SK88398A3 - Use of inhibitors of the cellular na+/h+ exchanger (nhe) for the preparation of a drug for respiratory stimulation - Google Patents

Abstract

The active ingredients identified as NHE inhibitors are particularly suitable for the preparation of a drug for respiratory stimulation. They are particularly good for treating sleep apnea or other respiratory disorders.

Description

The use of Na ⁺ / H ⁺ exchange inhibitors for the manufacture of a medicament for treating respiratory stimulation disorders is described. Substituted benzoylguanidines, ortho-substituted benzoylguanidines, diacyl-substituted guanidines, phenyl-substituted alkylcarboxylguanidides, heteroaroylguanidines, bicyclic heteroaroylguanidines, indenoylguanidines, substituted guiocyanide derivatives, substituted thiophenylalkenyl derivatives, substituted thiophenylalkenyl derivatives are substituted Na ⁺ / H ⁺ derivatives. parts, as well as substituents thereof. They can be used in combination with a carbonic anhydrase inhibitor.

TV 39 3 - 7 <f

Use of Na ⁺ / H ⁺ exchange inhibitors for the manufacture of a medicament intended to stimulate respiration

Technical field

The invention relates to the use of Na ⁺ / H ⁺ exchange inhibitors for the manufacture of a medicament for the treatment of a breathing stimulation disorder.

Known active substances which have been identified as Na ⁺ / H ⁺ exchange inhibitors are guanidine derivatives, preferably acylguanidines, which are described, inter alia, in the following publications and patent documents: Edward J. Crgoe, Jr., Diuretics, Chemistry, Pharmacology and Medicine, J.Wiley and Sons (1983), 303-341, in addition to the compounds of the following formulas:

(A) a benzoylguanidine of the formula I (HOE 89 / F

288-US 5292755

wherein one of R 6 or R ⁸ -S (O) _n or R ⁷ R ⁸ N-O 2 - and the other of R 6 or R 6 is hydrogen, fluoro, chloro, bromo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or phenoxy group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, methyl group and methoxy group, or

the second of R ¹ or R ² being R ⁶ -S (O) _n or R ⁷ R ⁸ N- wherein n is 0, 1 or 2,

R ⁶ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a cyclopentylmethyl group, a cyclohexylmethyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, methyl a group and a methoxy group, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ⁷ represents a phenyl- (CH ₂ ) _{m group} , wherein m represents 1 to 4, or

R ⁷ represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group, or

R ⁷ and R ⁸ together represent a straight or branched chain containing 4 to 7 carbon atoms, which chain may be interrupted by an oxygen atom, an atom

Q is sulfur or R, wherein

R 7 represents a hydrogen atom or a methyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system,

R ³ , R ⁴ , and R ⁵ independently of one another represent a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms, or

R ³ and R ⁴ together represent an alkylene chain containing from 2 to 4 carbon atoms or

R ⁴ and R ⁵ together represent an alkylene chain containing 4 to 7 carbon atoms, as well as pharmaceutically acceptable salts thereof,

(b) a benzoylguanidine of the formula I (HOE 92 / F

34-US 5373924)

in which

R ¹ is R ⁴ -SO 2 or R ⁵ R ⁶ N-SO 2 -, wherein m is 0, 1 or 2,

R ⁴ and r ⁵ are C 1 -C 8 alkyl, C 3 -C 5 alkenyl or -C _n H _{2 n} -R ⁷ where n is 0, 1, 2, 3 or 4,

R ⁷ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents

selected from the group consisting of fluorine atom, chlorine atom, CF ₂ group, methyl group, methoxy group and NR ⁸ R ^{9 group} , wherein:

Q Q

R @ 1 and R @ 2 are hydrogen or C1 -C4 alkyl, or

R ⁵ represents a hydrogen atom,

R ⁶ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or cc

R ³ and R 0 together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH _{3 group} or an N-benzyl group,

ABOUT

R is H, F, Br, alkyl having 1 to 4 carbon atoms, a group -O- (CH _{2) m} CpF ₂ p _{+ 1,} or a group -XR ¹⁰ in which m is 0 or 1, p is 1, 2 or 3,

X is O, S or NR ^11,

R ¹⁰ is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, cyclohexylmethyl, cyk12 lopentylmetylovú group or -C _n H _2n -R, n is 0, 1, 2, 3 or 4.

R ¹² represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom,

Q Q

CF ₃ , methyl, methoxy and NRR where

R ⁸ and R ⁸ represent a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; or

R ¹⁰ and R ¹¹ together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ³ is as R ¹ or is C 1 -C 6 alkyl, nitro, cyano, trifluoromethyl, fluoro, chloro, bromo, iodo, or -XR ¹⁰ , wherein:

X is O, S or NR ^11, R ¹⁰ is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, cyclohexylmethyl,

2 cyclopentylmethyl or -C _n H _2n -R, n is 0-4,

R ¹² represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, a methyl group, a methoxy group and an NR ⁸ R ⁹ group wherein

R ⁸ and R ⁹ are hydrogen or C 1 -C 4 alkyl, r H is C 1 -C 3 alkyl, or

R ¹⁰ and R ¹¹ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, and pharmaceutically acceptable salts thereof,

(c) ortho-substituted benzoylguanidine of the formula I (HOE 92 / F 035 EP-OS 556673)

(I)

in which

R ¹ represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl group having 1 to 6 carbon atoms or a -XR ⁶ group, wherein:

X is O, S, NR, or Y-ZO, n

Y is O or NR,

Z represents a carbon atom or a SO group,

R ⁶ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, cyclohexylmethyl, cyclopentylmethyl group, a - (C ^) m ^C n ^F 2p + ^{l, and} ^ ^e ^ ⁰ is - C _n H _2n -R,

m means 0 or 1, P means 1 to 3, n means 0 to 4, R ⁸ means a phenyl group which is unsubstituted

or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CFg group, methyl group, methoxy group and NR ⁹ R ^{10 group} , wherein:

R ⁹ and R ¹⁰ are hydrogen or (C 1 -C 4) -alkyl,

R ⁷ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, or

R ⁸ and R ⁷ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

-J g

R ⁵ represents a hydrogen atom or a group -XR where

X is O, S, NR, or Y-ZO,

R ⁷ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

Y represents an oxygen atom or a NR group, wherein Y is bonded to the phenyl radical of formula I,

Z represents a carbon atom or a SO group,

R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a cyclohexylmethyl group, a cyclopentylmethyl group, a - (CH 2) m ^< -p ^F 2p + 1 group ^{and a 1e} b ° group - CnH _2n -R ⁸ ,

m means 0 or 1 P means 1 to 3 n means 0 to 4 R ⁸ means a phenyl group which is unsubstituted

or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , methyl, methoxy and NR ⁹ R ¹⁰ , wherein:

R ⁹ and R ¹⁸ represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

Together R 4 and R 5 denote 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

R ² and R ⁴ , which are the same or different, represent a group R ¹¹ -SO 8 - or a group R ¹² R ¹³ N-SO ₂ -, q is 0 to 2, r H is an alkyl group containing 1 to 4 carbon atoms which is unsubstituted or which bears, as a substituent, a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF 3 group, methyl group, methoxy group and NR ⁹ R ^{10 group} , wherein:

R ⁹ and R ¹⁰ represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ¹² and R ¹³ have the meanings as R ⁶ and R ⁷ , or one of the two radicals R ² or R ⁴ is hydrogen or has the meaning of R ³ and

R ⁵ represents a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom or a methoxy group, as well as pharmaceutically acceptable salts thereof,

(d) benzoylguanidine of formula I (HOE 92 / F

036-US-5364868)

NH ₂

in which

R ¹ or R ² represents an amino group -NR ³ R ⁴ wherein R ³ and R ⁴ , which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, or

R ³ is phenyl- (CH ₂ ) p -, wherein p is 0, 1, 2, 3 or 4 or

R ³ represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group, or

R ³ and R ⁴ together represent a straight or branched methylene chain having 4 to 7 carbon atoms, wherein one member of the -CH ₂ -methylene chain may be replaced by an oxygen atom, a sulfur atom or a NR ⁵ group where

R ⁵ represents a hydrogen atom or a lower alkyl group, and the other of the substituents R ⁴ or R represents a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group containing 1. to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, CF _3, ^C _m ^F 2 m + l ^_CH 2 ^_ 'benzyl or phenoxy, where the phenyl radical is unsubstituted or substituted by 1 or 2 substituents selected from a group including a methyl group, a methoxy group, a fluorine atom and a chlorine atom, m represents 1, 2 or 3,

as well as its pharmaceutically acceptable salts,

(e) benzoylguanidine of the formula I (92 / F

197 K-NZ 248013)

(I)

in which

R ¹ is a group R ⁴ -SO 2 or a group R ⁵ R ⁶ N-SO 2 wherein m is 0, 1 or 2,

R ⁴ and R ⁵ are C 1 -C 8 alkyl, C 3 -C 6 alkenyl or -C _n H _{2 n} -R, where n is 0, 1, 2, 3 or 4,

R ⁷ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁸ R ^{9 group} , where

R ⁸ and R ⁹ represent a hydrogen atom or a (C 1 -C 4) alkyl group;

r5 represents a hydrogen atom,

R ⁶ represents a hydrogen atom or a C 1 -C 4 alkyl group or r ^{5 and} r ⁶ together represent 4 or 5 methylene groups, of which one CH 2 group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or N-benzyl,

R ² is H, straight or branched alkyl of 5 to 8 carbon atoms, -CR ¹³ = CHR ¹² group, or -CsCR ^12,

R ¹² represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ¹⁴ -R ¹⁵ group wherein

R ( ⁴⁾ and R ( ¹ ) are hydrogen or (C1-C4) -alkyl or

R ² represents a heteroaryl group containing 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group, or

R ¹² represents an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups, or

R ¹² represents a cycloalkyl group having 3 to 8 carbon atoms,

R ¹³ represents a hydrogen atom or a methyl group;

R ¹² represents a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkylalkyl group having a cycloalkyl radical having 3 to 8 carbon atoms and an alkyl radical having 1 to 4 carbon atoms, a phenyl group, a C 8 H ₅ -alkyl group in which the alkyl radical contains 1 up to 4 carbon atoms, naphthyl, biphenylyl, 1,1-diphenylalkyl, wherein the alkyl moiety contains 1 to 4 carbon atoms, cyclopentadienyl, pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, indenyl, quinolyl, indolyl, benzofurans

a benzyl group, a benzothienyl group, a benzothiazolyl group, a benzoxazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, an isoxazolyl group, an isothiazolyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an isoquinolinyl group, , quinazolinyl or cinolinyl,

R is as R 1, wherein the aromatic substituents R ² and R ³ are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , alkyl of 1 to 4 carbon atoms, alkoxy containing 1-4 carbon atoms or the group NrIGrU in which R R Q and R R l are hydrogen or an alkyl group containing 1 to 4 carbon atoms, as well as pharmaceutically acceptable salts thereof,

(f) benzoylguanidine of the formula I (HOE 92 / F 3 03 K-EP-OS 589336, NZ 248 703)

In which

1

R or R is R-S (O) _n or ^R &^lt; ¹ &gt;

N — O ₂ S ~

5 /

R 1 and the other of R ¹ or R ² are hydrogen, hydroxy, fluorine, chlorine, iodine, (C 1 -C 4) -alkyl,

(C 1 -C 4) alkoxy, benzyloxy or phenoxy group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, methyl group, methoxy group, hydroxy group or benzyloxy group R 3 -S (O) _n , -NR ⁴ R 4, or 3,4-dehydropiperidine, wherein r 3 is C 1 -C 6 alkyl, C 5 -C 7 cycloalkyl, cyclopentylmethyl, cyclohexylmethyl or phenyl which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, methyl group and methoxy group,

R ⁴ and r ⁵ , which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ⁴ represents a phenyl- (C 1-4) _{m group} , wherein m represents 1, 2, 3 or 4, or

R ⁴ represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group; or

R ⁴ and R ⁵ together represent a straight or branched chain containing 4 to 7 carbon atoms, which chain may additionally be interrupted by an oxygen atom, a sulfur atom or an NR ⁶ group, where

R represents a hydrogen atom or a methyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system, n represents 0, 1 or 2, and pharmaceutically acceptable salts thereof,

(g) isoquinoline of general formula I (92 / F 304-US 5416094)

(D

in which

R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group, an alkenyl group, a substituted aminoalkyl group or an aryl or heteroaryl ring, said rings being unsubstituted or substituted by 1 to 3 groups selected from halogen, nitro, amino a group, a mono (lower alkyl) amino group, a di (lower alkyl) amino group, a lower alkyl group, a benzyloxy group, a phenoxy group, a hydroxy group, a trifluoromethyl group, n

R represents a hydrogen atom, a halogen atom, an alkyl group or an aryl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, an amino group, a mono (lower alkyl) amino group, di (lower) alkyl) amino, lower alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxy,

G is a group of formula VII

(VII)

X ^2, X ³ and X ⁴ independently of one another are hydrogen, halogen, nitro, amino, alkyl, sulfonamide, mono (lower alkyl) amino, di (lower alkyl) amino; , lower alkylo13

benzyloxy, hydroxy,

X ¹ is hydrogen, oxygen, sulfur or NR ⁷ where

R ⁷ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group, an alkenyl group, a substituted aminoalkyl group or an aryl or heteroaryl ring, said rings being unsubstituted or substituted by 1 to 3 substituents selected from halogen, nitro, amino a group, a mono (lower alkyl) amino group, a di (lower alkyl) amino group, a lower alkyl group, a lower alkoxy group, a benzyloxy group, a phenoxy group, a hydroxy group and a trifluoromethyl group, each alkyl chain in said substituents or alkenyl can be interrupted by O, S or NR ^8,

Q

R represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group, an alkenyl group, a substituted aminoalkyl group or an aryl or heteroaryl ring, said rings being unsubstituted or substituted by 1 to 3 substituents selected from halogen, nitro, amino- a mono (lower alkyl) amino group, a di (lower alkyl) amino group, a lower alkyl group, a lower alkoxy group, a benzyloxy group, a phenoxy group, a hydroxy group and a trifluoromethyl group, and pharmaceutically acceptable salts thereof,

(h) compounds of the general formula I (92 / F 404-EP 602 522, NZ 250 438)

In which

R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a -NO 2 group, a cyano group, a trifluoromethyl group, an R ⁴ -SO _m group or an R 4 R 6 N-SO ₂ - group;

m is 0, 1 or 2,

R ⁴ and R ⁵ are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, -C _n H _{2 n} -R ⁷ or trifluoromethyl, n is 0, 1, 2, 3 or 4,

R ⁷ represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁸ R ^{9 group} , where qg

R c and R c are hydrogen or C 1 -C 4 alkyl, or

R ⁵ represents a hydrogen atom,

R is hydrogen or C 1 -C 4 alkyl; or

R ⁵ and R ⁶ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH _{3 group} or an N-benzyl group,

R ² is -SR ^10, -OR ^10, -NHR ^10, -NR ¹⁰ R ^11, -CHR ¹⁰ R ^12, a group - / CR ¹² R ¹³ OR ¹³ '/, a - / C / CH 2 -OR ¹³ '(R ¹² R ¹³ ) or - (CR ¹⁸ R ¹⁷ ) p -CO- / CR ¹⁹ R ²⁰ / _q -R ¹⁴ where

R ¹⁰ and R ¹¹ , which are the same or different, represent - (CHR ¹⁶ ) S- (CH 2) p - (CHOH) q - (CH 2) r - (CHOH) t R ²¹ or - (CH 2) _ - O - (CH ₂ -CH ₂ O) _q -R ²¹ ,

R is hydrogen or methyl, p, q, r, which are the same or different, are 0, 1, 2, 3 or 4, s is 0 or 1, t is 1, 2, 3 or 4,

R ¹² _and r 13 _f, which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached a cycloalkyl group having 3 to 8 carbon atoms,

R ¹³ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ¹⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a group -C _and H _2a -R ¹⁵ , and is 0, 1, 2, 3 or 4,

R ¹⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and an NR ⁸ R ⁹ group wherein

O Q

R @ 1 and R @ 2 are hydrogen or (C1 -C4) alkyl or

R ¹⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group,

R ¹⁵ represents an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups,

R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ represent a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

R ³ is as R ¹ or □

R represents an alkyl group having 1 to 6 carbon atoms or a group -XR ²² where

X represents an oxygen atom, a sulfur atom or an NR ¹⁶ group where η g

R represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; or

Ί 6

R and R ^xa together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

R ²² has the meaning as R ⁴ , as well as their pharmaceutically acceptable salts,

(i) benzoylguanidine of the formula I (HOE 92 / F 405-EP 602523, NZ 250 437)

(I)

in which

R ¹ represents a hydrogen atom, a fluorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, an R -CpH 2 p -Oq group, an R ⁴ -SO 2 group or a R ⁵ R ⁶ N-SO _{2 group} where m is 0 , 1 or 2, p is 0 or 1, q is 0, 1, 2 or 3,

R is C _r F _{2r + 1} , r is 1, 2 or 3,

R ⁴ and R ⁵ are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, -C _n H _{2 n} -R · ¹ · ⁷ or trifluoromethyl, n is 0, 1, 2, 3 or 4.

R is C 3 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ® R 6 where

Q Q

R @ 1 and R @ 2 are hydrogen or (C1 -C4) alkyl or

R ⁵ represents a hydrogen atom,

R ⁶ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms; or

R ⁵ and R ⁶ together represent 4 or 5 methylene groups,

of which one CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ² is heteroaryl having up to 9 carbon 1. or carbon atoms which are bonded via a carbon or nitrogen atom and which are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, hydroxy, amino, methylamino and dimethylamino; or

R ² is -SR ¹ ®, -OR ¹ ®, -NR ¹ ®R ¹¹ , -CR ¹ ®R ¹¹ R ¹² , where

® R ¹ is -C _a H ₂ -heteroaryl, wherein the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methoxy, hydroxy, amino, methylamino and dimethylamino, and is 0, 1 or 2,

R ¹¹ and R ¹² independently of one another have the meaning of R ¹¹ or are hydrogen or C 1 -C 4 alkyl,

R ³ is defined as R ¹ or alkyl of 1 to 6 carbon atoms or a group -XR ^13,

X represents an oxygen atom, a sulfur atom or an NR ¹⁴ group, R ¹⁴ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

R is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or-C ^ H ^ -R ^15, b is 0, 1, 2, 3 or 4, or

R ¹³ and R ¹⁴ together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ¹⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁸ R ^{9 group} ,

R ⁸ and R ⁹ represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, as well as pharmaceutically acceptable salts thereof,

(k) benzolyguanidine of formula I (HOE 92 / F

411-NZ 250450, EP 603650

(I) wherein one of R 1, R 2, R 3 or R ⁴ represents an amino group of the formula

R ⁵ /

--- N

X 6

A-R

R ⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, n represents 0, 1, 2, 3 or 4;

R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, one CH ₂ group being replaced by one sulfur atom or NR ⁷ group,

R is hydrogen, methyl, or ethyl; or g

R represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a group

-NR ⁸ R ⁹

R ⁸ and R ⁹ represent a hydrogen atom, a methyl group or an ethyl group;

R ⁵ and R ⁶ together with the nitrogen atom represent 5-, 6- or

A 7-membered ring in which one carbon atom can be replaced by a sulfur atom, an oxygen atom or an NR ¹⁰ group,

R ¹⁰ is hydrogen, C 1 -C 3 alkyl or benzyl, and another of R 1, R 2, R 3 or R ⁴ is hydrogen, fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, CF 3 -O-, ^c m ^F '2m + 1 ^H 2 ^- ? ^- or m is 1, 2 or 3, q is 0, 1, 2, 3 or 4, p means 0 or 1,

X is O or NR,

R ¹² represents a hydrogen atom or a C 1 -C 3 alkyl group, rH represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, methyl group, methoxy group and group nr ¹³ r ¹⁴ ,

R ¹³ and R ¹⁴ represent a hydrogen atom, a methyl group or an ethyl group, as well as pharmaceutically acceptable salts thereof,

1) a benzoylguanidine of the formula I (HOE 92 / F

422-EP 604852

O (I) in which

R ¹ represents a group R ⁴ R ⁵ NC (X) -,

X is O, S or NR ^6,

R ⁴ and R ⁵ , which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 6 carbon atoms or a group -C _n H 2 _n -R, n being 0, 1, 2 , 3 or 4

R ⁷ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of:

a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group and an alkyl group having 1 to 4 carbon atoms; or

R ⁴ and R 5 together are 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;

R ⁸ is as R ⁴ or is an amidine group,

R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl group containing 1 to 8 carbon atoms, a 1-alkenyl or 1-alkynyl group, a cycloalkyl group containing 3 to 8 carbon atoms, a cycloalkylalkyl group the radical contains 3 to 8 carbon atoms and the alkyl radical contains 1 to 4 carbon atoms, a phenyl group, a ^C 6 ^H 5 -alkyl group in which the alkyl radical contains 1 to 4 carbon atoms, a naphthyl group, a biphenylyl group, 1,1-diphenylalkyl a group in which the alkyl radical contains 1 to 4 carbon atoms, cyclopentadienyl, pyridyl, thiopyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, indenyl, quinolyl, indolyl, benzofurothienyl, benzofurothienyl benzothiazolyl, benzoxazolyl, and or -WR ⁸ ,

W represents an oxygen atom, a sulfur atom or an NR ⁸ group,

R® is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, cyclohexylmethyl, cyclopentylmethyl, - (CH ₂₎ m ^C p ^F 2p + l group -CgH ₂ gR ^10, , m is 0 or 1 p is 1, 2 or 3, q is 0, 1, 2, 3 or 4,

R ¹⁰ is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ^{i: l} R ^12,

R ( ¹¹⁾ and R ( ¹²⁾ are hydrogen or (C1-C4) -alkyl,

R ⁹ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; or

Q Q

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, N-CH-J or N-benzyl;

R ³ represents H, F, Cl, Br, I, alkyl having 1 to 6 carbon atoms, or a group -WR ^8, which is as defined for R, and a pharmaceutically-acceptable salt thereof,

m) benzoylguanidine of the formula I (93 / F 054-NZ 250919, EP-OS 612 723)

(D

o nh ₂

in which

R ¹ , R ² , R ³ are hydrogen, fluorine, chlorine, bromine, iodine or C 1 -C 12 alkyl, one of R ¹ , R ² or R ³ is N ₃ , cyano, a hydroxy group or an alkyloxy group having 1 to 10 carbon atoms, when at least one of the remaining substituents R ¹ , R ² or R ³ is a sufficiently lipophilic alkyl radical having 3 to 12 carbon atoms or one of the substituents R ¹ , R ² or R ³ is the group ^{R 4} - ^C n ^H 2n ° m <

m is 0 or 1, n is 0, 1, 2 or 3,

R ⁴ represents a group C p = p + 1 p represents 1, 2 or 3 when n is 0 or 1 or

R ⁴ represents a cycloalkyl group having 3 to 12 carbon atoms, a phenyl group, a pyridyl group, a quinolyl group or an isoquinolyl group, said aromatic and heteroaromatic ring systems being unsubstituted or substituted with one substituent selected from the group consisting of fluorine, chlorine, trifluoromethyl methyl, methoxy and NR ⁵ R ^6,

R ⁵ and R ⁶ represent a hydrogen atom or a (C 1 -C 4) alkyl group or one of R ¹ , R ² or R ³ represents a -C 5 R ⁶ group or a -C (R ⁶ ) = CR ^{5 group} ,

R ⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group and a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group or r5 is an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by up to 3 hydroxy groups, or

R ⁵ represents a cycloalkyl group having 3 to 8 carbon atoms,

R ⁶ represents a hydrogen atom or a methyl group, as well as pharmacologically acceptable salts thereof,

(o) benzoylguanidine of general formula 1 (93 / F

153-EP-OS 627413, NZ 260660

(I)

in which

R ¹ represents H, F, Cl, Br, I, nitro, cyano, a group XO (CH 2) p (CF 2) g-CF 3, R -SOMe, R @ ⁸ -COor R ° R ⁷ N-SO 2 -,

X is O, S or NR ^14, m is 0, 1 or 2, o is 0 or 1, p is 0, 1 or 2; q is 0, 1, 2, 3, 4, 5 or 6,

R ⁵ and R 6 are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, -C _n H _{2 n} -R ⁸ or trifluoromethyl, n is 0, 1, 2, 3 or 4,

R ⁸ represents a C 3 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ^{10 group} ,

R (R ⁾ and R (R ⁾ are hydrogen or (C1-C4) -alkyl; or

R @ 5 represents a hydrogen atom,

R ⁷ represents a hydrogen atom or a C 1 -C 4 alkyl group;

R @ ⁷ and R @ ⁷ together represent 4 or 5 methylene. groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH 2 group or a N-benzyl group, n

R is / = \ 0 "/ ^(C) IL-(° H ^CH) - (CH ₂₎ - (CHOH) -R ¹¹ or a group (C) - (CHOH) - _(CH2) - (CHOH) - R ¹¹ -Y or a group

(C) - (CHOH) - (CH ₂ ) - (CHOH) -R ¹¹

Y-

Y represents an oxygen atom, a sulfur atom or an -NR ¹² - group,

R ¹¹ and R ¹² represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, h is 0 or 1, i, independently of one another, being 0, 1, 2, 3 or 4, but h while not simultaneously 0 .

T

R is as R or is (1-6C) alkyl or -XR ¹³ ,

X represents an oxygen atom, a sulfur atom or an NR ¹⁴ group, R ¹⁴ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

R ¹³ represents an alkyl group having 1 to 6 carbon

b is 0, 1, 2, 3, or 4, or a (C 3 -C 8) cycloalkyl group or a C 1 H 4 -R ^{15 group} ;

R ¹³ and R ¹⁴ together represent 4 or 5 methylene groups,. of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH-j group or an N-benzyl group,

R ¹⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ^{10 group} , q 9 n

R @ 1 and R @ 2 are hydrogen or (C1 -C4) alkyl,

R ⁴ represents a hydrogen atom, -OR ¹⁶ or -NR ¹⁶ R ¹⁷ η zr

R and R are, independently of one another, a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, as well as pharmaceutically acceptable salts thereof,

(p) benzoylguanidine of formula I (HOE 93 / F

154-EP-OS 628543, NZ 260 681

In which

R ¹ is R ⁶ -CO or R ⁷ R ⁸ N-CO, g

R is C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 alkenyl or C _n H _{2 n} -R ⁹ , n is 0, 1, 2, 3 or 4,

R ⁹ represents a cycloalkyl group containing 3 to 8 carbon atoms

phenyl, biphenylyl or naphthyl, the aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁰ R ¹¹ ,

R ¹⁰ and R ¹¹ represent hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ⁷ is H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms or -C _n H _2n -R ^12, n is 0, 1, 2 , 3 or 4

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- and NR ^ R ^ ⁴ ,

R ¹³ and R ¹⁴ represent a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group,

Q

R c represents a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 perfluoroalkyl group, or

R 1 and R 0 together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

R is as R or is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, alkenyl containing 3 to 8 carbon atoms or -C _n H _{2 n} R ¹⁵ , n being 0, 1, 2, 3, 4,

R ¹⁵ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents. radical of a bicyclic selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ¹⁶ R ^17,

R ( ¹⁸⁾ and R ( ¹⁷⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl;

R represents a C 1 -C 9 heteroaryl group which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, hydroxy group, amino group a group, a methylamino group and a dimethylamino group; or

R ² is SR ^18, -OR ^18, -NR ¹⁸ R ^19, -CR ¹⁸ R ¹⁹ R ^20,

Ί Q

R is -C _and H _2a -heteroaryl wherein the heteroaryl radical contains 1 to 9 carbon atoms, which radical is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group -hydroxy, amino, methylamino and dimethylamino, and is 0, 1 or 2,

R ¹⁹ and R ²⁸ independently of one another have the meaning of R ¹⁸ or are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, or

R ² is R ²¹ -SO 2 or R ²² R ²³ N-SO 2 -, m is 1 or 2,

R is alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms, -C _n H _2n -R ^24, n is 0, 1, 2, 3 or 4 .

