HK1095584B

HK1095584B - Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same

Info

Publication number: HK1095584B
Application number: HK07102568.1A
Authority: HK
Inventors: Heinz-Werner Kleemann
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2003-11-13
Filing date: 2004-11-03
Publication date: 2009-08-28

Description

Pentafluorosulfanylbenzoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament containing them

Pentafluorosulfanylbenzoylguanidines of the formula I, in which R1 to R4 have the meanings indicated in the claims

And pharmaceutically acceptable salts thereof are substituted acylguanidines, inhibiting cellular sodium-proton antiporters (Na)⁺/H⁺Exchanger, NHE). Due to their NHE-inhibiting properties, the compounds of formula I and their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases caused by NHE activated or activated NHE as well as diseases secondary to NHE-related injuries.

The compounds of the invention are distinguished by Na inhibition in comparison with known compounds⁺/H⁺The activity of the exchange is extremely high and has improved ADMET properties. Xenobiotic structures (especially comparable "unnatural/artificial" SF₅Introduction of substituents) favorably influences the tissue distribution. This leads in particular to an increased exposure in vivo. This does not have a significant effect on the absorption characteristics, andretains the high bioavailability of acylguanidine.

Unlike some acylguanidines described in the literature, the compounds of formula I and their pharmaceutically acceptable salts described herein do not exhibit undesirable and disadvantageous saliduretic properties.

The invention relates to pentafluorosulfanyl benzoylguanidines of formula I

Wherein

R1 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, NR5R6, -O_p-(CH₂)_n-(CF₂)_o-CF₃Or- (SO)_m)_q-(CH₂)_r-(CF₂)_s-CF₃；

R5 and R6

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

m is 0, 1 or 2;

n, 0, p, q, r and s

Independently of one another, 0 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, -O_t-(CH₂)_u-(CF₂)_v-CF₃Or- (SO)_w)_x-(CH₂)_y-(CF₂)_z-CF₃；

R7 and R8

Independently of one another, are hydrogen, have 1, 2, 3 orAlkyl of 4 carbon atoms or-CH₂-CF₃；

w is 0, 1 or 2;

t, u, v, x, y and z

Independently of one another, 0 or 1;

r3 is Cl, Br, I, -CN, -SO₂CH₃Alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -O_a-(CH₂)_b-(CF₂)_c-CF₃、-(SO_d)_e-(CH₂)_f-(CF₂)_g-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

r9 and R10

a, b and c

Independently of one another, 0 or 1;

d is 0, 1 or 2;

e is 0 or 1;

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

g is 0 or 1;

or

R3 is- (CH)₂)_h-a phenyl group or-O-phenyl group,

wherein each phenyl group is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_j-(CH₂)_k-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

j is 0 or 1;

k is 0, 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

or

R3 is- (CH)₂)_aa-a heteroaryl group,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_bb-(CH₂)_cc-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

bb is 0 or 1;

cc is 0, 1, 2 or 3;

aa is 0, 1, 2, 3 or 4;

r4 is hydrogen, F, Cl, Br, I, -CN, -SO₂CH₃Alkoxy having 1, 2, 3 or 4 carbon atoms, NR11R12, -O_dd-(CH₂)_ee-(CF₂)_ff-CF₃、-(SO_gg)_hh-(CH₂)_jj-(CF₂)_kk-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

r11 and R12

dd, ee and ff

Independently of one another, 0 or 1;

gg is 0, 1 or 2;

hh is 0 or 1;

jj is 0, 1, 2, 3 or 4;

kk is 0 or 1;

or

R4 is- (CH)₂)_ll-a phenyl group or-O-phenyl group,

wherein each phenyl group is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_mm-(CH₂)_nn-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

mm is 0 or 1;

nn is 0, 1, 2 or 3;

ll is 0, 1, 2, 3 or 4;

or

R4 is- (CH)₂)_oo-a heteroaryl group,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_pp-(CH₂)_rr-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

pp is 0 or 1;

rr is 0, 1, 2 or 3;

oo is 0, 1, 2, 3 or 4;

and pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I in which the meanings are:

R5 and R6

m is 0, 1 or 2;

n, o, p, q, r and s

Independently of one another, 0 or 1;

r2 is hydrogen or F;

r9 and R10

a, b and c

Independently of one another, 0 or 1;

d is 0, 1 or 2;

e is 0 or 1;

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

g is 0 or 1;

or

R3 is- (CH)₂)_h-a phenyl group or-O-phenyl group,

j is 0 or 1;

k is 0, 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

or

R3 is- (CH)₂)_aa-a heteroaryl group,

bb is 0 or 1;

cc is 0, 1, 2 or 3;

aa is 0, 1, 2, 3 or 4;

r4 is hydrogen or F;

and pharmaceutically acceptable salts thereof.

Particular preference is given to compounds of the formula I in which the meanings are:

r1 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, NR5R6, -O-CH₂-CF₃Or- (SO)_m)_q-(CH₂)_r-CF₃；

R5 and R6

m is 0, 1 or 2;

q and r

Independently of one another, 0 or 1;

r2 is hydrogen or F;

r3 is Cl, Br, I, -CN, -SO₂CH₃Alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -O-CH₂-CF₃、-(SO_d)_e-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

r9 and R10

d is 0, 1 or 2;

e is 0 or 1;

or

R3 is a phenyl group, and R3 is a phenyl group,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_j-(CH₂)_k-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

j is 0 or 1;

k is 0, 1, 2 or 3;

or

R3 is a heteroaryl group, and R3 is a heteroaryl group,

bb is 0 or 1;

cc is 0, 1, 2 or 3;

r4 is hydrogen or F;

and pharmaceutically acceptable salts thereof.

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

r1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, -O-CH₂-CF₃Or- (SO)_m)_q-(CH₂)_r-CF₃；

R5 and R6

m is 0, 1 or 2;

q and r

Independently of one another, 0 or 1;

r2 is hydrogen or F;

r3 is Cl, -CN, -SO₂CH₃Methoxy, ethoxy, NR9R10, -O-CH₂-CF₃、-(SO_d)_e-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

r9 and R10

Independently of one another, hydrogen, methyl, ethyl or-CH₂-CF₃；

d is 0, 1 or 2;

e is 0 or 1;

or

R3 is a phenyl group, and R3 is a phenyl group,

which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, -O_j-(CH₂)_k-CF₃Methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

j and k

Independently of one another, 0 or 1;

or

R3 is a heteroaryl group, and R3 is a heteroaryl group,

which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, -O_bb-(CH₂)_cc-CF₃Methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

bb and cc

Independently of one another, 0 or 1;

r4 is hydrogen or F;

and pharmaceutically acceptable salts thereof.

In one embodiment, preference is given in this respect to compounds of the formula I in which R1 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, NR5R6 (in which R5 and R6 are each independently of the other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃)、-O-CH₂-CF₃Or- (SO)_m)_q-(CH₂)_r-CF₃(wherein m is 0, 1 or 2, q and r are independently of each other 0 or 1); particular preference is given to compounds of the formula I in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6 (in which R5 and R6 are each otherIndependently hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃)、-O-CH₂-CF₃Or- (SO)_m)_q-(CH₂)_r-CF₃(wherein m is 0, 1 or 2, q and r are independently of each other 0 or 1); very particular preference is given to compounds of the formula I in which R1 is hydrogen, methyl, ethyl, CF₃-CH₂-O-, F, Cl or CF₃. In another embodiment, compounds are preferred wherein R1 is hydrogen, methyl or ethyl, especially methyl or ethyl.

In another embodiment, preference is given to compounds of formula I wherein R2 is hydrogen or F; particular preference is given to compounds in which R2 is hydrogen.

