KR870000924B1 - Method for preparing 2- (N-substituted guanidino) -4-heteroarylthiazole - Google Patents

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Description

Method for preparing 2- (N-substituted guanidino) -4-heteroarylthiazole

The present invention relates to a method for preparing a novel 2,4-disubstituted thiazole compound of general formula (I) or a pharmaceutically toxic acid addition salt thereof useful for treating an ulcer.

In the above formula

X is NH and Y is CH or N, or X is S and Y is CH;

R ¹ is a straight or branched chain (C ₄ to C ₁₀ ) alkyl group, (R ³ ) ₂ C ₆ H ₃ or (R ³ ) ₂ Ar (CH ₂ ) _n where n is an integer from 1 to 4 and R ³ Is H, F, Cl, Br, I, CH ₃ , CH ₃ O, NO ₂ , OH, CN, COOR ⁵ or OCOR ⁵ , where R ⁵ is (C ₁ to C ₃ ) alkyl and Ar is phenyl Is a residue of a naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl or imidazolyl group;

R ² is H or (C ₁ to C ₄ ) alkyl;

R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-methoxyperazino group;

R ⁴ is H, (C ₁ to C ₅ ) alkyl, NH ₂ or CH ₂ OH.

The present invention provides that the guanidino group is a mono-, di- or trisubstituted, and that the hetero aryl substituent is an imidazol-4-yl, thiazol-4-yl or 1,2,4-triazol-5-yl group A novel process for preparing 2- (N-substituted guanidino) -4-heteroarylthiazoles is provided. These compounds have activity as secretory inhibitors, histamine-H ₂ receptor antagonists and / or ethanol-induced gastric ulcer inhibitors and are therefore useful as peptic ulcer inhibitors (prevention and treatment) in mammals, including humans.

Chronic gastric ulcer and duodenal ulcer, known as peptic ulcer, are common diseases that require a variety of treatments, including diet, medication, and surgical procedures, and the methods described may be applied depending on the severity of the condition. Particularly useful therapeutic agents for gastric acid secretion and peptic ulcers are histamine-H ₂ receptor antagonists that inhibit gastric acid secretion by blocking the action of histamine, a physiologically active compound, at the H ₂ -receptor site in the animal. The fact that many of the compounds of the invention can inhibit or inhibit ethanol-induced ulcers in rats reflects the clinical value of the compounds of the invention as gastric ulcer inhibitors.

US Pat. No. 4,374,843, issued February 22, 1983, to Lamat tina and Lipinski, is a 2-guanidino- formula of the following general formula (XII) useful as a therapeutic agent for gastric hypersecretion and peptic ulcer: 4-heteraryl thiazole compounds have been described:

In the above formula

X is S or NH;

Y is CH, CCH ₃ or N;

R is H, CH ₂ OH, (C ₁ to C ₆ ) alkyl, ph (CH ₂ ) _2-4 (where ph is phenyl or mono-substituted phenyl) or NH _2, which may optionally be alkylated or acylated .

In US Pat. No. 4,435,396, issued March 6, 1984, the inventors found that NH is X, N, Y is CH, and R is optionally mono- or di-substituted with a particular alkyl or phenylalkyl group, useful as a therapeutic agent for peptic ulcer. ₂ -guanidino-4- (2-substituted amino-4-imidazolyl) thiazoles of the general formula (XII) are described.

In the general formula (I), the carbon chain may be linear or branched, and the carbon atom range in parentheses means the total number of carbon atoms.

Pharmaceutically toxic acid addition salts are salts produced by reaction with 1 to 3, in particular 1 or 2 equivalents of acid. Directly acidic acids include, but are not limited to, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , CH ₃ SO ₃ H, p-toluenesulfonic acid, maleic acid, fumaric acid, succinic acid and citric acid no. Such salts are described in the references. See, eg, J. Pharm. Sci., 66 1-19 (1977).

The compound of general formula (I) is preferred because of its ease of manufacture and its excellent secretion inhibitory activity, histamine-H ₂ antagonist activity and / or cytoprotective activity as demonstrated in ethanol-induced ulcer inhibition tests. ), (2) and (3) are compounds of the following general formulas (VII), (IX) and (IX).

In the above formula

R ¹ , R ² and R ⁴ are as described above.

