Derivatives of 7-(2-amino-1-hydroxy-ethyl)-4-hydroxybenzothiazol-2(3h)-on as agonists of β2-adrenergic receptors

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and to their pharmaceutically acceptable salts. In formula (I)

, R1 represents hydrogen; each of R2, R3, R4, R5, R4 and R5 independently represents hydrogen or C1-C6alkyl; x equals 0 or 1; Arepresents oxygen, sulphur, S(O) or S(O)2; D represents oxygen or NR6; W represents bond or CR6aR6b; n equals integer number from 0 to 2; R6 represents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl; Y represents bond, CR2eR2f; R2a, R2b, R2c, R2d, R2e, R2f, R6a and R6b represent independently hydrogen or C1-C6alkyl; R7a represents hydrogen or NHR7b; R7b represents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl; R7 represents 6-12-member aromatic ring system, probably substituted with halogen, trifluoromethyl, C1-C6alkyl. Invention also relates to pharmaceutical composition, containing invention compound, as well as to

compounds ; , where R represents hydrogen or benzyl.

EFFECT: obtaining compounds, which possess properties of β2-adrenoreceptors agonist.

15 cl, 2 tbl, 50 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

where R1represents hydrogen;
each of R2, R3, R4, R5, R4'and R5'independently represents hydrogen or C1-C6alkyl;
x is 0 or 1;
And represents oxygen, sulfur, S(O) or S(O)2;
D represents oxygen is if NR 6;
W represents a bond or CR6aR6b;
n is an integer from 0 to 2;
R6represents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl;
Y represents a bond, CR2eR2f;
R2a, R2b, R2c, R2d, R2e, R2f, R6aand R6bare independently hydrogen or C1-C6alkyl;
R7arepresents a hydrogen or other7b;
R7brepresents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl;
R7is a 6 to 12-membered aromatic ring system, possibly substituted with halogen, trifluoromethyl, C1-C6by alkyl; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where each of R2, R3, R4, R5and, if they are present, R4'and R5'represents hydrogen.

3. The compound according to claim 1, where D represents NR6.

4. The compound according to claim 1, where D represents NR6and represents sulphur.

5. The compound according to claim 1, where x is equal to 0.

6. The compound according to claim 1, where Y represents a bond or CR2eR2fand n is 0.

7. The compound according to claim 1, where n is 1 or 2, and W represents CR6aR6bwhere R6aand R6bare independently hydrogen or C1-4and the keel.

8. The compound according to claim 1, where R7arepresents other7bwhere R7brepresents hydrogen, C1-C4alkyl or C1-C6alkoxycarbonyl.

9. The compound of formula (I) according to claim 1, where x is 0 or 1; a represents oxygen, sulfur or S(O)2; D represents an oxygen or NR6; Y is a bond or CH2; W represents CR6aR6b; n is 0; R1, R2, R3, R4, R5, R4', R5', R2a, R2b, R2cand R2dall represent hydrogen; R6represents hydrogen, C1-C4alkyl or C4alkoxycarbonyl; R6aand R6bare independently hydrogen or C1-C4alkyl; R7represents a 6-10 membered aromatic ring system, possibly substituted with halogen, C1-C4the alkyl or CF3; and R7arepresents hydrogen, MN(C4alkoxycarbonyl) or NH2; or its pharmaceutically acceptable salt.

