MXPA06004928A - Method for producing 4-pentafluoride-sulfanyl-benzoylguanidines - Google Patents

Abstract

The invention relates to a method for producing 4-pentafluoride-sulfanyl-benzoylguanidines of formula (I) wherein groups from R1 to R4 correspond to meanings given in claims. The compounds of the formula (I) constitute NHE1 inhibitors and can be used for curing cardiovascular diseases.

Description

METHOD TO PRODUCE 4-P-NTAFLUORURO-SULFANIL- BENZQILGUANÍDINAS The present invention relates to a process for preparing 4-pentafluorosulfanylbenzoylguanidines of the formula I. The compounds of the formula I are inhibitors of NHE1 and can be used, for example, for the treatment of cardiovascular disorders. Application DE 10222192 describes pentafluorosulfanylbenzoylguanidines as NHE1 inhibitors. However, the methods described in that document for preparing these compounds proceed with a low yield and require reagents and reaction conditions that require great technical complexity or are unsuitable for preparation on a relatively large scale. It has now been found that such disadvantages can be avoided by a new effective synthesis starting from 4-nitrophenylsulfur pentafluoride, which can be purchased. Thus, the present invention relates to a process for preparing compounds of the formula I in which the meanings are: R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy with 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 with 1, 2, 3 or 4 carbon atoms or -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R2 hydrogen, - (SOh) z- (CH2) k- (CF2)? -FC3l alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms can be replaced by fluorine atoms; h zero, 1 or 2; z zero or 1: k zero, 1, 2, 3 or 4; I zero or 1; or R 2 - (CH 2) t-phenyl or -O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O- (CH 2) -CF 3, alkoxy with 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3; t zero, 1, 2, 3 or 4; u zero or 1; v zero, 1, 2 or 3; or R2 - (CH2) w-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O? - (CH2) and -FC3, alkoxy with 1, 2, 3 or 4 carbon and alkyl atoms with 1, 2, 3 or 4 carbon atoms, -SO 2 CH 3; w zero, 1, 2, 3 or 4; x zero or 1; and zero, 1, 2 or 3; R3 and R4, independently of one another, hydrogen or F; and its salts; which comprises as described in scheme 1, L or N v t vi? Vile! Scheme 1 a) reduce a 4-nitrophenol-sulfur pentafluoride derivative of the formula II in the amine of the formula III, and b) halogen the compound of the formula III in the ortho position with respect 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 alkylboro compound, if 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 on the compound of the formula VI with a nitrile function, and f) hydrolyzing the nitrile function with a compound of the formula VII to give the carboxylic acid, and g) converting the carboxylic acid of the formula VIII in the acylguanidine of the formula I, in which in the compounds of the formulas II, III, IV, V, VI, VII and VIII R1 to R4 are as defined in formula I and X and Y are, independently of one another, F, Cl, Br or I. In one embodiment, preference is given to compounds of formula I, wherein R 1 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms , methoxy, ethoxy, NR10R11, -O- (CH2) -CF3 or -SOm- (CH2) r CF3, in which R10 and R11 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3, and wherein m is zero, 1 or 2 and r is zero or 1, with particular preference for compounds wherein R 1 is described by hydrogen or methyl. In a further embodiment preference is given to compounds of the formula I, wherein R2 is described by hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -SOn- (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 wherein R2 is described by hydrogen or methyl. In a further embodiment, preference is given to compounds of the formula I, wherein R3 and R4 are described by hydrogen. The process for preparing the compounds of the formula I is, initially, in step a) (Scheme 1), converting the compounds of the formula II, by methods known in principle for the reduction of aromatic nitro compounds into aromatic amines, into compounds of formula III. Methods of this type 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 bibliography cited therein. Subsequently (step b), the compounds of formula III 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 10 min to 20 h, depending on the composition of the mixture and the chosen temperature range. The resulting reaction mixture can be treated by subsequent filtration through a layer of silica gel, washing with organic solvent A and, after removal of the solvent in vacuo, by purifying the product by conventional purification methods such as recrystallization, distillation or chromatography. 0.1 to 10 mol of the compound of the formula II, 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 per 1 mol of the compound of the formula I to halogenate. The term "halogenating agent" means, for example, elemental halogens, halogen and amine complexes, carboxamides and N-halogenated, cyclic and acyclic carboximides, 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, 614-628 and in the bibliography 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-dimethylimidazoidine-2,4-dione, the latter being capable of transferring 2 bromine atoms per molecule. The term "brominating agent" means, for example, elemental bromine, complexes of bromine and amine, carboxamides and N-brominated, cyclic and acyclic carboximides, 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 in the bibliography 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, HBr in H2SO4 or 1 , 3-dibromo-5,5-dimethylimidazoidine-2,4-dione, the latter being capable of transferring 2 bromine atoms per molecule. 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, trichlorethylene 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. In this case, it is possible to add a base A and add a catalytic metal salt A. The reaction temperature in this case generally ranges between -20 ° C and + 150 ° C, preferably between 30 ° C and 100 ° C. generally from 0.5 to 20 h, depending on the composition of the mixture and the chosen temperature range.The resulting reaction mixture can be made by subsequent filtration through a layer of silica gel, washing with an organic solvent B and, after removal of the solvent in vacuo, by purifying the product by conventional purification procedures such as recrystallization, chromatography, for example on silica gel, distillation or distillation. With water vapor, 0.1 to 10 moles of the compound of the formula IV, for example, are dissolved in 1000 ml of organic solvent B. For example, 0.8 to 3 equivalents of the nucleophile R2"or of the compound element comprising the substituent R2 are used per 1 mole of the starting compound of the formula IV. The term "nucleophile R2" "means compounds resulting after deprotonation of a compound R2-H with strong bases such as, for example, alkyl- or aryl-lithium compounds, organomagnesium compounds, alcoholates or lithium diisopropylamide. organo elements comprising the substituent R2"means, for example, organolithium compounds R2-Li, organomagnesium compounds R2-Mg-Hal, where Hal = Cl, Br, I, organoboron compounds such as R2-B (OH) 2, R2-boronic esters, such as, for example, R2-boronic anhydrides such as, for example, or organozinc compounds R2-Zn-Z, with Z = Cl, Br, I. The term "base A" means bases such as those used as auxiliary bases in cross coupling reactions and mentioned, for example, in A. Suzuki et al. al., Chem. Rev. 1995, 95, 2457-2483 or M. Lamaire et al., Chem. Rev. 2002, 102, 1359-1469 or SP Stanforth, Tetrahedron 1998, 54, 263-303 and the literature cited therein in each case, for example Na 2 CO 3, Cs 2 CO 3, KOH, NaOH, K 3 PO 4, N (ethyl) 3. 