value 130-140°C and at this temperature the heat exposition is carried out for 30-60 min. Then the reaction mass is cooled and pure product is isolated by neutralization of propionic acid formed as result of the reaction with an aqueous solution of alkaline agent not evolving gas in the neutralization reaction. The proposed method provides synthesis of 5-methyl-2-propionylfuran with the yield above 93% with sufficient purity (T20 = 1.5080, the content is above 96%) with minimal energy consumption for the total period of the process 2-2.5 h and in the absence of toxic waste gases and not utilized waste.

EFFECT: improved method of synthesis.

4 cl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 2-propionyl-5-methylfuran. Method involves the acylation reaction of 2-methylfuran with propionic anhydride at heating in the presence of anhydrous ortho-phosphoric acid as a catalyst in the mole ratio 2-methylfuran : propionic anhydride = 1:(1.1-1.2) at temperature 130-135°C followed by cooling the reaction mass, its treatment with 10-25% ammonia an aqueous solution and isolation of the end substance. Catalyst is used in the amount 3-5 wt.-%. Invention provides simplifying the process.

EFFECT: improved preparing method.

2 cl, 2 ex

The invention relates to new derivatives of balkanov General formula (A)

< / BR>
where Ar is phenyl which may be unsubstituted or substituted one, two or three substituents independently chosen among Cl, Br, F, -OMe, NO2, CF3C1-4lower alkyl, -NMe2, -NEt2, -SCH3, -NHCOCH3; 2-thienyl, 2-furyl; 3-pyridyl; 4-pyridyl or 3-indolyl; R-OCH2R1where R1choose from a number of-CH= CME2The CME=CH2-The CCH; provided that when Ar is a phenyl,4-alkylphenyl, 4-methoxyphenyl or 3,4-acid, R can be any except 3-methyl-2-butenyloxy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

Up!