Substituted benzoylguanidines process for their preparation and pharmaceutical compositions containing them

108697/2

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SUBSTITUTED BENZOYLGUANIDINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUITCAL COMPOSITIONS CONTAINING THEM □ηζοη*? πϋ·υ ,αηηηιη □□ηίνια'ϊ'νιπι □bin □jonn ninpn n'eoni ί -/-

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HOECHST AKTIENGESELLSCHAFT HOE 93/F 054 Dr. VF/bs

Description

Substituted-benzoylguanidines,-process-for-their preparation, their use aa a pharmaceutical, as~ inhibitors- of—the- cellular N+/Hf exchange or as—a diagnostic,—and- 5 pharmaceutical containing Lheim?

The invention relates formula I to benzoylguanidines of the

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(I) in which: R(l), R(2), R(3) 10 are hydrogen, F, Cl, Br, I or (C3—C12)-alkyl, one of the substituents R(l), R(2) or R(3) is N3, CN, OH or (Ci-CioJ-alkyloxy, if at least one of the remaining substituents R(l), R(2) or R(3) is a sufficiently lipophilic alkyl radical having 3 to 12 15 carbon atoms, or one of the substituents R(l), R(2) or R(3) is R (4) -CnH2n-OB where m is zero or 1, n is zero, 1, 2 or 3, 20 R(4) is CpF2p+1 where p is 1, 2 or 3 if n is zero or 1, ox R(4) is (C3-C12)-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl, the aromatic and heteroaromatic ring systems being unsubstituted or substituted by a substituent selected from the group comprising 25 --- · —' r - - 108697/4 - 2 - F, Cl, CFj, methyl, methoxy or NR(5)R(6), where R(5) and R(6) are hydrogen or (Cj-CJ-alkyl, * 17.2.94 10 15 or one of the substituents R(l), R(2.) or R(3) is -CeCR(5), -C[R(6)] « CR(5)H, ' R(5) is phenyl which is unsubstituted or substituted by· 1-3 substituents selected from the group comprising F, Cl, CF3, methyl, methoxy, hydroxyl, amino, methylamino or dimethylamino, (Cj-C,)-heteroaryl, which is unsubstituted or substituted by- 1-3 substituents • selected from the group comprising F, Cl, CF3, methyl, methoxy, hydroxyl, amino, methylamino or dimethylamino,

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(CX-CJ-alkyl, which is unsubstituted or substituted by 1-3 OH, or (C3-C8)-cycloalkyl, R(6) is hydrogen or methyl, and the pharmacologically acceptable salts thereof, where, if R(4) is pyridyl, quinolyl or isoquinolyl, m and n must not simultaneously be zero, and with the exception of the compounds benzoylguanidine, 25 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine, and 3- or 4-methylbenzoylguanidine.

Preferred compounds are those in which R(l), R(2), R(3) are hydrogen, F, Cl, Br or (C3-C8)-alkyl , 30 one of the substituents R(l), R(2) or R(3) is OH or (Cj-CJ-alkyloxy, if at least one of the remaining substituents R(l), R(2) or R(3) i® a sufficiently lipophilic alkyl radical having 3 to 6 carbon atoms, 108697/2

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or one of the substituents R(l), R(2) or R(3) is R (4)-C„H2n-OB where m is zero or 1, n is zero, 1, 2 or 3, 5 R(4) is CpF2p+1 where p is 1 if n is zero or 1, or R(4) is (C5-C7)-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl, the aromatic and heteroaromatic ring systems being unsub- 10 stituted or substituted by a substituent selected from the group comprising F, Cl, CF3, methyl or methoxy, 17.2.94

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one of the substituents R(l), R(2) or R(3) is -CsCR(5), R(5) is phenyl or (Cj-CJ-alkyl, which is unsubstituted or substituted by OH, and the pharmacologically acceptable salts thereof, where, if R(4) is pyridyl, quinolyl or isoquinolyl, m and 20 n must not simultaneously be zero, and with the exception of the compounds benzoylguanidine, 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine and 3- or 4-methylbenzoylguanidine. 25 30

Particularly preferred are 3-trifluoromethylbenzoyl-guanidine hydrochloride, 3,5-bistrifluoromethylbenzoyl-guanidine hydrochloride, 3-methyl-5-trifluoromethyl-benzoylguanidine hydrochloride, 4-fluoro-3-trifluoro-methylbenzoylguanidine hydrochloride, 4-(4-fluoro-phenoxy)-3-trifluoromethylbenzoylguanidine hydrochloride, 5-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride, 3- chloro-4-isopropylbenzoylguanidine 4- tert-butyl-3-methoxybenzoylguanidine 3-tert-butyl-4-hydroxybenzoylguanidine 3-tert-butyl-4-is opropylben z oylguanidine hydrochloride, hydrochloride, hydrochloride, hydroc h1oride 35 and the pharmacologically acceptable salts thereof. 4 10 10 15 15 20 20 25 25

If one of the substituents R(l) to R(3) contains an asymmetric centre, then the invention also embraces S-and R-configurated compounds. The compounds can be in the form of optical isomers, diastereomers, racemates or mixtures of these.

