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(11) Patent Number: K.E 398
   
(73)0wner:Sanofi Aventis Deutschland GmbH of  65929 Frankfurt am Main, Germany   

(21)Application Nnmber:    KElP/ 2004/ 000368       

(72) Invento"    KLEEMANN, Heinz-Werner, Mainstrasse 29,65474 Bischofsheim, Germany           
               
(22) Filing Date'03/1112004               
               
(74) Agent/address for correspondence:    Kaphm & Stratton Advocates, P.O. Box 40111-00100,Nairobi
               
(86)  PCT data    PCT/EP04/0!2393    03/1112004        WO 2005/047239 AI    26/05/2005                           

(54) Title: PENTAFLUOROSULFANYL BENZOYLGUANIDINES, METHOD FOR THEIR PRODUCTION, THEIR USE AS MEDICAMENTS OR DIAGNOSTIC AGENTS AND MEDICAMENT CONTAThiTNGTHESAME

(57) Abstract: The invention relates to pentafluorosulfanyl benzoylguanidines of formular (1), in which Rl to R4 are defined as cited in the claims. Said substances are suitable for use as anti-arrhythmic medicaments comprising cardia-protective components for the prophylaxis and treatment of infarc, in addition to the treatment of angina pectoris. They also preventatively inhibit the pathophysiological events that occur during ischaemically induced traumas, in particular during the triggering of ischaemically induced cardiac arrhythmia
Pentafluorosulfanyl benzoylguanidines, method for their production, their

use as medicaments or diagnostic agents and medicament containing the

same

Pentafluorosulfanylbenzoylguanidines of the formula I

in which R1 to R4 have the meanings indicated in the claims, and the

pharmaceutically acceptable salts thereof are substituted acylguanidines

10    and inhibit the cellular sodium-proton antiporter (Na +/H + exchanger, NHE). Because of the NHE-inhibitory properties, the ccmpounds of the formula 1 and the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation or activated
NHE, and of diseases caused seccndarily by the NHE-related damage.

15

Compared with known compounds, the compounds of the invention are

distinguished by an extremely high activity in the inhibijion of Na +/H +

exchange, and by improved ADMET properties. The xenobiotic structure (in particular the introduction of the rather "unnatural/manmade" SF5

20    substituents) advantageously influences tissue distribution. This leads inter alia to increased exposures in vivo. This involves no significant influence on the absorption characteristics, and the high bioavailability of the acylguanidines is retained.

25    In ccntrast to some acylguanidines described in the literature, the ccmpounds of the formula I described herein and their pharmaceutically
acceptable salts show no unwanted and disadvantageous saliduretic properties.

The invention relates to pentafluorosulfanylbenzoylguanidines of the formula I

FFJXXF..'(R3'<:::A2   
FI    .
~    N~NH2
R4    ~~
A10    NH2


in which

R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 10 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CH2)n-

(CF2)o-CF3 or -(SOm)q -(CH2)r(CF2)s-CF3; R5 and R6
are, independenijy of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;

15    m is zero, 1 or 2 n, o, p, q, rand s

are, independently of one another, zero or 1;

R2    is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR7R8,

20 -Ot-(CH2)u-(CF2)v-CF3 or -(SOw)x-(CH2)y-(CF2)rCF3; R7 and R8
are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
w    is zero, 1 or 2

25    t, u, v, x, y and z

are, independently of one another, zero or 1;
 
is Cl, Br,l, -CN, -S02CH3, alkoxy having 1, 2, 3 or4 carbon atoms. NR9R10, -Oa-(CH2)b-(CF2)c-CF3, •(SOd)e-(CH2)t-(CF2)g•CF3.alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R9 and R10

are, independenHy of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;

a, band c

are, independently of one another, zero or 1;

is zero, 1 or 2;

e    iszeroor1;

is zero, 1, 2, 3 or4;

g    is zero or 1;

is -(CH2)h•phenyl or -0-phenyl,

in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting ofF, Cl, Br, I,

-Ot(CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl
 
having 1, 2, 3 or 4 carbon atoms and -S02CH3;

is zero or 1;

is zero, 1, 2 or 3;

is zero, 1, 2, 3 or 4;

is -(CH2laa•heteroaryl,

which is unsubst~uted or subst~uted by 1, 2 or 3 radicals selected from the group consisting ofF, Cl, Br,l, -Obb•(CH2lcc-CF3, alkoxy having 1, 2. 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3;

bb    is zero or 1;

cc    is zero, 1, 2 or 3;


aa    is zero, 1, 2, 3 or 4;

R4    is hydrogen, F, Cl, Br, I, -CN, -S02CH3, alkoxy having 1, 2, 3 or 4

carbon atoms, NR11R12, -Odd-(CH2)e0 -(CF2ltt-CF3; -(SOgg)hh-

(CH2)]-{CF2)kk-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R11 and R12

are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
dd, ee and ff

are, independently of one another, zero or 1;

gg    is zero, 1 or 2; hh is zero or 1;

iszero,1,2,3or4; kk is zero or 1;

or

R4    is -(CH2)u-phenyl or -0-phenyl,

in which the phenyl radicals are unsubstituted or substituted by 1, 2
 

20    or 3 radicals selected from the group consisting of F, Cl, Br, I, -Omm-(CH2)n0 -CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl

having 1, 2, 3 or 4 carbon atoms and -S02CH3;

mm    is zero or 1 ;

nn    is zero, 1, 2 or 3;

25    is zero, 1, 2, 3 or4;
or   
R4    is -(CH2)o0 -heteroaryl,
    which is unsubstituted or substituted by 1, 2 or 3 radicals selected
    from the group consisting ofF, Cl, Br, I, -Opp-(CH2)rrCF3, alkoxy

30    having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3;
pp    iszeroor1;

rr iszero,1,2or3;

oo    is zero, 1, 2, 3or4;

and the pharmaceutically acceptable salts thereof.


hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,

2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op•(CHz)n-(CFz)crCF3or -(SOm)q-(CHz)r(CFz)s-CF3;
R5 and R6

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CHz-CF3;
 
    m    zero, 1 or2
15    n, o, p, q, rands
        independently of one another zero or 1;
R2    hydrogen or F;   
R3    Cl, Br, I, -CN, -SOzCH3, alkoxy having 1, 2, 3 or 4 carbon atoms,

NR9R10, -00 -(CHz)b•(CFz)c-CFJ, -(SOd)e-(CHz)f-(CFz)g-CFJ, alkyl

20    having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R9 and RIO

independently of one another hydrogen, alkyl having 1,
25    2, 3 or 4 carbon atoms or -CHz-CF3;

a, band c

independently of one another zero or 1;

d    zero, 1 or 2;

e    zeroor1;

30    zero, 1, 2, 3 or4; zero or 1;

R3    -(CH2)h-phenyl or -0-phenyl,

in which the phenyl radicals are unsubstituted or substituted by 1, 2

or 3 radicals selected from the group consisting ofF, Cl, Br, I,

-Oj-(CH2)k-CF3, alkoxy having 1, 2, 3 or4 carbon atoms, alkyl

having 1, 2. 3 or 4 carbon atoms and -S02CH3;

zeroor1;

zero, 1, 2 or 3;

zero,1, 2, 3 or4;

or

10    R3    -(CH2laa-heteroaryl,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected

from the group consisting ofF, Cl, Br, I, -Obb-(CH2lcc-CF3. alkoxy

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

atoms and -S02CH3;

IS    bb    zero or 1;

cc zero,1,2or3;

aa    zero,1, 2, 3 or4;

R4    hydrogen or F;

and the pharmaceutically acceptable salts thereof.

20

Particular preference is given to compounds of the formula I, in which the

meanings are:

R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms. alkoxy having 1, 2. 3 or4 carbon atoms, F, Cl, Br,l, -CN, NR5R6, -O-CH2-CF3 or -(SOm)q-(CH2)rCF3;

R5and R6

independently of one another hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or-CH2-CF3;
m zero, 1 or 2 q and r

independently of one another zero or 1;
R2    hydrogen or F;

R3    Cl, Br, I, -CN, -S02CH3, alkoxy having 1, 2, 3 or 4 carbon atoms,

NR9R10, -O-CH2-CF3, -{S0d)e-CF3. alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine
atoms;

R9 and RIO

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;

10        zero, 1 or2;
    e    zeroor1;
or       
R3    phenyl,   
    which is unsubstituted or substituted by 1, 2 or 3 radicals selected

15    from the group consisting ofF, Cl, Br,l, -Oj-{CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon

atoms and -S02CH3;

zero or 1;

zero,1,2or3;

20    or

R3 heteroaryl,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected

from the group consisting ofF, Cl, Br, I, -Obb-{CH2lcc-CF3, alkoxy having 1, 2, 3 or4 carbon atoms, alkyl having 1, 2, 3 or4 carbon

25    atoms and -S02CH3;

bb    zero or 1;

cc    zero, 1, 2 or 3;

R4    hydrogen or F;

and the phanmaceutically acceptable salts thereof.

30

Very particular preference is given to compounds of the formula I in which

the meanings are:
 



8

R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon a1oms, methoxy, ethoxy, F, Cl, NR5R6, -O-CHz-CF3 or -(SOm)q-(CHz)rCF3;
R5and R6

independently of one another hydrogen, alkyl having 1,

2, 3 or 4 carbon atoms or -CHz-CF3;

m    zero, 1 or 2

q and r

independently of one another zero or 1;

R2    hydrogen or F;

10    R3    Cl, -CN, -SOzCH3, methoxy, ethoxy, NR9R10, -O-CHz-CF3,

-(S0d)e-CF3. alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R9 and R10

15    independently of one another hydrogen, methyl, ethyl or -CHz-CF3;
 


or 20 R3
 

zero, 1 or 2;

e    zeroor1;

phenyl,

which is unsubsmuted or subsmuted by 1 or 2 radicals selected from the group consisting ofF, Cl, -Oj-(CHz)k-CF3. methoxy, ethoxy, alkyl having 1, 2, 3 or4 carbon atoms and -SOzCH3;
j and k
 
25    independently of one another zero or 1;
or   
R3    heteroaryl,
    which is unsubstituted or substituted by 1 or 2 radicals selected from
    the group consisting ofF, Cl, -Obb-(CHz)cc-CF3. methoxy, ethoxy,

30    alkyl having 1, 2, 3 or 4 carbon atoms and -SOzCH3;

bb    and cc

independently of one another zero or 1;

R4    hydrogen or F;

and the pharmaceutically acceptable salts thereof.