R ²⁴ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ²⁷ R ²⁸ ,

R @ 1 and R @ 2 are hydrogen, C1 -C4 alkyl or C1 -C4 perfluoroalkyl,

R is H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms, -C _n H _2n -R ^29, n is 0, 1, 2, 3 or 4,

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- and NR ³⁰ R ³¹ ,

R ( ³⁰⁾ and R ( ³¹⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 4 carbon atoms, or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl,

2 2

R stands for R X-,

X is O, S, NR ³⁴ , (D = O) A-, NR ³⁴ C = MNR ³ , M is O or S,

A represents an oxygen atom or a group NR ³⁴ ,

D represents a carbon atom or an SO group,

R ³³ represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a (CH ₂ ) 4 O 2, R 2, -C ₁ H _{2 n} -R group, n being 0 or 1 , d is 1, 2, 3, 4, 5, 6, or 7, n is 0, 1, 2, 3, or 4,

R ³⁶ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy and NRR,

R ( ³⁷⁾ and R ( ³⁸⁾ are hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl,

R ³⁴ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group,

R ³⁵ is as R ³³ or

R ³³ and R ³⁴ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, where A and are attached to the phenyl ring benzoylguanidine skeleton, or -SR ⁴⁸ , -OR ⁴⁸ , -NHR ⁴⁸ , -NR ⁴ ° R ⁴¹ , -CHR ⁴⁸ R ⁴² , -C (R ⁴² R ⁴³ OH), -C = CR ⁴⁸ , - / CR ⁴⁷ R ⁴⁸ / U- (CO) - / CR ⁴⁹ R ⁵⁸ / VR ⁴⁴ , R ⁴⁸ and R ⁴¹ , which are the same or different, represent - (CH 2) p - (CHOH) q- (CH 2) r - (CHOH) t R ⁵¹ or - (CH 2) _p -O- (CH ₂ -CH ₂ O) -R ⁵¹

R is hydrogen or methyl, u is 1, 2, 3 or 4, v is 0, 1, 2, 3 or 4, p, q, r, which are the same or different, are 0, 1, 2, 3 or 4, t is 1, 2, 3 or 4,

R ⁴² and R ⁴³ , which are the same or different, represent an atom

hydrogen or alkyl having 1 to 6 carbon atoms; or

R ⁴² _and R ⁴ together are a 3 carbon atom to which they are attached, a cycloalkyl radical containing 3 to 8 carbon atoms,

R ⁴⁴ is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having up to 8 carbon atoms or ^_c _e ^H 2e, ^{R 45,} e is 0, 1, 2, 3 or 4,

R ⁴⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁵² group R ⁵³ ,

C n

R @ 1 and R @ 2 are hydrogen, C1 -C4 alkyl or

R ⁴⁵ represents a C 1 -C 9 heteroaryl group which is unsubstituted or substituted as a phenyl group, or

R ⁴⁵ represents an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups,

R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ and R ⁵⁸ represent a hydrogen atom or a methyl group;

R ² is R ⁵⁵ -NH-SO ₂ -,

R ⁵⁵ is R ⁵⁶ R ⁵⁷ N- (C = Y) -,

Y represents an oxygen atom, a sulfur atom or an NR ⁵⁸ group; c 7

R and R, which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, or a -C (R 1) f R ^{59 group} , f being 0, 1, 2, 3 or 4 .

R ⁵⁹ is cycloalkyl having 5 to 7 carbon atoms or phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethoxy, and alkyl of 1 to carbon atoms or _and R 57 _in L _the mean _of the 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ⁵⁸ is as R ⁵⁶ or is an amidino group, R ⁸ , R ⁴ and R ⁵ independently of one another have the meanings as R ¹ or R ² as well as pharmaceutically acceptable salts thereof,

q) benzoylguanidine of general formula I (HOE 93 / F 220-EP-OS 640593, NZ 264 117)

(I)

in which

R ¹ is H, fluoro, bromo, iodo, nitro, cyano, a group -X q (CH 2) q CF 3, R ⁵ -SoM-, R @ ⁶ --CO, R @ ⁶ R ⁷ -CO- or R ⁸ R ⁷ N-SO ₂ -,

X is O, S or NR ^14, m is 0, 1 or 2, o is 0 or 1, p is 0, 1 or 2; q is 0, 1, 2, 3, 4, 5 or 6,

R ⁵ and R ⁶ represent an alkyl group having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, - ^C n ^H 2n ^{R 8} or trifluoromethyl, n is 0, 1, 2, 3 or 4,

Q

R represents a cycloalkyl group containing 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents;

those selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, q 1 n methoxy group and NR R group,

R ⁹ and R ¹⁰ are hydrogen or C 1 -C 4 alkyl;

R ⁶ represents a hydrogen atom,

R ⁷ represents a hydrogen atom or a C 1 -C 4 alkyl group;

R ⁶ a. R ⁷ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH 3 group or an N-benzyl group,

R is a group

R ¹¹ represents a heteroaryl group having 1 to 9 carbon atoms which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group , hydroxy, amino, methylamino, dimethylamino and benzyl,

Y represents an oxygen atom, a sulfur atom or an NR ¹² group, R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ³ is as R ¹ or

R ³ represents an alkyl group having 1 to 6 carbon atoms or -XR ¹³ ;

X represents an oxygen atom, a sulfur atom or an NR ¹⁴ group, R ¹⁴ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

R ¹³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a group -ΟΟΟΗΗΗΡ ¹⁵ , b is 0, 1, 2, 3 or 4 or

R ¹³ and R ¹⁴ together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ¹⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ^{10 group} ,

R ⁹ and R ¹⁰ represent an alkyl group having 1 to 4 carbon atoms,

R ⁴ represents a hydrogen atom, -OR ¹⁶ , -NR ¹⁶ R ^17, or C _r F _{2r + 1} ,

R ( ¹⁶⁾ and R ( ¹⁷⁾ independently of one another are hydrogen or alkyl having 1 to 3 carbon atoms, r is 1, 2, 3 or 4,

as well as its pharmaceutically acceptable salts,

(r) 5-membered benzene ring fused heterocycle of formula I (HOE 93 / F 223 K-EP 639573,

NZ 264130)

(I)

in which

X represents a nitrogen atom or a CR ⁶ group,

Y is O, S or NR ^7,

A, B together represent a bond or

A, B are both hydrogen, X is at the same time as Cr 6 and Y is NR ^7, one of R ¹ to R ⁶ is -CO-N-C _{(NH2) 2} · the other substituents R ¹ to represent R® a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or an alkyl group containing 1 to 6 carbon atoms,

Ί C at most two of the other substituents R ^x -R 0 are cyano, nitro, N ₃ , alkoxy of 1 to 4 carbon atoms or trifluoromethyl, at most one of the other substituents is ^{R 8 -c} n ^H 2n ^'of n is 0 to 10, wherein the alkylene chain -C _n H _2n is a straight or branched carbon atom can be replaced by oxygen, sulfur or nitrogen atom,

Q

R represents a hydrogen atom, an alkenyl group of up to 6 carbon atoms or a cycloalkyl group of 3 to 10 carbon atoms which is unsubstituted or substituted by 1 to 4 methylene groups or a hydroxy group, or may contain an ethylene group CH = CH, the methylene group being it may be replaced by an oxygen atom or a sulfur atom or a nitrogen atom, or

Q

R 0 represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, CH ₃ -S (O) _s or R ⁹ -W _y -, s stands for 0, 1 or 2,

R ⁹ represents a hydrogen atom, a methyl group or an ethyl group,

W represents an oxygen atom or an NR ¹⁰ group,

R ¹⁰ represents a hydrogen atom or a methyl group,

Y is 0 or 1;

Q

R is C _m F 2 _{H 1 + 1} , m is 1 to 3, or

R ⁸ is 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl,

Z is -CO-, -CH ₂ - or - / CR ¹¹ (OH) / _q , q is 1, 2 or 3,

R ¹¹ is H or methyl, or

Z is oxygen or -NR-,

R is hydrogen or methyl, or

Z is -S (O) _g -, s is 0, 1 or 2, or

Z is -SO ₂ -NR ¹³ -,

R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, n

R is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms or a radical R ⁸ -C _{n 2n} -, and its pharmaceutically acceptable salts,

s) a benzoylguanidine of the formula I (HOE 93 / F

236-EP-OS 638548 NZ 264216

In which

R ¹ , R ³ or R ⁴ is -NR ⁶ C = X NR ⁷ R ⁸ ,

X represents an oxygen atom or a sulfur atom,

R ⁶ is H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms or -C _n H _2n -R ⁹ /

n represents Ο, 1, 2, 3 or 4,

R ⁹ is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and group ΝΚ ^ -θΗ ¹¹ ,

R ¹⁰ and R ¹¹ represent hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ⁷ represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 perfluoroalkyl group, a C 3 -C 8 alkenyl alkenyl group or a -C _Q H ₂₀ -R 10 group, o is 0, 1, 2, 3 or 4,

R ¹² represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ¹³ R ^14,

R @ ³ and R @ ⁴ · ¹ ·, H, alkyl having 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms,

R ⁸ is as R ⁷ or

Q

R and R together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, the other 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 represent H, F, Cl, Br, I, the group - Ota-alkyl in which the alkyl portion contains 1 to 8 carbon atoms, -0-alkenyl, wherein the alkenyl group contains 3 to 8 carbon atoms, -Otc (CH 2) b ^C d ^F 2d + L ^Item P ^inu - OtdC _p H ₂ pR ¹⁸ or at most two groups CN, NO ₂ , NR ^{1 S} R ¹⁷ ,

b means 0 or 1 D means 1, 2, 3, 4, 5, 6 or 7, the means 0 or 1 tb means 0 or 1 tc means 0 or 1 td means 0 or 1 P means 0, 1, 2, 3 or 4. R ¹⁸ means cycloalkyl group containing

carbon atoms, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ¹⁹ R ^20,

Ί Q O A

R @ 1 and R @ 2 denote a hydrogen atom or a C1 -C4 alkyl group or a C1 -C4 perfluoroalkyl group,

^Rj represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms or CGH ₂ q R ^21, q is 0, 1, 2, 3 or 4.

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- NR ²² R ²²

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R is H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms or the group C _r H _2r -R ^24, r is 0, 1, 2, 3 or 4,

-R represents a cycloalkyl group containing 3 to 8

carbon, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ²⁵ R ²⁸ ,

R ( ²⁸⁾ and R ^{( 26 )} are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, and their pharmaceutically acceptable salts,

t) a diacyl-substituted guanidine of the formula I (HOE 93 / F 249-EP-A 640 587, NZ 264 282) ^χ ^ ^Ν Η ^χ m YYTO NH O (I)

in which

X ¹ and X ² represent a group of the general formula

in which

Ti means 0, 1, 2, 3 or 4 Λ D

R and R are, independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group,

OR ^188, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, 0? (CH 2) Z ^c 2 m ^F 2ZM + L ^ ^θ η Υ 1ον ύ or benzyl, wherein the aromatics are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁸⁹ R ^{118 group} ,

R ¹⁰⁹ and R ¹¹⁰ are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, Z 1 is 0, 1, 2, 3 or 4, Z is 0 or 1, Z is 1, 2 , 3, 4, 5, 6, 7, or 8,

R is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, said aromatic groups are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ¹¹ ^ ^112,

R ( ¹¹¹⁾ and R ( ¹¹²⁾ are hydrogen, (C1-C4) -alkyl or perfluoroalkyl;

107 108

R and R are independently of one another as R ^{10 6} or R ¹⁰

107 inň

R and R ^xw together represent 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or

X and X are a group of formula

in which

T 2A and T 2b independently of one another represent 0, 1 or 2, wherein the double bond may be of the (E) or (Z) configuration, or

X ¹ and X ² represent a group of the general formula

in which

T3 is 0 or 2,

U, YY and Z independently represent a carbon atom or a nitrogen atom, wherein U, YY, Z may carry the following number of substituents:

U, YY or Z Bound in a double bond Number of possible substituents C Yes 1 C not 2 N Yes 0 N not 1

R ^D is H, alkyl of 1 to 8 carbon atoms or perfluoroalkyl of 1 to 8 carbon atoms, Rui, _R U2, _R Y1, R y2, rust, _r Z 2 _than independently, an of one another are hydrogen, F, Cl, Br, I, cyano, OR ^ · ^14, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, ° LA evil ^c grain ^F 2zma 'NR ¹¹⁵ R ¹³ · ^6, phenyl or benzyl, wherein the aromatics are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy, NR R,

R ¹¹⁷ and R ¹¹⁸ are hydrogen, alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, z is 0 or 1, evil is 0, 1, 2, 3 or 4, grains are 1, 2 , 3, 4, 5, 6, 7 or 8, rH · ⁴ represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 perfluoroalkyl group, a C 3 -C 8 alkenyl group, a C 3 -C 8 cycloalkyl group 3-8 carbon atoms, phenyl or benzyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ¹¹⁹ R ¹²⁰ ,

R ¹¹⁹ and R ¹²⁰ represent a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 perfluoroalkyl group,

R ¹¹ _and independently of one another have the meanings as R ¹¹⁴ or

R ¹¹⁵ and R ¹¹⁶ together represent 4 or 5 methylene groups, of which one CH 2 group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH _{3 group} or

N-benzyl, excluding constitution where U is nitrogen, YY is nitrogen and Z is carbon,

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ and R ¹⁰⁵ independently of one another represent a hydrogen atom, a fluorine atom, a bromine atom, an iodine atom, a cyano group _{Xa and} - (CH ₂ ) zpa ^(c zqa ^F 2zqa + 1 ⁾ 'is _{R et al} 110a_gQzb group R ^ R ^{110 110c} N-CO group, R ,, R @ ^IIIa -COalebo ^112a R ^113a N-SO 2, wherein the perfluoroalkyl group is straight or branched,

X represents an oxygen atom, a sulfur atom or a group NR ^114a , R ^114a represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, za represents 0 or 1, b represents 0, 1 or 2, and p represents 0, 1, 2, 3 or 4, zqa is 1, 2, 3, 4, 5, 6, 7 or 8,

RhoA, _R 110b, _{and R} 112a RlHa independently of one another are alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms, _marked ^{H _c} 2 Zn ^{and -R115a} b l ^e ° perfluoroalkyl group having 1 to 8 carbon atoms, n denotes 0, 1, 2, 3 or 4,

1

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- and NR ^{118a and} R ^117a ,

R and R ^e are hydrogen, C 1 -C 4 perfluoroalkyl or C 1 -C 4 alkyl or

R ^110b, R ^{112a IIIa} and R are H, _{and R} 113a rIIOc _than independently, an of one another are H, alkyl or perfluoroalkyl of 1 to 4 carbon atoms, or

RllOb _{and R} 110c, _and j as _R 112a _{and R} p _is H 3a _S] _ _u is 4 or 5 methylene groups, of which one CH ₂

it may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or

R ^101, R ^102, R ^103, R ^104, R ^105, independently of one another are alkyl having 1 to 8 carbon atoms, ^_c _for the ^H 2zal ^{R 118 but} ^ ° alkenyl, zal is 0, 1, 2, 3 or 4,

R 118a represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group or a group NR ¹¹⁹ R ^{119 a} ^.

R ( ^119a) and R ( ¹¹⁹ ) are hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl; or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another denote a heteroaryl group containing 1 to 9 carbon atoms which is bonded via a carbon atom or a nitrogen atom;

and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ^105, independently of one another, known as QQ, -C = CR,

Q Ό

R represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group or a group NR ¹⁹⁴ R ¹⁹⁵ , η q λ η qc

R @ ¹ and R @ ¹ '' represent a hydrogen atom or a methyl group, or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰ , independently of one another, represent a group

-Y-para-C ₆ H ₄ - (CO) _z - (CHOH) _z - (CH ₂ ) _z - (CHOH) _z R -R ¹²³ or a group

-Y-meta-C ₆ H ₄ - (CO) _zad - (CHOH) _zae - _{(CH2) zaf} - (CHOH) _zag-R ¹²⁴ or a group

-Y-ortho-C ₆ H ₄ - (CO) _za - (CHOH) _za - (CH ₂ ) _zap - (CHOH) _Zak -R ¹²⁵ ,

Y is O, S or -NR ^122d -, zh, back, and independently of one another are 0 or

1, zi, zz, zk, zae, zaf, zag, zao, zap and k and independently of one another are 0, 1, 2, 3 or 4,

while.

zh, zi and zk do not mean 0, back, zae and zag do not mean 0 and zah, zao and zak do not mean 0,

R ( ¹²³⁾ , R ( ¹²⁴⁾ , R ( ¹²⁵⁾ and R ( ^122d) independently of one another are hydrogen or alkyl having 1 to 3 carbon atoms, or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another are SR ¹²⁹ , -OR ¹³⁰ , -NR ¹³¹ R ¹³² or -CR ¹³³ R ¹³⁴ R ¹³⁵ ,

R ¹²⁹ , R ¹³⁰ , R ¹³¹ and R ¹³³ independently of one another denote the group -C _for bH 2 _For b-heteroaryl, in which the aryl radical contains 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom,

trifluoromethyl methoxy, a group, a methyl group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group, k and n are 0, 1 or 2,

R ( ¹³²⁾ , R ( ¹³⁴⁾ and R ( ¹³⁵⁾ independently of one another have the meaning of R ¹²⁹ or are hydrogen, (C 1 -C 4) alkyl or (C 1 -C 4) perfluoroalkyl, or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another denote the group -W-para- (CgH4) -R ¹⁹⁶ , the group -W-meta- (CgH4) -R ¹⁹⁷ or the group -W-ortho - (C 8 H 8) - R ¹⁹⁸ , κ Qg η αη -i qo

R, R and R independently of one another are a heteroaryl group having 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents;

substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group, dimethylamino group and benzyl group, n

W represents an oxygen atom, a sulfur atom or an NR group R ¹³⁶ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or

R ¹⁸¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another are R ¹⁴⁸ X ^1a -,

X ^1a represents an oxygen atom, a sulfur atom, NR ¹⁴⁷ , (D = O) A-, NR ¹⁴⁸ C = MN * R ¹⁴⁹ -,

M represents an oxygen atom or a sulfur atom,

A is O or NR ¹⁵⁸ ,

D represents a carbon atom or an SO group,

R ¹⁴⁸ represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a (CH ₂ ) group _from bz ^c zdz ^F 2zdz + 1 ^or a -CM-pl1 zxa2zxa 'zz means 0 or 1, zz = 1 , 2, 3, 4, 5, 6, or 7, zxa is 0, 1, 2, 3, or 4,

R ¹⁵¹ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy - group and group NR ¹⁸² -R ¹⁵³ ,

Ί CO Ί C3

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ( ⁴⁷⁾ , R ( ⁴⁸⁾ and R ( ^88), independently of one another, are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl,

R ¹⁴⁹ is as R ¹⁴⁸ or

R ¹⁴⁸ and R ¹⁴⁷ , respectively, R ¹⁴⁸ and R ¹⁴⁸ together represent 4 or 5 methylene groups, one of which is CH ₂

it may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, wherein A and N * are bonded to the phenyl core of the alkanoyl backbone, or

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another are -SR ¹⁶⁴ , -OR ¹⁶⁵ , -NHR ¹⁶⁶ ,

-NR ¹⁶⁷ R ¹⁶⁸ , -CHR ¹⁶⁹ R ¹⁷⁰ , -CR ¹⁵⁴ R ¹⁵⁵ OH, -CsCR ¹⁵⁶ , -CR ¹⁵⁸ = CR ¹⁸⁷ or - (CR ¹⁵⁹ R ¹⁶⁰ ) z - (C = O) - / cr ¹⁶¹ r ¹⁶² / r- ¹⁶³ ,

R ¹⁶⁴ , R ¹⁶⁵ , R ¹⁶⁶ , R ¹⁶⁷ , R ¹⁶⁹ , which are the same or different, represent a group

- _{(CH2) zy} - (CHOH) _zz - _{(CH2) zaa} - (CHOH) _Zt-R ¹⁷¹ or a group

- ^(ch 2> zab- ° - <CH ₂ -CH ₂ O) _zac -R ¹⁷² ,

R ¹⁷¹ and R ¹⁷² are hydrogen or methyl, zu is 1, 2, 3 or 4, z is 0, 1, 2, 3 or 4, zy, zz, z and z, z, z and z, which are the same or different, are 0 , 1, 2, 3, or 4, zt means 1, 2, 3, or 4,

R ¹⁶⁸ , R ¹⁷⁰ , R ¹⁵⁴ , R ¹⁵⁵ , which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ¹⁶⁹ and R ¹⁷⁰ and R ¹⁵⁴ and R ¹⁵⁵ together with the carbon atom to which they are attached represent a cycloalkyl group containing 3 to 8 carbon atoms,

^XOJ R is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or ^-C p ^H _of 2zeb ^-R173 "zeb is 0, 1, 2, 3 or 4,

R @ ¹⁵⁶ , R @ ¹⁵⁷ and R @ ¹⁷³ independently of one another represent a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁷⁴ group R ¹⁷⁵ , R ¹⁷⁴ and R ¹⁷⁵ represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

R ¹⁵⁶ , R ¹⁵⁷ and R ^{158 are,} independently of one another, a heteroaryl group containing 1 to 9 carbon atoms,

which is unsubstituted or substituted as a phenyl group,

R ¹⁵⁸ , R ¹⁵⁹ , R ¹⁶⁰ , R ¹⁶¹ and R ¹⁸² represent a hydrogen atom or a methyl group;

R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁵ independently of one another are R ¹⁷⁸ -NH-SO ₂ -,

R ¹⁷⁶ is R ¹⁷⁷ R ¹⁷⁸ N- (C = Y '),

7 QY 'is O, S or NR ¹⁷⁷ R ^178, and R are the same or different, are H, alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms or _the group -C f _and H _2z f _and -R ¹⁸⁰ , zfa means 0, 1, 2, 3 or 4,

R ¹⁸⁰ is C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from fluoro, chloro, trifluoromethyl, methoxy or C 1 -C 4 alkyl, or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

Ί 7Q Ί 77

R is as R or is an amidine group, or

R ^101, R ^182, R ^103, R ^184, R ^185, independently of one another are NR ^184a R ^185, OR ¹⁸⁴ ^ ^5, SR or-C ^184c _ZnX H _2znx R ^184d, ZnX is 0, 1 , 2, 3, or 4

R ^184d represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ^116k group R ^117k , _{and represents} a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ^184a , R ¹⁸⁴¹⁰ , r ^184c , r ¹⁸⁵ independently of one another

they have a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 8 carbon atoms, or a (CH ₂ ) group for _o -R ¹⁸⁴ , zao for 0, 1, 2, 3 or 4, r ¹⁸⁴ 9 for cycloalkyl a group containing 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ¹⁸⁴ R ^{184v group} ,

R ^184u and R ^184v represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, and their pharmaceutically acceptable salts,

u) benzoylguanidine of the formula I (HOE 93 / F 254-EP-OS 640588, NZ 264307)

In which

R ¹ represents H, F, Cl, Br, I, cyano, nitro, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or X _a - (CH ₂ ) _b - (CF ₂ ) _c -CF ₃ ,

X represents an oxygen atom, a sulfur atom or a group NR6, a represents 0 or 1, b represents 0, 1 or 2,

c is 0, 1, 2 or 3,

R ⁵ represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms or a group, d represents 0, 1, 2, 3 or 4,

R ⁸ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, 7 R is methoxy and NR is R,

A

R and R0 independently of one another represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

R ¹ is -SR ^10, -OR ^10, or -CR ¹⁰ R ^1: R ^{12 l,}

R ¹⁰ represents -CfH ₂ f -cycloalkyl wherein the cycloalkyl radical contains 3 to 8 carbon atoms, the heteroaryl group containing 1 to 9 carbon atoms or the phenyl group, said aromatic systems being unsubstituted or substituted with 1 to 3 substituent groups;

those selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methylene group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, f represents 0, 1 or 2,

R ¹¹ and R ¹² independently of one another have the meaning of R ¹⁰ or represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms or

R ¹ represents a phenyl group, a naphthyl group, a biphenylyl group or a heteroaryl group having 1 to 9 carbon atoms, the latter being bonded via a carbon atom or a nitrogen atom and said groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino,

or

R ¹ is -SR ¹³ , -OR ¹³ , -NHR ¹³ , -NR ¹³ R ¹⁴ , -CHR ¹³ R ¹³ , -C / R ¹⁸ R ¹⁸ OH, -C = CR ¹⁸ , -C (R ¹⁹ ) = CR ¹⁸ , - (CR ²⁰ R ²¹ ) k - (CO) - / CR ²² R ²³ R ^24/1 ,

R ¹³ and R ¹⁴ , which are the same or different, represent - (CH ₂ ) - (CHOH) _h - (CH 2 -) (CHOH) _j R ¹⁷ , wherein

R represents a hydrogen atom or a methyl group, or - (CH ₂ ) g O- (CH ₂ -CH ₂ O) 4 - R ²⁴ , wherein g, h, i, which are the same or different, are 0, 1, 2, 3 or 4, j is 1, 2, 3 or 4,

R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or, together with the carbon atom to which they are attached, a cycloalkyl group having 3 to 8 carbon atoms;

R represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ²⁵ R ^{26 group} ,

R ( ²⁸⁾ and R ( ²⁸⁾ are hydrogen or (C1-C4) -alkyl, or

R ¹⁸ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group, or

Ί fi

R represents an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups, or

Ί Q

R represents a cycloalkyl group containing 3 to 8 carbon atoms,

R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are hydrogen or methyl, k is 0, 1, 2, 3 or 4, is 0, 1, 2, 3 or 4,

R ²⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group containing

T 8 to 8 carbon atoms or -C _m H _{2 m} -R, m is 1, 2, 3 or 4,

R ² and R ³ independently of one another are defined as R ¹

R ⁴ represents an alkyl group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a - (CH ₂ ) _n - (CF ₂ ) θ-CF-j group, n being 0 or 1, o represents 0, 1 or 2, as well as pharmaceutically acceptable salts thereof,

(v) acylguanidine of the formula I (HOE 93 / F 436-EP-OS 659748, NZ 270 264)

in which

X represents a carbonyl group or a sulfonyl group,

R ¹ represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted by a hydroxy group, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, hydroxy, amino, methylamino or dimethylamino, o

R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms as well as pharmaceutically acceptable salts thereof,

w) phenyl-substituted alkylcarboxylguanidide which carries perfluoroalkyl groups of formula I (HOE 94 / F

014K-EP-OS 666252 ΝΖ 270370)

in which

R ^a is hydrogen, fluoro, chloro, brominated £ it, iodo, cyano, OR, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, 0 _r (CH ₂ ) _and C 1 _D F 2] _; ) _{+ 1} or NR ⁷ R ^8, r is 0 or 1, a is 0, 1, 2, 3 or 4, b is 1, 2, 3, 4, 5, 6, 7 or 8,

R ⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a cycloalkyl group having up to 8 carbon atoms, a phenyl group or a benzyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR R group,

R ⁹ and R ¹⁰ are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

8 G.

R and R 0 independently of one another have the meaning as R, p Δ

R is independently as R,

X is 1, 2 or 3,

R ¹ is H, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, _t -0 (CH ₂₎ d ^C e ^F 2e + ^l of ^m ^ F, Cl, Br, an iodine atom or a cyano group,

T means 0 or 1, D means 0, 1, 2, 3 or 4, e means 1, 2, 3, 4, 5, 6, 7 or 8, R ^2, R ^3, R ⁴ and R ⁵ independently of one another denote the meanings

as defined for R ^1, with the proviso that at least one of R

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^A and R ^b represent a group

-0 _t ( ^CH 2) d ^c e ^F 2e + I ^or lupine 0r (CH ₂ ) _a C _b F _{2b + 1} as well as pharmaceutically acceptable salts thereof,

x)

heteroaroylguanidine of formula I (HOE 94 / F

094-EP 676395, NZ 270894

(I)

in which

HA is SO _m , oxygen or NR ⁵ , m is 0, 1 or 2,

R ⁵ is H, alkyl of 1 to 8 carbon atoms or -C _{AM 2am} H R ^81, and m is 0, 1 or 2,

Q -1

R is C 3 -C 8 cycloalkyl or phenyl substituted with 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ⁸² R ⁸³ or unsubstituted,

R ⁸² and R ⁸³ represent a hydrogen atom or a methyl group, or

Q T

R represents a heteroaryl group having 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of

a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group, one of R ¹ and R ² being -CO-N = C- (NH ₂₎ 2 and one of these substituents is hydrogen, F, Cl, Br, I, alkyl having 1 to 3 carbon atoms, -OR®, ^C r ^F 2r + L ^p ^ ^u PI ^nu -CO-N = C (NH _{2) 2,} or -NR ⁶ R ^7,

R and R are, independently of one another, a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, r is 1, 2, 3 or 4,

R ³ and R ⁴ independently of one another represent H, F, Cl, Br, I, CN, X (CH2) p- (Cq-F2q + i), R @ ⁸ -SOj3m, a group R ⁹ R ¹ N-CO, R 4 -CO- or R ¹² R ¹³ N-SO ₂ -, wherein the perfluoroalkyl group is straight or branched,

X is O, S or NR ^14, R ¹⁴ is H or alkyl of 1 to 3 carbon atoms, bm = 0, 1, or 2, p is 0, 1 or 2; q is 0, 1, 2 , 3, 4, 5 or 6

R, R, R and R independently of one another are alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, -C _n H _2n -R ¹⁵ or trifluoromethyl, n is 0, 1, 2 , 3 or 4

R ¹⁵ represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group or NR ¹⁸ R ^{17 group} ,

R @ 1 and R @ 2 are hydrogen or (C1 -C4) alkyl or

R ⁹ , R ¹¹ and R ¹² are hydrogen,

R ( ¹⁾ and R ( ¹³⁾ independently of one another are hydrogen or (C1-C4) -alkyl or

R ⁹ and R ¹⁰ as well as R ¹² and R ¹³ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or and R ⁴ independently of one another represents an alkyl group having 1 to 8 carbon atoms or a group

a1 is 0 or 1 or 2,

A

R represents a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁹ R ²⁰ , ί gnn

R and R are hydrogen or methyl, or and R ⁴ independently of one another is a heteroaryl group which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom , trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino, or and R ⁴ independently of one another represent (C) - (CHOH) - (CH ₂ ) - (CHOH) -R ²³ or (C) 5- (CHOH) - (Ch 2 -CHOH 1 -R ²⁴ -Y) or

Y- (Cl- (CHOH) - (CH ₂ ) - (CHOH) _{and T} R ²⁵ is

an oxygen atom, a sulfur atom or a group h, ad, and h independently of one another represent 0 or 1, i, j, k, ae, af, ag, ao, ap and if independently of one another represent 0, 1, 2, 3 , 4, where h, however, do not simultaneously mean 0, ad, ae and g do not mean simultaneously 0 and ah, and o and if they do not mean simultaneously 0,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁵⁾ and R ( ²²⁾ independently of one another are alkyl having 1 to 3 carbon atoms, or R ( ³⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluorine, chlorine, bromine or iodine , cyano, (C 1 -C 8) alkyl, (C 1 -C 8) perfluoroalkyl, (C 3 -C 8) alkenyl or -C 8 H ₂ g R ²⁶ , g is 0, 1, 2, 3 or 4,

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- and NR ²⁷ R ²⁸ ,

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl; or

R ³ and R ^4, independently of one another, are SR ²⁹ , -OR ³⁰ , -NR ³¹ R ³² or

CR ³³ R ³⁴ R ³⁵

30 31 33

B, R, R and R · ^{JJ JJ,} independently of one another are -C _a H _2a ~ heteroaryl, wherein heteroaryl zvy57

the shock contains 1 to 9 carbon atoms and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group. pin, hydroxy, amino, methylamino and dimethylamino, and is 0, 1 or 2,

R ( ³²⁾ , R ( ³⁴⁾ and R ( ³⁸⁾ independently of one another have the meanings defined for R ( ²⁹⁾ or are C, C1 -C4 alkyl or (C1 -C4) perfluoroalkyl or R ( ³⁾ and R ( ⁴⁾ independently of one another means a group

or a group

W-

R ( ⁹⁸⁾ , R ( ⁹⁷⁾ and R ( ⁹⁸⁾ independently of one another denote a heteroaryl group containing 1 to 9 carbon atoms which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chloro, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl, W is O, S or NR-, R ³⁸ is hydrogen or alkyl a group containing from 1 to 4 carbon atoms; or

R ³ and R ⁴ independently of one another are R ³⁷ -SO _cm or

R ³⁸ R ³⁹ N-SO ₂ -, cm is 1 or 2,

R ³⁷ is alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms or -C _s H _{2 s} R ^48, s is 0, 1, 2, 3 or 4 .

R ⁴⁸ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ⁴¹ R ⁴² ,

R ( ⁴¹⁾ and R ( ⁴²⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ³⁸ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 alkenyl or -C _w H _2w -R ⁴³ , w is 0, 1, 2 , 3 or 4

R ⁴³ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ⁴⁴ R ⁴⁵ ,

R ( ⁴⁴⁾ and R ( ⁴⁵⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ³⁹ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group, or

Q □ Q

R and R together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH _{3 group} or a s

N-benzyl; or

R ³ and R ⁴ independently of one another represent a group R ⁴⁸ X ¹ -,

X ¹ is O, S, NR ⁴⁷ , (D = O) A-, NR ⁴⁸ C = MN * R ⁴⁸ ,

M represents an oxygen atom or a sulfur atom,

A is O or NR ⁸⁸ ,

D represents a carbon atom or an SO group,

R ⁴⁶ is C 1 -C 8 alkyl, C 3 -C 8 alkenyl, (CH 2) b ^c d ^F 2d + 1 or -CxH ₂ -R ⁵¹ , b is 0 or 1, d is 1 , 2, 3, 4, 5, 6, or 7, x is 0, 1, 2, 3, or 4,

R ⁵¹ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NRR group,

C O CQ

R and R ³ are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ( ⁴⁷⁾ , R ( ⁴⁸⁾ and R ( ⁵⁰⁾ independently of one another are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ⁴⁸ is as R ⁴⁸ or

R ⁴⁶ and R ^47, or R ⁴⁸ and R ⁴⁸ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, A and N * are attached to the phenyl core of the benzoylguanidine backbone, or

R ³ and R ^{4 are,} independently of one another, -SR ⁸⁴ , -OR ⁸⁵ , -NHR ⁶⁸ , NR ⁸⁷ R ⁸⁸ , -CHR ⁸⁸ R ⁷⁰ , -C (OH) R ⁵⁴ R ⁵⁵ , -CsCR ⁵⁸ , group

-CR ⁵⁸ = CHR ⁵⁷ , group

- / CR ⁵⁹ R ⁶⁰ / u - (CO) - / cr ⁶¹ r ⁶² / vr ⁶³ , r ⁸⁴ , R ⁶⁵ , R ⁶⁶ , R ⁶⁷ and R ⁶⁹ , which are the same or different, represent a group

- (CH _{2) y} - (CHOH) _z - (CH _{2) aa} - _(CH2 OH) _t R ⁷¹ or a group

- ^(CH 2> ab- ° - <CH ₂ -CH ₂ °) _and -R ⁷² ,

R ⁷¹ and R ⁷² are hydrogen or methyl, u is 1, 2, 3 or 4, v is 0, 1, 2, 3 or 4, y, z, and a, which are the same or different, are 0, 1 .

2, 3 or 4, t is 1, 2, 3 or 4,

R ⁶⁸ , R ⁷⁰ , R ⁵⁴ and R ⁵⁵ , which are the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or

R ⁸⁹ and R ⁷⁰ or R ⁵⁴ and R ⁸⁸ together with the carbon atom to which they are attached represent a cycloalkyl group containing 3 to 8 carbon atoms,

R ⁸³ represents a hydrogen atom, an alkyl group having 3 to 8 carbon atoms or a -C _e H _2e -R group, e being 0, 1, 2, 3 or 4,

R ⁵⁶ , R ⁵⁷ and R ^73, independently of one another, represent a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁷⁴ R ^{78 group} .

R ( ⁷⁴⁾ and R ( ⁷⁸⁾ are hydrogen or (C1-C4) -alkyl, or

R ⁸⁸ , R ⁸⁷ and R ⁷³ independently of one another denote a heteroaryl group containing 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group,

R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ and R ⁶² are hydrogen or methyl;

R ³ and R ⁴ independently of one another represent the group r ⁷⁶ -nh-s ₂ -,

R ⁷⁶ is R ⁷⁷ R ⁷⁸ N- (C = Y ') -,

Y 'is O, S or NR ⁷⁹ ,

7 A

R and R are the same or different, are H, alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms or -C _f H ₂ ⁸⁰ fR, f is 0, 1, 2, 3 or 4,

O n

R is C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy and alkyl of 1 to 4 carbon atoms, or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R is as R or is an amidine group, or

R ³ and R ⁴ independently of one another represent NR ⁸⁴ R ⁸⁸ , R ⁸⁴ and R ⁸⁵ independently of one another represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or together represent 4 or 5 methylene groups, of which one the CH 2 group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH 3 group or an N-benzyl group, or one or two of which CH 2 may be replaced by a ^CH- CdmH _{2 µm + 1 group} ; salt,

(y) a bicyclic heteroaroylguanidine of the formula I (HOE 94 / F 123-EP-OS 682017, NZ 272058)

(I)

in which

T, U, V, W, X, Y, and Z independently of one another are nitrogen or oxygen, provided that X and Z together are not nitrogen, and that T, U, V, W, X, Y, and Z bear no substituents when they are nitrogen, and that no more than four of them together are nitrogen,

Ί 9

R ^x and R independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, OR ⁸ , NR ⁸ R ^{8 9} or C (= O) N = C (NH ₂ ) ₂ , qg

R and R are, independently of one another, a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, or

Q g

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, cyano, Xk- (CH 2) p - (C 8 ^F 2q) + i)> group

R ^10a -SO 13 _m , R ¹⁰ -R ^{10 c} N-CO, R ¹¹ -CO- or 19 19 R ^XX R ^XJ N-SO ₂ , wherein the perfluoroalkyl group is straight or branched,

X is O, S or NR ^14, R ¹⁴ is H or alkyl of 1 to 3 carbon atoms, bm = 0, 1, or 2, p is 0, 1 or 2, k is 0 or 1, q means 1, 2, 3, 4, 5 or 6

RIOA, _R 10b, _R 11a _R 12 independently, an _than of one another are alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, -C _n H _2n-R ^15, or perfluoroalkyl of 1 to 8 carbon atoms, n is 0, 1, 2, 3 or 4,

R ¹³ represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and NR ¹⁸ R ¹⁷ ;

R ( ¹⁶⁾ and R ( ¹⁷⁾ are hydrogen or (C1-C4) -alkyl;

RlOb, _{R11 and} R12 _means a hydrogen atom Ju,

R ( ^10c) and R ( ¹³⁾ independently of one another are hydrogen or (C1-C4) -alkyl or

R ¹⁰ N, R ^10c, and R ¹² and R ¹³ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl or

R ^3, R ^4, R ^5, R ⁶ and R ⁷ independently of one another are alkyl having 1 to 8 carbon atoms, skuΊ fi _and pin C ^ H ^ R _2, or an alkenyl radical containing 3 to 8 carbon atoms, al means 0, 1 or 2,

R ¹⁸ is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ¹⁹ R ¹⁹ ^.

R ( ^19a) and R ( ¹⁹ * ³⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another represent a heteroaryl group containing 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of including a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group or a dimethylamino group, or

R ² , R ⁴ , R ⁸ , R ⁸ and R ⁷ independently of one another represent a group

(C) - (CHOH) - _(CH2) - (CHOH) -R or a group (C) ^ (OH) ^ _(CH2) ^ (OH) -R ²⁴ -Y

or (C 6 -C (CHOH) 4 (CH ₂ ) - (CHOH) 4 R ²⁵⁾

Y-

Y represents an oxygen atom, a sulfur atom or the group -NR ²² - h, ad, and h independently of one another represent 0 or 1, i, j, k, aa, af, ag, ao, ap and if independently of one another they represent 0 , 1, 2, 3 or 4, where h, however, do not simultaneously mean 0, ad, ae and g do not mean 0 and ah, and o and if they do not mean 0,

R, R, R, and R independently of one another represent a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms or

R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another are SR ²⁹ , -OR ³⁰ , -NR ³¹ R ³² or -CR ³³ R ³⁴ R ³⁵ ,

R ²⁹ , R ³⁰ , R ³¹ and R ^{33 are} independently of one another

-C _and H _2a -heteroaryl, wherein the heteroaryl radical contains 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, hydroxy group, amino, methylamino, and dimethylamino65

-group, and is 0, 1 or 2,

R ( ³²⁾ , R ( ³⁴⁾ and R ( ³⁵⁾ independently of one another are as defined for R ( ²⁹⁾ or are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another represent a group

w

R ⁹⁶ , R ⁹⁷ and R ⁹ independently of one another denote a heteroaryl group having 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, an atom chloro, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl, W is O, S or NR ³⁸ -, R ³⁸ is hydrogen or (C 1 -C 4) alkyl group; or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another represent a group R ⁴⁸ X ¹ -,

X ¹ represents an oxygen atom, a sulfur atom, a group NR ⁴⁷ , a (D = O) A- group or a group NR ⁴⁸ C = MN * R ⁴⁹ -,

M represents an oxygen atom or a sulfur atom,

A represents an oxygen atom or an NR ⁵ ® group,

D represents a carbon atom or an SO group,

R ⁴⁵ represents an alkyl group containing 1 to 8 carbon atoms, an alkenyl group containing 3 to 8 carbon atoms, a (CH ₂ ) b ^c d ^F 2d + 1 group or a

-C _X H -R ⁵¹ 2x ^K ' b means 0 or 1 D means 1, 2, 3, 4, 5, 6, or 7 x means 0, 1, 2, 3 or 4 R ⁵¹ means cycloalkyl containing

carbon atoms, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NRR,

R ( ⁵²⁾ and R ( ⁵³⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ( ⁴⁷⁾ , R ( ⁴⁸⁾ and R ( ⁵⁰⁾ independently of one another are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ⁴⁹ is as R ⁴⁸ , or

R ⁴⁶ and R ^47, or R ⁴⁶ and R ⁴⁸ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _NCH3 or N-benzyl, where A and N ^x are attached to the phenyl core of the basic heteroaroylguanidine skeleton, or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ^{7 are} each independently -SR ⁸⁴ , -OR ⁸⁵ , -NR ⁸⁷ R ⁸⁸ , -CHR ⁸⁹ R ^70, or -CR ⁵⁴ R ⁵⁵ OH , -C = CR ⁵⁶ , -CR ⁵⁸ = CR ^57, or - (cr ⁵⁹ r ⁸⁰ ) u-co- (cr ⁸¹ r ⁸²⁾ v ⁸³ ,

R ⁸⁴ , R ⁸⁵ , R ⁸⁸ , R ⁸⁷ and R ⁸⁹ , which are the same or different, represent a group

- (CH _{2) y} - (CHOH) _z - (CH _{2) aa} - (CHOH) _t -R ⁷¹ or a group

- < ^CH 2> ab- ° - (CH ₂ -CH ₂ O) _and -R ⁷² ,

R ⁷¹ and R ⁷² independently of one another represent a hydrogen atom or a methyl group, u represents 1, 2, 3 or 4, v represents 0, 1, 2, 3 or 4, y, z, aa which are the same or different , are 0, 1, 2, 3, or 4, t is 1, 2, 3, or 4,

R ⁸⁸ , _R 70, _R 54 _{and R} 55, which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ⁶⁹ and R ⁷⁰ , or R ⁵⁴ and R ⁵⁵ together with the carbon atom to which they are attached, represent a cycloalkyl group containing 3 to 8 carbon atoms,

R ⁶³ is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or -C _e H _2e -R ⁷³ , e is 0, 1, 2, 3 or 4,

R ⁵⁶ , R ⁵⁷ and R ^73, independently of one another, represent a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁷⁴ R ^{75 group} .

R ⁷⁴ and R ⁷ is a hydrogen atom or alkyl of 1 to 4 carbon atoms or R 56, _R 57 _ar 73 _than independently, an of one another are heteroaryl having 1 to 9 carbon atoms, which is unsubstituted or substituted as phenyl, _r 58, _r 59, r ⁸¹ and R ⁸² are hydrogen or methyl;

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another are R ⁷⁶ -NH-SO ₂ - or R ⁷⁸ R ⁷⁷ R ⁷⁸ N- (C = Y ') -,

Y 'is O, S, or NR ⁷⁹ , R and R, which are the same or different, are hydrogen, C 1 -C 8 alkyl, C 3 -C 6 alkenyl or -Cf H _{2 F} - R ⁸⁰ ,

f is 0, 1, 2, 3 or 4,

R ⁸⁰ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group and an alkyl group having 1 to 4 carbon atoms, or

R ⁷⁷ and R ⁷⁸ together are 4 or 5 methylene groups, of which one methylene group can be replaced by oxygen, S, NH, _NCH3 or N-benzyl;

R ⁷⁹ is as R ⁷⁷ or is an amidino group;

R ³ , R ⁴ , R ⁵ , R ⁶ and R ^7, independently of one another, are NR ^{84a and} R ⁸⁵ , OR ⁸⁴ * ³ , SR ^84c or ru p84d ^e n ^H 2n ^K n is 0, 1, 2 , 3 or 4

R ⁸⁴ ^ represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁶ R ¹⁷ .

R @ 1 and R @ 2 are hydrogen or (C1 -C4) alkyl,

R ^84a, R ⁸⁴ b, R ^84c, and R ⁸⁸ independently of one another are H, alkyl having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms or a (CH ₂₎ -R ⁸⁴ _{and x} ^ and x is 0, 1, 2, 3 or 4; r ⁸⁴ 9 is a cycloalkyl group containing 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl a methoxy group and a NR ^84u R ^{84v group} ,

R ( ^84u) and R ( ^84v) are hydrogen or (C1-C4) -alkyl or

R® and R®5 ⁴ together are 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, and their pharmaceutically acceptable salts,

(z) benzoylguanidine of formula I (HOE 94 / F

134-EP-OS 686627

in which

R is R -SO _m , m is 0, 1 or 2,

R represents a perfluoroalkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms which is straight or branched,

R and R independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, or a phenoxy group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group; or

R and R independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom , iodine, cyano, alkanoyl containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxycarbonyl containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, formyl, carboxy- a trifluoromethyl group, a methyl group and a methoxy group,

R ⁴ and R ⁵ independently of one another are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine, bromine, cyano, OR ⁷ , NR ⁸ R ⁸ or - ( 0Η _{2) n} (CF _{2) Q -CF3,} R ^7, R ⁸ and R ⁸ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, n is 0 or 1, o means 0, 1 or 2,

and its pharmacologically acceptable salts, and b) phenyl-substituted alkenylcarboxylguanidide bearing perfluoroalkyl groups of formula I (HOE 94 / F 168-EP-OS 690048, NZ 272373)

In which

R ^A is H, fluoro, bromo, iodo, cyano, hydroxy, OR ^6, alkyl of 1 to 8 carbon atoms, 0 _{r (CH2) a} C _b F _{2b + 1} , cycloalkyl having 3 to 8 carbon atoms or NR ⁷ R ^8, r is 0 or 1, a is 0, 1, 2, 3 or 4, b is 1, 2, 3, 4, 5, 6, 7, or 8

R represents an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms

carbon atoms, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl methyl, methoxy, and NR ⁹ R ¹⁰ ,

R ⁹ and R · ¹ · ^0, H, alkyl having 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms,

R ¹ and R ⁸ independently of one another are as defined for R 1 or R 2

Q

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or benzyl,

r ^b independently meaning as R ^A , x means 0, 1 or 2, Y means 0, 1 or 2, R ^C means an atom hydrogen, fluorine, bromine, iodine,

7 cyano, OR, alkyl having up to 8 carbon atoms, Op _(CH2) f ^C g ^F 2G + i or cycloalkyl having 3 to 8 carbon atoms, p is 0 or 1, f is 0, 1 , 2, 3 or 4, g is 1, 2, 3, 4, 5, 6, 7 or 8,

R is C 1 -C 8 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 alkenyl, C 3 -C 3 cycloalkyl, phenyl or benzyl, said aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹³ R ^{14 group} ,

R ¹³ and R ^14, independently of one another, are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ^{d is} independently as R ^c ,

R ¹ is H, alkyl of 1 to 8 carbon atoms, _t -0 (CH ₂₎ d ^C e ^F 2e + L ^c y ^ ľoalkylovú group having 3 to 8 carbon atoms of F, Cl, Br , iodine or cyano, t is 0 or 1, d is 0, 1, 2, 3 or 4, e is 1, 2, 3, 4, 5, 6, 7 or 8,

R ² , R ³ , R ⁴ and R ⁵ independently of one another are as defined for R ¹ , with the proviso that at least one of the substituents R ^A , R ^B , R ⁶ , r ¹ , r ² , r ⁴ or R ³ is a group 0r (CH 2) a ^C b ^F 2b + I 'group, Op (CH2) _f C _g F _{2G + 1} - or 0 _t (CH ₂₎ d ^C eF2e + 1 and that R ³ does not represent 0 t (CH ₂ ) d ^C e ^F 2e + 1 'as well as pharmaceutically acceptable salts thereof, and c) ortho-amino-substituted benzoylguanidine of formula I (HOE 94 / F 182-EP-OS 690048, NZ 272449)

in which

R ¹ is NR ⁵⁸ R ⁶ ,

R ⁵⁰ and R ⁶ independently of one another are hydrogen, C 1 -C 8 alkyl or C 1 -C 8 perfluoroalkyl,

R ² , R ³ , R ⁴ and R ³ independently of one another represent a group

R ¹⁰ -SO ² -, R ¹¹ R ¹² N-CO-, R ¹³ -CO-, or R ¹⁴ R ¹⁵ n -SO 2 -, and is 0, 1 or 2,

R ¹⁸ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁸ independently of one another. are C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 6 alkenyl or ^_c _and b ^H 2b ^{R 1b} is 0, 1, 2, 3 or 4;

R ¹⁶ represents a cycloalkylene having 3 to 7 carbon atoms, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy or NR ¹⁷ R ¹⁸

R and R are, independently of one another, a hydrogen atom, a trifluoromethyl group or an alkyl group having 1 to 4 carbon atoms, or

R ^11, R ¹² and R ¹⁴ and R ¹⁵ together are 4 or 5 methylene groups, of which one methylene group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, or

R ^11, R ^12, R ¹⁴ and R ¹⁵ independently of one another are hydrogen or

R ² , R ³ , R ⁴ and R ⁵ independently of one another represent a group

SR ²¹ , -OR ²² , -NR ²³ R ^24, or -CR ²⁵ R ²⁶ R ²⁷ ,

R ²¹ , R ²² , R ²³ and R ^{25 are} independently of one another

-C 1 -C 4 -heteroaryl in which the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy- a group, amino group, methylamino group and dimethylamino group, b represents 0, 1 or 2,

R, R and R independently of one another represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms

or a perfluoroalkyl group containing 1 to 4 carbon atoms; or

R ^3, R ⁴ and R ⁵ independently of one another represent H, F, Cl, I, a cyano group, a group - (X) o ^-C da ^H 2da + l, group

- (Xb) _dh - (CH ₂₎ db ^-C de ^F-I 'Ed alkenyl of q λ to 8 carbon atoms or -CjfH _t ^ ₂ R ^a, (Xa) is oxygen, S or NR ³³ R ³³ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, dg is 0 or 1, (Xb) is O, S or NR ³⁴ ,

R ³⁴ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group,

dh means 0 or 1 will give means 0 1, 2, 3 4 5 6 7 8 db means 0 1, 2, 3, 4, de means 0 1, 2, 3 4 5 6 7 df means 0 1, 2, 3, 4, R ³⁰ means cycloalkyl containing

said aromatic groups including phenyl, biphenylyl or naphthyl are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methyl group, methyl group, methyl group, and NR ³¹ R ³² ,

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl; or

R ³ , R ⁴ and R ⁸ independently of one another are NR ⁴⁰ R ⁴¹ or - (Xe) - (CH ₂ ) _e R ⁴⁵ ,

R ( ⁴⁰⁾ and R ( ^41), independently of one another, are hydrogen, (C 1 -C 8) alkyl, (C 1 -C 8) perfluoroalkyl or (CH ₂ ) _e -R ⁴² ,

e represents 0, 1, 2, 3 or 4,

R ⁴² represents a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁴³ R ^{44 group} ,

R ( ⁴³⁾ and R ( ^44), independently of one another, are hydrogen, trifluoromethyl or (C1 -C4) -alkyl or

R ⁴⁰ and R ⁴¹ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, (Xe) is oxygen, sulfur or NR ⁴⁷ , R ⁴⁷ represents a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 perfluoroalkyl group, where eb is 0, 1, 2, 3 or 4,

R ⁴⁵ represents a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, NR ⁵⁰ R ⁵¹ and is - (Xfa) - _{(CH2) ed} - (XFB) R ^46,

Xfa is CH ₂ , oxygen, sulfur or NR ⁴⁸ ,

X fb represents an oxygen atom, a sulfur atom or an NR ⁴⁹ group, and ed represents 1, 2, 3 or 4,

R represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms or a perfluoroalkyl group containing 1 to 4 carbon atoms,

R ( ⁴⁸⁾ , R ( ⁴⁹⁾ , R ( ⁸⁸⁾ and R ( ⁸¹⁾ independently of one another are hydrogen or (C1-C4) -alkyl or (C1-C4) perfluoroalkyl, wherein R ( ²⁾ and R ( ^{4) are} not hydrogen and pharmaceutically acceptable salts, and d) benzoylguanidine of formula I (HOE 94 / F

