SI9500211A - Ortho-amino-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic as well as medicament containing them - Google Patents

Abstract

2-Amino-benzoylguanidines (I) and their salts are new. R1 = NR6R7; R2-R5 = H, F, Cl, Br, I, CN, SOaR10, ZNR11R12, COR13, SR21, OR22, NR23R24, CR25R26R27, (X)c-CdH2d+1, (X)c-(CH2)b-CeF2e+1, 3-8C alkenyl, CbH2bR30 or -X-(CH2)bR19; R6, R7 = H or opt. perfluorinated 1-8C alkyl; R10 = opt. perfluorinated 1-8C alkyl, 3-6C alkenyl or CbH2b-R16; R11-R13 = H, opt. perfluorinated 1-8C alkyl, 3-6C alkenyl or CbH2b-R16; or R11+R12 = (CH2)4 or (CH2)5 (both opt. with one CH2 replaced by O, S, NH, N-Me or N-benzyl); R16 = phenyl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe or NR17R18) or 3-7C cycloalkyl; R17, R18 = H, CF3 or 1-4C alkyl; R19 = phenyl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe, NR17R18 or -X-(CH2)f-(X')R16); R21-R23, R25 = CaH2a-1-9C heteroaryl (opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OH, NH2, NHMe or NMe2); X, X' = O, S or NR33; Z = bond, CO or SO2; R24,R26, R27, R31-R33 = H or opt. perfluorinated 1-4C alkyl; R30 = phenyl, biphenylyl or naphthyl (all opt. mono-, di- or tri-substd. by F, Cl, CF3, Me, OMe or NR31R32) or 3-8C cycloalkyl; a = 0-2; b = 0-4; c = 0 or 1; d = 0-8; e = 0-7; f = 1-4; cpds. where R<3> = R<4> = H are excluded.

Description

HOECHST AKTIENGESELLSCHAFT

Ortho-amino-substituted benzoylguanidines, the process for their preparation, their use as medicaments or diagnostics, as well as the medicaments it contains.

The invention relates to ortho-amino-substituted benzoylguanidines of formula I

where they mean:

R (1) NR (50) R (6),

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

R (2), R (3), R (4) m R (5) independently of each other R (10) -SO _ri , R (1 l) R (12) N-C0-, R (13) - CO- or R (14) R (15) N-SO ₂ -; but nothing, 1 or 2,

R (10), R (11), R (12), R (13), R (14) and R (15) are independently (C ₁ -C _g ) -alkyl, (C ₁ -C _g ) -perfluoroalkyl, (C _g C 1 -C 4 -alkenylallyl-ChH 2 -R 1);

ab zero, 1, 2, 3 or 4;

R (16) (C ₃ -C ₇ ) -cycloalkyl, phenyl unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy or NR (17) R (18);

R (17) and R (18) are independently H, CF ₃ or (C ₁ -C ₄ ) -alkyl; or

R (11), R (12), as well as R (14) and R (15) total 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ 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 SR (21), -OR (22), -NR (23) R (24) or -CR (25) R ( 26) R (27);

R (21), R (22), R (23) and R (25) independently of one another -C _b H _2b - (C ₁ -C ₉ ) -heteroaryl, which is unsubstituted or substituted with 1 - 3 substituents selected from a group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; b is zero, 1 or 2;

R (24), R (26) and R (27) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl or (C 1 -C ₄ ) perfluoroalkyl;

or

R (2), R (3), R (4) and R (5) independently of one another are hydrogen, F, Cl, Br, J, CN;

- (Xa) _dg -C _d Η _{Μ3 + 1} , - (Xb) _dh - (CH ₂ ) _db -C _de F _{2de + 1} , (C ₃ -C _g ) -alkenyl or (Xa) O, S or NR (33);

R (33)

H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dg is zero or 1;

(Xb) O, S or NR (34);

R (34)

H, (C ₁ -C ₄ ) -alkyl or (C 1 -CJ-perfluoroalkyl; dh zero or 1; zero, 1, 2, 3, 4, 5, 6,7, 8; db zero, 1,2, 3,4;

where nothing, 1, 2, 3, 4, 5, 6, 7; df zero, 1, 2, 3, 4;

R (30) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatics phenyl, biphenylyl or naphthyl are unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (31) R (32);

R (31) andR (32)

H, (C _x -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or

R (2), R (3), R (4) and R (5) independently of one another NR (40) R (41) or - (Xe) - (CH ₂ ) _eb R (45);

R (40) and R (41) independently of one another are hydrogen, (C1-C8-alkyl, (C _x -C ₈ ) perfluoroalkyl or (CH ₂ ) _e -R (42); zero, 1, 2,3 or 4;

R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (43) R ( 44); R (43) and R (44) independently of one another are H, CF ₃ or (C ₁ -C ₄ ) -alkyl; or

R (40) and R (41) together are 4 or 5 methylene groups, of which one CH ₂ -group may be optionally substituted by oxygen, sulfur, NH, N-CH ₃ or N-benzyl;