The alkyl radicals mentioned can be either straight-chain or branched. (C^-Cj)-heteroaryl is to be understood as meaning, in particular radicals which are derived from phenyl or naphthyl and in which one or more CH groups are replaced by nitrogen and/or in which at least two adjacent CH groups (on the formation of a five-membered aromatic ring) are replaced by S, NH or 0. Moreover, it is also possible for one or both atoms of the condensation site of bicyclic radicals (such as in indolizinyl) to be nitrogen atoms.

Heteroaryl is, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxaliny1, quinazolinyl, cinnolinyl.

The invention furthermore relates to a process for the preparation of a compound I, which comprises reacting a compound of the formula II R(1) R(2) (II) in which R(l) to R(3) have the abovementioned meaning and L is a leaving group which can readily be substituted by 5 a nucleophile, with guanidine.

The activated acid derivatives of the formula II in which L is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are obtained advantageously, in a manner known per se, from the carboxylic acid chlorides on which they are based (formula II, L - Cl), which, in turn, can be prepared from the carboxylic acids on which they are based (formula II, L s OH), in a manner known per se, for example using thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II (L = Cl), further activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the benzoic acid derivatives on which they are based (formula II, L s OH), for example the methyl esters of the formula II where L = OCH3 by treating them with gaseous HCl in methanol, the imidazol-ides of the formula II by treating them with carbonyldi-imidazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), the mixed anhydrides II using C1-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and benzoic acids can be activated using dicyclohexylcarbodiimide (DCC) or using θ“[ (cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetra-methyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreeu, Escom, Ledien, 1991). A series of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II is given in J. March, Advanced Organic Chemistry, Third Edition (John Wiley &amp;amp; Sons, 1985), p. 350, where the references are cited.

An activated carboxylic acid derivative of the formula I is reacted with guanidine in a manner known per se, in a protic or aprotic polar, but inert, organic solvent. Substances which have proven themselves in the reaction 6

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of the methyl benzoates (II, L=OMe) with guanidine are methanol or THF between 20°C and the boiling point of these solvents. In most reactions of compounds II with salt-free guanidine, the procedure was advantageously 5 carried out in aprotic inert solvents, such as THF, dimethoxyethane or dioxane. If a base, such as, for example, NaOH is used as solvent, water can also be used in the reaction of II and III.

If L is Cl, the process is carried out advantageously 10 with the addition of an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid.

Some of the basic benzoic acid derivatives of the formula II are known and described in the literature. The unknown 15 compounds of the formula II can be prepared by methods known from the literature.

Carboxylic acids or their esters of the formula II (for example L - -OH or -O-methyl) where R(2) has the meaning of halogen or R(3) has the meaning of nitro can act as 20 useful starting compounds for other carboxylic acids of the formula II, it being possible for the halogen in the position R(2) to be exchanged very conveniently in a known manner for a large number of nucleophilic reagents, such as phenols or alcohols R(4) -CnH2n-OH or their alkali 25 metal salts giving the corresponding benzoic acid derivatives. Equally, nitro groups can be reduced to the corresponding aminobenzoic acid by means of Sandmeyer or Ullmann reactions and then lead to the desired, in particular halogen-substituted, benzoic acid derivatives. 30 In many cases, chlorine, bromine or iodine can also be introduced into a particular benzoic acid in a manner known per se by direct halogenation using a Friedel-Crafts catalyst.

In general, benzoylguanidines I are weak bases and can 35 bind acid with the formation of salts. Suitable acid

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addition salts axe salts of all pharmacologically acceptable acids, fox example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluene- 5 sulfonates.

The compounds I are substituted acylguanidines.

The best known representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. A large number 10 of other compounds of the amiloride type are described in the literature, such as, for example, dimethylamiloride or ethylisopropylamiloride.

