SI9600027B - Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them
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Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them
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SI9600027B
SI9600027BSI9600027ASI9600027ASI9600027BSI 9600027 BSI9600027 BSI 9600027BSI 9600027 ASI9600027 ASI 9600027ASI 9600027 ASI9600027 ASI 9600027ASI 9600027 BSI9600027 BSI 9600027B
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Abstract
Basic substd. benzoylguanidine derivs. of formula (I) and their salts are new. One of R1-R3 = Xf-CdH2d-B-A-R6 and the others of R1-R3 = H, F, Cl, Br, I, CN, 1-8C alkyl, 2-8C alkenyl, NR35R36 or Zh-CgH2g-R17; R6 = NR7R8, C(=NR9)NR7R8, NR10-C(=NR9)NR7R8 or basic heteroaromatic ring system with 1-9C; R7-R10 = H or 1-4C alkyl; or R7+R8 = C4H8 or CaH2a (opt. with one CH2 replaced by O, S(O)m or NR11; or R8+R9+R10 or R7+R10 = C2H4 or CcH2c (opt. with one CH2 replaced by O, S(O)m or NR11); A = CbH2b (opt. with one or two CH2 replaced by O, CO, CH(OR20), S(O)m, NR20, CONR20, NHCONR20, SO2NHCONR20, S(=O)(=NR19)NR20 or SO2NR20, or one CH2 replaced by CHR99); R7+R99 form pyrrolidine or piperidine; B = opt. substd. phenylene or naphthylene gp. of formula (i) or (ii); R12, R13 = H, Me, F, Cl, Br, I, CF3 or S(O)mR14; R14, R19 = H or 1-4C alkyl; X = O, CO, CH(OR21), SOm or NR21; R35, R36 = H or 1-6C alkyl; or R35+R36 = (CH2)4-7, with one CH2 opt. replaced by S, NH, NMe or N-benzyl; Z = O, CO, SOm, NR18, CONR18, NHCONR18 or SO2NR18; R17 = H, cyclopropyl, cyclopentyl, cyclohexyl, 1-3C perfluoroalkyl, 1-, 2- or 3-pyrrolyl (opt. substd. by 1-4 of F, Cl, Br, I, CN, 2-8C alkanoyl, 2-8C alkoxycarbonyl, CHO, COOH, CF3, Me and OMe) or 3-8C cycloalkyl or phenyl (both opt. substd. by 1-3 of F, Cl, CF3, Me, OH, OMe, NR37R38, SO2Me and SO2NH2); R11, R18, R20, R21, R37, R38 = H or Me; R4, R5 = H, 1-4C alkyl, F, Cl, OR32, NR33R34 or 1-4C perfluoroalkyl; R32-R34 = H or 1-3C alkyl; a = 5-7; b = 1-10; c = 3-5; d = 0-5; g = 0-4; f, h = 0 or 1; m = 0-2.
Claims (19)
1 PATENTNI ZAHTEVKI 1. Spojine s formulo R(0 R C 2 ) R C 3 )1. Compounds of formula R (0 R C 2) R C 3)o nh2 R(0 kjer pomenijo: eden od treh substituentov R(l), R(2) in R(3) R(6)-A-B-D-; R(6) bazični ostanek, ki se ga da protonirati, t.j. amino skupina -NR(7)R(8), amidino skupina R(7)R(8)N-C[=N-R(9)]- ali gvanidino skupina R(7) R(10)o nh2 R (0 where they represent: one of the three substituents R (1), R (2) and R (3) R (6) -ABD-; R (6) is a protonate base residue, ie an amino group -NR (7) R (8), amidino group R (7) R (8) NC [= NR (9)] - or guanidino group R (7) R (10)R(7), R(8), R(9) in R(10) neodvisno drug od drugega vodik ali alkil z 1, 2, 3 ali 4 C-atomi; ali R(7) in R(8) skupaj C H^; a 4, 5, 6 ali 7; pri čemer je lahko v primeru a = 5, 6 ali 7 ena metilenska skupina skupine CaH2a nadomeščena s heteroatomno skupino O, SOm ali NR(ll), ali R(8) in R(9) ali R(9) in R(10) ali R(7) in R(10) skupino CaH2a; a 2, 3, 4 ali 5; 2 pri čemer je lahko v primeru a = 3,4 ali 5 ena metilenska skupina skupine OH^ nadomeščena z eno heteroatomno skupino O, SOm ali NR(ll); m nič, 1 ali 2; R(ll) vodik ali metil; R(6) bazični heteroaromatski obročni sistem z 1-9 C-atomi; A CbH2b; b 1, 2, 3, 4, 5, 6, 7, 8, 9 ali 10; pri čemer sta lahko v skupini CbH2b ena ali dve metilenski skupini nadomeščeni z eno izmed skupin, izbrano iz skupine, ki sestoji iz -O-, -CO-, -CH[OR(20)]-, -SOm-, -NR(20)-, -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-CO-NH-SO2- (°)ao II [ N R ( 1 9 ) 1 h b m -SOaa[NR(19)]bb- in pri čemer je lahko v skupini CbH2b ena metilenska skupina nadomeščena s -CH-R(99), pri čemer R(99) skupaj z R(7) tvori pirolidinski ali piperidinski obroč; aa 1 ali 2; bb 0 ali 1; aa + bb = 2; R(19) vodik ali alkil z 1, 2, 3 ali 4 C-atomi R(20) vodik ali metil; B fenilenski ali naftilenski ostanek Rf12) R(12)R (7), R (8), R (9) and R (10) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (7) and R (8) together are C H 2; and 4, 5, 6 or 7; wherein in the case of a = 5, 6 or 7 one methylene group of the group CaH2a may be replaced by a heteroatomic group O, SOm or NR (11), or R (8) and R (9) or R (9) and R (10) ) or R (7) and R (10) are a CaH2a group; a 2, 3, 4 or 5; 2 wherein in the case of a = 3,4 or 5 one methylene group of the group OH ^ may be replaced by one heteroatom group O, SOm or NR (11); m is zero, 1 or 2; R (11) is hydrogen or methyl; R (6) is a basic heteroaromatic ring system having 1-9 C atoms; A CbH2b; b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein in the CbH2b group one or two methylene groups may be replaced by one of the groups selected from the group consisting of -O-, -CO-, -CH [OR (20)] -, -SOm-, -NR ( 20) -, -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO2- (°) ao II [NR (19) 1 hbm - SOaa [NR (19)] bb- and wherein in the group CbH2b one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2; bb 0 or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl; B phenylene or naphthylene residue Rf12) R (12)R(13) 3 R(12) in R(13) neodvisno drug od drugega vodik, metil, F, Cl, Br, J, CF3 ali -SOw-R(l4); R(14) metil ali NR(15)R(16); R(15) in R(16) neodvisno drug od drugega vodik ali alkil z 1, 2, 3 ali 4 C-atomi; w nič, 1 ali 2; D -CdH2d-Xf-; d nič, 1, 2, 3 ali 4; X -O-, -C0-, -CH[0R(21)]-, -SOm- ali -NR(21)-; f 1; R(21) vodik ali metil; m nič, 1 ali 2; in vsakokrat drugačni substituenti R(l) in R(2) in R(3) pomenijo neodvisno drug od drugega vodik, F, Cl, Br, J, -CN, -(Cj-Cgj-alkil, -(C2-C8)-alkenil, -NR(35)R(36) ali R(17)-CH2g-Zh-; g nič, 1, 2, 3 ali 4; h nič ali 1; R(35) in R(36) neodvisno drug od drugega vodik ali alkil z 1, 2, 3, 4, 5 ali 6 C-atomi; ali R(35) in R(36) skupaj 4 - 7 metilenskih skupin, od katerih je lahko ena CH2 skupina nadomeščena s kisikom, -S-, -NH-, -NCH3 ali -N-benzilom; Z -O-, -C0-, -SOv, -NR(18)-, -NR(18)-C0-, -NR(18)-CO-NH- ali NR(18)-S02-; R(18) vodik ali metil; v nič, 1 ali 2; R(17) vodik, cikloalkil s 3,5 ali 6 C-atomi ali CkF2k+1+; k 1, 2 ali 3, ali R(17) pirol-l-il, pirol-2-il ali pirol-3-il, kije nesubstituiran ali substituiran z 1 - 4 substituenti, izbranimi iz skupine, ki sestoji iz F, Cl, Br, J, -CN, (C2-Cg)-alkanoila, (C2-Cg)-alkoksikarbonila, formila, karboksi, -CF3, 4 metila in metoksi; ali R(17) -(C3-Cg)-cikloalkil ali fenil kije nesubstituiran ali substituiran z 1 - 3 substituenti, izbranimi iz skupine, ki sestoji iz F in Cl, -CF3, metila, hidroksi, metoksi, -NR(37)R(38), CH3S02- in H2N02S-; R(37) in R(38) vodik ali -CH3; R(4) in R(5) neodvisno drug od drugega vodik, alkil z 1, 2, 3 ali 4 C-atomi, F, Cl, -OR(32), -NR(33)R(34) ali -CF2r+1; R(32), R(33) in R(34) neodvisno drug od drugega vodik ali alkil z 1, 2 ali 3 C-atomi; r 1, 2, 3 ali 4; kot tudi njihove farmakološko prenesljive soli.R (13) 3 R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF3 or -SOw-R (14); R (14) is methyl or NR (15) is R (16); R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; w zero, 1 or 2; D -CdH2d-Xf-; d is zero, 1, 2, 3 or 4; X -O-, -CO-, -CH [OR (21)] -, -SO 2 - or -NR (21) -; f 1; R (21) is hydrogen or methyl; m is zero, 1 or 2; and in each case the different substituents R (1) and R (2) and R (3) independently of one another are hydrogen, F, Cl, Br, J, -CN, - (C 1 -C 8 alkyl, - (C 2 -C 8) -alkenyl, -NR (35) R (36) or R (17) -CH2g-Zh-; g zero, 1, 2, 3 or 4; h zero or 1; R (35) and R (36) independently from the other hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or R (35) and R (36) together 4 to 7 methylene groups, of which one CH2 group may be replaced by oxygen, S-, -NH-, -NCH3 or -N-benzyl, Z -O-, -CO-, -SOv, -NR (18) -, -NR (18) -CO-, -NR (18) -CO -NH- or NR (18) -SO2-, R (18) hydrogen or methyl, zero, 1 or 2, R (17) hydrogen, cycloalkyl having 3,5 or 6 carbon atoms or CkF2k + 1 +; 1, 2 or 3, or R (17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8) -alkanoyl, (C2-C8) -alkoxycarbonyl, formyl, carboxy, -CF3, 4 methyl and methoxy, or R (17) - (C3-C8) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents agents selected from the group consisting of F and Cl, -CF3, methyl, hydroxy, methoxy, -NR (37) R (38), CH3SO2- and H2NO2S-; R (37) and R (38) are hydrogen or -CH3; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF2r +1; R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is 1, 2, 3 or 4; as well as their pharmacologically tolerable salts.2. Spojine s formulo I po zahtevku 1, označene s tem, da v njih pomenijo R(l) vodik, F, Cl, -(C^CJ-alkil, -(C2-C4)-alkenil, -NR(35)R(36) ali R(17)-CH2g-Zh; R(35) in R(36) neodvisno drug od drugega vodik, metil ali etil; ali R(35) in R(36) skupaj 4 - 5 metilenskih skupin, od katerih je lahko ena CH2-skupina nadomeščena s kisikom, -S-, -NH-, ali -NCH3; R(17) vodik, cikloalkil s 5 ali 6 C-atomi ali CfcF2k+1; k 1, 2 ali 3, g nič, 1, 2, 3 ali 4; h nič ali 1; Z -O-, -CO-, -SOv-, -NR(18)-, -NR(l8)-CO-, -NR(18)-CO-NH- ali -NR(18)-S02-; R(18) vodik ali metil; v nič, 1 ali 2; ali, kadar sta g in h enaka nič, R(17) pirol-l-il, pirol-2-il ali pirol-3-il, kije nesubstituiran ali substituiran z 1 - 2 substituentoma, izbranima iz skupine, ki sestoji iz F, Cl, (C2-C5)-alkanoila, 5 (C2-C5)-alkoksikarbonila, formila, karboksi, -CF3, metila in metoksi; ali R(17) -(C3-C8)-cikloalkil ali fenil, ki je nesubstituiran ali substituiran z 1 - 2 substituentoma, izbranima iz skupine, ki sestoji iz F in Cl, -CF3, metila, metoksi, -NR(37)R(38), CH3S02- in H2N02S-; R(37) in R(38) neodvisno drug od drugega vodik ali -CH3; je eden od substituentov R(2) in R(3) R(6)-A-B-D-; R(6) -NR(7)R(8), amidino skupina R(7)R(8)N-C[ = N-R(9)]- ali gvanidino skupina R(7) R ( 1 0 )Compounds of formula I according to Claim 1, characterized in that R (1) is hydrogen, F, Cl, - (C 1 -C 4 -alkyl, - (C 2 -C 4) -alkenyl, -NR (35) R (36) or R (17) -CH2g-Zh, R (35) and R (36) independently of one another are hydrogen, methyl or ethyl, or R (35) and R (36) together are 4-5 methylene groups, of which one CH2 group may be replaced by oxygen, -S-, -NH-, or -NCH3, R (17) is hydrogen, cycloalkyl having 5 or 6 carbon atoms or CfcF2k + 1, k 1, 2 or 3, g zero, 1, 2, 3 or 4, h zero or 1, Z -O-, -CO-, -SOv-, -NR (18) -, -NR (18) -CO-, -NR (18) -CO-NH- or -NR (18) -SO2-, R (18) is hydrogen or methyl, zero, 1 or 2, or, when g and h are zero, R (17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, (C2-C5) -alkanoyl, 5 (C2-C5) -alkoxycarbonyl, formyl, carboxy, -CF3, methyl and methoxy, or R (17) - (C3-C8) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy, -NR (37) R (38), CH3SO2- and H2NO2S-; R (37) and R (38) independently of one another are hydrogen or -CH3; one of the substituents R (2) and R (3) is R (6) -A-B-D-; R (6) -NR (7) R (8), amidino group R (7) R (8) N-C [= N-R (9)] - or guanidino group R (7) R (1 0)R(7), R(8), R(9) in R(10) neodvisno drug od drugega vodik ali alkil z 1, 2, 3 ali 4 C-atomi; ali R(7) in R(8) skupaj CH2a; a 4, 5, 6 ali 7; pri čemer je lahko v primeru a = 5, 6 ali 7 ena metilenska skupina skupine CaH2a nadomeščena s heteroatomno skupino O, SO ali NR(ll); R(ll) vodik ali metil; ali R(8) in R(9) skupaj C H^; a 2, 3, 4 ali 5; pri čemer je lahko v primeru a = 3, 4 ali 5 ena metilenska skupina skupine OH^ nadomeščena s heteroatomno skupino O, SOm ali NR(ll), 6 m nič, 1 ali 2; ali R(6) imidazolil-, piridil-, kinolinil ali izokinolinil; ^ ^b^2b’ b 1, 2, 3, 4 ali 5, pri čemer sta lahko v skupini CbH2b ena ali dve metilenski skupini nadomeščeni z eno od skupin, izbrano iz skupine, ki sestoji iz -O-, -C0-, -CH[OR(20)]-. -SOm-, NR(20), -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-,R (7), R (8), R (9) and R (10) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (7) and R (8) together are CH2a; and 4, 5, 6 or 7; wherein in the