In another embodiment, preference is given to compounds of the formula I in which R3 is Cl, -CN, -SO₂CH₃Methoxy, ethoxy, NR9R10 (wherein R9 and R10 are each independently of the other hydrogen, methyl, ethyl or-CH₂-CF₃)、-O-CH₂-CF₃、-(SO_d)_e-CF₃(wherein d is 0, 1 or 2, e is 0 or 1), an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms or a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms (wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms), a phenyl group (which is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_j-(CH₂)_k-CF₃(wherein j is 0 or 1, k is 0, 1, 2 or 3), alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃) Or heteroaryl (which is unsubstituted or substituted by 1, 2 or 3 radicals selected from F, Cl, Br, I, -O_bb-(CH₂)_cc-CF₃(wherein bb is 0 or 1, cc is 0, 1, 2 or 3), alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃) (ii) a Particular preference is given to compounds in which R3 is Cl, -CN, -SO₂CH₃Methoxy, ethoxy, NR9R10 (which isWherein R9 and R10 are each independently of the other hydrogen, methyl, ethyl or-CH₂-CF₃)、-O-CH₂-CF₃、-(SO_d)_e-CF₃(wherein d is 0, 1 or 2, e is 0 or 1), an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms or a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms (wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms), a phenyl group (which is unsubstituted or substituted by 1 to 2 radicals selected from F, Cl, -O_j-(CH₂)_k-CF₃(wherein j and k are independently of each other 0 or 1), methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃) Or heteroaryl (which is unsubstituted or substituted by 1 to 2 radicals selected from the group consisting of F, Cl, -O_bb-(CH₂)_cc-CF₃(wherein bb and cc are independently of each other 0 or 1), methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃) (ii) a Very particular preference is given to compounds in which R3 is Cl, -CN or-SO₂CH₃。

In another embodiment, preference is given to compounds of the formula I in which R4 is hydrogen and F, particular preference to compounds in which R4 is hydrogen.

In another embodiment, preference is given to compounds of the formula I in which p, t, a and dd are each independently of the other 1.

If the substituents R1 to R4 contain one or more asymmetric centers, they may have the S and R configuration independently of one another. The compounds may be in the form of optical isomers, diastereomers, racemates or mixtures thereof.

The present invention includes all tautomeric forms of the compounds of formula I.

The alkyl group may be linear or branched. This also applies when they carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl groups 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 groups are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5, hydrogen atoms in the alkyl group may be replaced by fluorine atoms. Examples of such fluoroalkyl groups are trifluoromethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl. The substituted alkyl group may be substituted at any position. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for example 1, 2, 3 or 4, hydrogen atoms in the cycloalkyl group may be replaced by fluorine atoms. Substituted cycloalkyl groups may be substituted at any position.

The phenyl group may be unsubstituted or substituted once or more than once, for example once, twice or three times, by identical or different radicals. If the phenyl group is substituted, it preferably has one or two identical or different substituents. The same applies to substituted phenyl groups in phenylalkyl or phenoxy groups and the like. The substituents in the monosubstituted phenyl radicals may be in the 2-, 3-or 4-position. The disubstituted phenyl groups may be substituted in the 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. The substituents in the trisubstituted phenyl group may be in the 2, 3, 4-position, 2, 3, 5-position, 2, 4, 6-position, 2, 3, 6-position or 3, 4, 5-position.

Heteroaryl is an aromatic ring compound in which one or more ring atoms is an oxygen atom, a sulfur atom, or a nitrogen atom, for example 1, 2, or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or a combination of different heteroatoms. Heteroaryl groups may be attached through all positions, such as the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. Heteroaryl groups may be unsubstituted or substituted one or more times, for example one, two or three times, by the same or different radicals. The same applies to heteroaryl groups in the radical of heteroarylalkyl and the like. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.

Heteroaryl is 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-oxazolyl, 3-, 4-or 5-isoxazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 2, 3-oxadiazol-or-5-yl, 1, 3, 4-oxadiazol-2-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, pyridyl, pyrazinyl, pyridazin, 1-, 3-, 4-, 5-, 6-or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 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 included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, 3-or 4-pyridyl.

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 also relates to a process for the preparation of a compound of formula I, which process comprises reacting a compound of formula II with guanidine, said compound of formula II being

Wherein R1 to R4 have the stated meaning and L is a leaving group capable of undergoing nucleophilic substitution.

The activated acid derivatives of the formula II, in which L is alkoxy, preferably methoxy, phenoxy, phenylthio, methylthio, 2-pyridylthio, nitrogen heterocycles, preferably 1-imidazolyl, are advantageously obtained in a manner known to the person skilled in the art from the base phosgene (formula II; L ═ Cl), which can in turn be prepared in a known manner from the base carboxylic acid (formula II; L ═ OH), for example using thionyl chloride.

In addition to the phosgene of the formula II (L ═ Cl), it is also possible to prepare other activated acid derivatives of the formula II in a known manner directly from the basic benzoic acid compound (formula II; L ═ OH), for example by treatment with gaseous HCl in methanol₃By treatment with carbonyldiimidazoles, N-acylimidazoles of the formula II are prepared by reaction with Cl-COOC in the presence of triethylamine in an inert solvent₂H₅Or tosyl chloride treatment to prepare a mixed anhydride of formula II, with Dicyclohexylcarbodiimide (DCC) or with O- [ (cyano (ethoxycarbonyl) methylene) amino]1, 1, 3, 3-tetramethyluronium tetrafluoroborate ("TOTU") to activate benzoic acids. A number of suitable methods for preparing activated carboxylic acid derivatives of formula II are described in J.March, Advanced organic chemistry, 3 rd edition (John Wiley)&Sons, 1985, page 350), which gives a literature on the source.

The reaction of the activated carboxylic acid derivative of the formula II with guanidine is preferably carried out in a known manner in aprotic or aprotic polar organic solvents. Have proven suitable for the use of methyl benzoates (formula II; L ═ OCH)₃) The conditions for the reaction with guanidine are: methanol, isopropanol or THF, at a reaction temperature of 20 ℃ to the boiling point of these solvents. Most reactions of compounds of formula II with salt-free guanidine are carried out, for example, in aprotic inert solvents such as THF, dimethoxyethane, dioxane.However, it is also possible to use water as solvent for the reaction of the compound of the formula II with guanidine in the presence of a base such as NaOH.

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

The compounds of formula II may be prepared as follows,

a) reducing the 4-nitrophenyl sulphur pentafluoride derivative of formula III to an amine of formula IV,

b) halogenating the compound of formula IV at the ortho position of the amino group with a halogenating agent to obtain a compound of formula V,

c) replacement of the halogen substituent in the compound of formula V with a substituent R1 using a suitable nucleophile or organoelement compound (0 g anoelement compound), such as an alkylboron compound, if appropriate with catalysis,

d) replacing the amino functionality in the compound of formula VI with a halogen substituent,

e) replacing the halogen substituent in the compound of formula VII with a nitrile functionality,

f) the nitrile function in the compound of formula VIII is hydrolyzed to a carboxylic acid,

g) nitration of a compound of formula IX at the ortho position to the pentafluorothio group to give a compound of formula X,

h) reducing the nitro compound of formula X to aniline,

i) replacement of the amino function in the compound of formula XI with R3 using a suitable nucleophile, and

k) converting the compound of formula XII to a compound of formula II, wherein in the compounds of formulae II, III, IV, V, VI, VII, VIII, IX, X, XI and XII,

r1 to R4 are as defined in formula I,

l is as defined in formula II, and

x and Y are each independently of the other F, Cl, Br or I.

The process for preparing the compounds of the formula II starts in step a and the compounds of the formula III are converted into the compounds of the formula IV by known methods which can in principle be used for reducing aromatic nitro compounds to aromatic amines. Such methods are described, for example, in r.c. larock, Comprehensive Organic Transformations: AGuide to Functional Group precursors, VCH Publishers, New York, Weinheim, 1999, 821-828 and the references cited therein.

Subsequently (step b), the compound of formula IV is dissolved in an organic solvent a and reacted with a halogenating agent, e.g. a brominating agent. The reaction temperature in this case is generally from-30 ℃ to +150 ℃, preferably from 0 ℃ to 40 ℃. The reaction time is generally from 10min to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be worked up as follows: the product is subsequently purified by filtration through a layer of silica gel, washing with organic solvent A, removal of the solvent in vacuo and conventional purification methods such as recrystallization, distillation or chromatography.

