Novel oxabispidinic compounds and use thereof in treating cardiac arrhythmia

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

where R1represents a C1-12alkyl (and this alkyl group substituted by a group selected from phenyl, Het1N(R5aR6, -OR5c, -S(O)2N(R9bR9cand-N(R9b)S(O)2R9d)
R5arepresents H;
R5crepresents a C1-6alkyl (which is substituted by phenyl or phenyl;
R6represents H or-C(O)OR10b;
R10brepresents a alkyl;
R9bin each case the description of the invention represents N or C1-6alkyl;
R9cand R9din each case the description of the invention independently represent a1-6alkyl (possibly substituted by one or more substituents selected from halogen and phenyl), phenyl or Het7or R9crepresents H;
R2represents H or or13;
R3represents H;
R13represents H;
Het1and Het7independently represent a five-dvenadcatiletnie heterocyclic group containing one or more than one heteroatom selected from oxygen and nitrogen, and these groups possibly substituted by one or more substituents selected from halogeno and C1-6of alkyl;
Rather it represents a direct link, -J-, J-S(O)2N(R19b)- or-J-N(R19c)S(O)2-(the latter two groups-J is attached to the nitrogen oxybisethanol ring);
Represents a Z-{[(O)]aC(N)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (in the last six groups, Z is attached to the carbon atom bearing R2and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z -, or-N(R20h)C(O)O-Z- (in which Poslednij four groups, Z is attached to the phenyl group, which is possibly substituted by a group R4);
J represents a C1-6alkylen, possibly interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2and/or possibly substituted by the Deputy selected from-HE;
Z represents a direct bond or C1-4alkylen, possibly interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-;
a, b and C independently represent 0 or 1;
n represents 0, 1 or 2;
R19b-R19ein each case the description of the invention independently represent N or C1-6alkyl;
R20arepresents H or, together with one substituent R4position of the phenyl group, which orthopantogram position, which joined the group In, is a2-4alkylen possibly interrupted or terminated O, N(H) or a group N(C1-6alkyl);
R20brepresents N or C1-6alkyl;
R20c-R20jin each case the description of the invention independently represent N or C1-6alkyl; or R20gand R20iindependently represents a C1-6alkyl, substituted 3,5-dimethylisoxazole;
G represents CH;
R4represents one or more than one possible substitute selected from cyano, halogeno, With1-4the alkyl and C1-6alkoxy, possibly substituted by one or more halogen,
and the substituent R4position of the phenyl group, which orthopantogram position, which joined the group In may with R20ato be a2-4alkylen, interrupted or terminated On or N(H) or a group N(C1-6alkyl);
R41-R46independently represent H;
where each phenyl group possibly substituted by one or more substituents selected from halogeno, cyano, C1-6the alkyl and C1-6alkoxy (which latter two groups possibly substituted by one or more halogen atoms);
provided that
(a) is at least one of the following:
(1) R1represents a C1-12alkyl (and this alkyl group substituted by a group-S(O)2N(R9bR9cand/or-N(R9b)S(O)2R9d);
(2) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2,
(3) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
(4) represents-Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -N(R20f)S(O)2-Z -, or-S(O)2N(R20g)-Z-, and/or
(5) Z is interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-;
(b) when a represents-J-N(R19c)S(O)2-then
(1) J is the I 1alkylene or 1,1-C2-6alkylene; and
(2) does not represent-N(R20b)-, -N(R20c)S(O)2-, -S(O)n-, -O-, -N(R20f)S(O)2-Z -, or-N(R20h)C(O)O-Z-; and
(C) when R2represents-OR13then
(1) represents-J-N(R19c)S(O)2-; and
(2) does not represent-N(R20b)-, -N(R20c)S(O)2-, -S(O)n-, -O-, -N(R20f)S(O)2-Z -, or-N(R20h)C(O)O-Z-;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents a C1-8alkyl (and this alkyl group substituted by a group selected from a phenyl (which is possibly substituted by one or more substituents selected from halogeno, cyano, C1-4of alkyl, C1-4alkoxy (which latter two groups are substituted by one or more halogen atoms), Het1, -N(R5aR6, -OR5c, -S(O)2N(R9bR9cand-N(H)S(O)2R9d).

