Substituted benzoylguanidines, process for their preparation, their use as medicament, as inhibitor of the cellular Na+/H+ exchange or as diagnostic agent and medicament containing them.

【0001】

The present invention is based on Equation I [Chemical Formula 3].<img he="34" id="000002" wi="154" file="2_0003554352.tif" img-format="tif" img-content="drawing" />Benzoylguanidine and the pharmacologically acceptable salts of these compounds.

【0002】

In the above equation, R (1) and R (3) are F, Cl, Br, I or (C).₁~ C₁₂)-Alkyl, R (2) is hydrogen, F, Cl, Br, I or (C₁~ C₁₂)-Alkyl, if at least one of the remaining substitutions R (1), R (2) or R (3) is a fully lipophilic alkyl group with 3-12 carbon atoms One of the substitutions R (1), R (2) or R (3) is N₃, CN, OH or (C₁~ C₁₀)-Alkyloxy, or the substitution R (1), R (2) or R (3) is R (4) -C_nH_2n-O_m[In the equation, m is 0 or 1, n is 0, 1, 2 or 3, and R (4) is C._pF_{2p + 1}(In the equation, p is 1, 2 or 3 if n is 0 or 1) or R (4) is (C)₃~ C₁₂)-Cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl (aromatic and heteroaromatic systems are not substituted or F, Cl, CF₃, Methyl, methoxy or NR (7) R (8) (in the formula, R (7) and R (8) are hydrogen or (C₁~ C₄)-Replaced by (alkyl))], [0003]

Alternatively, one of the permutations R (1), R (2) or R (3) is -CCR (5), -C [R (6)] = CHR (5) [R (5 in the formula). ) Is phenyl (this group is not substituted or F, Cl, CF₃, Methyl, methoxy, hydroxyl, amino, methylamino or dimethylamino substituted by 1-3 substitutions selected from the group), (C₁~ C₉)-Heteroaryl (this group is unsubstituted or substituted like phenyl), (C₁~ C₆)-Alkyl (this group is unsubstituted or substituted with 1-3 OH) or (C₃~ C₈) Cycloalkyl, and R (6) is hydrogen or methyl], and if R (4) is pyridyl, quinolyl or isoquinolyl, then m and n cannot be 0 at the same time and Excludes compounds Benzoylguanidine, 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine and 3- or 4-methylbenzoylguanidine.

【0004】

Preferred compounds are R (1), R (2), R (3) hydrogen, F, Cl, Br or (C)₁~ C₈)-Alkyl, if at least one of the remaining substitutions R (1), R (2) or R (3) is a fully lipophilic alkyl group with 3-6 carbon atoms One of the substitutions R (1), R (2) or R (3) is OH or (C₁~ C₆)-Alkyloxy, or one of the substitutions R (1), R (2) or R (3) is R (4) -C_nH_2n-O_m[In the equation, m is 0 or 1, n is 0, 1, 2 or 3, and R (4) is C._pF_{2p + 1}(In the equation, p is 1 if n is 0 or 1) or R (4) is (C)₅~ C₇)-Cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl (aromatic and heteroaromatic systems are not substituted or F, Cl, CF₃, Substituted by a substitution selected from the group consisting of methyl or methoxy)].

Or one of the substitutions R (1), R (2) or R (3) is -CCR (5) [In the formula, R (5) is phenyl or (C)₁~ C₄)-Alkyl (this group is not substituted or substituted by OH)], and if R (4) is pyridyl, quinolyl or isoquinolyl, then m and n are 0 at the same time. And the compounds are compounds other than benzoylguanidine, 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine and 3- or 4-methylbenzoylguanidine and pharmacologically acceptable salts of these compounds.

【0006】

Particularly preferred compounds are 3-trifluoromethylbenzoylguanidine hydrochloride, 3,5-bistrifluoromethylbenzoylguanidine hydrochloride, 3-methyl-5-trifluoromethylbenzoylguanidine hydrochloride, 4-fluoro-3-trifluoromethyl. Benzoylguanidine hydrochloride, 4- (4-fluorophenoxy) -3-trifluoromethylbenzoylguanidine hydrochloride, 5-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride, 3-chloro-4-isopropylbenzoylguanidine hydrochloride, Pharmacologically of 4-th butyl-3-methoxybenzoyl guanidine hydrochloride, 3-th butyl-4-hydroxybenzoyl guanidine hydrochloride, 3-th butyl-4-isopropylbenzoyl guanidine hydrochloride and their compounds It is an acceptable salt. If one of the substitutions R (1) to R (3) has an asymmetric center, the present invention also includes S- and R-arranged compounds. The compounds can be in the form of optical isomers, diastereomers, racemates or mixtures thereof. The above-mentioned alkyl group may be linear or branched.

