The method of obtaining derivatives of dihydropyridines

 

(57) Abstract:

The inventive product is a derivative of dihydropyridine f-ly I (see drawing), where n is 1 or 2; R1hydrogen or methyl; X is oxygen or NR2R2hydrogen or butyl, and, if N is 1, Y is hydrogen; if N is 2, then Y hexamethylene group. Reaction conditions: interaction of acetoacetic ester or acetoacetamide f-crystals II (see drawing) with aldehyde f-ly III Y-(CHO)nand ammonia. Connection f-crystals I are thermo - and photostabilization for polymers. 1 Il.

The invention relates to a method of obtaining new compounds, derivatives of dihydropyridines including substituted piperidinyloxy group.

It is known that 2,6-dimethyl-3,5-dicarboxylate-1,4-dihydropyridines are used as stabilizers of polyvinyl chloride (PVC).

Also described synergism 2,6-dimethyl-3,5-in primary forms-1,4-dihydropyridine-diketones in relation to thermal stabilization of PVC.

However, the known derivatives of 1,4-dihydropyridines are ineffective for use as svetosobirayushchikh agents for polymers.

A method was developed to obtain new derivatives of 1,4-dihydropyridines, which are what indicate the General formula

< / BR>
(I) where n is 1 or 2;

R1means a hydrogen atom or methyl; x is an oxygen atom or a radical N-R2where R2means a hydrogen atom or a butyl radical, and, if n is 1, y represents a hydrogen atom, if n is 2, y represents a group -(CH2)6-.

The compounds of formula (I) can be obtained by the method of Chance by the reaction of acetoacetic ester or acetoacetamide formula

CH3-CO-CH2-CO-X

(II) with an aldehyde of formula (III): YCHO and ammonia, where the symbols n, x, R1, y in formulas (II), (III) have the values indicated above.

The reaction is carried out in known for this type of reactions conditions.

If y represents the hydrogen atom, it is better to use hexamine than a mixture of formaldehyde-ammonia. Acetoacetic esters and acetamide formula (II) can be obtained by reaction of diketene 4-hydroxypiperidine or with the corresponding 4-aminopiperidine formula

HX

(V) in which X denotes an oxygen atom or a radical-N-R2and R1and R2have the values specified above. Among the compounds of formula (I) can be named as examples the following:

-2,6-dimethyl-bis-3,5-[(1,2,2,6,6 - pentamethyl-4-piperidinylidene;

-2,6-dimethyl-bis-3,5-[(2,2,6,6-tetrameth - yl-4 - piperidinyl)-aminocarbonyl]-1,4-dihydropyridines;

-2,6-dimethyl-bis-3,5-bis[(2,2,6,6-Tetra - methyl-4-piperidinyl) -N-butylaminoethyl]-1,4-dihydropyridines;

-1,6-bis-[2,6-dimethyl-3,5-bis[(1,2,2,6,6-pentamethyl-4-piperidinyl) -oxycarbonyl]-1,4-dihydro-4-pyridinyl]-hexane.

The compounds of formula (I) can be used as thermal stabilizers and stabilizers to light in organic polymers. So, you can use them as antiultraviolet additives in polyolefins, polystyrenes, polyalkalene, polyurethanes, polyamides, polyesters, polycarbonates, polysulfones, polyethersulfone, polyetherketone, acrylic polymers, halogenated polymers, their copolymers and their mixtures.

The compounds of formula (I) are used in particular polyolefins and polyalkaline such as polypropylene, polyethylene of low or high density, linear low density polyethylene, polybutadiene, copolymers or mixtures thereof.

Stabilization of organic polymer in relation to the effects of light and to ultraviolet irradiation is carried out by introducing at least one of the compounds of formula (I).

Usually do 0,004-rat 0,020-4 mEq. group 2,2,6,6-tetramethyl-piperidinyl per 100 g of polymer.

As an example, the stabilized polymers contain from 0.01 to 5 wt. the compounds of formula (I).