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

The term "halogenating agent" means, for example, halogen elements, halogen-amine complexes, cyclic and acyclic N-halogenated amides and imides and ureas, for example r.c. larock, Comprehensive organic transformations: a Guide to Functional Group Preparations, VCHPublishes, New York, Weinheim, 1999, 619 + 628 and references cited therein or M.B.Smith and J.March, March's Advanced Organic Chemistry: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 704-707 and references cited therein, such as, for example, N-bromosuccinimide, N-chlorosuccinimideHBr H₂SO₄Solution or 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione. The term "brominating agent" means, for example, elemental bromine, bromine-amine complexes, cyclic and acyclic N-brominated amides and imides and ureas, such as r.c. larock, Comprehensive Organic Transformations: a Guide to functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 622-: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 704-707 and references cited therein, such as H, e.g., N-bromosuccinimide, HBr₂SO₄Solution or 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione, the latter being capable of transferring 2 bromine atoms per molecule.

The term "organic solvent a" preferably means an aprotic solvent, such as, for example, dichloromethane, chloroform, tetrachloromethane, pentane, hexane, heptane, octane, benzene, toluene, xylene, chlorobenzene, 1, 2-dichloroethane, trichloroethylene or acetonitrile.

Any HX formed in the reaction can be captured by an organic or inorganic base.

In step c, the compound of formula V is subsequently dissolved in an organic solvent B and reacted with a nucleophile R1^-Or an elemental compound containing substituent R1 to give a compound of formula VI. In this case it is possible to add the base A and to add the catalytic metal salt A.

The reaction temperature in this case is generally from-20 ℃ to +150 ℃, preferably from 30 ℃ to 100 ℃. The reaction time is generally from 0.5h to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be worked up as follows: the product is subsequently purified by filtration through a layer of silica gel, washing with organic solvent B, removal of the solvent in vacuo and subsequent purification by customary purification methods such as recrystallization, chromatography (e.g.silica gel chromatography), distillation or steam distillation.

For example, 0.1 to 10mol of a compound of the formula V are dissolved in 1000ml of an organic solventAnd (B) a solvent. For example, for 1mol of starting compound of the formula V, 0.8 to 3 equivalents of the nucleophile R1 are used^-Or an elemental compound comprising substituent R1.

The term "nucleophile R1^-By "is meant a compound produced by deprotonation of compound R1-H with a strong base, such as an alkyl-or aryl-lithium compound, an organomagnesium compound, an alkoxide, or lithium diisopropylamide.

"organoelement compounds comprising a substituent R1" means, for example, organolithium compounds R1-Li, organomagnesium compounds R1-Mg-Hal (Hal ═ Cl, Br, I), organoboron compounds such as R1-B (OH)₂R1-boronic esters, for example

R1-boronic anhydrides, for example

Or an organozinc compound R1-Zn-Z (Z ═ Cl, Br, I).

The term "base A" means those bases which are used as auxiliary bases in cross-coupling reactions and are mentioned, for example, in A.Suzuki et al, chem.Rev.1995, 95, 2457-2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263-303 and the references cited therein in each case, for example Na₂CO₃、Cs₂CO₃、KOH、NaOH、K₃PO₄N (ethyl)₃。

The term "organic solvent B" means a protic or aprotic solvent, such as diethyl ether, dimethoxyethane, THF, alcohol, water or mixtures thereof. In one embodiment, a mixture with water is preferred.

The term "catalytic metal salt A" means in particular Pd and Ni catalysts, such as those used in Suzuki and Negishi reactions and for example those described in A.Suzuki et al, chem.Rev.1995, 95, 2457-2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263 or G.C.Fu et al, J.Am.chem.Soc.2001, 123, 10099 or G.C.Fu et al, J.Am.chem.Soc.2002, 124, 13662 and the documents cited therein in each case, including the ligands added, such as Pd (OAc)₂、PdCl₂(dppf) or Pd₂(dba)₃。

In step d, the compound of formula VI is subsequently converted to a compound of formula VII by a diazo-halogenation process using a diazo-halogenating agent, for example using a diazo-brominating agent such as those described for other aromatic amines to replace amine functionality with halogen functionality, see for example m.b. smith and j.march, March's Advanced Organic Chemistry: reactions, mechanics, and Structure, Wiley, New York, 2001, 935-936 or R.C. Larock, Comprehensive Organic Transformations: a Guide to Functional groups precursors, VCH Publishers, New York, Weinheim, 1999, 678-679 and references cited therein, for example, by the Sandmeyer or Gattermann reaction. Methods of m.doyle et al, j.org.chem.1977, 42, 2426 or s.oae et al, fill.chem.soc.jpn.1980, 53, 1065 are preferred.

In step e, the compound of formula VII is reacted with a cyanating agent, e.g. catalytic metal salt B, in solvent C. The reaction temperature is generally 20 ℃ to 200 ℃, preferably 80 ℃ to 150 ℃. The reaction time is generally from 1h to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be filtered off with suction through a layer of silica gel or kieselguhr, and the filtrate can be worked up by extraction with water. After evaporation of the solvent in vacuo, the compound of formula VIII is purified by conventional purification methods such as recrystallization, silica gel chromatography, distillation or steam distillation.

For example, 0.1 to 10mol of the compound of the formula VII are dissolved in 1000ml of organic solvent C. For example, 1 to 10 equivalents of cyanating agent are used for 1mol of compound of the formula VII to be reacted.

The term "cyanating agent" is intended to mean, for example, alkali metal cyanide or Zn (CN)₂Alone or in admixture with metallic zinc, preferably in the form of zinc powder.

The term "organic solvent C" preferably means an aprotic polar solvent, such as for example DMF, dimethylacetamide, NMP, DMSO.

The term "catalytic metal salt B" means in particular Pd and Ni catalysts, such as those used in Suzuki reactions and for example A.Suzuki et al, chem.Rev.1995, 95, 2457 2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263 and those described in the documents cited therein, for example PdCl₂(dppf)、Pd(OAc)₂、Pd₂(dba)₃。

The resulting compound of formula VIII is then hydrolyzed in step f to the carboxylic acid of formula IX, for example in the presence of a base. This can be carried out by methods known to the skilled worker for the hydrolysis of aromatic nitriles, for example r.c. larock, Comprehensive Organic Transformations: a Guide to functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1986-: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 1179-1180 and those described in the references cited therein.

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

In step h, the nitro compound of formula X is converted to the compound of formula XI by known methods which are in principle useful for the reduction of aromatic nitro compounds to aromatic amines. Such methods are described, for example, in r.c. larock, Comprehensive Organic Transformations: a Guide to functional groups preparation, VCH Publishers, New York, Weinheim, 1999, 821-828 and the references cited therein.

In step i, the aniline of formula XI is converted to the compound of formula XII by replacing the amine group with R3 via the diazotization-replacement pathway. Such methods are known to the skilled worker and are described, for example, in Houben-Weyl, Methoden der organischen Chemie 4 th edition, Organo-Stickstoff-Verbindungen I, part 2, Georg Thieme Verlag Stuttgart1990, 1087. sup. 1136. pages and the references cited therein.

For example, an aniline of formula XI can be converted to a sulfonyl chloride of formula XII by a diazo-displacement route (R3 ═ SO₂Cl), for example as described in Houben-Weyl, Methoden der organischen Chemie 4 th edition, Organo-Schwefel-Verbindungen, part 2, Georg Thieme Verlag Stuttgart1985, page 1069-1070.

In step k, the compound of formula XII is derivatized to the compound of formula II by methods known to the skilled person and as described above.

For example, it is possible in this step to first start with a sulfonyl chloride of the formula XII (R3 ═ SO)₂Cl) into the corresponding sulfinic acid (e.g. as described in Houben-Weyl, Methoden der organischen Chemie 4 th edition, Organo-Schwefel-Verbindungen, part 1, Georg Thieme Verlag Stuttgart1985, page 620 and Houben-Weyl, Methoden der organischen Chemie, Schwefel-, Selen-, Tellur-Verbindungen, Georg Thieme Verlag Stuttgart 1955, page 304-. The carboxylation to the methyl ester takes place simultaneously.

By carrying out the synthesis without steps b and c, a compound of formula I is prepared wherein R1 is hydrogen.

By carrying out the synthesis without step I, a compound of formula I is prepared wherein R3 is NR9R 10.

