Amine compound and pharmaceutical use thereof


FIELD: chemistry.

SUBSTANCE: invention relates to an amine compound of formula (I), pharmaceutically acceptable addition salts, hydrates or solvates thereof, having immunodepressive effect , where R - H or P(=O)(OH)2; X - O or S; Y denotes -CH2CH2- or -CH=CH-; Z denotes C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene; R1 denotes CF3, R2 denotes C1-4-alkyl, substituted with OH or halogen; R3 and R4 independently denotes H < or C1-4-alkyl; A denotes optionally substituted C6-10-aryl, heteroaryl containing 5-10 ring atoms, where 1 or 2 atoms are selected from N, O and S, C3-7-cycloalkyl optionally condensed with optionally substituted benzene, or heterocycloalkyl containing 5-7 ring atoms, where 1 or 2 atoms are selected from N and O, where said substitutes are selected from C1-4-alkylthio, C1-4-alkylsulphanyl, C1-4-alkylsulphonyl, C2-5-alkylcarbonyl, halogen, cyano, nitro, C3-7-cycloalkyl, C6-10-aryl, C7-14-aralkyloxy, C6-10-aryloxy, optionally substituted with oxo or halogen, C2-3-alkyleneoxy, C3-4-alkylene or C1-2-alkylenedioxy, optionally substituted with halogen C1-4-alkyl or C1-4-alkoxy.

EFFECT: novel compound which is effective in reducing the level of lymphocytes in peripheral blood, suppresses tissue breakdown and exhibiting less side effects, such as bradycardia, is disclosed.

20 cl, 237 ex, 2 tbl

 

The text descriptions are given in facsimile form.

1. Aminosidine, represented by the following formula (I):

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, Y represents-CH2CH2- or-CH=CH-, Z is alkylene containing 1-5 carbon atoms, albaniles containing 2-5 carbon atoms, or akinyan containing 2-5 carbon atoms, R1represents trifluoromethyl, R2represents alkyl containing 1-4 carbon atoms, which is substituted by a hydroxyl group or a halogen atom, R3and R4are not necessarily the same or different and each is th represents a hydrogen atom or alkyl, containing 1-4 carbon atoms, and a represents an optionally substituted aryl containing 6 to 10 carbon atoms, optionally substituted heteroaryl containing 5-10 components of the ring atoms, which contains, as an atom(s) in the ring 1 or 2 atoms selected from nitrogen atom, oxygen atom and sulfur atom, optionally substituted cycloalkyl containing 3-7 carbon atoms, which is optionally condensed with an optionally substituted benzene, or heteroseksualci containing 5-7 components of the ring atoms, which contains, as an atom(s) in the ring optionally substituted by 1 or 2 atoms selected from of nitrogen atom and oxygen atom,
provided that, if a has substituents, the substituents are selected from alkyl comprising 1 to 4 carbon atom, which is optionally substituted with halogen; alkoxygroup having 1-4 carbon atoms, which is optionally substituted with halogen; ancilliary having 1-4 carbon atoms; alkylsulfonyl having 1-4 carbon atoms; alkylsulfonyl having 1-4 carbon atoms; alkylsulphonyl having 2-5 carbon atoms; halogen; cyano; nitro; cycloalkyl having 3-7 carbon atoms; aryl having 6-10 carbon atoms; Arakelov having 7-14 carbon atoms; aryloxy having 6-10 carbon atoms; alkylene having 3 or 4 carbon atoms, which long is correctly replaced by oxopropoxy or halogen; alkylene group having 2 or 3 carbon atoms, which is optionally substituted by oxopropoxy or halogen; alkylenedioxy having 1 or 2 carbon atoms, which is optionally substituted by oxopropoxy or halogen, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

2. Aminosidine according to claim 1, where X represents an oxygen atom, R3represents a hydrogen atom and R4represents a hydrogen atom, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

