WO1997024113A1 - UTILISATION D'INHIBITEURS DE L'ECHANGEUR CELLULAIRE Na+/H+ (NHE) POUR PREPARER UN MEDICAMENT STIMULANT LA RESPIRATION - Google Patents

UTILISATION D'INHIBITEURS DE L'ECHANGEUR CELLULAIRE Na+/H+ (NHE) POUR PREPARER UN MEDICAMENT STIMULANT LA RESPIRATION Download PDF

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WO1997024113A1
WO1997024113A1 PCT/EP1996/005614 EP9605614W WO9724113A1 WO 1997024113 A1 WO1997024113 A1 WO 1997024113A1 EP 9605614 W EP9605614 W EP 9605614W WO 9724113 A1 WO9724113 A1 WO 9724113A1
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alkyl
hydrogen
group
independently
zero
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PCT/EP1996/005614
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German (de)
English (en)
Inventor
Klaus Wirth
Wolfgang Scholz
Hans-Willi Jansen
Hans Jochen Lang
Joachim Brendel
Heinz-Werner Kleemann
Jan-Robert Schwark
Andreas Weichert
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Hoechst Aktiengesellschaft
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Priority to SK883-98A priority Critical patent/SK88398A3/sk
Priority to BR9612287-0A priority patent/BR9612287A/pt
Priority to AU13720/97A priority patent/AU717247B2/en
Priority to KR1019980704927A priority patent/KR19990076802A/ko
Priority to EP96943956A priority patent/EP0869779A1/fr
Priority to PL96327693A priority patent/PL327693A1/xx
Priority to IL12511496A priority patent/IL125114A0/xx
Publication of WO1997024113A1 publication Critical patent/WO1997024113A1/fr
Priority to NO982989A priority patent/NO982989L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L50/00—Electric propulsion with power supplied within the vehicle
    • B60L50/50—Electric propulsion with power supplied within the vehicle using propulsion power supplied by batteries or fuel cells
    • B60L50/60—Electric propulsion with power supplied within the vehicle using propulsion power supplied by batteries or fuel cells using power supplied by batteries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L7/00—Electrodynamic brake systems for vehicles in general
    • B60L7/10—Dynamic electric regenerative braking
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L7/00—Electrodynamic brake systems for vehicles in general
    • B60L7/10—Dynamic electric regenerative braking
    • B60L7/16—Dynamic electric regenerative braking for vehicles comprising converters between the power source and the motor
    • E—FIXED CONSTRUCTIONS
    • E01—CONSTRUCTION OF ROADS, RAILWAYS, OR BRIDGES
    • E01C—CONSTRUCTION OF, OR SURFACES FOR, ROADS, SPORTS GROUNDS, OR THE LIKE; MACHINES OR AUXILIARY TOOLS FOR CONSTRUCTION OR REPAIR
    • E01C19/00—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving
    • E01C19/22—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving for consolidating or finishing laid-down unset materials
    • E01C19/23—Rollers therefor; Such rollers usable also for compacting soil
    • E01C19/26—Rollers therefor; Such rollers usable also for compacting soil self-propelled or fitted to road vehicles
    • E—FIXED CONSTRUCTIONS
    • E01—CONSTRUCTION OF ROADS, RAILWAYS, OR BRIDGES
    • E01C—CONSTRUCTION OF, OR SURFACES FOR, ROADS, SPORTS GROUNDS, OR THE LIKE; MACHINES OR AUXILIARY TOOLS FOR CONSTRUCTION OR REPAIR
    • E01C19/00—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving
    • E01C19/22—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving for consolidating or finishing laid-down unset materials
    • E01C19/23—Rollers therefor; Such rollers usable also for compacting soil
    • E01C19/28—Vibrated rollers or rollers subjected to impacts, e.g. hammering blows

Definitions

  • the invention relates to the use of NHE inhibitors for the manufacture of a medicament for respiratory stimulation
  • NHE inhibitors are guanidine derivatives, preferably acylguanidines, among others as described in the following publications and patent publications: Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine” , J. WILEY & Sons (1983), 303-341, also for compounds of the following formulas:
  • R (9) H or methyl; or R (7) and R (8) together with the nitrogen atom to which they are attached, a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system; R (3), R (4) and R (5) independently of one another H or (C r C 2 ) alkyl, or R (3) and R (4) together form a (C 2 -C 4 ) alkylene chain; or R (4) and R (5) together form a (C 4 -C 7 ) alkylene chain; and their pharmaceutically acceptable salts; (HOE 92 / F 34 - US 5 373 924) b) Benzoylguanidines of the formula I
  • R (1) R (4) -SO m or R (5) R (6) N-SO 2 -; m zero, 1 or 2; R (4) and R (5)
  • R (7) C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R (9); R (8) and R (9)
  • R (10) H, C r C 6 alkyl, C 5 -C 7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl or -C n H 2n -R (12); n zero, 1, 2, 3 or 4;
  • R (9); R (8) and R (9) are H or C r C 4 alkyl
  • R (11) is hydrogen or C r C 3 alkyl
  • R (10) and R (11) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by O, S, NH, N-CH 3 or N-benzyl
  • R (3) is defined as R (1), or C r C 6 alkyl, nitro, cyano, trifluoromethyl, F, Cl, Br, J or -XR (10); XO, S or NR (11);
  • R (10) is H, C r C 6 alkyl, C 5 -C 7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl or -C n H 2n -R (12); n zero to 4; R (12) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R (9); R (8) and R (9)
  • R (6) H, C r Cg-alkyl, C 5 -C 7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, - (CH 2 ) m C p F 2p + 1 or -C n H 2n -R (8); m zero or 1; P 1-3; n zero to 4;
  • R (8) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of the groups F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and R (10)
  • R (7) H or C r C 4 alkyl; R (7) H or C r C 3 alkyl; or R (6) and R (7) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by an O, S, NH, N-CH 3 or N-benzyl; R (3) H or -XR (6);
  • YO or NR (7) where Y is bonded to the phenyl radical of the formula I, ZC or SO; R (6) H, C 1 -C 6 alkyl, C 5 -C 7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, - (CH 2 ) m C p F 2p + 1 or -C n H 2n -R (8); m zero or 1; P 1-3; n zero to 4; R (8) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and R (10)
  • R (12) and R (13) are defined as R (6) and R (7); or one of the two radicals R (2) or R (4) defines hydrogen or as R (1); R (5) H, methyl, F, Cl or methoxy, and their pharmaceutically acceptable salts.
  • R 92 / F 036 - US 5 364 868) d Benzoylguanidines of the formula I.
  • R (1) or R (2) is an amino group -NR (3) R (4);
  • R (3) and R (4), identical or different, are H, C r C 6 alkyl or C 3 -C 7 cycloalkyl; or
  • Oxygen, S or NR (5) can be replaced;
  • R (5) H or lower alkyl; the other substituent R (1) or R (2)
  • R (1) R (4) -SO m or R (5) R (6) N-SO 2 -; m zero, 1 or 2; R (4) and R (5)
  • R (7) C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R (9); R (8) and R (9)
  • R (6) H or C r C 4 alkyl; or R (5) and R (6) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by an O, S, NH, N-CH 3 or N-benzyl;
  • R (12) (C 3 -C ⁇ ) cycloalkyl;
  • R (13) is hydrogen or methyl, or
  • R (4) and R (5) together form a straight-chain or branched C 4 -C 7 chain, where the chain can additionally be interrupted by O, S or NR (6), R (6) H or methyl; or R (4) and R (5) together with the nitrogen atom to which they are attached, a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system; n zero, 1 or 2; and their pharmaceutically acceptable salts. (92 / F 304 - US 5416 094) g) isoquinolines of the formula I.
  • R (1) hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted aminoalkyl or an aryl or heteroaryl ring; the rings being unsubstituted or substituted with 1-3 groups selected from the group consisting of halogen, Nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxy, trifluoromethyl, R (2) hydrogen, halogen, alkyl, or aryl; which is unsubstituted or substituted with 1-3 groups selected from the group consisting of halogen, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxy,
  • X (2), X (3) and X (4) independently of one another hydrogen, halogen, nitro, amino, alkyl, sulfonamide, mono (lower alk ⁇ l) amino, di (lower alkyl) amino, lower alkyl, benzyloxy, hydroxy;
  • X (1) hydrogen, oxygen, sulfur or NR (7);
  • R (7) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted aminoalkyl or an aryl or heteroaryl ring; which rings are unsubstituted or substituted with 1-3 groups selected from the group consisting of halogen, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxy and trifluoromethyl; in which substituents each alkyl chain or alkenyl chain can be interrupted by oxygen, sulfur or NR (8); R (8) hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted aminoalkyl or an aryl or heteroaryl ring, which rings are unsubstituted or substituted with 1-3 groups selected from the group consisting of halogen, nitro, amino, mono (lower alkyl) amino, Di (lower alk ⁇ l)
  • R (7) (C 3 -C 7 ) cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R ( 9); ° R (8) and R (9)
  • R (6) H or (C r C 4 ) alkyl; or R (5) and R (6) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (2) -SR (10), -OR (10), -NHRdO), -NR (10) R (1 1), -CHR (10) R (12), - [CR (12) Rd 3) OR (13 ')], - ⁇ C- [CH 2 -OR (13')] R (12) (R (13) ⁇ or - [CR (18) Rd 7)] p - (CO) - [CR (19) R (20)] q -R (14); RdO), R (11) the same or different
  • R (21) hydrogen, methyl, p, q, r the same or different
  • R (12) and R (13), identical or different, are hydrogen, (C 1 -C 6 -alkyl or together with the carbon atom carrying them a (C 3 -C 8 ) cycloalkyl, R (13 ') hydrogen or (C r C 4 ) alkyl;
  • R (14) H, (C r C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl or -C a H 2a -R (15); a zero, 1, 2, 3 or 4;
  • X is oxygen, S or NR (16); R (16) H or (C r C 3 ) alkyl; or R (22) and R (16) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (22) is defined as R (14); and their pharmaceutically acceptable salts.
  • R (16) H or (C r C 3 ) alkyl; or R (22) and R (16) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (22) is defined as R (14); and their pharmaceutically acceptable salts.
  • HOE 92 / F 405 - EP 602 523, NZ 250437 i) Benzoylguanidines of the formula I
  • R (7) (C 3 -C 7 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R ⁇ 9); R (8) and R (9)
  • R (1 1) and R (12) independently of one another are defined as R (10) or hydrogen or (C r C 4 ) -alkyl; R (3) is defined as Rd), or (C r C 6 ) alkyl or -XR (13); X is oxygen, S, or NR (14); R (14) H or (C r C 3 ) alkyl; R (13) H, (C r C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl or -C b H 2b -R (15); b zero, 1, 2, 3 or 4; or R (13) and R (14) together 4 or 5 methylene groups, of which CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (15) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R (9); R (8) and R (9)
  • R (5) is hydrogen or C (1. 6) alkyl; n zero, 1, 2, 3 or 4;
  • R (6) H or C ⁇ 1-4r alkyl; wherein a CH 2 group can be replaced by 1 S atom or a group NR (7);
  • R (7) hydrogen, methyl or ethyl
  • R (5) and R (6) together with the nitrogen atom form a 5-, 6- or 7-membered ring in which 1 C atom can be replaced by oxygen, S or NRdO); Rd O) H, C ( 1.3 ) alkyl or benzyl; and the other substituents R (1), R (2), R (3), R (4):
  • X is oxygen or NR (12); R (12) H or C (1.3) alkyl; R (11) is hydrogen, C (1. 6) alkyl, C (3. 8) cycloalkyl or phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, CH 3 , CH 3 -O- and NR (13) R (14); Rd 3), R (14)
  • X is oxygen, S or NR (6); R (4) and R (5) the same or different, H, (C 1 -C 8 ) alkyl, (C 3 -C 6 ) alkenyl or
  • n 0, 1, 2, 3 or 4;
  • Rd O phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (1 1) R (12); R (1 1) and R (12)
  • Substituents R (1), R (2) or R (3) represent a sufficiently lipophilic alkyl radical having 3 to 12 carbon atoms; or one of the substituents R (1), R ⁇ 2) or R (3)
  • R (4) (C 3 -C 12 ) cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl, where the aromatic and heteroaromatic ring systems are unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF 3 , methyl, Methoxy and NR (5) R ⁇ 6); R (5) and R (6)
  • -C ⁇ CR (5) or -C [R (6)] CR (5); R ⁇ 5) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, hydroxy, amino, methylamino and dimethylamino, (C 1 -C 9 ) heteroaryl which is unsubstituted or substituted like phenyl, or R (5) (C r C 6 ) alkyl which is unsubstituted or substituted by 1-3 OH; or
  • X is oxygen, S or NR (14); m zero, 1 or 2; o zero or 1; p zero, 1 or 2; q zero, 1, 2, 3, 4, 5 or 6; R ⁇ 5) and R (6)
  • R (8) (C 3 -C 7 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R ( 10); R (9) and R (10)
  • R (7) H or (C r C 4 ) alkyl; or R (6) and R (7) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl;
  • Y- Y is oxygen, -S- or -NR (12) -; R (1 1) and R (12)
  • R (3) defines as R (1), or (CT-CgJ-alkyl or -XR (13); X is oxygen, S or NRJ 14); R (14) H or (C r C 3 ) alkyl;
  • R (4) is hydrogen, -OR (16) or -NR (16) R (17); R (16) and R (17) independently are hydrogen or (C r C 3 ) alkyl; and their pharmaceutically acceptable salts; (HOE 93 / F 154 - EP-OS 628 543, NZ 260 681) p) Benzo ⁇ lguanidines of the formula I.