The functional groups in the starting compounds may also be present in protected form or in precursor form, which may then be converted into the desired groups in the compounds of formula II prepared by the above-described process. Corresponding protecting group techniques are known to the skilled worker.

It is likewise possible to derivatize suitable functional groups by methods known to the skilled worker. For example, where R3 is NH₂Can be converted into compounds in which R3 is NR9R10, in which R9 and R10 are each independently of the other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH, by reaction with the appropriate alkyl halide or 2, 2, 2-trifluoroethyl halide, for example methyl iodide, ethyl iodide or 2, 2, 2-trifluoroethyl iodide₂-CF₃And are not both hydrogen at the same time.

Pentafluorosulfanylbenzoylguanidines of the formula I are generally weak bases which are capable of binding acids to form salts. Suitable acid addition salts are all salts of pharmaceutically acceptable acids, such as halides (especially hydrochloride), lactate, sulfate, citrate, tartrate, acetate, phosphate, methanesulfonate, p-toluenesulfonate.

The compounds of formula I are substituted acylguanidines inhibiting cellular sodium-proton antiporters (Na)⁺/H⁺Exchangeable, NHE), in particular the NHE-1 subtype.

Due to their NHE-inhibiting properties, the compounds of formula I and/or their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases caused by NHE activated or activated NHE as well as diseases secondary to NHE-related injuries.

The compounds of formula I may also be used for the treatment and prevention of diseases via NHE that are only partially inhibited, e.g. by using low doses.

Since NHE inhibitors act primarily via their effect on the regulation of the pH of the cell, they can generally be used advantageously in combination with other compounds which regulate the pH in the cell, suitable combination partners being inhibitors of the carbonic anhydrase family, of the system which transports bicarbonate ions, such as sodium bicarbonate cotransporter (NBC) or sodium-dependent chloride-bicarbonate ion exchanger (NCBE), and NHE inhibitors which have an inhibitory effect on other NHE subtypes, since it is possible by them to enhance or modulate the pharmacologically relevant pH-regulating effect of the NHE inhibitors described herein.

The use of the compounds of the present invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.

Therefore, the NHE inhibitor of the present invention is suitable for the treatment of diseases caused by ischemia and by reperfusion.

Due to their pharmacological properties, the compounds described herein are suitable as antiarrhythmic agents. Because of their cardioprotective action, NHE inhibitors are very suitable for use in infarction prevention and infarction treatment as well as for the treatment of angina pectoris, in which case they also preventively inhibit or greatly reduce the pathophysiological processes associated with the formation of ischemia-induced damage, in particular in the triggering of ischemia-induced arrhythmias. Because of their protective effect against pathological hypoxic and ischemic conditions, the compounds of the formula I and/or their pharmaceutically acceptable salts used according to the invention act as cytostatic Na⁺/H⁺The result of the exchange mechanism can be used as a medicament for the treatment of all acute or chronic ischemia-induced injuries or diseases induced thereby primarily or secondarily.

It also relates to their use as surgical interventions. Thus, these compounds can be used during organ transplantation, possibly with the compounds protecting the donor organ before and during the removal, protecting the removed organ, for example during its treatment or storage in a physiological bath and during its transfer to the recipient organism.

The compounds of the invention are also valuable pharmaceuticals having a protective effect when performing angioplasty interventions, for example on the heart as well as peripheral organs and blood vessels.

The compounds of the present invention may also be used when performing bypass surgery, such as bypass surgery on coronary vessels and Coronary Artery Bypass Grafting (CABG).

The compounds of the invention may similarly be used in resuscitation after cardiac arrest, based on their activity against ischemia-induced injury.

The compounds of the present invention are of interest for use in the administration of fatal cardiac arrhythmias. Which can terminate ventricular fibrillation and restore the physiological sinus rhythm of the heart.

Since inhibitors of NHE1 of human tissues and organs, especially the heart, are not only effective against damage caused by ischemia and reperfusion, but also against the cytotoxic effects of drugs, especially such as those used in cancer therapy and in the treatment of autoimmune diseases, administration in combination with a compound of formula I and/or a pharmaceutically acceptable salt thereof is suitable for inhibiting the cytotoxic, especially cardiotoxic side effects of said compound. Reducing cytotoxicity, particularly cardiotoxicity, resulting from co-administration with NHE1 inhibitors also makes it possible to increase the dose of cytotoxic therapeutic agents and/or to prolong the administration time of such drugs. The therapeutic benefit of such cytotoxic therapies can be greatly enhanced by the use in combination with NHE inhibitors.

Additionally, the NHE1 inhibitor of formula I of the present invention and/or a pharmaceutically acceptable salt thereof may be used when there is an overproduction of thyroid hormone, thyrotoxicosis or external supply of thyroid hormone with damage to the heart. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for use in the treatment of ameliorating cardiotoxic drugs.

The compounds according to the invention are also suitable, on the basis of their protective action against ischemia-induced damage, as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, and are suitable, for example, for the treatment of stroke or cerebral edema.

The compounds of formula I and/or their pharmaceutically acceptable salts are also suitable for the treatment and prevention of diseases and disorders which are induced by an excessive excitation of the central nervous system, in particular for the treatment of epileptic disorders, centrally-induced clonic and tonic spasms, psychogenic depressive states, anxiety disorders and psychoses. In these cases, the NHE inhibitors described herein may be used alone or in combination with other substances with anti-epileptic activity or antipsychotic active ingredients or carbonic anhydrase inhibitors such as acetazolamide as well as in combination with other NHE inhibitors or sodium-dependent chloride-bicarbonate ion exchange protein (NCBE) inhibitors.

The compounds of formula I and/or their pharmaceutically acceptable salts for use according to the invention are additionally suitable for the treatment of various types of shock, such as for example allergic shock, cardiogenic shock, hypovolemic shock and bacterial shock.

The compounds of formula I and/or pharmaceutically acceptable salts thereof are also useful in the prevention and treatment of thrombotic disorders because they inhibit platelet auto-aggregation as NHE inhibitors. They also inhibit or prevent the excessive release of inflammatory and coagulation mediators, in particular von willebrand factor and thromboselectin, that occurs after ischemia and reperfusion. Thus, it is possible to reduce and eliminate the pathogenic effects of important thrombotic factors. Thus, the NHE inhibitors of the invention may be used in combination with other anticoagulant and/or thrombolytic active ingredients, such as, for example, recombinant or native tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, pharmaceutical substances having fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine, and the like. It is particularly advantageous to use the NHE inhibitors of the invention in combination with NCBE inhibitors and/or with carbonic anhydrase inhibitors such as e.g. acetazolamide.

In addition, NHE1 inhibitors are also characterized by strong inhibition of cell proliferation, such as fibroblast proliferation and vascular smooth muscle cell proliferation. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for use as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, and thus useful as anti-atherosclerotic, anti-chronic renal failure, anti-cancer agents.

It can be demonstrated that: NHE inhibitors inhibit cell migration. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for use as valuable therapeutic agents for diseases in which cell migration is a primary or secondary cause, such as for example cancers with a pronounced tendency to metastasize.

Another feature of NHE1 inhibitors is that they may delay or prevent fibrotic disorders. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for use as medicaments for the treatment of cardiac fibrosis, pulmonary fibrosis, liver fibrosis, kidney fibrosis and other fibrotic disorders. They are therefore useful in the treatment of organ hypertrophy and hyperplasia, such as cardiac and prostate hypertrophy and hyperplasia. They are therefore suitable for the prophylaxis and therapy of heart failure (congestive heart failure ═ CHF) and for the therapy and prophylaxis of prostatic hyperplasia or prostatic hypertrophy.

Due to the marked increase in NHE in essential hypertension, the compounds of formula I and/or their pharmaceutically acceptable salts are suitable for the prevention and treatment of hypertension and for the treatment of cardiovascular disorders. In these cases, they may be used alone or with suitable combinations and formulation partners for the treatment of hypertension and cardiovascular disorders. Thus, for example, the following drugs can be combined: one or more diuretics having a thiazide-like action, loop diuretics, aldosterone and pseudo-aldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerene. The NHE inhibitors of the invention may also be combined with calcium channel blockers such as verapamil, diltiazemAmlodipine or nifedipine, and with ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further advantageous combination partners are also beta-blockers such as metoprolol, salbutamol and the like, angiotensin receptors and receptor subtype antagonists such as losartan, irbesartan, valsartan, omatrara, gemopatrilt, endothelin antagonists, renin inhibitors, adenosine receptor agonists, potassium channel inhibitors and activators such as glibenclamide, glimepiride, diazoxide, clocartelin, minoxidil and derivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitoK (ATP) channel), Kv1.5 inhibitors and the like.