265-NZ 272946, EP-OS 700904

2 R ¹ R \ / R ⁵ (I) 3 I 4 R 0 nh ₂ in which One of three R ^{@ 1} , R ^{@ 2,} and R ^{@ 3} represents

a heteroaryl-N-oxide group in which the heteroaryl radical contains 1 to 9 carbon atoms which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino or one of three substituents R ¹ , R ² and R ³ is -SR ¹⁰ , -OR ¹⁰ , -NR ¹⁰ R ^11L or -ΟΗ ¹ ^ ¹³ ^ ¹²

R ¹⁰ represents -C _and H _2a -heteroaryl-N-oxide in which the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl a group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group, and is 0, 1 or 2,

R ¹¹ and R ^12, independently of one another, are as defined for R ¹⁰ or are hydrogen or C 1 -C 4 alkyl, and the other substituents R ¹ , R ² and R ^{3 are,} independently of one another, C 1 -C 4 alkyl; 8 carbon atoms, an alkenyl group containing 2 to 8 carbon atoms or - W ¹⁴ 'm is 0, 1 or 2,

R ¹⁴ represents a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom,

methyl, hydrogen-hydrogen or methyl

R ³ independently of one another is F, Br,

X- (CH ₂ ) p - (CF _{2q + 1} ), the group R ² -CO or the bottom group is a straight or branched trifluoromethyl group, the pin and NR ¹⁵ R ¹⁸ , R ¹⁵ and R ¹⁶ represent an atom or ·

Ί n the other substituents R, R and are hydrogen, cyano, R @ ²² -SOu, a group R ²³ R ²⁴ N-CO R ²⁶ R ²⁷ N-SO 2, wherein the perfluoroalkyl SKUJA Highlights,

X means bond  / an oxygen atom, a sulfur atom or a group NR 28 at means 0 1 or 2, P means 0 1 or 2, q means 0 1 2, 3, 4, 5 or 6

R ^22, R ^23, R ²⁵ and R ²⁶ independently of one another are alkyl having 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, -C _n H _2n -R ^J, or trifluoromethyl, n is 0 , 1, 2, 3, or 4,

A

R represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

9

R represents a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ³⁰ R ^{31 group} ;

R ( ³⁰⁾ and R ( ³¹⁾ are hydrogen or (C1-C4) -alkyl or

R ²³ , R ²⁸ and R ²⁸ are also hydrogen,

R and R independently of one another are alkyl

a group containing from 1 to 4 carbon atoms; or

R ²³ and R ²⁴ as well as R ²⁶ and R ²⁷ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or the other substituents R ¹ , R ² and R ³ independently of one another are OR ³⁵ or NR ³⁵ R ³⁸ ,

R ( ³⁵⁾ and R ( ³⁶⁾ independently of one another are hydrogen or (C1-C6) -alkyl or

R ³⁵ and R ³⁸ together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ⁴ and R ^5, independently of one another, are hydrogen, C 1 -C 4 alkyl, fluoro, chloro, -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 to 3 carbon atoms, r is 1, 2, 3 or 4, and pharmaceutically acceptable salts thereof,

and d) benzoylguanidine of formula I (HOE 94 / F

266-EP-OS 702001, NZ 272 948

In which

R ¹ represents a hydrogen atom, a fluorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, a hydroxy group, an alkyl group having 1 to 8 carbon atoms,

C 3 -C 8 cycloalkyl or O _and - (CH ₂ ) _b - (CF ₂ ) _c -CF ₃ , a is 0 or 1, b is 0, 1 or 2, c is 0, 1 or 3, or

R ¹ is R ⁵ -SO 2 or R ⁶ R ⁷ N-SO 2 -, m is 0, 1 or 2,

R ⁵ and R ⁶ independently of one another represent an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, a trifluoromethyl Q group or a group ^- C _n H _2n -R ° n means 0, 1, 2, 3 or 4,

R ⁷ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ⁸ represents a C 3 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ^{10 group} ,

R ( ⁹⁾ and R ( ¹⁰⁾ independently of one another are hydrogen or (C1-C4) -alkyl or

R ⁸ is hydrogen or

R ⁶ and R ⁷ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or

R ¹ is -SR ^11, -OR ^11, or -CR ¹¹ R ¹² R ^13,

^R11 is -CpH ₂ p-cycloalkyl group in which the cycloalkyl portion contains 3 to 8 carbon atoms, heteroaryl of 1 to 9 carbon atoms or phenyl, where the aromatics are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group,

methylamino and dimethylamino,

R ¹² and R ¹³ independently of one another represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, p represents 0, 1 or 2, or

R ¹ represents a phenyl group, a naphthyl group, a biphenylyl group or a heteroaryl group having 1 to 9 carbon atoms, the latter being bonded via a carbon or hydrogen atom and said groups being unsubstituted or substituted by 1 to 3 substituents selected from fluorine , chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino,

R ² is -CF ² R ¹⁴ , -CF (R ¹⁵⁾ R ¹⁶ /, -CF / (CH 2) _q -CF ₃ // R ¹⁵ /, -C (CF ₂ ) _r -CF ₃ / = CR ¹⁵ R ¹⁶

R ¹⁴ is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl,

R and R independently of one another are hydrogen or (C1-C4) -alkyl, q is 0, 1 or 2, r is 0, 1 or 2,

R ³ is as defined for R ^1,

R ⁴ is H, alkyl of 1 to 3 carbon atoms, fluorine, chlorine, bromine, iodine, cyano, - (CH _{2) g} - (CF _{2) t} -CF _3, p is 0 or 1, t is 0, 1 or 2, and pharmaceutically acceptable salts thereof; and f) benzoylguanidine of the formula I (HOE 94 / F).

267-EP-OS 700899 NZ 272947

(I)

wherein one of the three substituents R, R and R is a group

-Y-4 - / (CH ₂ ) 3 -CHR ⁷ - (C = O) R ⁸ / -phenyl or a group

-Y-3 - / (CH ₂ ) 3 -CHR ⁷ - (C = O) R ⁸ -phenyl or a group

-Y-2 - / (CH ₂ ) 3 -CHR ⁷ - (C = O) R ⁸ / -phenyl, wherein in the above groups the phenyl radical is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of fluorine atom, chlorine atom , trifluoromethyl, methyl, hydroxy, methoxy or -NR ³⁷ R ³⁸ ,

R ( ³⁷⁾ and R ( ^38), independently of one another, are hydrogen or methyl,

Y represents a bond, an oxygen atom, a sulfur atom or an -NR ⁹ group,

Q

R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ⁷ is -OR ¹ ® or -NR ¹ ® R ¹¹ ,

R ^{@ 1} and R @ ¹¹ independently of one another are hydrogen, C1 -C8 alkyl, C1 -C8 alkanoyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 8 carbon atoms, benzyl or benzyloxycarbonyl or

R ⁸ is -OR ¹² or -NR ¹² R ¹³ ,

R and R independently of one another are hydrogen, C 1 -C 8 -alkyl or benzyl, k is 0, 1, 2, 3 or 4, and the other substituents R ¹ , R ² and R ^{3 are} independently of one another are (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl, or - (CH ₂ ) _m R ¹⁴ , m is 0, 1 or 2,

R ¹⁴ represents a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group 82

and -NR ¹⁵ R ¹⁶

R ¹⁵ and R ¹⁶ are hydrogen or methyl and the other substituents R ^1, R ² and R ³ independently of one another are R ¹⁸ R ¹⁹ N- (C = Y ¹⁾ -NH-SO _2,

Y ¹ is O, S or -NR ^with R ¹⁸ and R ¹⁹ independently of one another are H, alkyl having 1 to 8 carbon atoms, alkenyl or - (CH _{2) t} R, t means 0, 1, 2, 3 or 4,

R ²¹ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group and an alkyl group;

1-4 carbon atoms; or

Ί Q * 1 Q

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R is as R · ¹ · ^O or is an amidino group; or

Ί 2 other substituents R, R and R independently of one another represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a group X- (CH ₂ ) p - (CgF ₂ g ₊₁ ), R ²² -SOU, R ²³ R ²⁴ N-CO-, R ²⁵ -CO- or R ²⁶ R ²⁷ N-SO 2 -, wherein the perfluoroalkyl group is straight or branched,

X is a bond, an oxygen atom, a sulfur atom, or -NR ²⁸ , is 0 or 2, is 0, or 2, q is 1, 2, 3, 4, 5, or 6,

R ^22, R ^23, R ²⁵ and R ²⁶ independently of one another are alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, - (CH _{2) n} R ²⁹ or trifluoromethyl, n is 0, 1, 2, 3 or 4

R ²⁸ represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms,

R ²⁹ is cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and -NR ³⁸ R ³¹ ,

R ³⁰ and R ³¹ are hydrogen or alkyl having 1 to 4 carbon atoms or R ^23, R ² 5 26 _{ar znam} Enaje H,

R ( ²⁴⁾ and R ( ^27), independently of one another, are hydrogen or (C1-C4) -alkyl or

R ²³ and R ²⁴ as well as R ²⁸ and R ²⁷ together represent 4 or 5 methylene groups, of which one CH 2 group may be replaced by oxygen, sulfur, -NH-, -N-CH ₃ or -N -benzyl, or

The Ί * 2 the other substituents R, R, and ^Rj independently of one another, are -OR ³⁵ or -NR ³ R ⁸ R 3, t OC

R and R are, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or

R ³ and R 5 together represent ³⁸ 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, -NH-, _-N-CH3 or -N-benzyl;

R ⁴ and R ⁵ independently of one another are H, alkyl having 1 to 4 carbon atoms, F, Cl, -OR ^32, NR ³³ R ³⁴ or a group ^C ~ _r ^F 2r + I '

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1 to 3 carbon atoms, r is 1, 2, 3 or 4 and pharmaceutically acceptable salts thereof; and (g) benzoylguanidine of the formula I (HOE). 94 / F 352-EP-OS 713684, NZ 280 517

(I)

in which

R ¹ is R ⁸ -CO or R ⁷ R ⁸ N-CO,

R ⁸ represents an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms

Q carbon atoms or -C _n H _2n -R, n is 0, 1, 2, 3 or 4,

R ⁹ is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR ¹ ^ ^11,

R ¹⁰ and R ¹¹ represent hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ⁷ is H, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms or -C _n H _2n -R ^12, n is 0, 1, 2 , 3 or 4

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic group being unsubstituted or substituted by 1 to 3 substituents selected from fluoro, chloro, trifluoromethyl, methyl,

methoxy and NR ¹³ R ^14,

R ¹³ and R ¹⁴ represent a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group,

R ⁸ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 4 carbon atoms, or

R ⁷ and R ⁸ together represent 4 or 5 methyl groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

R ² is as R ¹ or is hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl atoms, alkenyl of 3-8 carbon atoms or -C _n H _{2 n} R ^13, n is 0, 1, 2, 3 or 4,

R ¹⁵ represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy -group and NR R group,

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl; or o

R is a C 1 -C 9 heteroaryl group bonded via a carbon or nitrogen atom and unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, hydroxy group , amino, methylamino, and dimethylamino, or

R ² is SR ^18, -OR ^18, -NR ¹⁸ R ¹⁹ or -CR ¹⁸ R ¹⁹ R ^20,

R ¹⁸ represents -C _and H _2a -heteroaryl in which it is selected

the roaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino, and is 0, 1 or 2,

R ( ¹⁹⁾ and R ( ²⁰⁾ independently of one another are as defined for R ( ¹⁸⁾ or are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R ² is R ² -I am ^ or a group R ²² R ²³ N-SO 2, m is 1 or 2,

R is alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms, an alkenyl radical containing 3 to 8 carbon atoms or -C _n H _2n -R ^24, n is 0, 1, 2, 3 or 4 .

R is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from fluoro, chloro, trifluoromethyl, methyl, methoxy- and NR ²⁷ R ²⁸ ,

R and R are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 alkenyl or C _n H _2n R ²⁹ , n is 0, 1, 2, 3 or 4.

R represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic group being unsubstituted or substituted by 1 to 3 substituents;

substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ³⁸ R ^{3 group]} ,

R ( ³⁰⁾ and R ( ³¹⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ²³ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group, or

R ²² and R ²³ together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, or

R ² is R ³³ -X-,

X is O, S, NR ³⁴ , (D = O) A- or NR ³⁴ C = MN * R ³⁸ -,

M represents an oxygen atom or a sulfur atom,

A represents an oxygen atom or a group NR ³⁴ ,

D represents a carbon atom or an SO group,

R ³³ represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a (CH ₂ ) b ^c d ^F 2d + 1 group or a group

' ^c n ^H _p 36 2n ^_R · b means 0 or 1, D means 1, 2, 3, 4, 5, 6 or 7, n means 0, 1, 2, 3 or 4, R ³⁶ represents a cycloalkyl group containing

carbon, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ³⁷ R ^{38 group} ,

R ( ³⁷⁾ and R ( ³⁸⁾ are hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl,

R ³⁵ is as R ³³ , or

R ³³ and R ³⁴ together represent 4 or 5 methylene groups,

of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, wherein A and N * are bonded to the phenylalkyl core of the basic benzoylguanidine skeleton, or

R ² is -SR ^40, -OR ^40, -NHR ^40, -NR ⁴⁰ R ^41, CHR ⁴⁰ R ^42, -CR ⁴² R ⁴³ OH, -CsCR ^45, -CR ⁴⁶ = CR ⁴⁵ or - / cr ⁴⁷ r ⁴⁸ / u-co- (CR ⁴⁹ R ⁵⁰ / v R ⁴⁴⁾ ,

R ( ⁴⁰⁾ and R ( ⁴³⁾ independently of one another are - (CH ₂ ) _p - (CHOH) _q - (CH ₂ ) _r - (CHOH) _t -R ⁵¹ or

- _(CH2) -O- _{(CH2 CH2} O) R ^51, C ~ ~ Ί

R ^3X represents a hydrogen atom or a methyl group, u represents 1, 2, 3 or 4, v represents 0, 1, 2, 3 or 4, p, q and independently of one another represent 0, 1, 2, 3 or 4; means 1, 2, 3 or 4,

R ( ⁴²⁾ and R ( ⁴³⁾ independently of one another are hydrogen or (C1-C6) -alkyl or

R ⁴² and R ⁴³ together with the carbon atom to which they are attached represent a C 3 -C 8 cycloalkyl group,

R ⁴⁴ is H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or -C _e H _2e -R ^45, e is 0, 1, 2, 3 or 4,

R ⁴⁵ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁵² group R ⁵³ ,

R ( ⁵²⁾ and R ( ⁵³⁾ are hydrogen or (C1-C4) -alkyl or

R ³ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted as a phenyl group, or

R ⁴⁸ represents an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups,

R ⁴⁸ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ and r ^{50 are} independently of one another. a hydrogen atom or a methyl group; or

R ² is R ⁸⁸ -NH-SO ₂ -, r ⁵⁵ is R ⁸ R ⁸ R ⁷ N- (C = Y) -,

C Q

Y is O, S or NR, R and R independently of one another are hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms or -CfH ₂ fR ⁵⁹ f is O, 1, 2, 3 or 4, c Q

R is C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy and alkyl of 1 to 4 carbon atoms, or

R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

C Q c G

R is as R or is an amidino group, R ³ , R ⁴ and R ⁵ are independently of one another as R ¹ or

R ^2, wherein at least one of R ^2, R ^3, R ⁴ and R ⁵ has is a hydroxyl group, and a pharmaceutically-acceptable salt thereof, and h) a benzoylguanidine of the formula I (HOE 95 / F 007 K-EP-723 956, NZ 280,887)

(D in which one of the three substituents R ¹ , R ² and R ³ represents a group R ⁶ -ABD,

R ⁶ represents a basic protonatable radical, i.e. amino group-NR ⁷ R ⁸ , an amidino group R ⁷ R ⁸ NC (% NR ⁹ ) or a guanidino group of the general formula

R ⁷ R ¹⁰

Q G 1 Π

R, R °, R and R independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R and R ° together represent C _and H _2a , and are 4, 5, 6 or 7, and when a = 5, 6 or 7, one methylene group of C _and H _{2a may} be replaced by an oxygen atom, SO _m or NR ¹¹ or

R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ⁷ and R ¹⁰ is ^C a ^H 2a 'a is 2, 3, 4 or 5, wherein, if a = 3, 4, or 5, can be, replace the methylene group of groups C _and H _2a with an oxygen atom, a SO _m group or a NR ¹¹ group, m being 0, 1 or 2,

R ¹¹ represents a hydrogen atom or a methyl group; or g

R is a basic heteroaromatic ring system containing 1 to 9 carbon atoms,

A is C _b H _2b , b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein in C _b H _2b one or two methylene groups may be replaced by a group selected from the group consisting of O, -CO ^-, -CH / OR ²⁰ / -, -SoM- group, -NR ²⁰ -, -NR ^Q2 -CO-, -NR ²⁰ -CO-NH-, -NR ²⁰ -CO -NH-SO 2 -, a group of the formula I ''

-s— ínr’X

and _aa SO (NR ¹⁹⁾ _bb, wherein the further group ^{is m} ° to one methylene group replaced with -CH-R ⁹⁹ and R ⁹⁹ forms together with R ⁷ pyrrolidine or piperidine ring, aa is 1 or 2, bb = 0 or 1, aa + bb = 2

R ( ¹⁹⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

R represents a hydrogen atom or a methyl group,

means phenylene or naphthylene residue of general formulas -12 R R ¹² / ΐν / + \ y r Ý \ t; R ¹³ vlz R ¹³

R ¹² and R ¹³ independently of one another represent a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group or a group -SO _W -R ¹⁴ ,

R ¹⁴ is methyl or NR ¹⁵ R ¹⁶ ,

Ί C * 1 £

R ^xo and R independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, w is 0, 1 or 2,

D is -ϋ ^ Η ₂ ^ -Χ £ -, d is 0,

X is O, -CO-, -CH (OR ²¹ ) -, -SO _m- or -NR ²¹ -,

F means 0 or 1, R ²¹ is hydrogen or methyl group m means 0, 1 or 2, and others the substituents R ^1, R ² and R ³ independently one on the other

are hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, -NR ³³ R ³⁶ or R ¹⁷ -C ⁹ H 2g -Z _n -, g is 0, 1, 2, 3 or 4, h is 0 or 1,

T c or

R and R independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

R and R ^JO together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or -N-benzyl;

Z is O, -CO-, -SO _in -, -NR ¹⁸ -, -NR ¹⁸ -CO-, -NR ¹⁸ -CO-NHor -NR ¹⁸ -SO ₂ -, fl

R represents a hydrogen atom or a methyl group, v represents 0, 1 or 2,

R is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or a radical C _{<F 2 c} j _{+ 1,} k is 1, 2 or 3, or

R represents a pyrrol-1-yl group, a pyrrol-2-yl group or a pyrrol-3-yl group which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano- C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxy, trifluoromethyl, methyl and methoxy; or

R ¹⁷ represents a cycloalkyl group containing 3 to 8 carbon atoms

or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a hydroxy group, a methoxy group, an -NR ³⁷ R ³⁸ group, a CH ₃ SO _{2 group} and H ₂ NO ₂ S-,

R ( ³⁷⁾ and R ( ³⁸⁾ are hydrogen or methyl, R ( ⁴⁾ and R ( ⁵⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, -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 is 1, 2, 3 or 4 as well as pharmacologically acceptable salts thereof, and (ii) indenoylguanidine of the formula I (HOE 95 / F

072-EP-OS 738712

(I) in which η O

R and R independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, O- alkyl having 1, 2, 3 or 4 carbon atoms, OC (= O) - an alkyl group in which the alkyl moiety contains 1, 2, 3 or 4 carbon atoms, or a C _m H _2m -NR ¹² R ^{13 group} ,

R and R independently of one another represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon 94

m atoms, m is 0, 2, 3 or 4, NH-C (O) -NH ₂ / C (= O) -O-alkyl in which the alkyl radical contains 1, 2, 3 or 4 carbon atoms , C (= O) -NH ₂ , C (= O) -NH-alkyl in which the alkyl radical contains 1, 2, 3 or 4 carbon atoms,

A C (= O) -N (alkyl) ₂ group in which each alkyl radical contains 1, 2, 3 or 4 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, an alkynyl group containing 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, an alkylaryl group in which the alkyl radical contains 1, 2, 3 or 4 carbon atoms, an alkenylaryl group in which the alkenyl group the residue contains 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, an alkynylaryl group in which the alkynyl residue contains 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, an aryl group substituted with an alkyl group containing 1 to 4 carbon atoms, an alkylheteroaryl group wherein the alkyl moiety contains 1-4 carbon atoms, an alkenylheteroaryl group wherein the alkenyl moiety contains 2-4 carbon atoms, an aminoalkylaryl group wherein the alkyl moiety contains 1, 2, 3 or 4 carbon atoms, substituted aryl, heteroaryl and substituted heteroaryl,

R ³ , R ⁴ , R ⁵ and R ^6, independently of one another, are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, O-alkyl having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom, aryl group, substituted aryl group, heteroaryl group, substituted heteroaryl group , O- (lower alkyl), O-aryl, O- (lower alkyl) -aryl, O-substituted aryl, O- (lower alkyl) -substituted aryl, O-C (= O) -alkylaryl in which the alkyl radical contains 1 to 4 carbon atoms, the O-C (= O) -NH-alkyl group in which the alkyl radical contains 1 to 4 carbon atoms,

O-C (= O) -N (alkyl) ₂ , nitro, cyano, trifluoromethyl, NH-C (= O) -alkyl wherein the alkyl moiety contains 1 to 4 carbon atoms, NH- C (= O) -NH ₂ , carboxyl, C (= O) -O-alkyl in which the alkyl moiety contains 1 to 4 carbon atoms, C (= O) -NH ₂ , C (= O) -NH-alkyl in which the alkyl radical contains 1 to 4 carbon atoms, the C (= O) -N (alkyl) _{2 group} in which each alkyl radical contains up to 4 'carbon atoms, the alkyl-C00H group in which the alkyl radical it contains 1 to 4 carbon atoms, an alkyl-C (= O) -O-alkyl group in which each alkyl moiety contains 1 to 4 carbon atoms, a SO-J group, a SO ₂ -alkyl group, a SO ₂ -alkylaryl group, SO ₂ -N- (alkyl) ₂ , SO ₂ -N (alkyl) (alkylaryl), C (= O) -R ¹¹ , alkyl-C (= O) -R ¹¹ , wherein the alkyl moiety contains 1 to 10 carbon atoms, alkenyl-C (= O) -R ¹¹ , in which the alkenyl radical o it contains up to 10 carbon atoms, an alkynyl-C (= O) -R ^{11 group} in which the alkynyl radical contains 2 to 10 carbon atoms, an NH-C (= O) -alkyl-C (= O) -R ^{11 group} , in wherein the alkyl radical contains 1 to 10 carbon atoms, the O-alkyl-C (= O) -R ^{11 group} , wherein the alkyl radical contains 1 to 11 carbon atoms,

R ¹¹ is alkyl of 1 to 4 carbon atoms, alkynyl of 1 to 4 carbon atoms, aryl, substituted aryl, NH _2, NH-alkyl having 1 to 4 carbon atoms, N- (alkyl) ₂ wherein each alkyl radical contains 1 to 4 carbon atoms, SO ₃ H, SO ₂ -alkyl, SO ₂ -alkylaryl,

SO ₂ -N- (alkyl) ₂ group and SO ₂ -N- (alkyl) (alkylaryl) group,

X represents an oxygen atom, a sulfur atom or an NH group,

R, R, R, and R independently of one another are hydrogen, alkyl, cycloalkyl, aryl, alkylaryl or

R ⁸ and R ⁹ together form a 5, 6 or 7-membered heterocyclic ring, A is absent or is a non-toxic organic or mineral acid if) a benzyloxycarbonylguanidine of formula I (HOE 95 / F 109-EP 748 795, NZ

583)

286

In which

R ^1, R ² and Eden

-Y- (4-R ⁸ -phenyl), -Y- (2-R ⁸ -phenyl), wherein the phenyl is unsubstituted or substituted by 1 or 2 of trifluoromethyl, methyl, methyl and methoxy; -NR λ, R ⁹⁶ and R ^97, independently of one another, are hydrogen or methylene,

Y represents a bond, a CH ₂ group, an oxygen atom, a sulfur atom Q or an -NR ^J group,

^R9 another are -Y- / 3-phenyl ^R8 / or a substituent group zvolefluóru, Cl, hydroxy-Item ⁹⁶ R ⁹⁷ with

R ⁸ represents a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms, means means b = 2, a SO 2 group _and / NR ⁹⁸ / _b NR ⁹⁹ R ¹⁰ , or 2, or 1, +

R ⁹⁸ , R hydrogen, the atoms in which each alkylene radical contains 2 to movs, or an alkylene-CR ³⁹ R ⁴⁸ -NR 'group and an R ¹⁰ alkyl group containing 1 benzyl group, the alkylene radical group contains 2 alkylene-NR group ¹³ independently of one another represent an atom of up to 8 carbon atoms

-alkylene-NR ¹¹ R ¹² , up to 8 carbon atoms

-alkylene-NR ³⁷ R ^38, wherein the carbon atóalebo group -alkylene-CR ^JY R ^of -CR ⁴¹ R ⁴² R ^{44 43} alkylene, wherein each alkylene radical has 2 to 8 carbon atoms,

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ³⁷⁾ , R ( ³⁸⁾ , R ( ⁴³⁾ and R ( ⁴⁴⁾ independently represent a hydrogen atom, an alkyl group containing 1 to 8 carbon atoms or a benzyl group,

R ( ³⁹⁾ , R ( ⁴⁰⁾ , R ( ⁴¹⁾ and R ( ^42), independently of one another, represent a hydrogen atom, an alkyl group containing 1 to 8 carbon atoms or an alkylene phenyl group in which the alkylene radical contains 2 or 3 carbon atoms, the phenyl group being unsubstituted or substituted 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl-

or a methoxy group; or q g i λ

R and R together represent 4 to 6 methylene groups, of which one CH2 group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, an -N-CHg group or an -N-benzyl group, or

R ⁸ is SOa (NR ⁹⁸ ) 13 NR ⁹⁵ -C = NR ⁹⁴ / NR ⁹³ R ⁹² , qo qq Q4 qc

R, R, R, and R independently of one another represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

R ^1, R ² and R ³ each independently pyrrol-l-yl group, of one another are pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of F, chlorine atom, bromine atom, atom

iodine, cyano, C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxy, trifluoromethyl, methyl, methoxy or

R, R and R independently of one another are hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or - (CH ₂ ) _m R ¹⁴ , m is 0, 1 or 2,

R ¹⁴ represents a cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group

pin, methoxy and -NR ¹⁵ R ¹⁶ ,

R ¹⁵ and R ¹⁶ represent a hydrogen atom or a methyl group;

R ¹ , R ² and R ^3, independently of one another, represent -Q-4 - / (CH 2) k -CHR ¹⁷ - (C = O) R ²⁰ / phenyl or -Q-3 - / (CH 2) _k - CHR ¹⁷ - (C = O) R ²⁰ / phenyl or -Q-2 - / (CH ₂ ) _to -CHR ¹⁷ - (C = O) R ²⁰ / phenyl, wherein the phenyl group is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, hydroxy group, methoxy group and -NR ³⁵ R ^{36 group} ,

R ³⁵ and R ³⁶ independently of one another are hydrogen or methyl,

Q is a bond, O, S or NR ^18,

R ¹⁸ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ¹⁷ is -OR ²¹ or -NR ²¹ R ²² ,