【0007】

(C₁~ C₉)-Heteroaryls are specifically derived from phenyl or naphthyl and one or more CH groups are substituted with nitrogen and / or at least two adjacent CH groups are substituted with S, NH or O. It should be understood to mean a group that has been (forming a 5-membered aromatic ring). In addition, one or two atoms at the condensation position of the bicyclic group may be nitrogen atoms (such as indridinyl). Heteroaryls are, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indrill, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinoxalinyl. Synnolinyl.

【0008】

Furthermore, the present invention relates to a method for producing Compound I, which is described in Formula II [Chemical Formula 4].<img he="32" id="000003" wi="154" file="3_0003554352.tif" img-format="tif" img-content="drawing" />(In the formula, R (1) to R (3) have the above-mentioned meanings, and L is a removing group that can be easily replaced by a nucleophile) from reacting with guanidine. Become.

【0009】

The activated acid derivative of formula II, wherein 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, is based in a manner known per se. It is obtained from carboxylic acid chloride (Formula II, L = Cl) and this carboxylic acid chloride can be prepared from the underlying carboxylic acid in a manner known per se, for example using thionyl chloride.

【0010】

In addition to the carboxylic acid chloride (L = Cl) of formula II, other activating acid derivatives of formula II are also produced directly from the underlying benzoic acid derivative (formula II, L = OH) in a manner known per se. can do. For example, the methyl ester of formula II (L = OCH)₃) Is produced by treatment with gaseous HCl in methanol, and the imidazolide of formula II (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 ~ 367 (1962)) Manufactured by treatment with carbonyldiimidazole, mixed anhydride II is Cl-COOC in the presence of triethylamine in an inert solvent.₂H₅Or manufactured using tosyl chloride and benzoic acid using dicyclohexylcarbodiimide (DCC) or O-[(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyluronium It can be activated using 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 producing activated carboxylic acid derivatives of formula II are described in J. March, Advanced Organic Chemistry, Third Edition (John Wiley &amp; Sons, 1985), p. 350. This document is cited as a reference.

【0011】

The activated carboxylic acid derivative of formula II is reacted with guanidine in a protic or aprotic polar inert organic solvent in a manner known per se. The solvent that has been proven to be advantageous in the reaction of methyl benzoate (II, L = OMe) with guanidine is methanol or THF between 20 ° C and the boiling points of these solvents. In most reactions of Compound II with salt-free guanidine, the procedure is favorably carried out in an aprotic inert solvent such as THF, dimethoxyethane or dioxane. When a base such as NaOH is used as the solvent, water can also be used in the reaction of II with guanidine.

【0012】

If L is Cl, the method is favorably carried out, for example in the form of excess guanidine, by adding an acid sweeping agent that binds the hydrohalic acid. Some of the benzoic acid derivatives on which Formula II is based are known and described in the literature. Unknown compounds of formula II can be prepared by methods known from the literature.

【0013】

Carboxylic acids of formula II or esters of these compounds (eg L = -OH or -O-methyl) in which R (2) has a halogen significance or R (3) has a nitro significance are of formula II. It can be used as a useful starting material for other carboxylic acids. Halogen at the R (2) position is known in a large number of nucleophiles, such as phenol or alcohol R (4) -C._nH_2nA very advantageous corresponding benzoic acid derivative can be obtained by exchanging with -OH or alkali metal salts of these compounds. Similarly, the nitro group can be reduced to the corresponding aminobenzoic acid by the Sandmeier or Ullmann reaction and led to the desired particularly halogen-substituted benzoic acid derivative. In many cases, chlorine, bromine or iodine can also be introduced into a particular benzoic acid by a method known per se, by direct halogenation using a Friedel-Crafts catalyst.

【0014】

In general, benzoylguanidine I is a weak base and can combine with acids to form salts. Suitable acid addition salts are salts with all pharmacologically acceptable acids such as hydrohalogenates, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates. , Methyl sulfonate and p-toluene sulfonate.

【0015】

Compound I is a substituted acylguanidine. The most promising known representative compound of acyls is the pyrazine derivative amylolide, which has been used therapeutically as a potassium-retaining diuretic. For example, many other compounds of the amylolide form, such as dimethyl amylolide or ethyl isopropyl amylolide, are also described in the literature.