Particularly preferred compounds are those wherein R _I is alkyl, (R ³ ) ₂ C ₆ H ₃ or (R ³ ) ₂ Ar (CH ₂ ) _n wherein one of the two R ³ is H and the other is H, CH ₃ O or Cl, and Ar is phenyl, furyl, thienyl, pyridyl or naphthyl. Particularly preferred compounds of formula IV are those wherein R ¹ is n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-octyl, phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, 4-chlorobenzyl , 4-chlorophenylethyl, 4-chlorophenylpropyl, 4-methoxybenzyl, 4-methoxyphenylethyl, furylmethyl, thienylmethyl, 3-pyridimethyl, 1-naphthylmethyl or 2-naphthylmethyl ;

R ² is H; R ⁴ is alkyl, in particular CH ₃ .

In the above formula

R ¹ is alkyl, (R ³ ) ₂ C ₆ H ₃ or (R ³ ) ₂ Ar (CH ₂ ) _n, wherein Ar is a residue of a phenyl group, and particularly preferred R ¹ is n-hexyl, 2 -Octyl or benzyl;

R ² is H;

R ⁴ is H, CH ₃ or NH ₂ .

In the above formula

R ¹ , R ² and R ⁴ are as defined in the general formula (VII).

The present invention also relates to a pharmaceutical composition for inhibiting gastric ulcer in a mammal, including a human, comprising a gastric ulcer inhibitory amount of the general formula (I) compound and a pharmaceutically nontoxic toxic diluent or carrier. The present invention also relates to a method for suppressing gastric ulcer in a mammal, characterized by administering a compound of the general formula (I) in an amount of inhibiting gastric ulcer to a patient.

Most preferred compounds of the present invention

N- [4- (2-methylimidazol-4-yl) thiazol-2-yl] -N'-n-hexylguanidine;

N- [4- (2-methylimidazol-4-yl) thiazol-2-yl] -N'-2-octanguanidine;

N- [4- (2-methylimidazol-4-yl) thiazol-2-yl] -N'-benzylguanidine;

N- [4- (2-methylimidazol-4-yl) thiazol-2-yl] -N '-(2-furylmethyl) guanidine;

N- [4- (2-methylimidazol-4-yl) thiazol-2-yl] -N '-(2-thienylmethyl) guanidine; Or acid addition salts of these compounds.

2- (N-substituted guanidino) -4- (imidazol-4-yl) -thiazole and 2- (N-substituted guanidino) -4- of the general formula (VI) The (thiazol-4-yl) thiazole compound is prepared according to the following scheme, for example:

Scheme 1

In the above formula

R ¹ , R ² and R ⁴ are as described above;

X is S or NH;

Hal is Cl or Br.

2- (N-substituted guanidino) -4- (1,2,4-triazol-5-yl) thiazole compound of the general formula (VII) which is the compound of the present invention is, for example, according to the following scheme To manufacture:

Scheme 2

In the above formula

R ¹ , R ² and R ⁴ are as described above.

In the first step of Scheme 1 above, the general (V) N-cyanoguanidine compound is prepared by reacting an appropriate amine with dicyanamide in approximately equimolar amounts as described in the literature.

[Reference Example: Curd et al. J. Chem. Soc., 1630 (1948); Redmon and Nagy, US Pat. No. 2,455,807] Typically, the reaction is carried out at 40 to 120 ° C. in the presence of a polar organic solvent [eg, (C ₂ to C ₄ ) alkanols, water or mixtures thereof, preferably n-butanol]. It is preferably heated at the reflux temperature of the solvent. After cooling, the salt precipitated by filtration is removed and the filtrate is evaporated to separate the N-cyanoguanidine product.

Guanylthiourea intermediates of formula (IV) are obtained by reacting the appropriate N-cyanoguanidine with hydrogen sulfide. This reaction is usually carried out in the presence of a polar organic solvent such as (C ₁ to C ₄ ) alkanol, acetone, ethyl acetate or dimethylsulfoxide, preferably methanol. Typically this reaction is carried out in the presence of a catalytic amount of a secondary amine, preferably diethylamine. In addition, this reaction can be carried out at atmospheric or high pressure (eg 3 to 10 atm) and about 10 to 100 ℃, preferably 25 to 80 ℃. When the reaction is carried out at a high temperature within the preferred range, the reaction time can be shortened. On the other hand, when carried out at low temperatures, the reaction time becomes long. The product is usually simply separated by evaporation of the solvent. The purity of the crude product obtained in this way is mostly sufficient for the next reaction step. Alternatively, the crude product may be purified by methods such as column chromatography.