R ²¹ and R ²² independently of one another are hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkanoyl, alkoxycarbonyl in which the alkyl radical contains 1 to 8 carbon atoms, benzyl, benzyloxycarbonyl or

R ²¹ represents a trityl group,

R ²⁰ is -OR ²³ or -NR ²³ R ²⁴ ,

R ²³ and R ^24, independently of one another, are hydrogen, C 1 -C 8 alkyl or benzyl, k is 0, 1, 2, 3 or 4, or

R ^X, R, and ^Rj independently of one another are heteroaryl having 1 to 9 carbon atoms, which is linked via carbon or nitrogen and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino

and dimethylamino or

R ¹ , R ² and R ³ are -SR ² -OR ² R 4, -NR ² R ²⁸ , -CR ²⁵ R ²⁶ R ²⁷ ,

R ²⁵ represents a -CfH ₂ f-heteroaryl group wherein the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy, amino, methylamino and dimethylamino, f is 0, 1 or 2,

97

R and R independently of one another are as defined for R ² R or are hydrogen or alkyl having 1 to 4 carbon atoms, or

R, R and R are, independently of one another, a heteroaryl-N-oxide group having 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chloro, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino, or

R ¹ , R ² and R ³ independently of one another are -SR ²⁸ , -OR ²⁸ , -NR ²⁸ R ²⁹ or -CR ²⁸ R ²⁹ R ³⁰ , -C ₈ H ₂ -heteroaryl-N-oxide wherein the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino a group and a dimethylamino group, g represents 0, 1 or 2,

R and R ^by independent of one another are as defined for R ²⁸ or are hydrogen or alkyl having 1 to 4 carbon atoms, or

7

R, R and R independently of one another represent a hydrogen atom, a fluorine atom, a bromine atom, an iodine atom, a cyano group, a T- (CH ₂ R ³¹ SO ₁ -) group,

100

R ³² R ³³ N-CO-, R ³⁴ -CO- or R ⁴⁵ R ⁴⁶ N-SO ₂ , the perfluoroalkyl group being straight or branched,

T means 47 means

-NR 'a bond, an oxygen atom, a sulfur atom or a group or 2, or 2,

2, 3, 4, 5 or 6, ⁴⁵ independently one alkyl group containing 1 to is

^R31 , ^R32 , ^R34

0,: o,: i,: and R 'on the other are carbon atoms,

(C až-C) alkenyl, (Q) (CH ₂ ) _n R R ° or trifluoromethyl, n = 0, 1, 2, 3 or 4,

R ⁴⁷ represents a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms;

R represents a cycloalkyl group containing 3 to 7

a carbon atom or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and an -NR ⁴⁹ R ^{50 group} ,

R ⁴⁹ and r 50 are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R ³² , R ³⁴ and R ⁴⁵ are hydrogen,

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 as well as R ⁴ and R ⁴ together represent 5 or 6 methyl groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, an -NCH ₃ group or a - N-benzyl or * 3

R, R, and ^Rj independently of one another are R ³¹ -AGD,

R ⁵¹ represents a basic protonatable radical, i.e. the amino group -NR ⁵² R ⁵³ , the amidino group R ⁵² R ⁵³ -NC (= NR ⁵⁴ ) or the guanidino group _r 52 _r 53 _n = _c / _{= n r} 54 / _ _nr 55_,

R ⁵² , R ⁵³ , R ⁵⁴ and R ⁵⁵ independently of one another represent a hydrogen atom or an alkyl group containing 1, 2, 3

101

or 4 carbon atoms; or

R ⁵² and R ⁵³ are C _alpha H _{2a and fa} , alpha is 4, 5, 6 or 7, and if alpha = 5, 6 or 7, then one carbon atom of the ^c alpha ^{H 2} alpha group can be replaced by hetero a group selected from the group consisting of oxygen, SO 4 or NR ⁸⁸ ;

R ⁵³ and R ⁵⁴ or R ⁵⁴ and R ⁵⁵ or R ⁵² and R ⁵⁵ represent an CYH ^, y is 2, 3, 4 or 5, wherein, if y = 3, 4 or 5, it may be one C replace the CyH ₂ atom with a hetero group selected from oxygen, SO 4 or NR ⁸⁸ , d represents 0, 1 or 2, represents a hydrogen atom or a methyl group, or

R ⁸¹ represents a basic heteroaromatic ring system containing 1 to 9 carbon atoms,

A is C _e H _2e , e is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and in C _e H _2e one carbon atom can be replaced by an oxygen atom, - CO-, -CH (OR ⁵⁷ ) -, -SO 2, -NR ⁵⁷ -CO-, -NR ⁵⁷ -CO-NH-, -NR ⁵⁷ -CO-NH-SO 2 -, or -NR ⁵⁷ -SO ₂ -, r is 0, 1 or 2,

G is a phenyl radical of formula

C Q CQ

R ³ and R ³⁵ independently of one another are hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl or a group -SO -R ^0,

ABOUT

R ⁶⁰ is methyl or NR ⁶¹ R ⁶² , gi 62

R 0 and R independently of one another are hydrogen

102 or an alkyl group containing 1, 2, 3 or 4 carbon-

Vé atoms, D means -C _{in H2v} -E _w , in means 0, 1, 2, 3 or 4 / E means oxygen atom, -CO- group -CH (OR ⁸³ ) -, i -SO _aa - or -NR -, w means 0 or 1 aa means 0, 1, or 2 R ⁸³ means a hydrogen atom; or a methyl group, or and R ³ independently of one the other mean group

-CF ₂ R ⁶⁴ , -CF (R ^{85) (} R ⁸⁸ ),

-CF ((CF ₂ ) _q -CF ₃ ) // R ⁶⁵ /, -C ((CF ₂ ) _p -CF ₃ ) = CR ⁶⁵ R ⁶⁶ ,

R ⁶⁴ represents an alkyl group having 1, 2, 3 or 4 carbon atoms or a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms,

R ( ⁸⁵⁾ and R ( ⁸⁸⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, q is 0, 1 or 2, p is 0, 1 or 2 or

R ^1, R ² and R ³ independently of one another, are -OR ⁸⁷ or -NR ⁸⁷ R ⁸ ®,

R ⁸⁷ and R ⁸ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or

R ⁸⁷ and R ⁸ ® together represent 4, 5, 6 or 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an SO ₂ group, an -NH- group, an -NCH ₃ group or an -N group benzyl,

R ⁴ and R 5 independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR ^89, -NR ⁷⁸ R ⁷¹ or C _z F _{2z + 1} .

R, R and R independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms, z is 1, 2, 3 or 4;

R and R independently of one another are hydrogen or

103 alkyl having 1, 2, 3 or 4 carbon atoms,

X is O or NR,

R ⁷² represents a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms, as well as pharmaceutically acceptable salts thereof, and (a) an alkeriylcarboxylguanidine bearing fluorophenyl groups of the formula I (HOE 95 / F 115-EP 744397,

NZ 286622)

(I)

in which £

R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group, the phenyl group being unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ⁹ R ¹⁰ ,

R ⁹ and R ¹⁰ are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R ⁷ is each independently defined as R ^6,

R ^1, R ^2, R ^3, R ⁴ and R ⁵ independently of one another are hydrogen or F, wherein at least one of R ^1, R ^2, R ^3, R ⁴ and R ⁵ has is F, as and pharmaceutically acceptable salts thereof,

104 am) benzoylguanidine of general formula I (HOE 95 / F 167-NZ 299015)

in which

R ¹ is R ⁴ -SO 2 or R ⁵ R ⁶ N-SO 2, m is 1 or 2,

R ⁴ and R ⁵ independently of one another denote alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon atoms, trifluoromethyl or - ^c n ^H 2n- ^{R 7} n represents 0, 1, 2, 3 or 4,

R ⁶ represents a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms,

R represents a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁸ R ⁹ ,

R ⁸ and R ⁹ represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms or

R ^{5 is} also hydrogen or

R ⁵ and R ⁶ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, or

R ¹ is -O _p - (CH ₂ ) _g - (CF ₂ ) _r -CF ₃ , p is 0 or 1, q is 0, 1 or 2,

105

r is 0, 1, 2 or 3, or

R ¹ is -SR ^10, -OR ^10, or -CR ¹⁰ R ^{and L} R ^12,

R ^10, R ¹¹ and R ¹² independently of one another are H, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -C _s H _2s -cycloalkyl, wherein the cycloalkyl moiety it contains 3 to 8 carbon atoms, or an aromatic system selected from the group consisting of pyridyl, pyrrolyl, quinolyl, isoquinolyl, imidazolyl or phenyl, s being 0, 1 or 2, said aromatic systems from the pyridyl group , pyrrolyl, quinolyl, isoquinolyl, imidazolyl and phenyl are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, hydroxy, amino, methylamino- group, a dimethylamino group, R ² is - (CH _{2) u} ~ _(CF2) .- ^ CF ^, t is 0, 1, 2 or 3, u is 0 or 1,

Q

R is hydrogen or independently has the meaning defined for R ¹ as well as its pharmaceutically acceptable salts, and an) a substituted guanidide of formula I (HOE 95 / F 173-NZ 299052)

(I)

106

wherein at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is a group of a ^ a ^ b ^ n ^

X is CR ¹⁶ R ¹⁷ , O, S or NR,

R ( ¹⁶⁾ , R ( ¹⁷⁾ and R ( ¹⁸⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, and is 0 or 1,

Y represents an alkylene group containing 1, 2, 3, 4, 5,

6, 7 or 8 carbon atoms, an alkylene-T group in which the alkylene radical contains 1, 2, 3, 4, 5, 6, 7 or carbon atoms, a T, T-alkylene group in which the alkylene radical contains 1, 2 , 3, 4, 5, 6, 7 or 8 carbon atoms,

Ω

T represents an NR group, an oxygen atom, a sulfur atom or a phenylene group, the phenylene group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom,

trifluoromethyl, methoxy and NR ²¹ R ²² ,

R ( ²⁰⁾ , R ( ²¹⁾ and R ( ²²⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, b being 0 or 1,

L is O, S, NR ²³ or a group <\ Η _2] ς, a is 1, 2, 3, 4, 5, 6, 7, 8, n is 0 or 1,

U is NR ²⁴ R ²⁸ or an N-containing heterocyclic group containing 1, 2, 3, 4, 5, 6, 7, 8 or carbon atoms,

R and R 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

107

R ²⁴ and R ²⁵ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, the N-containing heterocyclic group being bound through nitrogen or carbon and is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ²⁷ R ²⁸ ,

R ( ²³⁾ , R ( ²⁷⁾ and R ( ²⁸⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms and the other substituents R ¹ , R ² , R ^3, R ⁴ and R ⁵ independently of one another are hydrogen, F, Cl, cyano group, ° ^C _n ^H m + 2 m -O p L is (CH 2) s ^-C q ^F 2q + l ^{N e} group will -CrH ₂ R ^10,

n means 0 or 1, m means 0, 1, 2, 3, 4, 5, 6, 7 or 8, P means 0 or 1, q means 1, 2, 3, 4, 5, 6, 7 or 8, with means 0, 1, 2, 3 or 4, r means 0, 1, 2, 3 or 4, R ¹⁰ represents a cycloalkyl group containing 3, 4, 5, 6,

or 8 carbon atoms or a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹¹ R ^{12 group} ,

R and R independently of one another are hydrogen, 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 are hydrogen, F, Cl, Br, cyano, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl a group containing 1, 2, 3, 4,

5, 6, 7 or 8 carbon atoms, a cycloalkyl group

108 having 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR group ¹⁴ R ^15, R ¹⁴ and R ¹³ 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,

as well as its pharmaceutically acceptable salts, and o) a benzoylguanidine of the formula I (HOE 95 / F

220-NZ 299052

(I)

wherein at least one of R ¹ , R ² and R ³ is R ⁶ -C (OH) ₂ -,

R is a perfluoroalkyl group containing 1, 2 or 3 carbon atoms, which is straight or branched, and the other substituents R ¹ , R ² and R ^3, independently of one another, are hydrogen, hydroxy, fluorine, chlorine, bromine , iodine, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or phenoxy- a group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group or the other substituents R ¹ , R ² and R ³ independently of one another

109

have an alkyl-SO _x group, -CR ⁷ = CR ⁸ R ⁹ or -C ⁸ CR ⁹ , x being 0, 1 or 2,

R ⁷ represents a hydrogen atom or a methyl group,

R ⁸ and R ⁹ independently of one another represent a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7 or carbon atoms or a phenyl group which is unsubstituted or substituted 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl and methoxy; or

The Ί * 2 the other substituents R, R, and ^Rj independently of one another are phenyl, CGH-alkyl group in which the alkyl portion contains 1 to 4 carbon atoms, naphthyl, biphenylyl, quinolinyl, isoquinolinyl or imidazolyl wherein the quinolinyl, isoquinolinyl or imidazolyl group is bonded via a carbon or nitrogen atom and the phenyl, C 8 H 6 -alkyl, naphthyl, biphenylyl, quinolinyl, isoquinolinyl and imidazolyl groups are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group or the other substituents R ¹ , R ² and R ^3, independently of one another, represent a group SR ¹⁰ , -OR ¹⁰ , -CR ¹⁰ R ¹¹ R ¹² ,

R ¹⁰ is a group CFH _2f -cycloalkyl, wherein the cycloalkyl portion contains 3 to 8 carbon atoms, quinolinyl, isoquinolinyl, pyridinyl, imidazolyl or phenyl, where the aromatic systems include quinolinyl, isoquinolinyl, pyridinyl , the imidazolyl group and the phenyl group are unsubstituted or substituted with 1 to 3 substituents

110

selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, f represents 0, 1 or 2,

R and R independently of one another have the meanings defined for r10 or are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

R ⁴ and R ^8, independently of one another, are hydrogen, alkyl having 1, 2 or 3 carbon atoms, fluorine, chlorine, bromine, iodine, cyano, OR ¹³ , NR ¹⁴ R ¹³ , - (CH ₂ ) _n - (CF ₂ ) _o -cf ₃

R ^13, R ¹⁴ and R 1 ³ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, n is 0 or 1, o is 0, 1 or 2 and a pharmacologically acceptable salt thereof, (p) sulphonamide of formula I (HOE 95 / F 253-NZ 299682)

O = SR ²

R ⁴ / R ³ (I) wherein at least one of the three substituents R ¹ , R ² and R ³ represents a benzoylguanidine group of the formula

o nh ₂

111

which is unsubstituted or substituted by 1 to 4 substituents on the phenyl radical 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 , fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, R ²² SO 2, R ²³ R ²⁴ N-CO- , the group R ²⁵ CO-, a group R 26 _R 27 _N _ _{f SO} 2 -OR ^35, -SR ³⁵ or -NR ³⁵ R ^36, m is 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁶

R ¹⁵ and R ^16, independently of one another, are hydrogen or methyl,

R ( ²²⁾ , R ( ²³⁾ , R ( ²⁵⁾ and R ( ²⁶⁾ independently of one another denote 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 ) _n R ²⁹ or trifluoromethyl, n represents 0, 1, 2, 3 or 4, q

R is C 3 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy and -NR ³⁰ R ³¹ ,

R ( ³⁰⁾ and R ( ³¹⁾ are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R ²³ , R ²⁵ and R ²⁶ are hydrogen,

R and R * independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R ²³ and R ²⁴ as well as R ²⁶ and R ²⁷ together represent 5 or 6 me

112

tylene groups, of which one group may be replaced by oxygen, sulfur, -NH-, -NCH ₃ or -N-benzyl,

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 ³³ and R ³⁶ together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, -NH-, -CH ₃ or -N-benzyl,

R ³³ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, SO ² R ³ group, SO ² NR ⁶ R ⁷ group and -NR ³² R group ³³ ,

R ⁵ represents an alkyl group having 1, 2,3,4, 5 or 6 carbon atoms, g 7

R and R are, independently of one another, a hydrogen atom or an alkyl group containing 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 nc

R represents a heteroaryl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group

Ί OQ and the other substituents R, R and R independently of one another are alkyl having 1, 2, 3, 4, 5, 6, or 8 carbon atoms or a (CH ₂₎ p R ¹⁰ p is 0, 1, 2 , 3 or 4

R ¹⁰ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, -SO 2 NR ¹⁷ R ¹⁸ and -SO ² R ⁹ ,

113

R ( ¹⁷⁾ and R ( ¹⁸⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

R ⁹ represents an alkyl group containing 1, 2, 3 or carbon atoms, or the other substituents R ¹ and R ³ represent a hydrogen atom,

R ⁴ is H or alkyl having 1, 2, 3 or 4 carbon atoms, and the pharmaceutically acceptable salts thereof,

aq) a benzoylguanidine of the formula I (HOE 95 / F

265-NZ 299739

(I)

in which

R ¹ represents an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or NR ⁷ 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 H, alkyl having 1, 2, 3, 4.5, 6, 7 or 8 carbon atoms or a -SO ₂ R ^9, R ⁹ is independently as defined for R ^1,

R ³ represents a hydrogen atom, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ or -CR ²⁵ R ²⁶ R ²⁷ ,

R ²⁵ represents a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethoxy -methyl group

114

a group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group, or

R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, hydroxy group, amino group, methylamino group and dimethylamino -group,

R ²⁸ and R ²⁷ independently of one another are as defined for R ²⁸ or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

R ⁴ is H, fluoro, chloro, bromo, iodo, hydroxy, cyano, trifluoromethyl, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ > m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁸ .

R ( ¹⁵⁾ and R ( ^18), independently of one another, are hydrogen or methyl,

R ⁵ and R ⁸ independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, as well as pharmaceutically acceptable salts thereof,

115 (I) ar) Benzenedicarboxyldiguanidide of formula I (HOE 95 / F 269 K)

wherein one of R ¹ , R ² , R ³ and R ⁴ is a group

-co-n = c (nh ₂ ) ₂ and the other substituents R ¹ , R ² , R ³ and R ⁴ represent:

R ¹ is H, alkyl having 1, 2, or 4 carbon atoms, F, Cl, Br, I, -OR ^32, -NR ³³ R ³⁴ or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or carbon atoms,

4

R and R independently of one another represent H, F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, -CO-N-C _{(NH2) 2,} alkyl containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m means 0, 1, or 2

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹ ®,

E Ί ΖΓ

R and R ^o is hydrogen or methyl, or

4

R and R are, independently of one another, pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl;

116

n, which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, C 2 -C 8 alkanoyl group, C 2 -C 8 alkoxycarbonyl group, formyl group, a carboxyl group, a trifluoromethyl, methyl and methoxy, or R ² and R ⁴ independently of one another are -SO 2 R ^22, group R ²³ R ²⁴ N-CO-, R ²⁸ -CO-, or r29r ³⁰ N-SO2

R ( ²²⁾ and R ( ²⁸⁾ independently of one another are methyl or trifluoromethyl, R ( ^22), R ( ²⁴⁾ , R ( ²³ ) _and independently of one another are hydrogen or methyl;

R ² and R ⁴ independently of one another, are -OR ³⁵ or -NR ³⁵ R ^38,

R ( ³⁵⁾ and R ( ³⁸⁾ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or

R ³⁵ and R ³⁸ together form 4 to 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, -CH ₃ group, or -N-benzyl group,

R ³ represents a hydrogen atom, -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁸ , -CR ²⁵ R ²⁸ R ²⁷ ,

R

R represents a hydrogen atom, an alkyl group containing 1,

2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy- a group, an amino group, a methylamino group and a dimethylamino group; or

R represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino- group a dimethylamino group,

117

R ²⁶ and R ²⁷ independently of one another have the meanings defined for R ²⁵ or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

R ⁵ represents an alkyl group containing 1, 2, 3 or 4 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an X- (CH ₂ ) _y -CF ₃ group or a phenyl group which is unsubstituted or substituted 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ° R group,

R ⁶ and R ⁷ independently of one another represent a hydrogen atom or a methyl group,

X is a bond or an oxygen atom, y is 0, 1 or 2, as well as pharmaceutically acceptable salts thereof, and (a) a benzenedicarboxyldiguanidide of formula I (HOE 95 / F 269 BK)

(I) wherein one of R ¹ , R ² , R ³ and R ⁵ is -CO-N = C (NH ₂ ) _2, and the other R ¹ , R ² , R ^3, and R ⁵ are:

R ( ¹⁾ and R ( ⁵⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, -OR, -NR ³³ R ³⁴ or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or

118

carbon atoms,

R ² represents H, F, Cl, Br,, hydroxy, cyano, trifluoromethyl, -CO-N-C _(NH2) 2 · alkyl having 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁶ .

R and R ⁰ independently of one another are hydrogen or methyl, or

R ² is R ²² -SO ² -, R ²³ R ²⁴ N-CO-, R ²⁸ -CO or R ²⁹ R ³⁰ N-SO 2.

2 fi

R and R independently of one another are methyl or trifluoromethyl, r ²³ , r ²⁴ , r 29 _and r 30 independently of one another are hydrogen or methyl or

R ² is -OR ³⁸ or -NR ³⁸ R ³⁸

R ( ³⁸⁾ and R ( ³⁸⁾ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or

R ³⁸ and R ³⁶ together represent 4 to 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, an -NCH ₃ group or an -N-benzyl group,

R ³ represents a hydrogen atom, -SR ²⁸ , -OR ²⁸ , -NR ²⁸ R ²⁶ , -CR ²⁸ R ²⁶ R ²⁷ ,

R represents a hydrogen atom, an alkyl group containing 1,

2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy- amino,

119

methylamino and dimethylamino; or

R ²⁵ represents a heteroaryl group containing 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group - the group and the dimethylamino group, R ²⁸ and R ^27, independently of one another, are as defined for R ²⁵ or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

R ⁴ is trifluoromethyl, 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, cycloalkyl having 3 up to 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m being 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁶ .

R ( ¹⁵⁾ and R ( ^18), independently of one another, are hydrogen or methyl;

R ⁴ represents a phenyl group which is unsubstituted or substituted by 2, 3, 4 or 5 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and an -NR ¹⁵ R ¹⁸ η C Ί z group

· · R * ³ and R · ¹ · ^0, independently of one another represent hydrogen or methyl, and a pharmaceutically-acceptable salt thereof, v) diaryldikarboxyldiguanidid of formula I (HOE 96 / F 013)

120 (I)

wherein one of R ^1, R ^2, R ^3, R ^4, and R ⁵ is -CO-N = C'NH _{2) 2} the other radicals R ¹ and R ⁵ independently of one another are H, alkyl containing 1, 2, or 4 carbon atoms, fluorine atom, chlorine atom, -OR ³² , -NR ³³ R ^34, or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or alkyl having 1, 2, 3 or carbon atoms, the other substituents R ( ²⁾ and R ( ⁴⁾ independently of one another are hydrogen, fluorine or bromine, iodine atom, hydroxy group, cyano group, trifluoromethyl group, -CO-N = C (NH ₂ ) ₂ , alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁶ , tc η c

R and R are hydrogen or methyl or the other substituents R ² and R ⁴ independently of one another are pyrrol-1-yl, pyrrol-2-yl

121

or a pyrrol-3-yl group which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, C 2 -C 8 alkanoyl group, 2-alkoxycarbonyl group up to 8 carbon atoms, formyl, carboxy, trifluoromethyl, methyl, methoxy or the other substituents R ² and R ⁴ are R ²² -SO 2 -, R ²³ R ²⁴ N-CO, R ²⁸ - CO- or a group r ²⁹ r ³⁰ n-s 2,

R ²² and R ^28, independently of one another, are methyl or trifluoromethyl,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl or the other substituents R ( ²⁾ and R ( ⁴⁾ independently of one another are -OR ³⁵ or -NR ³⁵ R ³⁶ ,

R ³ and R 5 ³⁶ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or OC H £

R and R together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, -NH-, -NCH ₃ or -N-benzyl, the last R ³ is H, -OR ²⁵ , -SR ²⁵ , -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ , R ²⁵ is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, methyl group, hydroxy group, amino group, methylamino group and dimethylamino group or

R represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group,

122

amino, methylamino and dimethylamino, R ²⁶ and R ²⁷ independently of one another have the meanings defined for R ²⁵ or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, one of R ⁸ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is -co-n = c (nh ₂ ) ₂ , the other R ⁸ and R ¹⁰ independently of one another are hydrogen, alkyl a group containing 1, 2,3 or 4 carbon atoms, a fluorine atom, a chlorine atom, a -OR ¹³² , -NR ¹³³ R ¹³⁴ or trifluoromethyl group, R ¹³² , R ¹³³ and R ¹³⁴ independently of one another represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms, the other substituents R and R independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, trifluoromethyl, -CO -N = C (NH ₂ ) ₂ , an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH ₂ ) _mm R ¹¹⁴ , mm being 0, 1 or 2,

R ¹¹⁴ is C 3 -C 8 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹¹⁵ R ¹¹⁸ .