case of a = 5, 6 or 7, one methylene group of the group CaH2a may be replaced by a heteroatom group O, SO or NR (11); R (11) is hydrogen or methyl; or R (8) and R (9) together are C H 2; a 2, 3, 4 or 5; wherein in the case of a = 3, 4 or 5 one methylene group of the group OH ^ may be replaced by a heteroatom group O, SOm or NR (11), 6 m zero, 1 or 2; or R (6) is imidazolyl-, pyridyl-, quinolinyl or isoquinolinyl; ^ b b ^ 2b 'b 1, 2, 3, 4 or 5, wherein in the group CbH2b one or two methylene groups may be replaced by one of the groups selected from the group consisting of -O-, -C0-, -CH [OR (20)] -. -SOm-, NR (20), -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO2-,a o - R ( 2 O ) N -S - CNR(19)lbb in-SOaa[NR(19)]bb-; in pri čemer je lahko v skupini CbH2b ena metilenska skupina nadomeščena s -CH-R(99), pri čemer tvori R(99) skupaj z R(7) pirolidinski ali piperidinski obroč; aa 1 ali 2; bb O ali 1; aa + bb = 2; B R(19) vodik ali alkil z 1, 2,3 ali 4 C-atomi R(20) vodik ali metil; fenilenski ali naftilenski ostanek R ( * 2 )a o - R (2 O) N -S - CNR (19) lbb in-SOaa [NR (19)] bb-; and wherein in the CbH2b group one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2; bb O or 1; aa + bb = 2; B R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R (20) is hydrogen or methyl; phenylene or naphthylene residue R (* 2)R(13) R( l 2)R (13) R (l 2)R(12) in R(13) pomenita neodvisno drug od drugega vodik, metil, F, Cl, CF, ali -S02-R(14); 7 R(14) metil ali NR(15)R(16); R(15) in R(16) neodvisno drug od drugega vodik ali alkil z 1, 2, 3 ali 4 C-atomi; d nič, 1, 2, 3 ali 4; X -O-, -CO-, -CH[OR(21)], -SOm- ali -NR(21)-; f i; R(21) vodik ali metil; m nič, 1 ali 2; in pomeni vsakokrat drug ostanek R(2) in R(3) vodik, alkil z 1, 2, 3 ali 4 C-atomi, F, C1 ali CF3; R(4) in R(5) neodvisno drug od drugega vodik, alkil z 1,2 ali 3 C-atomi, F, C1 ali -CF3.R (12) and R (13) are independently hydrogen, methyl, F, Cl, CF, or -SO 2 -R (14); 7 R (14) is methyl or NR (15) R (16); R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; d is zero, 1, 2, 3 or 4; X is -O-, -CO-, -CH [OR (21)], -SO 2 - or -NR (21) -; f i; R (21) is hydrogen or methyl; m is zero, 1 or 2; and in each case the other radical R (2) and R (3) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl or CF3; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl or -CF3.3. Spojine s formulo I po zahtevku 1, označene s tem, da v njih pomenijo: R(l) vodik, F, Cl, alkil z 1, 2, 3 ali 4 C-atomi, -NR(35)R(36) ali R(17)-CH2g-Zh-; g nič, 1, 2, 3 ali 4; h nič ali 1; Z -0-, -CO-, -SOv-, -NR(18)-, -NR(18)-C0-, -NR(18)-CO-NH-, ali -NR(18)-S02-; R(18) vodik ali metil; v nič, 1 ali 2; R(17) vodik, cikloalkil z 5 ali 6 C-atomi ali CF3-; ali kadar sta g in h enaka nič, R(17) pirol-l-il, ki je nesubstituiran ali substituiran z 1 - 2 substituentoma, izbranima iz skupine, ki sestoji iz F, Cl, (C2C.)-alkanoila, (C2-C5)-aIkoksikarbonila, -CF3 in metila; ali R(17) -(C5-C6)-cikloalkil ali fenil, kije nesubstituiran ali substituiran s substituentom, izbranim iz skupine, ki sestoji iz F in Cl, -CF3, metila, CH3S02- in H2N02S-; R(35) in R(36) pomenita neodvisno drug od drugega vodik, metil ali etil; 8 ali R(35) in R(36) skupaj 4 - 5 metilenskih skupin, od katerih je lahko ena CH2 skupina nadomeščena s kisikom, -S-, -NH-, ali -NCH3; eden od substituentov R(2) in R(3) R(6)-A-B-D-; R(6) -NR(7)R(8), amidino skupina R(7)R(8)N-C[ = N-R(9)]- ali gvanidino skupinaCompounds of formula I according to Claim 1, characterized in that they represent: R (1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR (35) R ) or R (17) -CH2g-Zh-; g is zero, 1, 2, 3 or 4; h zero or 1; Z is -O-, -CO-, -SO 2 -, -NR (18) -, -NR (18) -CO-, -NR (18) -CO-NH-, or -NR (18) -SO 2 -; R (18) is hydrogen or methyl; to zero, 1 or 2; R (17) is hydrogen, cycloalkyl having 5 or 6 carbon atoms or CF3-; or when g and h are zero, R (17) is