In  one  embodiment,  preference  is  given  in  this  connection  to  the

compounds of the formula I in which R1 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, where R5 and R6 are, independently of one

another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3, or

10    -O-CHz-CF3 or -(SOm)q•(CH2)rCF3, where m is zero, 1 or 2, and q and r are, independently of one another, are zero or 1; particular preference is given to compounds in which R1 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, where R5 and R6,

are independently of one another, hydrogen, alkyl having  1, 2,  3,  or 4

15    carbon atoms or -CH2-CF3, -O-CH2-CF3 or -(SOm)q-(CH2)rCF3, where m is zero, 1 or 2, and q and r are, independently of one another, zero or 1; very particular preference is given to compounds in which R1 is described by hydrogen, methyl, ethyl, CF3-CHz-O-, F, Cl or CF3. In a further

embodiment, preference is given to compounds in which R1  is described

20    by hydrogen, methyl or ethyl, in particular methyl or ethyl.

In a further embodiment, preference is given to compounds of the formula I in which R2 is described by hydrogen or F; particular preference is given to compounds in which R2 is described by hydrogen.

25

In a further embodiment, preference is given to compounds of the formula I in which R3 is described by Cl, -CN, -S02CH3, methoxy, ethoxy, NR9R10, where R9 and R1 0 are, independently of one another, hydrogen, methyl, ethyl or -CH2-CF3, or -O-CHz-CF3, -(S0d)e-CF3, where d is zero, 1 or 2,

30    and e is zero or 1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms, phenyl which is unsubstiluted or

substituted by 1,2 or 3 radicals selected from the group consisting ofF, Cl, Br, I, -Ot(CH2)k-CF3, where j is zero or 1 and k is zero, 1, 2 or 3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3, or heteroaryl which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -ObiT (CH2)cc-CF3, where bb is zero or 1 and cc is zero, 1, 2 or 3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3; particular preference is given to compounds in which R3 is described by Cl, -CN, -S02CH3, methoxy, ethoxy, NR9R10, where R9 and

10    R10 are, independently of one another, hydrogen, methyl, ethyl or -CH2-CF3, or -O-CH2-CF3, -(SOd)e-CFJ, where d is zero, 1 or 2, and e is zero or 1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms, phenyl which is unsubstituted or substituted by

15    1-2 radicals selected from the group consisting ofF, Cl, -Oj-(CH2)k-CF3,

where j and k are, independently of one another, zero or 1, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3 , or heteroaryl which is unsubstituted or substituted by 1-2 radicals selected from the group consisting ofF, Cl, -Obb-(CH2)cc-CF3, where bb and cc are,

20    independently of one another, zero or 1, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3; very particular preference is given to compounds in which R3 is described by Cl, -CN or -S02CH3.

In a further embodiment, preference is given to compounds of the

25    formulae I in which R4 is described by hydrogen and F, with particular preference for compounds in which R4.is described by hydrogen.

In a further embodiment, preference is given to compounds of the formula I

in which p, I, a and dd are, independently of one another, 1.

30

lithe subsmuents R1 to R4 contain one or more centers of asymmetry,

these may independently of one another have both the S and the R

configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof.

The present invention encompasses all tautomeric forms of the compounds

of the formula I.

Alkyl radicals may be straight-chain or branched. This also applies if they

10    carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals are
methyl, ethyl, n-propyl, isopropyl(= 1-methylethyl), n-butyl, isobutyl(= 2-methylpropyl), sec-butyl(= 1-methylpropyl), tert-butyl (= 1,1-dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicals

15    are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5, hydrogen atoms in alkyl radicals may be replaced by fluorine atoms. Examples of such fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl. Substituted alkyl radicals may be substituted in any positions. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl,

20    cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for example 1, 2, 3 or 4, hydrogen atoms in cycloalkyl radicals may be replaced by fluorine atoms. Substituted cycloalkyl radicals may be substituted in any positions.

25    Phenyl radicals may be unsubstituted or be substituted one or more times, for example once, twice or three times, by identical or different radicals. If a phenyl radical is substituted, tt preferably has one or two identical or

different substituents. This likewise applies to substituted phenyl radicals in

groups such as, for example, phenylalkyl or phenyloxy. The substituent in

30    monosubstituted phenyl radicals may be in position 2, position 3 or posttion 4. Disubstituted phenyl may be substituted in the 2,3 posttion, 2,4 position, 2,5 position, 2,6 position, 3,4 position or 3,5 position. The substituents in trisubstttuted phenyl radicals may be in the 2,3,4 position, 2,3,5 position, 2,4,5 posttion, 2,4,6 posttion, 2,3,6 position or 3,4,5 position.
Heteroaryl radicals are aromatic ring compounds in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3

nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination

of various heteroatoms. The heteroaryl radicals may be attached by all positions, for example by the 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position. Heteroaryl radicals may be

unsubstituted or be substituted one or more times, for example once, twice

or three times, by identical or different radicals. This applies likewise to

10    heteroaryl radicals such as, for example, in the radical heteroarylalkyl. Examples of heteroaryl are !uranyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.

15

Heteroaryl radicals are, in particular, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,4- or 5-pyrazolyl, 1,2,3-triazol-1-,-4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-<>xazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-<>xadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,

20    1,3,4-<>xadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl,

pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-,

3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-,

25    7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-,7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Also encompassed are the corresponding N-oxides of these compounds, i.e. for example 1-<>xy-2-, 3- or 4-pyridyl.

30    Particularly preferred heteroaromatic radicals are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2- or 3-pyrazinyl, 2-, 4-, 5- or 6-pyrimidinyl and 3- or 4-pyridazinyl.


The invention further relates to a process for preparing the compounds of

the formula I which comprises reacting a compound of the fonmula II

,JS¢c;FR3
,~p  ""  "'
F    I ~  L
A4

A1    0

in which R1 to R4 have the stated meaning, and Lis a leaving group which

can undergo nucleophilic substitution, with guanidine.

The activated acid derivatives of the formula II in which L is an alkoxy, preferably a methoxy, group, a phenoxy group, phenylthio, methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are

10    advantageously obtained in a manner known to those skilled in the art from the underlying carbonyl chlorides (fonmula II; L = Cl), which in turn can themselves be prepared in a known manner from the underlying carboxylic acids (fonmula II; L = OH), for example using thionyl chloride.

Besides the carbonyl chlorides of the fonmula II (L = Cl) it is also possible to

15    prepare other activated acid derivatives of the formula II in a known manner directly from the underlying benzoic acids (fonmula II; L = OH), such as the methyl esters of the fonmula II with L = OCH3 by treatment with gaseous

HCI in methanol, the imidazolides of the fonmula II by treatment with

carbonyldiimidazole, the mixed anhydrides of the formula II by treatment

20    wtth CI-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with 0-[(cyano(ethoxycarbonyl}-methylene)amino]-1, 1 ,3,3-tetramethyluronium tetrafluoroborate ("TOTU") are also possible. A number of suitable methods for preparing activated

25    carboxylic acid derivatives of the fonmula II are indicated in J. March, Advanced Organic Chemistry, third edition (John Wiley & Sons, 1985, page 350), indicating source literature.
Reaction of an activated carboxylic acid derivative of the formula II with

guanidine preferably takes place in a known manner in a protic or aprotic

polar but inert organic solvent. Those which have proved suitable for the

reaction of the methyl benzoates {formula II; L = OCH3) wnh guanidine are

methanol, isopropanol or THF at temperatures from zooc to the boiling point of these solvents. Most reactions of compounds of the formula II with

salt-free guanidine are, for example, carried out in aprotic inert solvents

such as THF, dimethoxyethane, dioxane. However, it is also possible to

use water in the presence of a base such as, for example, NaOH as

10    solvent in the reaction of compounds of the formula II with guanidine.

If L is Cl, it is advantageous to add an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid.

15    The compounds of the formula II can be prepared as follows, by

a) reducing a 4-nitrophenylsulfur pentafluoride derivative of the formula Ill

to the amine of the formula IV,

b)    halogenating the compound of the formula IV in the ortho position to the amino group with a halogenating agent to give the compound of the formula V,
c)    replacing the halogen substituent in the compound of the formula V w~h

a suitable nucleophile or an organoelement compound, for example an

alkylboron compound, where appropriate with catalysis, by a substituent R1

10    and

d) replacing the amino function in the compound of the formula VI by a

halogen substituent,
e) replacing the halogen substituent in the compound of the formula VII by

a nitrile function,

f)    hydrolyzing the n~rile function of the compound of the formula VIII to the carboxylic acid,

g)    nW.ting the compound of the formula IX in the ortho position to the pentafluorosulfanyl group to give the compound of the formula X,
h)    reducing the nitro compound of the formula X to the aniline,

i) replacing the amino function in the compound of the formula XI by R3

using a suitable nucleophile

10    and

k) converting the compound of the formula XII into the compound of the formula II, where in the compounds of the formulae II, Ill, IV, V, VI, VII, VIII,
IX, X, XI and XII

R1 to R4 are defined as in formula I

15    L is defined as in formula II and

X andY are, independently of one another, F, Cl, Br or I.

The procedure for preparing the compounds of the formula II is initially in step a to convert the compounds of the formula Ill by methods known in

20    principle for the reduction of aromatic nitro compounds to aromatic amines into compounds of the formula IV. Such methods are described, for example, in: R.C. Larock, Comprehensive Organic Transfonnations: A

Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999,821-828 and the literature cited therein.

25

Subsequently (step b), the compounds of the formula IV are dissolved in an organic solvent A and reacted with a halogenating agent, for example a

brominating agent. The reaction temperature in this case is generally from -3o•cto +15o•c. preferably o•cto 40•c. The reaction time is generally

30    from 10 min to 20 h, depending on the compos~ion of the mixture and the chosen temperature range. The resulting reaction mixture can be worked up by subsequent filtration through a layer of silica gel, washing w~h organic solvent A and, after removal of the solvent in vacuo, purifying the product by conventional purification methods such as recrystallization,
35    distillation or chromatography.