The addition of compounds of the formula (I) may be performed while receiving or after receiving the polymers. Organic polymers containing the compounds of formula (I) may contain other additives and stabilizers that are commonly used, for example:

antioxidants, as alkylated monophenol, alkylated hydrochinone, hydroxyl diphenyl sulfides, alkylidene-bis-phenols, benzyl compounds, aceraminophen, esters of 3-(3,5-ditretbutyl-4-hydroxyphenyl)-propionic acid, esters of 3-(5-tertbutyl-4-hydroxy-3-were)-propionic acid, esters of 3-(3,5-DICYCLOHEXYL-4-guide - roxiprin)-propionic acid, amides of 3-(3,5-ditertbutyl-4-hydroxyphenyl)-Pro - pianoboy acid; the absorber of ultraviolet radiation stabilizers to light such as 2-(2'-hydroxyphenyl)-benzotriazole, 2-hydroxybenzophenones, esters of benzoic acid, possibly substituted, acrylic esters, compounds of Nickel, oxolamine;

the decontamination officers metals;

the phosphites and phosphonites;

compounds that destroy peroxides;

reagents okleinowania;
;

pigments;

optical asuransi;

protivovospalitel;

antistatic agents;

progeny.

Stabilized polymers can be used in various forms, for example, in the form of molded articles, films, fibers, porous materials, profiles, or coatings as binders (binders) for paints, varnishes, adhesives or cements. The compounds of formula (I) can also be used as stabilizers, for example, chlorinated polymers. Especially in these polymers, they play the role of UV stabilizers and thermal stabilizers. They can be used alone or in combination with other stabilizers, such as, for example, organic tin compounds. The compounds of formula (I) can also be used in chlorinated polymers in conjunction with other primary stabilizers.

Preferably, if such primary stabilizers are organic derivatives of zinc, calcium, barium, magnesium, and strontium, and in some cases, hydrotalcite.

Chlorinated polymers are, in particular polyvinyl chloride (PVC), grades, copolymers containing mostly parts of vinyl chloride obtained is C vinyl chloride.

In General organic compounds of calcium, barium, magnesium and strontium or hydrotalcite amount of 0.005 to 5 wt. relative to the chlorinated polymer, preferably of 0.02 to 2 wt.

For food applications, in particular for food bottles PVC used organic compounds of calcium or a mixture of organic compounds of calcium with organic compounds of magnesium. In the General case of the chlorinated polymer contains from 0.005 to 5 wt. the compounds of formula (I), relative to the chlorinated polymer. Preferably they contain 0.01 to 2 wt. the compounds of formula (I).

Compared with the 1,4-dihydropyridines of the prior art, which are used as stabilizers chlorinated polymers, the compounds of formula (I) have not less efficiency from the point of view of resistance to yellowing, with fewer 1,4-dihydropyridine links, but they also have an efficient protective effect against UV radiation.

The compounds of formula (I) in which R1means a hydrogen atom, is particularly effective as antioxidants in organic polymers mentioned above, i.e., such as polyolefins, polystyrenes, polyalkalene, polyurethanes, polyamides, polyesters, polycarbonates, polysol the Pacific polymers.

The use of these compounds as antioxidants especially suitable for polyolefins, such as low density polyethylene, linear low density polyethylene, high density polyethylene and polypropylene, polystyrene, polyamides, polyesters and polyurethanes.

Typically, these compounds are used is 0.01 to 5 wt. relative weight of the stabilized polymer, preferably 0.05 to 2 wt. It was also found that the compounds of formula (I) in which R1hydrogen, have a favorable effect on the "manufacturability" when thermoformed polymer.

For example, if the introduction of such a compound in the polymer, the latter during thermoforming is not destroyed (or few breaks), and does not form (or not form) cross-linking, in contrast to the polymer containing any one of the known connection with sterically hindered amino group, or one known connection with the dihydropyridine group, or a mixture of these two types of connections. This is for polyolefins and especially for propylene.

P R I m e R 1. Obtaining 2,6-dimethyl-3,5-bis[(2,2,6,6-tetramethyl-4-piperidinyl) oxycarbonyl]-1,4-dihydropyridines.

1A. Getting 4-acetate, what termometro, vertical refrigerator and addition funnel is placed to 31.4 g (0.2 mol) 4-hydroxy-2,2,6,6-tetramethylpiperidine; 200 cm3toluene; 1 cm3of triethylamine (catalyst).

Heated with stirring to 70aboutWith, then gradually within 30 minutes of entering a 16.8 g (0.2 mol) of diketene, maintaining the temperature at 70aboutC. This temperature is kept for 2 h 30 min after the end of the fill.

All these operations are carried out in nitrogen atmosphere.