In the third step of Scheme 1, the N-substituted guanylthiourea compound of formula (IV) is substituted with a molar equivalent of 2- (R ⁴ -substituted) -4-haloacetylimidazole of formula (X). Or 2- (R ⁴ -substituted) -4haloacetylthiazole intermediate. Among these compounds may be halogen or chloro or bromo, with bromo being usually preferred. This reaction is carried out in the presence of a reaction-inert organic solvent such as tetrahydrofuran, lower alkanols (e.g. methanol, ethanol or isopropanol), lower alkyl ketones (e.g. acetone or methylethylketone), dimethylsulfoxide or dimethylformamide. do. Preferred solvents of these are acetone and dimethylformamide. The preferred temperature for preparing the compound of formula (VI) of the present invention by the above reaction is about 20 to 120 ° C, particularly preferably about 50 to 60 ° C. The compound of formula (VI) is then separated by methods known in the art, for example by cooling to produce a precipitate or by evaporating the solvent, or by adding a non-solvent such as ethyl ether to give the product as a hydrobromide salt. To obtain. This hydrobromide salt is readily converted to the free base by standard neutralization / extraction methods. To prepare pharmaceutically harmless acid addition salts thereof, organic bases are added in a free solvent and at least one equivalent or two equivalents of acid corresponding to the desired salt is added. The salts are then recovered by filtration, concentration, nonsolvent addition or a combination of these steps.

As shown in Scheme 2, the triazolylthiazole compound of the general formula (VII) is obtained in three steps using the (N-substituted guanyl) thiourea intermediate of the general formula (IV) as a starting material. A suitable compound of formula (IV) is condensed with an equimolar amount of alkyl halopyruvate ester, preferably readily available bromopyruvate, in the presence of a reaction inert organic solvent to yield the corresponding 2- ( To yield a substituted guanidino) thiazole-4-carboxylate ester. This reaction is carried out at about 40 to 120 ° C, preferably 60 to 80 ° C. Examples of reaction inert solvents include (C ₁ to C ₄ ) alkanols, acetone, ethyl acetate, acetonitrile, benzene or toluene, preferred solvents are (C ₁ to C ₄ ) alkanols and the reaction at reflux temperature. Ethanol is particularly preferred when carried out normally at. The product of formula III is separated by standard methods such as evaporation / extraction and then purified if necessary by standard methods such as recrystallization or column chromatography on silica gel.

In the next step of Scheme 2, the compound of formula III is reacted with hydrazine or a salt or hydrate thereof. When using salts or hydrates of the general formula (III) compounds, a molar excess (eg, 10-40 molar excess) is usually used. The product is the corresponding acid hydrazide of general formula (II). This step is also carried out in the presence of a reaction inert solvent as described above in the reaction step. Ethanol is the preferred solvent because of economics and efficiency. Preferred temperatures for carrying out this step are about 40 to 120 ° C, in particular 60 to 80 ° C. If ethanol, which is the preferred solvent, is used, the reaction is most conveniently carried out at the reflux temperature of the mixture. Separation of the acid hydrazide intermediate is carried out by standard evaporation / extraction techniques as in the previous step.

In the final step of Scheme 2, the acid hydrazide is contacted with a thioamide of the general formula R ⁴ CSNH ₂ , wherein R ⁴ is as described above. This step is carried out at about 50-150 ° C. in the presence of a reaction inert organic solvent (as described in the first step of the scheme above). In a preferred process this step is carried out at reflux temperature in n-butanol in the presence of a molar excess to a 10-fold molar excess of thioamide. Under these conditions, the reaction usually terminates after 1 to 4 days, after which 2- (N-substituted guanidino) -4- (1,2,4-triazol-5-yl of formula ) The thiazole compound is separated by standard techniques, such as by evaporating the solvent, and the crude product is purified, if necessary, by crystallization or column chromatography.

2- (R ⁴ -substituted) -4-bromoacetylimidazoles of formula (X) and the corresponding 4-bromoacetylthiazole intermediates brominated the corresponding 4-acetyl compounds of formula (XI) It is prepared by reacting bromine in elemental state in the presence of hydrogen by the halogenation process of known methyl ketones.

In the above formula

R ⁴ and X are as described above.

A nearly equimolar amount of ketone of formula (XI), typically dissolved in 48% aqueous hydrogen bromide, is contacted with bromine at room temperature or near room temperature and then heated at 60-80 ° C. for 2-6 hours to complete the reaction. The bromoacetyl compound of formula (X) is then separated by standard methods, such as by evaporating the reaction mixture, and the crude product is purified by standard extraction and crystallization techniques.

Corresponding 4-chloroacetylimidazole and 4-chloroacetylthiazole intermediates of formula (X), wherein Hal is chloro, also react the appropriate compound of formula (XI) with sulfyl chloride, typically Manufacture. The compound of formula (XI) is dissolved in methylene chloride, anhydrous hydrogen chloride is added, and optionally methanol is added to dissolve the precipitated hydrochloride salt. An equimolar amount of sulfuryl chloride is then added at room temperature and the chloroketone is separated by standard methods.