(Xe) O, S or NR (47);

R (47)

H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl;

eb is zero, 1, 2, 3 or 4;

R (45) (C ₃ -C ₇ ) -cycloalkyl, phenyl unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy, NR (5O) R (51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46);

Xfa CH ₂ , O, S or NR (48);

Xfb O, S or NR (49);

ed 1,2, 3,4;

R (46) H, (C ₁ -C ₄ -alkyl or (C ₁ -C ₄ ) -perfluoro alkyl;

R (48) R (49) R (50) R (51) independently of one another H or (C ^ CJ-alkyl or a (C ₁ -C ₄₎ -perfluoroalkyl;

however, R (3) and R (4) cannot be hydrogen as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula I in which they mean:

R (1) NR (50) R (6);

R (50) and R (6) independently of one another are hydrogen, CF ₃ or (C ₁ -C ₄ ) -alkyl;

R (2) and R (5) are hydrogen;

R (4) R (10) -SO _a -, R (11) R (12) N-CO-, R (13) -CO- or R (14) R (15) N-SO ₂ - but zero , 1 or 2;

R (10), R (11), R (12), R (13), R (14) and R (15) independently of one another (C1-C8-alkyl, (C1-C8-perfluoroalkyl, (Cg- C 1-6 -alkenylally-CH 2 -R 3b);

ab zero, 1, 2, 3 or 4;

R (16) (C ₃ -C ₇ ) -cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents in the group consisting of F,

Cl, CF _3, methyl, methoxy or NR (17) R (18);

R (17) and R (18) are independently H, CF ₃ or (C ₁ -C ₄ ) -alkyl; or

R (11) and R (12), as well as R (14) and R (15), total 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ or N-benzyl;

or

R (11), R (12), R (14) and R (15) are independently hydrogen;

R (3) SR (21), -OR (22), -NR (23) R (24) or -CR (25) R (26) R (27);

R (21), R (22), R (23) and R (25) independently of one another -C _b H _2b - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

b is zero, 1 or 2;

R (24), R (26) and R (27) are independently hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or

R (3) and R (4) independently of one another F, Cl, Br, J, CN, - (Xa) _dg- C such _that H _{2da + 1} or ^^ - (CH ^ -C, _e F _{2de + 1} , (C ₃ -C _g) -alkenyl or ^^ (30);

(Xa) O, S or NR (33);

R (33)

H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dg zero, 1;

(Xb) O, S or NR (34);

R (34)

H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dh is zero or 1;

that zero, 1, 2, 3, 4, 5, 6, 7 or 8;

db zero, 1, 2, 3 or 4;

where zero, 1, 2, 3, 4, 5, 6 or 7;

df zero, 1, 2, 3 or 4;

R (30) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatics phenyl, biphenylyl or naphthyl are unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (31) R (32);

R (31) and R (32) are independently H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl;

or

R (3) NR (40) R (41) or (Xe) - (CH ₂ ) _eb R (45),

R (40) and R (41) are, independently of one another, hydrogen, (C1-C6-alkyl, (C1-C8-perfluoro alkyl or (CH ₂ ) _e -R (42); e is zero, 1, 2, 3 or 4 ;

R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl,

CF ₃ , methyl, methoxy and NR (43) R (44);

R (43) and R (44) independently of one another are H, CF ₃ or C 1 -C 6 alkyl; or

R (40) and R (41) together are 4 or 5 methylene groups, one of which may be substituted by oxygen, sulfur, NH, N-CH ₃ or N-benzyl;

(Xe) O, S or NR (47);

R (47)

H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; eb is zero, 1, 2, 3 or 4;

R (45) (C _{3 -C?)} Cycloalkyl, phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (50) R ( 51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46);

(Xfa) CH ₂ , O, S or NR (48);

(Xfb) O, S or NR (49); ed 1,2,3 or 4;

R (46) is H, (C1-C4-alkyl or (C1-C4-perfluoroalkyl);

R (48), R (49), R (50) and R (51) independently of one another are H, (C ₁ -C ₄ -alkyl or (C ₁ -C ₄ ) perfluoroalkyl;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I in which they mean:

R (1) NR (50) R (6),

R (50) and R (6) independently of one another are hydrogen or CH ₃ ;

R (2) and R (5) are hydrogen;

R (4) R (10) -SO _a -, R (11) R (12) N-CO-, R (13) -CO- or R (14) R (15) N-SO ₂ -;

2;

R (10), R (II), R (12) R (13) R (14) and R (15) independently of each other (C-C, _g) alkyl, (Cl-C _g) -perfluoroalkyl ab is zero, 1 or 2;

R (16) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (17) R (18);

R (17) and R (18) independently of one another are H, CF ₃ or CH ₃ ; or

R (11) and R (12), as well as R (14) and R (15) together have 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ or N- benzyl;

or

R (11), R (12), R (14) and R (15) independently of one another are hydrogen;