  • R (9) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (10) R (11); R (10) and R (1 1)
  • R (12) (C 3 -C 8 ) -C ⁇ cloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (13) R (14); R (13) and R (14)
  • R (19) and R (20) independently of one another are defined as R (18) or hydrogen, (C, - C 4 ) -alkyl or (C r C 4 ) -perfluoroalkyl; or
  • R (24) (C 3 -C 8 ) cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (27) R (28); R (27) and R (28)
  • R (29) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (30) R (31); R (30) and R (31)
  • R (36) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics not being substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, Methoxy and NR (37) R (38); R (37) and R (38)
  • R (34) H, (C r C 4 ) alkyl or ⁇ C r C 4 ) perfualkyl;
  • R (34) H, (C r C 4 ) alkyl or (C r C 4 ) perfualkyl;
  • R (35) defines like R (33); or
  • R (33) and R (34) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; where A and N (#) are bound to the phenyl core of the benzoylguanidine base body; or
  • R (2) -SR (40), -OR ⁇ 40), -NHR (40), -NR (40) R (41), -CHR (40) R (42), -C [R (42) R (43) OH], -C ⁇ CR (45), -CR (46) CHR (45), - [CR ⁇ 47) R (48)] u - (CO) - [CR49) R (50)] v -R (44); R (40), R (41) the same or different - (CH 2 ) p - (CHOH) q - (CH 2 ) r - (CHOH) t -R (51) or - (CH 2 ) p -O- ( CH 2 -CH 2 O) q -R (51); R (51) is hydrogen or methyl; u 1, 2, 3 or 4; v zero, 1, 2, 3 or 4;
  • R (42) and R (43), identical or different, are hydrogen or (C, -C 6 ) -alkyl; or R (42) and R (43) together with the carbon atom carrying them form a (C 3 -C 8 ) cycloalkyl; R (44) H, (C r C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl or -C ⁇ H 2 ⁇ -R (45); e zero, 1, 2, 3 or 4;
  • R (45) is phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (52) R (53) with
  • R (52) and R (53) are H or (C r C 4 ) alkyl, or R (45) (C r C 9 ) heteroaryl which is unsubstituted or substituted like phenyl; or R (45) (C r C 6 ) alk ⁇ l which is unsubstituted or substituted by 1-3 OH; R (46), R ⁇ 47), R (48), R ⁇ 49) and R (50) are hydrogen or methyl; or R (2) R (55) -NH-SO 2 -;
  • Y is oxygen, S or NR (58); R (56) and R (57), identical or different, are H, (C j -CgJ alkyl, (C 3 -C 6 ) alkenyl or -C f H 2f -R (59); f zero, 1, 2, 3 or 4;
  • R (59) (C 5 -C 7 ) cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methoxy and (C r C 4 ) alkyl; or R ⁇ 56) and R (57) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl;
  • R (58) is defined as R (56) or amidine;
  • R (3), R (4) and R (5) are independently defined as R (1) or R (2); and their pharmaceutically acceptable salts; (HOE 93 / F 220 - EP-OS 640 593, NZ 264 1 17) q) benzoylguanidines of the formula I.
  • Rd hydrogen, F, Cl, Br, I, -NO 2 , -C ⁇ N, -X 0 - (CH 2 ) p - (CF 2 ) q -CF 3 , R (5) -SO m - R ( 6) -CO-, R (6) R (7) N-CO- or R (6) R (7) N-SO 2 -;
  • X is oxygen, -S- or NR (14); m zero, 1 or 2; o zero or 1; p zero, 1 or 2; q zero, 1, 2, 3, 4, 5 or 6;
  • R (8) (C 3 -C 7 ) cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R ( 10); R (9) and RdO)
  • R (7) is hydrogen or (C r C 4 ) alk ⁇ l; or R (6) and R (7) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl;
  • X is oxygen, -S- or NR (14); R (14) H or (C r C 3 ) alkyl;
  • R (4) is hydrogen, -OR (16), -NR (16) R (17) or C r F 2r + 1 ; R (16) and R (17) independently are hydrogen or (C 1 -C 3 ) alkyl; r 1, 2, 3 or 4; and their pharmaceutically acceptable salts; (HOE 93 / F 223 K - EP 639 573, NZ 264 130) r) Benzo-fused 5-ring heterocycles of the formula
  • Y is oxygen, S or NR (7);
  • R (9) H, methyl, ethyl,
  • W is oxygen or NR (10);
  • X is oxygen or S
  • R (6) hydrogen, (C r C 8 ) alkyl, (C r C 8 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl or -C n H 2n -R (9); n zero, 1, 2, 3 or 4;
  • R (9) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (10) R (1 1); R (10) and R (11)
  • R (7) hydrogen, (C r C 8 ) alkyl, (C r C 8 ) perfluoroalkyl, (C 3 -C 8 ) -
  • R (12) (C 3 -C 8 ) -C ⁇ cloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (13) R (14); R (13) and R (14)
  • R (8) defines like R ⁇ 7); or R (7) and R (8) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; the remaining substituents R (2), R (3), R (4), R (5) or R (1), R (2), R (4), R (5) or R (1), R (2), R (3), R (5) independently of one another hydrogen, F, Cl, Br, I, -O ta (C, -C 8 ) alkyl,
  • R (21) (C 3 -C 8 ) cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents from the group F, Cl, CF 3 , methyl, methoxy or NR (22 ) R (23), R ⁇ 22) and R (23) hydrogen, (C r C 4 ) alkyl or (C r C 4 ) perfluoroalkyl; R (17) hydrogen, (C r C 8 ) alkyl, (C r C 8 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl, - C r H 2r -R (24); r zero, 1, 2, 3 or 4;
  • R (24) (C 3 -C 8 ) cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (25) R (26); R (25) and R ⁇ 26)
  • R (A) and R (B) independently are hydrogen, F, Cl, Br, I, CN, OR (106), (C r C 8 ) alkyl, (C 3 - C 8 ) cycloalkyl, O 2k (CH 2 ) zl C zm F 22m + 1 , NR (107) R (108), phenyl or benzyl, the aromatics being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl , Methoxy and NR (109) R (1 10); R (109) and R (1 10)
  • R (107) and R (108) independently of one another are defined as R (106), or R (107) and R (108) together have 4 or 5 methylene groups, one of which is a CH 2 group by oxygen, S, NH, N - CH 3 or N-benzyl can be replaced; or Xd) and X (2)
  • T2a and T2b independently of one another zero, 1 or 2; wherein the double bond can be (E) - or (Z) -configured; or
  • T3 zero, 1 or 2;
  • U, YY and Z independently of one another are C or N, where U, YY, Z can carry the following number of substituents:
  • R (1 15) and R (1 16) are independently defined as R (1 14); or
  • R (110c) and R (1 13a) independently are hydrogen, (C 1 -C 4 ) perfluoroalkyl or (C 1 -C 4 ) alkyl; or R (1 10b) and R (1 10c) and R (1 12a) and R (1 13a) together 4 or 5 methylene groups, one of which is a CH 2 group by oxygen, sulfur, NH, N-CH 3 or N -Benzyl can be replaced; or R (101), R (102), R (103), R (104), R (105) independently of one another (C ⁇ CgV-alkyl, -C za
  • R (101), R (102), R (103), R ⁇ 104), R (105) independently of one another -C C-R (193); R (193)
  • Phenyl which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy or NR (194) R (195); R (194) and R (195)
  • R (101), R (102), R (103), R (104), R (105) independently of each other
  • R (101), R (102), R (103), R (104) and R (105) independently of one another R (146) X (1a) -; Xd a)
  • -C 2xa H 22xa -R (151); eg zero or 1; zdz 1, 2, 3, 4, 5, 6 or 7; zxa zero, 1, 2, 3 or 4;
  • R (168), R (170), R (154), R (155), the same or different, are hydrogen or ⁇ C r C 6 ) -alkyl, or R (169) and R (170) or R (154) and R (155) together with the carbon atom carrying them a (C 3 -C 8 ) cycloalkyl; R (163)
  • R (156), R (157) and R (173) are independently phenyl which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (174) R (175 ); R (174) and R (175)
  • R (156), R (157) and R (173) independently (C ⁇ Cgl heteroaryl which is unsubstituted or substituted like phenyl;
  • R (158), R (159), R (160), R (161) and R (162) are hydrogen or methyl, or R (101), R (102), R ⁇ 103), R (104), R (105) independently of one another R (176) -NH-SO 2 -;
  • R (177) and R (178), identical or different, are hydrogen, (C -, - C 8 ) -alkyl, (C 3 -C 6 ) -alkenyl or -C zfa H 2zfa -R (180); zfa zero, 1, 2, 3 or 4; R (180)
  • R (177) and R (178) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl;
  • R (179) is defined as R (177) or the same as amidine, or R (101), R (102), R (103), R (104), R (105) independently of one another NR (184a) R (185), OR (184b), SR (184c) or
  • X is oxygen, S or NR (5); a zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3;
  • R (5) H, (C r C 4 ) alkyl or -C d H 2d R (6); d zero, 1, 2, 3 or 4;
  • R (6) (C 3 -C 8 ) cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatics are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (7) R (8); R (7) and R (8) independently represent H or (C r C 4 ) alkyl; or R (1) -SRdO), -OR (10) or -CR (10) R (1 1) R (12);
  • RdO -C f H 2f - (C 3 -C 8 ) -cycloalkyl, - (CT-CgJ-heteroaryl or phenyl, where the aromatic systems are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; f zero, 1 or 2;
  • R (11) and R (12) are independently defined as Rd O) or hydrogen or (C r C 4 ) alkyl; or
  • R ⁇ 13) and R (14) the same or different - (CH 2 ) 0 - (CHOH) h - (CH 2 ) r (CHOH) r R (17), R (17) hydrogen or methyl; - (CH 2 ) ⁇ -O- (CH 2 -CH 2 O) h -R (24), g, h, i the same or different zero, 1, 2, 3 or 4; j 1, 2, 3 or 4;
  • R (15) and R (16), identical or different, are hydrogen, (C
  • R (18) (C 3 -C 8 ) cycloalkyl; R (19), R (20), R (21), R (22) and R (23)
  • R (6) hydrogen, (C r C 8 ) alkyl, (C 3 -C 8 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl or benzyl, where the aromatics are not substituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and Rd O)
  • R (7) and R (8) are independently defined as R (6);
  • R (B) is independently defined as R (A); X 1, 2 or 3;
  • R (1) hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, -O t (CH 2 ) d C e F 2 ⁇ + 1 , F, Cl,
  • R (2), R (3), R (4) and R (5) are independently defined as R (1); but under the condition that at least one of the substituents R (1), R (2), R (3), R (4), R (5), R (A) and R (B) has an -O t (CH 2 ) d C e F 2e + 1 or an O r (CH 2 ) a C b F 2b + 1 group, and their pharmaceutically acceptable salts; (HOE 94 / F 094 - EP-OS 676 395, NZ 270 894) x) heteroaroylguanidines of the formula I.