0 NH

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R ' ’

Amiloride: R', R" = H Dimethylamiloride: R', R" = CH3 15 Ethylisopropylamiloride: R' = C2H5, R" = CH(CH3)2

Moreover, studies have been published which suggest that amiloride has antiarrhythmic properties (Circulation 79, 1257-63 (1989). However, a broad use as an antiarrhythmic is prevented by the fact that this effect is only weakly 20 pronounced and accompanied by a hypotensive and saluretic activity, and these side effects are undesired in the treatment of cardiac arrhythmias.

Results obtained in experiments with isolated animal hearts have also suggested that amiloride has anti- 25 arrhythmic properties (Eur. Heart J. 9 (suppl.1): 167 (1988) (book of abstracts). For example, it has been found on rats' hearts that an artificially induced 8

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ventricular fibrillation could be suppressed completely by amiloride. The abovementioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride in this model. 5 European Offenlegungsschrift 416,499 (HOE 89/F 288) describes benzoylguanidines which have a hydrogen atom in the position which corresponds to the radical R(l).

German Offenlegungsschrift 3,502,629 discloses benzoylguanidines which are substituted in the m-position with 10 a phenoxy group and which always have at least two substituents in the phenoxy group. These compounds are used in crop protection.

The publication Kumamoto, Pharm. Bull [1966], pages 7-13, describes a few substituted benzoylguanidines which can 15 be used as anticancer agents. US Patent 3,780,027 claims acylguanidines which are similar to the compounds of the formula I with regard to the structure and which are derived from commercially available loop diuretics, such as bumetanide. Accord- 20 ingly, powerful salidiuretic activity is reported for these compounds.

It was therefore surprising that the compounds according to the invention have no undesired and disadvantageous salidiuretic, but very good antiarrhythmic, properties, 25 such as, for example, in the case of oxygen deficiency symptoms. Due to their pharmacological properties, the compounds are outstandingly suitable for use as antiarrhythmic pharmaceuticals with a cardioprotective component for the prophylaxis and treatment of 30 infarctions and for the treatment of angina pectoris, and they also preventively inhibit, or greatly reduce, the pathophysiological processes involved in ischemically induced damage, in particular when ischemically induced cardiac arrhythmias are triggered. Due to their 9

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protective activities against pathological, hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, due to inhibition of the cellular Na*/H* exchange mechanism, as pharma- 5 ceuticals for the treatment of all acute or chronic, ischemia-triggered types of damage or diseases which are primarily or secondarily induced thereby. This applies to their use as pharmaceuticals for invasive treatment, for example in the case of organ transplants, where the com- 10 pounds can be used not only for protecting the organs in the donor before and during removal, for the protection of removed organs, for example when they are treated with, or stored in, physiological bath fluids, but also when they are transferred into the acceptor organism. The 15 compounds are also valuable protective pharmaceuticals for carrying out invasive angioplastic treatment, for example on the heart or on peripheral blood vessels. Due to their protective activity against ischemically induced types of damage, the compounds are also suitable for use 20 as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of apoplexy or of cerebral edema. Moreover, the compounds of the formula I according to the invention are 25 also suitable for the treatment of forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock.

Moreover, the compounds of the formula I according to the invention are distinguished by powerful inhibitory action 30 on cell proliferations, for example fibroblast cell proliferation and proliferation of the smooth vascular muscle cells. This is why the compounds of the formula I are suitable as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary 35 cause, and they can therefore be used as anti-atherosclerotic s, agents against late complications in diabetes, cancers, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ 10

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hypertrophias and hyperplasias, in particular in prostatic hyperplasia or prostatic hypertrophia.

The compounds according to the invention are valuable inhibitors of the cellular sodium proton antiporter 5 (Na+/H+ exchanger), which is elevated in a large number of diseases (essential hypertension, atherosclerosis, diabetes and the like) even in those cells which are readily accessible to measurements, such as in erythrocytes, thrombocytes or leukocytes. The compounds accord- 10 ing to the invention are therefore suitable as outstanding and simple scfeirtff le toolsfor example in their use -ee diagnostics for determining, and distinguishing between certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, and 15 the like. Moreover, the compounds of formula I are suitable for preventive therapy for preventing the genesis of hypertension, such as of essential hypertens ion.

Moreover, the compounds are distinguished by an inhibi-20 tion of the hydrochloric acid production of the parietal cells of the stomach, and they can therefore be used as pharmaceuticals for the treatment of gastrointestinal diseases. Such gastrointestinal disorders and diseases of the esophagus are, for example, gastric and intestinal 25 ulcers and reflux esophagitis.

Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhaling, the preferred way of administration being dependent on the particular symptom of the disease. The 30 compounds I can be used by themselves or together with pharmaceutical auxiliaries, and they can be employed both in veterinary medicine and human medicine. A person skilled in the art knows, on the basis of his expert knowledge, which auxiliaries are suitable for the 35 desired pharmaceutical formulation. Auxiliaries which can 11

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be used in addition to solvents, gel-formers, bases for suppositories, tableting auxiliaries, and other excipients for active substances are, for example, antioxidants, dispersants, emulsifiers, antifoamers, flavor 5 improvers, preservatives, solubilizers or colorants.

For an oral dosage form, the active compounds together with the additives suitable for this purpose, such as carriers, stabilizers or inert diluents, are mixed and formulated by customary methods to give suitable dosage 10 forms, such as tablets, sugar-coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions. Inert excipients which may be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, tjlucose or starch, in 15 particular maize starch. Dry granules or moist granules can be used for the preparation. Examples of oily excipients or examples of solvents are vegetable or animal oils, such as sunflower oil or codliver oil.

For subcutaneous or intravenous administration, the 20 active compounds, if desired together with the substances which are customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, are dissolved, suspended or emulsified. Examples of suitable solvents are: water, physiological saline, or alcohols, for 25 example ethanol, propanol, glycerol, and also sugar solutions, such as glucose or mannitol solutions, or else a mixture of the various solvents which have been mentioned above.

Pharmaceutical formulations which are suitable for 30 administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or else in a mixture of such solvents. 35 If required, the formulation can also contain other pharmaceutical auxiliaries, such as surfactants, 12 emulsifiers and stabilizers, and a propellant gas. The concentration of active substances in such a preparation is generally from about 0.1 to 10, in particular from about 0.3 to 3, % by weight.

The dose of the active substance of the formula I to be administered and the frequency of the administration will depend on the potency and duration of action of the compounds used; in addition also on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dosage rate of a compound of the formula I in the case of a patient of approximately 75 kg will be at least 0.001 mg/kg, preferably 0.01 mg/kg, up to not more than 10 mg/kg, preferably 1 mg/kg, of body weight. If the disease is acute, such as immediately after suffering a cardiac infarction, even higher, and in particular, more frequent, doses may also be required, for example up to 4 single doses per day. Up to 200 mg per day may be required, in particular for intravenous administration, such as in the case of a patient who has suffered an infarction and is under intensive care.

Experimental part

General protocol for the preparation of benzoyl-guanidines (I) from benzoic acids (II, L = OH) 0.01 mol of the benzoic acid derivative of the formula II is dissolved or suspended in 60 ml of anhydrous tetra-hydrofuran (THF), and 1.78 g (0.011 mol) of carbonyl-diimidazole are then added. After the reaction solution has been stirred for 2 hours at room temperature, 2.95 g (0.05 mol) of guanidine are introduced. After the mixture has been stirred overnight, the THF is distilled off under reduced pressure (Rotavapor), water is added, the pH is brought to 6-7 using 2N HCl, and the corresponding benzoylguanidine (formula I) is filtered off. The 108697/2 13

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resulting benzoylguanidines can be converted to the corresponding salts by being treated with aqueous or methanolic hydrochloric acid or other pharmacologically tolerated acids. 5 Example 1: 3,5-Dichlorobenzoylguanidine hydrochloride from 3,5-dichlorobenzoic acid following the general protocol; colorless crystals, m.p. 286°C.

Example 2: 10 3-Chlorobenzoylguanidine hydrochloride from 3-chlorobenzoic acid following the general protocol; colorless crystals, m.p. 175eC.

Example 3: 3.4- Dimethylbenzoylguanidine hydrochloride 15 from 3,4-dimethylbenzoic acid following the general protocol; colorless crystals, m.p. 276°C.

Example 4: 3-Trifluoromethylbenzoylguanidine hydrochloride from 3-trifluoromethylbenzoic acid following the general 20 protocol; colorless crystals, m.p. 170eC.

Example 5: not part of the invention. 3.5- Dichloro-4-hydroxybenzoylguanidine hydrochloride from 3,5-dichloro-4-hydroxybenzoic acid following the general protocol; colorless crystals, m.p. 254-256°C. 25 Example 6: 3.5- Di-tert-butyl-4-hydroxybenzoylguanidine hydrochloride from 3,5-di-tert-butyl-4-hydroxybenzoic acid following the general protocol; colorless crystals, m.p. 163-165eC.