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 in water are preferred. The expression "catalytic metal salt A" means, among others, Pd and Ni catalysts such as those used for the 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 et al., J. Am. Chem. Soc. 2002, 124, 13662 and the literature cited in each case, including the added ligands such as Pd (OAc) 2, PdCI2 (dppf) or Pd2 (dba) 3. In step d, the compounds of the formula V are subsequently converted to 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 MB 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 bibliography cited therein, for example by the reaction of Sandmeyer or Gattermann. The method of M. Doyle et al., J. Org. Chem. 1977, 42, 2426 or from S. Oae et al., Bull. Chem. Soc. Jpn. 1980, 53, 1065. In step e, the compounds of formula VI are reacted in a solvent C with a cyaniding agent, for example with the addition of a catalytic metal salt B. The reaction temperature is generally 20 ° C at 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 diatomaceous earth and the filtrate can be worked up by aqueous extraction. After evaporation of the solvent in vacuo, the compound of formula VII is purified by conventional purification procedures such as recrystallization, chromatography on silica gel, distillation or steam distillation. 0.1 to 10 moles 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 cyanide agent are used per 1 mole of the starting compound of the formula I saw that he has to react. The term "curing agent" means, for example, alkali metal cyanides or Zn (CN) 2 either alone or mixed with metallic zinc, preferably in the form of zinc powder. The term "organic solvent C" preferably means polar aprotic solvents such as, for example, DMF, dimethylacetamide, NMP, DMSO. The term "catalytic metal salt B" means, among others, Pd and Ni catalysts as used in the Suzuki reaction 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 SP Stanforth, Tetrahedron 1998, 54, 263 and the literature cited therein, for example PdCI2 (dppf), Pd (OAc) 2 or Pd2 (dba) 3. The resulting compounds of the formula VII are subsequently hydrolyzed in step f to form the carboxylic acids of the formula VIII, for example in the presence of a base. This can take place by methods 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 VIII are subsequently subsequently converted to the acylguanidines with the formula IX. For this purpose, the carboxylic acids are converted into activated acid derivatives such as carbonyl halides, preferably carbonyl chloridesesters, preferably methyl esters, phenyl esters, phenylthio esters, methylthio esters, 2-pyridylthio esters, or a nitrogenous heterocycle, preferably 1-dimethyloxy. The nitrogenous esters and heterocycles are advantageously obtained in a manner known to the skilled worker from the carbonyl chlorides on which they are based, which in turn can be prepared by themselves in a known manner from the carboxylic acids in those based, for example, with thionyl chloride. In addition to the carbonyl chlorides, it is also possible to prepare other activated acid derivatives in a known manner, directly from the benzoic acids on which they are based, such as the methyl esters by treatment with gaseous HCl in methanol, the imidazolides by treatment with carbonyldiimidazole, the mixed anhydrides with CI-COOC2H5 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) tetrafluoroborate) amino] -1, 1, 3,3-tetramethyluronium ("TOTU"). A number of suitable methods are indicated for preparing activated carboxylic acid derivatives, with indication of the source literature in 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. The reaction of a guanidine activated carboxylic acid derivative preferably takes place in a manner known per se in a polar organic solvent, protic or aprotic, but inert, either with a free guanidine base or with guanidinium chloride in the presence from a base. In this regard, methanol, isopropanol or THF have proved suitable for the reaction of methyl benzoates with guanidine at temperatures of 20 ° C up to the boiling point of these solvents. Most reactions of carboxylic acid derivatives with guanidine free of salts are advantageously carried out in inert aprotic solvents such as THF, dimethoxyethon, dioxane. However, water can also be used as a solvent in the guanidine reaction after the use of a base as such, for example NaOH. If a carbonyl chloride is used as a carboxylic acid derivative, it is advantageous to add an acid scavenger, for example in the guanidine form in excess, to fix the hydrohalic acid. To prepare compounds of formula I, wherein R 2 is hydrogen, the synthesis can take place without steps b and c. In order to prepare compounds of formula I with R2 = - (SOh) z- (CH2) (CF2)? - CF3, where h is 1 or 2, as described above, compounds are synthesized in which R2 is - (SOn) z- (CH2) k- (CF2 ) - CF3, in which h is zero, and subsequently converted, by oxidation reactions generally known, into the desired compounds of formula I. The reaction mixture can be made after each of the steps of the process a) , b), c), d), e), f) and g), or after two or more stages of the procedure. However, the synthesis of the compounds of the formula I by the process of the invention can also take place in two or more consecutive process steps without isolation of the compounds III, IV, V, VI, VII and HIV obtained in the steps of the procedure, in which case the treatment is unnecessary after each stage of the procedure. The treatment and, if desired, the purification of the products takes place by the usual methods such as extraction, separation by pH, chromatography or crystallization and the usual drying. The starting compounds of the formulas II can be obtained by acquiring them or they can be prepared by methods analogous to processes described in the literature and known to the skilled worker, for example as described in Bowden, RD, Comina, PJ, Greenhall, MP , Kariuki, BM, 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 they may be converted into the desired groups in the compounds of the formula I prepared by the process of the invention. Appropriate protective group techniques are known to the skilled worker. For example, the NH2 group in the compounds of the formula II, wherein R1 is NH2, may be present in a form protected by an acetyl, trifluoroacetyl or trityl group and may be deprotected again. A further aspect of the invention relates to new compounds of the formulas V, VI, VII, VIII and IX.