3. The compound according to claim 1, where R5srepresents a C1-6alkyl (which is replaced by a possibly substituted phenyl or phenyl (which is possibly substituted by one or more substituents selected from halogeno, cyano, C1-5the alkyl and C1-5alkoxy (which latter two groups possibly substituted by one or more halogen atoms).

4. The compound according to claim 1, where R10brepresents a C1-5alkyl.

5. The connection p is 1, where R9brepresents N or C1-3alkyl.

6. The compound according to claim 1, where R9cand R9din each case the description of the invention independently represent a1-5alkyl (possibly substituted by one or more substituents selected from halogeno and possibly substituted phenyl), possibly substituted phenyl or Het7or R9crepresents N.

7. The compound according to claim 1 where Het1and Het7independently represent four-desyatiletnie heterocyclic group containing one to two heteroatoms selected from oxygen and nitrogen, and these groups possibly substituted by one or more substituents selected from halogeno and C1-4the alkyl.

8. The compound according to claim 1, where a represents a C1-4alkylen, possibly substituted by a Deputy selected from HE group-C1-3-n-alkylen-S(O)2N(H)- or-C2-3-n-alkylene-N(H)S(O)2- (the latter two groups alkylene attached to the nitrogen oxybisethanol ring).

9. The compound according to claim 1, where In represents-Z-, -Z-N(H)-, -Z-C(O)N(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)2-, -Z-O- (in the last six groups, Z is attached to the carbon atom bearing R2and R3).

10. The compound according to claim 1, where Z represents a direct bond or C1-4alkylen

11. The compound according to claim 1, where R20brepresents N or C1-4alkyl.

12. The compound according to claim 1, where R20cand R20dindependently represent N or C1-3alkyl.

13. The compound according to claim 1, where R4represents one or more than one Deputy, selected from cyano, halogeno.

14. The compound according to claim 1, where the alkyl groups and the alkoxy group may, unless otherwise specified,
(1) to have a straight or branched chain;
(2) be rich; and/or
(3) to be substituted by one or more fluorine atoms.

