Cycloalkylamines as monoamine reuptake inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

 

The text descriptions are given in facsimile form.

1. The compound having a structure corresponding to formula (I):

or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form, where n is 0 or 1;
s is 1, 2 or 3;
m is an integer from 0 to 12;
AG is a
or< / br> where Y and Z are (i) both halogen; or (ii) one of Y and Z represents CF3or F3and the other represents hydrogen;
Y1, Z1, Y2and Z2each independently represents H or halogen;
each X independently represents H, halogen, CF3, OR5,
(C1-C4)alkyl, optionally substituted with halogen or HE, or NR6R7;
each R1and R2independently represents H or (C1-C6)alkyl; and
each R3and R4independently represents H or (C1-C9)alkyl, optionally substituted HIM;
where each R5independently represents H, (C1-C4)alkyl or phenyl; and
each R6and R7independently represents H or (C1-C4)alkyl;
where at least two of R1, R2, R3, R4and X together with the atoms to which they are attached, optionally associated with the formation of 5-6-membered rings, where 5-6-membered ring chosen from:
a) R3and R4together with the nitrogen atom to which they are attached, optionally form a pyrolidine, piperidine, pieperazinove or morpholine ring, which is optionally substituted (C1-C4)alkyl;
b) when R3represents H or lower alkyl, X and R4VM is the extent atoms, to which they are attached, optionally form a 1,3-oxazine ring;
c) two X substituent together with the carbon atom to which they are attached, optionally form a 1,3-dioxolane ring; and
d) when R1and R3represent hydrogen, R2and R4together with the atoms to which they are attached, optionally form a 5-or 6-membered saturated heterocyclic ring containing one nitrogen atom.

2. The compound according to claim,1, having the formula (II):

or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form. 3. The compound according to claim 1, having the formula (III):

or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form. 4. The compound according to claim 1, where AG is a

where Y and Z each independently represents F or CL.

5. The compound according to claim 4, where both Y and Z are CL.

6. The compound according to claim 1, where AG is a:
or.

7. The compound according to claim 1, where the specified connection has the following structure:

or pharmaceuticas is acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form;
where X1and X2independently represent an X.

8. The connection according to claim 7, where X1and X2each independently represents H, methyl, ethyl, propyl, OR5CH2IT, (C1-C4)alkyl, substituted with halogen, or halogen.

9. The connection according to claim 7, where X1and X2independently represent H, methyl, ethyl, n-propyl, HE, OMe, OEt, F, Cl or CH2HE.

10. The connection according to claim 7, where R1represents H or (C1-C4)alkyl.

11. The connection according to claim 7, where R3and R4each independently represents an optionally substituted alkyl.

12. The connection according to claim 7, where R1, R3and R4each independently represents H or (C1-C4)alkyl.

13. The connection according to claim 7, where R1, R3and R4each independently represents H or methyl.

14. The connection according to claim 7, where AG is a:
or.

15. The compound according to claim 1, where AG is a:

where Y and Z are halogen.