R ¹¹⁵ and R ¹¹⁸ are hydrogen or methyl or the other substituents R ⁷ and R ⁹ independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted 1-4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, C 2 -C 8 alkanoyl group, C 2 -C 8 alkoxycarbonyl group, formyl group,

123

carboxyl, trifluoromethyl, methyl and methoxy, or the other substituents R ⁷ and R ⁹ is R ¹²² -SO 2 ~, a group R ¹²³ R ¹²⁴ N-CO-, R ¹²⁸ -CO- or a radical _R 9 R 12 130j_ _S q ₂ ,

R ¹²² and R ¹²⁸ independently of one another are methyl or trifluoromethyl,

R ( ¹²³⁾ , R ( ¹²⁴⁾ , R ( ¹²⁹⁾ and R ( ^130), independently of one another, are hydrogen or methyl or the other substituents R and R, independently of one another, are -OR ¹³⁵ or -NR ¹³⁵ R ¹³⁸ ,

R ( ¹³⁵⁾ and R ( ¹³⁶⁾ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or

R ¹³⁵ and R ¹³ ^ together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, -NH-, -NCH ₃ or -N-benzyl, the last R ⁸ is a hydrogen atom, -SR ¹²⁵ , -OR ¹²⁵ , -NR ¹²⁵ R ¹²⁶ or

-CR ¹²⁵ R ¹²⁶ R ¹²⁷

R ¹²⁵ represents a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl methyl, methoxy, hydroxy, amino, methylamino and dimethylamino;

R represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino- group and a dimethylamino group, R and R independently of one another are as defined for R ¹²⁵ or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

124

A is absent or is -NR 4 - ^ - CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO ₂ -, NR ¹⁹ -SO ₂ -, -SO ₂ -NR ¹⁹ -SO 2, -SO 2 -NR ¹⁹ -CO-, -O-CO-NR ¹⁹ -SO ² - or -CR ²⁰ = CR ²¹ -, R ¹¹ , R ¹² , R ¹³ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms as well as pharmaceutically acceptable salts thereof, and u) substituted thiophenylalkenylcarboxylguanidide of formula I (HOE 96 / F 026)

wherein at least one of R ^1, R ² and R ³ is a group -O p (CH _{2) p} C _q F _{2q + 1,} the group R ⁴⁸ CO- group or R ³ R Soya _<-, p is 0 or 1, s is 0, 1, 2, 3 or 4, q is 1, 2, 3, 4, 5, 6, 7 or 8, k is 0, 1 or 2,

R ⁴⁰ represents an alkyl group containing 1, 2, 3, 4, 5,

6, 7 or 8 carbon atoms, a perfluoroalkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine , trifluoromethyl, methyl and methoxy, η

R is an alkyl group containing 1, 2, 3, 4, 5,

6, 7 or 8 carbon atoms, a perfluoroalkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

125

a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl or methoxy or

R ³¹ represents NR ⁴¹ R ⁴² ,

R ( ⁴¹⁾ and R ( ⁴²⁾ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms or

R ⁴¹ and R ⁴² together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, and the other R, R and R substituents independently of one another represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an ^-O to ^-C m ^-H 2ma + 1 group, or an Og _and C _{and H2r group} R7 ^{* * 10} ,

on the means 0 or 1 me means 0, 1, 2, 3, 4, 5, 6, 7, or 8, ga means 0 or 1 ra means 0, 1, 2, 3 or 4 R ¹⁰ means a cycloalkyl group containing 3,

or 8 carbon atoms or a phenyl group, the phenyl group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group and a methoxy group,

R ⁴ and R ⁵ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, cyano, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a perfluoroalkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom,

126 trifluoromethyl, methyl, methoxy and NR ¹⁴ R ^15,

R ( ¹⁴⁾ and R ( ¹⁵⁾ independently of one another are hydrogen, alkyl having 1, 2,3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms and their pharmaceutically acceptable salts, and (v) ortho-ortho substituted benzoylguanidine of formula I (HOE 96 / F 032)

(I)

in which n q

R and R are, independently of one another, a hydrogen atom, a chlorine atom, a bromine atom, an alkyl group containing 1 to 8 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms or a group -OR 4,

R ⁵ represents an alkyl group having 1 to 8 carbon atoms or -C 1 H 2 ₍ γ-cycloalkyl group in which the cycloalkyl radical contains 3 to 8 carbon atoms, d represents 0, 1 or 2, each of R ² and R ^{3 being} represents a hydrogen atom, but simultaneously both R ² and R ³ do not represent a hydrogen atom as well as its pharmaceutically acceptable salts, and x) benzoylguanidine of the general formula I (HOE 96 / F 042)

127

(D in which

R ¹ represents H, F, Cl, Br, I, cyano, nitro, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7 or 8 carbon atoms, a cycloalkoxy group containing 3, 4, 5, 6, 7 or 8 carbon atoms or X _and - (CH ₂ ) (CF ₂ ) _c -CF ₃ , X is O, S or NR 4, a is 0 or 1, b is 0, 1 or 2, c is 0 , 1, 2 or 3

R ⁵ represents a hydrogen atom, an alkyl group containing 1, 2, 3 or 4 carbon atoms or a -C 1 H 4 -R ^{8 group} ; d represents 0, 1, 2, 3 or 4;

R ^{D is a} cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatics comprising a phenyl group, a biphenylyl group or a naphthyl group being unsubstituted or substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and an NR ⁷ R ^{8 group} ,

R ⁷ and R ⁸ independently of one another represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms or

R ^{1 is} -SR ¹⁰ , -OR ^10, or -CR ¹⁰ R ¹¹ R ¹² , R ¹⁰ is -C ₍ H _{2 F)} -cycloalkyl containing 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl

128

or phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, methyl, hydroxy, amino, methylamino, and dimethylamino- a group, f is 0, 1 or 2,

R ¹¹ and R ¹² independently of one another have the meanings defined for R ³ · ⁸ or represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms or

R ¹ represents a phenyl group, a naphthyl group, a biphenylyl group or a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the latter being bonded via a carbon or ring nitrogen atom and said groups are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino; or

13 13 11

R ^x is -SR, -OR, -NHR ^XJ , -NR ¹³ R ¹⁴ , -CHR ¹³ R ¹⁵ , C- (R ¹⁵ R ¹⁶ OH), -CsCR ¹⁸ , -C (-R) R ¹⁹ = CHR ¹⁸ , -C (R ²⁰ R ²¹ ) k - (CO) - (CR ²² R ²³ ) -R ²⁴ , k is 0, 1, 2, 3 or 4 is 0, 1, 2, 3 or 4

R ¹³ and R ¹⁴ , which are the same or different, represent - (CH 2) g - (CHOH) h - (CH 2) (CHOH) j R ¹⁷ or - (ch ₂ ) -O- (ch ₂ -ch ₂ o) _h -R ²⁴ ,

R is hydrogen or methyl, g, h and i, which are the same or different, are 0, 1, 2, 3 or 4, j is 1, 2, 3 or 4,

R and R, which are the same or different, represent a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or carbon atoms or together with the carbon atom to which they are attached, represent a cycloalkyl group containing 3, 4, 5, 6, 7 or 8 carbon atoms,

129

R ¹⁸ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ²⁵ R ^{26 group} ,

R ²⁸ and R ²⁸ represent a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms or

R is a heteroaryl group containing 1,2,3,4,5,6. 7, 8 or 9 carbon atoms which is unsubstituted or substituted as a phenyl group, or fl

R represents an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxyl groups or

R is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms,

R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ which are the same or different,

have a hydrogen atom or a methyl group,

R ²⁴ represents a hydrogen atom, an alkyl group containing 1,

2, 3, 4, 5 or 6 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7 or 8 carbon atoms, a -C _m H _2m -R ^{18 group} , m being 1, 2, 3 or 4,

3 Ί

R and R have the meanings as R,

R ⁴ represents an alkyl group containing 1, 2, 3 or 4 carbon atoms, as well as pharmaceutically acceptable salts thereof, and y) an ortho-substituted benzoylguanidine of the formula I (HOE 96 / F 043)

(I)

130

in which

R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. atoms, an alkoxy group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms or a group X _and - (CH ₂ ) _b - (CF ₂ ) _c -CF ₃ ,

X is O, S or NR ^5, and a is 0 or 1, b is 0, 1 or 2, c is 0, 1, 2 or 3,

R ⁵ represents a hydrogen atom, an alkyl group containing 1,

2, 3 or 4 carbon atoms or -CjH _{2 (j} R ^8, d is 0, 1, 2, 3 or 4,

R ⁶ represents a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms, a phenyl group, a biphenylyl group or a naphthyl group, said aromatic groups comprising a phenyl group, a biphenylyl group and a naphthyl group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁷ R ® group,

R and R are, independently of one another, a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms or

R ¹ is -SR ^10, -OR ^10, or -CR ¹⁰ R ^{and L} R ¹²

R ¹⁰ is -C _f H _2f -cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl ring, or phenyl, where phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F , a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group and a dimethylamino group, f represents 0, 1 or 2,

131

R ¹¹ and R ¹² independently of one another are as defined for R ¹⁰ or are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R ¹ represents a phenyl, naphthyl, biphenylyl or heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the latter being bonded via a carbon atom or a nitrogen atom in the ring and said groups are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, or

R ¹ is -SR ¹³ , -OR ¹³ , -NHR ¹³ , -NR ¹³ R ¹⁴ , -CHR ¹³ R ¹⁵ , -C (R ¹⁵ R ¹⁶ OH), -C = CR ¹⁸ , - C (R ¹⁹ ) = CHR ¹⁸ , -C (R ²⁰ R ²¹ ) k - (CO) - / CR ²² R ²³ /1-R ²⁴ , k is 0, 1, 2, 3 or 4 is 0, 1, 2, 3 or 4

R ¹³ and R ¹⁴ , which are the same or different, represent - (CH 2) g - (CHOH) h - (CH 2) 1 - (CHOH) j R ¹⁷ or - (CH 2) -O- (CH ₂ -CH ₂₎ O) _h R ^24,

R is hydrogen or methyl, g, h and i, which are the same or different, are 0, 1, 2, 3 or 4, j is 1, 2, 3 or 4,

R and R, which are the same or different, represent a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or carbon atoms or together with the carbon atom to which they are attached, represent a cycloalkyl group containing 3, 4, 5, 6, 7 or 8 carbon atoms,

R ¹⁸ represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ²⁵ R ^{28 group} ,

R and R are hydrogen or alkyl

132

containing 1, 2, 3 or 4 carbon atoms; or

R ¹⁸ represents a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted as a phenyl group or R ¹⁸ represents an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by 1 to 3 hydroxy groups, or

R ¹⁸ represents a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms,

R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ , which are the same or different, represent a hydrogen atom or a methyl group,

R ( ²⁴⁾ is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms

Ί Q or -C _m H _2m -R, m is 1, 2, 3 or 4, one of R and R is hydroxy and the other R and R have the meanings defined for R, R ⁴ is an alkyl group containing 1, 2, 3 or 4 carbon atoms, alkoxy group containing 1, 2, 3 or 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or - (CH ₂ ) _n - (CF ₂ ) _O -CF ₃ , n is 0 or 1, o is 0 or 1, as well as pharmaceutically acceptable salts thereof.

II) Also suitable are compounds of the general formula (DE 195 02 895, DE 44 30 212, EP 667 341, DE 44 04 183,

EP 708 088, EP 723 963, EP 0 694 537, DE 44 21 495,

EP 699 660, EP 699 663, EP 699 666, DE 43 37 611, EP 0719 766,

WO 94/26709, WO 96 04 241, EP 726 254, US 4,251,545,

DE 35 02 629; WO 84/00875; Kumamoto et al., Pharm. Bull.

(1966), 7-13; US 3,780,027, JP 8225513)

133

in which

W, Y and Z are nitrogen or carbon substituted with R ² or R ³ or R ⁴ ,

R ¹ represents a hydrogen atom, A, a halogen atom, a trifluoromethyl group, -CH ₂ , -CH ₂ F, -CH ₂ CF ₃ , -C ₂ F ₅ , cyano, nitro, ethynyl or X-R '

A represents an alkyl group having 1 to 6 carbon atoms, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,

X represents an oxygen atom, a sulfur atom or a group NR ' ¹ , R ¹ ' represents a hydrogen atom, A or a cyclic methylene chain containing 3 to 7 carbon atoms,

R 'represents a hydrogen atom, A, HO-A, HOOC-A-, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 6 to 8 carbon atoms, trifluoromethyl, CH ₂ F, CH ₂ -CF ₃ , Ph, -CH ₂ -Ph or Het, Ph represents an unsubstituted, one, two or three times substituted phenyl, naphthyl or biphenylyl group, the substituents selected from the group consisting of A, OA, NR'R ' ¹ , Hal and trifluoromethyl,

Het means a mono- or di-core, saturated or unsaturated or aromatic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, trifluoromethyl, A,

134 is hydroxy, OA, -X-R ', cyano, nitro and CO-O, wherein Het is bonded via a nitrogen atom or an alkylene chain ^c _m ^H 2 m' m is 0, 1, 2 , 3, 4, 5 and 6 or

R 1 and R ¹ together represent an alkylene group containing 4 or 5 carbon atoms, one of which CH ₂ may be replaced by an oxygen atom, a sulfur atom, an NH group, a NA group, an N-Ph group or an N-CH ₂ -Ph group .

R and R independently of one another are hydrogen, halogen, A, HO-A, X-R ', -C (= N-OH) -A, AO-CO-alkyl, in which the alkyl radical it contains 1 to 4 carbon atoms, cyano, nitro, carboxy, substituted with A, in particular trifluoromethyl, CH ₂ F, CHF ₂ , C ₂ ^F 5, CH ₂ CF ₃ or S (O) _n R ', R ^1' 'is A, Ph or Het, n is 0, 1 or 2 and

R ² and R ³ independently of one another are a group SO 2 ^NR, R ', Ph, O-Ph, O-CH2-Ph, -CO-A, -CHO, -COO group, -CSNR 'R' ¹ , CONR'R ¹ ', CH = CH-COOH, -CH = CH-COOA, indenyl, indanyl, decahydronaphthyl, cyclopentenyl, dihydrothienyl, dihydrofuryl, heterobicyclyl, alkylthienyl , halothienyl, haloalkylthenyl, acylthienyl, halofuryl, haloalkylfuryl or pyrrolyl, or

R ² and R ³ independently of one another represent a group R ⁵ -O-,

R ⁵ represents a hydrogen atom, A, an alkenyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms,

R ⁴ represents Ph, Het, -Ο-Het, trifluoromethyl, S (O) _n R ''', -SO ₂ NR'R'', Alk or a group of the formula

135

or two of R ¹ to R ⁴ together represent -O-CR ⁸ R ⁷ -CO-NR ⁸ or a group of the formula

or a group of formula

(R) o4 where

R ² has the abovementioned meaning,

R ⁸ , R ⁷ , R ⁸ and R ⁹ independently of one another are hydrogen or A or

R ⁸ represents a cycloalkyl group containing 5 to 7 carbon atoms; or

R ⁹ represents a cyano group,

Alk represents a straight or branched alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which is unsubstituted or substituted one, two or three times with substituent A, or

136

Alk represents an ethenyl group or an ethynyl group substituted with substituents selected from the group consisting of hydrogen, A, Ph or Het,

III) compounds of the general formula (DE 41 27 026, DE 4337609, JP 07025768, Edward J. Cragoe, Jr., Diuretics [Chemistry, Pharmacology and Medicine], J. Wiley and Sons (1983), 303-341];

in which

X represents a hydrogen atom, Hal, (Hal) ₃ C-, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted phenyl group, an alkyl-S- group in which the alkyl radical contains 1 to 5 or an alkyl-SO ₂ - group in which the alkyl moiety contains 1 to 5 carbon atoms,

Y represents an amino group or a substituted amino group, or

X and Z together are a - (CH _{2) 4} or 1,3-butadienylene chain or

Z represents a hydrogen atom, a halogen atom, a hydroxy group, a HS group, an alkyl group containing 1 to 5 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a substituted phenyl group or

Z is an amino group or an -NR ^2,

R ¹ represents a hydrogen atom or a straight or branched and optionally substituted alkyl group having 1 to 8 carbon atoms, which may be interrupted by an oxygen atom, or

137

R ¹ is C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 7 cycloalkyl, hydroxy substituted phenyl, phenylalkyl in which the alkyl radical contains 1 to 4 carbon atoms and which is substituted with a hydroxy group or a cycloalkyl group having 3 to 7 carbon atoms and substituted with up to 7 carbon atoms,

R ² is 1-morpholino, hydrogen or a linear or branched alkyl group having 1 to 8 carbon atoms which may be interrupted by oxygen, an amino radical wherein the linear or branched alkyl group having 1 to 8 carbon atoms unsubstituted or substituted with a substituted or unsubstituted mono- or multinuclic heterocycle containing as the heteroatoms a nitrogen, oxygen or sulfur atom, or said alkyl group being substituted by a phenyl group, optionally mono- or poly-substituted by an alkoxy group containing 1 to carbon atoms and optionally substituted hydroxy a group, an alkylamino group, an alkyl group or a phenyl group, or said alkyl group is substituted by an aminocarbonyl group or a hydroxy group or an alkoxy group having 1 to 4 carbon atoms, or

R represents a phenyl group which is unsubstituted or substituted by an alkyl group, an alkoxy group which bears as a substituent a hydrogen atom, a mono- or multinuclic heterocycle containing as heteroatoms a nitrogen atom, an oxygen atom or a sulfur atom and which is unsubstituted or substituted by a hydrogen atom , a halogen atom or an alkyl group, or a phenyl radical which is unsubstituted or substituted by substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen and hydroxy, or

138

R ² is 1-piperidino which is unsubstituted or substituted in the 4-position by an acyl radical of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid, alkyl of 1 to 8 carbon atoms which may be substituted by hydroxy or alkoxy containing 1 to 4 carbon atoms or a phenyl radical substituted with an alkoxy group; or o

R represents an amidino group which is unsubstituted or substituted by a phenyl group which is unsubstituted or substituted by a halogen or an alkyl group, or

R is an acyl radical of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid, or

R represents an alkyl group having 1 to 8 carbon atoms which may be substituted by a hydroxy group, an alkoxy group or a phenyl group bearing alkyl radicals, or

R and R * together with the nitrogen atom to which they are attached denote a piperazine ring which is unsubstituted or carries a mono- or multinuclic heterocyclic group containing through the methylene chain containing from 1 to 6 carbon atoms as heteroatoms containing a nitrogen atom, an oxygen atom or an atom sulfur (DE 41 27 026 and DE 43 37 609), and Hal represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

IV) Also suitable is an indoylguanidine derivative of the general formula (EP 708 091, EP 622 356, JP 5-125085) (R ¹ ) with

139

in which

R ² is H, an unsubstituted or substituted alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, a hydroxyl radical, an alkyl-0- group in which the alkyl portion contains 1 to 6 carbon atoms, an aromatic sku2 o a pin or a -CH ₂ -R group,

R ²⁰ represents a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group,

R ¹ represents 1 to 5 identical or different substituents which are hydrogen, unsubstituted or substituted C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 cycloalkyl up to 7 carbon atoms, halogen, nitro, alkanoyl of 2 to 8 carbon atoms, arylalkanoyl of up to 10 carbon atoms, aroyl of up to 11 carbon atoms, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms, aromatic a group and any of the following groups: -OR ³ , -NR ⁶ R ⁷ or -S (O) _n R ⁴⁰ ,

ABOUT

R is hydrogen, alkyl of 1 to 8 carbon atoms, substituted alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aromatic, -CH ₂ R ³⁰ ,

Q A

R is an alkenyl or alkynyl group;

R and R independently of one another are hydrogen, unsubstituted or substituted alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkanoyl of 2 to 8 carbon atoms, arylalkanoyl of up to 10 carbon atoms, aroyl a group containing not more than 11 carbon atoms, an aromatic group or a -CH ₂ -R ⁶⁰ - group,

140

R ⁸⁰ is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, or

R ⁸ and R ⁷ together with the nitrogen atom represent a 5- to 7-membered cyclic amine group which may contain further heteroatoms in the ring, n being 0, 1 or 2,

R ⁴⁸ represents an unsubstituted or substituted C 1 -C 8 alkyl group or an aromatic group or group

A is O, S (O) _n - or -NR ⁵⁰ -,

R ⁵⁰ represents a hydrogen atom or an alkyl group containing 1 to 8 carbon atoms,

R ¹ represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms;

is a saturated 3- to 8-membered heterocyclic group having one nitrogen atom, and said substituted alkyl group carries one or more groups selected from the group consisting of halogen, hydroxy, (C 1 -C 6) alkoxy, cyano - a carboxyl group, a C 2 -C 6 alkoxycarbonyl group, a C 2 -C 8 alkanoyl group, an arylalkanoyl group having a maximum of 10 carbon atoms, an aroyl group having a maximum of 11 carbon atoms, an aromatic group or a -CONR ⁴ R ^{5 group} ,

R ⁴ and R ⁵ , which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 8 carbon atoms,

141

R ⁴ and R ⁵ together represent a 5- to 7-membered cyclic amine group which may contain further heteroatoms in the ring, or said substituted alkyl group carries a

in which

E represents a nitrogen atom or a CH group,

R '' represents a hydrogen atom, an unsubstituted or hydroxy-substituted alkyl group having 1 to 8 carbon atoms or a substituted alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a cyano group, a carboxyl group, an alkoxycarbonyl group 2 to 6 carbon atoms, alkanoyl of 2 to 8 carbon atoms, aralkanoyl of up to 10 carbon atoms, aroyl of up to 11 carbon atoms, aromatic group, -NR ⁸ R ⁷ , -CONR ⁴ R ⁵ ,

R ⁴ and R ⁵ independently of one another represent a hydrogen atom or an alkyl group containing 1 to 8 carbon atoms, the cyclic system

means a 3- to 8-membered saturated aliphatic or heterocyclic ring system with a nitrogen atom and said aromatic groups are an aryl group containing up to 10 carbon atoms, a 5- or 6-membered heteroaryl group having 1 to 4 nitrogen atoms, a 5 or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms and one heteroatom selected from the group

142

comprising an oxygen and sulfur atom or a furyl group, and said aryl groups are unsubstituted or substituted by an unsubstituted alkyl group containing 1 to 8 carbon atoms or a substituted alkyl group containing 1 to 8 carbon atoms, a halogen atom, a nitro group, an alkoxycarbonyl group, 77 with a boxyl group, -OR, NR ° R, -CONR ⁴ R ⁵ , -SO ² NR ⁶ R ^7, or S (O) n R ⁴⁰ , wherein R ¹ and the guanidinocarbonyl radical may be located at any 5- or a 6-membered ring of the indole system, as well as pharmaceutically acceptable salts thereof. It is also suitable

V) heterocyclic guanidine derivative of the general formula (WO 95 04052)

in which

X is O, S, -NH-, -N (alkyl) - in which the alkyl radical contains 1 to 4 carbon atoms, or -N (phenyl) -,

R, R and R are hydrogen, halogen, C 1 -C 4 alkyl, alkyl-O-, wherein the alkyl radical contains 1 to 4 carbon atoms, phenyl, benzyl or two of R ¹ , R ² and R ³ together with the side of the benzo system is a 4-, and 6-membered carbocyclic ring,

R ⁴ and R ⁵ independently of one another represent a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a benzhydryl group, an aralkyl group which is unsubstituted or substituted by one or more

143 substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, an alkyl-0- group in which the alkyl portion contains 1 to 4 carbon atoms, a trifluoromethyl group or a group- _{(CH2) m-CH2-T} , m is 0 to 3

T is -CO-OT ¹ ,

T ¹ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

Cy represents a benzo-fused unsaturated or dihydro-5-membered heterocycle of formula

a pyrazole or imidazole ring of formula or formula

naphthyl or dihydro- or tetrahydronaphthyl

A 2-, 3- or 4-pyridyl group of the formula

R ^z

144 represents a nitrogen atom or a CH group, a thienyl group of the formula

R ⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group containing 1 to 10 carbon atoms, an alkyl-O group in which the alkyl group contains 1 to 10 carbon atoms, a phenoxy group, an alkyloxymethyloxy group in which the alkyl group contains 1 up to 10 carbon atoms or - (O) _n SR ⁹ ,

R ⁹ represents an alkyl group having 1 to 10 carbon atoms, a thienyl group, a pyridyl group, a thiazolyl group, a thiadiazolyl group, an imidazolyl group, a pyrazolyl group or a phenyl group which are unsubstituted or substituted once or twice with a halogen atom; carbon atoms or an alkyl-Ο- group in which the alkyl radical contains 1 to 4 carbon atoms;

R and R 0 are hydrogen, halogen, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkyl, phenyl, phenoxy or alkoxymethyloxy- a group in which the alkoxy radical is 1 to 10 carbon atoms; or

Cy represents a phenyl group which is unsubstituted or substituted once or twice by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkyl-O- group in which the alkyl radical contains 1 to 4 carbon atoms, or

Cy is -Gr-Am,

G is the group -R ¹³ R ¹² (CH 2) g C / W / ZW ¹ / - (CH2) _q, R ¹³ R ¹⁴ - or -R ¹⁵ -,

R ¹² represents a single bond, an oxygen atom, - (O) _n S-, -CO- or -CONH-,

145

R ¹³ represents a single bond, a phenyl group, a thienyl group, a pyridyl group, a thiazolyl group, a thiadiazolyl group, an imidazolyl group or a pyrazolyl group,

R ¹⁴ represents a single bond or a SO ₂ - group,

R ¹³ represents a C 2 -C 10 alkenyl or C 2 -C 10 alkynyl group,

W and W ¹ independently of one another, H or alkyl having 1 to 4 carbon atoms, or

W and W ¹ , which are cyclically bonded to each other, are a hydrocarbon ring of 3 to 8 carbon atoms, q and q 'are 0 or 1 to 9, and Am is -NR-'-Qr ¹¹ ,

R ¹⁸ represents a hydrogen atom, a (C 1 -C 4) alkyl group or a benzyl group,

R ¹¹ represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a benzyl group, or

R ¹⁰ and R ¹¹ together represent an alkylene group having 3 to 10 carbon atoms which is unsubstituted or substituted by a carboxyl group, an alkoxycarbonyl group having an alkyl radical having 1 to 5 carbon atoms, a hydroxyalkylene group having 2 to 4 carbon atoms or a benzyl group, or Am represents a pyrrolyl group, a pyridyl group, a pyrazolyl group, a morpholinyl group, a dihydropyridyl group, a tetrahydropyridyl group, a quinuclidinyl group, an imidazolyl group, a 3-azabicyclo [3.2.1] octyl group which is unsubstituted or substituted with 1 to 4 alkyl groups carbon atoms; or

Am represents an azabicyclo (3.2.2) nonyl group, or

Am represents a piperazine group of the general formula

N.