  • HA SO m 0 or NR (5); m zero, 1 or 2;
  • R (81) (CT -C 9 ) heteroary I which is linked via C or N and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy , Hydroxy, amino, methylamino and dimethylamino; one of the two substituents R (1) and R ⁇ 2)
  • R (3) and R (4) independently of one another hydrogen, F, Cl, Br, I, -C ⁇ N, X- (CH 2 ) p - (C q - F 2q + 1 ), R (8) -SO bm , R (9) R (10) N-CO, R (1 1) -CO- or R (12) R (13) N-SO 2 -, where the perfluoroalkyl group is straight-chain or branched, X is oxygen, S or NR (14); R (14) H or ( ⁇ -C ⁇ alkyl; bm zero, 1 or 2; p zero, 1 or 2; q zero, 1, 2, 3, 4, 5 or 6;
  • R (8), R (9), R (1 1) and R (12) independently (C r C 8 ) alkyl, (C 3 -C 6 ) alkenyl, -C n H 2n -R (15) , CF 3 ; n zero, 1, 2, 3 or 4; R (15) (C 3 -C 7 ) cycloalkyl or phenyl; which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy or NR (16) R (17); R (16) and R (17)
  • RdO) and R (13) independently H or (C 1 -C 4 ) alkyl; or R (9) and Rd O) and R (12) and R (13) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl , or R (3) and R (4) independently of one another (C r C 8 ) -alkyl or -C a
  • R (18) (C 3 -C 8 ) cycloalkyl or phenyl; which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (19) R (20); R (19) and R (20)
  • R (3) and R (4) independently of one another (C r C 9 ) heteroaryl, which is linked via C or N and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or
  • Y is oxygen, -S- or -NR (22) -; h, ad, ah independently zero or 1; i, j, k, ae, af, ag, ao, ap and ak independently zero, 1, 2, 3, 4, but with h, i and k not simultaneously zero, ad, ae and ag not simultaneously zero and ah , ao and ak are not zero at the same time,
  • R (23), R (24) R (25) and R (22) independently are hydrogen or (C 1 -C 3 ) alkyl; or R (3) and R (4) independently of one another are hydrogen, F, Cl, Br, I, CN, (C 1 -C 8 ) -alkyl, (C ⁇
  • C 8 perfluoroalkyl, (C 3 -C 8 ) alkenyl or -C 8 H 2g R (26); g zero, 1, 2, 3 or 4;
  • R (26) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (27) R (28); R (27) and R (28)
  • R (29), R (30), R (31) and R (33) independently -CaH ⁇ -fC, -C 9 ) heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F. , Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; a zero, 1 or 2;
  • R (32), R (34) and R (35) independently of one another are defined as R (29) or hydrogen, (C -, - C 4 ) -alkyl or (C r C 4 ) -perfluoroalkyl; or R (3) and R (4) independently of one another
  • R (96), R (97) and R (98) independently (C ⁇ Cgl-heteroaryl which is linked via C or N and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl; W oxygen, S or NR (36) -; R (36) H or (C r C 4 ) alkyl; or R (3) and R (4) independently of one another R (37) -SO cm or R (38) R (39) N-SO 2 -; cm 1 or 2;
  • R (37) (C r C 8 ) alkyl, (C r C 8 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl or -C 3 H 2s R (40); s zero, 1, 2, 3 or 4;
  • R (40) (C 3 -C 8 ) cycioalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (41) R (42); R (41) and R (42)
  • R (51) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (52) R (53); R (52) and R ⁇ 53)
  • R (47), R (48) and R (50) independently are hydrogen, (C r C 4 ) alkyl or (C r C 4 ) perfluoroalkyl;
  • R (49) defines like R (46); or
  • R (68), R (70), R (54) and R (55), identical or different, are hydrogen, (C, -C 6 ) -alkyl; or R (69) and R (70) or R (54) and R (55) together with the carbon atom carrying them is a (C 3 -C 8 ) cycloalkyl; R (63)
  • R (76) -NH-SO 2 -; R (76) R (77) R (78) N- (C - Y ') -; Y' oxygen, S or NR (79); R (77) and R (78) identical or different H, (C r C 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, - C f H 2f -
  • R (80) (C 5 -C 7 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methoxy and (C r C 4 ) alkyl; or R (77) and R (78) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl, R (79) is defined as R (77) or the same as amidine; or R (3) and R (4) independently of one another NR (84) R (85); R (84) and R (85) independently of one another H, (C ⁇ C ⁇ alkyl, or together 4 or 5 methylene groups, one of which is a CH 2 group by oxygen, S, NH, N-CH 3 or N-benzyl may be replaced; or one or two CH 2 groups of which may be replaced by CH-C dm H 2dm + 1 , and their pharmaceutically acceptable
  • T, U, V, W, X, Y and Z are independently nitrogen or carbon; however with the restriction that X and Z are not nitrogen at the same time and that T, U, V, W, X, Y and Z do not bear a substituent if they
  • RdOa), RdOb), R (11) and R (12) independently of one another (C 1 -C 8 ) alkyl, (C 3 -C 6 ) alkenyl, n zero, 1, 2, 3 or 4;
  • RdOc) and R (13) independently are hydrogen or (C 1 -C 4 ) alkyl; or R (10b) and R (10c) and R (12) and R (13) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl can; or R (3), R (4), R (5), R (6) and R (7) independently of one another (C 1 -C 8 ) -alkyl, -C a
  • Y is oxygen, -S- or -NR (22) -; h, ad, ah independently of one another zero or 1; i, j, k, ae, af, ag, ao, ap and ak independently of one another zero, 1, 2, 3 or 4; however, h, i and k are not simultaneously zero, ad, ae and ag are not simultaneously zero, and ah, ao and ak are not simultaneously zero,
  • R (23), R (24) R (25) and R (22) independently of one another are hydrogen or (C r C 3 ) -alkyl; or R (3), R ⁇ 4), R (5), R (6) and R (7) independently of one another SR (29), -OR (30), -NR (31) R (32) or
  • R ⁇ 32), R (34) and R (35) are independently defined as R (29) or hydrogen, (C r
  • R (96), R (97) and R (98) independently of one another (C, -C 9 ) heteroaryl which is linked via C or N and which is unsubstituted or substituted with 1 to 3 substituents from the group consisting of F. , Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl; W oxygen, S or NR (36) -; R (36) H or (C r C 4 ) alkyl; or R (3), R (4), R (5), R (6) and R (7) independently of one another R (46) X (1) -;
  • R (51) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (52) R (53); R (52) and R (53)
  • R (68), R (70), R (54) and R (55), the same or different, are hydrogen or (C 1 -C 6 alkyl); or R (69) and R (70) or R (54) and R (55 ) together with the carbon atom carrying them (C 3 -C 8 ) -
  • R (56), R (57) and R (73) independently
  • Phenyl which is unsubstituted or substituted by 1-3
  • Y ' is oxygen, S or NR (79); R (77) and R (78) the same or different hydrogen, (C-
  • R (80) (C 5 -C 7 ) cycloalkyl or phenyl which is unsubstituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methoxy and (C r C 4 ) alkyl; or R (77) and R (78) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl; R (79) is defined as R (77) or the same as amidine; or R (3), R (4), R (5), R (6) and R (7) independently of one another NR (84a) R (85), OR (84b), SR (84c) or -C n H 2n -R (84d); n zero, 1, 2, 3 or 4;
  • R (84d) (C 3 -C 7 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (16) R ⁇ 17 ); R (16) and R (17)
  • R (84a), R (84b), R (84c) and R (85) independently of one another are hydrogen, (C, -C 8 ) -alkyl, (C., - C 8 ) - perfluoroalkyl or (CH 2 ) ax - R (84g); ax zero, 1, 2, 3 or 4;
  • R (84g) (C 3 -C 7 ) -C ⁇ cloalk ⁇ l or phenyl, which is unsubstituted or substituted by 1-3 Substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (84u) R (84v); R (84u) and R (84v)
  • Rd R (6) -SO m ; m zero, 1 or 2;
  • R ⁇ 2) and R ⁇ 3) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or phenoxy, that is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, methyl and methoxy; or
  • R (6) (C r C 8 ) alkyl, (C r C 4 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl or benzyl; wherein the aromatics are unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and Rd O)
  • R (7) and R (8) are independently defined as R (6); or R (7) and R (8) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl;
  • R (B) is independently defined as R (A); X is zero, 1 or 2; Y is zero, 1 or 2;
  • R (13) and R (14) independently of one another H, (C 1 -C 4 ) alkyl or (C ⁇ C 4 ) perfluoroalkyl;
  • R (D) is independently defined as R (C),
  • R (2), R (3), R (4) and R (5) are independently defined as Rd); but under the condition that at least one of the substituents R (A), R (B), R (C), R (D), R (1), R (2), R (4) or R (5) is one O r (CH 2 ) a C b F 2b + 1 -, O p (CH 2 ) f C 0 F 2g + 1 - or O t (CH 2 ) d C e F 2 ⁇ + 1 - group and R (3) is not an O t (CH 2 ) d C ⁇ F 2 ⁇ + ⁇ group; and their pharmaceutically acceptable salts; (HOE 94 / F 182 - EP-OS 690 048, NZ 272 449) ac) Ortho-amino-substituted benzoylguanidines of the formula I.
  • R (50) and R (6) independently of one another are hydrogen, (C r C 8 ) -alkyl or (C, -C 8 )
  • R (2), R (3), R (4) and R (5) independently of one another R (10) -SO a -, R (1 1) R (12) N-CO-, R (13) -CO - or
  • RdO R (1 1), R (12), R (13), R (14) and R ⁇ 15) independently of one another (C., - C 8 ) -alkyl, (C r C 8 ) -perfluoroalkyl, (C 3 -C 6 ) alkenyl or -C ab H 2ab -R (16); from zero, 1, 2, 3 or 4; R (16) (C 3 -C 7 ) cycloalkyl, phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy or NR (17) R ( 18); R (17) and R (18) independently of one another H, CF 3 or (C 1 -C 4) alkyl; or R (11), R ⁇ 12), and R (14) and R (15) together 4 or 5 methylene groups, of which one CH 2 group is replaced by oxygen, S, NH, N-CH 3 or N-benzyl can be; or
  • R (21), R (22), R ⁇ 23) and R (25) independently of one another which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; b zero, 1 or 2;
  • R (24), R (26) and R (27) independently of one another are hydrogen, (C, -C 4 ) -alkyl or (C.
  • R (2), R (3), R (4) and R (5) independently of one another hydrogen, F, Cl, Br, I, CN, - (Xa) dg -C da H 2da + 1 , - (Xb ) dh - (CH 2 ) db -C d ⁇ F 2d ⁇ + 1 , (C 3 -C 8 ) alkenyl or -C df H 2df R (30); (Xa) 0, S or NR (33); R (33)
  • Aromatic phenyl, biphenylyl or naphthyl are unsubstituted or substituted with 1-3 substituents selected from the group
  • R (2), R (3), R (4) and R (5) independently of one another NR (40) R (41) or - (Xe) - (CH 2 ) eb R (45); R ⁇ 40) and R (41) independently of one another are hydrogen, (C 1 -C 8 ) -alkyl, (C ⁇ Cg) -perfluoroalkyl or (CH 2 ) ⁇ -R (42); e zero, 1, 2, 3 or 4;
  • R (3) and R (4) cannot be hydrogen, and the pharmaceutically acceptable salts thereof; HOE 94 / F 265 - NZ 272 946, EP-OS 700 904) ad) benzoylguanidines of the formula I.