10. The compound according to claim 1, including:
4-hydroxy-7-((1R)-1-hydroxy-2-{[3-({2-[2-(1-naphthyl)ethoxy]ethyl}thio)-propyl]amino}ethyl)-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-((1R)-1-hydroxy-2-{[3-({2-[2-(1-naphthyl)ethoxy]ethyl}-sulfonyl)propyl]amino}ethyl)-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-[(1R)-1-hydroxy-2-({3-[2-(2-phenylethane)ethoxy]propyl}-AMI is about)ethyl]-1,3-benzothiazol-2(ZN)-he,
4-hydroxy-7-((1R)-1-hydroxy-2-{[2-({2-[2-(1-naphthyl)ethoxy]ethyl}thio)ethyl]-amino}ethyl)-1,3-benzothiazol-2(3H)-he,
7-((1R)-2-{[3-({3-[2-(4-bromophenyl)ethoxy]propyl}thio)propyl]amino}-1-hydroxyethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-{(1R)-1-hydroxy-2-[(3-{[3-(2-phenylethane)propyl]thio}-propyl)amino]ethyl}-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-{(1R)-1-hydroxy-2-[(3-{2-[2-(1-naphthyl)ethoxy]ethoxy}-propyl)amino]ethyl}-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-{(1R)-1-hydroxy-2-[(2-{[3-(2-phenylethane)propyl]thio}-ethyl)amino]ethyl}-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-{(1R)-1-hydroxy-2-[(3-{[2-(2-phenylethane)ethyl]thio}-propyl)amino]ethyl}-1,3-benzothiazol-2(3H)-he,
tert-butyl{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}(2-phenylethyl)carbamate,
4-hydroxy-7-((1R)-1-hydroxy-2-{[2-({3-[(2-phenylethyl)amino]propyl}thio)-ethyl]amino}ethyl)-1,3-benzothiazol-2(3H)-he,
4-hydroxy-7-((1R)-1-hydroxy-2-{[2-({3-[methyl(2-phenylethyl)amino]-propyl}thio)ethyl]amino}ethyl)-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(4-ethylphenyl)ethyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(4-ethoxyphenyl)ethyl]{3-[(2-{[(2H)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
7-[1R)-2-({2-[(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl{3-[(2-{[(2H)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}{2-[3-(trifluoromethyl)phenyl]-ethyl}carbamate,
4-hydroxy-7-{(1R)-1-hydroxy-2-[(2-{[3-({2-[3-(trifluoromethyl)phenyl]ethyl}-amino)propyl]thio}ethyl)amino]ethyl}-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(2-chlorophenyl)ethyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl((1S)-2-{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propoxy}-1-phenylethyl)carbamate,
7-((1R)-2-{[2-({3-[(2S)-2-amino-2-phenylethane]propyl}thio)ethyl]amino}-1-hydroxyethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl((1R)-2-{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propoxy}-1-phenylethyl)carbamate,
7-((1R)-2-{[2-({3-[(2R)-2-amino-2-phenylethane]propyl}thio)ethyl]amino}-1-hydroxyethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-he,
7-[(1R)-2-({2-[(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl{2-[(3-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)thio]ethyl}[(2R)-2-phenylpropyl]carbamate,
4-hydroxy-7-[(1R)-1-hydroxy-2-({3-[(2-{[(2R)-2-phenylpropyl]amino}ethyl)-thio]propyl}amino)ethyl]-1,3-Ben is thiazol-2(3H)-he,
tert-butyl{2-[(3-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)thio]ethyl}[(2S)-2-phenylpropyl]carbamate,
4-hydroxy-7-[(1R)-1-hydroxy-2-({3-[(2-{[(2S)-2-phenylpropyl]amino}ethyl)-thio]propyl}amino)ethyl]-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(2-chlorophenyl)ethyl]{2-[(3-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)thio]ethyl}carbamate,
7-[(1R)-2-({3-[(2-{[2-(2-chlorophenyl)ethyl]amino}ethyl)thio]propyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(3-chlorophenyl)ethyl]{2-[(3-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)thio]ethyl}carbamate,
7-[(1R)-2-({3-[(2-{[2-(3-chlorophenyl)ethyl]amino}ethyl)thio]propyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(N)-he,
tert-butyl[2-(2,3-dichlorophenyl)ethyl]{2-[(3-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)thio]ethyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(2,3-dichlorophenyl)ethyl]amino}propyl)thio]ethyl}-amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
7-((1R)-2-{[2-(3-{[2-(3-chlorophenyl)ethyl]amino}propoxy)ethyl]amino}-1-hydroxyethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(2,3-dichlorophenyl)ethyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(2,3-dichlorophenyl)ethyl]amino}propyl)thio]ethyl}-amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzodiaz the l-2(3H)-he,
tert-butyl[2-(3-chlorophenyl)ethyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-(3-chlorophenyl)ethyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)sulfanyl]propyl}carbamate,
7-[(1R)-2-({2-[(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)sulfonyl]ethyl}-amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
(+/-)-tert-butyl-[2-(phenyl)propyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
(+/-)-7-[(1R)-2-({2-[(3-{[2-(phenyl)propyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
(R)-(+)-tert-butyl-[2-(phenyl)propyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
(R)-(+)-7-[(1R)-2-({2-[(3-{[2-(phenyl)propyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
(S)-(-)-tert-butyl-[2-(phenyl)propyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate,
(S)-(-)-7-[(1R)-2-({2-[(3-{[2-(phenyl)propyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he,
tert-butyl[2-methyl-2-(phenyl)propyl]{3-[(2-{[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzo is a thiazol-7-yl)ethyl]amino}ethyl)thio]propyl}carbamate or
7-[(1R)-2-({2-[(3-{[2-methyl-2-(phenyl)propyl]amino}propyl)thio]ethyl}-amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-he
or a pharmaceutically acceptable salt of any of them.