R (3) -OR (22) or -NR (23) R (24);

R (22) and R (23) independently of one another -C _b H _2b - (C 1 -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

b is zero, 1 or 2;

R (24) is hydrogen, CH ₃ or CF ₃ ; or

R (3) and R (4) independently of one another F, Cl, Br, J, CN, - (Xa) _dg -C _to H _{2da + 1} or - (Xb) _dh - (CH ₂ ) _db -C _d F _{2de + 1} ;

(Xa) O, S or NR (33); R (33) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dg nothing; (Xb) O, S or NR (34); R (34) H, (C ₁ -C ₄ -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dh nothing; Yes 1,2, 3, 4; db nothing;

de 1,2, 3, 4; or

R (3) NR (40) R (41) or (Xe) - (CH ₂ ) _eb R (45);

R (40) and R (41) independently of one another hydrogen, (C ^ Cgj-alkyl, (Cl-Cs) -perfluoroalkyl or (CH _{2) e} -R (42); e is zero, 1 or 2;

R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl,

CF ₃ , methyl, methoxy and NR (43) R (44);

R (43) and R (44) independently of one another H, CF ₃ or CH ₃ ; or

R (40) and R (41) together are 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, sulfur, NH, N-CH ₃ or N-benzyl;

(Xe) O, S or NR (47);

R (47)

H, (C ₁ -C ₄ ) -alkyl or CF ₃ ; eb is zero, 1 or 2;

R (45) (C ₃ -C ₇ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy, NR (50) R ( 51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46);

(Xfa) CH ₂ , O, S or NR (48);

(Xfb) O, S, NR (49); ed 1 or 2;

R (46) H, (C ₁ -C ₄ ) -alkyl or CF ₃ ;

R (48) R (49) R (50) R (51) independently of one another H, (Cj-C ^ -alkyl, or CF _3;

as well as their pharmaceutically acceptable salts.

The term (C 1 -C 8 heteroaryl means in particular residues derived from phenyl or naphthyl in which one or more CH groups are replaced by N and / or in which at least two adjacent CH groups are formed (at the formation of a five-membered aromatic ring ), replaced by S, NH or O. Further, one or both atoms of the condensation site of the bicyclic moiety (as in indolizinyl) may be an N atom.

In particular heteroaryl include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolin, quinolinyl, quinolin, quinolinyl, quinolin, quinolinyl, quinolin, quinolinyl, quinolin, quinolinyl, quinolin. .

If one of the substituents R (1) to R (5) contains one or more asymmetric centers, these can be configured both S and R. The compounds may exist as optical isomers, as diastereomers, as racemates, or as mixtures thereof.

Labeled alkyl- and pertluoroalkyl radicals can be both unbranched and branched.

The invention further relates to a process for the preparation of compounds I, wherein the compounds of formula II

where R (1) to R (5) have the meanings given above and where L stands for a leaving group which is readily nucleophilic substituted, is reacted with guanidine. Activated acid derivatives of formula II, wherein L represents an alkoxy, preferably a methoxy group, a phenoxy group, a phenylthio, methylthio, 2-pyridylthio group, a nitrogen hetero ring, preferably 1-imidazolyl, are obtained in a known manner from known carboxylic acid chlorides in a known manner. (formula II, L = C1), which can, however, be prepared in a known manner from existing carboxylic acids (formula II, L ~ OH), e.g. with thionyl chloride. In addition to the carboxylic acid chlorides of formula II (L = C1), further activated acid derivatives of formula II can be prepared in a known manner directly from existing benzoic acid derivatives (formula II, L = OH), such as e.g. methyl esters of formula II with L = OCH ₃ treated with gaseous HCl in methanol, imidazolides of formula II treated with carbonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. E. Engl. 1,351-367 (1962)], mixed anhydrides II with C1-COOC ₂ H ₅ or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activation of benzoic acids by dicyclohexylcarbodiimide (DCC) or by O - [(cyano (ethoxycarbonyl) methylene) ) amino] -l, 1,3,3tetramethyluronium tetrafluoroborate (TOTU) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of Formula II are given under the references of literature sources in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The metabolism of an activated carboxylic acid derivative of formula II with guanidine proceeds in a known manner in a protic or aprotic polar but inert organic solvent. In the process of the reaction of the methyl esters of benzoic acid (II, L = OMe) with guanidine, the temperature of methanol, isopropanol or THF is kept between 20 ° C and the boiling point of these solvents. For most metabolites of Compounds II with guanidine without salt, it is preferable to act in inert solvents such as THF (tetrahydrofuran), dimethoxyethane or isopropanol. Water can also be used as a solvent.

When L = Cl, it is preferable to work with the addition of an acid trap, e.g. in the form of excess guanidine for the cleavage of hydrochloric acid.