15. The compound according to claim 1, which represents the
(1) N-(2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)propane-2-sulfonamide;
(2) N-(2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-phenylmethanesulfonyl;
(3) N-(tert-butyl)-3-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propane-1-sulfonamide;
(4) tert-butyl{2-[7-(2-{[(4-forfinal)sulfonyl]amino}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl)carbamate;
(5) N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-4-forbindelsesfaneblad;
(6) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-phenylmethanesulfonyl;
(7) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1 ]non-3-yl}ethyl)propane-2-sulfonamide;
(8) N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-4-tzia is benzosulfimide;
(9) N-[2-(7-{2-[3,4-bis(deformedarse)phenyl]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-4-cyanobenzenesulfonyl;
(10) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(11) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,4-diftorbenzofenonom;
(12) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-forbindelsesfaneblad;
(13) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;
(14) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-forbindelsesfaneblad;
(15) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;
(16) 4-cyano-N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(17) 1-(3-chlorophenyl)-N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1 ]non-3-yl}ethyl)methanesulfonamide;
(18) 4-cyano-N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(19) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1,1,1-triftormetilfullerenov;
(20) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-phenylmethanesulfonyl;
(21) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-methyl-1H-imidazole-4-sulfonamide;
(22) N-(2-{7-[3-(4-cianfrocca)propyl]-9-OK the-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl) - butane-1-sulfonamide;
(23) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-methyl-1H-imidazole-4-sulfonamide;
(24) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-[4-(trifluoromethyl)phenyl]methanesulfonamide;
(25) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl) - for 3,5-dimethylisoxazol-4-sulfonamide;
(26) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-[4-(trifluoromethyl)phenyl]-methanesulfonamide;
(27) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl) - for 3,5-dimethylisoxazol-4-sulfonamide;
(28) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2-(triptoreline)benzosulfimide;
(29) 1-(3-chlorophenyl)-N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)methanesulfonamide;
(30) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(31) 4-cyano-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(32) 4-cyano-N-{2-[7-(4-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(33) 4-cyano-N-(2-{7-[4-(deformedarse)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(34) 4-cyano-N-(2-{7-[2-(4-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(35) 4-cyano-N-(2-{7-[2-(4-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide is;
(36) 4-cyano-N - (2-{7-[3-(4-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(37) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,3-dihydro-1-benzofuran-5-sulfonamide;
(38) 5-chloro-N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1,3-dimethyl-1 H-pyrazole-4-sulfonamide;
(39) 2-cyano-N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(40) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-methoxybenzenesulfonamide;
(41) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,3-dihydro-1-benzofuran-5-sulfonamide;
(42) 5-chloro-N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide;
(43) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-methoxybenzenesulfonamide;
(44) 4-cyano-N-(2-{7-[3-(2-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(45) 4-cyano-N-(2-{7-[3-(2,5-divergence)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(46) 4-cyano-N-(2-{7-[3-(3,4-divergence)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(47) 4-cyano-N-(2-{7-[2-(2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(48) 4-cyano-N-(2-(7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}the Teal)benzosulfimide;
(49) 4-cyano-N-[2-(7-{2-[(4-terbisil)oxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]benzosulfimide;
(50) 4-cyano-N-(2-{7-[2-(3,4-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(51) 4-cyano-N-(2-{7-[2-(3,5-dimethyl-1H-pyrazole-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(52) 4-cyano-N-{2-[7-(2-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(53) 4-cyano-N-(2-{7-[(3,5-dimethylisoxazol-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(54) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3,3 .1]non-3-yl}ethyl)-3-forbindelsesfaneblad;
(55) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-3-forbindelsesfaneblad;
(56) N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-5-methylisoxazol-4-sulfonamide;
(57) N-{2-[7-(1-benzofuran-3-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-4-cyanobenzenesulfonyl;
(58) 4-cyano-N-{2-[7-(1H-indol-3-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(59) 4-cyano-N-(2-{7-[(1-methyl-1H-indol-3-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(60) 4-cyano-N-(2-{7-[(5-fluoro-1H-indol-3-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(61) N-(3-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-4-forbindelsesfaneblad;
(62) N-(3-{7-[2-(4-cyanobenzoate]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-2,4-diftorbenzofenonom;
(63) N-(3-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(64) 14-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-1-phenylmethanesulfonyl;
(65) N-(3-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-1-phenylmethanesulfonyl;
(66) N-(3-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(67) 4-cyano-N-(2-{7-[(2-methyl-1H-indol-3-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(68) 4-cyano-N-(2-{7-[2-(3-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(69) 4-cyano-N-(2-{7-[3-(3-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(70) 4-cyano-N-(2-{7-[3-(4-cyano-2-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(71) 4-cyano-N-(2-{7-[3-(4-cyano-2,6-divergence)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(72) 4-cyano-N-(2-{7-[2-(2,6-divergence)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(73) N-(3-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)propane-2-sulfonamide;
(74) N-(3-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-1-phenylmethanesulfonyl;
(75) N-(3-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)for 3,5-dimethylisoxazol-4-sulfonamide;
(76) N-(3-{7-[2-(4-cianfrocca)this is l]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)for 3,5-dimethylisoxazol-4-sulfonamide;
(77) N-{3-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl} - for 3,5-dimethylisoxazol-4-sulfonamide;
(78) N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl} - for 3,5-dimethylisoxazol-4-sulfonamide;
(79) N-{2-[7-(1,3-benzoxazol-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-4-cyanobenzenesulfonyl;