It has been shown that: NHE1 inhibitors have significant anti-inflammatory effects and are therefore useful as anti-inflammatory agents. Of note in this regard is the inhibition of the release of inflammatory mediators. These compounds can therefore be used alone or in combination with anti-inflammatory agents for the prevention or treatment of chronic and acute inflammatory conditions. Combination partners that can advantageously be used are steroidal and non-steroidal anti-inflammatory drugs. The compounds of the invention are also useful in the prevention or treatment of protozoan disorders such as malaria and coccidiosis in poultry.

It has additionally been found that: inhibitors of NHE1 have beneficial effects on serum lipoproteins. It is generally accepted that excessive blood lipid levels, so-called hyperlipoproteinemia, are an important risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart diseases. Thus, reducing elevated serum lipoproteins is important for the prevention and regression of atherosclerotic lesions. In addition to lowering total serum cholesterol, it is particularly important to reduce the proportion of specific atherogenic lipid moieties, in particular Low Density Lipoprotein (LDL) and Very Low Density Lipoprotein (VLDL), in the total cholesterol, since these lipid moieties are risk factors for atherogenesis. In contrast, the protective effect against coronary heart disease is due to high density lipoproteins. Thus, a hypolipidemic agent should not only lower total cholesterol, but should also in particular lower the VLDL and LDL serum cholesterol fraction. It has now been found that NHE1 inhibitors exhibit valuable therapeutically utilizable properties in affecting serum lipid levels. Thus, they significantly reduce elevated serum concentrations of LDL and VLDL, such as those observed due to increased dietary intake of cholesterol-and lipid-rich foods or pathological metabolic changes, such as genetically-related hyperlipidemia. Thus, they are useful for preventing and resolving atherosclerotic lesions by eliminating pathogenic risk factors. This document includes not only primary hyperlipidemia, but also certain secondary hyperlipidemia, such as secondary hyperlipidemia associated with diabetes. In addition, NHE1 inhibitors significantly reduced infarctions induced by metabolic abnormalities, particularly significantly reduced infarct area induced and its severity. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof may be advantageously used in the manufacture of a medicament for the treatment of hypercholesterolemia; for the preparation of a medicament for the prevention of atherogenesis; for the preparation of a medicament for the prevention and treatment of atherosclerosis; for the preparation of a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels; for the preparation of a medicament for the prevention and treatment of diseases induced by endothelial dysfunction; for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced hypertension; for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced thrombosis; for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced ischemic injury and post-ischemic reperfusion injury; for the preparation of a medicament for the prevention and treatment of hypercholesterolaemia-induced and endothelial dysfunction-induced cardiac hypertrophy and cardiomyopathy and for the prevention and treatment of Congestive Heart Failure (CHF); for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced coronary spasm and myocardial infarction; for the preparation of a medicament for the treatment of said conditions in combination with a hypotensive substance, preferably with an Angiotensin Converting Enzyme (ACE) inhibitor and an angiotensin receptor antagonist. The combination of an NHE inhibitor of formula I and/or a pharmaceutically acceptable salt thereof with a lipid-lowering active ingredient, preferably with an HMG-CoA reductase inhibitor (e.g. lovastatin or pravastatin), which latter produces a lipid-lowering effect, and thus enhances the lipid-lowering properties of the NHE inhibitor of formula I and/or a pharmaceutically acceptable salt thereof, has proven to be an advantageous combination with an enhanced effect and a reduced amount of active ingredient.

Therefore, the compound of the formula I and/or the pharmaceutically acceptable salt thereof has effective protection effect on endothelial injury caused by various reasons. This vasoprotective effect against endothelial dysfunction syndrome implies that the compounds of formula I and/or their pharmaceutically acceptable salts are valuable medicaments for the prevention and treatment of coronary artery spasm, peripheral vascular diseases, in particular intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy as well as thrombotic disorders.

It has also been found that: NHE1 inhibitors are suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM) in which insulin resistance is inhibited. In this respect, it may be beneficial to enhance the anti-diabetic activity and quality of action of the compounds of the invention, to use them in combination with biguanides, such as metformin, with anti-diabetic sulfonylureas, such as glibenclamide, glimepiride, tolbutamide, etc., with glucosidase inhibitors, with PPAR agonists, such as rosiglitazone, pioglitazone, etc., with insulin products in different administration forms, with DB4 inhibitors, with insulin sensitizers or with meglitinide.

In addition to the acute antidiabetic effect, the compounds of formula I and/or pharmaceutically acceptable salts thereof block the development of late complications of diabetes and are therefore useful as agents for the prevention and treatment of late damage caused by diabetes such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy and other conditions caused by diabetes. In this respect, they may advantageously be used in combination with an antidiabetic agent as described in the treatment of NIDDM. In this respect, the combination with a beneficial dosage form of insulin should be of particular importance.

In addition to a protective effect against acute ischemic events and subsequent equivalent acute stress reperfusion events, NHE1 inhibitors also show a direct therapeutically utilizable effect on diseases and conditions of the whole mammalian body which are associated with the manifestation of a chronic progressive aging process and which occur under normal, non-ischemic conditions independently of acute hypoperfusion states. These pathological, age-related manifestations induced in long-term aging, such as illness, disability and death, are diseases and disorders mainly caused by age-related changes in vital organs and their functions and become increasingly important in the aging body, which can now be treated with NHE inhibitors.

Conditions associated with age-related hypofunction or age-related manifestations of organ aging are, for example, inadequate responsiveness and responsiveness of blood vessels to systolic and diastolic responses. This age-related decline in vascular responsiveness to systolic and diastolic stimuli, which are important processes in the cardiovascular system and thus vital processes of life and health, can be significantly eliminated or reduced by NHE inhibitors. An important function and measure of maintaining vascular reactivity is to block or delay the age-related progression of endothelial dysfunction, which can be very significantly eliminated by NHE inhibitors. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore very suitable for the treatment and prevention of age-related progression of endothelial dysfunction, especially intermittent claudication.

Another example of variables that characterize the aging process are a decrease in contractility of the heart and a decrease in the adaptability of the heart to the amount of cardiac pumping required. In most cases, this reduced cardiac efficiency resulting from the aging process is associated with cardiac dysfunction, which is caused in particular by the deposition of connective tissue in the myocardial tissue. This connective tissue deposition is characterized by increased heart weight, enlarged heart and limited cardiac function. Surprisingly, it is almost entirely possible to inhibit this ageing of the heart organs. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are well suited for the treatment and prevention of heart failure, Congestive Heart Failure (CHF).

With NHE inhibitors, it is not only possible to cure an already existing cancer by inhibiting proliferation, but also to reduce and very significantly delay the age-related onset of cancer. It is particularly noteworthy to find that not only certain types of cancer, but also all organs of the disease that occurs as a result of aging, are inhibited or very significantly delayed in their occurrence. Accordingly, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for the treatment, in particular prevention, of age-related types of cancer.

It was found that the onset of age-related disorders of all organs studied, including heart, blood vessels, liver, etc., can be delayed very significantly with NHE inhibitors, and that cancer in elderly people is also delayed very significantly. In contrast, it is surprising that the life is also extended to the extent that no other class of drugs or any natural products are available to date. In addition to the use of this active ingredient alone in humans and animals, this unique effect of NHE inhibitors also makes it possible to use these NHE inhibitors in combination with other active ingredients, measures, substances and natural products used in geriatrics and based on different mechanisms of action. Such active ingredients used in geriatrics are in particular vitamins and substances with antioxidant activity. Due to the interrelationship between caloric load or food intake and the aging process, the combination with dietary measures can be carried out, for example, with appetite suppressants. Combinations with hypotensive agents are also contemplated, e.g. with ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca⁺²Antagonists and the like or in combination with metabolism-normalizing drugs such as cholesterol-lowering drugs.