From 0.1 to 10 mol of the compound of the formula IV for example are
dissolved in 1000 ml of organic solvent A. For example, from 0.8 to 1.2 equivalents of the halogenating agent are used for 1 mol of the compound of the formula IV to be halogenated.

The tenm "halogenating agenr'means for example elemental halogens,

halogen-amine complexes, cyclic and acyclic N-halogenated carboxamides

and -imides, and ureas, as described, for example, in R.C. Larock, Comprehensive Organic Transfonmations: A Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999,619-628, and the literature cited therein or M.B. Smith and J. March, March'sAdvanced

10    Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001. 704-707, and the literature cited therein, such as, for example,
N-bromosuccinimide, N-chlorosuccinimide, HBr in H2S04 or 1,3-dibromo-

5,5-dimethylimidazolidine-2,4-<lione. The tenm "brominating agent" means,

tor example, elemental bromine, bromine-amine complexes, cyclic and

15    acyclic N-brominated carboxamides and -imides, and ureas, as described, tor example, in R.C. Larock, Comprehensive Organic Transfonnations: A
Guide to Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 622-624, and the literature cited therein or M.B. Smith
and J. March, March'sAdvanced Organic Chemistry: Reactions,

20    Mechanisms, and Structure, Wiley, New York, 2001,704-707, and the literature cited therein, for example N-bromosuccinimide, HBr in H2S04 or 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, the latter being able to
transfer 2 bromine atoms per molecule.

The tenn "organic solvent A" preferably means aprotic solvents such as, for

25    example, dichloromethane, chloroform, tetrachloromethane, pentane, hexane, heptane, octane, benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, trichloroethylene or acetonitrile.

Any HX produced in the reaction can be trapped by organic or inorganic

bases.

30

In step c, the compounds of the fonmula V are subsequently dissolved in an organic solvent B and reacted with a nucleophile R f or an element compound comprising the substituent R1 to give compounds of the formula VI. It is possible in this case to add a base A and to add a catalyzing metal

35    saltA.

The reaction temperature in this case is generally between -20"C and

+150"C, preferably between 30"C and 100"C. The reaction time is generally from 0.5 h to 20 h, depending on the composition of the mixture and the chosen temperature range. The resulting reaction mixture can be


worked up by subsequent filtration through a layer of silica gel, washing

with an organic solvent 8 and, after removal of the solvent in vacuo,

purifying the product by conventional purification processes such as recrystallization, chromatography, for example on silica gel, distillation or steam distillation.
From 0.1 to 10 mol of the compound of the formula V for example are dissolved in 1000 ml of organic solvent B. For example, from 0.8 to 3

equivalents of the nucleophile R1- or of the element compound comprising

the substituent R1 are used for 1 mol of the starting compound of the

10    formula V.

The term "nucleophile R1-" means compounds which result on deprotonation of a compound R1-H with strong bases such as, for example, alkyl- or aryllithium compounds, organomagnesium compounds,
alcoholates or !Hhium diisopropylamide.

15    "Organoelement compounds comprising the substituent R1" mean for example organolithium compounds R1-Li, organomagnesium compounds
R1-Mg-Hal, wHh Hal= Cl, Br, I, organoboron compounds such as R1-B(OH)z. R1-boronic esters such as, for example,
R1-Bb*

or organozinc compounds R1-Zn-Z, with Z = Cl, 8r, I.

The term "base A" means bases like those used as auxiliary bases in

25    cross-coupling reactions and mentioned for example in A. Suzuki eta!., Chern. Rev. 1995, 95, 2457-2483 or M. Lamaire et al., Chern. Rev. 2002, 102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54, 263-303 and the literature cHed therein in each case, for example NazC03, Cs2C03, KOH,

NaOH, K3P04, N(ethyl)3.

30    The term "organic solvent 8" means protic or aprotic solvents such as diethyl ether, dimethoxyethane, THF, alcohols, water or mixtures thereof. In one embodiment, mixtures with water are preferred.
 
The term "catalyzing metal salt A" means inter alia Pd and Ni catalysts like

those used for Suzuki and Negishi reactions and described for example in

A. Suzuki et al., Chern. Rev. 1995, 95,2457-2483 or M. Lamaire et al., Chern. Rev. 2002, 102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54,263 or G.C. Fu et al., J. Am. Chern. Soc. 2001, 123, 10099 or G. C. Fu et al., J. Am. Chern. Soc. 2002, 124, 13662 and the l~erature cited therein in each case, including the added ligands such as Pd(OAc)z, PdCiz(dppf) or Pdz(dba)3.

10    In step d, the compounds of the formula VI are subsequenUy converted into

the compounds of the formula VII by a diazotization-halogenation process with a diazotizing-halogenating agent, for example with a diazotizing-brominating agent, as described for other aromatic amines to replace the amine function by a halogen function for example in M.B. Smith and

15    J. March, March'sAdvanced Organic Chemistry: Reactions. Mechanisms, and Structure, Wiley, New York, 2001, 935-936 or R.C. Larock,
Comprehensive Organic Transfonnations: A Guide to Functional Group

Preparations, VCH Publishers, New York, Weinheim, 1999, 678-679 and

the literature cited therein, for example by the Sandmeyer or Gatterrnann

20    reaction. The process of M. Doyle et al., J. Org. Chern. 1977, 42, 2426 or of S. Oae et al., Bull. Chern. Soc. Jpn. 1980, 53, 1065 is preferred.

In step e, the compounds of the formula VII are reacted in a solvent C with

a cyanidating agent, for example with addition of a catalyzing metal salt B.

25    The reaction temperature is generally from 20"C to 200"C, preferably 80"C to 150"C. The reaction time is generally from 1 h to 20 h, depending on the composition of the mixture and the chosen temperature range. The

resulting reaction mixtures can be filtered with suction through a layer of

silica gel or kieselguhr and the filtrate can be worked up by aqueous

30    extraction. After evaporation of the solvent in vacuo, the compound of the formula VIII is purified by conventional purification processes such as recrystallization, chromatography on silica gel, distillation or steam

distillation.

From 0.1 to 10 mol of the compound of the formula VII for example are

35    dissolved in 1000 ml of organic solvent C. For example, from 1 to 10 equivalents of the cyanidating agent are used for 1 mol of the compounds having the formula VII to be reacted.

The term "cyanidating agent" means, for example, alkali metal cyanides or Zn(CN)z either alone or mixed w~h metallic zinc, preferably in the form of

zinc dust.

The term "organic solvent C" preferably means aprotic polar solvents such

as, for example, DMF, dimethylacetamide, NMP, DMSO.

The term "catalyzing metal salt B" means inter alia Pd and Ni catalysts like those employed in Suzuki reactions and described for example in A. Suzuki et al., Chern. Rev. 1995, 95, 2457-2483 or M. Lamaire et al., Chern. Rev. 2002, 102, 1359-1469 or S.P. Stanforth, Tetrahedron 1998, 54,263 and the literature c~ed therein, for example PdCI2(dppf), Pd(OAc}2, Pd2(dba)3.

10    The resulting compounds of the formula VIII are subsequently hydrolyzed in step f to.the carboxylic acids of the formula IX, for example in the presence of a base. This can take place by processes known to the skilled worker for hydrolyzing aromatic nitriles, as described, for example, in
R.C. Larock, Comprehensive Organic Transformations: A Guide to

15    Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1986-1987 or M.B. Sm~h and J. March, March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 1179-1180 and the l~erature cited therein.

20    In step g, compounds of the formula IX are nitrated with a nitrating agent as described, for example, in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Stickstoff-Verbindungen IV, part 1, Georg Thieme Verlag Stuttgart 1992, pages 262-341.

25    In step h, the nitro compounds of the formula X are converted into

compounds of the formula XI by methods known in principle for reducing aromatic nitro compounds to aromatic amines. Such methods are
desclibed for example in: R.C. Larock, Comprehensive Organic Transformations: a Guide to Functional Group Preparations, VCH
30    Publishers, New York, Weinheim, 1999, 821-828 and the literature cited therein.

In step i, the anilines of the formula XI are converted by the diazotization-

replacement route into the compounds of the formula XII with replacement

35    of the amine group by R3. Such methods are known to the skilled worker and are desclibed for example in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-Stickstoff-Verbindungen I, part 2, Georg Thieme Verlag Stuttgart 1990, pages 1087-1136 and the references cited therein.

For example, an aniline of the formula XI can be converted by the diazotization-replacement route into a sulfochloride of the formula XII (R3 = S02CI) as described, for example, in Houben-Weyl, Melhoden der organischen Chemie 4th edition, Organo-Schwefei-Verbindungen, part 2, Georg Thieme Verlag Stuttgart 1985, pages 1069-1070.

In step k, the compounds of the formula XII are derivatized to the compounds of the formula II by methods known to the skilled worker and as described above.

10    11 is possible in this step for example for the sulfochlorides of the formula XII (R3 = S02CI) to be converted initially into the corresponding sulfinic acids (as described for example in Houben-Weyl, Method en der

organischen Chemie 4th edition, Organo-Schwefei-Verbindungen, part 1,

Georg Thieme Verlag Stuttgart 1985, pages 620-621 and Houben-Weyl,

15    Methoden der organischen Chemie, Schwefel-, Selen-, Tellur-Verbindungen, Georg Thieme Verlag Stuttgart 1955, pages 304-309) and subsequently alkylated to give the methyl sulfone as described for example in Houben-Weyl, Methoden der organischen Chemie 4th edition, Organo-

Schwefei-Verbindungen, part 2, Georg Thieme Verlag Stuttgart 1985,

20    pages 1145-1149. Simultaneous esterification of the carboxylic acid to the methyl ester takes place.

Compounds of the formula I in which R1 is hydrogen are prepared by

carrying out the synthesis without steps b and c.

25    Compounds of the formula I in which R3 is NR9R1 0 are prepared by carrying out the synthesis without step i.
Functional groups in the starting compounds may also be present in protected form or in the form of precursors, and then be converted into the
desired groups in the compounds of the formula II prepared by the process

30    described above. Corresponding protective group techniques are known to the skilled worker.
It is likewise possible for appropriate functional groups to be derivatized by methods known to the skilled worker. For example, compounds in which R3 is NH2 can be converted by reaction wijh appropriate alkyl halides or

35    2,2,2-trifluoroethyl halides, for example methyl iodide, ethyl iodide or 2,2,2-trifiuoroethyl iodide, into compounds in which R3 is NR9R1 0, where R9 and R10 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3 and are not both simultaneously hydrogen.

