ZA200602575B

ZA200602575B - Method for producing 4-pentafluoride-sulfanyl-benzoyl-guanidines

Info

Publication number: ZA200602575B
Application number: ZA200602575A
Authority: ZA
Inventors: Schubert Gerrit; Kleemann Heinz-Werner
Original assignee: Sanofi Aventis Deutschland
Priority date: 2003-11-13
Filing date: 2006-03-29
Publication date: 2007-05-30
Also published as: IL175238A0; IL175238A; PL1685097T3; NO20062664L; AU2004288760B2; WO2005047241A1; DE502004006216D1; PT1685097E; CN101475519B; HK1095582A1; NZ547170A; KR101207223B1; EP1685097B1; DK1685097T3; ATE386019T1; EP1685097A1; RU2006120473A; HK1133870A1; RU2382030C2; CN100480237C

Description

@® Method for producing 4-pentafluoride-sulfanyl-benzoylguanidines

The present invention relates to a process for preparing 4-pentafluoro- sulfanylbenzoylguanidines with the formula I. The compounds of the formula | are NHE1 inhibitors and can be employed for example for the treatment of cardiovascular disorders.

DE application 10222192 describes pentafluorosuifanylbenzoylguanidines as NHE1 inhibitors. However, the processes described therein for preparing these compounds proceed with low yield and require reagents and reaction conditions which necessitate great technical complexity or are unsuitable for preparation on a relatively large scale.

It has now been found that said disadvantages can be avoided by a novel efficient synthesis which starts from 4-nitrophenylsulfur pentafluoride, which can be bought.

The present invention thus relates to a process for preparing compounds of the formula

R3.

FS R2

Ra NS

Rl O NH,

I 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, NR10R11, -Op-(CH2)n-(CF2)o-CF3 or -(SOm)q-(CH2)r--(CF2)s-CF3;

R10 and R11 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH,-CF 5; m zero, 1 or2 n,o, p,q, rands independently of one another zero or 1;

R2 hydrogen, -(SOn)z-(CH2)k-(CF,), -CF,, alkyl having 1,2, 3,4, 5 or 6 carbon atoms, 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 i Co atoms; ® h zero, 1 or 2; z zero or 1; k zero, 1, 2, 3 or 4,

I zero or 1; or

R2 -(CH,),-phenyl or —O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O,-(CH,),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO,CH; t zero, 1, 2,3 or 4; u zero or 1; v zero, 1,2 or 3; or

R2 -(CH,), heteroaryl which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,-(CH,),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO,CH,; w zero, 1, 2,3 or 4;

X zero or 1; y zero, 1, 2 or 3;

R3 and R4, independently of one another hydrogen or F; and the salts thereof; which comprises, as depicted in scheme 1,

R3 R3 R3

FS H FS H F.S Xx ip > - R4 | NH, iy ; -

Al a R1 b R1 ¢ 1} Li] wv

R3 R3 R3

N ; ~ F.S : R2 - ;

R CN

~ R1 hk d ™ R1 Y e ‘ A1 ! \' vi vii

R3 R3 ; 8 Cr

Re co, 0 4 Nop

R1 Rt O NH, vil

® Scheme 1 a) reducing a 4-nitrophenylsulfur pentafluoride derivative of the formula Il to the amine of formula lll, and b) halogenating the compound of the formula Ill in the ortho position to the amino group with a halogenating agent to give the compound of the formula IV, and c) replacing the halogen substituent in the compound of the formula IV with a suitable nucleophile or an organoelement compound, for example an alkylboron compound, where appropriate with catalysis, by a substituent

R2, and d) replacing the amino function in the compound of the formula V by a halogen substituent, and e) replacing the halogen substituent in the compound of the formula VI by a nitrile function, and f) hydrolyzing the nitrile function of the compound of the formula Vil to the carboxylic acid, and g) converting the carboxylic acid of the formula VIII into the acyiguanidine of the formula I, where in the compounds of the formulae Ii, lil, IV, V, VI, Vl and VIII

R1 to R4 are as defined in formula | and

X and Y are independently of one another F, Cl, Bror |.