16. The connection according to claim 7, where AG represents 3,4-dichlorophenyl or 2-naphthyl.

17. The compound according to claim 1, where the compound is:
1-(1-(3,4-dichlorophe who yl)cyclohexyl)ethanamine (2);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-methylbutane-1-amine (3);
(1-(naphthalen-1-yl)cyclohexyl)methanamine (12);
1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (13);
(1-(4-(triptoreline)phenyl)cyclohexyl)methanamine (15);
1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (16);
1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-amine (17);
1-(1-(4-(triptoreline)phenyl)cyclohexyl)ethanamine (19);
1-(1-(3,4-dichlorophenyl)cyclohexyl)pentane-1-amine (25);
1-(1-(3,4-dichlorophenyl)cyclohexyl)heptane-1-amine (26);
(1-(3,4-dichlorophenyl)cyclohexyl)-methanimidamide (27);
(1-(3,4-differenl)cyclohexyl)methanimidamide (30);
(1-(3-chloro-4-forfinal)cyclohexyl)-methanamine (32);
(1-(naphthalen-2-yl)cyclohexyl)methanamine (33);
(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (34);
(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (36);
(1-(6-fornatale-2-yl)cyclohexyl)methanamine (39);
(1-(4-fornatale-1-yl)cyclohexyl)methanamine (40);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylethanamine (43);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,3-dimethylbutan-1-amine (45);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N,3 trimethylbutane-1-amine (46);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48);
N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (53);
N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (55);
N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56);
N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (57);
N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58);
N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59);
N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (60);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-DIMETHYLPROPANE-1-amine (61);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62);
N,N-dimethyl-1-(1-(4-triptoreline)phenyl)cyclohexyl)ethanamine (63);
N-methyl-1-(1-(4-(triptoreline)phenyl)cyclohexyl)ethanamine (64);
1-(1-(6-fornatale-2-yl)cyclohexyl)-N-methylmethanamine (67);
1-(1-(6-fornatale-2-yl)cyclohexyl)-N,N-dimethylethanamine (68);
1-(1-(4-fornatale-1-yl)cyclohexyl)-N-methylmethanamine (69);
1-(1-(4-fornatale-1-yl)cyclohexyl)-N^N-dimethylethanamine (70);
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-tiletamine (73);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylethanamine (74);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (75);
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine (76);
N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine (77);
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropane (78);
(1-(3,4-differenl)cyclohexyl)-N-methylmethanamine (81);
(1-(3,4-differenl)cyclohexyl)-N,N-dimethylethanamine (83);
(1-(3,4-dichlorophenyl)cyclopentyl)methanamine (87);
(1-(3,4-dichlorophenyl)cyclopentyl)-N-methylmethanamine (88);
(1-(3,4-dichlorophenyl)cyclopentyl)-N,N-dimethylethanamine (89);
N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine (93);
N,N-dimethyl (--(naphthalen-2-yl)-cyclohexyl)methanamine (94);
(1-(4-chloro-3-forfinal)cyclohexyl)-N-methylmethanamine (95);
(1-(3-chloro-4-forfinal)cyclohexyl)-N-methylmethanamine (96);
(1-(3-chloro-4-forfinal)cyclohexyl)-N,N-dimethylethanamine (97);
(1-(4-chloro-3-forfinal)cyclohexyl)-methanamine (98);
(1-(4-chloro-3-forfinal)cyclohexyl)-N,N-dimethylethanamine (99);
N-methyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (100);
N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (101);
N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (104);
N,N-dimethyl-1-(1-(3-(trifluoromethyl)-phenyl)cyclohexyl)-methanamine (105);
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (108);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)piperidine (109);
4-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)morpholine (110);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)pyrrolidin (111);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-4-methylpiperazine (112);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)-2,3-dihydro-1H-inden-2-ol (113);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-3-methylpiperidin (114);
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-2-methylpyrrolidine (115);
2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)Cyclopentanol (116);
2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclohexanol (117);
CIS-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (CIS 121);
TRANS-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (TRANS 121);
CIS-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethane is n (CIS 124);
TRANS-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine (TRANS 124);
CIS-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N,N-dimethylethanamine (CIS 125);
TRANS-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N,N-dimethylethanamine (TRANS 125);
CIS-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexanol (133);
TRANS-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (134);
CIS-2-(4-chloro-3-forfinal)-2-((methylamino)methyl)cyclohexanol (141);
TRANS-2-(4-chloro-3-forfinal)-2-((methylamino)methyl)cyclohexanol (142);
CIS-2-((methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)-cyclohexanol (143);
TRANS-2-((methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)-cyclohexanol (144);
CIS-2-((methylamino)methyl)-2-(4-(triptoreline)phenyl)-cyclohexanol (145);
TRANS-2-((methylamino)methyl)-2-(4-(triptoreline)phenyl)cyclohexanol (146);
CIS-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (147);
TRANS-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (148);
CIS-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (149);
TRANS-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (150);
CIS-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (152);
TRANS-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (153);
CIS-2-(4-chloro-3-forfinal)-2-((dimethylamino)methyl)cyclohexanol (157);
TRANS-2-(4-chloro-3-forfinal)-2-((dimethylamino)methyl)cyclohexanol (158);
CIS-2-{(dimethylamine is)methyl)-2-(4-(trifluoromethyl)phenyl)-cyclohexanol (159);
TRANS-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)-cyclohexanol (160);
CIS-2-((dimethylamino)methyl)-2-(4-(triptoreline)phenyl)-cyclohexanol (161);
TRANS-2-((dimethylamino)methyl)-2-(4-(triptoreline)phenyl)-cyclohexanol (162);
CIS-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (163);
TRANS-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (164);
CIS-4A-(3,4-dichlorophenyl)-3-methyloctadecane-2H-benzo[e][1,3]oxazin (165);
TRANS-4A-(3,4-dichlorophenyl)-3-methyloctadecane-2H-benzo[e][1,3]oxazin (166);
CIS-3-(aminomethyl)-3-(3,4-dichlorophenyl)Cyclopentanol (CIS 167);
TRANS-3-(aminomethyl)-3-(3,4-dichlorophenyl)Cyclopentanol (TRANS 167);
(2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)cyclohexyl)methanol (169);
CIS-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclohexyl)-methanol (170);
CIS-(2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexyl)-methanol (172);
CIS-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)-methanol (173);