pyrrol-1-yl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, (C2Cl) -alkanoyl, (C2 -C5) -alkoxycarbonyl, -CF3 and methyl; or R (17) - (C5-C6) -cycloalkyl or phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl, -CF3, methyl, CH3SO2- and H2NO2S-; R (35) and R (36) are, independently of one another, hydrogen, methyl or ethyl; 8 or R (35) and R (36) together are 4 - 5 methylene groups, of which one CH2 group may be replaced by oxygen, -S-, -NH-, or -NCH3; one of the substituents R (2) and R (3) R (6) -A-B-D-; R (6) -NR (7) R (8), amidino group R (7) R (8) N-C [= N-R (9)] - or guanidino groupR(7 ) R('°) R(7) vodik ali alkil z 1,2, 3 ali 4 C-atomi; R(8), R(9) in R(10) neodvisno drug od drugega vodik, metil ali etil; ali R(7) in R(8) skupaj C H2a; a 4 ali 5; pri čemer je lahko v primeru a = 5 ena metilenska skupina skupine C nadomeščena z NR(ll), R(ll) vodik ali metil; ali R(6) imidazolil- ali piridil; A b 1,2, 3, 4 ali 5, pri čemer sta lahko v skupini CbH2b ena ali dve metilenski skupini nadomeščeni z eno od skupin, izbrano iz skupine, ki sestoji iz -CO-, -CH[OR(20)]-, -NR(20)-CO-,R (7) R (10) R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (8), R (9) and R (10) independently of one another are hydrogen, methyl or ethyl; or R (7) and R (8) together are C H2a; a 4 or 5; wherein in case a = 5 one methylene group of group C may be replaced by NR (11), R (11) hydrogen or methyl; or R (6) is imidazolyl- or pyridyl; A b 1,2, 3, 4 or 5, where in the group CbH2b one or two methylene groups may be replaced by one of the groups selected from the group consisting of -CO-, -CH [OR (20)] - , -NR (20) -CO-,- R ( 2 0 ) N -S - I! t N R ( 1 9 ) 1bb 9 -S0aa[NR(19)]bbin-S02-; in pri čemer je lahko v skupini C2bH2b ena metilenska skupina nadomeščena s -CH-R(99), pri čemer R(99) skupaj z R(7) tvori pirolidinski ali piperidinski obroč; aa 1 ali 2; bb 0 ali 1; aa + bb = 2; R(19) vodik ali alkil z 1, 2, 3 ali 4 C-atomi R(20) vodik ali metil; ali kadar je b enak 2, 3, 4 ali 5 je lahko en C-atom v CbH2b nadomeščen s skupino -O-, -S-, NR(20)-, -NR(20)-CO- ali -NR(20)-CO-NH-; B fenilenski ostanek R(12)- R (2 0) N -S - I! t N R (19) 1bb 9 -SO0aa [NR (19)] bbin-SO2-; and wherein in the C2bH2b group one methylene group may be replaced by -CH-R (99), wherein R (99) together with R (7) forms a pyrrolidine or piperidine ring; aa 1 or 2; bb 0 or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl; or when b is 2, 3, 4 or 5, one C atom in CbH2b may be replaced by the group -O-, -S-, NR (20) -, -NR (20) -CO- or -NR (20 ) -CO-NH-; B phenylene residue R (12)R(13) R(12) in R(13) neodvisno drug od drugega vodik, metil, F, Cl, CF3 ali -S02R(14); R(14) metil ali NH2; D -CH2-, -O-, -CO-, -SOm- ali -NR(21)-; m nič ali 2; R(21) vodik ali metil; in vsakokrat drug ostanek R(2) in R(3) vodik; R(4) in R(5) neodvisno drug od drugega vodik, alkil z 1, 2 ali 3 C-atomi, F, Cl, ali -CF3.R (13) R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, CF3 or -SO2R (14); R (14) is methyl or NH2; D is -CH2-, -O-, -CO-, -SO2- or -NR (21) -; m zero or 2; R (21) is hydrogen or methyl; and in each case another residue R (2) and R (3) is hydrogen; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, or -CF3.4. Spojine s formulo I po zahtevku 1, označene s tem, da v njih pomenijo: R(l) vodik, F, Cl, alkil z 1,2, 3 ali 4 C-atomi, -NR(35)R(36) aliCompounds of formula I according to Claim 1, characterized in that they represent: R (1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR (35) R ) org nič ali 1; 10 h nič ali 1; Z -O-, -CO-, -NR(18)-CO-, -NR(18)-CO-NH-, ali -NR(18)-SC>2-; R(18) vodik ali metil; ali kadar je g enak 1; pomenijo Z -S02-; R(17) vodik ali CF3-; R(35) in R(36) neodvisno drug od drugega vodik, metil ali etil; ali R(35) in R(36) skupaj 4 - 5 metilenskih skupin od katerih je lahko ena CH2 skupina nadomeščena s kisikom, -S-, -NH-, ali -NCH3; eden od substituentov R(2) in