In one embodiment, preference is given to compounds of the formula | in which R1 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, NR10R11, -O-CH2-CF3 or —-SOm-(CH2)~CF3 where R10 and R11 are independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —-CH2-CF3, and where m is zero, 1 or 2 and r is zero or 1, with particular preference for compounds in which R1 are described by hydrogen or methyl. In a further embodiment, preference is given to compounds of the formula | in which R2 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —SOh-(CH2)k-CF3 where h is zero, 1 or 2 and k is zero or 1, phenyl or —O-phenyl, which are unsubstituted or substituted as indicated, with particular preference for compounds in which

R2 is described by hydrogen or methyl.

In a further embodiment, preference is given to compounds of the formula in which R3 and R4 are described by hydrogen.

The procedure for preparing the compounds of the formuia | is initially in step a (Scheme 1) to convert the compounds of the formula Il by methods @ known in principle for the reduction of aromatic nitro compounds to aromatic amines into compounds of the formula lil. Such methods are described, for example, in: R.C. Larock, Comprehensive Organic

Transformations: A Guide to Functional Group Preparations, VCH

Publishers, New York, Weinheim, 1999, 821-828 and the literature cited therein.

Subsequently (step b), the compounds of the formula Il 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 -30°C to +150°C, preferably 0°C to 40°C. The reaction time is generally from 10 min 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 organic solvent A and, after removal of the solvent in vacuo, purifying the product by conventional purification methods such as recrystallization, distillation or chromatography.

From 0.1 to 10 mol of the compound of the formula Il 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 Il to be halogenated.

The term “halogenating agent” 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 Transformations: 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's Advanced

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 H2SO4 or 1,3-dibromo- 5,5-dimethylimidazolidine-2,4-dione, the latter being able to transfer 2 bromine atoms per molecule. The term “brominating agent” means, for example, elemental bromine, bromine-amine complexes, cyclic and acyclic

N-brominated carboxamides and —imides, and ureas, as described, for example, in R.C. Larock, Comprehensive Organic Transformations: 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’s Advanced Organic Chemistry: Reactions,

Mechanisms, and Structure, Wiley, New York, 2001, 704-707, and the ® literature cited therein, for example N-bromosuccinimide, HBr in HoSO4 or 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, the latter being able to transfer 2 bromine atoms per molecule. 5 The term “organic solvent A” preferably means aprotic solvents such as, for 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.

In step c, the compounds of the formula IV are subsequently dissolved in an organic solvent B and reacted with a nucleophile R2 or an element compound comprising the substituent R2 to give compounds of the formula

V. It is possible in this case to add a base A and to add a catalyzing metal salt A.

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 B 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 IV for example are dissolved in 1000 ml of organic solvent B. For example, from 0.8 to 3 equivalents of the nucleophile R2™ or of the element compound comprising the substituent R2 are used for 1 mol of the starting compound of the formula lV.

The term “nucleophile R2™ means compounds which result on deprotonation of a compound R2-H with strong bases such as, for example, alkyl- or aryllithium compounds, organomagnesium compounds, alcoholates or lithium diisopropylamide. “Organoelement compounds comprising the substituent R2" mean for example organolithium compounds R2-Li, organomagnesium compounds

R2-Mg-Hal, with Hal = Cl, Br, |, organoboron compounds such as

R2-B(OH)2, R2-boronic esters such as, for example,

\

Oo

R2-boronic anhydrides such as, for example,

Meng Orp

Op ©

R2 or organozinc compounds R2-Zn-Z, with Z = Cl, Br, |.

The term “base A” means bases like those used as auxiliary bases in cross-coupling reactions and 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 literature cited therein in each case, for example NapoCO3, Cs2CO3, KOH,

NaOH, K3PO4, N(ethyl)s.