The introduction of substituted sulfur, oxygen, or nitrogen nucleophiles, sulfur, oxygen, or nitrogen is carried out in the literature by known methods of nucleophilic aromatic substitution. Halides and trifluoromethanesulfonates were the leaving groups in this substitution. Preferably we work in a dipolar aprotic solvent such as e.g. DMF or TMU at a temperature between 0 ° C and the boiling point of the solvent, preferably between 80 ° C and the boiling point of the solvent. Preferably, the alkali or earth alkali metal salt with an anion of higher basicity and lower nucleophilicity, such as e.g. κ ^ ο ₃ .

The introduction of alkyl or aryl substituents is carried out by known in the literature methods of palladium-mediated cross-couplings of aryl halides with e.g. organocin compounds, organostannans, organoboric acids or organoborans.

Benzoylguanidines I are generally weak bases and can bind acids when salt is formed. Acid addition salts include salts of all pharmacologically tolerable acids, e.g. halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

li

Compounds I are substituted acylguanidines.

The most prominent representative of acylguanidines is the pyrazine derivative amiloride, which is used in treatment as a potassium-sparing diuretic. A number of further amiloride-type compounds have been described in the literature, such as e.g. dimethylamiloride or ethylisopropylamiloride.

amiloride: R ', R = H dimethylamiloride: R', R ~ CH ₃ ethylisopropylamiloride: R '= C ₂ H ₅ , R - CH (CH ₃ ) ₂

In addition, research has become known to indicate the antiarrhythmic properties of amiloride [Circulation 79,1257 - 63 (1989)]. Widespread use as antiarrhythmics, however, is hampered by the fact that this effect is only weakly expressed and accompanied by a blood pressure of diminishing and saluretic activity, and these side effects are undesirable in the treatment of heart rhythm disorders.

Hints on the antiarrhythmic properties of amiloride have also been obtained from experiments on isolated animal hearts [Eur. Heart J. 9 (suppl. 1): 167 (1988), book of abstracts]. Thus, for example, found in rat hearts that artificially induced ventricular tremor can be completely suppressed by amiloride. Even stronger than amiloride, the above-mentioned amiloride derivative was ethylisopropylamiloride in this model.

US Patent 3,780,027 requires protection for acylguanidines, which are structurally similar to the compounds of formula I and from which commercially available diuretics, helium pentane as bumetanide, are commercially available. It is appropriately reported that these compounds have potent salidiuretic activity.

Surprisingly, the compounds of the invention do not exhibit any undesirable and deleterious salidiuretic but very good antiarrhythmic properties; for this reason they are well suited for treating conditions that e.g. occur when oxygen deficiency occurs. Due to their pharmacological properties, the compounds are extremely suitable as antiarrhythmic drugs with a radioprotective component for infarct prophylaxis and treatment of infarction, as well as for the treatment of angina pectoris, while also preventing or severely preventing pathophysiological transitions in the production of ischemically induced injuries, especially in triggering ischemically induced arrhythmia of the heart. Due to their protective effects against pathological hypoxic and ischemic situations, the compounds of the invention of Formula I may be used as a medicament for the treatment of all acute and chronic, ischemia-derived injuries, or therefore primary or secondary, due to inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism. induced diseases. This concerns their use as a cure for surgery, e.g. organ transplants, wherein the compounds can be used both to protect organs in the donor before and after collection, to protect organs removed, e.g. when handling or storing them in a bath of saline fluids, as well as when being converted into a receiving organism. The compounds are also valuable, protectively acting drugs in performing angioplasty surgeries, e.g. on the hearts as well as on the peripheral scar. In accordance with their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular ZNS, for example. suitable for the treatment of stroke or cerebral edema. In addition, the compounds of the invention of formula I are also suitable for the treatment of shock forms, e.g. allergic, cardiogenic, hypovolemic and bacterial shocks.

In addition, the compounds of the invention of formula I are characterized by a potently inhibitory effect on cell proliferation, e.g. fibroblast cell proliferation and vascular smooth muscle cell proliferation. For this reason, compounds of formula I are considered to be valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as anti-atherosclerotic agents, anti-diabetic agents, cancers, fibrotic diseases, such as lung fibrosis, fibrosis liver or kidney fibrosis, organohypertrophies and hyperplasia, especially in prostate hyperplasia or. prostate hypertrophy.

The compounds of the invention are effective inhibitors of the cellular antiporter sodium proton (Na ⁺ / H ⁺ exchanger), (Exchanger), which in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) is elevated in such cells, measurements may be feasible, such as in erythrocytes, platelets or leukocytes. The compounds of the invention are therefore suitable as exceptional and simple scientific tools, e.g. in their use as diagnosticians to identify and differentiate certain forms of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventative treatment to prevent the genesis of high blood pressure, e.g. essential hypertension.

Medicaments containing compound I may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the particular occurrence of the disease.

Compounds I can be used alone or together with galenic excipients, both in veterinary and human medicine.