R(3) R(6)-A-B-0-; R(6) -NR(7)R(8) ali gvanidino skupina R ( 7 ) R(10) «to R ( 9 )/N R(7) vodik ali alkil z 1, 2, 3 ali 4 C-atomi; R(8), R(9) in R(10) neodvisno drug od drugega vodik, metil ali etil; ali R(7) in R(8) skupaj C H2a; a 4 ali 5; pri čemer je lahko v primeru a = 5 ena metilenska skupina skupine CH^ nadomeščena z -NH- ali -NCH3-, ali R(6) imidazolil-; A CbH2b; b 1,2, 3 ali 4; pri čemer sta lahko v skupini CbH„b ena ali dve metilenski skupini nadomeščeni z eno od skupin, izbrano iz skupine, ki sestoji iz -CO-, 11g zero or 1; 10 h zero or 1; Z is -O-, -CO-, -NR (18) -CO-, -NR (18) -CO-NH-, or -NR (18) -SCα- 2-; R (18) is hydrogen or methyl; or when g is 1; Z represents -SO2-; R (17) is hydrogen or CF3-; R (35) and R (36) independently of one another are hydrogen, methyl or ethyl; or R (35) and R (36) together are 4 - 5 methylene groups of which one CH2 group may be replaced by oxygen, -S-, -NH-, or -NCH3; one of the substituents R (2) and R (3) R (6) -A-B-O-; R (6) -NR (7) R (8) or guanidino group R (7) R (10) 'to R (9) / N R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (8), R (9) and R (10) independently of one another are hydrogen, methyl or ethyl; or R (7) and R (8) together are C H2a; a 4 or 5; wherein in case a = 5 one methylene group of the group CH 2 may be replaced by -NH- or -NCH 3 -, or R (6) is imidazolyl-; A CbH2b; b 1,2, 3 or 4; wherein in the group CbH 'b one or two methylene groups may be replaced by one of the groups selected from the group consisting of -CO-, 11- R ( 2 Ο ) N -s - II I NR( 1 9 ) ] bb -SOaa[NR(19)]bb- in -S02- in pri čemer je lahko v skupini ena metilenska skupina nadomeščena s -CH-R(99), pri čemer lahko tvori R(99) skupaj z R(7) pirolidinski ali piperidinski obroč; ali kadar je b enak 2,3 ali 4, je lahko ena metilenska skupina skupine CfeH2b nadomeščena s skupino -O-, -S-; aa 1 ali 2; bb O ali 1; aa + bb = 2; R(19) vodik ali alkil z 1, 2, 3 ali 4 C-atomi R(20) vodik ali metil; B fenilenski ostanek, R(t2)- R (2 Ο) N -s - II I NR (19)] bb -SOaa [NR (19)] bb- and -SO2- and wherein in the group one methylene group may be replaced by -CH-R 99), wherein R (99) together with R (7) may form a pyrrolidine or piperidine ring; or when b is 2, 3 or 4, one methylene group of the group CfeH2b may be replaced by a group -O-, -S-; aa 1 or 2; bb O or 1; aa + bb = 2; R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (20) is hydrogen or methyl; B phenylene residue, R (t2)R C1 3) R(12) in R(13) vodik, in vsakokrat drug ostanek R(2) in R(3) vodik; R(4) in R(5) vodik.R C1 3) R (12) and R (13) are hydrogen, and in each case another radical R (2) and R (3) is hydrogen; R (4) and R (5) are hydrogen.5. Spojina s formulo I po zahtevku 1, označena s tem, da je izbrana iz skupine, v kateri so 4-[4-N-(dimetilaminoetil)-metilsulfamoil]fenoksi-3-trifluormetil-benzoil-gvanidin, dihidroklorid; 4-[4-(4-metilpiperazinosulfonil)fenoksi]-3-trifluormetil-benzoilgvanidin, dihidroklorid; 4-[4-(2-pirolidinetilaminosulfonil)fenoksi]-3-trifluormetil-benzoilgvanidin,. dimaleinat; 12 4-[4-(2-piperidinetilaminosulfonil)fenoksi]-3-trifluormetil-benzoilgvanidin, dimaleinat; 4-[4-(N-dimetilamino-n-propil)sulfamoil]fenoksi-3-trifluormetil-benzoilgvanidin; 4-[4-(N-dimetilaminoetil)sulfamoil]fenoksi-3-trifluormetil-benzoilgvanidin; 3- metil-4-(4-(l-metilpiperazin-4-ilsulfonil)fenoksi)-benzoilgvanidin; 4- (4-gvanidinosulfonil)fenoksi-3-trifluormetil-benzoilgvanidin; 4-[4-(2-imidazoliltio-acetil)fenoksi]-3-metilsult'onil-benzoil-gvanidin dihidroklorid; 4-[4-(N,N’-dimetil-S-izotiuronil-acetil)fenoksi]-3-metilsulfonil-benzoilgvanidin dihidroklorid; 4-[4-(2-benzimidazoliltio-acetil)fenoksi]-3-metilsulfonil-benzoilgvanidin dihidroklorid; 4-[4-(2-N-imidazolil-l-hidroksietil)fenoksi]-3-metilsulfonil-benzoilgvanidin dihidroklorid; 4-[4-(N,N-dimetilglicilamino)fenoksi]-3-metilsulfonilbenzoil-gvanidin dihidroklorid; 