  • one of the three substituents R (1), R (2) and R (3) (C. -C 9 ) heteroaryl N-oxide which is linked via C or N and which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or one of the three substituents R (1), R (2) and R (3)
  • R (1 1) and R (12) independently defined as R (10), hydrogen or (C r C 4 ) alkyl; and the respective other substituents R (1), R (2) and R (3) independently of one another (C, -C 8 ) alkyl, (C 2 -C 8 ) alkenyl or -C m H 2m Rd4); m zero, 1 or 2;
  • R (14) (C 3 -C 8 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (15) R ( 16), R (15) and R (16)
  • R (1), R (2) and R ⁇ 3) independently of one another are hydrogen, F, Cl, Br, I, -C ⁇ N, X- (CH 2 ) p - (C q F 2q + 1 ), R (22) -SO u , R (23) R (24) N-CO, R (25) -CO- or R (26) R (27) N-SO 2 -, the perfluoroalkylene group being straight-chain or is branched; X is a bond, oxygen, S or NR (28); u zero, 1 or 2; p zero, 1 or 2; q zero, 1, 2, 3, 4, 5 or 6;
  • R ⁇ 22), R (23), R (25) and R (26) independently (C r C 8 ) alkyl, (C 2 -C 6 ) alkenyl, -C n H 2n -R (29) or CF 3 ; n zero, 1, 2, 3 or 4;
  • R (28) is hydrogen or (C r C 3 ) alkyl
  • R (29) (C 3 -C 7 ) cycloalkyl or phenyl; which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (30) R (31); R (30) and R (31)
  • R (23) and R (24) and R (26) and R (27) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl ; or the other substituents R (1), R (2) and R (3) independently of one another OR (35) or NR (35) R (36); R (35) and R (36) independently of one another are hydrogen or (C 1 -C 6 alkyl); or R (35) and R (36) together have 4-7 methylene groups, one of which is a CH 2 group by oxygen, S, NH, N-CH 3 or N-benzyl can be replaced, R (4) and R (5) independently of one another hydrogen, (C r C 4 ) alkyl, F, Cl, -OR (32), - NR (33) R ⁇ 34) or C r F 2r + 1 ; R (32), R (33) and R (34) independently of one another are hydrogen or (C 1 -C 3 ) -alkyl; r 1, 2, 3 or 4
  • Rd hydrogen, F, Cl, Br, I, CN, NO 2 , OH, (C r C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, O a - (CH 2 ) b - (CF 2 ) c -CF 3 ; a zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3; or
  • R (7) is hydrogen or (C r C 4 ) alkyl;
  • R (8) (C 3 -C 7 ) cycloalkyl or phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R ( 10);
  • R (9) and R (10) independently of one another are hydrogen or (C r C 4 ) -alkyl; or R (6) H; or R (6) and R (7) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl, or R (1) -SR (1 1), -OR (1 1) or -CR (1 1) R (12) R (13);
  • R (2) -CF 2 R (14), -CF [R (15)] [R (16)], -CF [(CF 2 ) q -CF 3 )] [R (15)], -C [ (CF 2 ) r -CF 3 ] CR (15) R (16);
  • R (15) and R (16) independently of one another are hydrogen or (C r C 4 ) -alkyl;
  • R (3) is defined as Rd); R (4) hydrogen, (C r C 3 ) alkyl, F, Cl, Br, I, CN, - (CH 2 ) s - (CF 2 ) t -CF 3 ; s zero or 1; t zero, 1 or 2; and their pharmaceutically acceptable salts; (HOE 94 / F 267 - EP-OS 700 899, NZ 272 947) af) Benzoylguanidines of the formula I.
  • R (9) is hydrogen or - (C r C 4 ) -alkyl; R (7) -ORdO) or -NR (10) R (1 1); RdO) and R (1 1) independently of one another hydrogen, - (C, -C 8 ) -alkyl, - (C, - C 8 ) -alkanoyl, - (C., - C 8 ) -alkoxycarbonyl, benzyl, benzyloxycarbonyl; or RdO) trityl; R (8) -OR (12) or -NR (12) R (13); R (12) and R (13) independently of one another are hydrogen, - (C 1 -C 8 ) -alkyl or benzyl; k zero, 1, 2, 3 or 4; and the other radicals Rd), R (2) and R (3) independently of one another - ⁇ C j -CgJ alkyl, - (C 2 -C 8 ) alkenyl or
  • Y ' is oxygen, -S- or -NR (20); R (18) and R (19) independently of one another are hydrogen, - (C 1 -C 8 ) -alkyl, - (C 3 -C 6 ) -
  • R (26) R (27) N-SO 2 -, wherein the perfluoroalkyl group is straight-chain or branched;
  • X is a bond, oxygen, -S- or -NR (28); u zero, 1 or 2; p zero, 1 or 2; q 1, 2, 3, 4, 5 or 6;
  • R (22), R ⁇ 23), R (25) and R (26) independently of one another - (C 1 -C 8 ) alkyl, - (C 3 -C 6 ) alkenyl,
  • n zero, 1, 2, 3 or 4;
  • R (28) is hydrogen or - (C r C 3 ) -alkyl
  • R (24) and R (27) independently of one another are hydrogen or - (C 1 -C 4 ) -alkyl; or
  • R (23) and R (24) and R (26) and R (27) together have 4 or 5 methylene groups, of which one CH 2 group is replaced by oxygen, -S-, -NH-, - N-CH 3 or - N-benzyl can be replaced; or the other radicals Rd), R (2) and R (3) independently of one another -OR ⁇ 35) or -NR (35) R (36); R (35) and R (36) independently of one another are hydrogen or - (C., - C 6 ) -alkyl; or R (35) and R (36) together 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -N-CH 3 or -N-benzyl; R (4) and R (5) independently of one another are hydrogen, - (C r C 4 ) -alkyl, F, Cl, -OR (32), - NR (33) R (34) or -C r F 2r + 1 ; R (32), R (33) and R
  • R (6) (C r C 8 ) alkyl, (C 1 -C 8 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl or -C n H 2n -R (9), n zero, 1, 2 , 3 or 4;
  • R (9) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (10) R (1 1), RdO) and R (11)
  • R (12) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (13) R (14); R (13) and R (14)
  • R (2) is defined as Rd), or H, OH, F, Cl, Br, I, CN, NO 2 , (C r C 8 ) alk ⁇ l, (C r C 8 ) perfluoroalkyl, (C 3 -C 8 ) alkenyl or -C n H 2n R (15); n zero, 1, 2, 3 or 4;
  • R (19) and R (20) are independently defined as R (18) or hydrogen, (C r C 4 ) alkyl or (C r C 4 ) perfluoroalkyl; or
  • R (29) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (30) R (31); R (30) and R (31)
  • R (23) is hydrogen, (C r C 4 ) alkyl or (C r C 4 ) perfluoroalkyl; or R (22) and R (23) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; or R (2) R (33) X-;
  • M oxygen or S A oxygen or NR (34); DC or SO; R (33) (C r C 8 ) alkyl, (C 3 -C 8 ) alkenyl, (CH 2 ) b C d F 2d + 1 or -C n H 2n - R (36); b zero or 1; d 1, 2, 3, 4, 5, 6 or 7; n zero, 1, 2, 3, or 4;
  • R ⁇ 36) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, Methoxy and NR (37) R (38); R (37) and R (38)
  • R (34) is hydrogen, (C r C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl;
  • R (35) defines like R (33); or R (33) and R (34) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; where A and N ⁇ # 1 are bonded to the phenyl nucleus of the benzoylguanidine base body; or
  • R (2) -SR (40), -OR (40), -NHR (40), -NR (40) R (41), -CHR (40) R (42), -CR (42) R (43 ) OH, -C ⁇ CR (45), -CR (46) CR (45) or -ICR (47)
  • R (40) and R (41) independently of one another - (CH 2 ) p - (CHOH) q - (CH 2 ) r - (CHOH) t -R (51) or - (CH 2 ) p -O- (CH 2 -CH 2 O) q -R (51);
  • R (51) is hydrogen or methyl; u 1, 2, 3 or 4; v zero, 1, 2, 3 or 4; p, q and r independently of one another zero, 1, 2, 3 or 4; t 1, 2, 3 or 4;
  • R ⁇ 42) and R ⁇ 43) independently of one another are hydrogen or (C r C 6 ) -alkyl; or R (42) and R ⁇ 43) together with the carbon atom carrying them is a (C 3 -C 8 ) cycloalkyl; R (44) hydrogen, (C r C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, -C ⁇ H 2 ⁇ -R (45); e zero, 1, 2, 3 or 4;
  • R (45) phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (52) R (53); R ⁇ 52) and R (53)
  • Y is oxygen, S or N-R (58);
  • R (56) and R (57) independently of one another hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 6 ) alkenyl or -C f H 2f -R (59); f zero, 1, 2, 3 or 4;
  • R (59) (C 5 -C 7 ) cycloalkyl, phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methoxy and (C., - C 4 ) - Alkyl; or R (56) and R ⁇ 57) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (58) is defined as R (56) or the same as amidine; R ⁇ 3), R (4) and R (5) are defined independently of one another like R ⁇ 1) or R (2), but at least one of the substituents R (2), R (3), R (4) and R (5) must be equal to OH; and their pharmaceutically acceptable salts; (HOE 95 / F 007 K - EP-OS 723 956, NZ 280 887) ah) Benzoylguanidines of the formula I.
  • R (6) a basic heteroaromatic ring system with 1-9 C atoms; AC b H 2b ; b 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where in the group C b H 2b one or two methylene groups are selected by one of the groupings from the group consisting of -0-, -CO-, -CH [OR (20)] -, -SO m -, -NR (20) -, -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO 2 -
  • R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms
  • R (20) is hydrogen or methyl; a phenylene or naphthylene radical,
  • R (12) and R (13) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF 3 or -SO w -R (14);
  • R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2,
  • R (21) is hydrogen or methyl; m zero, 1 or 2; and the other substituents R (1) and R (2) and R (3) independently of one another are hydrogen, F, Cl, Br, J, -CN, - (C r C ⁇ ) -alkyl, - (C 2 - C 8 ) -alkenyl, -NR (35) R (36) or R (17) -C 8 H 2g -Z h -; g zero, 1, 2, 3 or 4; h zero or 1;
  • R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (35) and R (36) together 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -NCH 3 or -N-benzyl; Z -O-, -CO-, -SO v -, -NR (18) -, -NR (18) -CO-, -NR (18) -CO-NH- or -NR (18) -SO 2 - ;
  • R (18) is hydrogen or methyl; v zero, 1 or 2; R ⁇ 17) hydrogen, cycloalkyl with 3, 5 or 6 carbon atoms or C k F 2k + 1 -; k 1, 2 or 3, or R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl , Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl and methoxy; or R (17) - (C 3 -C 8 ) -cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F and Cl, -CF 3 , methyl, hydroxy, methoxy, -NR (37) R (38),
  • 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 -C r F 2r +1 ; R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; r 1, 2, 3 or 4; and their pharmacologically acceptable salts; (HOE 95 / F 072 - EP-OS 738 712, NZ 286 380 ai) indenoylguanidines of the formula I.
  • Rd) and R (2) independently of one another hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7, 3, 9 or 10 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms.