The invention thus relates to 4-pentafluorosubstituted compounds of the formula X wherein the meanings are: R1 hydrogen, alkyl having 1, 2 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, NR10R11, -Op- (CH2) n- (CF2) or- 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 -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R6 - (SOh) z- (CH2) k- (CF2)? - CF3, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 atoms of carbon, in which 1, 2, 3 or 4 hydrogen atoms can be replaced by fluorine atoms; h zero, 1 or 2; z zero or 1: k zero, 1, 2, 3 or 4; I zero or 1; or R6 - (CH2) t-phenyl or -O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O- (CH2) v- CF3, alkoxy with 1, 2 , 3 or 4 carbon atoms, alkyl with 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3; t zero, 1, 2, 3 or 4; u zero or 1; v zero, 1, 2 or 3; or R6 - (CH2) w-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O? - (CH2) and -FC3, alkoxy with 1, 2, 3 or 4 carbon and alkyl atoms with 1, 2, 3 or 4 carbon atoms, -SO 2 CH 3; w zero, 1, 2, 3 or 4; x zero or 1; and zero, 1, 2 or 3; R3 and R4, independently of one another, hydrogen or F; and its salts. 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) rCF3, in which R10 and R11 are, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or -CH2-CF3, and in which m is zero, 1 or 2 and r is zero or 1, with particular preference for compounds wherein R 1 is described by hydrogen or methyl. In an additional mode, preference is given to compounds of formula X, in which R6 is described by hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms or ~ SOh- (CH2) k-CF3 , in which 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, wherein R6 is described by F, Cl, Br or I, in particular by Br. In a further embodiment, preference is given to compounds of the formula X, in that R3 and R4 are described by hydrogen. Similarly, the invention relates to 4-pentafluorosulfanyl-substituted compounds of the formula XI wherein the meanings are: R1 hydrogen, alkyl having 1, 2 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, NR10R11, -Op- (CH2) n- (CF2) or- CF3 or - (SOm) q- (CH2) r (CF2) s-CF3; R10 and R11, independently of one another, hydrogen, alkyl with 1, 2, 3, 04 carbon atoms or -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R 2 hydrogen, F, Cl, Br, I, - (SOh) z- (CH 2) k- (CF 2) - CF 3 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; I zero or 1; R3 and R4, independently of one another, hydrogen or F; R7 CN; and its salts. In one embodiment preference is given to compounds of the formula XI, 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) r-CF3, in which R10 and R11 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3, and in which m is zero, 1 or 2 and r is zero or 1, with particular preference for compounds wherein R 1 is described by hydrogen or methyl. In a further embodiment, preference is given to compounds of the formula XI, wherein R2 is described by hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms or -SOh- (CH2 ) k-CF3, in which h is zero, 1 or 2 and k is zero or 1, 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 XI, wherein R2 is described by F, Cl, Br or I, in particular by Br. In a further embodiment, preference is given to compounds of the formula XI, wherein R3 and R4 are described by hydrogen. If the substituents R1, R2, R3, R4 and R6 contain one or more centers of asymmetry, these may have, independently of one another, the S or R configuration. The compounds may exist in the form of optical isomers, in the form of diastereomers, in the form of racemates or their mixtures in all ratios. The present invention encompasses all tautomeric forms of the compounds of formula I. Alkyl radicals can be straight chain or branched. This also applies if they carry substituents or appear in the form of substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec.-butyl (= 1-methylpropyl), tere-butyl (= 1 , 1-dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicals are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5 hydrogen atoms in the alkyl radicals may be replaced by fluorine atoms. Examples of fluoroalkyl radicals of this type are trifluoromethyl, 2,2,2-trifluoroethylene and pentafluoroethyl. Alkyl substituted radicals may be substituted at any positions.

Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for example 1, 2, 3 or 4 hydrogen atoms in the cycloalkyl radicals can be replaced by fluorine atoms. Substituted cycloalkyl radicals may be substituted at any positions. Phenyl radicals can be unsubstituted or can be substituted one or more times, for example once, twice or three times, by identical or different radicals. If a phenyl radical is substituted, it preferably has one or two identical or different substituents. This also applies to substituted phenyl radicals in groups such as, for example, phenylalkyl or phenyloxy. The substituent on monosubstituted phenyl radicals can be in position 2, position 3 or position 4. Disubstituted phenyl can be substituted at the position 2,3, position 2,4, position 2,5, position 2,6, position 3,4 or position 3,5. Substituents on trisubstituted phenyl radicals can be in the 2-position, 3,4, 2,3,5 position, 2,4,5 position, 2,4,6 position, 2,3,6 position or 3,4,5 position, heteroaryl radicals are aromatic ring compounds, in the that one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, for example 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of various heteroatoms . The heteroaryl radicals can be fixed at all positions, for example by position 1, position 2, position 3, position 4, position 5, position 6, position 7 or position 8. Heteroaryl radicals can be unsubstituted or they may be substituted one or more times, for example once, twice or three times, by identical or different radicals. These also apply to heteroaryl radicals, such as, for example, the heteroarylalkyl radical. Examples of heteroaryl are furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinolinyl. Heteroaryl radicals are, in particular, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolid, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazole-1-, -4- or -5-yl, 1, 2,4-triazole-1-, -3- or -5-yl, 1- or 5-tetrazoyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1, 2,3-oxadiazoI-4- or -5-yl, 1, 2,4-oxadiazoI-3 - or - 5-I, 1, 3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazoyl, 3-, 4- or 5-isothiazoyl, 1, 3,4- thiadiazoI-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazoI-4- or -5-yl, 2-, 3- or 4- pyridyl, 2-, 4-, 5- or 6-pyrimidinium, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2 -, 4- or 5-benzimidazole, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoxy, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding N-oxides of these compounds are also encompassed, that is to say, for example, 1-oxy-2-, 3- or 4-pyridyl. Particularly preferred heteroaromatic radicals are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrroxy, 1-, 2-, 4- or 5-imidazolium, 2-, 3-, 4- , 5-, 6-, 7- or 8-quinolone, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2- or 3-pyrazinyl, 2-, 4-, 5- or 6-pyrimidinium and 3- or 4-pyridazinyl. The compounds of the formula I can be isolated in the form of their salts. These are obtained by conventional methods, by reaction with acids or bases. Examples of suitable acid addition salts in this respect are halides, especially hydrochlorides, hydrobromides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, benzenesulfonates, p-toluenesulfonates, adipates, fumarates, gluconates, glutamates, glycerophosphates, maleates, benzoates, oxalates and pamoates and trifluoroacetates, in the case of the preparation of active ingredients, preferably pharmaceutically suitable salts. If the compounds contain an acidic group, they can form salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example of salts with ammonia or organic amines or amino acids. They can also be in the form of a hybrid ion.