11. 7-[(1R)-2-({2-[(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one or its pharmaceutically acceptable salt.

12. 7-[(1R)-2-({2-[(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)thio]ethyl}amino)-1-hydroxyethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she dihydrobromide.

13. The compound of the formula

where R represents hydrogen or benzyl.

14. The compound of the formula:

15. Pharmaceutical composition having the properties of agonist β2-adrenergic receptors containing the compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 12, together with a pharmaceutically acceptable adjuvant, diluent or carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in free form or in form of a pharmaceutically acceptable salt, where T denotes C1-C10alkyl which is substituted in one position with a -NR1R2 group or C3-C15carboxylic group selected from indan, phenyl, C3-C8cycloalkyl, wherein said C3-C15carboxylic group is optionally substituted in one or two positions with a halogen group, -NR3R4 or C1-C10alkoxy group, or T denotes C3-C15carboxylic group selected from indan, phenyl, C5cycloalkyl which is optionally substituted in one or two positions with a C1-C10alkyl group, C5cycloalkyl or C1-C10alkoxy group which is optionally substituted in one position with phenyl, and R1, R2 independently denote C1-C10alkyl or phenyl, and R3, R4 independently denote C1-C10alkyl. The formula I compound has β2-adrenoreceptor agonist activity.

EFFECT: more effective use as an active ingredient of a pharmaceutical composition.

7 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I), in which Ar represents group of formula (A), (B1), (B2) or (C), or (D1), or (D2); R1, R2, R3, R4, R5, n, A1, A2, A3, A4, A5, Ka, Kb, L, M, V, W, X, Y, Z havevalues, determined in i.1 of invention formula, fungicide composition and method of combatting phytopathogenic fungi or their elimination, using compounds of formula (I).

EFFECT: high fungicide activity.

22 cl, 142 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for synthesis of 2-cyano-6-methoxybenthiazole that is a key intermediate compound used in synthesis of luminescent biological systems, in particular, lupiferin. Method involves cyaniding reaction of 2-chloro-6-methoxybenzthiazole wherein acetonecyanohydrine is used as a cyaniding agent that is treated with alkaline metal alcoholate alcoholic solution, benzene is added and azeotropic mixture alcohol-benzene is distilled off followed by addition of dimethylsulfoxide and 2-chloro-6-methoxybenzthiazole. Method allows avoiding contact of workers with highly toxic cyanides and to obtain 2-cyano-6-methoxybenzthiazole with higher yield 50-50.8% as compared with the prototype (40%).

EFFECT: improved method of synthesis.

3 ex

The invention relates to amide derivative of the formula I

< / BR>
in which R3stands WITH1-C6alkyl or halogen; Q1denotes heteroaryl, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group comprising hydroxy, halogen, trifluoromethyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, etc., R2denotes hydroxy, halogen, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, p = 0, 1, or 2; q = 0, 1, 2, 3 or 4; and Q2denotes aryl, aryl-C1-C6alkoxy, aryloxy, arylamino, N-C1-C6alkylamino, aryl-C1-C6alkylamino, cycloalkyl, heteroaryl, heteroallyl, heteroaryl-C1-C6alkylamino or heterocyclyl and so on, or its pharmaceutically acceptable salt or cleaved in vivo ester

The invention relates to a new derived benzothiazolone formulas I and II, where X denotes naphthyl and its pharmaceutically acceptable salts

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicinal agents and combination for treatment of respiratory disease, containing (a) efficient amount of β2-agonist selected from group that consists of formoterol and salmeterol not necessarily in the form of their racemic compounds, their enantiomers, their diastereoisomer and their mixtures and their mixtures and not necessarily their pharmacologically compatible acid-additive salts, and (b) efficient amount of antagonist of muscarinic receptors M3, which represents 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonibicyclo[2.2.2]octane in the form of salt with anion X, which represents pharmaceutically acceptable anion of mono- or polyvalent acid. Also product, set and package are disclosed, which contain (a) β2-agonist and (b) antagonist of muscarinic receptors M3, as well as use of active ingredients (a) and (b) for production of medicinal agent and method for treatment of patient suffering from respiratory disease.

EFFECT: reduced maximum frequency of heart contractions and its duration.

19 cl, 3 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) (Å) obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.