4-[4-(N,N-dietilaminoetil)aminosulfonilfenoksi]-3-metilsulfonilbenzoil-gvanidin dihidroklorid; 4-[4-(4-imidazoliletil)aminosulfonil-fenoksi]-3-metilsulfonil-benzoil-gvanidin dihidroklorid; 4-[4-(3-N-imidazolil-l-propil)aminosulfonil-fenoksi]-3-metilsulfonilbenzoil-gvanidin dihidroklorid; 4-[4-(l-metil-2-pirolidiniletil)aminosulfonil-fenoksi]-3-metilsulfonilbenzoil-gvanidin dihidroklorid; 4-[4-(N-piperidinoetil)aminosulfonil-fenoksi]-3-metilsulfonil-benzoil-gvanidin dihidroklorid; 4-[4-(2-dimetilaminoetil)sulfonilmetil-fenoksi]-3-metilsulfonilbenzoil-gvanidin dihidroklorid; 4-[4-(2-dimetilaminoetil)sulfonilmetil-fenoksi]-3-trifluormetilbenzoil-gvanidin dihidroklorid. 13A compound of formula I according to claim 1, selected from the group consisting of 4- [4-N- (dimethylaminoethyl) -methylsulfamoyl] phenoxy-3-trifluoromethyl-benzoyl-guanidine, dihydrochloride; 4- [4- (4-Methylpiperazinosulfonyl) phenoxy] -3-trifluoromethyl-benzoylguanidine, dihydrochloride; 4- [4- (2-pyrrolidinetylaminosulfonyl) phenoxy] -3-trifluoromethyl-benzoylguanidine ,. dimaleinate; 12 4- [4- (2-Piperidinetylaminosulfonyl) phenoxy] -3-trifluoromethyl-benzoylguanidine, dimaleate; 4- [4- (N-dimethylamino-n-propyl) sulfamoyl] phenoxy-3-trifluoromethyl-benzoylguanidine; 4- [4- (N-dimethylaminoethyl) sulfamoyl] phenoxy-3-trifluoromethyl-benzoylguanidine; 3-Methyl-4- (4- (1-methylpiperazin-4-ylsulfonyl) phenoxy) -benzoylguanidine; 4- (4-Guanidinosulfonyl) phenoxy-3-trifluoromethyl-benzoylguanidine; 4- [4- (2-Imidazolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoyl-guanidine dihydrochloride; 4- [4- (N, N'-Dimethyl-S-isothiuronyl-acetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; 4- [4- (2-Benzimidazolylthio-acetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; 4- [4- (2-N-Imidazolyl-1-hydroxyethyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; 4- [4- (N, N-Dimethylglycylamino) phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (N, N-Diethylaminoethyl) aminosulfonylphenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (4-Imidazolylethyl) aminosulfonyl-phenoxy] -3-methylsulfonyl-benzoyl-guanidine dihydrochloride; 4- [4- (3-N-Imidazolyl-1-propyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (1-Methyl-2-pyrrolidinylethyl) aminosulfonyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (N-Piperidinoethyl) aminosulfonyl-phenoxy] -3-methylsulfonyl-benzoyl-guanidine dihydrochloride; 4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-methylsulfonylbenzoyl-guanidine dihydrochloride; 4- [4- (2-Dimethylaminoethyl) sulfonylmethyl-phenoxy] -3-trifluoromethylbenzoyl-guanidine dihydrochloride. 136. Postopek za pripravo spojine I po zahtevku 1, označen s tem, da spojino s formulo II R(1)Process for the preparation of compound I according to Claim 1, characterized in that the compound of formula II R (1)kjer imajo R(l) do R(5) podani pomen in stoji L za odhodno skupino, ki se jo da zlahka nukleofilno substituirati, presnovimo z gvanidinom, in v danem primeru prevedemo v farmakološko prenesljivo sol.wherein R (1) to R (5) have the meaning given and L stands for a leaving group which can be easily nucleophilically substituted, reacted with guanidine, and optionally converted to a pharmacologically tolerable salt.7. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje aritmij.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias.8. Uporaba učinkovite količine spojine I po zahtevku 1 skupaj z običajnimi dodatki za pripravo primernih dajalnih oblik za zdravljenje aritmij.Use of an effective amount of Compound I according to claim 1 together with conventional additives for the preparation of suitable dosage forms for the treatment of arrhythmias.9. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje ali profilakso srčnega infarkta.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of a heart attack.10. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje ali profilakso angine pektoris.