Thus, the compounds of formula I and/or pharmaceutically acceptable salts thereof are very suitable for the prevention of age-related tissue changes and for prolonging life, while maintaining a high quality of life.

The compounds of the invention are potent inhibitors of cellular sodium-proton antiporters (Na/H exchanger), which are also increased in easily detectable cells such as, for example, erythrocytes, platelets or leukocytes, in a variety of conditions (essential hypertension, atherosclerosis, diabetes, etc.). The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example as diagnostic agents for determining and distinguishing between different types of hypertension and advanced complications of atherosclerosis, diabetes and diabetes, proliferative disorders, etc.

Also claimed is a medicament for human, veterinary or plant protection use comprising an effective amount of a compound of formula I and/or a pharmaceutically acceptable salt thereof, alone or in combination with other pharmacologically active ingredients or medicaments, together with pharmaceutically acceptable carriers and additives.

In this regard, medicaments comprising a compound of formula I and/or a pharmaceutically acceptable salt thereof may be administered, for example, orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred mode of administration depending on the particular characteristics of the condition. The compounds of formula I can also be used in veterinary and human medicine, alone or together with pharmaceutically acceptable excipients. In general, the medicament comprises from 0.01mg to 1g of the active ingredient of formula I and/or a pharmaceutically acceptable salt thereof per dosage unit.

The skilled worker is familiar, on the basis of his expert knowledge, with excipients which are suitable for the desired pharmaceutical preparation. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active ingredient carriers, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or colorants.

For oral use, the active compounds can be mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by customary methods, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. It is also possible to use dry granules and wet granules for the preparation. Examples of suitable oily carriers or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous, intramuscular or intravenous administration, the active compounds can be formulated as solutions, suspensions or emulsions, if desired with the addition of substances customary for this purpose, such as solubilizers, emulsifiers or other excipients. Examples of suitable solvents are water, physiological saline or alcohols, for example ethanol, propanol, glycerol, and sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Pharmaceutical preparations which are suitable 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 a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water or a mixture of such solvents. The formulations may also contain other pharmaceutically acceptable excipients such as surfactants, emulsifiers and stabilisers and propellant gases, if desired. Such formulations typically contain the active ingredient in a concentration of about 0.1 to 10%, particularly about 0.3 to 3%, by weight.

The dosage and frequency of administration of the active ingredients of formula I depend on the potency and duration of action of the compounds used; but also on the nature and severity of the condition to be treated, as well as the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of formula I and/or a pharmaceutically acceptable salt thereof is at least 0.001mg/kg body weight, preferably 0.01mg/kg body weight up to 10mg/kg body weight, preferably 1mg/kg body weight, for a patient weighing about 75 kg. Higher and especially more frequent doses, e.g. up to 4 single doses per day, may also be required for acute episodes of the condition, e.g. immediately after experiencing a myocardial infarction. Doses up to 700mg per day may be necessary, in particular for intravenous administration, for example for infarcted patients in intensive care units, and the compounds of the invention may be administered by infusion.

List of abbreviations:

ADMET absorption-distribution-metabolism-excretion-toxicology

CDI diimidazol-1-yl methanones

dba dibenzylidene acetone

DIP diisopropyl ether

DIPEA diisopropylethylamine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EA acid ethyl ester

eq. equivalent

HOAc acetic acid

KOtBu 2-methylpropan-2-ol potassium salt

MeOH methanol

mp melting point

MTB Tert-butyl methyl Ether

NMP N-methyl-2-pyrrolidone

OAc acetate

dppf 1, 1' -bis (diphenylphosphino) ferrocene

RT Room temperature

THF hydrofuran

TMEDA N, N, N ', N' -tetramethylethane-1, 2-diamine

Experimental part

Example 1: n- (5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) guanidine

a) 4-aminophenyl sulfur pentafluoride

A solution of tin (II) chloride (1465g, 7.73mol) in concentrated (32%) aqueous HCl was heated to 80 ℃ with stirring and then 4-nitrophenyl sulphur pentafluoride (584g, 2.344mol) was introduced in 8 portions over 1h under ice cooling. During which the internal temperature is kept below 100 ℃. Subsequently, the mixture was stirred at an internal temperature of 85 ℃ for 1.5h and then cooled to 45 ℃ over a further 1 h. A mixture of ice (12kg), NaOH (2kg) and dichloromethane (1.5L) was prepared and the reaction mixture was added with vigorous stirring. Separating the phases, extracting the aqueous phase with dichloromethane 3 times, 1L each time, combining the organic phases, and adding Na₂SO₄Dried and evaporated in vacuo. 510g of 4-aminophenylsulfur pentafluoride are obtained as pale yellow crystalline powder, m.p.63-65 ℃.

b) 4-amino-3-bromophenyl-sulfur pentafluoride

4-Aminophenylsulfur pentafluoride (510g, 2.327mol) was dissolved in methylene chloride (7L), the solution was cooled to 5 ℃ and 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (326g, 1.14mol) was introduced in several portions while stirring, while cooling with ice so as to keep the internal temperature at 3 to 8 ℃ (about 1 h). The mixture was then stirred in the absence of external cooling and allowed to warm to room temperature for 1 h. The mixture was filtered through a bed of silica gel (volume about 1L), washed with dichloromethane (5.5L) and the filtrate was evaporated in vacuo. About 700g of a red-brown crystalline substance was obtained, which was dissolved in n-heptane (600ml) at 60 ℃ and then crystallized in a refrigerator at 4 ℃. Suction filtration gave 590g (85%) of 4-amino-3-bromophenyl-sulfur pentafluoride as brownish crystals m.p.59-59.5 ℃.

c) 4-amino-3-methylphenyl sulfur pentafluoride

Mixing Cs₂CO₃A mixture of (794g, 2.7mol), dimethoxyethane (2L), water (300ml) and trimethylboroxocyclohexene (boroxine) (50% in THF, 225g, 0.9mol) was heated to 70 deg.C and PdCl was added₂(dppf)×CH₂Cl₂(37g, 45mmol), a solution of 4-amino-3-bromophenyl sulfur pentafluoride (270g, 0.9mol) in dimethoxyethane (400ml) was added dropwise over 2h while the reaction mixture was heated to reflux. It was then heated at reflux for a further 3h, then cooled to room temperature, diluted with MTB ether (500ml), filtered through a column of silica (14X 7cm, 70-200 μm) and washed with MTB ether (2500 ml). The filtrate was evaporated in vacuo. 490g of a black semicrystalline material are obtained which are subjected to steam distillation. A total of 5.5L of condensate was collected, from which the crystals of the product were separated. Extracting the condensate with MTB ether for 3 times, combining the organic phases, and adding Na₂SO₄Dried and evaporated in vacuo. 4-amino-3-methylphenyl-pentafluoride (181g, 76%) was obtained as colorless crystals at m.p.65-66 ℃.

d) 4-bromo-3-methylphenyl sulfur pentafluoride

Tert-butyl nitrite (90% pure, 37ml, 280mmol) was reacted with CuBr₂A mixture (35.8g, 160mmol) in acetonitrile (260ml) was cooled to 5 ℃ with stirring and ice-coolingSimultaneously, a solution of 4-amino-3-methylphenylsulfpentafluoride (30.9g, 132.5mmol) in MTB ether (140ml) was added dropwise over a period of 1h at 5-8 ℃. After about 2min nitrogen evolution began. The mixture was then allowed to warm to room temperature over 1h with stirring, and ice (250g), 26% NH were added₃A mixture of aqueous solution (50ml) and MTB ether (250ml) was stirred for 10 min. The phases were separated, the aqueous phase was extracted 3 times with MTB ether (150ml each), the organic phases were combined and shaken once with 400ml of water. With Na₂SO₄The organic phase was dried and evaporated to give 39g of 4-bromo-3-methylphenyl sulfur pentafluoride as a red-brown oil contaminated with 8 mol% of 4, 5-dibromo-3-methylphenyl sulfur pentafluoride, but used without further purification. The yield was 89% based on 90% purity.