CIS-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methanimidamide (174);
CIS-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylethanamine (175);
CIS-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanamine (176);
CIS-N-((1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methyl)ethanamine (177);
3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (182);
CIS-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (184);
TRANS-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (185); 3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (186);
CIS-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (187);
TRANS-3-[3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (188);
3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (189);
CIS-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (190);
TRANS-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (191);
CIS-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine (192);
3-aminomethyl-3-(3,4-dichlorophenyl)-1-methyl-cyclohexanol (193);
CIS-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine (194);
TRANS-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine (195);
CIS-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-methylmethanamine (196);
CIS-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-dimethylethanamine (197);
CIS-3-(3,4-dichlorophenyl)-1-methyl-3-((methylamino)methyl)cyclohexanol (198);
CIS-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-1-methylcyclohexanol (199);
CIS-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-methylmethanamine (200);
CIS-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-dimethylethanamine (201);
CIS-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (202);
CIS-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (203);
(1-(3,4-dichlorophenyl)-3,3-diverticulosis)-methanamine (204);
1-(1-(3,4-dichlorophenyl)-3,3-diverticulosis)-N-methylmethanamine (205);
1-(1-(3,4-dichlorophenyl)-3,3-diverticles the KSIL)N,N-dimethylethanamine (206);
4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (207);
4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (208);
4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)diclohexal (209);
4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (210);
(4-chloro-1-(naphthalen-2-yl)cyclohexyl)methanamine (211);
(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (212);
(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (213);
4-(aminomethyl)-1-(permitil)-4-(naphthalen-2-yl)cyclohexanol (217);
4-(aminomethyl)-1-(permitil)-4-(naphthalen-2-yl)cyclohexanol (218);
4-(aminomethyl)-1-methyl-4-(4-(triptoreline)phenyl)-cyclohexanol (219);
4-(aminomethyl)-4-(4-(triptoreline)phenyl)cyclohexanol (220);
(4,4-debtor-1-(naphthalen-2-yl)cyclohexyl)methanamine (221);
1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-yl)-cyclohexanol (222);
1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (223);
4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (224);
4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (225);
4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (226);
4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (227);
4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (228);
4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (229);
1-(4-chloro-1-(naphthalen-2-yl)cyclohexyl)-N,N-dimethylethanamine (230);
1-methyl-4-(1-(methylamino)ethyl)-4-(naphthalen-2-yl)cyclohexanol (231);
1-(4-fluoro-1-(naphthalen-2-yl)shall illogical)-N-methylmethanamine (232);
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-dimethylethanamine (233);
4-(1-(dimethylamino)ethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (234);
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-dimethylethanamine (235);
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine (236);
1-(permitil)-4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (243);
4-((dimethylamino)methyl)-1-(permitil)-4-(naphthalen-2-yl)cyclohexanol (244);
1-(permitil)-4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (245);
4-((dimethylamino)methyl)-1-(permitil)-4-(naphthalen-2-yl)cyclohexanol (246);
1-methyl-4-((methylamino)methyl)-4-(4-(triptoreline)phenyl)cyclohexanol (247);
4-((dimethylamino)methyl)-1-methyl-4-(4-(triptoreline)phenyl)cyclohexanol (248);
4-((methylamino)methyl)-4-(4-(triptoreline)phenyl)cyclohexanol (249);
4-((dimethylamino)methyl)-4-(4-(triptoreline)phenyl)cyclohexanol (250);
1-(4,4-debtor-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine (251);
1-(4,4-debtor-1-(naphthalen-2-yl)cyclohexyl)-N,N-dimethylethanamine (252);
(1-(3,4-dichlorophenyl)-4-forcelogix)methanamine (253);
1-(1-(3,4-dichlorophenyl)-4-forcelogix)-N,N-dimethylethanamine (254);
(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (255);
1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-dimethylethanamine (256);
(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (257);
1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-dimethylethanamine (258);
1-(1-(34-dichlorophenyl)-4-methoxycyclohexyl)-N-methylmethanamine (259);
(1-(3,4-dichlorophenyl)-4-forcelogix)methanamine (260);
1-(1-(3,4-dichlorophenyl)-4-forcelogix)-N,N-dimethylethanamine (261);
4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (262);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (263);
1-(1-(3,4-dichlorophenyl)-4-forcelogix)-N-methylmethanamine (264);
(1-(3,4-dichlorophenyl)-4-phenoxytoluene)methanamine (265);
1-(1-(3,4-dichlorophenyl)-4-phenoxytoluene)-N,N-dimethylethanamine (266);
(1-(3,4-dichlorophenyl)-4,4-diverticulosis)methanamine (267);
1-(1-(3,4-dichlorophenyl)-4,4-diverticulosis)-N-methylmethanamine (268);
1-(1-(3,4-dichlorophenyl)-4,4-diverticulosis)-N,N-dimethylethanamine (269);
1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]Decan-8-yl)-N-methylmethanamine (270);
1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]Decan-8-yl)-N,N-dimethylethanamine (271);
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (272);
4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol (273);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol (274);
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (275);
4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol (276);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol (277);
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexane (278);
4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol (279);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexane (280); 4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexane (281);
4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol (282);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexane (283);
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-propylcyclohexane (284);
4-(3,4-dichlorophenyl)-4-((methylamino)methyl)-1-propylcyclohexane (285);
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-propylcyclohexane (286);
CIS-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol (287);
(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (288);
TRANS-4-(aminomethyl)-4-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclo-hexanamine (290);
2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidin(296); or
2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidin (297);
or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form.