The starting acetylthiazole compound of formula (XI), wherein X is S, is reacted, for example, by reacting 1-bromo-2,3-butanedione with thiourea or thioamide of formula R ⁴ CSNH _{2 in} an equimolar amount To obtain. Typically, this reaction is carried out at 20 to 80 ° C., preferably at room temperature, in a reaction inert solvent such as ethanol or isopropanol. The product of formula (XI) is isolated by standard methods known in the art.

Starting acetylimidazoles of formula (XI) wherein X is NH are described, for example, in U.S. Patent No. 4,374,843 (LaMattina and Lipinski) and U.S. Patent Application No. 445,787, assigned to the same assignee as the assignee of the present invention (12 December 1982). 1 March) and 483,787 (filed Apr. 11, 1983).

Starting alkylamines of the general formula R ¹ R ² NH can be purchased commercially. (R ³ ) ₂ C ₆ H ₃ NH ₂ and aralkylamines, (R ³ ) ₂ Ar (CH ₂ ) _n HN ₂ required as starting aniline compounds are prepared by methods commercially available or known to those skilled in the art. Aralkylamines where n is 1 are prepared, for example, by reducing the corresponding nitrile with hydrogen and a noble metal catalyst according to known methods, or with an alkali metal hydride such as lithium aluminum hydride. Aralkylamines of the corresponding general formula (R ³ ) ₂ ArCH ₂ CH ₂ NH ₂ , for example, react the halomethyl compound of the corresponding general formula (R ³ ) ₂ Ar CH ₂ Cl (Br) with sodium cyanide To prepare arylacetonitrile intermediates, which can then be prepared by a number of known methods, such as hydrogenation to yield the desired 2-arylethylamine.

The appropriate aldehyde of Formula (R ³ ) ₂ ArCHO, or its acetyl, is reacted with a 2-cyanoacetate ester and hydrolyzed, followed by decarboxylation to give 3-arylacrylonitrile intermediate, followed by step reduction To obtain an amine of the general formula (R ³ ) ₂ Ar (CH ₂ ) ₃ NH ₂ .

4-arylbutylamines can be prepared by, for example, reacting the appropriate aldehyde of the general formula (R ³ ) ₂ ArCHC with a Wittig reagent (prepared from 3-bromopyrionic acid) to produce the corresponding 4-aryl-3-butenoic acid. After obtaining, the reduction is carried out to obtain the corresponding 4-arylbutyric acid. The 4-arylbutyric acid is then converted to an amide and, for example, hydrogenated with a metal hydride to give the desired 4-arylbutylamine.

Secondary amines of formula (R ³ ) ₂ Ar (CH ₂ ) _n NHR ^2, where R ² is (C ₁ to C ₄ ) alkyl] correspond to the corresponding primary amines, for example (C ₁ to C ₄ ) known methods such as reaction with alkyl halides or alkyl sulfates or catalytic hydrogenation of suitable Schiff bases [e.g. (R ³ ) ₂ Ar (CH ₂ ) _n NH = CH (CH ₂ ) ₂ CH ₃ ] Prepared by alkylating the corresponding primary amine.

Pharmaceutically toxic acid addition salts of the novel compounds of general formula (I) are also included in the present invention. These salts are readily prepared by contacting the free base with an appropriate inorganic or organic acid in an aqueous solution or a suitable organic solvent. Precipitation or the solvent may then be evaporated to yield a solid salt. Particularly preferred salts are hydrochlorides and dihydrochlorides.

The ulcer inhibitory effect of the general formula (I) compound in mammals, including humans, has been shown to have an effect on inhibition of secretion, histamine-H ₂ antagonism and / or ethanol-induced ulceration in rats, as detailed in the Examples below. Is reflected. To inhibit (prevent or treat) gastric ulcers in mammals, the products of the invention are administered by a variety of conventional routes of administration, including oral and parenteral routes. The compound of the present invention is preferably administered orally. In general, the compounds of the present invention are administered orally in a single or divided dose of about 0.1 to 20 mg, preferably about 0.2 to 2.5 mg per kg body weight of the patient to be treated per day. In the case of parenteral administration, the compound of the present invention may be administered about 0.1-1.0 mg / kg body weight of the patient to be treated per day. However, at the discretion of the treating physician, the dosage may vary depending on the condition of the patient being treated and the particular compound used.