Which of the excipients is suitable for the desired formulation of the drug is known to one skilled in the art based on his or her expertise. In addition to solvents, gel-forming agents, suppositories of substrates, excipients for tablets and other carriers of the active substance, e.g. use antioxidants, dispersants, emulsifiers, antifoams, flavor correctors, preservatives, mediated solubilizers or colorants.

For the oral dosage form, the active compounds are mixed with suitable additives such as carriers, stabilizers or inert diluents, and by conventional methods are introduced into suitable dosage forms such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. As inert stretchers, for example, gum arabicum, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular maize starch. The preparation can be obtained either as a dry or as a wet granulate. As oily carrier materials or as solvents, e.g. vegetable or animal oils such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired, are converted to the usual substances, such as mediated by dissolutions, emulsions or further excipients, into solution, suspension or emulsion. As solvents, for example, for example: water, saline or alcohols, e.g. ethanol, propanol, glycerin, and in addition sugar solutions such as glucose or mannitol, or a mixture of the various solvents mentioned.

As a pharmaceutical formulation for administration in the form of aerosols or sprays, e.g. solutions, suspensions or emulsions of the active substance of formula I in pharmaceutically acceptable solvents, such as in particular ethanol or water, or mixtures of such solvents. The formulation may also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as propellants. Such a preparation contains the active substance typically in a concentration of about 21 to 0.1 to 10, in particular of about 0.3 to 3% by weight.

The dosage of the active substance of formula I for administration and the frequency of administration depend on the potency and the duration of effect of the compounds used; in addition, the manner and severity of the disease to be treated, as well as the sex, age, weight and individual acceptability of the mammal in need of treatment.

On average, the daily dose of the compound of Formula I in about 75 kg to a patient is at least 0.001 mg, preferably 0.01 mg to 10 mg, preferably 1 mg. Acute disease outbreaks, such as the immediate aftermath of a heart attack, may require even higher and more frequent doses, e.g. up to 4 individual doses per day. Especially with i.v. up to 100 mg per day may be required, for example in a patient with an intensive care unit.

In accordance with the rules given in the embodiments, the following compounds of the invention of formula I or the following may be prepared: their physiologically tolerable salts:

List of abbreviations:

MeOH methanol

DMF N, N-dimethylformamide

TMU

NBS

AIBN

El

DCI

RT

EE

SEC

MTB mp

HEP

Ν, Ν, Ν ', Ν′-tetramethylurea N -br omsuccinimide a, Q! -Azo-bis-isobutyronitrile electron collision desorption - chemical ionization room temperature ethyl acetate diisopropyl ether methyl tertiary butyl ether melting point n-heptane

DME dimethoxyethane FAB rapid atom bombardment ch ₂ ci ₂ dichloromethane THF tetrahydrofuran eq equivalent ES electrospray ionization Me methyl Et ethyl Bn benzyl ZNS the central nervous system Brine saturated aqueous NaCl solution

The experimental part

General regulation for the preparation of acyl guanidines (I)

Option A: from carboxylic acids (II, L = OH)

1,0 eq. of the carboxylic acid derivative of formula II is dissolved or resp. was suspended in anhydrous THF (5 ml / mmol) and then made up with 1.1 eq. carbonyldiimidazole. After stirring for 2 hours at RT, 5.0 eq was introduced into the reaction solution. guanidine. After stirring overnight, the THF was distilled off under reduced pressure (rotavapor), supplemented with water, adjusted with 2 N HCl to pH 6 to 7 and the corresponding acylguanidine (formula I) filtered. The acyl-guanidines thus obtained can be converted to the corresponding salts by treatment with aqueous, methanolic or ether hydrochloric acid or other pharmacologically acceptable acids.

General regulation for the preparation of acyl guanidines (I)

Option B: from alkyl carboxylic acid residues (II, L = O-alkyl)

1,0 eq. of the carboxylic acid alkyl residue of formula II as well as 5.0 eq. guanidine (free base) is dissolved in isopropanol or suspended in THF and cooked to complete metabolism (thin layer control) at reverse flow (typical reaction time 2 to 5 h). The solvent was distilled off under reduced pressure (rotavapor), taken up in EE and washed with 3 x NaHCO ₃ solution. It is dried over Na ₂ SO ₄ , the solvent is distilled off in vacuo and chromatographed on silica with a suitable developer, e.g. EE / MeOH 5: 1.

(Salt formation compares variant A).

EXAMPLE 1

2-Amino-4-chloro-5-sulfamoyl-benzoylguanidine dihydrochloride is prepared according to variant B from the corresponding benzoic acid ester.

M.p .: 288-290 ° C.

EXAMPLE 2

2-Amino-4-chloro-5- (N-ethyl-sulfamoyl) -benzoylguanidine dihydrochloride is prepared according to variant B from the corresponding benzoic acid ester. M.p .: 242 ° C.