  • O-alkyl with 1, 2, 3 or 4 carbon atoms, OC ( O) alkylene with 1, 2, 3 or 4 carbon atoms or C m H 2m -NR (12) R (13);
  • R (12) and R (13) independently of one another hydrogen or alkyl with 1, 2, 3 or 4 C-
  • Rd), R (2) and R (3) independently of one another are -Y- [4-R (8) -phenyl], -Y- [3-R (8) -phenyl] or -Y- [2 - R (8) -phenyl], the phenyl in each case being unsubstituted or substituted by 1 -
  • R (96) and R (97) independently of one another are hydrogen or -CH 3 ;
  • Y is a bond, CH 2 , oxygen, -S- or -NR (9);
  • R (9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (8) SO a [NR (98)] b NR (99) R (10); a 1 or 2; b 0 or 1; a + b 2;
  • R (98), R (99) and R (10) independently of one another are hydrogen, - (C r C 8 ) -alkyl, benzyl,
  • R (11), R (12), R (13), R (37), R (38), R (43) and R (44) independently of one another are hydrogen, - (C, -C 8 ) -alkyl or benzyl : R (39), R (40), R (41) and R (42) independently of one another hydrogen, - (C 1 -C 8 ) -alkyl or - (C 0 -C 3 ) -alkylene-phenyl, where the Phenyl is not substituted or substituted with 1-3 substituents selected from the group consisting of F, CI, -CF 3 , methyl and methoxy; or R (99) and R (10) together 4-6 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -N-CH 3 or -N-benzyl; or
  • R (8) SO a [NR (98)] b NR (95) -C [ NR (94) ⁇ - NR (93) R (92); R (92), R (93), R (94) and R (95) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or Rd), R (2) and R (3) independently of one another pyrrol-1 -yl, pyrrol-2-yl or pyrrol-3-yl, which is not substituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl, methoxy; or R (1), R ⁇ 2) and R (3) independently of one another are hydrogen, - (C 1 -C 8 ) -alkyl, - (C 2 -C 8 ) -alkenyl or - (CH
  • R (18) is hydrogen or - (C r C 4 ) -alkyl; R (17) -OR (21) or -NR (21) R (22); R (21) and R (22) independently of one another are hydrogen, - (C, -C 8 ) -alkyl, - (C, - C 8 ) -alkanoyl, - (C ⁇ CgJ-alkoxycarbonyl, benzyl, benzyloxycarbonyl; or R (21) trityl; R (20) -OR (23) or -NR (23) R (24);
  • R (23), R (24) independently of one another
  • R (26) and R (27) independently of one another are defined as R (25) or hydrogen or (C r C 4 ) -alkyl, or Rd), R (2) and R (3) independently of one another (C., - C 9 ) -Heteroaryl-N-oxide which is linked via C or N and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (1), R (2 ⁇ and R (3) independently of one another -SR (28), -OR (28), -NR (28) R (29) or
  • R (28) -C 8 H 2fl - (C 1 -C 9 ) heteroaryl-N-oxide which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , Methoxy, hydroxy, amino, methylamino and dimethylamino; g zero, 1 or 2;
  • T is a bond, oxygen, -S- or -NR ⁇ 47);
  • I zero, 1 or 2; h zero, 1 or 2; i 1, 2, 3, 4, 5 or 6;
  • R (31), R ⁇ 32), R (34) and R (45) independently of one another - (C 1 -C 8 ) alkyl, - (C 3 -C 6 ) alkenyl,
  • R (47) is hydrogen or alkyl having 1, 2 or 3 carbon atoms
  • R (33) and R (46) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (32) and R (33) and R (45) and R (46) together 5 or 6 methylene groups, one of which is a CH 2 group by oxygen, -S-, -NH-, -NCH 3 or -N -Benzyl can be replaced; or Rd), R (2) and R (3) independently of one another R (51) -AGD-;
  • R (51) is a basic protonatable residue, i.e. an amino group
  • R (52), R (53), R (54) and R (55) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4
  • R (56) is hydrogen or methyl
  • R (51) is a basic heteroaromatic ring system with 1 - 9 C atoms;
  • A is a group C ⁇ H 2e ; e zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where in the group C ⁇ H 2e a C atom is one of the groupings -O-, -CO-, -CH [OR (57)] -, -SO r -, -NR (57) -, -NR (57 ) - CO-, -NR (57) -CO-NH-, -NR (57) -CO-NH-SO 2 - or -NR (57) -SO 2 - can be replaced; r zero, 1 or 2;
  • G is a phenylene radical
  • R (58) and R ⁇ 59) independently of one another hydrogen, methyl, methoxy, F, Cl, Br, J, CF 3 or -SO s -R (60); R (60) methyl or NR (61) R (62); R (61) and R (62) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; -C v H 2v -E w -; v zero, 1, 2, 3 or 4;
  • R (63) is hydrogen or methyl, or Rd), R (2) and R (3) independently of one another -CF 2 R (64), -CF [R (65) HR (66)], -CF [(CF 2 ) q -
  • R ⁇ 65) and R (66) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; q zero, 1 or 2; p zero, 1 or 2; or R (1), R (2) and R (3) independently of one another -OR (67) or -NR (67) R (68);
  • R (67) and R (68) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (67) and R (68) together 4, 5, 6 or 7 methylene groups, one of which is CH 2 -
  • Group can be replaced by oxygen, -S-, SO 2 , -NH-, -NCH 3 or -N-benzyl;
  • R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (69), -NR (70) R (71) or -C 2 F 2z + 1 ;
  • R (69), R (70) and R (71) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms.
  • Atoms; z 1, 2, 3 or 4; R (6) and R (7) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms.
  • X is oxygen or NR (72);
  • R ⁇ 72 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; and their pharmaceutically acceptable salts; (HOE 95 / F 115 - EP 744 397, NZ 286 622) al) alkenylcarboxylic acid guanidides of formula I bearing fluorophenyl groups
  • R (6) is hydrogen, (C r C 8 ) -alkyl, (C 3 -C 8 ) -cycloalkyl or phenyl, the phenyl group not being substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and RdO)
  • R (7) is independently defined as R (6); Rd),
  • R (2), R (3), R (4) and R (5) independently of one another are hydrogen or F; however, at least one of the radicals R (1), R (2), R (3), R (4) and R (5) must be fluorine; and their pharmaceutically acceptable salts; (HOE 95 / F 167 - NZ 299 015) am) benzoylguanidines of the formula I
  • Rd R (4) -SO m or R (5) R (6) N-SO 2 -; m 1 or 2; R (4) and R (5) independently of one another alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl with 3, 4, 5 or 6 carbon atoms, CF 3 or -C n H 2n -R (7); n zero, 1, 2, 3 or 4;
  • R (6) is H or alkyl having 1, 2, 3 or 4 carbon atoms; R (7) cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (8) R (9); R (8) and R (9)
  • R (5) is also hydrogen; or R (5) and R (6) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; or
  • R (3) defines hydrogen or independently as Rd); and their pharmaceutically acceptable salts; (HOE 95 / F 173 - NZ 299 052) an) Substituted cinnamic acid guanidides of the formula I.
  • R (16), R (17) and R (18) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; a zero or 1;
  • alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms
  • alkylene T with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms in the alkylene group
  • T, T-alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the alkylene group
  • T NR (20) 0, S or phenylene, where the phenylene is unsubstituted or substituted with 1 -3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and
  • R (20), R (21) and R (22) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; b zero or 1; LO, S, NR (23) or C k H 2k ; k 1, 2, 3, 4, 5, 6, 7, 8; n zero or 1;
  • R (24) and R (25) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; wherein the N-containing heterocycles are N- or C-bridged and are not substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (27) R (28); R (23), R (27) and R (28) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; and the respective other substituents R (1), R (2), R (3), R (4) and R (5) independently of one another H, F, Cl, Br, I, CN, -O n -C m H 2m + 1 , -O p - (CH 2 ) s -
  • R (7) is hydrogen or methyl
  • R (8) and R (9) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted is selected with 1-3 substituents on the group consisting of F, Cl, CF 3 , methyl and methoxy; or the other substituents R (1), R (2) and R (3) independently of one another phenyl, C 6 H 5 - (C 1 -C 4 ) alkyl, naphthyl, biphenylyl, quinolinyl, isoquinolinyl or imidazolyl, where quinolinyl, Isoquinolinyl or imidazolyl are bonded via C or N, and where phenyl, C 6 H 5 - (C 1 -C 4 ) alkyl, naphthyl, biphenylyl, quinolinyl, isoquinolinyl and imidazolyl are un
  • R (1 1) and R (12) are independently defined as R (10), hydrogen or
  • R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, F,
  • R (13), R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4
  • At least one of the three substituents R (1), R (2) and R (3) is a benzoylguanidine
  • O which is unsubstituted or substituted in the phenyl part with 1-4 radicals selected from the group consisting of alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, - (CH 2 ) m -R (14), F, Cl, Br, I, -C ⁇ N, CF 3 , R (22) SO 2 -, R (23) R (24) N-CO-, R (25) -CO-, R (26) R (27) N-SO 2 , -OR (35), -SR (35) or -NR (35 ) R (36); m zero, 1 or 2; R (14)
  • R (16 ) independently of one another are hydrogen or - CH 3 ;
  • R (22), R (23), R (25) and R (26) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
  • R (24) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
  • R (23) and R ⁇ 24) and R (26) and R ⁇ 27) together have 5 or 6 methylene groups, one of which is a CH 2 group through oxygen, -S-, -NH-, -NCH 3 or -N- Benzyl can be replaced;
  • Phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, -CF 3 , methyl, methoxy, SO 2 R (5), SO 2 NR (6) R (7) and - NR (32) R (33); R (5) alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms R (6) and R (7) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (32) and R ⁇ 33) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R ⁇ 35)
  • R (2) and R (3) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
  • Rd O phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, -CF 3 , methyl, methoxy, -SO 2 NR (17) R (8) and -SO 2 R ⁇ 9); R (17) and R ⁇ 8) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (9) alkyl having 1, 2, 3 or 4 carbon atoms; or the other remainder Rd) and R (3)
  • R (8); R (7) and R (8) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • R (2) is hydrogen or alkyl having 1, 2, 3, 4, 5 , 6, 7 or 8 carbon atoms or -SO 2 R (9)
  • R (9) is defined independently as Rd);
  • R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27);
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (25)
  • R (1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -OR (32),
  • R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (2) and R ⁇ 4) independently of one another hydrogen, F, Cl, Br, I, OH, -CN, CF 3 ,
  • -CO-N C (NH 2 ) 2 , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 C- Atoms or - (CH 2 ) m R (14); m zero, 1 or 2;
  • R (2) and R (4) independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl , Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl, methoxy; or R ⁇ 2) and R (4) independently of one another R (22) -SO 2 -, R (23) R (24) N-CO-, R (28) -CO- or
  • R (22) and R (28) independently of one another are methyl or -CF 3 ;
  • R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF. 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (25) - (C, -C 9 ) heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and Dimethylamino; R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (5) alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X- (CH 2 ) y -CF 3 or phenyl, which is unsubstituted
  • R ⁇ 25 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF. 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (25 - (C 1 -C 9 ) heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino
  • R (26) and R (27) independently of one another are defined as R ⁇ 25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (4) CF 3 , alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C atoms, - (
  • R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; the other radicals R (2) and R (4) independently of one another hydrogen, F, Cl, Br, I, OH, -CN, CF 3 ,
  • -CO-N C (NH 2 ) 2 , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 C- Atoms or - (CH 2 ) m R (14); m zero, 1 or 2;
  • R (35> and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF.