146

R ¹⁶ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a tolyl group, a methoxyphenyl group, a halophenyl group, a diphenylmethylene group, a benzyl group or a pyridyl group or

Am is azido - (O) _t - (CH ₂ ) g C / W / ZW ¹ / - (CH ₂ ) gi-N ₃ , t is 0 or 1, wherein W and W ¹ are as defined above,

as well as its optical enantiomers and pharmacologically acceptable

Preferably, Na ⁺ / H ⁺ subtype 3 exchange inhibitors are used:

r) benzene-fused 5-membered heterocycle of formula I (HOE 93 / F 223 K-EP 639573, NZ 264130)

In which

X represents a nitrogen atom or a CR ⁸ group,

Y is O, S or NR ^7,

A, B together represent a bond or

A, B are both hydrogen when both X is CR ⁸ and Y is NR ⁷ , one of R ¹ to R ⁸ is -CO-N = C- (NH ₂ ) ₂ and the other R is ¹ to R ⁸ represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or an alkyl group containing 1 to 6 carbon atoms, at most two other substituents R ¹ to R ⁸ represent

147

cyano, nitro, N _3, alkyloxy radicals containing 1 to 4 carbon atoms or trifluoromethyl, not more than one of the other substituents ^{R 8} is the group - ^C n ^H 2n ^of n is 0 or 1 to 10, wherein the alkylene -C _n H _2n is straight or branched and the carbon atom can be replaced by an oxygen atom, a sulfur atom or a nitrogen atom,

R ⁸ represents a hydrogen atom, an alkenyl group of up to 6 carbon atoms or a cycloalkyl group of 3 to 10 carbon atoms which is unsubstituted or substituted by 1 to 4 methylene groups or a hydroxy group or may contain an ethylene group CH = CH, one methylene group it may be replaced by an oxygen atom or a sulfur atom or a nitrogen atom, or

Q

R is phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, trifluórmetylénovú group, a CH ₃ S (O) _g - or a group R ⁹ -Wy- , s is 0, 1, or 2,

Q

R ⁵ represents a hydrogen atom, a methyl group or an ethyl group,

W is O or NR ^18,

R ( ⁸⁾ is hydrogen or methyl, y is 0 or 1 or

Q

R c is C _m F _{2m + 1} , m is 1 to 3, or

Q

R is 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl,

Z is -CO-, -CH ₂ - or - / CR ¹¹ (OH) / _q -, q is 1, 2 or 3, r H is hydrogen or methyl, or

148

Z is oxygen or -NR-,

R ¹² represents a hydrogen atom or a methyl group, or

Z is -S (O) _s -, s is 0, 1 or 2, or

Z is -SO 2 -NR ¹³ R ¹³ is hydrogen or C 1 -C 4 alkyl,

R ⁷ represents a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, an alkenyl group containing

Q up to 10 carbon atoms or a group ^R-C _n ^{2n -} '

as well as a pharmaceutically acceptable salt thereof,

v) acylguanidine of the formula I

(I)

in which

X represents a carbonyl group or a sulfonyl group,

R ¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted by a hydroxy group, a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino or dimethylamino, n

R represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms,

149 as well as its pharmaceutically acceptable salts,

w) phenyl substituted alkylcarboxylguanidide bearing perfluoroalkyl groups of the general formula I (HOE 94 / F 014 K-EP-OS 566252, NZ 270 370)

in which

R ^A is H, F, Cl, Br, I, cyano, OR ^6, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, O _r (CH ₂ ) _a ^c b ^F 2b + 1 ^and 1 ^e = 0 NR ⁷ R ⁸ , r is 0 or 1, a is 0, 1, 2, 3 or 4, b is 1, 2, 3, 4, 5, 6 , 7 or 8,

R ⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group or a benzyl group, said aromatic groups being substituted or unsubstituted; when substituted, they are substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group,

Q 1 Λ methoxy and NR R,

Q 1 Π

R and R ^xw represent a hydrogen atom, a (C 1 -C 4) alkyl group or a (C 1 -C 4) perfluoroalkyl group,

A

R and R independently of one another have the meanings given for R ⁶ ,

R ^b independently has the meanings given for R ^A ,

X is 1, 2 or 3,

150

R ¹ is H, alkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, -O _{t (CH2)} d ^C e ^F 2e + I ^{'m at} ° F, CI, Br , iodine, or cyano-

nu, t is 0 or 1, d is 0, 1, 2, 3 or 4, e is 1, 2, 3, 4, 5, 6, 7 or 8,

R ² , R ³ , R ^{4 and} R ⁵ independently of one another are as defined for R ¹ , but with the proviso that at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^a and R ^b represents the group -O _t (CH ₂ ) _d C _e F _{2 e + 1} , or the group _r (CH ₂ ) _a C _b F _{2 b + 1} , as well as its pharmaceutically acceptable salts,

(y) a bicyclic heteroarylguanidine of the formula I (HOE 94 / F 123-EP-OS 682017, NZ 272058)

in which

T, U, V, W, X, Y and Z independently of one another are nitrogen or carbon, but with the proviso that

X and Z do not simultaneously represent a nitrogen atom that

T, U, V, W, X, Y and Z bear no substituents when they represent a nitrogen atom and that no more than four of them simultaneously represent a nitrogen atom, η p

R and R are, independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C 1 -C 3 alkyl group, a C 1 -C 3 perfluoroalkyl group, an OR group, NR ⁸ R ⁹ or C (= O) N = C (NH ₂ ) ₂

151

R ( ⁸⁾ and R ( ⁹⁾ independently of one another are hydrogen or alkyl having 1 to 3 carbon atoms, or

R® and R ⁹ together are 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ³ , R ⁴ , R ⁵ , R ⁶ and R ^7, independently of one another, represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a group X 1 - (CH ₂ ) p - (C) _q F _{q + 1} ), a group

-SObm R ^10, R ¹⁰¹⁾ R ¹ Q ^N N-CO group, R ¹¹ -CO- or a group R ¹² R ¹³ N-SO 2, wherein the perfluoroalkyl group is straight or branched,

X is O, S or NR ^14, R ¹⁴ is H or alkyl of 1 to 3 carbon atoms, bm = 0, 1, or 2, p is 0, 1 or 2, k is 0 or 1, q is 1, 2, 3, 4, 5 or 6, _R 10a, _R 10b, R 11, independently, an _ar 12 _than of one another are alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, -C _n H _2n -R ¹ ® or a perfluoroalkyl group containing 1 to 8 carbon atoms, n being 0, 1, 2, 3 or 4,

R ¹ 5 is a cycloalkyl having 3 to 7 carbon atoms or phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ^^ R ¹⁷ ,

R ( ¹⁶⁾ and R ( ¹⁷⁾ are hydrogen or (C1-C4) -alkyl or _{R (} 10b), R ₍ 11) _and R ₍ 12 ₎ are not hydrogen,

R ( ^10c) and R ( ¹³⁾ independently of one another are hydrogen or (C1-C4) -alkyl or

152

R ¹⁰ * ³ and R ^10c, and R ¹² and R ¹³ together are 4 or 5 methylene groups, of which one methylene group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl,

R ^3, R ^4, R ^5, R ⁶ and R ⁷ independently of one another are alkyl having 1 to 8 carbon atoms, ^_c al ^H 2al ^{R 1} 8 or an alkenyl group having 3 to 8 carbon atoms, Al represents 0, 1 or 2,

R ¹⁸ is C 3 -C 8 cycloalkyl, phenyl, biphenylyl or naphthyl, said aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, 19a 19b methoxy and NRR,

R ( ^19a) and R ( ¹⁹ * ³⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another represent a heteroaryl group containing 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of comprising a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group or a dimethylamino group, or

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another represent a group -Y- (C) - (CHOH) - (CH ₂ ) - (CHOH) -R ²³ or a group (z> - (Q) R @ ²⁴ -YCHOH @ 1 -CH2CHOH-R @ ²⁴ -Y

153 or a group

O (C 1 - (CHOH) - (CH _{2 -} (CHOH) -R ²⁵⁾

Y represents an oxygen atom, a sulfur atom or the group -NR - h, ad, and h independently of one another represent 0 or 1, i, j, k, ae, af, ag, ao, ap and if independently of one another represent 0, 1, 2, 3 or 4, where h, although not simultaneously 0, ad, ae and g do not simultaneously mean 0 and ah, and o and if not simultaneously 0,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁵⁾ and R ( ^22), independently of one another, represent a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another

SR ²⁹ , the -OR ³⁰ group, the other group is a group

-NR ³¹ R ³² or a group

CR ³³ R ³⁴ R ³⁵ nq

R, R, R and R independently of one another are -C _and H _2a -heteroaryl in which the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents

selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, and represents 0, 1 or 2

R ( ³²⁾ , R ( ³⁴⁾ and R ( ³⁵⁾ independently of one another have the meanings defined for R or are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl; or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another represent a group

154 or a group

or a group

W-

R ⁹⁶ , R ⁹⁷ and R ⁹⁸ independently of one another represent a heteroaryl group having 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom , trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino, dimethylamino or benzyl;

nu, * 3 g

W is O, S or NR ^D -, R ³⁸ is H or alkyl of 1 to 4 carbon atoms, or

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another represent a group R ⁴⁶ X ¹ -,

X ¹ represents an oxygen atom, a sulfur atom, a group NR ⁴⁷ , a (D = O) A- group or a group NR ⁴⁸ C = MN * R ⁴⁹ -,

M represents an oxygen atom or a sulfur atom,

A represents an oxygen atom or a NR ⁸⁰ group,

D represents a carbon atom or an SO group,

R ⁴⁶ represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a (CH ₂ ) b ^c d ^F 2d + 1 group or a group

-C _X H -R ⁵¹ 2x ^r ' b means 0 or 1 D means 1, 2, 3, 4, 5, 6 or 7, x means 0, 1, 2, 3 or 4. R ⁸¹ means cycloalkyl group containing

carbon atoms, phenyl, biphenylyl

155

or a naphthyl group, the aromatic groups being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁵² R ^{53 group} ,

R ( ⁵²⁾ and R ( ⁵³⁾ are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R ( ⁴⁷⁾ , R ( ⁴⁸⁾ and R ( ⁵⁰⁾ independently of one another are hydrogen, (C1-C4) -alkyl or (C1-C4) perfluoroalkyl,

R ⁴⁹ is as defined for R ⁴⁶ ,

R ⁴⁸ and R ^47, or R ⁴⁸ and R ⁴⁸ together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, A and N * are attached to the phenyl core of the basic heteroaroylguanidine skeleton or

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another represent -SR ⁸⁴ , -OR ⁸⁵ , -NHR ⁸⁸ , -NR ⁸⁷ R ⁸⁸ , -CHR ⁸⁹ R ⁷⁰ or -CR ⁵⁴ R ⁵⁵ OH, -CsCR ⁵⁸ , -CR ⁵⁸ = CR ⁵⁷ or - / CR ⁵⁹ R ⁶⁰ / U-CO- / CR ⁶¹ R ⁶² / VR ⁶³ ,

R ⁸⁴ , R ⁸⁵ , R ⁸⁸ , R ⁸⁷ and R ⁸⁹ , which are the same or different, represent a group

- (CH _{2) y} - (CHOH) _z - (CH _{2) aa} - (CHOH) _t -R ⁷¹ or a group

- <CH ₂ ) _ab -O- (CH ₂ -CH ₂ O) _ac -R ⁷² ,

R and R independently of one another represent a hydrogen atom or a methyl group, u represents 1, 2, 3 or 4, v represents 0, 1, 2, 3 or 4, y, z, and a which are the same or different represent 0 , 1, 2, 3 or 4, t is 1, 2, 3 or 4, r ⁶⁸ , r ⁷⁰ , r ⁵⁴ _and r ⁵⁵ , which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ⁸⁹ and R ⁷⁰ , respectively R ⁵⁴ and R ⁸⁵ together represent carbon

156

C 3 -C 8 -cycloalkyl group to which they are attached,

R ⁸³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a group -C _e H 2 _e -R 4, e being 0, 1, 2, 3 or 4,

R ⁵⁸ , R ⁵⁷ and R ⁷³ independently of one another represent a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ⁷⁴ R ^{78 group} .

R ( ⁷⁴⁾ and R ( ⁷⁸⁾ are hydrogen or (C1-C4) -alkyl or

R ⁵⁸ , R ⁵⁷ and R ^73, independently of one another, represent a heteroaryl group which is unsubstituted or substituted as a phenyl group,

R ⁵⁸ , R ⁵⁹ , R ⁸⁰ , R ⁸¹ and R ⁸² are hydrogen or methyl;

R ³ , R ⁴ , R ⁵ , R ⁸ and R ⁷ independently of one another represent the group r ⁷⁸ -nh-s _2- , R ⁷⁶ , R ⁷⁷ R ⁷⁸ N- (C = Y ') -,

Y 'is O, S, or NR ⁷⁹ , R ⁷⁷ and R ⁷⁸ , which are the same or different, are hydrogen, C 1 -C 8 alkyl, C 3 -C 6 alkenyl or -C 1 -C 6 ? f R ⁸⁰ , f is 0, 1, 2, 3 or 4,

R ⁸⁸ represents a cycloalyl or phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methoxy group and alkyl group having 1 to 4 carbon atoms, or

R ⁷⁷ and R ⁷⁸ together are 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl;

R ⁷⁹ is as R ⁷⁷ or is an amidino group;

157

R ^3, R ^4, R ^5, R ⁶ and R ⁷ independently of one another are NR ^84a R ^85, OR ^{84 b,} SR ^84c, or a group R * in the p84d ^L n ^H 2n ^_K n is 0, 1, 2 , 3 or 4

R ^84c1 is a cycloalkyl having 3 to 7 carbon atoms or phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, methoxy and NR ¹⁸ R ^17,

R ( ¹⁸⁾ and R ( ¹⁷⁾ are hydrogen or (C1-C4) -alkyl,

R ^84a, R ⁸⁴ BFR ^84c and R ⁸⁵ independently of one another are H, alkyl having 1 to 8 carbon atoms, perfluoroalkyl of 1 to 8 carbon atoms or a (CH 2) _ax ~ ^R84 ^, and x is 0, 1, 2, 3 or 4, _R 8 ₄ g represents a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy and NR ^84u R ^84v ,

R ( ^84u) and R ( ^84v) are hydrogen or (C1-C4) -alkyl or

Q / and Q C

R and R together are 4 or 5 methylene groups, of which one CH ₂ group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl, and the pharmaceutically acceptable salts thereof, and b) phenyl substituted alkenylcarboxylguanidide which carries perfluoroalkyl groups of formula I (HOE 94 / F 168-EP-OS 690048, NZ 272373)

158

in which

R ^a represents a hydrogen atom, a fluorine atom, a bromine atom, an iodine atom, a g cyano group, a hydroxy group, an OR group, an alkyl group containing 1 to 8 carbon atoms, a 0 _r (CH ₂ ) group and a ^c b ^F 2b + 1 cycloalkyl NR ⁷ R ⁸ , r is 0 or 1, and is 0, 1, 2, 3 or 4, b is 1, 2, 3, 4, 5, 6, 7 or 8,

R ⁶ represents an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group or a benzyl group, said aromatic groups being unsubstituted or substituted by 1 to 3 carbon atoms selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group IA pin and NR R group,

R ⁹ and R ¹⁰ are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

A

R and R independently of one another have the meanings indicated by g for R or

R ⁷ and R ⁸ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group,

159

R ^B independently has the meanings given for R ^A ,

X is 0, 1 or 2,

Y is 0, 1 or 2,

R ^c is hydrogen, fluorine, chlorine, bromine, iodine, cyano, OR, alkyl of 1 to 8 carbon atoms, O _{p (CH2) f} C _g F _{2G + 1,} or cycloalkyl, a group of 3 to 8 carbon atoms, p is 0 or 1, f is 0, 1, 2, 3 or 4, g is 1, 2, 3, 4, 5, 6, 7 or 8,

R ¹² is C 1 -C 8 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, wherein said aromatic groups include phenyl or benzyl are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ¹³ R ¹⁴ ,

R ¹³ and R ^14, independently of one another, are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl,

R independently has the meanings given for R,

R ¹ is H, alkyl of 1 to 8 carbon atoms, _t -0 (CH ₂₎ d ^C e ^F 2e + I 'cycloalkyl having 3 to 8 carbon atoms, F, Cl, Br, I or cyano, t is 0 or 1, d is 0, 1, 2, 3 or 4, e is 1, 2, 3, 4, 5, 6, 7 or 8,

R ² , R ³ , R ⁴ and R ⁵ independently of one another have the meanings given for R ¹ as well as pharmaceutically acceptable salts thereof,

160

Ά R provided, however, that at least one of R, R ^c , R ^c , R ^d , R ¹ , R ² , R ⁴ or R ⁵ is Or (CH 2) and ^c b ^F 2b + 1 · Op _(CH2) fC _g F _{2G +} i- or O _{t (CH2)} j C _g F _{2e + 1} _ and R ³ does not represent 0 _{t (CH2)} d ° 'e ^F 2e + l' and h) a benzoylguanidine of the formula I (HOE 95 / F

007K-EP-OS 723956 NZ 280 887

(I) wherein "as one of the three substituents R, R and R is R ⁶ -ABD, t

R represents a basic protonatable radical, i.e. the amino group -NR ⁷ R ⁸ , the amidino group R ⁷ R ⁸ NC (= NR ⁹ ) or the guanidino group of the general formula

o q 1 Π>

R, R, ^RJ and R independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or

R and R together represent C _and H _2a , and are 4, 5, 6 or 7, and if a = 5 or 7 then one methylene group of C _and H _2a may be replaced by an oxygen atom, SO _m or NR ¹¹ , or

R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ⁷ and R ¹⁰ represent an N ° 2 'a is 2, 3, 4 or 5,

161

provided that when a = 3, 4 or 5, then one methylene group of groups C _and H _{2a may} be replaced by an oxygen atom, a SO _m group or a NR ¹¹ group, m being 0, 1 or 2,

R ¹¹ is H or methyl, or

R ⁶ represents a basic heteroaromatic ring system containing 1 to 9 carbon atoms,

A is C ^ H ^, b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein in the group% Η ₂ ^ one or two methylene groups may be replaced by a group selected from the group consisting of oxygen atom, -CO-, -CH (OR ² R ⁾ -, -SOm-, -NR ²⁰ -CO-, -NR ²⁰ -CO-NH-SO ² -, formula (O) ' | 'aa -s—

II 19 [NR] _bb and -SO _aa / NR ¹⁹ / j _D j ₃ , and in the group one methylene group may be replaced by a gggg -CH-R ^{3 group} , where R together with R ⁷ forms a pyrrolidine or piperidine ring,

aa is 1 or 2, bb is 0 or 1, aa + bb = 2,

Q

R represents a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms,

R ²⁰ represents a hydrogen atom or a methyl group,

B represents a phenylene or naphthylene radical of the formulas

162

R ¹² and R ¹³ independently of one another represent a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom, an iodine atom, a bromine atom, a trifluoromethyl group or a group -SO _W -R ¹⁴ ,

R ¹⁴ is methyl, or NR ¹⁵ R ^18,

R ¹⁵ and R ¹⁸ independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, w is 0, 1 or 2,

D is -C (H) -Xf -, d is 0, 1, 2, 3 or 4,

X represents O, -CO-, -CH / OR ²¹ / -, a group of -S0 _m - or -NR ^21,

F means 0 or 1, R ²¹ is hydrogen or methyl group m means 0, 1 or 2, and others the substituents R ^1, R ² and R ³ independently one on the other

are hydrogen, fluorine, bromine, iodine, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, -NR ³⁵ R ³⁸ or g is 0, 1, 2 , 3 or 4, h is 0 or 1,

R ( ³⁵⁾ and R ( ³⁸⁾ independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or not;

R and R together represent 4 to 7 of which one CH ₂ group can be replaced by a sulfur atom, an -NH- group, a methylene group, an -NCH ₃ atom or an -N-benzyl group,

Z is -O-, -CO-, -SO _{H -,} -NR ^18, -NR ¹⁸ -CO-NH- or -NR ¹⁸ -SO ₂ -,

R represents a hydrogen atom or a methyl group, v represents 0, 1 or 2,

R represents a hydrogen atom, a cycloalkyl group containing 3, 5 or 6 carbon atoms or a group C _to F _{2k + 1} -,

163

k is 1, 2 or 3, or

R ¹⁷ represents a pyrrol-1-yl group, a pyrrol-2-yl group or a pyrrol-3-yl group which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano - a group having from 2 to 8 carbon atoms, an alkoxycarbonyl group having from 2 to 8 carbon atoms, a formyl group, a carboxy group, a trifluoromethyl group, a methyl group and a methoxy group, or

R ¹⁷ represents a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 carbon atoms from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, hydroxy group, methoxy group, - NR ³⁷ R ³⁸ , CH ₃ SO ₂ and H ₂ NO ₂ S-,

R and R are hydrogen or methyl,

R ⁴ and R ⁵ independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR ^32, -NR ³³ R ³⁴ or the radical _R ~ C 2R + I '

2 3 3 35 - * i

R, R and R independently of one another represent a hydrogen atom or an alkyl group containing 1, 2, 3 carbon atoms, r represents 1, 2, 3 or 4 as well as pharmacologically acceptable salts thereof, and (i) indenoylguanidine of the formula I (HOE 95) / F 072-EP-OS 738712, NZ 286 380

164

in which

R ^{@ 1} and R @ ² independently of one another represent a hydrogen atom, an alkyl group containing from 1 to 10 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, an O-alkyl group containing from 1 to 4 carbon atoms, O-C (= O) alkyl in which the alkyl portion contains 1 to 4 carbon atoms, or ^{C H2m -NR12R13 'to <e} ^ ^R12 and ^R12, independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms, m represents 0, 2, 3 or 4, NH-C (= O) -NH ₂ , C (% O) -O-C 1-4 alkyl, C (= O) -NH ₂ , C (= O) -NH-alkyl in which the alkyl moiety contains 1 to 4 carbon atoms, C (= O) -N- (alkyl) ₂ in which each alkyl moiety contains 1 to 4 carbon atoms, alkenyl containing from 1 to 10 carbon atoms, alkynyl group containing from 2 to 10 carbon atoms, alkylaryl, wherein the alkyl moiety contains 1 to 4 carbon atoms, an alkenylaryl moiety wherein the alkenyl moiety contains 2 to 10 carbon atoms, an alkynylaryl moiety wherein the alkynyl moiety contains 2 to 10 carbon atoms, an aryl group substituted with an alkyl moiety of 1 to 4 carbon atoms , an alkylheteroaryl group in which the alkyl radical contains 1 to 4 carbon atoms, an alkenylheteroaryl group in which the alkenyl radical contains 1 to 4 carbon atoms, an aminoalkylaryl group in which the alkyl radical contains 1 to 4 carbon atoms, a substituted aryl group, a heteroaryl group and a substituted heteroaryl,

R ³ , R ⁴ , R ⁵ and R ⁸ independently of one another represent a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, an O-alkyl group containing 1 to 10 carbon atoms, a halogen atom such as a fluorine atom, a chlorine atom, an atom bromine and iodine, hydroxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, O- (lower alkyl),

165

O-aryl, O- (lower alkyl) aryl, O-substituted aryl, O- (lower alkyl) -substituted aryl, O-C (= O) -alkylaryl in which the alkyl moiety contains 1 to 4 carbon atoms, O-C (= O) -NH-alkyl in which the alkyl moiety contains 1 to 4 carbon atoms, O-C (= O) -N- (alkyl) ₂ , nitro, cyano- trifluoromethyl, amino, NH-C (= O) -NH ₂ , carboxyl, C (= O) -O-alkyl in which the alkyl radical contains 1 to 4 carbon atoms, C (= 0) ) -NH ₂ , C (= O) -NH-alkyl in which the alkyl moiety contains 1 to 4 carbon atoms, C (= O) -N- (alkyl) ₂ in which each alkyl moiety contains 1 to 4 carbon atoms 4 carbon atoms, an alkyl-COOH group in which the alkyl moiety contains 1 to 4 carbon atoms, an alkyl-C (= O) -O-alkyl group in which each alkyl moiety contains 1 to 4 carbon atoms, the SO ₃ H group S0 ₂ alkyl radical, alkylaryl radical S0 _2, S0 ₂ N (alkyl) ₂ alkyl, SO ₂ -N (alkyl (aryl) alkyl, C (= O) R ^11, alkyl-C (= 0 ) -R ¹¹ in which the alkyl radical contains 1 to 10 carbon atoms, an alkenyl-C (= O) -R ¹¹ radical in which the alkenyl radical contains 2 to 10 carbon atoms, an alkynyl-C (= O) -R ¹¹ radical wherein the alkynyl radical contains 2 to 10 carbon atoms, the NH-C (= O) -alkyl-C (= O) -R ^{11 group} , wherein the alkyl radical contains 1 to 10 carbon atoms, the O-alkyl-C ( = O) -R ¹¹ in which the alkyl radical contains 1 to 11 carbon atoms,

R ¹¹ is alkyl of 1 to 4 carbon atoms, alkynyl of 1 to 4 carbon atoms, aryl, substituted aryl, amino, NH-alkyl having 1 to 4 carbon atoms, N- (alkyl) ₂ - wherein each alkyl radical contains 1 to SO ₃ H, SO ₂ -alkyl, SO ₂ -N- (alkyl) ₂ , a group, carbon atoms,

SO ₂ -alkylaryl, SO ₂ -N- (alkyl) -alkylaryl means an oxygen atom, a sulfur atom or an NH group,

166

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 are part of a 5-, 6- or 7-membered heterocyclic ring,

A is absent or is a non-toxic organic or mineral acid if a) benzyloxycarbonylguanidine of formula I (HOE 95 / F 109-EP 748795, NZ 286583)

in which

7 O 7

R, R and R are each independently -Y- (4-R ⁸ -phenyl), -Y- (3-R ⁸ -phenyl) or -Y- (2-R ⁸ -phenyl), wherein: the phenyl radical is unsubstituted

or substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, hydroxy, methoxy and -NR ⁹⁶ R ⁹⁷ ,

R ⁷ and R ⁷ independently of one another represent a hydrogen atom or a methyl group,

Y represents a bond, a CH ₂ group, an oxygen atom, a sulfur atom or an -NR ⁹ group,

R ⁹ represents a hydrogen atom or an alkyl group containing 1, 2, 3 or 4 carbon atoms,

R ⁸ is SOa / NR ⁹⁸ / bNR ⁹⁹ R ¹⁰ , a is 1 or 2, b is 0 or 1, a + b = 2,

R, R ^S and R - * - ^u, independently of one another are H, alkyl having 1 to 8 carbon atoms, benzyl group, -alkylene-NR ¹¹ R ^12,

167

wherein the alkylene radical contains 2 to 8 carbon atoms, the alkylene-NR ¹³ -alkylene-NR ³⁷ R ^{38 group} , wherein each alkylene radical contains 2 to 8 carbon atoms, or the alkylene-CR ³⁹ R ⁴⁰ -CR ⁴¹ R ⁴² - alkylene-NR ⁴³ R ⁴⁴ , wherein each alkylene radical contains 2 to 8 carbon atoms,

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ³⁷⁾ , R ( ³⁸⁾ , R ( ⁴³⁾ and R ( ^44), independently of one another, represent a hydrogen atom, an alkyl group containing 1 to 8 carbon atoms or a benzyl group,

R ( ³⁹⁾ , R ( ⁴⁰⁾ , R ( ⁴¹⁾ and R ( ^42), independently of one another, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an alkylenephenyl group in which the alkylene radical contains 2 or 3 carbon atoms, the phenyl radical being unsubstituted or substituted up to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group and methoxy group; or

Q Q 1 n

R 1 and together represent 4 to 6 methylene groups of which one CH ₂ group may be replaced by an oxygen atom, a -ΝΉ- group, a sulfur atom, an -N-CH ₃ group or an -N-benzyl group, or

R ⁸ is SOa (NR ⁹⁸⁾ NR ⁹⁵ -C = NR ⁹⁴ / -NR ⁹³ R ⁹²

92 94 qc

R, R, R, and R independently of one another represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or

R, R and R independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine, chlorine, a bromine atom, an iodine atom, a cyano group, a C 2 -C 8 alkanoyl group, a C 2 -C 8 alkoxycarbonyl group, a formyl group, a carboxy group, a trifluoromethyl group, a methyl group and a methoxy group; or

R ^1, R ² and R ³ independently of one another are H, alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms or - (CH _{2) m} R ^14,

168

tn represents 0, 1 or 2,

R ¹⁴ represents a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- and -NR ¹⁵ R ¹⁸ ,

R ( ¹⁵⁾ and R ( ¹⁸⁾ are hydrogen or methyl;

R ¹ , R ² and R ^3, independently of one another, represent -Q-4 / (CH 2) _k -CHR ¹⁷ - (C = O) R ²⁰ / -phenyl or -Q-3 / (CH 2) _k -CHR ¹⁷ - (C = 0) ^R20 / phenyl group or -Q-2 / (CH _{2) a} -CHR ¹⁷ - (C = 0) ^R20 / phenyl, where the phenyl radical is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, hydroxy group, methoxy group and -NR ³⁵ R ³⁶ , gc Qg

R and R are, independently of one another, a hydrogen atom or a methyl group,

Q is a bond, O, S or NR ^18,

R ¹⁸ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

R ¹⁷ is -OR ²¹ or -NR ²¹ R ²² ,

R and R independently of one another are hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkanoyl, alkoxycarbonyl in which the C 1 -C 8 alkoxy radical is benzyl, benzyloxycarbonyl or

R is trityl,

R ²⁰ is -OR ²³ or -NR ²³ R ²⁴ ,

R and R independently of one another represent a hydrogen atom, an alkyl group containing 1 to 8 carbon atoms or a benzyl group, k represents 0, 1, 2, 3 or 4, or

3

R, R and R independently of one another are heteroaryl

169

(C 1 -C 9) group bonded via a carbon or nitrogen atom and unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group , amino, methylamino, and dimethylamino, or

R ¹ , R ² and R ³ are -SR ²⁵ , -OR ²⁵ , -NR ²⁵ R ²⁶ ,

-CR ²⁵ R ²⁶ R ²⁷

R ²⁵ represents a -CfH ₂ f-heteroaryl group in which the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy- a hydroxy group, an amino group, a methylamino group and a dimethylamino group, f is 0, 1 or 2,

R @ ²⁶ and R @ ²⁷ independently of one another have the meanings given for R or are hydrogen or (C1 -C4) -alkyl or