List of abbreviations: DMF N, N-dimethylformamide DMSO dimethylsulfoxide dba dibenzylideneacetone OAc acetate p.f. melting point MTB tert.-butyl methyl ether NMP N-methyl-2-pyrroidone dppf 1,1 '-bis- (diphenylphosphino) -ferrocene THF tetrahydrofuran Experimental section Example 1: a) 4-aminophenylsulfur pentafluoride A solution of tin (II) chloride (1465 g, 7.73 mol) in concentrated aqueous HCl solution (32 percent) was heated with stirring to 80 ° C and then, with cooling with ice, was introduced into the reaction mixture. portions, over 1 h, 4-nitrophenylsulfur pentafluoride (584 g, 2.344 mol). The internal temperature remained below 100 ° C during this. Subsequently, the mixture was stirred at an internal temperature of 85 ° C for 1.5 h and then cooled to 45 ° C over an additional hour. A mixture of ice (12 kg), NaOH (2 kg) and dichloromethane (1.5 I) was prepared and added to the reaction mixture with vigorous stirring. The phases were separated, the aqueous phase was extracted 3 times with 1 l of dichloromethane each time, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 510 g (99%) of 4-aminophenylsulfur pentafluoride in the form of a pale yellow crystalline powder, m.p. 63-65 ° C (Bowden, R.D., Comina, P.J., Greenhall, M.P., Kariuki, B.M., Loveday, A., Philip, D. Tetrahedron 2000, 56, 3399: 57-59 ° C). 1 H-NMR 400 MHz, CDCl 3: d = 3.99 (broad s, 2H), 6.61 (d, J = 9 Hz, 2H), 7.52 (d, J = 9 Hz, 2H) ppm. b) 4-Amino-3-hromophenylsulfur pentafluoride 4-aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 I), the solution was cooled to 5 ° C and, while stirring, was introduced in several portions, with ice cooling, 1, 3-dibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol), so that the internal temperature was maintained at 3-8 ° C (ca. 1 h). Then, the mixture was allowed to stir and warmed to room temperature without external cooling for 1 h. The mixture was filtered through a pad of silica gel (volume, approximately 1 L) and washed with dichloromethane (5.5 L), and the filtrate was evaporated in vacuo. Approximately 700 g of a reddish brown crystalline mass were obtained and dissolved in n-heptane (600 ml) at 60 ° C and then crystallized in a refrigerator at 4 ° C. Filtration with suction resulted in 590 g (85%) of 4-amino-3-bromophene sulfur pentafluoride in the form of brownish crystals, m.p. 59-59.5 ° C. H-NMR 400 MHz, CDCl 3: d = 4.45 (broad s, 2H), 6.72 (d, J = 9 Hz, 1 H), 7.49 (dd, J? = 9 Hz, J2 = 2 , 5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1 H) ppm. C6H5BrF5NS (298.07): cale. C 24.18, H 1, 69, N 4.70; Found C 24.39, H 1.45, N 4.77. c) 4-Amino-3-methylphenylsulfur pentafluoride A mixture of CS2CO3 (794 g, 2.7 mol), dimethoxyethane (2 I), water (300 ml) and trimethylboroxin (50 percent solution in THF, 225 g, 0.9 mol) was heated to 70 ° C. , PdC _ (dppf) x CH2Cl2 (37 g, 45 mmol) was added, and a solution of 4-amino-3-bromophenylosulfur pentafluoride (270 g, 0.9 mol) in dimethoxyethane (400 ml) was added dropwise drop over the course of 2 h, while the reaction mixture was heated to reflux. Subsequently, it was heated to reflux for an additional 3 h and then cooled to room temperature, diluted with MTB-ether (500 ml), filtered through a column of silica gel (14 x 7 cm, 70-200 μm) and washed with MTB-ether (2500 ml). The filtrate was evaporated in vacuo. They were obtained 490 g of a black semicrystalline mass that was subjected to steam distillation. A total of 5.5 I of condensate was collected from which the crystals of the product were separated. The condensate was extracted 3 times with MTB-ether, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 4-Amino-3-methylphenylsulfur pentafluoride (181 g, 76%) was obtained as colorless crystals, m.p. 65-66 ° C, 400 MHz H-NMR, CDC3: d = 2.18 (s, 3H), 3.92 (broad s, 2H), 6.60 (d, J = 8.5 Hz, 1H), 7.40 (dd, J? = 8.5 Hz, J2 = 2.5 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1H) ppm. CdH8F5NS (233,30): cale. C 36.05, H 3.46, N 6.01; found C 36.43, H 3.30, N 6.09. d) 4-Bromo-3-methylphenylsulfur pentafluoride A mixture of tere-butyl nitrite (90 percent pure, 37 ml, 280 mmol) and CuBr 2 (35.8 g, 160 mmol) in acetonitrile (260 ml) was cooled to 5 ° C and, while stirring and cooled with ice, a solution of 4-amino-3-methylphenylsulfur pentafluoride (30.9 g, 132.5 mmol) in MTB was added dropwise at 5-8 ° C and over 1 h. -tether (140 mi). Nitrogen evolution started after approximately 2 min. Then, the mixture was allowed to warm with stirring to room temperature over the course of 1 h, an ice mixture (250 g) of 26 percent NH3 aqueous solution (50 ml) and MTB ether (250 ml) was added, and the mixture was stirred for 10 min. The phases were separated and the aqueous was extracted 3 times with MTB-ether (150 ml each time), and the combined organic phases were shaken once with 400 ml of water. Drying with Na 2 SO 4 and evaporation of the organic phase resulted in 39 g of 4-bromo-3-methylphenylsulphur pentafluoride in the form of a reddish-brown oil which, according to 1 H-NMR, was contaminated with 8% by moles. 