  • R (25) - (C r C 9 ) heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino
  • R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; one of the residues R ⁇ 6), R (7), R (8), R (9) and RdO)
  • -CO-N C (NH 2 ) 2 ;
  • the other radicals R (6) and R (10) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (132), -NR (133) R (134) or CF 3 ;
  • R (132), R (133) and R (134) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • the other radicals R (7) and R (9) independently of one another hydrogen, F, Cl, Br, I, OH, -CN, CF 3 , -CO-N C (NH 2 ) 2 , alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C. Atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH 2 ) mm R (1 14); mm zero, 1 or 2;
  • R (135) and R (136) together have 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -NCH 3 or -N-benzyl; the other R (8)
  • R (126) and R ⁇ 127) independently of one another as R (125) defined or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
  • a absent, -NR (1 1) -CO-, -NR (12) -CO-NR (13) -, -NR (17) -CO-NR (18) -SO 2 -, - NR (19) - SO 2 -, -SO 2 -NR (19) -SO 2 -NR (19) -CO 2 -NR (19) -CO 2 -NR (19) -CO-, -O-CO-NR (19) -SO 2 - or -CR (20) CR (21) -; R (1 1), R (12), R (13), R (17), R (18), R (19), R (20) and R (2
  • R (41) and R (42) independently of one another hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, or R (41) and R (42) together 4 or 5 methylene groups, one of which is CH 2 - group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; and the respective other substituents R (1), R (2) and R (3) independently of one another H, F, Cl, Br, I, CN, -O na -C ma H 2ma + 1 or -
  • RdO cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, the phenyl being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl and methoxy
  • R (4) and R (5) independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of from F, Cl, CF 3 , methyl, methoxy and NR (14)
  • R (15); R (14) and R (15) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon
  • R (2) and R (3) independently of one another hydrogen, Cl, Br, I, (C-
  • R (5) (-C -C ⁇ ) alkyl or -C d H 2d - (C3-C8) cycloalkyl; d zero, 1 or 2; where one of the two substituents R (2) and R (3) is always hydrogen, but not both substituents R (2) and R (3) are simultaneously hydrogen, and their pharmaceutically acceptable salts; (HOE 96 / F 042) ax) Benzoylguanidines of the formula I
  • X is oxygen, S, NR (5), a zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3; R (5) H, alkyl having 1, 2, 3 or 4 carbon atoms or -C d H 2d R (6); d zero, 1, 2, 3 or 4;
  • R (6) cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl, biphenylyl or naphthyl, the aromatics phenyl, biphenylyl or naphthyl being unsubstituted or substituted with 1-3 substituents selected from the group consisting of from F, Cl, CF3, methyl, methoxy and NR (7) R (8); R (7) and R (8) independently are H or alkyl having 1, 2, 3 or 4 carbon atoms; or R (1) -SR (10), -OR (10) or -CR (10) R (11) R (12);
  • R (11) and R (12) independently of one another are defined as R (10) or hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
  • R (13) and R (14) the same or different - (CH2) g- (CHOH) h - (CH2) r (CHOH) r R (17) or - (CH2) gO- (CH2-CH2 ⁇ ) hR (24 ), R (17) hydrogen or methyl, g, h and i, identical or different, zero, 1, 2, 3 or 4, j 1, 2, 3 or 4,
  • R (15) and R (16), the same or different, are hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or together with the carbon atom carrying them cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, R (18)
  • Phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (25) R (26), R (25) and R (26)
  • Rd H, F, Cl, Br, I, CN, NO2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy with 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkoxy with 3, 4, 5, 6, 7 or 8 carbon atoms or X a - (CH2) b- (CF2) c-CF 3 ; X is oxygen, S, NR (5), a zero or 1; b zero, 1 or 2; c zero, 1, 2 or 3;
  • R (5) H, alkyl having 1, 2, 3 or 4 carbon atoms or -C d H 2d R (6); d zero, 1, 2, 3 or 4;
  • R (6) cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl, biphenylyl or naphthyl, the aromatics phenyl, biphenylyl or naphthyl being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (7) R (8); R (7) and R (8) independently are H or alkyl having 1, 2, 3 or 4 carbon atoms; or Rd) -SR (IO), -ORdO) or -CR (10) R (1 1) R (12);
  • R (11) and R (12) independently of one another are defined as RdO) or are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
  • R (1) phenyl, naphthyl, biphenylyl or heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the latter linked via a carbon or nitrogen atom of the ring, each of which is unsubstituted or are substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino, or Rd) -SR (13), -OR (13), -NHR ( 13), -NR (13) R (14), -CHR (13) R (15),
  • R (13) and R (14) the same or different - (CH2) g - (CHOH) h - (CH 2 ) j- (CHOH) jR (17) or - (CH 2 ) gO- (CH2-CH 2 O ) h -R (24);
  • R (17) is hydrogen or methyl, g, h and i, identical or different, are zero, 1, 2, 3 or 4; j 1, 2, 3 or 4; and
  • R (16), the same or different, is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or together with the carbon atom carrying it, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms ;
  • Phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR (25) R (26); R (25) and R (26)
  • W, Y and Z represent a nitrogen atom or a C atom substituted by R (2) or R (3) or R (4); Rd) hydrogen, A, Hal, -CF3, -CH2F, -CHF 2 , -CH 2 CF 3 , -C 2 F 5 , -CN, -NO2,
  • Ethinyl or an X-R '; A alkyl with 1 to 6 carbon atoms;
  • X is oxygen, S or NR ";
  • R " is hydrogen, A or a cyclic methylene chain with 3 to 7 C atoms; R 'H, A, HO-A, HOOC-A, (C 3 -C 7 ) cycloalkyl, (C 6 -C 8 ) -Cycloalkyl- alkyl, CF 3 , CH 2 F, CHF 2 , CH 2 -CF 3 , Ph, -CH 2 -Ph or Het; Ph unsubstituted or one, two or three times by A, OA, NR'R ", Hal, CF3 substituted phenyl, naphthyl, or biphenylyl; Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O, and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, CF3, A, OH, OA, -X-R ', -CN,
  • R (2) and R (3) independently of one another R (5) -O-;
  • R (5) is hydrogen, A, (C r C 6 ) alkenyl or (C 3 -C 7 ) cycloalkyl;
  • R (2) in the meaning given;
  • R (6), R (7), R (8) and R (9) independently of one another H or A; or
  • R (8) (C 5 -C 7 ) cycloalkyl
  • R (9) cyano; Alk straight-chain or branched (C 1 -C 8 ) alkyl or (C 3 -C 8 ) cycloalkyl, which is unsubstituted or substituted by A once, twice or three times; or Alk is an ethenyl or ethynyl radical substituted by H, A, Ph or Het; (DE 41 27 026, DE 4337609, JP 07025768, Edward J. Cragoe, Jr.,
  • Z is an amino group -NR (1) R (2);
  • H a mono- or polynuclear heterocycle containing nitrogen, oxygen or sulfur atoms, which is unsubstituted or substituted with H, Hal or (C r C 4 ) alkyl; a phenyl radical, unsubstituted or substituted by a substituent selected from the group consisting of (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, Hal and OH; or R (2) 1 -piperidino, unsubstituted or substituted in the 4-position by an acyl radical of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid, (C r C 8 ) alkyl, which in turn can be substituted by OH or (C1 - C4) alkoxy or a (C 1 -C 4 ) alkoxy-substituted phenyl radical; or R (2) amidino which is unsubstituted or substituted with phenyl which is unsubstitute
  • R (2) hydrogen, unsubstituted or substituted (C 1 -C 8 ) alkyl, (C 3 -C 7 > cycloalkyl, OH, ⁇ C, -C 6 ) alkyl-O-, an aromatic radical or a group -CH2-R (20);
  • R (3) hydrogen, (C r C 8 ) -alkyl, substituted (C r C 8 ) -alkyl, (C 3 -C 7 > - cycloalkyl, an aromatic radical or a group -CH2-ROO) R (30) Alkenyl or alkynyl; R (6) and R ⁇ 7) independently of one another hydrogen, unsubstituted or substituted (C r C 8 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 8 ) alkanoyl, an arylalkano ⁇ l group with up to 10 C atoms, an aroyl group with up to 1 1 C atoms, an aromatic group or -CH2- R (60);
  • R (50) is hydrogen or ⁇ C r C 8 ) alkyl;
  • R ' is hydrogen, unsubstituted or substituted (C, -C 8 ) alkyl, in which the ring represents a saturated 3-8 membered heterocycle with an N atom, said substituted alkyl carries one or more groups selected from the group consisting of halogen, -OH, (C, -Cg) alkoxy, -CN, -COOH, (C 2 -C 6 ) alkoxycarbonyl, (C 2 -C 8 ) alkanoyl, arylalkanoyl with up to 10 C atoms, aroyl with up to 1 1 carbon atoms, an aromatic group, -CONR (4) (R5), R (4) and R (5), the same or different, hydrogen or (C 1 -C 8 ) alkyl; or R (4) and R (5) are bonded to one another and together form a 5-7-membered cyclic amine
  • E is an N atom or a CH group
  • R is hydrogen, unsubstituted or substituted by OH (C 1 -C 8 ) -
  • R (4) and R (5) independently of one another are hydrogen or (C 1 -C 8 ) -alkyl; the cyclic system of
  • Atoms a 5- or 6-membered heteroaryl radical with 1 -4 N atoms, a 5- or 6-membered heteroaryl group containing 1 or 2 N atoms and one
  • Aralkyl which is unsubstituted or substituted by one or more substituents from the groups halogen, (C r C 4 ) -alkyl, (C 1 -C 4 ) -alkyl-O- or -CF 3 , - (CH 2 ) m -CH 2 -T, m zero to 3; T -CO-OT ⁇ 1);
  • T hydrogen or (C1 -C4) alkyl; a benzo-fused unsaturated or dihydro-5 ring heterocycle
  • R (6) hydrogen, halogen, hydroxy, (C r C 10 ) -alkyl, (C r C 10 ) -alkyl-O-, phenoxy, (C r C 10 ) -alkyloxymethyloxy- or - (O) n SR ( 9); R (9) (C r C 10 ) alkyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl or phenyl which are unsubstituted or mono- or disubstituted by halogen, (C r C 4 ) -alkyl or ( C r C 4 ) alkyl-O-; R (7) and R (8) Hydrogen, halogen, hydroxy, (C r C 10 ) alkyl, (C r C 10 ) alkyl-O-, phenyl, phenoxy or (C r C 10 ) alkoxymethyloxy; or
  • R (12) is a single bond, -O-, - (O) n S-, -CO- or -CONH-;
  • R (13) is a single bond, phenyl, thienyl, pyridyl, thiazolyl,
  • R (14) is a single bond SO2-;
  • RdO hydrogen, (C r C 4 ) -alkyl or benzyl
  • R (1 1) (C r C 4 ) alkyl, phenyl or benzyl; or
  • RdO) and R (1 1) together form a (C 3 -C 10 ) alkylene group which is unsubstituted or substituted by -COOH, (C r C 5 ) alkoxycarbonyl, (C 2 -C 4 ) hydroxyalkylene or benzyl; or
  • NHE exchange inhibitors of subtype 3 are preferably used:
  • Y is oxygen, S or NR (7); A, B together a bond or
  • R (9) H, methyl, ethyl,
  • W is oxygen or NR (10);
  • RdO H or methyl; y zero or 1; or
  • R (1 1) H or methyl; or Z oxygen or -NR (12) -;
  • R (13) H or (C r C 4 ) alkyl; R ⁇ 7) hydrogen, (C r C 10 ) alkyl, (C 2 -C 10 ) alkenyl or R (8) -C n H 2n -; and their pharmaceutically acceptable salts;
  • Rd H, (C r C 8) -alkyl, unsubstituted or substituted by hydroxy, (C 3 -C 8 ) cycloalkyl, phenyl which is unsubstituted or substituted with 1-3 substituents from the group F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino or dimethylamino,
  • R (6) hydrogen, (C r C 8 ) alkyl, (C 3 -C 8 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl or benzyl, the aromatics being unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and R (10)
  • R (7) and R (8) are independently defined as R (6);
  • R (B) is independently defined as R (A); X 1, 2 or 3;
  • Rd hydrogen, (C r C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, -O t (CH 2 ) d C e F 2 ⁇ + 1 , F, Cl,
  • R (2), R (3), R (4) and R (5) are independently defined as R (1); but under the condition that at least one of the substituents R (1), R (2), R (3), R (4), R (5), R (A) and R (B) has an -O t (CH 2 ) d is C ⁇ F 2 ⁇ + 1 or an O r (CH 2 ) a C b F 2b + 1 group, and their pharmaceutically acceptable salts;
  • T, U, V, W, X, Y and Z are independently nitrogen or carbon; however with the restriction that X and Z are not nitrogen at the same time and that T, U, V, W, X, Y and Z do not bear a substituent if they
  • Group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; R (3), R (4), R (5), R (6) and R (7) independently of one another hydrogen, F, Cl, Br, I, -C ⁇ N, X k - (CH 2 ) p - (C q F 2q + 1 ), R (10a) -SO bm .
  • X is oxygen, S or NR (14 );
  • R (14) H or C r C 3 ) alkyl; bm zero, 1 or 2; p zero. 1 or 2; k zero or 1; q 1, 2, 3, 4, 5 or 6; RdOa), Rd Ob), R (11) and R (12) independently of one another ⁇ -C 8 ) alkyl, (C 3 -C 6 ) alkenyl,
  • RdOc) and R (13) independently are hydrogen or (C 1 -C 4 ) alkyl; or R (10b) and R (10c) and R (12) and R (13) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl can; or R (3), R (4), R (5), R (6) and R (7) independently of one another (C 1 -C 8 ) -alkyl, -C a
  • Y is oxygen, -S- or -NR (22) -; h, ad, ah independently of one another zero or 1; i, j, k, ae, af, ag, ao, ap and ak independently of one another zero.1, 2, 3 or 4; however, h, i and k are not simultaneously zero, ad, ae and ag are not simultaneously zero, and ah, ao and ak are not simultaneously zero,
  • R (23), R (24) R (25) and R (22) independently of one another are hydrogen or (C r C 3 ) -alkyl; or R (3), R (4), R (5), R (6) and R (7) independently of one another SR (29), -OR (30), -NR (31) R (32) or
  • R ⁇ 29), R (30), R (31) and R (33) independently of one another -C a H 2a - (C 1 -C 9 ) heteroaryl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, Methylamino and dimethylamino; a zero, 1 or 2;
  • R (32), R (34) and R (35) independently of one another are defined as R (29) or hydrogen, (C, -
  • R (96), R (97) and R (98) independently of one another (C ⁇ CgJ heteroaryl which is linked via C or N and which is unsubstituted or substituted with 1 to 3 substituents from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl;
  • R (51) (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (52) R (53); R (52) and R (53)
  • R (71) and R (72) independently of one another are hydrogen or methyl; u 1, 2, 3 or 4; v zero, 1, 2, 3 or 4; y, z, aa the same or different zero, 1, 2, 3 or 4; t 1, 2, 3 or 4;
  • R (68), R (70), R (54) and R (55), identical or different, are hydrogen or (C 1 -C 6 -alkyl); or R (69) and R ⁇ 70) or R (54) and R (55) together with the carbon atom carrying them a (C 3 -C 8 ) -
  • Phenyl which is unsubstituted or substituted by 1-3
  • R ⁇ 77) and R (78), the same or different, are hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 6 ) alkenyl or -C f H 2f -R (80); f zero, 1, 2, 3 or 4;
  • R (80) (C 5 -C 7 ) cycloalkyl or phenyl, which is unsubstituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methoxy and (C 1 -C 4 ) alkyl; or R (77) and R (78) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl; R (79) is defined as R (77) or the same as amidine; or R (3), R (4), R (5), R (6) and R (7) independently of one another NR (84a) R (85), OR (84b), SR (84c) or -C n H 2n -R (84d); n zero, 1, 2, 3 or 4;
  • R (84d) (C 3 -C 7 ) cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (16) R (17th ); R (16) and R (17)
  • R (84a), R (84b), R (84c) and R (85) independently of one another are hydrogen, (C 1 -C 8 ) -alkyl, ⁇ C * -C 3 ) -perfluoroalkyl or (CH 2 ) ax -R (84g); ax zero, 1, 2, 3 or 4;
  • R (84g) (C 3 -C 7 ) cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 Substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (84u) R (84v); R (84u) and R (84v)
  • R (84a) and R (85) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl, and their pharmaceutically acceptable salts;
  • R (7) and R (8) are independently defined as R (6); or R (7) and R (8) together have 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, sulfur, NH, N-CH 3 or N-benzyl;
  • R (B) is independently defined as R (A); X is zero, 1 or 2; Y is zero, 1 or 2;
  • R ⁇ 2), R (3), R (4) and R (5) are independently defined as R (1); but under the condition that at least one of the substituents R (A), R (B), R (C), R (D), R (1), R (2), R (4) or R (5) is one O r (CH 2 ) a C b F 2b + 1 -, O p (CH 2 ) f C g F 2g + 1 - or O t (CH 2 ) d C e F 2 ⁇ + 1 - group and R ⁇ 3) is not an O t (CH 2 ) d C e F 2e + 1 group; and their pharmaceutically acceptable salts; (HOE 95 / F 007 K - EP-OS 723 956, NZ 280 887) ah) Benzoylguanidines of the formula I.