3. Aminosidine according to claim 1, where a represents an optionally substituted aryl containing 6 to 10 carbon atoms, or optionally substituted heteroaryl containing 5-9 components of the ring atoms, which contains, as an atom(s) in the ring 1 or 2 atoms selected from sulfur atom and oxygen atom, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

4. Aminosidine according to claim 1, where a is unsubstituted or when it contains substituents, the number of substituents is 1 to 3 and the substituents are the same or different and each represents alkyl containing 1-4 carbon atoms, which is optionally substituted by a halogen atom; alkoxy containing 1-4 carbon atoms, which I have is optionally substituted by a halogen atom; alkylthio containing 1-4 carbon atoms; alkylsulfonyl containing 1-4 carbon atoms; alkylsulfonyl containing 1-4 carbon atoms; alkylaryl containing 2-5 carbon atoms; halogen atom; cyano; nitro; cycloalkyl containing 3-7 carbon atoms; aryl containing 6 to 10 carbon atoms, aralkylated containing 7 to 14 carbon atoms, or aryloxy containing 6-10 carbon atoms; or alkylene containing 3 or 4 carbon atoms, which is optionally substituted by oxo or halogen atom, alkylene containing 2 or 3 carbon atoms, which is optionally substituted by oxo or halogen atom or alkylenedioxy containing 1 or 2 carbon atoms, which is optionally substituted by oxo or halogen atom, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

5. Aminosidine according to claim 1, where a is represented by the formula

where R5and R6may be the same or different and each represents a hydrogen atom, alkyl containing 1-4 carbon atoms, which is optionally substituted by halogen atom, alkoxy containing 1-4 carbon atoms, which is optionally substituted by halogen atom, or halogen atom, or its pharmaceutically acceptable acid additive salt, or hydrate, or with whom liwat.

6. Aminosidine according to claim 1, where Z represents trimethylene, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

7. Aminosidine according to claim 1, where R2represents hydroxymethyl, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

8. Aminosidine according to claim 1, where R represents a hydrogen atom, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

9. Aminosidine according to claim 1, where the compound of formula (I) is any of the following: a-z and aa-ff, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES:
A. 2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
b. 2-amino-2-(phosphorylmethyl)-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
C. 2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-triptoreline)propoxy]phenyl}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
d. 2-amino-2-(phosphorylmethyl)-4-{3-trifluoromethyl-4-[3-(3-triptoreline)propac and]phenyl}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
E. 2-amino-2-(2-{4-[3-(3-were)propoxy]-3-triptoreline}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
f. 2-amino-4-(4-[3-(3-were)propoxy]-3-triptoreline}-2-(phosphorylmethyl)butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
g. 2-amino-2-(2-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
h. 2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-(phosphorylmethyl)butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;