[Chemical 5]<img he="42" id="000004" wi="154" file="4_0003554352.tif" img-format="tif" img-content="drawing" />Amylolide: R , R = H Dimethylamilolide: R , R = CH₃Ethylisopropylamilolide: R'= C₂H₅, R = CH (CH₃)₂【0016】

In addition, studies suggesting that amylolide has antiarrhythmic properties have been disclosed [Circulation 79, 1257-63 (1989)]. However, widespread use as an antiarrhythmic agent is hampered by the fact that this effect is negligible and is associated with hypotensive and salt excretion effects, and these side effects are undesirable in the treatment of cardiac arrhythmias. Has been done.

【0017】

Results obtained in experiments with excised animal hearts also suggest that amylolide has antiarrhythmic properties [Eur. Heart J. 9 (suppl.1): 167 (1988) ( book of abstracts).] For example, in the rat heart, it was found that artificially induced ventricular fibrillation can be completely suppressed by amylolide. The aforementioned amylolide derivative, ethylisopropylamilolide, is even more potent than amylolide in this model.

【0018】

European published patent 416,499 (HOE 89 / F 288) describes benzoylguanidine having a hydrogen atom at the position corresponding to group R (1). German published patent 3,502,629 discloses a benzoylguanidine that is substituted with a phenoxy group at the m-position and always has at least two substitutions in the phenoxy group. These compounds are used for crop protection.

【0019】

Kumamoto, Pharm. Bull [1966], pp. 7-13, describes slightly substituted benzoylguanidines that can be used as anticancer agents. U.S. Pat. No. 3,780,027 describes acylguanidine derived from a commercially available loop diuretic, such as bumetanide, which is similar in structure to the compound of formula I. Therefore, strong salt diuretic activity has been reported for these compounds.

【0020】

Therefore, it is surprising that the compounds according to the invention do not have the undesired and unfavorable salt diuresis, as in the case of anoxia, for example, and have very good antiarrhythmic properties. Is. Due to its pharmacological properties, this compound is highly suitable for use as a cardioprotective anti-arrhythmic drug for the prevention and treatment of infarction and the treatment of angina, and these compounds are also particularly ischemic. Prophylactically inhibits or greatly reduces the pathophysiological processes involved in ischemic-induced injury when a provocative cardiac arrhythmia is triggered. Due to the protective action of the compounds against pathological hypoxia and ischemic conditions, the compounds of formula I according to the invention are Na of cells.⁺/ H⁺As a result of inhibiting the exchange mechanism, it can be used as a therapeutic agent for the type of injury caused by all acute or chronic ischemia or the diseases caused by it, primary or secondary. This involves, for example, the use of compounds as pharmaceuticals for infiltration treatments in organ transplants. In this case, the compound is used to protect the donor's organs before and during removal, as well as the removed organs, for example when the organs are treated with or stored in a physiological bath. It can be used not only, but also when the organ is transplanted into the recipient's body. The compound is also a valuable protective agent for performing an invasive angioplasty treatment on the heart or shootless blood vessels. Due to the protective action of the compound against ischemic-induced injuries, the compound is also suitable for use as a medicine for treating ischemia of the nervous system, especially the central nervous system. In this case, the compound is suitable for the treatment of, for example, stroke or cerebral edema. In addition, the compounds of formula I according to the invention are also suitable for the treatment of forms of shock, such as allergic, cardiac, blood deficiency and bacterial shock.

【0021】

In addition, the compounds of formula I according to the invention are characterized by a potent inhibitory effect on cell proliferation, such as fibroblast proliferation and vascular smooth muscle cell proliferation. Therefore, the compound of formula I is suitable as a valuable therapeutic agent for diseases in which cell proliferation is the primary and secondary cause, and therefore the compound is an anti-atherosclerosis agent, a late complication in diabetes. It can be used as an agent for diseases, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hyperplasia and hyperplasia, especially prostatic hyperplasia or prostatic hyperplasia.

【0022】

The compounds according to the invention are the mechanism of alternating sodium proton transport of cells that occurs in a number of diseases (essential hypertension, atherosclerosis, diabetes, etc.), even in easily measurable cells such as in erythrocytes, platelets or leukocytes. (Na⁺/ H⁺It is a valuable inhibitor of exchange). Therefore, the compounds according to the invention are suitable as excellent and simple reagents used as diagnostic agents for determining and differentiating, for example, certain forms of hypertension and also atherosclerosis, diabetes, proliferative disorders and the like. In addition, the compounds of formula I are suitable for prophylactic treatment to prevent the development of hypertension, eg essential hypertension.