4,5-dibromo-3-methylphenylsulfur, but was used further without further purification. Performance, 89% based on a purity of 90%. For the combustion analysis, a sample was purified by chromatography on silica gel (35-70 μm, heptane). 1 H-NMR 400 MHz, CDCl 3: d = 2.47 (s, 3H), 7.43 (dd, J? = 9 Hz, J2 = 3 Hz, 1H), 7.62 (m, 2H) ppm. Signals of 4,5-dibromo-3-methylphenylsulfur pentafluoride (contaminant): 2.56 (s, 3H), 7.56 (d, J = 2.5 Hz, 1 H), 7.85 (d, J) = 2.5 Hz, 1 H). C7H6BrF5S (297.09): cale. C 28.38, H 2.04; found C 28.42, H 1, 78. e) 4-Cyano-3-methylphenylsulfur pentafluoride A mixture of 4-bromo-3-methylphenylsulfur pentafluoride (136.4 g, purity 80%, 0.367 mol), Zn (CN) 2 (72.8 g, 0.62 mol) and Zn powder (7, 2 g, 0.11 mol) in dimethylacetamide (900 ml) and water (40 ml) was heated with stirring and blanketing with nitrogen to 125 ° C, and PdC _ (dppf) x CH2Cl2 (32.7 g, 40 g) was added. mmol). After stirring at 125 ° C for one hour PdC (pppd) x CH2Cl2 (16.3 g, 20 mmol) and Zn powder (3.6 g, 55 mmol) were added again and the stirring was continued at 125 ° C. for 2 h. Then, the mixture was cooled to room temperature, diluted with n-heptane (400 ml) and stirred vigorously with the addition of 5N NH 4 Cl aqueous solution (250 ml) and water (450 ml) for 15 min. The mixture was filtered with suction through a layer of diatomaceous earth, the phases were separated, and the aqueous was extracted twice with n-heptane (200 ml). The combined organic phases were shaken with water (450 ml), dried over MgSO 4 and evaporated in vacuo. The resulting black residue was dissolved in 200 ml of n-heptane, filtered and evaporated again in vacuo. 78 g of a dark brown liquid were obtained and purified by chromatography on a column of silica gel (7 x 55 cm, 50-200 μm, n-heptane / dichloromethane 4: 1 to 3: 2). The first fraction obtained consisted of 6.5 g of 4-bromo-3-methylphenylsulphur pentafluoride (precursor) in the form of a yellowish liquid, and then 71.1 g (80%) of 4-cyano-3-methylphenylsulfur pentafluoride in the form of a pale yellow oil. 1 H-NMR 400 MHz, CDCl 3: d = 2.65 (s, 3 H), 7.71 (m, 3 H) ppm. f) 2-Methyl-4-pentafluorosulfanylbenzoic acid A mixture of 4-cyano-3-methylphenylisulfur pentafluoride (41.2 g, 169.4 g), NaOH (20.4 g, 510 mmol) and water (60 mL) in ethylene glycol (160 mL) was heated to 130 ° C and stirred at this temperature for 4 h. It was then cooled to room temperature and diluted with MTB-ether (150 ml) and water (250 ml), and the mixture was filtered with suction. The filtrate phases were separated and the aqueous was acidified with concentrated aqueous HCl solution, and the precipitated solid was filtered off with suction. 41.1 g (93%) of 2-methyl-4-pentafluorosulfanylbenzoic acid were obtained as colorless crystals, m.p. 138-139 ° C. 1 H-NMR 400 MHz, DMSO-d 6: d = 2.60 (s, 3H), 7.81 (dd, J? = 8.5 Hz, J2 = 2 Hz, 1 H), 7.89 (d, J = 2 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 13.43 (broad s, 1H) ppm. C8H7F5O2S (262.20): cale. C 36.65, H 2.69; found C 36.85, H 2.59. g) 2-methyl-4-pentafluorosulfanylbenzoylguanidine 2-Methyl-4-pentafluorosulfanylbenzoic acid (77.5 g, 295 mmol) was suspended in toluene (300 ml), thionyl chloride (36 ml, 0.5 mol) and 5 drops of DMF were added, and the mixture was heated to reflux with stirring for 2 h. After it was filtered with suction, the filtrate was evaporated in vacuo, the residue was taken up twice in toluene (100 ml each time) and evaporated in vacuo each time. 78.8 g of the acid chloride were obtained in the form of a pale brown liquid which was further used without purification. Guanidine hydrochloride (172 g, 1.8 mole) was added to a solution of NaOH (84 g, 2.1 mol) in water (600 ml), and the mixture was cooled to -3 ° C. Then, while stirring and cooling with ice, the solution of the crude acid chloride in dichloromethane (600 ml) was added dropwise over the course of 1 h. The mixture was allowed to stir at room temperature for an additional 30 min and then the precipitated solid was filtered off with suction, washed with dichloromethane and dried at room temperature in vacuo. 74.3 g (87%) of 2-methyl-4-pentafluorosulfanylbenzoylguanidine were obtained in the form of beige crystals, m.p. 183-183.5 ° C. 1 H-NMR 400 MHz, CD 3 OD: d = 2.51 (s, 3 H), 4.84 (broad s, 5 H), 7.62 (m, 2 H), 7.65 (s, 1 H) ppm. C9H10F5N3OS (303.26): cale. C 35.65, H 3.32, N 13.86; found C 35.69, H 3.18, N 14.04.