1. 2-amino-2-(2-{4-[3-(4-trifloromethyl)propoxy-3-trifluoromethyl]phenyl}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
j. 2-amino-2-(phosphorylmethyl)-4-{4-[3-(4-trifloromethyl)propoxy]-3-triptoreline}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
k. 2-amino-2-(2-{4-[3-(3-trifloromethyl)propoxy-3-trifluoromethyl]phenyl}ethyl)propane-1,3-diol, or its pharmaceutically pickup is acceptable acid additive salt, or its hydrate, or MES;
l. 2-amino-2-(phosphorylmethyl)-4-{4-[3-(3-trifloromethyl)propoxy]-3-triptoreline}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
m. 2-amino-2-(2-{4-[3-(3-fluoro-4-triptoreline)propoxy]-3-triptoreline}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
n. 2-amino-4-{4-[3-(3-fluoro-4-triptoreline)propoxy]-3-triptoreline}-2-(phosphorylmethyl)butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
O. (R)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
R. mono(2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butyl)ester (R)-phosphoric acid, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
q. (R)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
r. mono(2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butyl)ester (R)-phosphoric acid, or E. what about the pharmaceutically acceptable acid additive salt, or its hydrate, or MES;
s. 2-amino-2-(2-{4-[3-(3-chlorophenyl)allyloxy]-3-triptoreline}ethyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
t. 2-amino-4-{4-[3-(3-chlorophenyl)allyloxy]-3-triptoreline}-2-(phosphorylmethyl)butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
u. (E)-2-amino-2-(2-[4-(3-phenylpropoxy)-3-triptoreline]vinyl}propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
v. (E)-2-amino-4-[4-(3-phenylpropoxy)-3-triptoreline]-2-(phosphorylmethyl)-3-butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
w. (E)-2-amino-2-(2-{4-[3-(2-forfinal)propoxy]-3-triptoreline}vinyl)propane-1,3-diol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
H. (E)-2-amino-4-{4-[3-(2-forfinal)propoxy]-3-triptoreline}-2-(phosphorylmethyl)-3-butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
. (R)-2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-methylbutanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
z. mono(2-amino-4-{4-[3-(3,4-dichloropheny is)propoxy]-3-triptoreline}-2-methylbutanoyl)ester of phosphoric acid, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
AA. (R)-2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-ethylbutanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
bb. mono(2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-ethylbutylamine) ester (R)-phosphoric acid, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
cc. (R)-2-amino-2-ethyl-4-{4-[3-(4-trifloromethyl)propoxy]-3-triptoreline}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
dd. mono(2-amino-2-ethyl-4-{4-[3-(4-trifloromethyl)propoxy]-3-triptoreline} butyl) ester (R)-phosphoric acid, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
her. (R)-2-amino-2-ethyl-4-{4-[3-(3-trifloromethyl)propoxy]-3-triptoreline}butanol, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES;
ff. mono(2-amino-2-ethyl-4-{4-[3-(3-trifloromethyl)propoxy]-3-triptoreline}butyl)ester (R)-phosphoric acid, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES.

10. Aminosidine according to claim 1, in which expletive from
2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-triptoreline)-propoxy]phenyl}ethyl)propane-1,3-diol,
2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-triptoreline)-propoxy]phenyl}ethyl)propane-1,3-diol,
2-amino-2-(2-{4-[3-(3-were)propoxy]-3-triptoreline}ethyl)propane-1,3-diol,
2-amino-2-(2-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline} ethyl)propane-1,3-diol,
2-amino-2-(2-{4-[3-(4-trifloromethyl)propoxy-3-trifluoromethyl]phenyl}ethyl)propane-1,3-diol,
2-amino-2-(2-{4-[3-(3-trifloromethyl)propoxy-3-trifluoromethyl]phenyl}ethyl)propane-1,3-diol,
2-amino-2-(2-{4-[3-(3-fluoro-4-triptoreline)propoxy]-3-triptoreline}ethyl)propane-1,3-diol,
(R)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butanol,
(R)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-triptoreline)propoxy]phenyl}butanol,
2-amino-2-(2-{4-[3-(3-chlorophenyl)allyloxy]-3-triptoreline}ethyl)propane-1,3-diol,
(E)-2-amino-2-{2-[4-(3-phenylpropoxy)-3-triptoreline]vinyl}propane-1,3-diol,
(E)-2-amino-2-(2-{4-[3-(2-forfinal)propoxy]-3-triptoreline}vinyl)propane-1,3-diol,
(R)-2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-methylbutanol,
(R)-2-amino-4-{4-[3-(3,4-dichlorophenyl)propoxy]-3-triptoreline}-2-ethylbutanol,
(R)-2-amino-2-ethyl-4-{4-[3-(4-trifloromethyl)-propoxy]-3-triptoreline}butanol,
(R)-2-amino-2-ethyl-4-{4-[3-(3-trifloromethyl)-propoxy]3-triptoreline}butanol.

11. Pharmaceutical composition having effect in relation to the reduction in the number of lymphocytes in the peripheral blood-containing compound according to any one of claims 1 to 9, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES or the connection of claim 10 or its hydrochloride and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, suitable for the treatment or prevention of autoimmune diseases; prevention or suppression of resistance or acute rejection or chronic rejection in transplantation of an organ or tissue; treatment or prevention of graft-versus-host (GvH)caused by bone marrow transplantation; or treatment or prevention of allergic diseases.