Pentafluorosulfanylbenzoylguanidines of the formula I are generally weak bases and are able to bind acids to form salts. Suitable acid addttion salts are salts of all pharmaceutically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

The compounds of the formula I are substituted acylguanidines and inhibtt the cellular sodium-proton antiporter (Na+/H+ exchanger, NHE), in
10    particular the subtype NHE-1.

Because of the NHE-inhibitory properties, the compounds of the formula 1 and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation of or by an

15    activated NHE, and of diseases caused secondarily by the NHE-related damage.

The compcunds of the formula I may also be used for treating and preventing diseases by the NHE being only partially inhibtted, tor example by use of a low dosage.
20

Since NHE inhibttors predominantly act via their effect on cellular pH regulation, they can generally be combined beneficially with other compounds which regulate the intracellular pH, wtth suitable combination partners being inhibitors of the carbonic anhydrase enzyme group,

25    inhibttors of systems transpcrting bicarbonate ions, such as of the sodium bicarbonate cotransporter (NBC) or of the sodium.<Jependent chloride-bicarbonate exchanger (NCBE). and NHE inhibitors with inhibitory effect on other NHE subtypes, because it is possible through them to enhance or modulate the pharmacologically relevant pH-regulating effects of the NHE

30    inhibttors described herein.

The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.
Thus, the NHE inhibitors of the invention are suitable for the treatment of

diseases caused by ischemia and by reperfusion.

The compounds described herein are suitable because of their

pharmacological properties as antiarrhythmic medicaments. Owing to their cardioprotective component, the NHE inhib~ors are

outstandingly suitable for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, in which cases they also preventively inhibit or greatly reduce the pathophysiological processes

10    associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof used according to the invention can, because of inhib~ion of the

!5    cellular Na+JH+ exchange mechanism, be used as medicaments for the

treatment of all acute or chronic ischemia-induced damage or diseases

induced primarily or secondarily thereby.

This also relates to their use as medicaments for surgical interventions.

The compounds of the invention are likewise valuable medicaments with a

protective effect when performing angioplastic surgical interventions, for

example on the heart as well as on peripheral organs and vessels.

30    The compounds of the invention may also be used when performing bypass operations, for example bypass operations on coronary vessels and in Coronary Artery Bypass Graft (CABG).

Depending on their activity w~h regard to ischemia-induced damage, the

compounds of the invention I may similarly be used in resuscitation after a

cardiac arest.

The compounds of the invention are of interest for medicaments for l~e­ threatening arrhythmias. Ventricular fibrillation is terminated and the physiological sinus rhythm of the heart is restored.

Since NHE1 inhib~ors of human tissue and organs, especially the heart, protect effectively not only against damage caused by ischemia and
10    reperfusion but also against the cytotoxic effect of medicaments like those used in particular in cancer therapy and the therapy of autoimmune diseases, combined administration with compounds of the formula I and/or the pharmaceutically acceptable salts thereof is suitable for inhib~ing the cytotoxic, especially cardiotoxic, side effects of said compounds. The

15    reduction in the cytotoxic effects, especially the cardiotoxicity, resulting from comedication with NHE1 inhibitors makes~ additionally possible to increase the dose of the cytotoxic therapeutic agents and/or to prolong the medication with such medicaments. The therapeutic benefits of such a cytotoxic therapy can be considerably increased by combination with NHE
20    inhib~ors.

In addHion, the NHE1 inhibitors of the invention of the formula I and/or the

pharmaceutically acceptable salts thereof can be used when there is heart-

damaging overproduction of thyroid hormones, thyrotoxicosis, or on

25    external supply of thyroid hormones. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable for improving therapy with cardiotoxic medicaments.

In accordance with their protective effect against ischemia-induced

30    damage, the compounds of the invention are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the central nervous system, being suitable for example for the treatment of stroke or of cerebral edema.

The compounds of the formula I and/or the pharmaceutically acceptable

salts thereof are also suitable for the therapy and prophylaxis of diseases

and disorders induced by overexcitability of the central nervous system, in

particular for the treatment of epileptic disorders, centrally induced clonic and tonic spasms, states of psychological depression, anxiety disorders and psychoses. In these cases it is possible to use the NHE inhibitors

described herein alone or in combination with other substances with

antiepi\eptic activity or antipsychotic active ingredients, or carbonic

anhydrase inhibttors, for example with acetazolamide, and wtth other

10    inhibitors of NHE or of the sodium-<lependent chloride-bicarbonate exchanger (NCBE}.

The compounds used according to the invention of the formula I and/or the

pharmaceutically acceptable salts thereof are additionally likewise suitable

15    for the treatment of types of shock such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of the formula I and/or the pharmaceutically acceptable

salts thereof can likewise be used for the prevention and treatment of

20    thrombotic disorders because they, as NHE inhibitors, are able to inhibtt platelet aggregation themselves. They are additionally able to inhibit or prevent the excessive release, occurring after ischemia and reperfusion, of mediators of inflammation and coagulation, especially of von Willebrand factor and of thrombogenic selectin proteins. It is thus possible to reduce

25    and eliminate the pathogenic effect of significant thrombogenic factors. The NHE inhibitors of the present invention can therefore be combined with other anticoagulant and/or thrombolytic active ingredients such as, for example, recombinant or natural tissue plasminogen activator,

streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor

30    Xa antagonists, medicinal substances with fiblinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibttors, factor VIla antagonists, clopidogrel, ticlopidine etc. Combined use of the present NHE inhibitors with NCBE inhibttors and/or wtth inhibitors of carbonic anhydrase such as, tor example, with acetazolamide, is particularly beneficial.
 

NHE1 inhibitors are additionally distinguished by a strong inhibitory effect on the prol~eration of cells, for example fibroblast proliferation and the proliferation of smooth vascular muscle cells. The compounds of the formula I and/or the pharmaceutically acceptable sails thereof are therefore suitable as valuable therapeutic agents for diseases in which proliferation
represents a primary or secondary cause, and can therefore be used as

antiatherosclerotics, agents for chronic renal failure, cancers.

10    It was possible to show that cell migration is inhibited by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for dieases in which cell migration represents a primary or secondary cause, such as, for example, cancers with a pronounced tendency to metastasis.
!5

NHE1 inhibitors are further distinguished by a retardation or prevention of fibrotic disorders. Compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable as agents for the treatment of
cardiac fibroses, and of pulmonary fibrosis, hepatic fibrosis, renal fibrosis

20    and other fibrotic disorders. They can thus be used for the treatment of organ hypertrophies and hyperplasias, for example of the heart and the
prostate. They are therefore suitable for the prevention and treatment of heart failure (congestive heart failure = CHF) and for the treatment and prevention of prostate hyperplasia or prostate hypertrophy.

Since there is significant elevation in NHE in essential hypertensives, the

compounds of the formula I and/or the pharmaceutically acceptable salts

thereof are suitable for the prevention and treatment of high blood pressure

and for the treatment of cardiovascular disorders. In these cases they can

30    be used alone or with a suitable combination and formulation partner for the treatment of high blood pressure and for the treatment of cardiovascular disorders. Thus, for example, one or more diuretics with a thiazide-like action, loop diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide,

furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene,

spironolactone or eplerone, can be combined. The NHE inhibitors of the

present invention can further be used in combination with calcium channel

blockers such as verapamil, diltiazem, amlodipine or nifedipine, and with

ACE inhibttors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further beneficial combination partners are also beta-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor and tts receptor subtypes such as losartan, irbesartan, valsartan,
omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors,

10    adenosine receptor agonists, inhibitors and activators of potassium channels such as glibenclamide, glimepiride, diazoxide, cromakalim, minoxidil and derivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of Kv1.5 etc.

!5    It has emerged that NHE1 inhibitors have a significant antiinflammatory

effect and can thus be used as antiinflammatory drugs. Inhibition of the

release of mediators of inflammation is noteworthy in this connection. The compounds can thus be used alone or in combination with an antiinflammatory drug for the prevention or treatment of chronic and acute

20    inflammatory disorders. Combination partners advantageously used are steroidal and non-steroidal antiinflammatory drugs. The compounds of the invention can additionally be employed for the prevention or treatment of disorders caused by protozoa, such as malaria and coccidiosis in poultry.

25    It has additionally been found that NHE1 inhibitors show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood fat levels which are too high, called hypertipoproteinemias, represent an essential risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum

30    lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. Besides the reduction in total serum cholesterol, tt is particularly important to reduce the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low density lipoproteins (LDL) and of the very low density lipoproteins (VLDL),

because these lipid fractions represent an atherogenic risk factor. By

contrast, a protective function against coronary heart disease is ascribed to

the high density lipoproteins. Accordingly, hypolipidemics should be able to reduce not only total cholesterol but, in particular, the VLDL and LDL serum cholesterol fractions. It has now been found that NHE1 inhibitors show valuable therapeutically utilizable properties in relation to influencing the serum lipid levels. Thus, they significantly reduce the elevated serum concentrations of LDL and VLDL as are to be observed, for example, due
to increased dietary intake of a cholesterol- and lipid-rich diet or in cases of

10    pathological metabolic alterations, for example genetically related hyper1ipidemias. They can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor.
Included herein are not only the primary hyper1ipidemias but also certain

secondary hyper1ipidemias occurring, for example, in association with

15    diabetes. In addition, the NHE1 inhibitors lead to a marked reduction in the infarctions induced by metabolic abnormalities and, in particular, to a significant reduction in the induced infarct size and the severity thereof. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore advantageously used for producing a

20    medicament for the treatment of hypercholesterolemia; for producing a medicament for the prevention of atherogenesis; for producing a

medicament for the prevention and treatment of atherosclerosis, for

producing a medicament for the prevention and treatment of diseases

induced by elevated cholesterol levels, for producing a medicament for the

25    prevention and treatment of diseases induced by endothelial dysfunction, for producing a medicament for the prevention and treatment of atherosclerosis-induced hypertension, for producing a medicament for the prevention and treatment of atherosclerosis-induced thromboses, for producing a medicament for the prevention and treatment of

30    hyperchole~terolemia-induced and endothelial dysfunction-induced

ischemic damage and post-ischemic reperfusion damage, for producing a

medicament for the prevention and treatment of hypercholesterolemia-

induced and endothelial dysfunction-induced cardiac hypertrophies and

cardiomyopathies and of congestive heart failure (CHF), for producing a
medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced coronary vasospasms and myocardial infarctions, for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably

with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I and/or the phanmaceutically acceptable salts thereof with an active ingredient lowering the blood fat levels, preferably with an HMG-CoA reductase inhibitor (for example lovastatin or pravastatin), the latter

1o bringing about a hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE inhibitor of the fonmula I and/or the phanmaceutically acceptable salts thereof, proves to be a favorable combination with

enhanced effect and reduced use of active ingredients.