  • R (8) and R (9) or R (9) and R (10) or R (7) and R ⁇ 10) a group C a H 2a ; a 2, 3, 4 or 5; where in the case of a 3, 4 or 5 a methylene group of the group C a H 2a can be replaced by a hetero atom group O, SO m or NR (11); m zero, 1 or 2; R (11) is hydrogen or methyl; or
  • R (6) a basic heteroaromatic ring system with 1-9 C atoms; AC b H 2b ; b 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein in group C b H 2b one or two methylene groups are selected by one of the groupings from the group consisting of -O-, -CO-, -CH [OR (20)] -, -SO m -, -NR (20) -, -NR (20) -CO-, -NR (20) -CO-NH-, -NR (20) -CO-NH-SO 2 -
  • R (19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms
  • R (20) is hydrogen or methyl
  • B is a phenylene or naphthylene radical
  • R (12) and R (13) independently of one another hydrogen, methyl, F, Cl, Br, J, CF 3 or -SO w -R (14);
  • R (15) and R (16) independently of one another are hydrogen or alkyl having 1, 2,
  • R (21) is hydrogen or methyl; m zero, 1 or 2; and the other substituents R (1) and R (2) and R (3) independently of one another are hydrogen, F, Cl, Br, J, -CN, - (C r C 8 ) -alkyl, - (C 2 - C 8 ) -alkenyl, -NR (35) R (36) or R (17) -C 8 H 2g -Z h -; g zero, 1, 2, 3 or 4; h zero or 1; R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (35) and R (36) together 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -NCH 3 or -N-benzyl; Z -O-, -CO-, -SO v -, -NR (18) -, -NR (18) -CO-, -NR (18) -CO
  • R (18) is hydrogen or methyl; v zero, 1 or 2; R (17) is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or C k F 2k + 1 -; k 1, 2 or 3, or R (17) pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl , Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl and methoxy; or R (17) - (C 3 -C 8 ) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF 3 , methyl, hydroxy, methoxy, - NR (37) R (38), CH
  • 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 -C r F 2r + 1 ; R (32), R (33) and R (34) independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms; r 1, 2, 3 or 4;
  • Rd) and R (2) independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms.
  • O-alkyl with 1, 2, 3 or 4 C-atoms, OC ( O) -alkyl with 1, 2, 3 or 4 C-atoms or C m H 2m -NR (12) R ⁇ 13);
  • R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; m nuill, 2, 3 or 4;
  • R (1 1) C r C 4 alkyl, C r C 4 alkynyl, aryl, substituted aryl, NH 2 , NH-C r C 4 alkyl, N- (C r C 4 alkyl) 2 , SO 3 H, SO 2 -alkyl, SO 2 - alkylaryl, SO 2 -N- (alkyl) 2, SO 2 -N (alkyl) (alkylaryl);
  • R (7), R (8), R (9) and R (10) independently of one another are hydrogen, alkyl, cycloalkyl, aryl, alkylaryl; or
  • R (8) and R (9) together form part of a 5, 6 or 7-membered heterocyclic ring
  • R (1), R (2) and R (3) independently of one another are -Y- [4-R (8) -phenyl], -Y- [3-R (8) -phenyl] or -Y- [2- R (8) -phenyl], where the phenyl is in each case unsubstituted or substituted with 1-2 substituents from the group consisting of F, Cl, -CF 3 , methyl, hydroxy, methoxy and -NR (96) R ( 97); R (96) and R (97) independently of one another are hydrogen or -CH 3 ; Y is a bond, CH 2 , oxygen, -S- or -NR (9);
  • R ⁇ 9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (8) SO a [NR (98)] b NR (99) R (10); a 1 or 2; b 0 or 1; a + b 2;
  • R (98), R (99) and R (10) independently of one another are hydrogen, - (C r C 8 ) -alkyl, benzyl,
  • R (1 1), R (12), R (13), R (37), R (38), R (43) and R (44) independently of one another are hydrogen, - (C r C 8 ) -alkyl or benzyl : R (39), R (40), R (41) and R (42) independently of one another are hydrogen, - (C r C 8 ) -alkyl or - ⁇ C 0 -C 3 ) -alkylene-phenyl, the phenyl not is substituted or substituted with 1-3 substituents selected from the group consisting of F, CI, -CF 3 , methyl and methoxy; or R (99) and R (10) together 4-6 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -N-CH 3 or -N-benzyl; or
  • R (8) SO a [NR (98)] b NR (95) -C [ NR (94)] - NR (93)
  • R (92); R (92), R (93), R (94) and R (95) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or Rd), R (2) and R ⁇ 3) independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl, methoxy; or Rd), R (2) and R (3) independently of one another are hydrogen, - (C r C 8 ) -alkyl, - (C 2 -C 8 ) -alkenyl or
  • R (18) is hydrogen or - (C r C 4 ) -alkyl;
  • R (21) and R (22) independently of one another are hydrogen, - (C r C 8 ) -alkyl, - (C r C 8 ) -alkanoyl, - (C., - C 8 ) -alkoxycarbonyl, benzyl, benzyloxycarbonyl; or
  • R (23), R (24) independently of one another
  • R (26) and R (27) independently of one another are defined as R (25) or hydrogen or (C r C 4 ) -alkyl, or Rd), R (2) and R (3) independently of one another (C ⁇ CgJ-heteroaryl -N-oxide which is linked via C or N and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (1), R (2) and R (3) independently of one another -SR ⁇ 28), -OR (28), -NR (28) R (29) or
  • R (28) -C 8 H 2g - (C 1 -C 9 ) heteroaryl-N-oxide which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , Methoxy, hydroxy, amino, methylamino and dimethylamino; g zero, 1 or 2; R (29), R (30) independently defined as R (28), hydrogen or (C r C 4 ) alkyl; or Rd), R (2) and R (3) independently of one another hydrogen, F, Cl, Br, I, -C N, T- (CH 2 ) h -
  • T is a bond, oxygen, -S- or -NR (47);
  • I zero, 1 or 2; h zero, 1 or 2; i 1, 2, 3, 4, 5 or 6;
  • R (31), R (32), R (34> and R (45) independently of one another - (C 1 -C 8 ) alkyl, - (C 3 -C 6 ) alkenyl,
  • R ⁇ 47 hydrogen or alkyl having 1, 2 or 3 carbon atoms
  • R (33) and R (46) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (32) and R (33) and R (45) and R (46) together have 5 or 6 methylene groups, one of which is a CH 2 group by oxygen, -S-, -NH-, -NCH 3 or -N- Benzyl can be replaced; or Rd), R (2) and R (3) independently of one another R (51) -AGD-;
  • R (51) is a basic protonatable residue, i.e. an amino group
  • R (52), R (53), R (54) and R (55) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4
  • R (56) is hydrogen or methyl; or R (51) is a basic heteroaromatic ring system with 1-9 C atoms;
  • A is a group C ⁇ H 2 ⁇ ; e zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where in the group C ⁇ H 2e a carbon atom is defined by one of the groupings -O-, -CO-, -CH (OR (57)] -, -SO r -, -NR (57) -, -NR (57 ) - CO-, -NR (57) -CO-NH-, -NR (57) -CO-NH-SO 2 - or -NR (57) -SO 2 - can be replaced; r zero, 1 or 2;
  • G is a phenylene radical
  • R (58) and R (59) independently of one another hydrogen, methyl, methoxy, F, Cl, Br, J, CF 3 or -SO S -R (60);
  • R (61) and R (62) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D -C v H 2v -E w -; v zero, 1, 2, 3 or 4;
  • Group can be replaced by oxygen, -S-, SO 2 , -NH-, -NCH 3 or -N-benzyl;
  • R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (69), -NR (70) R (71) or -C 2 F 2z + 1 ;
  • R (69), R (70) and R (71) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms.
  • R (6) and R (7) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; X is oxygen or NR (72);
  • R (72) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; and their pharmaceutically acceptable salts; (HOE 95 / F 1 1 5 - EP 744 397, NZ 286 622) al) alkenylcarboxylic acid guanidides of formula I bearing fluorophenyl groups
  • R (6) is hydrogen, (C r C 8 ) -alkyl, (C 3 -C 8 ) -cycloalkyl or phenyl, the phenyl group not being substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (9) R (10); R (9) and RdO)
  • R (7) is independently defined as R (6); Rd), R (2), R (3), R ⁇ 4) and R (5) independently of one another are hydrogen or F; however, at least one of the radicals R (1), R (2), R (3), R (4) and R (5) must be fluorine; and their pharmaceutically acceptable salts;
  • X CR (16) R (17), O, S or NR (18); R (16), R (17) and R (18) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; a zero or 1;
  • alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms
  • alkylene T with 1, 2, 3, 4, 5, 6, 7 or 8 C atoms in the alkylene group
  • T, T-alkylene with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the alkylene group
  • T NR (20) O, S or phenylene, the phenylene being unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and
  • R (20), R (21) and R ⁇ 22) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; b zero or 1;
  • R (24) and R (25) independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or R (24) and R (25) together 4 or 5 methylene groups, of which one CH 2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; wherein the N-containing heterocycles are N- or C-bridged and are not substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR (27) R (28); R (23), R (27) and R (28) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; and the respective other substituents R (1)
  • R (12); R (11) and R (12) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; R (6) and R (7) independently of one another hydrogen, F, Cl, Br, I, CN, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 C atoms, or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , Methyl, methoxy and NR
  • one of the radicals R (1), R (2), R (3) and R (4) -CO-N C (NH 2 ) 2 ; and the other radicals R (1), R (2), R (3) and R (4):
  • Rd hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -OR (32), -NR (33) R (34) or CF 3 ;
  • R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (2) and R (4) independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl , Br, I, -CN, (C 2 -C 8 ) alkanoyl, (C 2 -C 8 ) alkoxycarbonyl, formyl, carboxy, -CF 3 , methyl, methoxy; or R (2) and R (4) independently of one another R (22) -SO 2 -, R (23) R (24) N-CO-, R (28) -CO- or
  • R (22) and R (28) independently of one another are methyl or -CF 3 ;
  • R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R ⁇ 35) and R (36) together 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -NCH 3 or -N-benzyl;
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF. 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (25) - (C r C 9 ) heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 # CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino ; R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (5) alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X- (CH 2 ) y -CF 3 or phenyl, which is unsubstituted
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF. 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (25 - (C r C 9 ) heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino;
  • R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (4) CF 3 , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 carbon atoms, - (C 3 -C
  • R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; the other radicals R (2) and R (4) independently of one another hydrogen, F, Cl, Br, I, OH, -CN, CF 3 ,
  • -CO-N C (NH 2 ) 2 , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 C- Atoms or - (CH 2 ) m R (14); m zero, 1 or 2;
  • R (23), R (24), R (29) and R (30) independently of one another are hydrogen or methyl; or the respective other radicals
  • R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF.