EXAMPLE 3

2- (N-Butyl-amino) -4-chloro-5-sulfamoyl-benzoylguanidine dihydrochloride is prepared according to variant B from the corresponding benzoic acid ester. M.p .: 286 ° C.

EXAMPLE 4

2- (N-ethyl-amino) -4-chloro-5-sulfamoyl-benzoylguanidine dihydrochloride is prepared in the B variant from the corresponding benzoic acid ester. M.p .: 290 ° C.

EXAMPLE 5

2-Amino-5- (1-piperidyl) -benzoylguanidine dihydrochloride is prepared according to variant B from the corresponding benzoic acid ester. M.p .: 170 ° C.

EXAMPLE 6

2-Amino-3-bromo-5-methyl-benzoylguanidine dihydrochloride is prepared according to variant A from the corresponding benzoic acid.

Melting point:> 300 ° C.

EXAMPLE 7

2-Amino-3-methyl-benzoylguanidine dihydrochloride is prepared analogously to variant B from the corresponding benzoic acid methyl ester. M.p .:> 270 ° C.

EXAMPLE 8

2-Amino-3,5-dichloro-benzoylguanidine dihydrochloride is prepared according to variant A from the corresponding benzoic acid.

M.p .: 190 ° C.

EXAMPLE 9

2-Amino-5-chloro-benzoylguanidine dihydrochloride is prepared according to variant A from the corresponding benzoic acid.

Melting point:> 390 ° C upon decomposition.

R _p = 0.27 (ethyl acetate)

EXAMPLE 10

2-Amino-4,5-dimethoxy-benzoylguanidine dihydrochloride is prepared according to variant A from the corresponding benzoic acid.

M.p .: 177 ° C.

EXAMPLE 11

2-amino-4,5-dibromo-benzoylguanidine is prepared according to variant B from the corresponding benzoic acid methyl ester.

M.p .: 158 ° C.

EXAMPLE 12

2-Dimethylamino-5-chloro-benzoylguanidine dihydrochloride is prepared according to variant B from the corresponding benzoic acid methyl ester.

M.p .: 135 -145 ° C.

PHARMACOLOGICAL INFORMATION:

Inhibition of the rabbit erythrocyte Na ⁺ / H ⁺ exchanger

White New Zealand rabbits (Ivanovas) were given a standard diet with 2% cholesterol for 6 weeks to activate the Na ⁺ / H ⁺ exchange, allowing the flame photometric determination of Na ⁺ influx into erythrocytes via Na ⁺ / H ⁺ exchange. Blood was withdrawn from the ear artery and made 25 mg of potassium-heparin non-invasive. A portion of each sample was used for double determination of hematocrit by centrifugation. Aliquots of 100 μ \ each were used to measure Na-output content in erythrocytes.

For determination of amiloride-sensitive sodium influx, 100 μί of each blood sample, each in 5 ml of hyperosmolamem-salt-sucrose-medium (mmol / 1: 140 NaCI, 3 KC1, 150 sucrose, 0.1 Ouabain, 20 tris-hydroxymethylaminomethane) , incubated at pH 7.4 and 37 ° C. The erythrocytes were then washed 3 times with ice-cold MgCl ₂ Ouabain solution (mmol / 1: 112 MgCl ₂ , 0.1 Ouabain) and hemolysed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry.

Na ⁺ net influx was calculated from the difference between sodium baseline and erythrocyte sodium content after incubation. Amiloride inhibited sodium influx was obtained from the difference in sodium content of erythrocytes after incubation with and without amiloride 3 x 10 ^-4 mol / l. In this way, the compounds of the invention were also treated.

Claims (16)