e) 4-cyano-3-methylphenyl sulfur pentafluoride

4-bromo-3-methylphenylsulfpentafluoride (136.4g, 80% purity, 0.367mol), Zn (CN) under stirring and nitrogen blanketing₂A mixture of (72.8g, 0.62mol) and Zn powder (7.2g, 0.11mol) in dimethylacetamide (900ml) and water (40ml) was heated to 125 ℃ and PdCl was added₂(dppf)×CH₂Cl₂(32.7g, 40 mmol). After stirring at 125 ℃ for 1 hour, PdCl was added again₂(dppf)×CH₂Cl₂(16.3g, 20mm0l) and Zn powder (3.6g, 55mmol), stirring was continued at 125 ℃ for 2 h. The mixture was then cooled to room temperature, diluted with N-heptane (400ml), and 5N NH was added₄Aqueous Cl (250ml) and water (450ml) with vigorous stirring for 15 min. The mixture was filtered with suction through a layer of celite, the phases were separated and the aqueous phase was extracted 2 times with n-heptane (200 ml). The combined organic phases were shaken with water (450ml) and MgSO₄Dried and evaporated in vacuo. The resulting black residue was dissolved in 200ml of n-heptane, filtered and evaporated again in vacuo. 78g of a dark brown liquid are obtained which is purified by column chromatography on silica gel (7X 55cm, 60-200. mu.m, n-heptane)Dichloromethane 4: 1 to 3: 2). The first fraction obtained was 6.5g of 4-bromo-3-methylphenyl sulfur pentafluoride (precursor) as a yellowish liquid, and 71.1g (80%) of 4-cyano-3-methylphenyl sulfur pentafluoride was then obtained as a pale yellow oil.

f) 2-methyl-4-pentafluorosulfanylbenzoic acid

A mixture of 4-cyano-3-methylphenyl-sulfur pentafluoride (41.2g, 169.4mmol), NaOH (20.4g, 510mmol) and water (60ml) in ethylene glycol (160ml) was heated to 130 ℃ and stirred at this temperature for 4 h. It was then cooled to room temperature, diluted with MTB ether (150ml) and water (250ml) and the mixture was filtered with suction. The filtrate phases were separated, the aqueous phase was acidified with concentrated aqueous HCl and the precipitated solid was filtered off with suction. 41.1g (93%) 2-methyl-4-pentafluorosulfanylbenzoic acid are obtained as colorless crystals m.p.138-139 ℃.

g) 2-methyl-5-nitro-4-pentafluoro-thiobenzoic acid

6.0g of 2-methyl-4-pentafluorosulfanylbenzoic acid are dissolved in 60ml of 90% HNO₃Aqueous solution, 6ml of 96% H are added dropwise at RT₂SO₄. The mixture is left at RT for 28h and then poured into 300g of ice, 300ml of water are added, stirring is carried out for 1h, and the product is filtered off. Air dried to give 6.5g of a pale yellow solid, mp.218-220 ℃.

R_f(DIP/2％HOAc)＝0.27 MS(ES^-)：306

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

6.5g 2-methyl-5-nitro-4-pentafluorosulfanylbenzoic acid were dissolved in 100ml MeOH and 20ml HOAc, and 500mg 10% Pd/C were added. Hydrogenation under hydrogen at atmospheric pressure and RT for 20 h. The reaction was incomplete and therefore hydrogenation was continued at 6 bar hydrogen pressure and RT for 48 h. The catalyst was then filtered off and the solvent was removed in vacuo. 5.7g of a pale grey solid are obtained, mp.187-189 ℃.

R_f(DIP/2％HOAc)＝0.23 MS(ES^-)：276

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

1.0g of 5-amino-2-methyl-4-pentafluorosulfanylbenzoic acid was dissolved in 30ml of HOAc, and 30g of ice and 30ml of saturated aqueous HCl were added. 274mg of NaN0 were then added dropwise over a period of 1 minute at 0 deg.C₂Solution in 1ml of water. The mixture was stirred at 0 ℃ for 15 minutes. The resulting suspension was then added portionwise to 6.1mg CuCl and 61.5mg CuCl cooled to 0 deg.C₂×2H₂O in 30ml of saturated SO₂In a solution of HOAc. The mixture was stirred at 0 ℃ for 1h, then at RT for 1 h. The reaction mixture is subsequently extracted 3 times with 200ml of diethyl ether each time. With MgSO₄Dried and the volatile components removed in vacuo. 1.3g of product are obtained, which is immediately reacted further.

k) 2-methyl-5-sulfin-4-pentafluoro-thiobenzoic acid

1.2g of 5-Chlorosulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid was added portionwise to 4.2g of Na heated to 70 deg.C₂SO₃In a solution of 50ml of water, the pH of the solution was maintained between pH 9 and pH 11 with 2N aqueous NaOH during this time. The mixture was stirred at 70 ℃ for 20 minutes, cooled to RT and adjusted to pH 1-2 with aqueous HCl. The mixture was left at RT for 16h, then the product was filtered off and dried in vacuo. 1.0g of a white solid is obtained, mp.288-290 deg.C (with decomposition).

R_f(EA/MeOH 1∶1)＝0.52

l) 5-Methylsulfonyl-2-methyl-4-pentafluorosulfanylbenzoic acid methyl ester

1.0g of 2-methyl-5-sulfin-4-pentafluorosulfanylbenzoic acid are suspended in 10ml of water, and 3.1ml of 2N aqueous NaOH solution (phenolphthalein: basic) are added. The water was removed in vacuo and then co-evaporated twice with 20ml of toluene each time. The disodium salt was then dissolved in 40ml anhydrous DMF and after addition of 0.69ml methyl iodide, it was stirred first at 60 ℃ for 4h and then at RT for 15 h. The reaction mixture was poured into 100ml of water and the first portion of product (500mg) was filtered off with suction. The filtrate was adjusted to pH 2 with aqueous HCl and extracted 3 times with EA, 30ml each time. With MgSO₄Dried and the solvent removed in vacuo. Chromatography on silica gel eluting with DIP gave an additional 460mg of white crystals, mp.127 ℃. R_f(DIP)＝0.36

m) N- (5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) guanidine

0.70g of guanidinium chloride and 0.68g of KOtBu are stirred in 20ml of anhydrous DMF for 30 minutes at RT. The suspension is then added to 0.43g of methyl 5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoate and stirred at RT for 16 h. The reaction mixture is then poured into 200ml of water, adjusted to pH 8 with aqueous HCl and extracted 3 times with 100ml of EA each time. With MgSO₄Dried and the solvent removed in vacuo. The residue was suspended in 5ml CH₂Cl₂In (3), the product is filtered off. 190mg of colourless crystals are obtained, mp.254-256 ℃.

R_f(EA)＝0.22 MS(ES⁺)：382

Example 2: n- (5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) -guanidine methanesulfonate

9.3g of the title compound of example 1 are suspended in 100ml of water, and a solution of 2.3g of methanesulfonic acid in 10ml of water is added. The mixture was subsequently stirred at RT for 30 minutes, after which water was removed under reduced pressure to give 11.7g of methanesulfonate which was subsequently recrystallized from 110ml of water to give 10.0g of N- (5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) guanidine methanesulfonate as white crystals, m.p.230 ℃.

Example 3: n- (5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl) -guanidine hydrochloride

300mg of the title compound of example 2 were suspended in 50ml of saturated Na₂CO₃In the aqueous solution, 40ml each time, are extracted 2 times with EA. The EA phase is subsequently separated with MgSO₄Dried and the solvent removed under reduced pressure. The residue was dissolved in 10ml MeOH and mixed with 2ml 10% aqueous HCl. Volatiles were removed under reduced pressure leaving 230mg of white crystals, m.p.276-278 ℃.

Measurement of NHE inhibition

Inhibitory concentration IC of NHE-1 inhibition was determined as follows₅₀：

In the FLIPR assay, the pH was determined in transfected cell lines expressing human NHE-1_iRecovery to determine IC for NHE-1 inhibition₅₀。

The assay was performed in a FLIPR (fluorescence imaging plate reader) using a black-walled 96-well microtiter plate with a transparent bottom. Transfected cell lines expressing various NHE subtypes were seeded the previous day at a density of-25,000 cells/well (the parental cell line LAP-1 had no endogenous NHE activity as a result of mutagenesis and subsequent selection).