Thus, compounds of the fonmula I and/or the phanmaceutically acceptable

15    salts thereof lead to effective protection against endothelial damage of various origins. This protection of the vessels against the syndrome of endothelial dysfunction means that the compounds of the formula I and/or

the phanmaceutically acceptable salts thereof are valuable medicaments for

the prevention and treatment of coronary vasospasms, peripheral vascular

20    diseases, in particular intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.

It has add~ionally been found that NHE1 inhibitors are suitable in the

25    treatment of non-insulin-<lependent diabetes (NIDDM), with the insulin resistance being restrained. It may in this connection be beneficial, to enhance the antidiabetic activity and quality of the effect of the compounds of the invention, to combine them with a biguanide such as metformin, with
an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide

30    etc., with a glucosidase inhibitor, with a PPAR agonist such as rosigl~azone, pioglitazone etc., with an insulin product of different administration form, with a DB4 inhibitor, with an insulin sensitizer or with meglitinide.

Besides the acute antidiabetic effects, the compounds of the formula 1 and/or the pharmaceutically acceptable salts thereof counteract the development of late complications of diabetes and can therefore be used as medicaments for the prevention and treatment of late damage from diabetes, such as diabetic nephropathy, diabetic retinopathy, diabetic

cardiomyopathy and other disorders occurring as a consequence of

diabetes. They can in this connection be advantageously combined with

the antidiabetic medicaments just described under NIDDM treatment. The

combination with a beneficial dosage form of insulin should be particularly

10    important in this connection.

NHEI inhibitors show, besides the protective effects against acute ischemic events and the subsequent equally acutely stressing reperfusion
events, also direct therapeutically utilizable effects against diseases and

IS disorders of the entire mammalian organism which are associated with the manifestations of the chronically progressive aging process and which occur independently of acute hypoperfusion states and under normal, non-
ischemic cond~ions. These pathological, age-related manifestations

induced over the long aging period, such as illness, invalidity and death,

20    which can now be made amenable to treatment with NHE inhibitors, are diseases and disorders which are essentially caused by age-related changes in vital organs and the function thereof and become increasingly
important in the aging organism.

Disorders connected with an age-related functional impairment or with age-

25    related manifestations of wear of organs are, for example, the inadequate response and reactivity of the blood vessels to contraction and relaxation reactions. This age-related decline in the reactivity of vessels to constricting and relaxing stimuli, which are an essential process of the cardiovascular system and thus of life and health, can be significantly eliminated or

30    reduced by NHE inhiboors. One important function and a measure of the maintenance of the reactivity of vessels is the blockade or retardation of the age-related progression in endothelial dysfunction, which can be eliminated highly significantly by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly

suitable for the treatment and prevention of the age-related progression in

endothelial dysfunction, especially of intermittent claudication.

An example of another variable characterizing the aging process is the

decline in the contractability of the heart and the decline in the adaptation of the heart to a required pumping output of the heart. This diminished
efficiency of the heart as a consequence of the aging process is in most

cases connected with a dysfunction of the heart which is caused inter alia

by deposition of connective tissue in the myocardial tissue. This deposition

10    of connective tissue is characterized by an increase in the weight of the heart, by an enlargement of the heart and by restrictive cardiac function. It was surprising that it was possible almost completely to inhibit such aging of the heart organ. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable

15    for the treatment and prevention of heart failure, of congestive heart failure

(CHF).

Not only is it possible to cure a cancer which has already occurred through

inhiMion of prol~eration, but there is also reduction and highly significant

20    retardation of the age-related incidence of cancer through NHE inhibitors. A particularly noteworthy finding is that the disorders, occurring as a result of aging, of all organs and not only certain types of cancer are suppressed or occur with a highly significant delay. The compounds of the formula I and/or

the pharmaceutically acceptable salts thereof are thus suitable for the

25    treatment and, in particular, the prevention of age-related types of cancer. With NHE inhibitors, a delay, shifted highly significanijy in time is found in
the occurrence of age-related disorders of all the organs investigated,

including the heart, vessels, liver etc., and a highly significant delay in

30    cancer of the elderly. On the contrary, there is also surprisingly a prolongation of life to an extent which has to date been achievable by no other group of medicaments or by any natural products. This unique effect of NHE inhibitors also makes it possible, besides the use of the active ingredients alone on humans and animals, to combine these NHE inhibitors

with other active principles, measures, substances and natural products

which are used in gerontology and which are based on a different

mechanism of action. Such classes of active ingredients used in

gerontological therapy are: in particular vitamins and substances with

antioxidant activity. Since there is a correlation between caloric load or food

intake and the aging process, the combination with dietary measures can

take place for example wtlh appetite suppressants. It is likewise possible to

consider a combination with hypotensive medicaments such as with ACE

inhiibitors, angiotensin receptor antagonists, diuretics, Ca+2 antagonists etc.

10    or wtth metabolism-normalizing medicaments such as cholesterol-lowering agents.
The compounds of the fonmula I and/or the phanmaceutically acceptable salts thereof are thus outstandingly sutlable for the prevention of age-related tissue changes and for prolonging life while retaining a high quality

15    oflife.

The compounds of the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which in a large number of
disorders (essential hypertension, atherosclerosis, diabetes etc.) is also

20    increased in cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or leucocytes. The compounds used according to the invention are therefore sutlable as outstanding and simple scientific tools, for example in their use as diagnostic agents for detenmining and distinguishing different types of hypertension, but also of
25    atherosclerosis, diabetes and the late complications of diabetes, prol~erative disorders etc.

Also claimed is a medicine for human, veterinary or phytoprotective use,

comprising an effective amount of a compound of the fonmula I and/or the

30    phanmaceutically acceptable salts thereof, together wtlh phanmaceutically acceptable caniers and addttives, alone or in combination with other active pharmaceutical ingredients or medicaments.

Medicaments which comprise a compound of the fonmula I and/or the phanmaceutically acceptable salts thereof can in this connection be

administered, for example, orally, parenterally, intravenously, rectally,

transdennally or by inhalation, the preferred administration being

dependent on the particular characteristics of the disorder. The compounds

of the formula I may moreover be used alone or together wijh

phannaceutical excipients, both in veterinary medicine and in human

medicine. The medicaments generally comprise active ingredients of the

formula I and/or the pharmaceutically acceptable saHs thereof in an amount

of from 0.01 mg to 1 g per dose unit.

10    The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled wor1<er on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or
15    colors.

For a form for oral administration, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suHable dosage
20    forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert caniers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate,
lactose, glucose or starch, especially corn starch. It is moreover possible

for the preparation to lake place both as dry granules and as wet granules.

25    Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.

For subcutaneous, intramuscular or intravenous administration, the active

compounds used are converted, ij desired with the substances customary

30    for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suttable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
Suitable as pharmaceutical formulation for administration in the form of

aerosols or sprays are, for example, solutions, suspensions or emulsions of

the active ingredient of the formula I and/or the pharmaceutically

acceptable salts thereof in a pharmaceu~cally acceptable solvent such as,

in particular, ethanol or water, or a mixture of such solvents. The

formulation may, if required, also contain other pharmaceutical excipients

such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such

a preparation normally contains the active ingredient in a concentration of

10    about0.1 to 10, in particularofabout0.3to3% by weight.

The dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the potency and duration of

action of the compounds used; additionally also on the nature and severity

15    of the disorder to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of the formula I and/or the

pharmaceutically aoceptable salts thereof for a patient weighing about

20    75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg, preferably 1 mg/kg, of body weight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, higher and, in particular, more frequent dosages may also be necessary,
e.g. up to 4 single doses a day. Up to 700 mg a day may be necessary, in

25    particular on i.v. administration, for example for a patient with infarction in the intensive care unit, and the compounds of the invention can be administered by infusion.

List of abbreviations:

30    ADMET absorption- distribution- metabolism- excretion -toxicology CDI diimidazol-1-ylmethanone
dba dibenzylideneacetone

DIP    diisopropyl ether

DIPEA    diisopropylethylamine
    DME    1,2-<limelhoxyelhane
    DMF    N,N-<Iimethylfonnamide
    DMSO    dimethyl sulfoxide
    EA    ethyl acetate
    eq.    equivalent
    HOAc    acetic acid
    KO!Bu    potassium 2-methylpropan-2-olate
    MeOH    methanol
    mp    matting point
10    MTB    tert-butyl methyl ether
    NMP    N-methyl-2-pyrrolidone
    OAc    acetate
    dppf    1,1'-bis(diphenylphosphino)ferrocene
    RT    room temperature
15    THF    tetrahydrofuran
    TMEDA    N,N,N',N'-tetramethylethane-1,2-diamine


Experimental part

20

Example 1: N-(5-Methanesulfonyl-2-methyl-4-pentafluorosulfanyl-benzoyl)guanidine

a) 4-Aminophenylsulfur penlafluoride
F5S'r0
 

25
 
~NH2
 

A solution oftin(ll) chloride (1465 g, 7.73 mol) in concentrated (32 percent) aqueous HCI solution was heated with stirring to eooc and then, with ice


cooling, 4-nitrophenylsulfur pentafluoride (584 g, 2.344 mol) was introduced in B portions over the course of 1 h. The internal temperature was kept below 1OO"C during this. Subsequently, the mixture was stirred at an internal temperature of 85"C for 1.5 h and then cooled to 45"C over the course of a further hour. A mixture of ice (12 kg), NaOH (2 kg) and dichloromethane (1.51) was prepared and the reaction mixture was added

with vigorous stirring. The phases were separated, the aqueous phase was

extracted 3 times with 1 I of dichloromethane each time, and the combined

organic phases were dried over NazS04 and evaporated in vacuo. 510 g of

10    4-aminophenylsulfur pentafluoride were obtained as a pale yellow crystalline powder, m.p. 63-65"C

b) 4-Amino-3-bromophenylsulfur pentafluoride



15    4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 1), the solution was cooled to 5"C and, while stirring, 1,3-<iibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol) was introduced in several portions with ice cooling so that the internal
temperature was kept at 3-B"C (approx. 1 h). The mixture was then left to