Example 7: 30 3,5-Difluorobenzoylguanidine hydrochloride from 3,5-di- fluorobenzoic acid following the general protocol; colorless crystals, m.p. 224°C. 14

Example 8: 4-Trif luoromethylbenzoylguanidine hydrochloride from 4- trif luoromethylbenzoic acid following the general protocol; colorless crystals, m.p. 215°C.

Example 9: 3- Chloro-5-trif luoromethylbenzoylguanidine hydrochloride from 3-chloro-5-trif luoromethylbenzoic acid following the general protocol; colorless crystals, m.p. 162°C.

Example 10: 3.5- Bistrifluoromethylbenzoylguanidine hydrochloride from 3,5-bistrif luoromethylbenzoic acid following the general protocol; colorless crystals, m.p. 214°C.

Example 11: 5- Trifluoromethyl-3-iodobenzoylguanidine hydrochloride from 5-trifluoromethyl-3-iodobenzoic acid following the general protocol; colorless crystals, m.p. 263°C.

Example 12: 3.5- Dimethylbenzoylguanidine hydrochloride from 3,5-di-methylbenzoic acid following the general protocol; colorless crystals, m.p. 216-219°C.

Example 13: 4- tert-Butylbenzoylguanidine hydrochloride from 4-tert-butylbenzoic acid following the general protocol; colorless crystals, m.p. 237-240’C.

Example 14: 4-Chloro-3-methylbenzoylguanidine hydrochloride from 4-chloro-3-methylbenzoic acid following the general protocol; colorless crystals, m.p. 249-251°C.

Example 15: 3.5- Dichloro-4-(4-chlorobenzyloxy)benzoylguanidine hydrochloride from 3,5-dichloro-4-(4-chlorobenzyloxy)benzoic acid 108697/2 15 following the general protocol; colorless crystals, m.p. 230-231*C. 3.5- Dichloro-4-(4-chlorobenzyloxy)benzoic acid was obtained by reacting 3,5-dichloro-4-hydroxybenzoic acid with 4-chlorobenzyl chloride in DMF in the presence of potassium carbonate at 40eC, followed by hydrolysis of the 4-chlorobenzyl 3,5-dichloro-4-(4-chlorobenzyloxy) benzoate in aqueous/methanolic solution with NaOH and subsequent acidification using 2N HCl, m.p. 215-220°C.

Example 16: 4-tert-Butylbenzoylguanidine is obtained by treating the corresponding hydrochloride of Example 19 with triethylamine in dimethylformamide and water. Colorless, crystalline substance, m.p. 255-258eC.

Example 17: 3.5- Dibromobenzoylguanidine hydrochloride is obtained from 3,5-dibromobenzoylguanidine (Example 28) by treatment with methanolic hydrochloric acid. Colorless crystals, m.p. 275’C.

Example 18 · uot part of the invention. 3- Azido-5-trifluoromethylbenzoylguanidine hydrochloride is obtained from 3-azido-5-trifluoromethylbenzoic acid following the general protocol (m.p. 123-125eC), which is prepared from 3-amino-5-trifluoromethylbenzoic acid and sodium azide by diazotization and then by Sandmeyer reaction.

Colorless, crystalline compound. m.p. 197’C.

Example 19: 4- Bromo-3-methylbenzoylguanidine hydrochloride is obtained from 4-bromo-3-methylbenzoic acid following the general protocol.

Colorless crystals, m.p. 250’C. 16

Example 20: 3-Chloro-4-fluorobenzoylguanidine hydrochloride is obtained from 3-chloro-4-fluorobenzoic acid following the general protocol.

Colorless crystals, m.p. 188-189’C.

Example 21: 3,5-Di-tert-butylbenzoylguanidine hydrochloride is obtained from 3,5-di-tert-butylbenzoic acid following the general protocol.

Colorless crystals, m.p. 180’C.

Example 22: 3- Bromo-5-chlorobenzoylguanidine hydrochloride is obtained from 3-bromo-5-chlorobenzoic acid following the general protocol.

Colorless crystals, m.p. 268°C.