(80) 3-cyano-N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(81) 3-cyano-N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(82) 3-cyano-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(83) 2-cyano-N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(84) 2-cyano-N-(2-{7-[3-(4-cianfrocca)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(85) N-(4-cyanobenzyl)-2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]econsultant;
(86) N-(4-cyanobenzyl)-2-[7-(2-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]econsultant;
(87) N-(4-cyanobenzyl)-N-[(3,5-dimethylisoxazol-4-yl)methyl]-2-{7-[(3,5-dimethylisoxazol-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}econsultant;
(88) 4-cyano-N-(3-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(89) N-(3-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-4-forbindelsesfaneblad;
(90) N-(3-{7-[2-(4-tzia is openvxi)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-2-forbindelsesfaneblad;
(91) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2-forbindelsesfaneblad;
(92) N-(3-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-2,4-diftorbenzofenonom;
(93) N-(3-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(94) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-forbindelsesfaneblad;
(95) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-3-forbindelsesfaneblad;
(96) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl) - for 3,5-dimethylisoxazol-4-sulfonamide;
(97) 3-cyano-N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(98) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(99) N-(2-{7-[2-(4-chlorophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-cyanobenzenesulfonyl;
(100) 4-cyano-N-[2-(7-{2-[4-(trifluoromethyl)phenyl]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]benzosulfimide;
(101) 4-cyano-N-(2-{7-[2-(2,6-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(102) 4-cyano-N-(2-{7-[2-(2-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(103) 4-cyano-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(104) 4-cyano-N-{2-[7-(4-qi is mobinil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-methylbenzenesulfonamide;
(105) N-[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-4-cyano-N-methylbenzenesulfonamide;
(106) 4-cyano-N-{2-[7-(4-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-N-methylbenzenesulfonamide;
(107) 4-cyano-N-methyl-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(108) 4-cyano-N-(2-{7-[2-(3-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(109) 4-cyano-N-(2-{7-[2-(2-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(110) N-(4-cyanobenzyl)-2-{7-[(3,5-dimethylisoxazol-4-yl)methyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}econsultant;
(111) N-(4-cyanobenzyl)-2-{7-[2-(4-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}econsultant;
(112) N-(4-cyanobenzyl)-2-{7-[2-(3-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}econsultant;
(113) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N,3,5-trimethylsilanol-4-sulfonamide;
(114) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-1-phenylmethanesulfonyl;
(115) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,3-dihydro-1-benzofuran-5-sulfonamide;
(116) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,4-diftorbenzofenonom;
(117) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,4-diftorbenzofenonom;
(118) N-{2-[7-(cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-4-forbindelsesfaneblad;
(119) 4-fluoro-N-{2-[7-(4-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(120) N-(2-{7-[2-(4-cyanophenyl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-forbindelsesfaneblad;
(121) 4-fluoro-N-(2-{7-[2-(4-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(122) 4-cyano-N-[2-(7-{2-[4-(deformedarse)phenyl]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]benzosulfimide;
(123) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-2,4-debtor-N-methylbenzenesulfonamide;
(124) 4-cyano-N-(2-{7-[2-(2,6-divergence)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(125) 4-cyano-N-(2-{7-[2-(2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(126) N-(2-{7-[2-(1,2-benzisoxazol-3-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-4-cyanobenzenesulfonyl;
(127) N-(3-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)-N-methylbenzenesulfonamide;
(128) N-(2-{7-[2-(4-cyano-2-pertenece)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methyl-2,3-dihydro-1-benzofuran-5-sulfonamide;
(129) N-(2-{7-[2-(4-cianfrocca)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methyl-2,3-dihydro-1-benzofuran-5-sulfonamide;
(130) 4-cyano-N-{2-[7-(4-cyano-2-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(131) 4-cyano-N-{2-[7-(4-cyano-2-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-the l]ethyl}-N-methylbenzenesulfonamide;
(132) 4-cyano-N-[2-(7-{2-[4-(deformedarse)phenyl]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-N-methylbenzenesulfonamide;
(133) 4-fluoro-N-(2-{7-[2-(3-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(134) 4-fluoro-N-(2-{7-[2-(2-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(135) 4-fluoro-N-{2-[7-(2-phenylethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzosulfimide;
(136) N-{2-[7-(1,2-benzisoxazol-3-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}-4-cyanobenzenesulfonyl;
(137) 4-cyano-N-(2-{7-[2-(4-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(138) 4-cyano-N-(2-{7-[2-(3,4-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(139) 4-cyano-N-{3-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}benzosulfimide;
(140) 4-cyano-N-{3-[7-(4-terbisil)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}benzosulfimide;
(141) 4-cyano-N-(3-{7-[2-(4-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(142) 4-cyano-N-(3-{7-[2-(3-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(143) 4-cyano-N-(3-{7-[2-(2-forfinal)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(144) 4-cyano-N-(3-{7-[2-(2,6-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(145) 4-cyano-N-(3-{7-[2-(3,4-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(146) N-[3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]-4-cyanobenzenesulfonyl;
(147) 4-cyano-N-(3-{7-[3-(4-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(148) 4-cyano-N-(3-{7-[2-(2,6-divergence)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)benzosulfimide;
(149) 4-cyano-N-(2-{7-[3-(4-pertenece)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(150) 4-cyano-N-(2-{7-[3-(2,4-divergence)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
(151) 4-cyano-N-(2-{7-[2-(2,4-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(152) 4-cyano-N-(2-{7-[3-(2,4-divergence)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzosulfimide;
(153) N-(2-{7-[2-(4-chlorophenyl)ethyl]-9-oxa-3,7-diazabicyclo [3.3.1]non-3-yl}ethyl)-4-cyano-N-methylbenzenesulfonamide; or
(154) 4-cyano-N-(2-{7-[2-(2,4-differenl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-N-methylbenzenesulfonamide;
or its pharmaceutically acceptable salt.