Ί O * 2

R, R and R independently of one another are a heteroaryl-N-oxide group in which the heteroaryl radical contains 1 to 9 carbon atoms, which is bonded via a carbon or nitrogen atom and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of including fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino group, or

R ^1, R ² and R ³ independently of one another are -SR ^28, -OR ^28, -NR ²⁸ R ²⁹ or -CR ²⁸ R ²⁹ R ^30, R ²⁸ is a group -CgH _{2 g} -heteroaryl-N an oxide in which the heteroaryl radical contains 1 to 9 carbon atoms and which is unsubstituted or substituted by a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group or dimethylamino group,

170

g is 0, 1 or 2,

R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are as defined for R ( ²⁸⁾ or are hydrogen or (C1-C4) -alkyl or

R ^1, R ² and R ³ independently of one another are hydrogen, chloro, fluoro, bromo, iodo, cyano, T- (CH 2) ^(C i ^F 2i + l) <group, R ³¹ radical sulphate; R ³² R ³³ N-CO-, R ³⁴ -CO- or R ⁴⁵ R ⁴⁶ N-SO ₂ , wherein the perfluoroalkyl group is straight or branched,

T represents a bond, an oxygen atom, a sulfur atom or a group -NR ⁴⁷ , represents 0, 1 or 2, h represents 0, 1 or 2, i represents 1, 2, 3, 4, 5 or 6,

R ( ³¹⁾ , R ( ³²⁾ , R ( ³⁴⁾ and R ( ⁴⁵⁾ independently of one another are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, (CH ₂ ) _n R ⁴⁸ or trifluoromethyl, n being 0, 1, 2, 3 or 4

R represents a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms;

R is C 3 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and -NR ⁴⁹ R ⁸⁰ ,

R ( ⁴⁹⁾ and R ( ⁵⁰⁾ are hydrogen or (C1-C4) -alkyl or

R ³² , R ³⁴ and R ⁴⁵ are hydrogen,

R ( ³³⁾ and R ( ⁴⁸⁾ independently of one another are hydrogen or (C1-C4) -alkyl or

R ³² and R ³³ as well as R ⁴⁵ and R ⁴⁸ together represent 5 or 6 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, an -NCH ₃ group or an -N- group benzyl, or

171

R ¹ , R ² and R ^3, independently of one another, represent the group r ⁵¹ -aGD-,

R ⁵¹ represents a basic protonable radical, i.e. amino group -NR ⁸² R ⁸³ , amidino group R ⁸² R ⁸³ NC (= NR ⁸⁴ ) or guanidino group R ⁸² R ⁸³ NC / = NR ⁸⁴ / -NR ⁸⁸ -,

R ( ⁵²⁾ , R ( ⁵³⁾ , R ( ⁸⁴⁾ and R ( ⁸⁸⁾ independently of one another are hydrogen or (C1-C4) -alkyl or en

R and R ^J is _{^C, and} if _a ^H 2.alpha. 'alpha' is 4, 5, 6 or 7, wherein, if the alpha is a 5, 6 or 7, then one carbon atom of the group _{^C, and} if _a ^H 2.alpha. ^{is m} ° that it can be replaced by an oxygen atom, an SO4 group or an NR ⁸⁸ group or a

R ⁸³ and R ⁸⁴ or R ⁸⁴ and R ⁸⁸ or R ⁸² and R ⁸⁸ represent a group CyH _2y , y represents 2, 3, 4 or 5, provided that when y = 3,4 or 5, one carbon atom of the group Cy 4 may be replaced by an oxygen atom, SO 4 or NR ⁸⁸ , d being 0, 1 or 2,

R represents a hydrogen atom or a methyl group;

R ⁸¹ represents a basic heteroaromatic ring group containing 1 to 9 carbon atoms,

A is ^C e ^H 2 e 'e is 0 or 1 to 10, wherein in C _e H 2 _e one carbon atom can be replaced by an oxygen atom, -CO-, -CH (OR ⁸⁷ ) -, -SOr- , -NR ⁸⁷ -, -NR ⁸⁷ -CO-, -NR ⁵⁷ -CO-NH, -NR ⁸⁷ -CO-NH-SO ₂ - or -nr ⁵⁷ -so ₂ -, r is 0, 1 or 2,

G is phenyl

172

R ⁵⁸ and R ⁵⁹ independently of one another are hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl or a group -SO _g R ^60,

R ⁶⁰ is methyl, or NR ⁶¹ R ^62, R ⁶¹ and R ⁶² independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms, D is-C _in H _2v -E _w, v is 0, 1, 2, 3 or 4

E represents an oxygen atom, a -CO- group, a group

-CH (OR ⁶³ ), -SO _aa - or -NR ⁶³ -, w is 0 or 1, and a is 0, 1 or 2,

R ⁶³ represents a hydrogen atom or a methyl group, or

R ^{@ 1} , R ^{@ 2} and R @ ³ independently of one another are - CF2 R @ ⁶⁴ , --CF (R @ ⁶⁵ ) - R @ ⁶⁶ -, - CF ₍ R @ ₂ ) - CF @ _{3 -} R @ ⁶⁵ -, -C) (CF ₂ ) _p -CF ₃ = CR ⁶⁵ R ⁶⁶ ,

R ⁶⁴ represents an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms,

R ( ⁶⁵⁾ and R ( ⁶⁶⁾ independently of one another are hydrogen or (C1-C4) -alkyl, q is 0, 1 or 2, p is 0, 1 or 2, or

R ^1, R ² and R ³ independently of one another, are -OR ⁶⁷ or -NR ⁶⁷ R ^68,

R ⁶⁷ and R ⁶⁸ independently of one another represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or

R ⁶⁷ and R ⁶⁸ together represent 4, 5, 6 or 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, -SO ₂ -, -NH-, -NCH ₃ or - N-benzyl,

R ⁴ and R ^5, independently of one another, are hydrogen, C 1 -C 4 alkyl, fluoro, chloro, -OR ⁶⁹ , -NR ⁷ R ⁷¹ or -C ₂ F _{2 Z + 1} , rq τη 7i

R, R and R ^χ independently H or alkyl

A hunting group containing 1 to 3 carbon atoms, z being 1, 2, 3 or 4,

R ⁸ and R ⁷ independently of one another represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

X is O or NR ⁷² ,

R ⁷² represents a hydrogen atom or a C 1 -C 4 alkyl group, as well as pharmaceutically acceptable salts thereof, and a) alkenylcarboxylguanidine which carries fluorophenyl groups of the general formula I (HOE 95 / F 115-EP 744397, NZ 286622)

(I)

in which g

R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ⁹ R ¹⁰ ,

R ⁹ and R ¹⁰ represent a hydrogen atom, a (C 1 -C 4) alkyl group or a perfluoroalkyl group,

R independently of one another have the meanings as R °,

R ^1, R ^2, R ^3, R ⁴ and R ⁵ independently of one another are hydrogen or F, wherein at least one of R ^1, R ^2, R ^3, R ⁴ and R ⁵ has is F, as and pharmaceutically acceptable salts thereof,

And (n) a substituted cinnamic acid guanidide of formula I

(I)

wherein at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is - ^x and ^Y b - ^L n - ^U '

X is CR ¹⁶ R ¹⁷ , oxygen, sulfur f or NR, c Ί n ig

R ^x, R and R independently of one another are H, alkyl having 1 to 4 carbon atoms, or per fluoro alkyl of 1 to 4 carbon atoms, a is 0 or 1,

Y represents an alkylene group having 1 to 8 carbon atoms, an alkylene-T group having an alkylene radical having 1 to 8 carbon atoms, a Τ, až-alkylene having 1 to 8 carbon atoms in the alkylene radical,

T is NR ²⁰ , oxygen, sulfur or phenylene, wherein the phenylene group is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ²¹ R ²² ,

R, R and R independently of one another are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, b is 0 or 1,

L is O, S, NR ²³ , or

175

C 1 H 4, k is 1, 2, 3, 4, 5, 6, 7 or 8, n is 0 or 1,

U is NR ²⁴ R ²⁵ or an N-containing hetero ring containing 1 to 9 carbon atoms,

R ²⁴ and R ^25, independently of one another, are hydrogen, C 1 -C 8 alkyl or C 1 -C 8 perfluoroalkyl; or

R ²⁴ and R ²⁵ together represent 4 or 5 methylene groups, one of which may be replaced by an oxygen atom, a sulfur atom, an NH group, an N-CH ₃ group or an N-benzyl group, the N-containing heterocycle being linked via a nitrogen atom or a carbon atom and is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ²⁷ R ^{28 group} ,

R ( ²³⁾ , R ( ²⁷⁾ and R ( ^28), independently of one another, are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, and the other substituents R ( ¹⁾ , R ( ²⁾ , R ( ³⁾ , R ( ⁴⁾ and R (1) ^{8 are,} independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a -O _n -C _m H _{2 m + 1} group, an -Op- (CH ₂ ) _s -CqF ₂ q group ₊ even or-C _r H _2r R ^10,

n means 0 or 1 m means 0 1, 2, 3, 4, 5, 6, 7 or 8 P means 0 or 1 q means 1 / 2/3, 4, 5, 6, 7 or 8 with means 0 1, 2, 3 or 4, r means 0 1, 2, 3 or 4, R ¹⁰ means a cycloalkyl group containing from 3 to 8 carbons;

or phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and a ¹¹ ^ ² ,

176

R ( ¹¹⁾ and R ( ¹²⁾ independently of one another are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl,

R and R independently of one another are hydrogen, fluorine, bromine, chlorine, iodine, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 cycloalkyl, or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹⁴ R ^{15 group} ,

R ( ¹⁴⁾ and R ( ^15), independently of one another, are hydrogen, (C1-C4) alkyl or (C1-C4) perfluoroalkyl, and pharmaceutically acceptable salts thereof, (a) benzene dicarboxyldiguanidide of the formula I (HOE 95 / F 269) K)

(I) wherein one of R ¹ , R ² , R ³ and R ⁴ is -CO-N = C (NH ₂ ) ₂ , and the other R ¹ , R ² , R ^3, and R ⁴ have the following meanings :

R ¹ represents a hydrogen atom, a C 1 -C 4 alkyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, -OR ³² , -NR ³³ R ³⁴ or triflu177

a methyl group,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or (C1-C4) -alkyl,

R ² and R ⁴ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, trifluoromethyl, -CO-N = C (NH ₂ ) 2 -alkyl (C 1 -C 8), (C 2 -C 8) alkenyl, or - (CH ₂ ) _m R ¹⁴ , m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁶ .

R ( ¹⁵⁾ and R ( ¹⁸⁾ are hydrogen or methyl;

R ² and R ^4, independently of one another are pyrrol-l-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of F, Cl, a bromine atom, an iodine atom, a cyano group, a C 2 -C 8 alkanoyl group, a C 2 -C 8 alkoxycarbonyl group, a formyl group, a carboxy group, a trifluoromethyl group, a methyl group, a methoxy group or

R and R independently of one another are R -S0 ₂ -, R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or a group R ²⁹ R ³⁰ N-SO ₂ -, R ²² and R ²⁸ independently of one the other is methyl or trifluoromethyl, after p 4 pq

R, R, R, and R independently of one another are hydrogen or methyl or

R ² and R ⁴ independently of one another, are -OR ³⁵ or -NR ³⁵ R ^36,

R ³⁵ and R ³⁸ independently of one another represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms178

mov or

R ³⁵ and R ³⁶ together represent 4 to 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH group, an -NCH ₃ group or an -N-benzyl group, q 7 c 7 c

R is hydrogen, -SR, -OR, -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ ,

R ²⁵ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, an atom chloro, trifluoromethyl, methyl, methoxy, hydroxy, amino, methylamino and dimethylamino; or

R ²⁵ represents a heteroaryl group containing 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group - the group and the dimethylamino group, R ²⁶ and R ^27, independently of one another, have the meanings given for R ^J or represent a hydrogen atom or an alkyl group containing 1 to 8 carbon atoms,

R ⁵ represents an alkyl group having 1 to 4 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an X- (CH ₂ ) y-CF ₃ group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a group -NR ^e R ⁷ ,

R ⁶ and R ⁷ independently of one another represent a hydrogen atom or a methyl group,

X is a bond or an oxygen atom, y is 0, 1 or 2, as well as pharmaceutically acceptable salts thereof,

179 as) benzenedicarboxyldiguanidide of formula I (HOE 95 / F 269 BK)

(I)

wherein one of R ¹ , R ² , R ³ and R ⁵ is -CO-N = C (CH ₂ ) ₂ and the other of R ¹ , R ² , R ^3, and R ⁵ have the following meanings:

R ( ¹⁾ and R ( ⁵⁾ independently of one another are hydrogen, alkyl having 1 to 4 carbon atoms, fluorine, chlorine, -NR ³³ R ³⁴ or trifluoromethyl,

R ( ³²⁾ , R ( ³³⁾ and R ( ³⁴⁾ independently of one another are hydrogen or (C1-C4) -alkyl,

R ² represents H, F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, -CO-N-C _{(NH2) 2,} alkyl having 1 to 8 carbon atoms, , (C 1 -C 8) alkenyl or - (CH ₂ ) _m R ¹⁴ , m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹⁵ R ¹⁸ .

R ( ¹⁵⁾ and R ( ^16), independently of one another, are hydrogen or methyl;

R ² is R ²² -SO ₂ , R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or

180

R ²⁹ R ³ ®N-SO ₂

R ²² and R ^28, independently of one another, are methyl or trifluoromethyl,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl; or

R ² is -OR ³⁸ or -NR ³⁸ R ^ ^3,

R ( ³⁸⁾ and R ⁽ 36) independently of one another are hydrogen or (C1-C6) -alkyl or

R ³⁵ and R ³⁶ together are 4-7 methylene groups, of which one _CH2 group can be replaced by oxygen, S, -NH-, -NCH ₃ or -N-benzyl;

R is hydrogen, -SR, -OR, -NR ²⁵ R ²⁶ , -CR ²⁵ R ²⁶ R ²⁷ ,

R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino, methylamino and dimethylamino; or

R ²⁵ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group - the group and the dimethylamino group, R and R independently of one another have the meanings given for R or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

R ⁴ is trifluoromethyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkyl or - (CH ₂ ) _m R ¹⁴ , m is 1 or 2,

181

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹³ R ¹⁶ .

R ¹³ and R ^16, independently of one another, are hydrogen or methyl;

R ⁴ represents a phenyl group which is substituted by 2 to 5 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and an -NR ¹³ R ^{16 group} ,

R ¹³ and R ^16, independently of one another, represent a hydrogen atom or a methyl group, as well as their pharmaceutically acceptable salts, etc. (a) diaryldicarboxyldiguanidide of the formula I (HOE 96 / F 013)

(I) wherein one of R ¹ , R ² , R ³ , R ⁴ and R ³ is -CO-N = C (NH ₂ ) ₂ / the other R ¹ and R ⁵ independently of one another are hydrogen , (1-4C) alkyl, fluoro, chloro, -OR ³² , -NR ³³ R ³⁴ or trifluoromethyl, R ³² , R ³³ and R ^34, independently of one another, are hydrogen or alkyl 1 to 4 carbon atoms, the other substituents R ² and R ⁴ independently of one another Unknown

182 Naju hydrogen, F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, -CO-NC _(NH2) 2 »alkyl of 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms or - (CH ₂ ) _m R ¹⁴ , m being 0, 1 or 2,

R ¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group and a group -NR ¹⁵ R ¹⁸ ,

R ¹⁵ and R ¹⁸ represent a hydrogen atom or a methyl group

or the other substituents R and R independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine, chlorine , bromine, iodine, cyano, C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxy, trifluoromethyl, methyl, methoxy or other R ² substituents and R ⁴ is R ²² -SO ₂ -, R ²³ R ²⁴ N-CO-, R ²⁸ -CO- or r 29r ³⁰ N-SO ₂ ,

7 7 fi

R and R independently of one another are methyl or trifluoromethyl,

R ( ²³⁾ , R ( ²⁴⁾ , R ( ²⁹⁾ and R ( ³⁰⁾ independently of one another are hydrogen or methyl or the other substituents R ( ²⁾ and R ( ⁴⁾ independently of one another are -OR ³⁸ or -NR ³⁸ R ³⁸ ,

R and R are, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or

R ( ³⁵⁾ and R ( ³⁸⁾ together represent 4 to 7 methylene groups,

183

of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -NH- group, an -NCH ₃ group or an -N-benzyl group, another R ³ substituent is a hydrogen atom, a group -SR ²⁸ , a group -OR ²⁸ , a group -NR ²⁸ R ²⁸ , -CR ²⁸ R ²⁸ R ²⁷ ,

R ²⁸ represents a hydrogen atom, a C 1 -C 8 alkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group , amino, methylamino, and dimethylamino, or

R ²⁸ represents a heteroaryl group having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, methylamino group and dimethylamino group -group,

R @ 1 and R @ 2 independently of one another are as defined for R @ ²⁸ or are hydrogen or C1 -C8 alkyl, one of R @ ⁶ , R @ ⁷ , R @ ⁸ , R @ ⁹ and R @ ¹⁰ is --CO - N = C _{(NH2) 2} the other radicals R ⁸ and R ⁸ independently of one another are H, alkyl having 1 to 4 carbon atoms, F, Cl, -OR ^132, -NR ¹³³ R ¹³⁴ or trifluoromethyl, R ¹³² , R ¹³³ and R ¹³⁴ independently of one another are hydrogen or C 1-4 alkyl, the other R ⁷ and R ⁹ independently of each other are hydrogen, fluoro, chloro, bromo, iodo, hydroxy, cyano, trifluoromethyl, -CO-N-C _{(NH2) 2,} alkyl having 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms or - <CH2> mm ^R114 · mm stands for 0, 1 or 2,

184

R ¹¹⁴ represents a C 3 -C 8 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and -NR ¹¹⁵ R ¹¹⁶ .

R ¹¹⁵ and R ¹¹⁸ denote a hydrogen atom or a methyl group or the other substituents R ⁷ and R ^9, independently of one another,

a pyrrol-1-yl group, a pyrrol-2-yl group or a pyrrol-3-yl group which is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group , C 2 -C 8 alkanoyl, C 2 -C 8 alkoxycarbonyl, formyl, carboxy, trifluoromethyl, methyl and methoxy or the other substituents R ⁷ and R ⁹ represent R ¹²² -SO 2 -; , a group R ¹²³ R ¹²⁴ N-CO-, R ¹²⁸ -CO- or a group R 129 _R 130 _N _ _SO2í

R ¹²² and R ¹²⁸ independently of one another are methyl or trifluoromethyl,

R ^123, R ^124, R ¹²⁹ and R ¹³⁰ independently of one another are hydrogen or methyl and the other substituents R and ^Rj independently of one another are -OR ¹³⁵ or -NR ¹³⁵ R ^138,

R ( ¹³⁵⁾ and R ( ¹³⁸⁾ independently of one another are hydrogen or (C1-C6) -alkyl or

R ¹³⁵ and R ¹³⁸ together represent 4 to 7 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an -N-benzyl group, another R ⁸ substituent -OR ¹²⁵ , _CR 125 _R 126 _R 127 η nc

R is -NH-, -NCH _3, or is -SR ¹²⁵ , -NR ¹²⁵ R ^126, or H, alkyl having 1;

185

up to 8 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group and dimethylamino -group, or c

R represents a heteroaryl group containing 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, hydroxy group, amino group, methylamino group and dimethylamino, R ¹²⁸ and R ¹²⁷ independently of one another represent the meanings given for R ¹²⁵ or represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,

A is absent or is -NR 1 -CO-, -NR ¹² -CO-NR ¹³ -, -NR ¹⁷ -CO-NR ¹⁸ -SO ₂ -,

NR ¹⁹ -SO2-, -SO2-NR ¹⁹ -SO 2 ~, -SO ₂ NR ¹⁹ CO-, -O-CO-NR ¹⁹ -SO ₂ - or -CR ² = CR ²¹ ®,

R ( ¹¹⁾ , R ( ¹²⁾ , R ( ¹³⁾ , R ( ¹⁷⁾ , R ( ¹⁸⁾ , R ( ¹⁹⁾ , R ( ²⁰⁾ and R ( ²¹⁾ independently of one another are hydrogen or alkyl having 1 to 8 carbon atoms and pharmaceutically acceptable salts thereof; Thiophenylalkenylcarboxylguanidide of formula I (HOE 96 / F 026)

(I) wherein at least one of R ¹ , R ² and R ³ is a group

186

-Op- (CH ₂ ) _s -C _q F _{2q +} 1, R ⁴⁸ CO- or R ³¹ SO _k -, p is 0 or 1, s is 0, 1, 2, 3 or 4, q is 1, 2, 3, 4, 5, 6, 7 or 8, k is 0, 1 or 2,

R ⁴⁸ represents an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, trifluoromethyl, methyl and methoxy,

R ³¹ represents an alkyl group having 1 to 8 carbon atoms, a perfluoroalkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chloro, trifluoromethyl, methyl or methoxy; or

R ³¹ represents NR ⁴¹ R ⁴² ,

R ( ⁴¹⁾ and R ( ^42), independently of one another, are hydrogen, (C1-C4) alkyl, (C1-C4) perfluoroalkyl; or

R ⁴¹ and R ⁴² together are 4 or 5 methylene groups, of which one CH2 group is O, S, -NH, N-CH3 or N-benzyl and the other substituents R ^1, R ² and R ³ independently of one another are hydrogen, F, Cl, Br, I, cyano, a group -0na ^_c ~ ^H m l + 2 mA or an -oG _and C H _{2 R r and} R ¹⁸ is 0 or the 1, m and is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and g is 0 or 1, and r is 0, 1, 2, 3, or 4,

R ¹⁸ represents a cycloalkyl group containing 3 to 8 carbon atoms

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or phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl and methoxy,

R ⁴ and R ^3, independently of one another, are hydrogen, fluorine, bromine, iodine, cyano, C 1 -C 8 alkyl, C 1 -C 8 perfluoroalkyl, C 3 -C 8 cycloalkyl a carbon atom or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ¹⁴ R ^{15 group} ,

R ¹⁴ and R ¹⁵ independently of one another are hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, as well as pharmaceutically acceptable salts thereof.

Numerous medical applications have already been described for the Na ⁺ / H ⁺ exchange inhibitors described above, for example their use in the treatment of diseases that result from poor chronic or

or acute supply of organs, especially the heart, with blood (ischemia). These inhibitors are therefore suitable, for example, for the treatment of ischemic-induced arrhythmias, various forms of angina pectoris, heart transplants, angioplastic surgical, and further for use in cardiac surgery and surgery. Other reported indications for Na ⁺ / H ⁺ exchange inhibitors are stroke, brain swelling and pro-differentiated induced diseases including atherosclerosis, late diabetic complications, fibrosis diseases, and organ hypertrophy.

It has been found that Na ⁺ / H ⁺ exchange inhibitors can stimulate respiration by increasing the chemosensibility of respiratory chemoreceptors. Chemoreceptors are crucially responsible for maintaining

188 not proper breathing. Chemoreceptors are activated in the body by hypoxia, a decrease in pH and an increase in carbon dioxide, and lead to a rhythm adjustment in response to changes in these factors. Breathing is particularly impaired during sleep and its proper course is highly dependent on the activity of these chemoreceptors.

Improvement in breathing capacity due to stimulation of these chemoreceptors with agents that inhibit sodium-proton exchange leads to improved breathing in the following clinical conditions and diseases: central respiratory stimulation disorders (eg short-term respiratory arrest, sudden death of children, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders following long-term artificial respiration, respiratory disorders during adaptation in a high-altitude environment, obstructive and mixed forms of respiratory arrest during sleep, and acute and chronic pulmonary disease with hypoxia and hypercapnia.

Said compounds are preferably found singly or in mixtures, for use in the manufacture of medicaments for the treatment of respiratory disorders, in the manufacture of medicaments for the treatment of muscular respiratory disorders, in the manufacture of medicaments for the treatment of respiratory disorders after long-term artificial respiration. adaptation to an alpine environment, in the manufacture of medicaments for the treatment of obstructive, central or mixed forms of short-term sleep sleep, in the manufacture of medicines for the treatment of acute and chronic pulmonary diseases associated with hypoxia and hypercapnia, and in particular carboanhydratases, preferably with acetazolamide.

Combining a Na ⁺ / H ⁺ exchange inhibitor with a carbonic anhydrase inhibitor (such as acetazolamide), which causes metabolic acidosis and thus already stimulates respiratory activity, is a preferred combination by which an enhanced effect is obtained using lower doses of the active ingredients.

189

It is an object of the present invention to administer sodium proton exchange inhibitors as a novel respiratory enhancer, wherein said inhibitors are optionally used in combination with carbonic anhydrase inhibitors.

190

Claims (2)

Use of NA ⁺ / H ⁺ exchange inhibitors for the manufacture of a medicament for the treatment of a respiratory stimulation disorder. Use according to claim 1, characterized in that the Na ⁺ / H ⁺ exchange inhibitor used is: (A) a benzoylguanidine of the formula O HN _X 3 R (I) wherein one of R ¹ or R ² is R ⁶ -S (O) or R ⁷ R ⁸ N-O 2 - and the other of R ¹ or R ² is hydrogen, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a phenoxy group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom , methyl and methoxy, or the other of R ¹ or R ² is R ⁶ - S (O) _n or R ⁷ R ⁸ N- wherein n is 0, 1 or 2, 191 R ⁶ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a cyclopentylmethyl group, a cyclohexylmethyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from fluorine, chlorine, methyl a group and a methoxy group, R ⁷ and R ®, which are the same or different, represent a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or R ⁷ represents a phenyl- (CH ₂ ) _{m group} , wherein m represents 1 to 4, or R ⁷ represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group, or R and R together represent a straight or branched chain of 4 to 7 carbon atoms, which chain may in addition be interrupted by an oxygen atom, a sulfur atom or a group R ⁹ where R ⁹ represents a hydrogen atom or a methyl group, or R 8 and R ° together with the nitrogen atom to which they are attached represent a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system, R ³ , R ⁴ , and R ⁵ independently of one another represent a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms, or R ³ and R ⁴ together represent an alkylene chain containing from 2 to 4 carbon atoms or R ⁴ and R ⁵ together represent an alkylene chain containing 4 to 7 carbon atoms, as well as pharmaceutically acceptable salts thereof, b) a benzoylguanidine of the formula I 192 (D in which R ¹ is a group R ⁴ -SO 2 or a group R ⁵ R ⁸ N-SO 2 -, wherein m is 0, 1 or 2, R ⁴ and R ⁵ are C 1 -C 8 alkyl, C 3 -C 6 alkenyl, or -C _n H _{2 n} -R, where n is 0, 1, 2, 3 or 4, R ⁷ represents a C 5 -C 7 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, methyl group, methoxy group and NR ⁸ R ^{9 group} , where R ⁸ and R ⁹ represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or R ⁵ represents a hydrogen atom, R ⁸ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, or cc R and R together are 4 or 5 methylene groups, of which one _CH2 group can be replaced by oxygen, S, NH, _N-CH3 or N-benzyl; R ² is H, F, Cl, Br, alkyl having 1 to 4 carbon atoms, a group -O- (CH _{2) m} CpF ₂ p _{+ 1,} or a group -XR ¹⁰ in which m is 0 or 1, p is 1 , 2 or 3 X is O, S or NR ^11, R ¹⁰ is H, alkyl of 1 to 193