The compounds of the present invention may be administered alone or in combination with a pharmaceutically innocuous carrier or diluent in single or multiple doses. Suitable pharmaceutical carriers include inert diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions prepared by combining the novel compounds of formula (I) or salts thereof with pharmaceutically toxic carriers are readily administered in multiple forms, such as tablets, powders, capsules, lozenges, syrups and the like. If desired, these pharmaceutical compositions may contain additional ingredients such as flavors, binders, excipients and the like. That is, tablets for oral administration of various excipients such as sodium citrate include disintegrants such as starch, alginic acid and certain complex silicates; Binders such as polyvinylpyrrolidone, sucrose, genlatin and acycia are used. Also, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting. Solid compositions of a similar type may also be used as fillers in soft and hard genlatin capsules. Preferred materials for use for this purpose include lactose or lactose and high molecular weight polyethylene glycols. In the case of oral administration of an aqueous suspension or elixir, its essential active ingredients may be formulated with various sweetening, flavoring, coloring or dyeing agents and, if necessary, emulsifying or suspending agents, diluents (e.g. water, ethanol, propylene glycol, glycerin or mixtures thereof). It can be combined with.

The product of the invention is preferably administered orally in unit dose form, ie in single divided dose units containing an appropriate amount of the active compound and a pharmaceutically nontoxic carrier or diluent. Examples of unit dosage forms include tablets or capsules containing about 5 to 1000 mg of the active ingredient of a compound of formula (I), which constitutes 10 to 90% of the total weight of the unit dosage form.

For parenteral administration, a solution or suspension of the compound of formula (I) in a sterile aqueous solution such as aqueous propylene glycol, sodium chloride, dextrose or sodium bicarbonate solution is used. If necessary, the formulation is appropriately buffered. Methods of preparing sterile liquid media suitable for parenteral administration are well known to those skilled in the art.

The invention is explained in detail in the following examples. However, it should be understood that the present invention is not limited to the details of these examples. All temperatures represent degrees Celsius. Nuclear magnetic resonance spectra (NMR) were measured in CDCl ₃ , CD ₃ OD or DMSO-d ₆ , where peak positions were reported in ppm down from tetramethylsilane. Abbreviations for the peak form are as follows: bs, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet; m, polyline.

Example 1

Ethyl 2- (1-n-hexyl-3-guanidino) -thiazole-4-carboxylate

A mixture of 4.05 g (20 mmol) of 1- (n-hexylguanyl) thiourea, 4.09 g (21 mmol) ethyl bromopyruvate and 200 mL of ethanol is heated at reflux for 4 hours and then cooled. The reaction mixture is concentrated in vacuo to afford a yellow solid which is treated with saturated sodium bicarbonate solution and then extracted with chloroform. The dried extract is concentrated in vacuo to give an orange oil which solidifies on grinding with hexane. Recrystallization from hexane / ethyl acetate gave 3.72 g (62% yield) of a yellow oil. The mother liquor was manipulated to yield an additional 1.20 g (20% yield) of product. Recrystallization from hexane / ethyl acetate yields a sample for analysis. Melting point: 118 to 119 캜;

Mass spectrum (m / e): 298 (M ⁺ ): ¹ H-NMR (CDCl ₃ ) ppm (δ): 0.6 to 1.8 (m, 14H), 3.2 (m, 2H), 4.3 (q, J = 7H _{2, 2H), 7.03 (s} , br, 3H), 7.41 (s, 1H).

Elemental Analysis for C ₁₃ H ₂₂ N ₄ O ₂ S:

Calculated Value: C, 52.32; H, 7.43; N, 18.7%

Found: C, 52.41; H, 7.55; N, 18.36%

Example 2

2- (1-n-hexyl-3-guanidino) thiazole-4-carboxylic acid hydrazide

A mixture of 3.36 g (11.3 mmol) of ethyl 2- (1-n-hexyl-3-guanidino) thiazole-4-carboxylate and 6.5 mL (110 mmol) of 85% hydrazine hydrate in 110 mL of ethanol Heat for hours. Add 6.5 ml of hydrazine hydrate and continue to heat for 24 hours. The resulting mixture was cooled and the solvent was evaporated under vacuum, and the resulting residual colorless solid was ground with isopropanol to give 2.52 g (78% yield) of a colorless powder. Recrystallization with isopropanol yields a sample for analysis.

Melting point: 136-137 degreeC.

Mass spectrum (m / e): 284 (M ⁺ ): ¹ H-NMR (DMSO-d ₆ / CD ₃ OD) ppm (δ): 0.7 to 1.7 (m, 11H), 3.2 (m, 2H), 7.31 (s, 1 H).