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina pectoris.11. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje ali profilakso ishemičnih stanj srca.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions.12. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje ali profilakso ishemičnih stanj perifernega in centralnega živčnega sistema in srčne kapi.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and heart attack.13. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje ali profilakso ishemičnih stanj perifernih organov in okončnin. 14Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and extremities. 1414. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje stanj v šoku.Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of shock conditions.15. Uporaba spojine I po zahtevku 1 za pripravo zdravila za uporabo pri kirurških operacijah in transplantacijah organov.Use of a compound I according to claim 1 for the preparation of a medicament for use in surgical operations and organ transplants.16. Uporaba spojine I po zahtevku 1 za pripravo zdravila za konzerviranje in skladiščenje transplantatov za kirurške ukrepe.Use of a compound I according to claim 1 for the preparation of a medicament for the preservation and storage of grafts for surgical measures.17. Uporaba spojine I po zahtevku 1 za pripravo zdravila za zdravljenje bolezni, pri katerih predstavlja proliferacija celic primarni ali sekundarni vzrok in s tem njena uporaba kot antiarterosklerotika, sredstva proti kasnejšim diabetičnim komplikacijam, rakavim obolenjem, fibrotičnim obolenjem, kot pljučni fibrozi, jetrni fibrozi ali ledvični fibrozi, hiperplaziji prostate.Use of a compound I according to Claim 1 for the preparation of a medicament for the treatment of diseases in which cell proliferation is the primary or secondary cause and thus its use as an anti-atherosclerotic, anti-diabetic agent, cancer, fibrotic disease, such as pulmonary fibrosis, liver fibrosis or renal fibrosis, prostate hyperplasia.18. Uporaba spojine I po zahtevku 1 za pripravo znanstvenega orodja za inhibicijo Na+/H+-izmenjevalca za diagnozo hipertonije in proliferativnih obolenj.Use of a compound I according to claim 1 for the preparation of a scientific tool for inhibiting a Na + / H + inverter for the diagnosis of hypertension and proliferative diseases.19. Farmacevtik, ki obsega učinkovito količino spojine I kot je zahtevana v zahtevku 1.A pharmaceutical comprising an effective amount of Compound I as claimed in claim 1.
SI9600027A1995-01-301996-01-29Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them
SI9600027B
(en)
Substituted benzoyl guanidines, process for their preparation, their use as antiarrhythmics or diagnostic agent as well as pharmaceuticals containing them
Sulfonylamino-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them
Novel substituted derivatives of benzoyloguanidine, method of obtaining them, their application in production of pharmaceutic and diagnostic agents and pharmaceutic agent as such
New bis-acylguanidine compounds are subtype-1 cellular sodium ion-proton antiporter inhibitors useful e.g. for treating arrhythmia, angina pectoris, infarction and insulin-independent diabetes mellitus
Pentafluorosulfanylphenyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them
Pentafluorosulfanylphenyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them
2,4-Substituted 5-(N-substituted-sulfamoyl) benzoylguanidines, as antiarrhythmic agents, inhibitors of the proliferation of cells and inhibitors of sodium-hydrogen exchange
SUBSTITUTED BENZYLOXYCARBONILGUANIDINES, METHOD FOR THEIR RECOVERY, THEIR APPLICATION AS A MEDICINAL OR DIAGNOSTIC MEDICINE, AND ALSO CONTAINING THEIR MEDICINE
Substituted bicyclic heteroaroylguanidines, methods for their preparation, their use as medicaments or diagnostic agents and medicaments containing the same