【0023】

In addition, the compounds have the property of inhibiting the production of hydrochloric acid in gastric parietal cells, and therefore the compounds can be used as pharmaceuticals for the treatment of gastrointestinal disorders. Such gastrointestinal and esophageal disorders are, for example, gastric and intestinal ulcers and reflux esophagitis. Drugs containing Compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, and preferred methods of administration depend on the symptoms of the particular disease. Compound I can be used on its own or in combination with pharmaceutical supplements and the compound can be used in both veterinary and human medicine. Auxiliary agents suitable for the desired pharmaceutical formulation based on expertise are known to those of skill in the art. Auxiliaries that can be used in addition to solvents, gel-forming agents, suppository bases, tableting aids and other excipients for active substances include, for example, antioxidants, dispersants, emulsifiers, foam stoppers. Agents, flavor improvers, preservatives, solubilizers or colorants.

【0024】

In oral dosage forms, the active compound is mixed with an additive suitable for this purpose, such as a carrier, stabilizer or inert diluent, and formulated by conventional methods to suit suitable dosage forms, eg tablets. , Sugar-coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions. The Inactive excipients that can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. Dry or wet granules can be used in the production. Oily excipients or solvents include plant or animal oils such as sunflower oil or cod liver oil.

【0025】

For subcutaneous or intravenous administration, the active compound is dissolved, suspended or emulsified, optionally with substances commonly used for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents include water, saline, or alcohols such as ethanol, propanol, glycerol, and sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents described above.

【0026】

Pharmaceutical formulations suitable for administration in the form of aerosols or sprays are, for example, solutions of active substances of formula I in pharmaceutically acceptable solvents, such as ethanol, or water or mixtures of such solvents, suspensions. It is a liquid or an aerosol. If desired, the formulation can also contain other pharmaceutical aids such as surfactants, emulsifiers and stabilizers and propellants. The concentration of active substance in such formulations is generally about 0.1-10% by weight, especially about 0.3-3% by weight. The dose and frequency of administration of the active agent of formula I to be administered includes the titer and duration of action of the compound used, as well as the nature and extent of the disease to be treated and the sex and year of the mammal to be treated. Depends on age, weight and individual responsiveness.

【0027】

On average, the daily dose of the compound of formula I for a patient of about 75 kg is at least 0.001 mg / kg / kg body weight, preferably 0.01 mg / kg to 10 mg / kg or less, preferably 1 mg / kg. is there. If the disease is acute, for example immediately after suffering a myocardial infarction, higher and especially more frequent doses are required, eg single doses up to 4 times per day. Up to 200 mg per day is required, especially for intravenous administration, such as in patients with infarction and intensive care.

【0028】

Part of the Experiment 0.01 mol of a benzoic acid derivative of the general protocol II for producing benzoylguanidine (I) from benzoic acid (II, L = OH) was dissolved or suspended in 60 ml of anhydrous tetrahydrofuran (THF), and then suspended. Add 1.78 g (0.011 mol) of carbonyldiimidazole. After stirring the reaction solution at room temperature for 2 hours, 2.95 g (0.05 mol) of guanidine is introduced. After stirring the mixture overnight, THF is distilled off under reduced pressure (rotor vapor), water is added, the pH is adjusted to 6-7 using 2N HCl and the corresponding benzoylguanidine (formula I) is distilled off. The resulting benzoylguanidine can be converted to the corresponding salt by treatment with aqueous or methanolic hydrochloric acid or other pharmacologically acceptable acid.

【0029】

Example 1 3,5-Dichlorobenzoylguanidine hydrochloride was prepared from 3,5-dichlorobenzoic acid according to a general protocol. Colorless crystals. Melting point 286 ° C. Example 2 3-Chlorobenzoylguanidine hydrochloride was prepared from 3-chlorobenzoic acid according to a general protocol. Colorless crystals. Melting point 175 ° C. Example 3 3,4-Dimethylbenzoylguanidine hydrochloride was prepared from 3,4-dimethylbenzoic acid according to a general protocol. Colorless crystals. Melting point 276 ° C.

【0030】

Example 4 3-Trifluoromethylbenzoylguanidine hydrochloride was prepared from 3-trifluoromethylbenzoic acid according to a general protocol. Colorless crystals. Melting point 170 ° C. Example 5 According to a general protocol, 3,5-dichloro-4-hydroxybenzoylguanidine hydrochloride was prepared from 3,5-dichloro-4-hydroxybenzoic acid. Colorless crystals. Melting point 254 ~ 256 ° C. Example 6 The 3,5-dith butyl-4-hydroxybenzoylguanidine hydrochloride was prepared from 3,5-dith butyl-4-hydroxybenzoic acid according to a general protocol. Colorless crystals. Melting point 163 ~ 165 ° C.