16. Connection tert-butyl ether (2-{7-[2-(4-cyano-2-pertenece)-ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-carbamino acid.

17. Pharmaceutical composition having activity of blockers of HERG channels containing the compound as defined in any one of claims 1 to 15, in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

18 the Method of obtaining the compounds of formula I, as defined in claim 1, including the interaction of the compounds of formula II,

where R2, R3, R4, R41-R46, A, b and G are such as defined in claim 1, with a compound of formula III,

where L1represents a leaving group; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

19. The method of obtaining the compounds of formula I according to claim 1, where R1represents a C1-12alkyl, substituted Deputy, as defined in claim 1 in respect of R1and the Deputy is a/includes a group-N(R9b)S(O)2R9dthat includes the interaction of the compounds of formula IV

where R1arepresents a C1-12alkylen, replaced by Deputy, as defined in claim 1 in respect of R1and R2, R3, R4, R41-R46And, and G are, as defined in paragraph 1, with a compound of formula V

where L2represents a leaving group;
and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

20. The method of obtaining the compounds of formula I according to claim 1, where R1 represents a C1-12alkyl, substituted Deputy, as defined in claim 1 in respect of R1and the Deputy is a/includes a group-S(O)2N(R9bR9cthat includes the interaction of the compounds of formula II, as defined in paragraph 18, with a compound of formula VA

where L1represents a leaving group, R1arepresents a C1-12alkylen, replaced by Deputy, as defined in claim 1 in respect of R1and R9band R9csuch as defined in claim 1; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

21. The method of obtaining the compounds of formula I according to claim 1, including the interaction of the compounds of formula IX

where R1and R41-R46such as defined in claim 1, with a compound of formula X,

where L3represents a leaving group, and R2, R3, R4, A, b and G are such as defined in claim 1; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

22. The method of obtaining the compounds of formula I according to claim 1, where a represents CH2and R2not only is em a HE, including the interaction of the compounds of formula IX, as defined in item 21, with the compound of the formula XI

where Y is Oh, and R3, R4In and G such as defined in claim 1; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

23. The method of obtaining the compounds of formula I according to claim 1, where In represents-Z-O-, including the interaction of the compounds of formula XII

where R1, R2, R3, R41-R46And Z are such as defined in claim 1, with a compound of formula XIII

where R4and G such as defined in claim 1; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

24. The method of obtaining the compounds of formula I according to claim 1, where R2represents H or HE, and R3represents H, including the restoration of the compounds of formula I, where R2and R3together represent = O; and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

25. The method of obtaining the compounds of formula I according to claim 1, where R1before the hat is 1-12alkyl, substituted Deputy, as defined in claim 1 in respect of R1that includes the interaction of the compounds of formula II

where R2, R3, R4, R41-R46, A, b and G are such as defined in claim 1,
with the corresponding aldehyde, for example under conditions known to experts in the art (for example, at room temperature, such as 15-30°C) in the presence of a reducing agent (such as cyanoborohydride sodium, triacetoxyborohydride sodium or similar compounds) and an appropriate solvent (such as 1,2-dichloroethane, dichloroethane, methanol, ethanol or mixtures thereof); and may become one substituent R4in another or the addition of one or more (additional) substituents R4in the aromatic ring.

26. The compound of formula II

where R2, R3, R4, R41-R46, A, b and G are such as defined in claim 1, provided that
(1) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2-,
(2) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
(3) represents-Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -N(R20f)S(O)2-Z - or
-S(O)2N(R20g)-Z-, and/or
(4) Z is interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-,
where R19b -R19e, R20c, R20d, R20f, R20g, R20iand R20jsuch as defined in claim 1.

27. The compound of formula IV

where R1arepresents a C1-12alkylen, replaced by Deputy, as defined in claim 1 in respect of R1and R2, R3, R4, R41-R46, A, b and G are such as defined in claim 1, provided that
(1) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2-,
(2) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
(3) represents-Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -N(R20f)S(O)2-Z - or
-S(O)2N(R20g)-Z-, and/or
(4) Z is interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-,
where R19b-R19e, R20c, R20d, R20f, R20g, R20iand R20jsuch as defined in claim 1.