20    stir and warm to room temperature without external cooling for 1 h. The mixture was filtered through a bed of silica gel (volume about 1 I) and washed with dichloromethane (5.5 1), and the filtrate was evaporated in vacuo. About 700 g of a red-brown crystalline mass was obtained and was

dissolved in n-heptane (600 ml) at 60"C and then crystallized in a

25    refrigerator at 4"C. Fi~ration with suction resulted in 590 g (85%) of 4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m.p. 59-59.5"C.

c) 4-Amino-3-methylphenylsulfur pentafluoride

30



A mixture of CszC03 (794 g, 2.7 mol), dimethoxyethane (2 1), water

(300 ml) and trimethylboroxine (50 percent solution in THF, 225 g, 0.9 mol)

was heated to 70°C, PdCI2 (dppf) x CH2CI2 (37 g, 45 mmol) was added, and a solution of 4-amino-3-bromophenylsulfur pentafluoride (270 g,

0.9 mol) in dimethoxyethane (400 ml) was added dropwise over the course of 2 h while the reaction mixture was heated to reflux. It was subsequently heated under reflux for a further 3 h and then cooled to room temperature, diluted wtth MTB ether (500 ml), filtered through a silica gel column

(14 x 7 em, 70-200 ~m) and washed with MTB ether (2500 ml). The filtrate

was evaporated in vacuo. 490 g of a black, semicrystalline mass was

obtained and was subjected to a steam distillation. A total of 5.5 I of

10    condensate was collected, from which the crystals of the product separated out. The condensate was extracted 3 x wtth MTB ether, and the combined organic phases were dried over Na2S04 and evaporated in vacuo.

4-Amino-3-methylphenylsulfur pentafluoride (181 g, 76%) was obtained as colorless crystals, m.p. 65-66°C,

15

d) 4-Bromo-3-methylphenylsulfur pentafluoride

F5S~CH3

~ Br

A mixture of tert-butyl nitrite (90 percent pure, 37 ml, 280 mmol) and CuBr2 (35.8 g, 160 mmol) in acetonttrile (260 ml) was cooled to soc and, while

20    stirring and cooling wtth ice, a solution of 4-amino-3-methylphenylsulfur pentafluoride (30.9 g, 132.5 mmol) in MTB ether (140 ml) was added dropwise at s~oc over the course of 1 h. Evolution of nitrogen started after about 2 min. The mixture was then allowed to warm with stirring to room

temperature over the course of 1 h, a mixture of ice (250 g), 26 percent

25    aqueous NH3 solution (50 ml) and MTB ether (250 ml) was added, and the mixture was stirred for 10 min. The phases were separated, the aqueous was extracted 3 x with MTB ether (150 ml each time), and the combined organic phases were shaken once wtth 400 ml of water. Drying with Na2S04 and evaporaUon of the organic phase resulted in 39 g of 4-bromo-

30    3-methylphenylsulfur pentafluoride as a red-brown oil which was contaminated wtth 8 mol% of 4,5-<libromo-3-methylphenylsulfur pentafluoride, but was used further without further purification. Yield 89% based on a purity of 90%.


e) 4-Cyano-3-methylphenylsuffur pentafluoride

F5S~CH3

v.--CN

A mixture of 4-brom<>-3-methylphenylsulfur pentafluoride (136.4 g, purity 80%, 0.367 mol), Zn(CN)2 (72.8 g, 0.62 mol) and Zn dust (7.2 g, 0.11 mol) in dimethylacetamide (900 ml) and water (40 ml) was heated with stirring and nitrogen blanketing to 125°C, and PdCI2(dppf) x CH2CI2 (32.7 g,

40 mmol) was added. After stirring at125oC for one hour, PdCI2(dppf) x CH2CI2 (16.3 g, 20 mmol) and Zn dust (3.6 g, 55 mmol)

were again added, and stirring was continued at125oC for 2 h. The mixture

10    was then cooled to room temperature, diluted with n-heptane (400 ml) and stirred vigorously wHh addition of 5 N aqueous NH4CI solution (250 ml) and water (450 ml) for 15 min. The mixture was filtered with suction through a layer of kieselguhr, the phases were separated, and the aqueous was

extracted 2 x wHh n-heptane (200 ml). The combined organic phases were

IS shaken with water (450 ml), dried over MgS04 and evaporated in vacuo. The resulting black residue was dissolved in 200 ml of n-heptane, fiHered
and again evaporated in vacuo. 78 g of a dark brown liquid were obtained

and were purified by chromatography on a silica gel column (7 x 55 em,

60-200 ~m. n-heptane/dichloromethane 4:1 to 3:2). The first traction

20    obtained was 6.5 g of 4-bromo-3-methylphenylsulfur pentafluoride (precursor) as yellowish liquid, and then 71.1 g (80%) of 4-cyano-3-methyl-phenylsulfur pentafluoride as pale yellow oil.

f) 2-Methyl-4-pentafluorosuffanylbenzoic acid



25

A    mixture of 4-cyan<>-3-methylphenylsulfur pentafluoride (41.2 g,

169.4    mmol), NaOH (20.4 g, 510 mmol) and water (60 ml) in ethylene glycol (160 ml) was heated to 130oc and stirred at this temperature for 4 h. It was then cooled to room temperature and diluted with MTB ether

30    (150 ml) and water (250 ml), and the mixture was filtered with suction. The phases of the filtrate were separated, and the aqueous was acidified with concentrated aqueous HCI solution, and the precipitated solid was filtered off with suction. 41.1 g (93%) of 2-methyl-4-pentafluorosuffanylbenzoic acid
 



39

were obtained as colorless crystals, m.p. 138-139"C.

g) 2-Methyl-5-nitro-4-pentafluorosulfanylbenzoic acid

:JXXrf""I
o::I +      -&      0
~
0    OH

6.1    g of 2-methyl-4-pentafluorosulfanylbenzoic acid were dissolved in 60 ml of a 90% aqueous HN03 solution and, at RT, 6 ml of a 96% H2S04 were added dropwise. The mixture was left to stand at RT for 28 h and then
poured into 300 g of ice, 300 ml of water were added and, after stirring for 1 h, the product was filtered off. Drying in air resulted in 6.5 g of a pale

10    yellow solid, mp. 218-220"C.

Rt (DIP/2%HOAc) = 0.27    MS (ES} 306

h) 5-Amino-2-methyl-4-pentafluorosulfanylbenzoic acid





15    6.5 g of 2-methyl-5-nitro-4-pentafluorosulfanylbenzoic acid were dissolved in 100 ml of MeOH and 20 ml of HOAc, and 500 mg of 10% Pd/C were added. Hydrogenation was carried out under hydrogen at atmospheric pressure and RT for 20 h. The reaction was incomplete and therefore hydrogenation was continued under a pressure of 6 bar of hydrogen and at

20    RT for 48 h. The catalyst was then filtered off and the solvents were removed in vacuo. 5.7 g of a pale grey solid were obtained, mp. 187-189"C.

Rt (DIP/2%H0Ac) = 0.23    MS (ES\276
 



40

i) 5-Chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid

:~?CCtf"""'FI
CI-s    ~  O
0'"'0    OH

1.0 g of 5-amino-2-methyl-4-pentafluorosulfanylbenzoic acid was dissolved in 30 ml of HOAc, and 30 g of ice and 30 ml of a saturated aqueous HCI solution were added. Then, at ooc, a solution of 274 mg of NaN02 in 1 ml

of water was added dropwise over the course of one minute. The mixture was stirred at aoc for 15 minutes. The resulting suspension was then

added in portions to a suspension, cooled to ooc. of 6.1 mg of CuCI and

10    61.5 mg of CuCI2 x 2H20 in 30 ml of a saturated solution of S02 in HOAc. The mixture was stirred at ooc for 1 h and then at RT for 1 h. The reaction mixture was subsequently extracted 3 times with 200 ml of diethyl ether each time. MgS04 was used for drying, and the volatile constituents were

removed in vacuo. 1.3 g of the product were obtained and immediately

15    reacted further.

k) 2-Methyl-5-sulfino-4-pentafluorosulfanylbenzoic acid

FJ,F
vp~
Ha:s  I .o    o

II
0    OH

1.2    g of 5-chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid were 20 added in portions to a solution, heated to 70°C, of 4.2 g of Na2S03 in 50 ml
of water and, during this, the pH of the solution was kept between pH = 9 and pH = 11 with a 2N aqueous NaOH solution. The mixture was stirred at 70oc for 20 minutes, cooled to RT and adjusted to pH = 1-2 with an aqueous HCI solution. The mixture was lefl to stand at RT for 16 hand then

25    the product was filtered ofl and dried in vacuo. 1.0 g of a white solid was
 


41 obtained, mp. 288-290oc (with decomposition).

Rt(EA/MeOH 1:1) = 0.52

I) Methyl 5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoate





1.0 g of 2-methyl-5-sulfino-4-pentafluorosu~anylbenzoic acid was suspended in 10 ml of water, and 3.1 ml of an aqueous 2N NaOH solution

were added (phenolphthalein: basic). The water was removed in vacuo and

then coevaporated twice with 20 ml of toluene each time. The disodium salt

10    was then dissolved in 40 ml of anhydrous DMF and, after addition of

0.69    ml of methyl iodide, stirred initially at 60°C for 4 h and then at RT for 15 h. The reaction mixture was poured into 100 ml of water and a first
portion of the product (500 mg) was fittered off with suction. The filtrate was adjusted to pH = 2 with aqueous HCI solution and extracted 3 times with

IS 30 ml of EA each time. MgS04 was used for drying, and the solvent was removed in vacuo. Chromatography on silica gel wtth DIP afforded a further 460 mg of white crystals, mp 12rc.