【0031】

Example 7 3,5-Difluorobenzoylguanidine hydrochloride was prepared from 3,5-difluorobenzoic acid according to a general protocol. Colorless crystals. Melting point 224 ° C. Example 8 4-trifluoromethylbenzoylguanidine hydrochloride was prepared from 4-trifluoromethylbenzoic acid according to a general protocol. Colorless crystals. Melting point 215 ° C. Example 9 3-Chloro-5-trifluoromethylbenzoylguanidine hydrochloride was prepared from 3-chloro-5-trifluoromethylbenzoic acid according to a general protocol. Colorless crystals. Melting point 162 ° C.

【0032】

Example 10 According to a general protocol, 3,5-bistrifluoromethylbenzoylguanidine benzoic acid was prepared from 3,5-bistrifluoromethylbenzoic acid. Colorless crystals. Melting point 214 ° C. Example 11 5-trifluoromethyl-3-iodobenzoylguanidine hydrochloride was prepared from 5-trifluoromethyl-3-iodobenzoic acid according to a general protocol. Colorless crystals. Melting point 263 ° C. Example 12 According to a general protocol, 3,5-dimethylbenzoylguanidine hydrochloride was prepared from 3,5-dimethylbenzoic acid. Colorless crystals. Melting point 216 ~ 219 ° C.

【0033】

Example 13 A 4-thirth butylbenzoylguanidine hydrochloride was prepared from 4-thirth butylbenzoic acid according to a general protocol. Colorless crystals. Melting point 237 ~ 240 ° C. Example 14 4-Chloro-3-methylbenzoylguanidine hydrochloride was prepared from 4-chloro-3-methylbenzoic acid according to a general protocol. Colorless crystals. Melting point 249 ~ 251 ° C.

【0034】

Example 15 According to a general protocol, 3,5-dichloro-4- (4-chlorobenzyloxy) benzoylguanidine hydrochloride was prepared from 3,5-dichloro-4- (4-chlorobenzyloxy) benzoic acid. Colorless crystals. Melting point 230 ~ 231 ° C. 3,5-Dichloro-4- (4-chlorobenzyloxy) benzoic acid, in the presence of potassium carbonate at 40 ° C, in DMF, 3,5-dichloro-4-hydroxybenzoic acid with 4-chlorobenzyl chloride By reacting and then hydrolyzing 4-chlorobenzyl 3,5-dichloro-4- (4-chlorobenzyloxy) benzoate with NaOH in aqueous / methanol solution and then acidifying with 2N HCl. Obtained. Melting point 215 ~ 220 ° C.

【0035】

Example 16 Dimethylformamide and the corresponding hydrochloride of Example 13 in water were treated with triethylamine to give 4-th butylbenzylguanidine. A colorless crystalline substance. Melting point 255 ~ 258 ° C. Example 17 Treatment with methanolic hydrochloric acid gave 3,5-dibromobenzoylguanidine hydrochloride from 3,5-dibromobenzoylguanidine. Colorless crystals. Melting point 275 ° C.

【0036】

Example 18 According to a general protocol, 3-azido-5-trifluoromethylbenzoylguanidine hydrochloride was obtained from 3-azido-5-trifluoromethylbenzoic acid (melting point 123-125 ° C). The above benzoic acid was prepared from 3-amino-5-trifluoromethylbenzoic acid and sodium azide by diazotization and then Sandmeyer reaction. Colorless crystalline compound. Melting point 197 ° C. Example 19 4-Bromo-3-methylbenzoylguanidine hydrochloride was obtained from 4-bromo-3-methylbenzoic acid according to a general protocol. Colorless crystals. Melting point 250 ° C.

【0037】

Example 20 3-Chloro-4-fluorobenzoylguanidine hydrochloride was obtained from 3-chloro-4-fluorobenzoic acid according to a general protocol. Colorless crystals. Melting point 188 ~ 189 ° C. Example 21 According to a general protocol, 3,5-di-tertiary butylbenzoylguanidine hydrochloride was obtained from 3,5-di-tertiary butylbenzoic acid. Colorless crystals. Melting point 180 ° C. Example 22 3-Bromo-5-chlorobenzoylguanidine hydrochloride was obtained from 3-bromo-5-chlorobenzoic acid according to a general protocol. Colorless crystals. Melting point 268 ° C.