PATENT APPLICATIONS An ortho-amino-substituted benzoylguanidine of formula I R (2) R (4) R (3) R (5) NH2 NH2 where: R (1) NR (50) 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) m R (5) independently of each other R (10) -SO _a , R (11) R (12) N-CO-, R (13) -CO - or R (14) R (15) N-SO ₂ -; but nothing, 1 or 2, R (10), R (11), R (12), R (13), R (14) and R (15) independently of one another (C 1 -C 8 -alkyl, (C 1 -C 8 -perfluoroalkyl, (C ₃ C ₆ -alkemyl or -C _b H _2ab -R (16); ab zero, 1, 2, 3 or 4; R (16) (C _{3 -C?)} Cycloalkyl, phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy or NR (17) R (18); R (17) and R (18) independently of one another are H, CF ₃ or _(C -C ₄₎ -alkyl; or R (11), R (12), as well as R (14) and R (15) total 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ or N -benzyl; or R (11), R (12), R (14) and R (15) are independently hydrogen; R (2), R (3), R (4) and R (5) independently of one another SR (21), -OR (22), -NR (23) R (24) or -CR (25) R (26) R (27); R (21), R (22), R (23) and R (25) independently of one another -C _b H _2b - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; b is zero, 1 or 2; R (24), R (26) and R (27) independently of one another are hydrogen, (C-C ₄ ) -alkyl or (C-C ₄ ) perfluoroalkyl; or R (2), R (3), R (4) and R (5) independently of one another are hydrogen, F, Cl, Br, J, CN; - (X ^a ) dg- ^C d H2da + 1 '' (^) d _h (CH ₂ ) _db -C _de F _{2de + 1} , (C ₃ -C ₈ ) -alkeml or -Cd _f H _2df R (30 ); (Xa) O, S or NR (33); R (33) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dg is zero or 1; (Xb) O, S or NR (34); R (34) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dh zero or 1; Yes zero, 1, 2, 3, 4, 5, 6, 7, 8; db zero, 1, 2, 3, 4; 2 de zero, 1, 2, 3, 4, 5, 6, 7; df zero, 1, 2, 3, 4; R (30) (C-C ₈ ) -cycloalkyl, phenyl, biphenyllyl or naphthyl, wherein the aromatics are phenyl, biphenyl or naphthyl unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (31) R (32); R (31) and R (32) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; R (2), R (3), R (4) and R (5) independently of one another NR (40) R (41) or - (Xe) - (CH ₂ ) _eb R (45); R (40) and R (41) independently of one another hydrogen, (C ₁ -C _g) alkyl, (Cl-C _g) -perfluoroalkyl or (CH _{2) e} -R (42); e is zero, 1, 2, 3 or 4; R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (43) R ( 44); R (43) and R (44) are independently H, CF ₃ or (C ₁ -C ₄ ) -alkyl; or R (40) and R (41) together are 4 or 5 methylene groups, of which one CH ₂ -group may be optionally substituted by oxygen, sulfur, NH, N-CH ₃ or N-benzyl; (Xe) O, S or NR (47); R (47) H, (C ₁ -C ₄ ) -alkyl or (C 1 -CJ-perfluoroalkyl; eb is zero, 1, 2, 3 or 4; R (45) (C _{3 -C?)} Cycloalkyl, phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (50) R ( 51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46); Xfa CH ₂ , O, S or NR (48); Xfb O, S or NR (49); ed 1, 2, 3, 4; R (46) is H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; R (48) R (49) R (50) and R (51) independently of one another, H or (Cj-CJ-alkyl or a (C -C ₄₎ -perfluoroalkyl; however, R (3) and R (4) cannot be hydrogen as well as their pharmaceutically acceptable salts. A compound of formula I according to claim 1, characterized in that: R (1) NR (50) R (6); R (50) and R (6) independently of one another are hydrogen, CF ₃ or (Cl-C ₄₎ -alkyl; R (2) and R (5) are hydrogen; R (4) R (10) -SO _a -, R (11) R (12) N-CO-, R (13) -CO- or R (14) R (15) N-SO ₂ - but zero , 1 or 2; R (10), R (II), R (12) R (13) R (14) and R (15) independently of one another are (C, -C _g) alkyl, (Cl-Cgj-perfIuoralkil ( C ₃ -C ₆ ) -alkenyl or -C _b H _2ab -R (16); ab zero, 1, 2, 3 or 4; R (16) (C ₃ -C ₇ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 - 3 substituents in the group consisting of F, Cl, CF _3, methyl, methoxy or NR (17) R (18); R (17) and R (18) are independently H, CF ₃ or (C 1 -C ₄ ) -alkyl; or R (11) and R (12), as well as R (14) and R (15) together have 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ or N-benzyl; or R (11), R (12), R (14) and R (15) are independently hydrogen; R (3) SR (21), -OR (22), -NR (23) R (24) or -CR (25) R (26) R (27); R (21), R (22), R (23) and R (25) independently of one another -C _b H _2b - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; b is zero, 1 or 2; R (24), R (26) and R (27) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl or (C 1 -CJ-perfluoroalkyl; or R (3) and R (4) independently of one another F, Cl, Br, J, CN, - (Xa) _da -C _da H _{2da + 1} or (C ₃ -C ₈ ) -alkemyl or -C _df H _2df R (30); (Xa) O, S or NR (33); R (33) H, (Cl-C ₄₎ -alkyl or _(C] -C ₄₎ -perfluoroalkyl; dg zero, 1; (Xb) O, S or NR (34); R (34) H, (C1-CJ-alkyl or (C1-CJ-perfluoroalkyl; dh is zero or 1; that zero, 1, 2, 3, 4, 5, 6, 7 or 8; db zero, 1, 2, 3 or 4; where zero, 1, 2, 3, 4, 5, 6 or 7; df zero, 1, 2, 3 or 4; R (30) (C ₃ -C ₈ ) -cycloalkyl, phenyl, biphenyl or naphthyl, wherein