Example 23:

4- Bromo-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 211’C

Synthesis route:

a) 4-Bromo-3-trifluoromethylbenzonitrile from 4-bromo-3-tri fluoromethyl aniline under Sandmeyer conditions: diazotization of the amine using sodium nitrite in half-concentrated sulfuric acid at 0*C followed by reaction with Cu(I)CN (from copper sulfate, sodium sulfite and NaCN), first at 0°C then slowly heating at room temperature. Aqueous work-up is followed by column chromatography using ethyl acetate/n-heptane 2:8, colorless crystals, m.p. 77-80’C b) 4-Bromo-3-trifluoromethylbenzoic acid from a) by acid catalyzed hydration by means of glacial acetic acid/concentrated sulfuric acid under reflux for 17

4 hours, aqueous work-up, colorless crystals, m.p. 177-80eC c) 4-Bromo-3-trifluoromethylbenzoylguanidine hydro chloride from b) following the general protocol

Example 24: 4-Isopropyl-3-trifluoromethylbenzoylguanidine hydro chloride

Colorless crystals, m.p. 213-14°C

Synthesis route: a) Methyl 4-bromo-3-trifluoromethylbenzoate from

4-bromo-3-trifluoromethylbenzoic acid (23b) by heating in methanol in the presence of acetyl chloride, aqueous work-up, colorless crystals, m.p. 56-57°C b) Methyl 4-isopropyl-3-trifluoromethylbenzoate from methyl 4-bromo-3-trifluoromethylbenzoate (a) by cross-coupling using 1.5 equivalents of isopropyl-zinc chloride (obtained from isopropylmagnesium chloride by transmetallation using zinc (II) chloride etherate in THF) by stirring at room temperature in the presence of catalytic amounts of palladium(II) [1,1'-bis (diphenylphosphino)-ferrocene]chloride and copper(I) iodide, aqueous work-up, extraction using ethyl acetate, followed by column chromatography on silica gel using ethyl acetate/cyclohexane (2:8), colorless oil. c) 4-Isopropyl-3-trifluoromethylbenzoylguanidine hydrochloride by heating to the boil in THF in the presence of guanidine followed by hydrochloride formation

Example 25: 4-Cyclopentyl-3-trifluoromethylbenzoylguanidine 18 hydrochloride

Colorless crystals, m.p. 229-31°C

Synthesis route: a) Methyl 4-cyclopentyl-3-trifluoromethylbenzoate from methyl 4-bromo-3-trifluoromethylbenzoate (24a) by crosscoupling with cyclopentylzinc chloride analogously to Example 24b), colorless oil b) 4-Cyclopentyl-3-trifluoromethylbenzoylguanidine hydrochloride analogously to 24c).

Example 26:

3-Methyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 181-82°C

Synthesis route: a) Methyl 3-iodo-5-trifluoromethylbenzoate from 3-iodo- 5-trifluoromethylbenzoic acid analogously to Example 24a), colorless oil b) Methyl 3-methyl-5-trifluoromethylbenzoate from methyl 3-iodo-5-trifluoromethylbenzoate by crosscoupling using methylzinc chloride analogously to Example 24b), colorless oil b) 3-Methyl-5-trifluoromethylbenzoylguanidine hydro chloride analogously to 24c)

Example 27: 3-Isopropyl-5-trifluoromethylbenzoylguanidine hydro chloride

Colorless crystals, m.p. 110-12eC

Synthesis route: a) Methyl 3-isopropyl-5-trifluoromethylbenzoate from methyl 3-iodo-5-trifluoromethylbenzoate (26a) by cross-coupling with isopropylzinc chloride analogously to 24b), colorless oil 19 b) 3-1sopropyl-5-trifluoromethylbenzoylguanidine hydrochloride analogously to 24c)

Example 28: 3-Cyclopentyl-5-trifluoromethylbenzoylguanidine hydrochloride

Colorless crystals, m.p. 110°C with decomposition

Synthesis route: a) Methyl 3-cyclopentyl-5-trifluoromethylbenzoate from methyl 3-iodo-5-trifluoromethylbenzoate (26a) (by cross-coupling with cyclopentyl zinc chloride analogously to 24b), colorless oil b) 3-Cyclopentyl-5-trifluoromethylbenzoylguanidine hydrochloride analogously to 24c)

Example 29:

3-Phenyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 217-21°C

Synthesis route: a) Methyl 3-phenyl-5-trifluoromethylbenzoate from methyl 3-iodo-5-trifluoromethylbenzoate (26a) by cross-coupling with 1.1 equivalents of phenylboronic acid in aqueous methanol/toluene mixture (reflux, 4 hours) in the presence of catalytic amounts of palladium acetate, triphenylphosphine and sodium carbonate, distill off the solvent, take up the residue in ethyl acetate, render the mixture neutral using dilute hydrochloric acid and, after aqueous work-up, subject to column chromatography on silica gel using ethyl acetate/cyclohexane (3:7), colorless oil b) 3-Phenyl-5-trifluoromethylbenzoylguanidine hydro chloride analogously to 24c) 108697/2 - 20 -