【0038】

Example 234-Bromo-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 211 ° C. Synthesis method: (a) Diazotization of the amine using sodium nitrite under Sandmeier conditions, ie in semi-concentrated sulfuric acid at 0 ° C, then first at 0 ° C and then gradually heating at room temperature to Cu ( I) 4-Bromo-3-trifluoromethylbenzonitrile was obtained from 4-bromo-3-trifluoromethylaniline by reacting with CN (from copper sulfate, sodium cyanide and NaCl). It was treated aqueous and then column chromatographed using 2: 8 ethyl acetate / n-heptane. Colorless crystals. Melting point 77-80 ° C. (b) 4-Bromo-3-trifluoromethylbenzoic acid was produced from (a) by acid contact hydration with glacial acetic acid / concentrated sulfuric acid for 4 hours under reflux and aqueous treatment. Colorless crystals. Melting point 177 ~ 180 ° C. (c) 4-Bromo-3-trifluoromethylbenzoylguanidine hydrochloride was obtained from (b) according to a general protocol.

【0039】

Example 244-Isopropyl-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 213 ~ 214 ° C. Synthesis method: (a) Methyl 4-bromo-3-trifluoromethylbenzoate (23b) to methyl 4-bromo-3-trifluoromethylbenzoate by heating in methanol in the presence of acetyl chloride and treating with water. Manufactured. Colorless crystals. Melting point 56-57 ° C. (b) Isopropyl-zinc chloride (in THF) by stirring at room temperature in the presence of contact amounts of palladium (II) [1,1'-bis (diphenylphosphino) -ferrocene] chloride and copper (I) iodide. Cross-coupled with 1.5 equivalents (obtained from isopropylmagnesium chloride by metal exchange with zinc (II) chloride etherate), treated aqueous, extracted with ethyl acetate and then ethyl acetate / cyclohexane ( Methyl 4-isopropyl-3-trifluoromethylbenzoate was produced from methyl 4-bromo-3-trifluoromethylbenzoate (a) by column chromatography on silica using 2: 8). .. Colorless oil. (c) 4-Isopropyl-3-trifluoromethylbenzoylguanidine hydrochloride was obtained by boiling in THF in the presence of guanidine and then forming a hydrochloride.

【0040】

Example 254-Cyclopentyl-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 229 ~ 231 ° C. Synthesis Method: (a) Cross-coupling with cyclopentyl zinc chloride as in Example 24 (b) from 4-bromo-3-trifluoromethylbenzoate methyl 24 (a) to 4-cyclopentyl- 3-Trifluoromethyl Methyl benzoate was obtained. Colorless oil. (b) 4-Cyclopentyl-3-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0041】

Example 263-Methyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 181 ~ 182 ° C. Synthesis method: (a) Methyl 3-iodo-5-trifluoromethylbenzoate was obtained from 3-iodo-5-trifluoromethylbenzoic acid in the same manner as in Example 24 (a). Colorless oil. (b) Methyl 3-iodo-5-trifluoromethylbenzoate to 3-methyl-5-trifluoromethyl by cross-coupling with methylzinc chloride in the same manner as in Example 24 (b). Methyl benzoate was obtained. Colorless oil. (c) 3-Methyl-5-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0042】

Example 273-Isopropyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 110-112 ° C. Synthesis Method: (a) Methyl 3-iodo-5-trifluoromethylbenzoate (26a) to 3-isopropyl-5-tri by cross-coupling with isopropyl zinc chloride in the same manner as in Example 24 (b). Methyl fluoromethylbenzoate was obtained. Colorless oil. (b) 3-Isopropyl-5-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0043】

Example 283-Cyclopentyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 110 ° C (decomposition). Synthesis Method: (a) Similar to Example 24 (a), by cross-coupling with cyclopentyl zinc chloride, 3-iodo-5-trifluoromethylbenzoate methyl (26a) to 3-cyclopentyl-5- Methyl trifluoromethyl benzoate was obtained. Colorless oil. (b) 3-Cyclopentyl-5-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0044】

Example 293-Phenyl-5-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 217 ~ 221 ° C. Synthesis Method: (a) Cross-coupling (perfusion, 4 hours) with 1.1 equivalents of phenylboronic acid in an aqueous methanol / toluene mixture in the presence of contact amounts of palladium acetate, triphenylphosphine and sodium carbonate. The solvent was distilled off, the residue was taken up in ethyl acetate, the mixture was neutralized with dilute hydrochloric acid, treated aqueous, and then column chromatographed on silica gel using ethyl acetate / cyclohexane (3: 7). -Methyl 3-phenyl-5-trifluoromethylbenzoate was obtained from methyl iodo-5-trifluoromethylbenzoate (26a). Colorless oil. (b) 3-Phenyl-5-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0045】