Then remove the toluene, triethylamine and traces of diketene under reduced pressure by gradual heating, the pressure 2000 PA with a gradual decrease to 65 PA, the temperature of the 20aboutWith increases to 65aboutWith the end of the operation. Get to 48.1 g of yellow-orange homogeneous oil containing 393 mEq. 100 g-ketoamine groups (theory 414,9 mEq./100 g), which corresponds to a purity of 95%

The proposed structure is confirmed by IR spectra and mass spectra.

1B. Obtaining 2,6-dimethyl-bis-3,5-[(2,2,6,6-tetramethyl-4-piperidinyl)oxycarbonyl]-1,4-dihydropyridines.

In the apparatus according to example 1A is placed 38,05 g (0.15 mol); -4-acetoacetate-2,2,6,6-tetramethyl-piperidine, obtained in example 1A (95%); 2,00 g (0.014 mol); GU the reaction mixture is stirred and heated at 72aboutC for 2 h 50 min, in nitrogen atmosphere.

After cooling, the pH value was adjusted to 11.4 by adding 5N caustic sodium. Then add 700 cm3water with vigorous stirring, a precipitate, which is dewatered, washed with water and dried under reduced pressure at 80aboutC. Receive and 26.8 g of a yellow solid substance with a melting point 189-190aboutWith almost pure, its IR spectrum and mass spectrum are in agreement with the proposed structure. The obtained yield of pure product in relation to the connection 1A is 75%

P R I m m e R 2. 2A. Getting 4-acetoacetate-1,2,6,6-pentamethyl-piperidine.

Repeat example 1A, using 4-hydroxy-2,2,6,6-tetramethyl-N-methyl-Piperi-DIN.

Get a yellow-orange oil, which after titration by allometries contains 369 mEq/100 g (according to theory of 392 mEq/100 g), purity 94%

2B. Obtaining 2,6-dimethyl-bis-3,5[1,2,2,6,6-pentamethyl-4-piperidinyl)OK - dicarbonyl]-1,4-dihydropyridines.

Repeat example 1B, with substituted 4-acetoacetate-2,2,6,6 - tetramethylpiperidine the same molar quantity of 4-Aceto-acetoxy - 1,2,2,6,6-pentamethylpiperidine obtained in example 2A. Receive 2,6-dimethyl-bis-3,5[(1,2,2,6,6-pins - tamati the P>With the structure confirmed by IR spectra, the spectra of nuclear magnetic resonance (NMR) and mass spectra.

P R I m e R 3. 3A. Getting 4-acetoacetamide-2,2,6,6-tetramethylpiperidine.

Repeat example 1A, when I take 4-amino-2,2,6,6-tetramethylpiperidine, the catalyst is not used, and prelivanje diketene carried out at 0 to 10aboutTo get 4 acetoacetamide-2,2,6,6-tetramethyl-Pipa - ridin in the form of a white solid with a melting point 115aboutC.

The output of the product in relation to the 4-amino-2,2,6,6-tetramethyl-piperidine is 90%

3b. Obtaining 2,6-dimethyl-bis-3,5[(2,2,6,6-tetramethyl-4-piperidinyl)AMI - noncarbonyl]-1,4-dihydropyridines.

Into a flask of Erlenmeyer capacity of 100 cm3placed 1.50 g (0,050 mol) of formaldehyde; 21,3 g (0,089 mol) -acetoacetamide-2,2,6,6 - tetramethylpiperidine received - tion in example 3A; 20 cm3absolute ethanol; 5 drops of diethylamine.

The obtained homogeneous reaction mixture is left at 4aboutC for 24 h and then at room temperature for 48 hours Then add 4,6 cm3aqueous ammonia solution, with a content of NH3290 g/l (or 0,078 mol NH3). Heated to 75-80aboutC for 5 h, and then when the situation get 23 g of orange solid, slightly pasty. This solid is dissolved in 200 cm3methanol and then precipitated by adding 500 cm3water with vigorous stirring. The precipitate is filtered, washed with water and dried under reduced pressure at 40aboutC.

Obtain 4.5 g of solid yellow substance with a melting point 170aboutWith the structure of 2,6-dimethyl-bis-3,5[(2,2,6,6-tetramethyl-4 piperidinyl)aminocarbonyl]-1,4-dihydropyridines confirmed by NMR spectra.

P R I m e R 4.