The growth medium of the transfected cells (Iscove + 10% fetal bovine serum) also contained G418 as a selection antibiotic to ensure the presence of the transfection sequence.

The actual assay was performed to remove growth medium and 100. mu.l loading buffer (5. mu.M in 20mM NH) was added to each well₄Cl, 115mM choline chloride, 1mM MgCl₂、1mM CaCl₂5mM KCl, 20mM HEPES, 5mM glucose; pH 7.4[ adjusted with KOH]BCECF-AM [2 ', 7' -bis (carboxyethyl) -5- (and-6) -carboxyfluorescein, acetoxymethyl ester of (E)]) And starting. The cells were then incubated at 37 ℃ for 20 minutes. This incubation loads the cells with a fluorescent dye whose fluorescence intensity depends on pHi and NH which makes the cells slightly basic₄Cl。

The ester form of the non-fluorescent dye precursor BCECF-AM is membrane permeable. The true dye BCECF is not membrane permeable and is released intracellularly by esterases.

After 20 minutes of incubation, the cells were washed by washing with 400. mu.l each time of wash buffer (133.8mM choline chloride hydrochloride, 4.7mM KCl, 1.25mM MgCl. sub.1.25 mM) in a cell washer (Tecan C0lumbus)₂、1.25mM CaCl₂、0.97mM K₂HPO₄、0.23mM KH₂PO₄5mM HEPES, 5mM glucose; pH 7.4[ adjusted with KOH]) Washing three times to remove NH₄Cl and free BCECF-AM. The residual volume remaining in the wells was 90. mu.l (possibly 50-125. mu.l). This washing step removes free BCECF-AM and due to the removal of the external NH₄ ⁺Ions lead to intracellular acidification (. about.pHi 6.3-6.4).

Due to intracellular NH₄ ⁺And NH₃And H⁺The balance between them being due to the removal of extracellular NH₄ ⁺And then NH₃Instantaneously passing through cell membrane to be destroyed, so that the washing process makes H⁺Remains intracellular, which is responsible for intracellular acidification. This can eventually lead to cell death if maintained for a sufficient period of time.

In this regard, it is important that the wash buffer is sodium free (< 1mM) because extracellular sodium ions can transiently restore pHi through activity of the cloned NHE isoform. It is also important that all buffers used (loading buffer, washing buffer, recovery buffer) do not contain any HCO₃ ^-Ion, because the presence of bicarbonate activates the intervening bicarbonate-dependent pHi regulatory system present in the parent LAP-1 cell line.

The microtiter plates containing the acidified cells were then transferred (no more than 20 minutes after acidification) to a FLIPR. In the FLIPR, the fluorochromes in the cells are excited with light of 488nm wavelength generated by an argon laser, and the measurement parameters (laser power, irradiation time and aperture of the CCD camera fitted in the FLIPR) are chosen so that the mean fluorescence signal per well is between 30,000 and 35,000 relative fluorescence units.

The real measurement in FLIPR starts with the CCD camera taking a picture every two seconds under software control. After 10 seconds, 90. mu.l recovery buffer (133.8mM NaCl, 4.7mM KCl, 1.25mM MgCl) was added by pipetting through 96-well equipped in FLIPR₂、1.25mM CaCl₂、0.97mMK₂HPO₄、0.23mM KH₂PO₄10mM HEPES, 5mM glucose; pH 7.4[ adjusted with NaOH]) Triggering intracellular pH recovery.

Positive control wells (100% NHE activity) were those to which pure recovery buffer was added, while negative control wells (0% NHE activity) were to which wash buffer was added. Recovery buffer containing twice the concentration of the test substance was added to all other wells. The measurement in the FLIPR was stopped after 60 measurements (two minutes).

Raw data is input to the ActivityBase program. The program first calculates the NHE activity for each test substance concentration and therefrom calculates the IC of said substance₅₀The value is obtained. Since the pHi recovery process is not linear throughout the experiment, but decreases at the end due to the decrease in NHE activity at higher pHi values, it is important to select the portion where the increase in fluorescence of the positive control is linear for assay evaluation.

Examples	NHE1 inhibitory IC[nM]
Examples	NHE1 inhibitory IC[nM]	1	49

In vivo pharmacokinetics-described by "n in one approach

Exposure data and volume of distribution were determined as characteristic pharmacokinetic data as follows:

the NHE-1 inhibitor of example 1 of the invention and a known NHE-1 inhibitor of the formula Carripolide as reference substance

Dissolved in an aqueous, slightly acidic medium (water, pH 4, adjusted with 1M hydrochloric acid). The concentration of the aqueous preparation prepared in this way was about 1.5mg of each substance per 1g of solution. 10ml of this formulation was administered as a single bolus via catheter into the jugular vein of fasted male beagle dogs (dose of about 1mg of each substance administered per kg of dog body weight). Blood samples were collected via a second catheter after 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h and centrifuged at 1000G in a suitable plasma tube to prepare heparinized plasma.

Plasma samples were post-processed, separated by HPLC and quantified by MS/MS. The method has high specificity, and can simultaneously detect multiple substances. Using the WinNonlin computer program, the exposure can be calculated from a concentration-time plot (see fig. 1), which is compared to the exposure of a known NHE-1 reference substance. Since different substances are measured in the same animal at the same time, the result is an accurate comparison of these compounds, and an arrangement of distribution volumes is possible.

Compound (I)	Volume distribution [ l/kg body weight]
Compound (I)	Volume distribution [ l/kg body weight]	Example 1	1.67
Reference substance cariporide	2.94	Example 1	1.67

As is evident from the concentration-time plot of fig. 1, the compounds of the present invention are retained in the blood for longer periods of time, and thus exposure is about 2-3 times higher than the reference substance cariporide. After 24 hours, cariporide could no longer be detected in the plasma.

The illustrations and symbols in the figures are as follows:

FIG. 1: canine plasma concentration-time profiles post-carisoprodane administration of about 1mg/kg of the compound of example 1 and, respectively

And a y axis: the concentration of the compound determined in the plasma is measured in μ g/ml

The x axis is as follows: time in h

Claims

1. A compound of formula I

The compound is N- (5-methylsulfonyl-2-methyl-4-pentafluorosulfanyl benzoyl) guanidine or a pharmaceutically acceptable salt thereof.

2. A process for preparing a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula II with guanidine, wherein said compound of formula II is:

wherein R1 to R4 have the meaning as indicated in claim 1, L is a leaving group capable of undergoing nucleophilic substitution.

3. The use of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of acute or chronic injury, disorders or indirect sequelae of organs and tissues resulting from ischemic or reperfusion events; for the treatment or prevention of cardiac arrhythmias, fatal ventricular fibrillation, myocardial infarction, angina pectoris; for treating or preventing ischemic conditions of the heart, peripheral and central nervous system, stroke, or peripheral organs and tissues; for the treatment or prevention of a state of shock, a disease in which cell proliferation is of primary or secondary origin, cancer, metastasis, prostatic hypertrophy or hyperplasia, atherosclerosis or a disorder of lipid metabolism, hypertension, essential hypertension, a disorder of the central nervous system, a disorder resulting from central nervous system hyperexcitability, epilepsy or a centrally induced convulsion; for the treatment or prevention of non-insulin dependent diabetes mellitus or diabetes-induced late stage injury, thrombosis, endothelial dysfunction-induced conditions, intermittent claudication; for treating or preventing fibrotic disorders of internal organs, fibrotic disorders of blood vessels; for the treatment or prevention of heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, malaria and poultry coccidiosis; for surgery and organ transplantation; for storage and storage of surgical grafts; for bypass surgery; for resuscitation after cardiac arrest; for preventing age-related tissue changes; for combating ageing or for prolonging life; can be used for treating and relieving cardiotoxic effects of thyrotoxicosis.

4. The use of claim 3, wherein the central nervous system disorder is an anxiety state, depression or psychosis.

5. The use of claim 3, wherein the fibrotic disorder of an internal organ is a liver fibrosis disorder, a kidney fibrosis disorder, or a cardiac fibrosis disorder.

6. The use of claim 3, wherein the heart failure is congestive heart failure.