<img img-format="tif" img-content="drawing" file="IL108697AD000215.tif" id="idf0015" />

Example 30:

4 -Fluoro-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 159-60°C from 4-fluoro-3-trifluoromethylbenzoic acid following the 5 general protocol

Example 31:

4-Phenoxy-3-trifluoramethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 162-65°C from 4-fluoro-3-trif luoromethylbenzoylguanidine (30 base) 10 by reaction with phenol in the presence of potassium carbonate in DMF at 120*°C, aqueous work-up, column chromatography, methylene chloride/methanol 9:1, followed by hydrochloride formation

Example 32: 15 4-(4-Fluorophenoxy) -3-trif luoromethylbenzoylguanidine hydrochloride

Colorless crystals, m.p. 165-67°C from (30 base) analogously to process (31) by means of 4-fluorophenol 20 Example 33: 4-(4-Chlorophenoxy)-3-trif luoromethylbenzoylguanidine hydrochloride

Colorless crystals, m.p. 195-97°C from (30 base) analogously to process (31) by means of 25 4-chlorophenol

Example 34:

5-Fluoro-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals, m.p. 150-51eC from 5-fluoro-3-trifluoromethylbenzoic acid following the 30 general protocol 17.2.94

Example 35: 4-Phenylethynyl-3-trifluoromethylbenzoylguanidine hydrochloride

Colorless crystals, m.p. 150°C with decomposition 21

Synthesis route: a) Methyl 4-phenylethynyl-3-trifluoromethylbenzoate from methyl 4-bromo-3-trifluoromethylbenzoate (24a) by Stephans-Castro coupling with 2.5 equivalents of phenylacetylene, stirring at room temperature for 24 hours in the presence of catalytic amounts (5 mol%) of bis(triphenylphosphine)palladium(II) chloride, 15 mol% of copper(I) iodide and 3 equivalents of n-butylamine, work-up with aqueous ammonium chloride, extraction with ethyl acetate followed by column chromatography on silica gel using ethyl acetate/cyclohexane (3:7), pale brownish oil. b) 4-Phenylethynyl-3-trifluoromethylbenzoylguanidine hydrochloride analogously to 24c)

Example 36: 3-Bromo-4-methylbenzoylguanidine hydrochloride is obtained from 3-bromo-4-methylbenzoic acid analogously to the general protocol.

Colorless crystals, m.p. 250°C.

Example 37: 3-Chloro-4-isopropylbenzoylguanidine hydrochloride is obtained from 3-chloro-4-isopropylbenzoic acid analogously to the general protocol.

Colorless crystals. m.p. 185°C.

Example 38: 3,4,5-Trichlorobenzoylguanidine hydrochloride is obtained from 3,4,5-trichlorobenzoic acid analogously to the general protocol.

Colorless crystals, m.p. 194°C.

Example 39: 3-Bromo-5-methylbenzoylguanidine hydrochloride - 22

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is obtained from 3-bromo-5-methylbenzoic acid analogously to the general protocol.

Colorless crystals, m.p. 235-236®C. 5 Example 40: 4-Chloro-3,5-dimethylbenzoylguanidine hydrochloride is obtained from 4-chloro-3,5-dimethylbenzoic acid analogously to the general protocol.

Colorless crystals. 10 m.p. 244-247®C.

Example 41: 3-Trifluoromethyloxybenzoylguanidine hydrochloride is obtained from 3-trifluoromethyloxybenzoic acid analogously to the general protocol. 15 Crystals. m.p. 146-148®C.

Example 42: 4-Trifluoromethyloxybenzoylguanidine hydrochloride is obtained from 4-trifluoromethyloxybenzoic acid analog 20 ously to the general protocol.

Crystals, m.p. 259®C.

Example 43: 4-Cyclohexylbenzoylguanidine hydrochloride 25 is obtained from 4-cyclohexylbenzoic acid analogously to the general protocol.

Crystals. m.p. 273®C.

Example 44: 30 3-Chloro-4-cyclopentyloxybenzoylguanidine hydrochloride is obtained from 3-chloro-4-cyclopentyloxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 273®C. 23 -

<img img-format="tif" img-content="drawing" file="IL108697AD000217.tif" id="idf0017" />

3-Chloro-4-cyclopentyloxybenzoic acid, of m.p. 148-151°C, is obtained by hydrolysis of methyl 3-chloro-4-cyclo-pentyloxybenzoate (amorphous oily substance) in a mixture of aqueous NaOH and dioxane followed by acidification of 5 the alkaline hydrolysis solution using half-concentrated hydrochloric acid.