Rt (DIP) = 0.36

20 m) N-(5-Methanesufunyl-2-methyl-4-pentafluorosulfanylbenzoyl)guanidine 0.70 g of guanidine chloride and 0.68 g of KotBu were stirred in 20 ml of anhydrous DMF at RT for 30 minutes. This suspension was then added to 0.43 g of methyl 5-methanesufunyl-2-methyl-4-pentafluorosulfanyl-benzoate and stirred at RT for 16 h. The reaction mixture was then poured
25    into 200 ml of water, adjusted to pH = 8 wtth aqueous HCI solution and extracted 3 times with 100 ml of EA each time. MgS04 was used for drying, and the solvent was removed in vacuo. The residue was suspended in 5 ml of CH2CI2 and the product was filtered off. 190 mg of colorless crystals
 



42

were obtained, mp. 254-256°C.

Rt (EA) = 0.22

Example 2: N-(5-MethanesuWonyl-2-methyl-4-pentafluorosulfanylbenzoyl}-

guanidine methanesulfonic acid salt

0 o~S-
HO'



9.3 g of the tttle compound of example 1 were suspended in 100 ml of

water and a solution of 2.3 g of methanesulfonic acid in 10 ml of water was

10    added. The mixture was subsequently stirred at RT for 30 minutes and then the water was removed under reduced pressure to obtain 11.7 g of the methanesuWonic acid salt, which was subsequently recrystallized from

110 ml of water to obtain 10.0 g of N-(5-methanesulfonyl-2-methyl-4-pentafluorosuWanylbenzoyf)guanidine melhanesulfonic acid salt as white

15    crystals, m.p. 230°C.

Example 3: N-(5-Methanesulfonyf-2-methyl-4-pentafluorosulfanylbenzoyl)-guanidine hydrochloride






20

300 mg of the title compound of example 2 were suspended in 50 ml of a saturated aqueous Na2CO, solution and extracted twice with 40 ml of EA each time. The EA phase was subsequently dried over MgS04 and the
 



43

solvent was removed under reduced pressure. The residue was dissolved

in 10 ml of MeOH and admixed with 2 ml of a 10% aqueous HCI solution.

The volatiles were removed under reduced pressure to leave 230 mg of

white crystals, m.p. 276-278°C.

Determination of the NHE inhibition

The inhibitory concentration IC,. for NHE-1 inhibition was determined as follows:
!0

IC50 for NHE-1 inhibition was determined in an FLIPR assay by

measurement of the pHj recovery in transfected cell lines which express

human NHE-1.

15    The assay was carried out in an FLIPR (ftuorometric imaging plate reader) with black-walled 96-well microliter plates with clear bases. The transfected cell lines expressing the various NHE subtypes (the parental cell line LAP-1 shows no endogenous NHE activity as a result of mutagenesis and subsequent selection) were seeded the preceding day at a density of

20    -25 000 cells/well.

The growth medium for the transtected cells (lscove +1 0% fetal calf serum) additionally contained G418 as selection antibiotic in order to ensure the presence of the transfected sequences.

25    The actual assay started with the removal of the growth medium and addition of 100 ~I of loading buffer per well (5 ~M BCECF-AM [2',7'-bis(carboxyethyl)-5- (and -6-)carboxyftuorescein, acetoxymethyl ester] in 20 mM NH4CI, 115 mM choline chloride, 1 mM MgCiz, 1 mM CaCiz, 5 mM

KCI, 20 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The cells

30    were then incubated at 3rC for 20 minutes. This incubation led to loading of the cells with the fluorescent dye whose fluorescence intensity depends

on pHi, and with NH4CI which made the cells slightly alkaline.

The nonftuorescent dye precursor BCECF-AM is, as ester, membrane-
 



44

permeable. The actual dye BCECF is not membrane-permeable but is liberated inside cells by esterases.

After this incubation for 20 minutes, the loading buffer which contained NH4CI and free BCECF-AM was removed by washing three times in a cell washer (Tecan Columbus) with in each case 400 ~I of washing buffer

(133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM MgCiz, 1.25 mM CaCiz, 0.97 mM KzHP04, 0.23 mM KHzP04, 5 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The residual volume which remained in the wells

10    was 90 ~I (50-125 ~I possible). This washing step removed the free

BCECF-AM and results, as a consequence of the removal of the external NH4+ ions, in intracellular acidification(- pH; 6.3- 6.4).

Since the equilibrium of intracellular NH4 + with NH3 and W was disturbed

by the removal of the extracellular NH4+ and by the subsequent

15    instantaneous passage of the NH3 through the cell membrane, the washing

process resulted in H+ remaining inside the cells, which was the cause of the intracellular acidification. This may eventually lead to cell death if it
persists long enough.

It was important at this point that the washing buffer was sodium-free

20    (<1 mM) because extracellular sodium ions would lead to an instantaneous recovery of the pH; through the activity of the cloned NHE isoforms.

It was likewise important for all the buffers used (loading buffer, washing buffer, recovery buffer) not to contain any HC03- ions, because the

presence of bicarbonate would lead to activation of interfering bicarbonate-

25    dependent pH; regulatory systems present in the parental LAP-1 cell line.

The microliter plates with the acidified cells were then (up to 20 minutes after the acidification) transferred to the FLIPR. In the FLIPR, the
intracellular fluorescent dye was excited by light with a wavelength of

30    488 nm generated by an argon laser, and the measured parameters (laser power, illumination time and aperture of the CCD camera incorporated in
 



45

the FLIPR) were chosen so that the average fluorescence signal per well is between 30 000 and 35 000 relative fluorescence units.

The actual measurement in the FLIPR started with a photograph being taken by the CCD camera every two seconds under software control. After ten seconds, the recovery of the intracellular pH was initialed by adding 90 ~I of recovery buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mM MgCiz. 1.25 mM CaCiz. 0.97 mM K2HP04, 0.23 mM KHzP04, 10 mM HEPES,

5 mM glucose; pH 7.4 [adjusted w~h NaOH]) by means of the 96-well

10    pipettor incorporated in the FLIPR.

Pos~ive control wells (100% NHE activity) were those to which pure recovery buffer is added, while negative controls (0% NHE activity) received washing buffer. Recovery buffer with twice the concentration of test substance was added to all the other wells. Measurement in the FLIPR
15    terminated after 60 measurements (two minutes).

The raw data are exported into the ActivityBase program. This program firstly calculates the NHE activ~ies for each tested substance concentration

and, from these, the IC5o values for the substances. Since the progress of

20    pH; recovery was not linear throughout the experiment, but fell at the end owing to decreasing NHE activity at higher pH; values, it was important to
select for evaluation of the measurement the part in which the increase in fluorescence of the positive controls was linear.

NHE1 inhibition IC50 [nM]

49

25

In vivo pharmacokinetics - profiling with the "n in one method"

The exposure data and the volumes of distribution were determined as characteristic pharmacokinetic data as follows:

30
 



46

The NHE-1 inhibitor of example 1 of the invention and, as reference

substance, the known NHE-1 inhibitor cariporide with the formula







were dissolved in an aqueous, sligh~y acidic medium (water, pH 4, adjusted with 1M hydrochloric acid). The concentration of the aqueous

formulation prepared in this way was about 1.5 mg of each substance per

1 g of solution. 10 ml of this formulation were administered as a single

bolus by catheter into the jugular vein of a fasting male beagle dog (dose

about 1 mg of each substance administered per kg of the dog'sbody

10    weight). Blood samples were taken by means of a second catheter after 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h, and heparinized plasma was prepared by centrifugation at 1000 G in appropriate plasma tubes.

The plasma samples were worked up and, after an HPLC separation,

IS    quantified by MS/MS. The high specificity of this method permitted

simultaneous detennination of a plurality of substances. The exposures

could be calculated using the WinNonlin computer program from the

concentration-time plots (see figure 1) and compared with the exposure of

the known NHE-1 reference substance. Since the various substances were

20    measured in the same animal at the same time, the result was an accurate comparison of the compounds, and a ranking of the volumes of distribution was possible.

Compound    Volume of distribution
    ptkg of body weight]
   
Example 1    1.67
   
Reference substance    2.94
cariporide   


It is clearly evident from the concentration-time plots in figure 1 that the

compound of the invention is retained in the blood also over a longer period

and thus the exposure is about 2-3 times higher than with the reference

substance cariporide. Cariporide is no longer detectable in the plasma after

24 hours.

The captions and signs in the figure were as follows:

Fig.!: concentration-time plots in the blood plasma of dogs after

10    administration of in each case approx. 1 mglkg of the compound of example 1 and of cariporide.
y axis: concentration of the measured compound in the IJg/ml in plasma x axis: time in h
 



48

Patent claims

1.    A compound ofthe fonmula I

in which

R1    is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CH2)n-

    (CF2)0 -CF3 or -(SOm)q -(CH2)r(CF2)8 -CF3;
10    R5 and R6
        are, independenijy of one another, hydrogen, alkyl
        having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
    m    is zero, 1 or2
    n, o, p, q, rand s
IS        are, independently of one another, zero or 1;
R2    is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having  1,
    2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR7R8,
    -Or(CH2)u-(CF2)v-CF3 or -(SOw)x-(CH2)y-(CF2)z-CF3;
    R7 and RS
20        are, independently of one another, hydrogen, alkyl
        having 1, 2, 3 or 4 carbon atoms or -CH~F3;
    w    is zero, 1 or 2

t, u. v, x, y and z

are, independently of one another, zero or 1 ;
 


49

R3 is Cl, Br, I, -CN, -SOzCHJ, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -Oa-(CHz)b-(CFz)c-CFJ, -(SOd)e-(CHz)t-(CFz)g-CFJ, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R9 and R10

are, independenUy of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CHz-CF3;

a,bandc

10    are, independently of one another, zero or 1;

is zero, 1 or 2;

e    is zero or 1;

is zero, 1, 2, 3 or 4;

g    iszeroor1;