The term “organic solvent B” 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., 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 etal., J. Am. Chem. Soc. 2002, 124, 13662 and the literature cited therein in each case, including the added ligands such as Pd(OAc)2, PdCiz(dppf) or Pda(dba)s.

In step d, the compounds of the formula V are subsequently converted into the compounds of the formula VI 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

J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 935-936 or R.C. Larock,

Comprehensive Organic Transformations: 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 Gattermann ® reaction. The process of M. Doyle et al., J. Org. Chem. 1977, 42, 2426 or of

S. Oae et al., Bull. Chem. Soc. Jpn. 1980, 53, 1065 is preferred.

In step e, the compounds of the formula VI are reacted in a solvent C with a cyanidating agent, for example with addition of a catalyzing metal salt B.

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 extraction. After evaporation of the solvent in vacuo, the compound of the formula VII 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 VI for example are 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 compound having the formula VI to be reacted.

The term “cyanidating agent” means, for example, alkali metal cyanides or

Zn(CN)2 either alone or mixed with 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., 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 the literature cited therein, for example PdCl(dppf), Pd(OAc)2, Pd2(dba)s.

The resulting compounds of the formula Vil are subsequently hydrolyzed in step f to the carboxylic acids of the formula VIII, 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

Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1986-1987 or M.B. Smith and J. March, March’s Advanced Organic

Chemistry: Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 1179-1180 and the literature cited therein.

@® In step g, the carboxylic acids of the formula VII are then subsequently converted into the acylguanidines having the formula IX. For this purpose, the carboxylic acids are converted into activated acid derivatives such as carbonyl halides, preferably carbonyl! chlorides, esters, preferably methyl esters, phenyl esters, phenylthio esters, methylthio esters, 2-pyridyithio esters, or a nitrogen heterocycle, preferably 1-imidazolyl. The esters and nitrogen heterocycles are advantageously obtained in a manner known to the skilled worker from the underlying carbonyl chlorides, which in turn themselves can be prepared in a known manner from the underlying carboxylic acids, for example with thionyl chloride.

Besides the carbonyl chlorides, it is also possible to prepare other activated acid derivatives in a known manner directly from the underlying benzoic acids, such as the methyl esters by treatment with gaseous HCI in methanol, the imidazolides by treatment with carbonyldiimidazole the mixed anhydrides with CI-COOC2Hs5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)- methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU") are possible. A number of suitable methods for preparing activated carboxylic acid derivatives are indicated with indication of source literature

M.B. Smith and J. March, March’s Advanced Organic Chemistry:

Reactions, Mechanisms, and Structure, Wiley, New York, 2001, 506-516 or

R.C. Larock, Comprehensive Organic Transformations: a Guide to

Functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1941-1949.

Reaction of an activated carboxylic acid derivative with guanidine preferably takes place in a manner known per se in a protic or aprotic polar but inert organic solvent either with free guanidine base or with guanidinium chioride in the presence of a base. In this connection, methanol, isopropanol or THF at temperatures from 20°C to the boiling point of these solvents have proved suitable for the reaction of the methyl benzoates with guanidine. Most reactions of carboxylic acid derivatives with salt-free guanidine are advantageously carried out in aprotic inert solvents such as

THF, dimethoxyethane, dioxane. However, water can also be used as solvent in the reaction with guanidine on use of a base such as, for example, NaOH.

If a carbonyl chloride is employed as carboxylic acid derivative, it is advantageous to add an acid scavenger, for example in the form of excess ® guanidine, to bind the hydrohalic acid.

For preparing compounds of the formula | in which R2 is hydrogen, can the synthesis takes place without steps b and c.

In order to prepare compounds of the formula | with R2 = -(SOn)z-(CH2)k- (CF2), -CF3, where his 1 or 2, as described above compounds in which R2 is —(SOn)z~(CH2)k-(CF2)-CF3, where h is zero, are synthesized and subsequently converted by generally known oxidation reactions into the desired compounds of the formula |.