18. The compound according to claim 1, where the connection is a

or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form.

19. The compound according to claim 1, where the connection is a

or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form.

0. The compound according to any one of claims 1 to 19, where the compound is chiral.

21. Connection claim 20, where the compound is enantiomerically pure.

22. Connection claim 20, where the compound is enantiomerically enriched.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, for inhibiting the activity of at least one conveyor monoamine, such as the serotonin Transporter, the Transporter dopamine or norepinephrine Transporter, or a combination of two or more conveyors.

24. A method of inhibiting the activity of at least one conveyor monoamine, such as the serotonin Transporter, the Transporter dopamine or norepinephrine Transporter, or a combination of two or more conveyors, comprising contacting the specified conveyor monoamine and connection according to claim 1.

25. A method of treating disorders of the Central nervous system associated with activity of at least one conveyor monoamine, such as the serotonin Transporter, the Transporter dopamine or norepinephrine Transporter, where the specified disorder of the Central nervous system is a depression, impaired cognitive abilities, fibromyalgia, pain, sleep disorder, a disorder associated with attention deficit ADD), disorder attention deficit/hyperactivity disorder (ADHD), tired leg syndrome, schizophrenia, anxiety, obsessive-complusive disorder, post-traumatic stress disorder, premenstrual restlessness and neurodegenerative disease, comprising the administration to a subject in need, a therapeutically effective amount of a compound according to claim 1.

26. The method according A.25 in which the specified disorder of the Central nervous system is a neuropathic pain.

27. The method according A.25 in which the specified disorder of the Central nervous system represents fibromyalgia.

28. The method according A.25 in which the specified disorder of the Central nervous system is a major depressive disorder, unipolar depression, bipolar disorder, seasonal affective disorder (SAD) and dysthymia.

29. The method according A.25 in which the specified disorder of the Central nervous system represents Parkinson's disease.