15    or

R3 is -(CHz)h-phenyl or -0-phenyl,

in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting ofF, Cl, Br, I,

-Oj-(CHz)k-CFJ, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl

20    having 1, 2, 3 or 4 carbon atoms and -SOzCH3;

is zero or 1;

k is zero, 1, 2or3; is zero, 1, 2, 3 or 4;

or

25    R3    is -(CHz)aa-heteroaryl,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected

from the group consisting ofF, Cl, Br, I, -Obb-(CHz)cc-CFJ, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SOzCH3;
30    bb    is zero or 1;

cc    is zero, 1, 2 or 3;
 
R4    is hydrogen, F, Cl, Br, I, -CN, -SOzCH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR11R12, -0dd-(CHz)ee-(CFz)ff-CF3; -(SOgg)hh-

(CHz)n-(CF2)k!<-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R11 and R12

are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CHz-CF3;

dd, ee and If

are, independently of one another, zero or 1;

gg    is zero, 1 or 2;

hh    is zero or 1;

is zero, 1, 2, 3 or4;

kk    is zero or 1;

or

R4    is -(CHz)u-phenyl or -0-phenyl,

in which the phenyl radicals are unsubstituted or substituted by 1, 2
 

20    or 3 radicals selected from the group consisting ofF, Cl, Br, I, -Omm-(CHz)nn-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SOzCH3;

mm    is zero or 1;

nn    is zero, 1, 2 or 3;

25    is zero, 1, 2, 3 or4;
or   
R4    is -(CHz)00-heteroaryl,
    which is unsubstituted or substituted by 1, 2 or 3 radicals selected
    from the group consisting ofF, Cl, Br, I, -Opp-(CHz)rrCF3, alkoxy

30    having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SOzCH3;

pp    is zero or 1;

rr is zero, 1, 2 or 3;

oo    is zero, 1, 2, 3 or4;

and the pharmaceutically acceptable salts thereof.

2.    A compound of the formula I as claimed in claim 1, in which the

meanings are:

R1    hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,

2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -Op-(CHz)n-(CFz)o-CF3 or -(S0m)q-(CHz)r(CFz)s-CF3;

R5 and R6

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CHz-CF3;
m    zero, 1 or2

n, o, p, q, rand s

independently of one another zero or 1;

R2    hydrogen or F;

R3 Cl, Br, I, -CN, -SOzCH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R1 0, -Oa-(CHz)b-(CFz)c-CF3, -(SOd)e-(CHz)f-(CFz)g-CF3, alkyl
 
20    having 1, 2, 3, 4, 5 or 6 carbon atoms or cydoalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R9 and R10

independently of one another hydrogen, alkyl having 1,
25    2, 3 or 4 carbon atoms or -CHz-CF3;

a,bandc

independently of one another zero or 1; zero, 1 or 2;
e    zeroor1;

30    zero, 1, 2, 3 or4; zero or 1;


R3    -(CHz)h-phenyl or -0-phenyl,

in which the phenyl radicals are unsubsmuted or substituted by 1, 2

or 3 radicals selected from the group consisting ofF, Cl, Br, I,

-Oj-(CHz)k-CFJ, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl

having 1, 2, 3 or 4 carbon atoms and -SOzCH3;

zeroor1;

zero, 1, 2 or 3;

zero, 1, 2, 3 or4;

or

10    R3    -(CHz)aa-heteroaryl,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected

from the group consisting ofF, Cl, Br, I, -0bb-(CHz)cc-CF3. alkoxy

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

atoms and -SOzCH3;
IS    bb    zero or 1;

cc zero, 1, 2 or 3;

aa    zero, 1, 2, 3 or4;

R4    hydrogen or F;

and the phannaceutically acceptable salts thereof.

20

3.    A compound of the fonnula I as claimed in claim 1 or 2, in which the

meanings are:
R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or4 carbon atoms, F, Cl, Br,l, -CN, NR5R6, -O-CHz-CF3 or -(SOm)q-(CHz)rCFJ;

R5and R6

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CHz-CF3;

m    zero, 1 or 2

q and r

independently of one another zero or 1;
 


53

R2    hydrogen or F;

R3    Cl, Br, I, -CN, -S02CH3, alkoxy having 1, 2, 3 or 4 carbon atoms,

NR9R10, -O-CH2-CF3, -(SOct)e-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine
atoms;

R9 and R10

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH;t-CF3;

10    d zero, 1 or 2; e zero or 1;

or

R3    phenyl,

which is unsubstttuted or substituted by 1, 2 or 3 radicals selected

15    from the group consisting ofF, Cl, Br, I, -Oj-(CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon

atoms and -S02CH3;

zero or 1;

zero, 1, 2 or3;

20    or

R3 heteroaryl,

which is unsubstttuted or substituted by 1, 2 or 3 radicals selected

from the group consisting ofF, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon

25    atoms and -S02CH3;

bb    zero or 1;

cc    zero, 1, 2 or 3;

R4    hydrogen or F;

and the pharmaceutically acceptable salts thereof.

30

4. A compound of the formula I as claimed in one or more of claims 1, 2 and 3, in which the meanings are:
 

R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, -O-CHz-CF3 or -(SOm)q-(CH2)rCF3;
R5 and R6

independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
 

independently of one another zero or 1; hydrogen or F;

Cl, -CN, -S02CH3, methoxy, ethoxy, NR9R10, -O-CHz-CF3, -(SOd)e-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R9 and R10

independently of one another hydrogen, methyl, ethyl or -CHz-CF3;
zero, 1 or2;

e    zero or 1;
 

or   
20R3    phenyl,
    which is unsubstituted or substituted by 1 or 2 radicals selected from
    the group consisting ofF, Cl, -Oj-(CH2)k-CF3, methoxy, ethoxy, alkyl
    having 1, 2, 3 or 4 carbon atoms and -S02CH3;
    j and k
25    independently of one another zero or 1 ;
or   
R3    heteroaryl,
    which is unsubstnuted or substituted by 1 or 2 radicals selected from
    the group consisting ofF, Cl, -Obb-(CH2)cc-CF3, methoxy, ethoxy,

30    alkyl having 1, 2, 3 or 4 carbon atoms and -S02CH3;

bb    and cc
 

independently of one another zero or 1;

R4    hydrogen or F;

and the phannaceutically acceptable salts thereof.


5    5. A compound of the lonnula I as claimed in any of claims 1 to 4 and selected from: N-(5-methanesullonyl-2-methyl-4-pentafluorosu~anyl­ benzoyl)guanidine, and the pharmaceutically acceptable salts thereof.

6.    A process for preparing a compound of the formula I as claimed in

10    one or more of claims 1, 2, 3, 4 and 5 and/or the phannaceutically acceptable salts thereof, which comprises reacting a compound of the formula II,


in which R1to R4 have the meaning stated in claims 1 to 4 and Lis a

15    leaving group which can undergo nucleophilic substitution, with guanidine.


7.    A compound of the lonnula I and/or the phannaceutically acceptable

salts thereof as claimed in one or more of claims 1 to 5 for use as

medicament.

20

B.    The use of a compound of the lonnula I and/or the phannaceutically

acceptable salts thereof as claimed in one or more of claims 1 to 5 for

producing a medicament lor the treatment or prophylaxis of acute or

chronic damage, disorders or indirect sequelae of organs and tissues

25    caused by ischemic or repertusion events, lor the treatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, lor the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and


tissues, for the treatment or prophylaxis of states of shock, of diseases in

which cellular proliferation represents a primary or secondary cause, of

cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from overexcitability of the CNS, epilepsy or centrally induced convulsions, of disorders of the central nervous system,

especially of anxiety states, depressions or psychoses, for the treatment or

prophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) or late

10    damage from diabetes, of thromboses, of disorders resulting from endothelial dysfunction, of intermittent claudication, for the treatment or
prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the

liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and

fibrotic disorders of the heart, for the treatment or prophylaxis of heart

15    failure or of congestive heart failure, of acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in pou~ry. and for use for surgical operations and organ transplantations, for
preserving and storing transplants for surgical procedures, for use in

bypass operations, for use in resuscitation after a cardiac arrest, for

20    preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.

9.    The use of a oompound of the formula I and/or the pharmaceutically

25    acceptable salts thereof as claimed in one or more of claims 1 to 5 in

combination with other medicaments or active ingredients for producing a

medicament for the treatment or prophylaxis of acute or chronic damage,

disorders or indirect sequelae of organs and tissues caused by ischemic or

repertusion events, for the treatment or prophylaxis of arrhythmias, of life-

30    threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis of states of shock, of diseases in which cellular proliferation
 


57

represents a primary or secondary cause, of cancer, of metastasis, of

prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from overexcitability of the CNS, epilepsy or centrally induced convulsions, of disorders of the central nervous system, especially of anxiety states, depressions or psychoses, for the treatment or prophylaxis of non-insulin-dependent diabetes meiiHus (NIDDM) or late damage from diabetes, of thromboses, of disorders resulting from endothelial

10    dysfunction, of intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive

heart failure, of acute or chronic inflammatory disorders, of disorders

15    caused by protozoa, of malaria and of coccidiosis in poultry, and for use for surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for use in bypass operations, for use in

resuscitation after a cardiac arrest, for preventing age-related tissue

change, for producing a medicament directed against aging or for

20    prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.

10.    The use of a compound of the formula I and/or the pharmaceutically

acceptable salts thereof as claimed in claim 9 in combination wHh

25    cardiotoxic and cytotoxic medicaments or active ingredients for producing a medicament with reduced cardiotoxic and cytotoxic properties.

11.  The use of a compound of the formula I and/or the pharmaceutically

acceptable salts thereof alone or in combination with other medicaments or

30    active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events.
 
58

12.    The use of a compound of the formula I and/or the pharmaceutically

acceptable satts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment of life-threatening cardiac ventricular fibrillation.

13. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a
10    medicament for the treatment or prophylaxis of metastasis.

14. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a

15    medicament for the treatment or prophylaxis of fibrotic disorders of the heart, of heart failure or of congestive heart failure.

15.    A medicine for human, veterinary and/or phytoprotective use

comprising an effective amount of a compound of the fonnula I and/or the

20    pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5, together with pharmaceutically acceptable carriers and addnives.

16.  A medicine for human, veterinary and/or phytoprotective use

25    comprising an effective amount of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5, together wnh pharmaceutically acceptable carriers and additives in combination with other pharmacological active ingredients or medicaments.
 

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