Elemental Analysis for C ₁₁ H ₂₀ N ₆ OS:

Calc .: C, 46.45; H, 7.09; N, 29.55%

Found: C, 46.16; H, 7.18; N, 29.93%

Example 3

2- (1-n-hexyl-3-guanidino) -4- (3-methyl-1H-1,2,4-triazol-5-yl) thiazole (Ⅶ, R ¹ = nC ₆ H ₁₃ , R ² = H, R ⁴ = CH ₃ )

A mixture of 568 mg (2.0 mmol) of 2- (1-n-hexyl-3-guanidino) thiazole-4-carboxylic acid hydrazide and 751 mg (10 mmol) of thioacetamide in 20 ml of n-butanol was prepared. Heat to reflux for 48 hours. After the reaction mixture was cooled down and concentrated in vacuo, the residue was chromatographed on a silica gel column to give 241 mg (39% yield) of pure thiazole as a yellow foam. Melting point: 207-209 degreeC.

Mass spectrum (m / e): 307 (M ⁺ ); ¹ H-NMR (CD ₃ OD) ppm (δ): 0.7 to 1.8 (m, 11H), 2.43 (s, 3H), 3.3 (m, 2H), 7.22 (s, 1H).

Elemental Analysis for C ₁₃ H ₂₁ N ₇ S · 0.5H ₂ O:

Calc .: C, 49.34; H, 7.01; N, 30.99%

Found: C, 49.42; H, 6.73; N, 30.82%

Example 4

2- (1-n-hexyl-3-guanidino) -4- (3-amino-1H-1,2,4-triazol-5-yl) thiazole (Ⅶ, R ¹ = nC ₆ H ₁₃ , R ² = H, R ⁴ = NH ₂ )

852 mg (3.0 mmol) of 2- (1-n-hexyl-3-guanidino) thiazole-4-carboxylic acid hydrazide in 30 ml of n-butanol, 835 mg (3.0 of s-methylisothiouronium sulfate Mmol) and 492 mg (6.0 mmol) sodium acetate are heated at reflux for 4 hours and then cooled. The resulting mixture was filtered and the filtrate was concentrated in vacuo and the residue was chromatographed twice on a silica gel column, first eluting with 85: 15 chloroform / methanol and then with acetone to give 491 mg (53% yield) of the title compound. To a yellow solid. Melting point: 210 to 211 ° C,

Mass spectrum (m / e): 308 (M ⁺ ); ¹ H-NMR (CD ₃ OD) ppm (δ): 0.7 to 1.9 (m, 11H), 3.2 (m, 2H), 7.13 (s, 1H).

Elemental Analysis for C ₁₂ H ₂₀ N ₈ S:

Calc .: C, 46.73; H, 6.54; N, 36.34%

Found: C, 46.63; H, 6.42; N, 36.03%

Example 5

2- (N-hexyl-N'-guanidino) -4- (2-methylimidazol-4-yl) thiazole dihydrochloride

A. 1- (n-hexylguanine) in 50 ml of acetone in a solution of 13.08 g (46.05 mmol) of 2-bromo-1- (2-methylimidazol-4-yl) ethanone hydrobromide in 150 ml of acetone After adding 10.25 g (50.66 mmol) of solution of thiourea, the mixture is refluxed for 6 hours and left at room temperature for 16 hours. The reaction mixture is heated at reflux for further 1 hour and cooled, then the products are combined to give 19.44 g (yield 90%) of a yellow solid (dihydrobromide salt). This solid is dissolved in 300 ml of water and added to a solution of 20.59 g (166 mmol) of sodium carbonate monohydrate in 200 ml of water. After standing for 15 minutes, the solid is filtered and washed with water. The wet solid is dissolved in 400 ml of acetone and filtered to remove insoluble matters, and the filtrate is then treated with 8 ml of 3 7% (weight / volume) concentrated hydrochloric acid. The acidification mixture is stirred for 1.5 hours, filtered and the dried solids are combined to give 16.31 g of a pale yellow solid. This solid is dissolved in 50 ml of methanol, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is diluted with isopropyl ether and then filtered to combine solid precipitates and dried to afford 11.50 g (yield 6 6%) of the desired product as a pale yellow powder. Melting point: 303 to 305 캜.

Mass spectrum (m / e): 306 (M ⁺ ); ¹ H-NMR (SMSO-d ₆ ) ppm (δ): 0.7 to 1.8 (m, 11H), 2.70 (s, 3H), 3.25 (m, 2H), 7.83 (s, 1H), 8.03 (s, 1H ), 8.6 (m, 3 H).

Elemental Analysis for C ₁₄ H ₂₂ N ₆ S · 2HCl:

Calc .: C, 44.32; H, 6.38; N, 22.15%

Found: C, 43.83; H, 6.29; N, 21.89%

B. Repeat the above procedure, except that 114 mg (0.71 mmol) of 4-chloroacetyl-2-methylimidazole in 7 ml of acetone, 114 mg (0.71 mmol) of 1- (n-hexylguanyl) thiourea and Heating at reflux with hydrogen chloride (8 mmol) for 65 hours gives the desired product as a tan powder (yield 36%).