EFFECT: wider field of use of the compounds.

8 cl, 9 dwg, 9 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology, and can be used for treating bronchial obstruction syndrome in a patient with bacterial inflammation of airway. That is ensured by inhalations of 250 mg of "Fluimucil-antibiotic IT". In 30 minutes after inhalation, the patient's chest is exposed to vibrations generated by HIVAMAT 200 apparatus for 15 minutes. In 6-7 hours later, inhalation of 250 mg of "Fluimucil-antibiotic IT" is performed again. Treatment is daily for 5-7 days.

EFFECT: method is effective, provides recovery in a relatively short time, being herewith noninvasive, painless and without by-effects that allows to be recommended for wide use in paediatrics.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutics and concerns a medical agent for treatment of chronic obstructive lung disease, the agent includes (A) glycopyrrolate and (B) (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyetyl] -8-hydroxy-1H-quinolin-2-one in free form or in the form of salt or solvate, with specified amount being intended for simultaneous, sequential or separate administration.

EFFECT: agent enhances therapy efficacy.

12 cl, 4 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (II) and their pharmaceutically acceptable salts and stereoisomers as β2-adrenergic receptor agonists, to a pharmaceutical composition based on the said compounds, a treatment method, to a method of producing said compounds, their use, as well as to crystalline hydrochloride of N-[5-((R)-2-{2-[4-((R)-2-amino-2-phenylethylamino)phenyl]ethylamino}-1-hydroxyethyl)-2-hydroxyphenyl]formamide. The compounds can be used for treating and preventing β2-adrenergic receptor mediated diseases such as asthma and chronic obstructive pulmonary disease. In general formula (II) , R1 is NHCHO, and R2 is hydrogen; or R1 and R2, taken together, represent -NHC(=O)CH=CH- or -CH=CHC(=O)NH-; each of R5 and R6 is independently selected from hydrogen or C1-6-alkyl.

EFFECT: improved method.

14 cl, 3 dwg, 12 ex

FIELD: medicine.

SUBSTANCE: invention covers drugs and concerns a combination intended for treating respiratory disease, containing (a) effective amount of corticosteroid, and (b) effective amount of antagonist of muscarine receptors M3 representing (3R)-1-phenethyl-3-(9N-xantene-9-xarbonyloxy)-1-azoniumbicyclo[2.2.2]octane in the form of salt with an anion X which represents a pharmaceutically acceptable anion of mono- or polyvalent acid. There is also disclosed application of (3R)-1-phenethyl-3-(9N-xantene-9-carbonyloxy)-1-azoniumbicyclo[2.2.2]octane and corticosteroid for making a drug for respiratory disease and the method of treating respiratory disease.

EFFECT: improved therapeutic effect in treating respiratory diseases.

20 cl, 1 dwg, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: for treating broncho-obstructive syndrome combined with pneumonia and tracheobronchitis in newborns, nebuliser inhalations with oxygen supplement 30-60% one session of which consists in consistent introduction of Salbutamol and Budesonid. The initial dose includes 0.15 mg/kg of Salbutamol and 0.125 mg of Budesonid - 2-3 sessions a day. The stabilisation requires 0.15 mg/kg of Salbutamol and 0.25-0.3 mg/kg of Budesonid once a day. The therapeutic course is 3-14 days.

EFFECT: method allows improving respiratory pulmonary function, reducing symptoms of respiratory insufficiency, relieving severity and duration of infectious-inflammatory process in airways.

8 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine and can be used in treatment of the patients suffering from respiratory and cardiovascular diseases. That is ensured by drug inhalations with underlying simulated hypercapnic hypoxia at concentration of carbon dioxide exceeding 5%. Herewith the liquid form of a drug is transformed into highly dispersed medium by ultrasonic vibration.

EFFECT: method allows improving inhalation effectiveness ensured by specified gas concentration in the inhaled mixture that enables to combine breath activation, stimulation of pulmonary blood circulation and bronchodilatation to achieve the fullest penetration of the drug and related therapeutic effect.

6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to the development of new drugs for inflammatory diseases, particularly asthma. The pharmaceutical compositions under the invention contain 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole in the effective amount or its pharmaceutically acceptable salts and/or hydrates as an active ingredient. The drug can be presented in the form of tablets, capsules, injections or aerosol.

EFFECT: provided anti-inflammatory and antiasthmatic action, as well as practically absolute absence of by-effects proper for the formerly known drugs administered for the same intended purpose.

10 cl, 4 tbl, 7 ex

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