Methyl 3-chloro-4-cyclopentyloxybenzoate is obtained by boiling methyl 3-chloro-4-hydroxybenzoate and iodocyclopentane in acetone in the presence an excess of solid, 10 ground potassium carbonate. After the acetone has been evaporated, the oily residue is taken up in water, the mixture is subsequently extracted using ethyl acetate, the extract is dried over sodium sulfate, and the solvent is then evaporated. 15 Example 45: 3-Isopropy1-4-methoxybenzoylguanidine hydrochloride is obtained from 3-isopropyl-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 214°C. 20 Example 46: 3-Chloro-4-cyclooctyloxybenzoylguanidine hydrochloride is obtained from 3-chloro-4-cyclooctyloxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 243°C. 25 3-Chloro-4-cyclooctyloxybenzoic acid, of m.p. 110-112®C, is obtained by hydrolysis of methyl 3-chloro-4-cyclo-octyloxybenzoate (amorphous oily substance) in a mixture of aqueous NaOH and methanol, followed by acidification of the alkaline hydrolysis solution with half-concen- 30 trated hydrochloric acid.

Methyl 3-chloro-4-cyclooctyloxybenzoate is obtained by heating methyl 3-chloro-4-hydroxybenzoate and cyclooctyl bromide in dimethylformamide for 20 hours in the presence of an excess of solid, ground potassium carbonate. After 35 the solvent has been evaporated, the oily residue is taken up in water, the mixture is subsequently extracted 108697/2 ' - 24 - using ethyl acetate, the extract is dried over sodium sulfate, and the solvent is then evaporated.

Example 47: 4-tert-Butyl-3-methoxybenzoylguanidine hydrochloride is obtained from 4-tert-butyl-3-methoxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 227-231’C.

The 4-tert-Butyl-3-methoxybenzoic acid used is obtained by oxidation of 4-tert-butyl-3-methoxytoluene in an aqueous/alkaline solution of potassium permanganate.

Example 48: 3-Bromo-4-fluorobenzoylguanidine hydrochloride is obtained from 3-bromo-4-fluorobenzoic acid analogously to the general protocol. Colorless crystals, m.p. 215°C.

Example 49: 3-tert-Buty1-4-hydroxybenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-hydroxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 216°C.

Example 50: Not part of invention 3-Cyano-4-methoxybenzoylguanidine hydrochloride is obtained from 3-cyano-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 236eC.

Example 51: 3-tert-Butyl-4-methoxybenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals, m.p. 260-62°C.

Example 52: 3-Chloro-4-(1-hexyl)benzoylguanidine hydrochloride 25

<img img-format="tif" img-content="drawing" file="IL108697AD000218.tif" id="idf0018" />

is obtained from 3-chloro-4-(1-hexyl)benzoic acid analogously to the general protocol. Colorless crystals, m.p. 286’C (decomposition).

Example 53: 5 3-tert-Butyl-4-(2-methyl-l-propyl)benzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-(2-methyl-l-propyl)-benzoic acid analogously to the general protocol. Colorless crystals. 10 m.p. 218-228°C (decomposition).

Example 54: 4-Isopropyl-3-pentafluoroethylbenzoylguanidine hydrochloride is obtained from 4-isopropyl-3-pentafluoroethylbenzoic 15 acid analogously to the general protocol. Colorless, amorphous solid.

Example 55: 3-tert-Butyl-4-isopropylbenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-isopropylbenzoic acid 20 analogously to the general protocol. Colorless crystals, m.p. 145-165’C.

Example 56: 4-Isopropylbenzoylguanidine hydrochloride is obtained from isopropylbenzoic acid analogously to the 25 general protocol. Colorless crystals, m.p. 193-198’C.

Example 57: 3-Trifluoromethylbenzoylguanidine is obtained from 3-trifluorobenzoic acid analogously to 30 the general protocol. Colorless, amorphous-oily compo sition.

Example 58: 3-Trifluoromethylbenzoylguanidine methanesulfonate 26 ι·

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is obtained analogously to the general protocol from 3-trifluoromethylbenzoylguanidine by treating the latter with methanesulfonic acid in ethyl acetate. Colorless crystals. 5 m.p. 167-170®C.

Example 59: 4-Fluoro-3-isobutylbenzoylguanidine hydrochloride is obtained from 4-fluoro-3-isobutylbenzoylguanidine analogously to the general protocol. 10 m.p. 136-140®C.