4A. Getting 4-N-N-butylacetoacetate-2,2,6,6-tetramethyl-piperidine.

Conduct operations as in example 3A, when I take 4-N-n-butylamino-2,2,6,6-tetramethyl-piperidine and receive a 4-N-N. butylacetoacetate-2,2,6,6-tetramethyl-PI - peridin in the form of a yellow viscous liquid with a purity of above 95%

4B. Obtaining 2,6-dimethyl-bis-3,5[(2,2,6,6-tetramethyl-4-piperidinyl) called butylaminoethyl]-1,4-dihydropyri-DIN.

Repeat example 3b using instead 4-acetoacetamide - 2,2,6,6-tetramethyl-piperidine substance obtained in example 4A. Receive 2,6-dimethyl-bis-3,5-[(2,2,6,6-tetramethyl-4 - piperidinyl)-called butylaminoethyl]-1,4-dihydropyridines in the form of a white solid with a melting point of 172aboutC. IR spectra and M1,2,2,6,6 - pentamethyl-4-piperidinyl-oxycarbonyl]-1,4-dihydro-4-pyrid - inyl]hexane.

Repeat example 3b, thus replacing formaldehyde on 3.55 g (0,025 mol) of octangula and use 4-Aza - tooclose-1,2,2,6,6-pentamethyl-piperid-in obtained in example 2A. Get (yield 70%) of 19.7 g of a yellow solid with a melting point of 110aboutS, and its structure confirmed by NMR spectra.

The METHOD of OBTAINING DERIVATIVES of DIHYDROPYRIDINES of General formula

< / BR>
where n is 1 or 2;

R1hydrogen or methyl;

X is oxygen or a radical

N R2,

where R2hydrogen or butyl,

moreover, if n1, Y is hydrogen, if n2, Y (-CH2)6,

characterized in that conduct the reaction of acetoacetic ester or acetoacetamide formula

< / BR>
with an aldehyde of the formula

Y -(CHO)n,

where n, X, Y, R1have the specified values,

and ammonia and produce the target product.

 

Same patents:

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The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing formula I compounds and their salts, , where R1 is H or F; and Boc is tert-butoxycarbonyl. These compounds are useful as intermediate products during production of tryptase inhibitors.

EFFECT: invention also relates to intermediate products, which can be used when producing said compounds, as well as to methods of producing such intermediate products and their use in production of said compounds.

20 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

Phenyl derivative // 2639875

FIELD: pharmacology.

SUBSTANCE: invention relates to a compound of the general formula (I) having a high antagonistic activity with respect to human S1P2, and can be used to prepare a drug for treatment of a disease mediated by S1P2, such as a disease caused by vasoconstriction, fibrosis and respiratory disease.

EFFECT: compound application efficiency increase.

14 cl, 2 tbl, 9 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, polymers, chemical technology.

SUBSTANCE: invention relates to a method for preparing oligomer based on epoxy resin E-40. Method involves carrying out the condensation reaction of epoxy resin E-40 and 4-hydroxy-2,2,6,6-tetramethylpiperidine in melt at temperature 130-200°C for 2-14 h. Prepared oligomer can be used as a highly effective non-staining photostabilizing agent of polymer materials (polyolefins, polyurethanes and others). Invention provides reducing the process time and energy consumptions and to carry out the process in the absence of solvent.

EFFECT: improved preparing method.

4 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or solvates wherein m represents 0, 1, 2 or 3; each R1 represents halogen atom or (C1-C6)-alkylcarbonyl; Z1 represents a bond or group -(CH2)q wherein q represents 1 or 2; Z2 represents a bond or group -CH2 under condition that both Z1 and Z2 don't represent a bond simultaneously; Q represents oxygen or sulfur atom or group -CH2 or -NH; R2 represents group of the formula: ; n = 0; each R4, R5, R6 and R7 represents hydrogen atom; R8 represents hydrogen atom or (C1-C6)-alkyl group; R15 represents -C(O)NR17R18 or -NHC(O)R20; t represents 0, 1, 2 or 3; each R16 represents halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, phenyl or (C1-C6)-alkyl; each R17 and R18 represents hydrogen atom or (C1-C6)-alkyl; R20 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heterocyclic system that can be substituted with (C1-C6)-alkyl. Compounds of the formula (I), their salts and solvates possess a modulating activity with respect to chemokine MIP-1α receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

19 cl, 64 ex

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