13. The pharmaceutical composition according to item 12, where the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus-nephritis, nephrotic syndrome, psoriasis or diabetes mellitus type I.

14. The pharmaceutical composition according to item 12, where the allergic disease is atopic dermatitis, allergic rhinitis or asthma.

15. The use of compounds according to any one of claims 1 to 9, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES or connection of claim 10 or hydroch oride for the manufacture of tools for the treatment or prevention of autoimmune disease; means for the prevention or suppression of resistance or acute rejection or chronic rejection in transplantation of an organ or tissue; means for treatment or prevention of graft-versus-host (GvH)caused by bone marrow transplantation; or means for the treatment or prevention of allergic diseases.

16. The application indicated in paragraph 15, where the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus-nephritis, nephrotic syndrome, psoriasis or diabetes mellitus type I.

17. The application indicated in paragraph 15, where the allergic disease is atopic dermatitis, allergic rhinitis or asthma.

18. Method for the treatment or prevention of autoimmune diseases; prevention or suppression of resistance or acute rejection or chronic rejection in transplantation of an organ or tissue; treatment or prevention of graft-versus-host (GvH)caused by bone marrow transplantation; or treatment or prevention of allergic diseases containing an introduction to the subject an effective amount of a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable acid additive salt, or hydrate, or MES or connection of claim 10 or its hydrochloride.

19. The method according to p, where the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus-nephritis, nephrotic syndrome, psoriasis or diabetes mellitus type I.

20. The method according to p, where the allergic disease is atopic dermatitis, allergic rhinitis or asthma.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: synthesis of lubricant oiliness addends.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-benzotriazol and O-(n-butyl)-O-(3,4,5-trithiatricyclodez-8-yl-methyl))-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product of general formula:

.

EFFECT: ash-free addend for lubricant oils processing under high pressure, in particular lubricant oiliness addend of improved antiscoring properties.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-benzotriazole salt of general formula 2 is disclosed. 1-(N,N-dimethylaminomethyl)-benzotriazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

The invention relates to new P,N-bidentate ligands of formula (I):

where a is S or NR,

where R represents a C1-C4alkyl,

R1and R2represent hydrogen, C1-C4alkyl, or R1and R2can be locked in the benzene ring,

R3and R4submit C1-C4alkyl or phenyl,

R5and R6submit C1-C4alkyl

The invention relates to new heteroaryl-alldifferent formulas (I) and (II) for compounds of formula (I) A=S if V=C; A=N, if B=N, R1is hydrogen or C1-C4alkyl, R2-R5-phenyl, R6and R7is hydrogen, n=0 or 1, R8-R11is hydrogen; compounds of f-crystals (II) A=N, if I=S, R1=C1-C4alkyl, A=C, if B= N, R1is hydrogen; A=N if I=N, R1=0; And=O, if=S, R1=0, R2-R5- phenyl, R8-R11is hydrogen or C1-C4alkyl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula VIII suitable in medicine as T3 mimetic drugs: VIII, where G is O, -S(=O)2- or -CH2-; R2 is halogen, alkyl, -CF3, -OCF3, alkoxy or cyano; R3 and R4 are H, halogen, alkyl or -(CRa2)maryl; T is selected from -(CRa2)k-, -CRb=CRb-(CRa2)n-, -(CRa2)n-CRb=CRb, -(CRa2)-CRb=CRb-(CRa2)-, O(CRa2)(CRa2)n-, -S(CRa2)(CRa2)n-, -N(Rc)(CRb2)(CRa2)n-, -N(Rb)C(O)(CRa2)n-, -(CRa2)nCH(NRbRc) -C(O)(CRa2)m-, -(CRa2)mC(O)-, -(CRa2)C(O)(CRa2)n-, -(CRa2)n C(O)(CRa2)- and -C(O)NH(CRb2)(CRa2)p-; Ra, Rb, Rc, R1, R6, R7, R8 and R9 are H, halogen or alkyl; or R6 and T with C atom form a 5-6-members ring with 0-2 groups -NRi-, -O- or -S-; Ri is H, -C(O)alkyl, alkyl or aryl; R5 is OH, alkoxy, -OC(O)Re, -OC(O)ORh, -F, -NHC(O)Re, -NHS(=O)Re, -NHS(=O)2Re, -NHC(S)NH(Rh) or -NHC(O)NH(Rh); Re is alkyl, -(CRa2)n-aryl, -(CRa2)n-cycloalkyl or -(CRa2)n- heterocycloalkyl; Rh is H or alkyl; X is P(O)YRllY'Rll; Y and Y' are O or -NRv-; R11 is H, alkyl, -C(Rz)2-OC(O)Ry, -C(RZ)2-O-C(O)ORy, -alkyl-S-C(O)Ry, -[C(Rz)2]q-COORy, -cycloalkylene-COORy, aryl, -C(Rz)2OC(O)SRy, -C(Rx)2COORy or two R11 and R11 form a cycle; k is within 1 to 4; m is within 0 to 3; n is within 0 to 2; p is within 0 to 1; q is 2 or 3; Rv, Rz, Ry and Rx are H or alkyl, or two Rx and Rx form a cycle.