Example 30 4-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride was obtained from 4-fluoro-3-trifluoromethylbenzoic acid according to a general protocol. Colorless crystals. Melting point 159 ~ 160 ° C. Example 31 By reacting with phenol in the presence of potassium carbonate in DMF at 120 ° C, aqueous treatment, column chromatography with 9: 1 methylene chloride / methanol and then hydrochloride formation. 4-Phenoxy-3-trifluoromethylbenzoylguanidine hydrochloride was obtained from fluoro-3-trifluoromethylbenzoylguanidine (30 bases). Colorless crystals. Melting point 162 ~ 165 ° C.

【0046】

Example 32 In the same manner as in Example 31, 4- (4-fluorophenoxy) -3-trifluoromethylbenzoylguanidine hydrochloride was obtained from (30 bases) by 4-fluorophenyl. Colorless crystals. Melting point 165 ~ 167 ° C. Example 33 In the same manner as in Example 31, 4- (4-chlorophenoxy) -3-trifluoromethylbenzoylguanidine hydrochloride was obtained from (30 bases) by 4-chlorophenol. Colorless crystals. Melting point 195 ~ 197 ° C. Example 34 According to a general protocol, 5-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride was obtained from 5-fluoro-3-trifluoromethylbenzoic acid. Colorless crystals. Melting point 150-151 ° C.

【0047】

Example 354-Phenylethynyl-3-trifluoromethylbenzoylguanidine hydrochloride Colorless crystals. Melting point 150 ° C (decomposition). Synthesis method: (a) Stir at room temperature for 24 hours in the presence of contact amount (5 mol%) of bis (triphenylphosphine) palladium (II) chloride, copper (I) 15 mol% and n-butylamine 3 eq. Stefance-castro coupling using 2.5 eq of phenylacetylene, treatment with aqueous ammonium chloride, extraction with ethyl acetate, then column chromatography on silica gel using ethyl acetate / cyclohexane (3: 7). By imaging treatment, methyl 4-phenylethynyl-3-trifluoromethylbenzoate was obtained from methyl 4-bromo-3-trifluoromethylbenzoate (24a). Light brown oil. (b) 4-Phenylethynyl-3-trifluoromethylbenzoylguanidine hydrochloride was obtained in the same manner as in Example 24 (c).

【0048】

Example 36 3-Bromo-4-methylbenzoylguanidine hydrochloride was obtained from 3-bromo-4-methylbenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 250 ° C. Example 37 3-Chloro-4-isopropylbenzoylguanidine hydrochloride was obtained from 3-chloro-4-isopropylbenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 185 ° C. Example 38 3,4,5-Trichlorobenzoylguanidine hydrochloride was obtained from 3,4,5-trichlorobenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 194 ° C.

【0049】

Example 39 3-Bromo-5-methylbenzoylguanidine hydrochloride was obtained from 3-bromo-5-benzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 235 ~ 236 ° C. Example 40 4-Chloro-3,5-dimethylbenzoylguanidine hydrochloride was obtained from 4-chloro-3,5-dimethylbenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 244 ~ 247 ° C. Example 41 3-trifluoromethyloxybenzoylguanidine hydrochloride was obtained from 3-trifluoromethyloxybenzoic acid in the same manner as the general protocol. crystal. Melting point 146 ~ 148 ° C.

【0050】

Example 42 4-trifluoromethyloxybenzoylguanidine hydrochloride was obtained from 4-trifluoromethyloxybenzoic acid in the same manner as the general protocol. crystal. Melting point 259 ° C. Example 43 4-Cyclohexylbenzoylguanidine hydrochloride was obtained from 4-cyclohexylbenzoic acid in the same manner as the general protocol. crystal. Melting point 273 ° C.

【0051】

Example 44 3-Chloro-4-cyclopentyloxybenzoyl guanidine hydrochloride was obtained from 3-chloro-4-cyclopentyloxybenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 273 ° C. 3-Chloro-4-cyclopentyloxybenzoic acid (melting point 148-151 ° C) hydrolyzes methyl 3-chloro-4-cyclopentyloxybenzoate (atypical oily substance) in a mixture of aqueous NaOH and dioxane. It is then obtained by acidifying the alkaline hydrolyzed solution with semi-concentrated hydrochloric acid. Methyl 3-chloro-4-cyclopentyloxybenzoate is obtained by boiling methyl 3-chloro-4-hydroxybenzoate and iodocyclopentane in acetone in the presence of excess solid ground potassium carbonate. After evaporating the acetone, the oily residue is taken in water, the mixture is then extracted using ethyl acetate, the extract is dried over sodium sulfate and the solvent is evaporated.