Example 6

In the process of Example 5, an appropriate N-substituted guanylthiourea in place of 1- (n-hexylguanyl) thiourea is used to obtain a compound of the general formula as acid addition salt.

^* Using hydrochloric acid instead of 48% hydrobromic acid to produce the hydrobromide salt.

Example 7

2- (Nn-hexyl-N'-guanidino) -4- (imidazol-4-yl) thiazole dihydrobromide (VI, R ¹ = nC ₆ H ₁₃ , R ² , R ⁴ = H)

A solution of 511 mg (4.64 mmol) of 4-acetylimidazole in 6 mL of acetic acid is treated with 1 mL (9 mmol) of 48% hydrobromic acid followed by 741 mg (4.64 mmol) of bromine in 4 mL of acetic acid. The reaction mixture is stirred at 50 ° C. for 4 hours, 938 mg (4.64 mmol) of 1- (n-hexylguanyl) thiourea is added and stirring is continued at 50 ° C. for 20 hours. The reaction mixture is cooled, diluted with acetone and filtered to give 735 mg (35% yield) of the title compound as a white solid. Melting point: 254 ~ 255 ° C,

Mass spectrum (m / e): 292 (M ⁺ ); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 0.7 to 1.9 (m, 1H), 3.5 (m, 2H), 7.87 (s, 1H), 8.25 (s, 1H), 8.6 (s, br , 3H), 9.28 (s, H).

Elemental Analysis for C ₁₃ H ₂₀ N ₆ S · 2HBr:

Calc .: C, 34.37; H, 4.88; N, 18.50%

Found: C, 34.24; H, 5.01, N, 18.48%

Example 8

2- (Nn-hexyl-N'-guanidino) -4- (imidazol-4-yl) thiazole dihydrobromide (VI, R ¹ = nC ₆ H ₁₃ , R ² = H, R ⁴ = C ₂ H ₅ )

The process of the above example was repeated, except that 1.45 g (10.5 mmol) of 4-acetyl-2-ethyl-imidazole was used as a starting material, followed by stirring at 50 DEG C for 6 hours, followed by equimolar amount of 1-. (n-hexylguanyl) thiourea is added and stirred at 50 ° C. for 20 hours. The reaction mixture is then concentrated in vacuo into a syrup, added to acetone and cooled to yield 1.58 g (31%) of a pink solid. This solid is treated with saturated sodium bicarbonate solution and extracted with ethyl acetate, then the extract is concentrated to dryness and the residue is purified by chromatography on a silica gel column. The product fractions are combined, concentrated to an oil, dissolved in 100 ml of methanol and treated with 2 ml of 37% hydrochloric acid. Evaporation under vacuum gave a yellow solid which was triturated with acetone and filtered to give 776 mg (19%) of a tan powder. Melting point: 285-287 degreeC.

Mass spectrum (m / e): 320 (M ⁺ ); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 0.7 to 2.0 (m, 14H), 3.05 (q, J = 7Hz, 2H), 3.5 (m, 2H), 7.88 (s, 1H), 8.02 (m, 3 H).

Elemental Analysis for C ₁₅ H ₂₄ N ₆ S · 2HCl:

Calculated Value: C, 45.80; H, 6.66; N, 21.37%

Found: C, 45.42; H, 6.61, N, 21.10%

Example 9

4- (2-aminothiazol-4-yl) -2- (1-n-hexyl-3-guanidino) thiazole (VII, R ¹ = nC ₆ H ₁₃ , R ² = H, R ⁴ = NH ₂ )

A. 2-amino-4-bromoacetylthiazole hydrobromide

Masaki et al. In 50 ml of acetic acid [Masaki et al., Bull. Chem. Soc. Japan 39. 2747 (1966)] was added to 5 drops of 48 in a slurry of 1.11 g (5.0 mmol) of 2-amino-4-acetyl thiazole hydrobromide prepared from 1-bromo-2,3-butanedione and thiourea. % Hydrobromic acid and bromine 799 mg (5.0 mmol) are added and the reaction mixture is warmed at 60 ° C. for 1 h. The product precipitated out by filtration is combined and washed with acetic acid and acetone to yield 1.32 g (88%) of a pale tan powder. Melting point: 198 ° C (decomposes without melting).

Mass spectrum (m / e): 220 (M ⁺ ), 222 (M ⁺ +2); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 4.83 (s, 2H), 8.27 (s, 1H).

