SI9600027B - Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them - Google Patents

Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them Download PDF

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SI9600027B
SI9600027B SI9600027A SI9600027A SI9600027B SI 9600027 B SI9600027 B SI 9600027B SI 9600027 A SI9600027 A SI 9600027A SI 9600027 A SI9600027 A SI 9600027A SI 9600027 B SI9600027 B SI 9600027B
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hydrogen
group
methyl
alkyl
replaced
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SI9600027A
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SI9600027A (en
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Heinz-Werner Kleemann
Hans-Jochen Lang
Jan-Robert Schwark
Andreas Weichert
Wolfgang Scholz
Udo Albus
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Hoechst Ag
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Priority claimed from DE19502795A external-priority patent/DE19502795A1/en
Priority claimed from DE1995104805 external-priority patent/DE19504805A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of SI9600027A publication Critical patent/SI9600027A/en
Publication of SI9600027B publication Critical patent/SI9600027B/en

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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 group R(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 ) or g 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. 13 6. 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. 14 14. 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.
SI9600027A 1995-01-30 1996-01-29 Base-substituted benzoylguanidines, process for their preparation, use thereof as a medicament or diagnostic as well as a medicament containing them SI9600027B (en)

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ATE185557T1 (en) 1999-10-15
IL116940A0 (en) 1996-05-14
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CN1087285C (en) 2002-07-10
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FI960369A (en) 1996-07-31
CZ290268B6 (en) 2002-06-12
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EP0723956B1 (en) 1999-10-13
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