  • R (25) - (C r C g ) heteroaryl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxy, amino, methylamino and dimethylamino
  • R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; one of the radicals R (6), R (7), R (8), R ⁇ 9) and R (10)
  • -CO-N C (NH 2 ) 2 ;
  • the other radicals R (6) and R (10) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (132), -NR (133) R (134) or CF 3 ;
  • R (132), R (133) and R (134) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (135) and R (I 36) together have 4-7 methylene groups, of which one CH 2 group can be replaced by oxygen, -S-, -NH-, -NCH 3 or -N-benzyl; the other R (8)
  • R (126) and R (127) independently of one another are defined as R (125) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
  • a absent, -NR (1 1) -CO-, -NR (12) -CO-NR (13) -, -NR (17) -CO-NR (18) -SO 2 -, - NR (19) - SO 2 -, -SO 2 -NR (19) -SO 2 -NR (19) -CO 2 -NR (19) -CO 2 -NR (19) -CO-, -O-CO-NR (19) -SO 2 - or -CR (20) CR (21) -; R (1 1), R (12), R (13), R (17), R (18), R (19), R (20) and
  • R (41) and R ⁇ 42) independently of one another hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, perfluoroalkyl with 1, 2, 3 or 4 carbon atoms, or R (41) and R (42) together 4 or 5 methylene groups, one of which is CH 2 - group can be replaced by oxygen, S, NH, N-CH 3 or N-benzyl; and the other substituents R (1), R (2) and R (3) independently of one another are H, F, Ci, Br, I, CN, -O na -C ma H 2ma + 1 or -
  • R (10) cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, the phenyl not being substituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , methyl and methoxy;
  • R (4) and R (5) independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of from F, Cl, CF 3 , methyl, methoxy and NR (14)
  • R (14) and R (15) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atom
  • NHE inhibitors are therefore suitable, for example, for the treatment of ischemically induced arrhythmias, different forms of angina pectoris, for heart transplants, in cardiac surgery and for angioplasty surgical interventions.
  • Other described indications for NHE inhibitors are stroke and cerebral edema, shock and proliferation-related diseases such as atherosclerosis, late diabetic damage, fibrotic diseases and organ hypertrophy.
  • NHE inhibitors can stimulate respiration by increasing the chemosensitivity of the respiratory chemoreceptors.
  • These chemoreceptors are largely responsible for maintaining orderly breathing. They are activated by hypoxia, a drop in pH and an increase in CO2 (hypercapnia) in the body and lead to an adjustment of the minute ventilation. Breathing is particularly susceptible to disruption during sleep and is highly dependent on the activity of the chemoreceptors.
  • An improvement in respiratory drive through stimulation of the chemoreceptors with substances that inhibit sodium-proton exchange leads to an improvement in breathing in the following clinical conditions and diseases: impaired central respiratory drive (e.g. central sleep apnea, sudden child death, postoperative hypoxia), muscular-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders when adapting to high mountains, obstructive and mixed form of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.
  • impaired central respiratory drive e.g. central sleep apnea, sudden child death, postoperative hypoxia
  • muscular-related breathing disorders e.g. central sleep apnea, sudden child death, postoperative hypoxia
  • muscular-related breathing disorders e.g. central sleep apnea, sudden child death, postoperative hypoxia
  • muscular-related breathing disorders e.g. central sleep apnea, sudden child death, postoperative hypoxia
  • muscular-related breathing disorders e.g. central sleep ap
  • the compounds mentioned are therefore advantageously used individually or in groups for the manufacture of a medicament for the treatment of disturbed respiratory drive; for the manufacture of a medicament for the treatment of muscular breathing disorders; for the manufacture of a medicament for the treatment of breathing disorders after long-term ventilation; for the manufacture of a medicament for the treatment of breathing disorders when adapting to high mountains; for the manufacture of a medicament for the treatment of obstructive, central and mixed forms of sleep apneas; for the manufacture of a medicament for the treatment of acute and chronic lung diseases with hypoxia and hypercapnia; especially for the manufacture of a medicament for the treatment of the conditions mentioned in combinations with an inhibitor of carbonic anhydratase, preferably with acetazolamide.
  • a combination of an NHE inhibitor with a carbonic anhydrase inhibitor e.g. acetazolamide
  • a carbonic anhydrase inhibitor e.g. acetazolamide
  • sodium proton exchange inhibitors is claimed as a novel medicine to improve breathing, respiratory stimulants, and the combination of sodium proton exchange inhibitors with carbonic anhydrase inhibitors.

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Abstract

Les principes actifs identifiés comme étant des inhibiteurs de l'échangeur Na+/H+ (NHE) sont particulièrement indiqués pour préparer un médicament stimulant la respiration. Ces principes actifs sont particulièrement bien adaptés au traitement des apnées du sommeil ou d'autres troubles de la respiration.
PCT/EP1996/005614 1995-12-27 1996-12-13 UTILISATION D'INHIBITEURS DE L'ECHANGEUR CELLULAIRE Na+/H+ (NHE) POUR PREPARER UN MEDICAMENT STIMULANT LA RESPIRATION WO1997024113A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
SK883-98A SK88398A3 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular na+/h+ exchanger (nhe) for the preparation of a drug for respiratory stimulation
BR9612287-0A BR9612287A (pt) 1995-12-27 1996-12-13 Emprego de inibidores de troca de na+ /h+ (nhe) celular para a preparação de um medicamento para estimular a respiração
AU13720/97A AU717247B2 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular Na+/H+ exchanger (NHE) for the production of a medicament for respiratory stimulation
KR1019980704927A KR19990076802A (ko) 1995-12-27 1996-12-13 호흡 자극용 약제를 제조하기 위한 세포성 na+/h+ 교환기(nhe) 억제제의 용도
EP96943956A EP0869779A1 (fr) 1995-12-27 1996-12-13 UTILISATION D'INHIBITEURS DE L'ECHANGEUR CELLULAIRE Na?+ /H?+ (NHE) POUR PREPARER UN MEDICAMENT STIMULANT LA RESPIRATION
PL96327693A PL327693A1 (en) 1995-12-27 1996-12-13 Application of cellular na+/h+(nhe) ions exchanger inhibitors in production of a respiration stimulating drug
IL12511496A IL125114A0 (en) 1995-12-27 1996-12-13 Use of inhibitor of the cellular na+/h+ exchanger (nhe) for the production of a medicament for respiratory stimulation
NO982989A NO982989L (no) 1995-12-27 1998-06-26 Anvendelse av inhibitorer av den cellulµre Na+/H+-utbytteren (NHE) for fremstilling av et medikament for respiratorstimulering

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19548812.1 1995-12-27
DE19548812A DE19548812A1 (de) 1995-12-27 1995-12-27 Verwendung von Inhibitoren des zellulären Na·+·/H·+·-Exchangers (NHE) zur Herstellung eines Medikaments zur Atemstimulation

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WO1997024113A1 true WO1997024113A1 (fr) 1997-07-10

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EP (1) EP0869779A1 (fr)
KR (1) KR19990076802A (fr)
CN (1) CN1207676A (fr)
AU (1) AU717247B2 (fr)
BR (1) BR9612287A (fr)
CA (1) CA2241531A1 (fr)
CZ (1) CZ202198DA3 (fr)
DE (1) DE19548812A1 (fr)
HU (1) HUP9900807A3 (fr)
IL (1) IL125114A0 (fr)
MX (1) MX9805141A (fr)
NO (1) NO982989L (fr)
PL (1) PL327693A1 (fr)
SK (1) SK88398A3 (fr)
TR (1) TR199801235T2 (fr)
WO (1) WO1997024113A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021582A1 (fr) * 1999-09-22 2001-03-29 Merck Patent Gmbh Derives biphenyliques utilises comme inhibiteurs de nhe-3
WO2002046169A1 (fr) * 2000-12-05 2002-06-13 Aventis Pharma Deutschland Gmbh 2-anilino-benzimidazoles substitues et leur utilisation en tant qu'inhibiteurs de nhe
WO2014029983A1 (fr) 2012-08-21 2014-02-27 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
KR20170034897A (ko) 2014-07-25 2017-03-29 다이쇼 세이야꾸 가부시끼가이샤 헤테로아릴로 치환된 페닐테트라히드로이소퀴놀린 화합물
WO2018129552A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés utiles pour le traitement de troubles du tractus digestif
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
WO2018129557A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibiteurs d'antiport à médiation par nhe
EP3351248A1 (fr) 2008-12-31 2018-07-25 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
WO2019060051A1 (fr) 2017-08-04 2019-03-28 Ardelyx, Inc. Dérivés d'acide glycyrrhétinique de traitement de l'hyperkaliémie
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
WO2020163642A1 (fr) 2019-02-07 2020-08-13 Ardelyx, Inc. Dérivés d'acide glycyrrhétinique destinés à être utilisés dans le traitement de l'hyperkaliémie
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

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WO2001021582A1 (fr) * 1999-09-22 2001-03-29 Merck Patent Gmbh Derives biphenyliques utilises comme inhibiteurs de nhe-3
WO2002046169A1 (fr) * 2000-12-05 2002-06-13 Aventis Pharma Deutschland Gmbh 2-anilino-benzimidazoles substitues et leur utilisation en tant qu'inhibiteurs de nhe
US6686384B2 (en) 2000-12-05 2004-02-03 Aventis Pharma Deutschland Gmbh Substituted benzimidazoles, processes for their preparation, their use as medicaments, and medicaments comprising them
US6958357B2 (en) 2000-12-05 2005-10-25 Aventis Pharma Deutschland Gmbh Substituted benzimidazoles, processes for their preparation, their use as medicaments, and medicaments comprising them
EP3939964A1 (fr) 2008-12-31 2022-01-19 Ardelyx, Inc. Combinaisons d'inhibition d'un antiport a mediation par nhe dans le traitement de troubles associes a une retention de fluide ou a une surcharge de sel et de troubles du tractus gastro-intestinal
EP3351248A1 (fr) 2008-12-31 2018-07-25 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
WO2014029983A1 (fr) 2012-08-21 2014-02-27 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
EP3988120A1 (fr) 2013-04-12 2022-04-27 Ardelyx, Inc. Composés de liaison à nhe3 et procédés d'inhibition du transport de phosphate
US10940146B2 (en) 2013-04-12 2021-03-09 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
EP3552630A1 (fr) 2013-04-12 2019-10-16 Ardelyx, Inc. Composés de liaison à nhe3 pour inhiber le transport de phosphate
US9932331B2 (en) 2014-07-25 2018-04-03 Taisho Pharmaceutical Co., Ltd. Phenyl tetrahydroisoquinoline compound substituted with heteroaryl
KR20170034897A (ko) 2014-07-25 2017-03-29 다이쇼 세이야꾸 가부시끼가이샤 헤테로아릴로 치환된 페닐테트라히드로이소퀴놀린 화합물
WO2018129557A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibiteurs d'antiport à médiation par nhe
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
US11147884B2 (en) 2017-01-09 2021-10-19 Ardelyx, Inc. Inhibitors of NHE-mediated antiport
WO2018129552A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés utiles pour le traitement de troubles du tractus digestif
US11242337B2 (en) 2017-01-09 2022-02-08 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
WO2019060051A1 (fr) 2017-08-04 2019-03-28 Ardelyx, Inc. Dérivés d'acide glycyrrhétinique de traitement de l'hyperkaliémie
EP4397366A2 (fr) 2017-08-04 2024-07-10 Ardelyx, Inc. Dérivés de l'acide glycyrrhétinique pour le traitement de l'hyperkaliémie
WO2020163642A1 (fr) 2019-02-07 2020-08-13 Ardelyx, Inc. Dérivés d'acide glycyrrhétinique destinés à être utilisés dans le traitement de l'hyperkaliémie
EP4234016A2 (fr) 2019-02-07 2023-08-30 Ardelyx, Inc. Dérivés d'acide glycyrrhétinique destinés à être utilisés dans le traitement de l'hyperkaliémie
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

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DE19548812A1 (de) 1997-07-03
AU717247B2 (en) 2000-03-23
IL125114A0 (en) 1999-01-26
HUP9900807A2 (hu) 1999-07-28
BR9612287A (pt) 2005-05-24
NO982989D0 (no) 1998-06-26
CZ202198DA3 (cs) 1998-11-11
PL327693A1 (en) 1998-12-21
AU1372097A (en) 1997-07-28
KR19990076802A (ko) 1999-10-15
HUP9900807A3 (en) 2000-11-28
MX9805141A (es) 1998-10-31
NO982989L (no) 1998-08-06

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