The reaction mixture can be worked up after each of process steps a), b), c), d), e), f) and g) or after two or more process steps. Synthesis of the compounds of the formula | by the process of the invention can, however, also take place in two or more consecutive process steps without isolation of the compounds lll, IV, V, VI, VII or VIII obtained in the individual process steps, in which case workup after each process step is unnecessary. The workup and, if desired, the purification of the products takes place by the usual methods such as extraction, pH separation, chromatography or crystallization and the usual dryings.

The starting compounds of the formulae Il are obtainable by purchase or can be prepared by or in analogy to processes described in the literature and known to the skilled worker, for example as described in Bowden,

R.D., Comina, P.J., Greenhall, M.P., Kariuki, B.M., Loveday, A., Philip, D.

Tetrahedron 2000, 56, 5660. 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 prepared by the process of the invention. Appropriate protective group techniques are known to the skilled worker. For example, the NH2 group in compounds of the formula Il in which R1 is NH2 can be present in a form protected by an acetyl, trifluoroacetyl or trityl group and be deprotected again.

A further aspect of the invention relates to novel compounds of the formulae V, VI, VII and VIII.

R3 [ F.S R2

R4 NH,

R1 V

R3 R3 R3 R3

FS R5 FS R5 FS R5 FS RS

R4 Y R4 CN R4 CO,H R4 COR8

RT Rt wi R1 vin R1 IX

The invention thus relates to 4-pentafluorosulfanyl-substituted compounds of the formula X

R3

FS R6

R4 NH,

R1

X 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, NR10R11, -0p-(CH2)n-(CF2)o-CF3 or -(SOpp)q-(CH2)~(CF2)s-CF3;

R10 and R11 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH,-CF 5; m zero, 1 or 2 n,o, p,q, rands independently of one another zero or 1;

RG -(SO,),~(CH,), -(CF,), -CF 5, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, 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; h zero, 1 or 2; z zero or 1; k zero, 1, 2, 3 or 4; zero or 1; or

R6 -(CH,)-phenyl or —O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O -(CH,), -CF 5, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO,CHy; ® t zero, 1,2,3 or 4; u zero or 1,

Vv zero, 1, 2 or 3; or

R6 -(CH,),,-heteroaryl which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,-(CH,),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO,CHg; w zero, 1, 2,3 or 4;

X zero or 1; y zero, 1,2 or 3;

R3 and R4, independently of one another hydrogen or F; and the salts thereof;

In one embodiment, preference is given to compounds of the formula X in which R1 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, NR10R11, -O-CH2-CF3 or —SOm-(CH2)CF3, where R10 and R11 are independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3, and where m is zero, 1 or 2 and r is zero or 1, with particular preference for compounds in which R1 are described by hydrogen or methyl. in a further embodiment, preference is given to compounds of the formula X in which R6 is described by hydrogen, F, Cl,

Br, |, alkyl having 1, 2, 3 or 4 carbon atoms or —-SOh-(CH2)k-CF3 where h is zero, 1 or 2 and k is zero or 1, phenyl or —O-phenyl, which are unsubstituted or substituted as indicated, with particular preference for compounds in which R6 is described by hydrogen or methyl, for example by hydrogen. In a further embodiment, preference is given to compounds of the formula X in which R6 is described by F, Cl, Br or |, in particular by Br.

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

X in which R3 and R4 are described by hydrogen.