Claims (7)

1. - A process for preparing compounds of the formula I wherein the meanings are: R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, NR10R11, -Op- (CH2) n- (CF2) or -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 -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R2 hydrogen, - (SOh) z- (CH2) k- (CF2)? -FC3, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms can be replaced by fluorine atoms; h zero, 1 or 2; z zero or 1: k zero, 1, 2, 3 or 4; I zero or 1; or R2- (CH2) t-phenyl or -O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O- (CH2) v- CF3, alkoxy with 1, 2 , 3 or 4 carbon atoms, alkyl with 1, 2, 3 or 4 carbon atoms and -S? 2CH3; t zero, 1, 2, 3 or 4; u zero or 1; v zero, 1, 2 6 3; or R2 - (CH2) w-roaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -Ox- (CH2) and -FC3, alkoxy with 1, 2, 3 or 4 atoms carbon and alkyl with 1, 2, 3 or 4 carbon atoms, -SO 2 CH 3; w zero, 1, 2, 3 or 4; x zero or 1; and zero, 1, 2 or 3; R3 and R4, independently of one another, hydrogen or F; and its salts; which comprises II Ut SV vpi l a) reducing a 4-nitrophenylazurine pentafluoride derivative of the formula II in the amine of the formula III, and b) halogenating the compound of the formula III 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 alkylboro compound, if appropriate with catalysis, by a substituent R2, and d) replacing the amino function in the compound of formula V with a halogen substituent and e) replacing the halogen substituent in the compound of formula VI with a nitrile function, and f) hydrolyzing the nitrile function with a compound of formula VII to give the carboxylic acid, and g) converting the carboxylic acid of the formula VIII to the acylguanidine of the formula I, wherein in the compounds of the formulas II, III, IV, V, VI, VII and VIII R1 to R4 are as they are defined in formula I and X and Y are, independently of one another, F, Cl, Br or I.