28. The compound of formula VI

where R2, R3, R4, R41-R46, A, b and G are such as defined in claim 1, and L1represents a leaving group, provided that
(1) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2-,
(2) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
(3) represents-Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -N(R20f)S(O)2-Z - or
-S(O)2N(R20g)-Z-, and/or
(4) Z is interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-,
where R19b-R19e, R20c, R20d, R20f, R20g, R20iand R20jsuch as defined in claim 1.

29. The compound of formula IX

where R1and R41-R46such as defined in claim 1, provided that R1represents a C1-12alkyl (and this alkyl group substituted by a group-S(O)2N(R9bR9cor-N(R9b)S(O)2R9d),
where R9b, R9cand R9dsuch as defined in claim 1.

30. The compound of formula XII

where R1, R2, R3, R41-R46And Z are such as defined in claim 1, provided that
(1) R1represents a C1-12alkyl (substituted by a group S(O)2N(R9bR9cor-N(R9b)S(O)2R9d),
(2) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2and/or
(3) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
where R9b-R9dand R19b-R19esuch as defined in claim 1.

31. The compound of formula XVII

where R1, R3, R4, R41-R46, A, b and G are such as defined in claim 1, and E is a bond or C1-4alkylen; when the service is provided what
(1) R1represents a C1-12alkyl (and this alkyl group substituted by a group-S(O)2N(R9bR9cor-N(R9b)S(O)2R9d),
(2) A represents-J-S(O)2N(R19b)- or-J-N(R19c)S(O)2-,
(3) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
(4) represents-Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -N(R20f)S(O)2-Z - or
-S(O)2N(R20g)-Z-, and/or
(5) Z is interrupted by a group-N(R20i)S(O)2- or-S(O)2N(R20j)-,
where R9b-R9d, R19b-R19e, R20c, R20d, R20f, R20g, R20iand R20jsuch as defined in claim 1.

32. The compound of formula XXII

where R1, R20e, R41-R46and J such as defined in claim 1, provided that
(1) R1represents a C1-12alkyl (and this alkyl group substituted by a group-S(O)2N(R9bR9cor-N(R9b)S(O)2R9d), and/or
(2) J is interrupted by a group-S(O)2N(R19d)- or-N(R19e)S(O)2-,
where R9b-R9d, R19dand R19esuch as defined in claim 1.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 3-aminorifampicin-S representing semi-product in synthesis of anzamycine antibiotics, such as rifabutin - an anti-tuberculosis antibiotic with prolonged effect. Invention describes a method for preparing3-aminorifampicin-S that involves interaction of 3-bromorifampicin-S with hexamethylenetetramine in the amount 2-6-fold molar excess of hexamethylenetetramine with respect to 3-bromorifampicin-S at temperature 40-65°C in organic solvent medium and isolation of the end product. Trichloroethylene is used as a solvent in preparing 3-aminorifampicin-S followed by its change for butyl acetate by addition of butyl acetate to reaction mass in the amount 2-5-fold excess with respect to trichloroethylene volume followed by distilling off trichloroethylene. Prepared 3-aminorifampicin-S butyl acetate solution is filtered through aluminum oxide layer and 3-aminorifmapicin-S is isolated by evaporation until dry. Also, invention describes variant of method for preparing 3-aminorifampicin-S. Invention provides reducing reaction time in preparing the end product, reduced cost and simplified reaction, enhanced yield and purity of the end product.

EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: chemistry.

SUBSTANCE: invention relates to a class of sulphur-containing compounds of general formula R1-S(O)n-CH2-CH2-SR2, where n = 1 or 2, when n = 1 R2 = (X=Cl, Br, H2PO4), R1= lower alkyl, substituted or unsubstituted aryl; when n = 2 R2=H, C(O)CH3, SO3Na, (X=Cl, Br, H2PO4) R1=straight or branched C1-C8 alkyl, substituted alkyl; aryl, substituted aryl, with antiarhythmic activity, as well as medicinal agents and pharmaceutical compositions based on said compounds.

EFFECT: proposed compounds in low doses have antiarhythmic activity, have low toxicity and can be used as active substances in medicinal agents for treating and preventing heart rhythm disorder.