The invention likewise relates to 4-pentafluorosulfanyl-substituted compounds of the formula XI

Claims

( Claims

1. A process for preparing compounds of the formula

R3. FS R2 Ra Ny Rl O NH, I 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, NR10R11, -Op-(CH2)n- CF2)o-CF3 or -(SOm)q-(CH2)~(CF2)s-CF 3; R10 and R11 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH,-CF; m zero, 1 or 2 n,o, p,q rands independently of one another zero or 1; R2 hydrogen, -(SOn)z-(CH2)k (CF), -CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, 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; h zero, 1 or 2; z zero or 1; Kk zero, 1, 2, 3 or 4; zero or 1; or R2 -(CH,)-phenyl or —O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,-(CH,),CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and t zero, 1,2,3 or 4; u zero or 1; \Y zero, 1,2 or 3;

or ( R2 -(CH,), heteroaryl which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,-(CH,),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO,CHg; w zero, 1, 2, 3 or 4, X zero or 1; y zero, 1,2 or 3; R3 and R4, independently of one another hydrogen or F; and the salts thereof; which comprises

R3 R3 R3 XX he “ R4 r NO, . R4 T NH, X R4 f NH, . Hi] Hi Vv R3 R3 R3 “CXC FS OC Fs XC R4 I NH, d R4 I Y o R4 f CN ; v vi vil R3 f3 FS R2 FeS R2 LC, g CC R1 RI O NH, vill a) reducing a 4-nitrophenylsulfur pentafluoride derivative of the formula ll to the amine of formula lil, and b) halogenating the compound of the formula lil in the ortho position to the amino group with a halogenating agent to give the compound of the formula IV, and c) replacing the halogen substituent in the compound of the formula IV with a suitable nucleophile or an organoelement compound, for example an alkylboron compound, where appropriate with catalysis,

by a substituent R2, and ® d) replacing the amino function in the compound of the formula V by a halogen substituent, and e) replacing the halogen substituent in the compound of the formula VI by a nitrile function, and f) hydrolyzing the nitrile function of the compound of the formula VII to the carboxylic acid, and g) converting the carboxylic acid of the formula Vil into the acylguanidine of the formula |, where in the compounds of the formulae Il, lll, IV, V, VI, Vil and VII! R1 to R4 are as defined in formula | and X and Y are independently of one another F, Cl, Bror I.

2. The process as claimed in claim 1, where steps a), b), ¢), d), e), f) and g) are managed independently of one another continuously or discontinuously.

3. The process as claimed in claim 1 and/or 2, in which R2 is hydrogen, and steps b) and c) are omitted.

4, A compound of the formula X R3 FS R6 R4 NH, R1 X 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, NR10R11, -Op-(CH2)n- (CF2)o-CF3 or -(SOm)q-(CH2)r(CF2)s-CF3; R10 and R11 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH,-CF ; m zero, 1 or 2 n,o, p,q rands independently of one another zero or 1; R6 -(SO),-(CH,), -(CF,), -CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, 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; . h zero, 1 or 2; z zero or 1; k zero, 1,2,3 or 4; zero or 1; or R6 -(CH,)-phenyl or —O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,-(CH,),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO,CH,; t zero, 1, 2, 3 or 4; u zero or 1; v zero, 1,2 or 3; or R6 -(CH,),-heteroaryl which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -0,~(CHy),-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO,CHg; w zero, 1, 2, 3 or 4; X zero or 1; y zero, 1, 2 or 3; R3 and R4, independently of one another hydrogen or F,; and the salts thereof;

5. A compound of the formula X and/or the pharmaceutically suitable salts thereof as claimed in claim 4 for use as synthesis intermediate.

6. A compound of the formula XI

® N FS R2 R4 R7 R1 Xi 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, NR10R11, -Op-(CH2)n- (CF2)o-CF3 or -(SOm)q-(CH2)-(CF2)s-CF 3; R10 and R11 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —-CH,-CF 5; m zero, 1 or 2 n,o, p,q, rands independently of one another zero or 1; R2 hydrogen, F, Cl, Br, I, -(SO,,),-(CH,), -(CF,), -CF or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; h zero, 1 or 2; z zero or 1; k zero, 1, 2,3 or 4, l zero or 1, R3 and R4, independently of one another hydrogen or F; R7 CN; and the saits thereof.

7. A compound of the formula XI and/or the pharmaceutically suitable salts thereof as claimed in claim 6 for use as synthesis intermediate.