2. The method according to claim 1, wherein steps a), b), c), d ), e), f) and g) are carried out independently of each other continuously or discontinuously.

3. The process according to claim 1 and / or 2, wherein R2 is hydrogen, and steps b) and c) are omitted.

4. A compound of formula X wherein the meanings are: R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, NR10R11, -Op- (CH2) n- (CF2) or -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 -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R6 - (SOh) z- (CH2) k- (CF2)? - CF3, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 atoms of carbon in which 1, 2, 3 or 4 hydrogen atoms can be replaced by fluorine atoms; h zero, 1 or 2; z zero or 1: k zero, 1, 2, 3 or 4; I zero or 1; or R6 - (CH2) t-phenyl or -O-phenyl, which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O- (CH2) v-CF3, alkoxy with 1, 2 , 3 or 4 carbon atoms, alkyl with 1, 2, 3 or 4 carbon atoms and -SO 2 CH 3; t zero, 1, 2, 3 or 4; u zero or 1; v zero, 1, 2 or 3; or R6 - (CH2) w-roaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of -O? - (CH2) y-CF3, alkoxy with 1, 2, 3 or 4 carbon and alkyl atoms with 1, 2, 3 or 4 carbon atoms, -SO 2 CH 3; w zero, 1, 2, 3 or 4; x zero or 1; and zero, 1, 2 or 3; R3 and R4, independently of one another, hydrogen or F; and its salts.

5. A compound of the formula X and / or its pharmaceutically suitable salts according to claim 4, for use as an intermediate product of the synthesis.

6. A compound of the formula XI in which the meanings are: R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, NR10R11, -Op- (CH2) n- (CF2) o-CF3 or - (SOm) q- R10 and R11, independently of one another, hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or -CH2-CF3; m zero, 1 or 2 n, o, p, q, r and s, independently of one another, zero or 1; R2 hydrogen, F, Cl, Br, I, - (SOh) z- (CH2) k- (CF2)? -CF3 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; I zero or 1; R3 and R4, independently of one another, hydrogen or F; R7 CN; and its salts.

7. A compound of the formula XI and / or its pharmaceutically suitable salts according to claim 6, for use as an intermediate product in the synthesis.