11 dwg, 4 cl, 45 ex

FIELD: medicine.

SUBSTANCE: present invention concerns pharmaceuticals, particularly method of reducing risk of drug-caused torsade de pointes, according to which Azimilide and Aspirin and, additionally optionally Statin are introduced to the patient.

EFFECT: reduced risk of torsade de pointes ensured by introduction of specified pharmaceutical combination.

4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there is offered application of glutaric acid derivatives of general formula where R1 = imidazole, indole, R2 = COOH, H, or its pharmaceutically acceptable salt as an antiarrhythmic drug (versions), a medical product, a pharmaceutical composition and method of appropriate prescription. There is presented effectiveness of Nαglutaryl-L-histidine, Nαglutaryl-L-tryptophan in arrhythmia caused by adrenal heart rhythm disorder, in nicotine arrhythmia and acute occlusive myocardium disorder.

EFFECT: effective in arrhythmia.

5 cl, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new benzopyran derivatives of formula (I) whereat X is NR6, R6 is hydrogen atom r C1-4-alkyl group; Y is bond SO, SO2; Z is C1-4-alkyl group (whereat C1-4-alkyl group can be arbitrary substituted with 1-5 atoms of halogen) or phenyl group (whereat phenyl group can be arbitrary substituted with C1-4-alkyl group); W is hydrogen atom, halogen atom, hydroxy group, C1-6-alkoxygroup, C1-4-alkyl group, C1-6-alkyl sulphonylamino group; R1 and R2 independently of each other represent C1-3-alkyl group; R3 is hydrogen atom, hydroxy group or methoxy group; m is integer number from 0 to 4; n is integer number from 0 to 4; V is ordinary bond; R4 is hydrogen or C1-6-alkyl group; and R5 is - hydrogen atom,- C1-6-alkyl group,- C3-8-cycloalkyl group or C3-8-cycloalkenyl group or - C6-14-aryl group (whereat every C6-14-aryl group can be arbitrary substituted with 1-3 R12 whereat R12 is halogen atom) and pharmaceutical composition thereof.

EFFECT: compounds are applicable as antiarrhythmic drug.

27 cl, 60 tbl, 20 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to pharmacology, and concerns an agent having an effect on cardiovascular system. The agent contains acetylsalicylic acid and succinic acid or its pharmaceutically acceptable salt in the ratio, weight parts: 1:20-20:1. The agent can be used for treatment of various forms of coronary heart disease (CHD), acute myocardial infarction, coronary insufficiency, cerebral ischemia, hypoxic stroke.

EFFECT: invention provides extended range of the agents possessing cardioprotective, antiarrhythmic and anti-ischemic action.

2 cl, 5 tbl, 5 ex

FIELD: medicine; cardiology.

SUBSTANCE: preparation of ω-3-polynonsaturated fatty acids "Omacor" is entered for prevention of auricles fibrillation after operation of coronary shunting at patients with ischemic heart disease in a dose of 2 grams a day in the preoperative period not less than 7 days and in the postoperative period not less than 10 days.

EFFECT: effective prevention of auricles fibrillation after coronary shunting.

1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to method of antiarhythmic episode treatment and/or prevention in human, preferentially with conversion of recent onset atrial fibrillation (Afib) or normal sinus rhythm (NSR) flutters in the patients, including step, completely discontinuous or partially continuous introduction of a liquid pharmaceutical composition containing therapeutically effective amount of 3,7-diazabicyclo[3,3,1]nonane derivatives of formula (1)

EFFECT: more effective treatment.

14 cl, 1 dwg, 9 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: medicine; cardiosurgery.

SUBSTANCE: invention relates to medicine, namely to cardiosurgery and can be used in early post-operative period after cardiosurgical operations for prevention of auricle fibrillation. For this purpose after performing main stage of operation at the background of artificial blood circulation two electrodes are sewn to right auricle myocardium. After finishing operation during early post-operative period bipolar electric stimulation is carried out through said electrodes with frequency exceeding spontaneous rhythm frequency on 10 impulses a minute. Simultaneously continuous intravenous infusion of amyodarone (cordarone) solution is performed at rate 5.2 mkg/kg/min.

EFFECT: efficient prevention of auricle fibrillation and development of cardiac insufficiency, caused by sinus tachycardia.

1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

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