EFFECT: production of new thymomimetic drugs.

19 cl, 80 ex, 10 tbl, 13 dwg

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: synthesis of lubricant oiliness addends.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-benzotriazol and O-(n-butyl)-O-(3,4,5-trithiatricyclodez-8-yl-methyl))-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product of general formula:

.

EFFECT: ash-free addend for lubricant oils processing under high pressure, in particular lubricant oiliness addend of improved antiscoring properties.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing phosphorus- and chlorine-containing methacrylates of general formula: ,

where R = lower alkyl, chloroalkyl, alkoxyl, phenoxyl or a group -

R1 = lower alkoxyl, phenoxyl or a group

,

which can be used to produce polymer materials, including uncoloured, optically transparent materials, as well as low-inflammability composite materials. The method involves reaction of acid chlorides of pentavalent phosphorus with glycidyl ether of methacrylic acid in the presence of a quaternary ammonium salt as a catalyst, as well as a polymerisation inhibitor when adding the glycidyl ether of methacrylic acid to the mixture of acid chloride of pentavalent phosphorus with the catalyst and polymerisation inhibitor and raising temperature from 40°C to 75°C, and then heating the reaction mass to 70÷80°C.

EFFECT: method enables stabilisation of the temperature conditions of the process and avoiding formation of polymer in the reaction mass.

2 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a biocidal composition containing hydrogen peroxide in concentration of 0.05-50% (wt/wt) and a compound of formula 1: (OH)(2-m)(X)(O)P-[(O)p-(R')q-(CH(Y)-CH2-O)n-R]m, where X is H or OH; each Y is independently H or CH3; m equals 1 and/or 2; each p and q is independently equal to 0 or 1, provided that if p equals 0, q equals 1; each n is independently equal to 2-10; each R' is independently an alkylene radical containing 1-18 carbon atoms; each R is independently H or an alkyl radical containing 1-18 carbon atoms; and R'+R≤20; in concentration of 0.01-60% (wt/wt), as a biocidal composition. The invention also relates to use of the disclosed composition as a biocidal composition, as well as for purposes where there is need for disinfection and/or sanitation activity.

EFFECT: composition has excellent biocidal activity.

25 cl, 9 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aminophosphate derivatives of general formula (1a), pharmaceutically acceptable salts or hydrates thereof, which can be used in medicine as S1P (sphingosine-1-phosphate) receptor modulators,

where R3 is a straight alkyl group containing 1-3 carbon atoms; X is an oxygen or sulphur atom and n equals 2 or 3.

EFFECT: obtaining novel biologically active compounds with high S1P receptor modulating action.

9 cl, 59 ex, 1 tbl

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