the aromatics are phenyl, biphenyl or naphthyl unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (31) R (32); R (31) and R (32) are independently H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or R (3) NR (40) R (41) or (Xe) - (CH ₂ ) _eb R (45), R (40) and R (41) independently of one another are hydrogen, (C-C _g ) -alkyl, (C-C _g ) -perfluoroalkyl or (CH ₂ ) _e -R (42); e is zero, 1, 2, 3 or 4; R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (43) R (44); R (43) and R (44) independently of one another are H, CF ₃ or C-C-alkyl; or R (40) and R (41) together are 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, sulfur, NH, N-CH ₃ or N-benzyl; (Xe) O, S or NR (47); R (47) H, (C 1 -C 6 -alkyl or (C 1 -C 1 -perfluoroalkyl; eb is zero, 1, 2, 3 or 4; R (45) (C ₃ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy, NR (50) R ( 51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46); (Xfa) CH ₂ , O, S or NR (48); (Xfb) O, S or NR (49); ed 1, 2, 3 or 4; R (46) is H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; R (48), R (49), R (50) and R (51) independently of one another are H, (C ₁ -C ₄ ) -alkyl or (C-C ₄ ) perfluoroalkyl. Compound of formula I according to at least one of claims 1 to 2, characterized in that: R (1) NR (50) R (6), R (50) and R (6) independently of one another are hydrogen or CH ₃ ; R (2) and R (5) are hydrogen; R (4) R (10) -SO _a -, R (11) R (12) N-CO-, R (13) -CO- or R (14) R (15) N-SO ₂ -; a 2; R (10), R (II), R (12) R (13) R (14) and R (15) independently of one another are (C ₁ -C _g) alkyl, (Cl-Cgj-perfluoroalkyl ^AL1 - ^C ab ^H 2ab- ^R ( ¹⁶ ); ab zero, 1 or 2; R (16) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (17) R (18); R (17) and R (18) independently of one another are H, CF ₃ or CH ₃ ; or R (11) and R (12), as well as R (14) and R (15), total 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, S, NH, N-CH ₃ or N -benzyl; or R (11), R (12), R (14) and R (15) are independently hydrogen; R (3) -OR (22) or -NR (23) R (24); R (22) and R (23) independently of one another -C _b H _2b - (C 1 -C ₉ ) -heteroaryl unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; b is zero, 1 or 2; R (24) is hydrogen, CH ₃ or CF ₃ ; or R (3) and R (4) independently of one another F, Cl, Br, J, CN, - (Xa) _dg -C _that H _{2da + 1} or (^) dh '(^' ^ 2) db'Qle ^ 2de + l ' (Xa) O, S or NR (33); R (33) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ -perfluoroalkyl; dg nothing; (Xb) O, S or NR (34); R (34) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; dh nothing; Yes 1, 2, 3, 4; db nothing; de 1,2, 3, 4; or R (3) NR40) R (41) or (Xe) - (CH ₂ ) _eb R (45); R (40) and R (41) independently of one another are hydrogen, (C _x -C ₈ ) -alkyl, (C 1 -C 8) perfluoroalkyl or (CH ₂ ) _g -R (42); is zero, 1 or 2; R (42) (C ₃ -C ₇ ) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (43) R ( 44) R (43) and R (44) independently of one another H, CF ₃ or CH ₃ ; or R (40) and R (41) together are 4 or 5 methylene groups, of which one CH ₂ group may be replaced by oxygen, sulfur, NH, N-CH ₃ or N-benzyl; (Xe) O, S or NR (47); R (47) H, (C ₁ -C ₄ ) -alkyl or CF ₃ ; eb is zero, 1 or 2; R (45) (C ₃ -C ₇ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy, NR (50) R ( 51) and - (Xfa) - (CH ₂ ) _ed - (Xfb) R (46); (Xfa) CH ₂ , O, S or NR (48); (Xfb) O, S, NR (49); ed 1 or 2; R (46) H, (C ₁ -C ₄ ) -alkyl or CF ₃ ; R (48), R (49), R (50) and R (51) independently of one another are H, (C1-CJ-alkyl or CF3 ₎ . A process for the preparation of compound I according to claim 1, characterized in that a compound of the formula wherein R (1) to R (5) is defined as in claim 1 and wherein L is a readily substituted nucleophilic leaving group , is reacted with guanidine, and optionally converted into a pharmaceutically acceptable salt. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of a heart attack. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and extremities. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of conditions in shock. Use of compound I according to claim 1 for the preparation of a medicament for use in surgery and organ transplants. Use of compound I according to claim 1 for the preparation of a medicament for the preservation and storage of transplants for surgical purposes. The use of compound I according to claim 1 for the preparation of a medicament for the treatment of diseases in which cellular proliferation is the primary or secondary cause, and their use as anti-atherosclerotic agents, anti-diabetic agents, cancers, fibrotic diseases, such as lung fibrosis, liver fibrosis, or kidney fibrosis, prostate hyperplasia. Use of compound I according to claim 1 for the preparation of a scientific tool for inhibiting the Na ⁺ / H ⁺ exchanger, for the diagnosis of hypertension and proliferative disorders. 16. A medicament comprising an effective amount of compound I according to one or more of claims 1 to 3.