【0052】

Example 45 3-Isopropyl-4-methoxybenzoylguanidine hydrochloride was obtained from 3-isopropyl-4-methoxybenzoic acid in the same manner as the general protocol. Colorless crystals. Oily 214 ° C. Example 46 3-Chloro-4-cyclooctyloxybenzoylguanidine hydrochloride was obtained from 3-chloro-4-cyclooctyloxybenzoic acid in the same manner as the general protocol. Colorless crystals. Oily 243 ° C. 3-Chloro-4-cyclooctyloxybenzoic acid (melting point 110-112 ° C) hydrolyzes methyl 3-chloro-4-cyclooctyloxybenzoate (atypical oily substance) in a mixture of aqueous NaOH and methanol. It is obtained by decomposition and then acidifying the alkaline hydrolyzed solution with semi-concentrated hydrochloric acid. Methyl 3-chloro-4-cyclooctyloxybenzoate heats methyl 3-chloro-4-hydroxybenzoate and cyclooctyl bromide in dimethylformamide in the presence of excess solid ground potassium carbonate for 20 hours. Obtained by doing. After evaporating the solvent, the oily residue is taken in water, then the mixture is extracted using ethyl acetate, the extract is dried over sodium sulfate and then the solvent is evaporated.

【0053】

Example 47 A 4-thyl butyl-3-methoxybenzoylguanidine hydrochloride was obtained from 4-th butyl-3-methoxybenzoic acid in the same manner as in the general protocol. Colorless crystals. Melting point 227 ~ 231 ° C. The 4-thirth butyl-3-methoxybenzoic acid used is obtained by oxidizing 4-third butyl-3-methoxytoluene in an aqueous / alkaline solution of potassium permanganate. Example 48 3-Bromo-4-fluorobenzoylguanidine hydrochloride was obtained from 3-bromo-4-fluorobenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 215 ° C.

【0054】

Example 49 The third butyl-4-hydroxybenzoylguanidine hydrochloride was obtained from the third butyl-4-hydroxybenzoic acid in the same manner as in the general protocol. Colorless crystals. Melting point 216 ° C. Example 50 3-Cyano-4-methoxybenzoylguanidine hydrochloride was obtained from 3-cyano-4-methoxybenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 236 ° C. Example 51 The third butyl-4-methoxybenzoylguanidine hydrochloride was obtained from the third butyl-4-methoxybenzoic acid in the same manner as in the general protocol. Colorless crystals. Melting point 260-262 ° C.

【0055】

Example 52 3-Chloro-4- (1-hexyl) benzoylguanidine hydrochloride was obtained from 3-chloro-4- (1-hexyl) benzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 286 ° C (decomposition). Example 53 Similar to the general protocol, 3-thyl butyl-4- (2-methyl-1-propyl) benzoate to 3-thibyl-4- (2-methyl-1-propyl) benzoylguanidine Hydrochloride was obtained. Colorless crystals. Melting point 218 ~ 228 ° C (decomposition). Example 54 4-Isopropyl-3-pentafluoroethylbenzoylguanidine hydrochloride was obtained from 4-isopropyl-3-pentafluoroethyl benzoic acid in the same manner as the general protocol. A colorless amorphous solid.

【0056】

Example 55 The third butyl-4-isopropylbenzoylguanidine hydrochloride was obtained from the third butyl-4-isopropylbenzoic acid in the same manner as in the general protocol. Colorless crystals. Melting point 145 ~ 165 ° C. Example 56 4-Isopropylbenzoylguanidine hydrochloride was obtained from isopropylbenzoic acid in the same manner as the general protocol. Colorless crystals. Melting point 193 ~ 198 ° C. Example 57 3-Trifluoromethylbenzoylguanidine was obtained from 3-trifluoromethylbenzoic acid in the same manner as the general protocol. Colorless amorphous-oily composition.

【0057】

Example 58 To 3-trifluoromethylbenzoylguanidine to 3-trifluoromethylbenzoylguanidine methanesulfonic acid by treating 3-trifluoromethylbenzoylguanidine with methanesulfonic acid in ethyl acetate, similar to the general protocol. I got salt. Colorless crystals. Melting point 167 ~ 170 ° C. Example 59 4-Fluoro-3-isobutylbenzoylguanidine hydrochloride was obtained from 4-fluoro-3-isobutylbenzoylguanidine in the same manner as the general protocol. Melting point 136-140 ° C.