30. The method according A.25 in which the specified disorder of the Central nervous system is a syndrome of sleep apnea.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

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

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

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

20 cl, 5 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

32 cl, 1 tbl, 132 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

The invention relates to new substituted benzo/a/acridinium formula (II), where R1and R2are independently IT, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R1and R2together represent-OCH2O-; R3represents H; R5and R6are independently H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R5and R6together represent-co2O-; R7represents H or (C1-C8)alkyl, or R1, R2, R3, R5, R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R1and R2together represent-OCH2O-; R2and R3together represent-co2O-; R5and R6together represent-OCH2O-; R7represents H or (C1-C8)alkyl, provided that one of R1and R2is (C1-C8)alkoxy, or R1and R2together represent-co2O-, or R1, R5and R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R2

FIELD: chemistry.

SUBSTANCE: present invention relates to novel dibenzosuberone derivatives of formula , where R1 and R2 each independently represent hydrogen or halogen. These compounds are used for treating and/or preventing diseases related to CB1 receptor modulation. The invention also relates to a pharmaceutical composition based on these compounds.

EFFECT: obtaining novel dibenzosuberone derivatives.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: chemistry; medicine.

SUBSTANCE: in novel spiropentacyclic compounds of formula (I) R1 and R2 collectively with nitrogen atom, to which they are bound, form 6-member monocyclic saturated heterocyclic ring, which can optionally contain 1 additional O or N; R3 represents hydrogen, halogen or lower alkyl; R4 and R5 each independently represents halogen; and X represents -C(O)- or -SO2-; or their pharmaceutically acceptable salts, intended for application as therapeutically active substances for treatiment and/or prevention of diseases connected with modulation of CB1 receptors and also pharmaceutical composition based on said compounds.

EFFECT: novel compounds possess useful biological properties.

12 cl, 1 tbl, 6 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

The invention relates to new derivatives of thiourea, and containing antimicrobial agent against Helicobacter pylori and anti-ulcer agent

FIELD: chemistry.

SUBSTANCE: described are heterobicyclic derivatives of formula (I)

, in which V denotes -C(R7)-; W denotes a single bond or -C(R8R9)-; X denotes O, S, SO, SO2 or N(R10); Y denotes -C(R11R12)-, -C(R11R12)C(R13R14)C(R11R12)C(R13R14)C(R15R16)-, -C(R11R12)C(R13R14)C(R15R16)C(R17R18)- or- C(R11)=C(R12)-; R1, R2, R3, R4 and R5 independently denote hydrogen, halogen, (lower)alkyl, fluoro(lower)alkyl, (lower)alkoxy group, fluoro(lower)alkoxy group, NH2-C(O); R6 denotes a phenyl, pyridyl, pyrazolyl or thiazolyl group, where the group is optionally substituted with 1-4 substitutes selected from a group consisting of halogen, cyano group, (lower)alkyl, (lower)alkoxy group, COOH, 1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl, where (lower)alkyl is optionally substituted with COOH. A pharmaceutical composition is also described.

EFFECT: said compounds inhibit L-CPT1 and can be used as medicinal agents.

27 cl, 120 ex

FIELD: organic chemistry, luminophores.

SUBSTANCE: invention relates to colorless at daylight organic luminophores, in particular, to novel, water-soluble, colorless luminophores A of the formula:

wherein X means oxygen (O) or sulfur (S) atom; Q means compounds of the formulas and wherein R1 and R2 taken separately or in common mean compounds of the formulas: -NHCH2COOM, -N(CH2COOM)2, Cl wherein M means Na, K, NH4. As comparing with the known colorless organic luminophores - optical whitening agents possessing with blue-sky blue fluorescence only, novel luminophores show fluorescence in the range from blue to yellow-orange color and can be used as components of fluorescent, colorless at daylight, inks for jet printers or stamp dyes.

EFFECT: improved and valuable properties of luminophores.

14 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new individual compounds of benzoxazine class and to a method for their preparing. Invention describes 2-aroylmethylene-2,4-dihydro-1H-3,1-benzoxazine-4-ones of the formula (I): wherein R means hydrogen atom (H) (a), -CH3 (b), -OCH3 (c), -OC2H5 (d), chlorine atom (Cl) (e) eliciting fluorescent properties and stable in UV-light. Also, invention a method for preparing abovementioned compounds. Proposed compounds elicit fluorescent properties and can be used as the parent substances for synthesis of new heterocyclic systems.

EFFECT: improved preparing method, valuable properties of compounds.

4 cl, 6 ex

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