Elemental Analysis for C ₅ H ₅ N ₂ OSBr · HBr:

Calc .: C, 19.88; H, 2.00; N, 9.28%

Found: C, 20.33; H, 2.04, N, 9.28%

B. A mixture of 1.316 g (4.35 mmol) of 2-amino-4-bromo-acetylthiazole hydrobromide and 880 mg (4.35 mmol) of 1- (n-hexylguanyl) thiourea in 44 ml of dimethylformamide was added. Heat at 4 ° C. The reaction mixture is cooled and concentrated in vacuo to give an oil which is then made alkaline by addition of 10% sodium carbonate solution and extracted with ethyl acetate. The dried extract was filtered and concentrated in vacuo, and the residue was then chromatographed twice on silica gel column using 9: 1 chloroform / methanol as eluent. The solvent is evaporated to recover the purified product, added to ethyl acetate and treated with excess hydrogen chloride gas. The resulting solids were combined and washed with ethyl acetate to give 640 mg (37%) of the desired product as a colorless powder. Melting point: 205-207 degreeC (decomposition).

Mass spectrum (m / e): 324 (M ⁺ ); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 0.89 (m, 3H), 1.32 (m, 6H), 1.60 (m, 2H), 3.44 (m, 2H), 7.36 (s, 1H) , 7.80 (s, 1H), 8.63 (s, br, 2H), 8.92 (s, br, 1H).

Elemental Analysis for C ₁₃ H ₂₀ N ₆ S · 2HCl:

Calc .: C, 39.29; H, 5.58; N, 21.15%

Found: C, 33.89; H, 5.56; N, 21.09%

Example 10

2- (1-n-hexyl-3-guanidino) -4- (2-methyl-thiazol-4-yl) thiazole (VII, R ¹ = nC ₆ H ₁₃ , R ² = H, R ⁴ = NH ₃ )

A. 2-acetyl-2-methylthiazole hydrobromide

1.13 g (15.0 mmol) of thioacetamide and 2.47 g (1 5.0 mmol) of 1-bromo-2,3-butanedione are stirred at room temperature for 10 days. The precipitated products were combined by filtration and washed with isopropanol to give 0.619 g (18%) of colorless powder. The filtrate is evaporated and the residual solid is triturated with acetone to give 2.329 g (70%) of a yellow powder. Melting point: 200 ° C. (sublimation).

Mass spectrum (m / e): 141 (M ⁺ ); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 2.60 (s, 3H), 2.78 (s, 3H), 8.42 (s, 1H).

Elemental Analysis for C ₆ H ₇ NOS · HBr:

Calc .: C, 32.44; H, 3.63; N, 6.31%

Found: C, 32.41; H, 3.71; N, 6.29%

B. 4-Bromoacetyl-2-methylthiazole hydrobromide

A slurry of 828 mg (3.7 3 mmol) of 4-acetyl-2-methyl-thiazole hydrobromide in 37 ml of acetic acid was treated with 4 drops of 48% hydrobromic acid and 596 mg (3.73 mmol) bromine and the mixture was 60 Warm at ° C. After 3 hours at this temperature, the reaction mixture is cooled to room temperature and allowed to stand overnight by adding nuclei. The precipitated product was combined, washed with acetic acid and dried to yield 1.01 g (90%) of brown crystals. Melting point: 187-189 degreeC.

Mass spectrum (m / e): 219 (M ⁺ ), 221 (M ⁺ +2); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 2.77 (s, 3H), 4.82 (s, 2H), 8.30 (s, 1H).

Elemental Analysis for C ₆ H ₆ NOSBr · HBr:

Calc .: C, 23.94; H, 2.34; N, 4.65%

Found: C, 23.71; H, 2.30; N, 4.51%

C. A mixture of 960 mg (3.19 mmol) of 4-bromo-acetyl-2-methylthiazole hydrobromide, 645 mg (3.19 mmol) of 1- (n-hexylguanyl) thiourea and 32 ml of dimethylformamide was added. Heat at 60 ° C. for hours. The cooled mixture is diluted with ethyl ether and the precipitates are combined to give 801 mg (52%) of off-white powder. This powder is recrystallized to give 332 mg (21%) of product. Melting point: 160-162 degreeC.

Mass spectrum (m / e): 323 (M ⁺ ); ¹ H-NMR (DMSO-d ₆ ) ppm (δ): 0.7 to 2.0 (m, 11H), 2.75 (s, 3H), 3.43 (m, 2H), 7.60 (s, 1H), 7.98 (s, 1H ), 8.55 (s, br, 2H), 8.90 (s, br, 1H).

Elemental Analysis for C ₁₄ H ₂₁ N ₅ S ₂ · 2HBr:

Calc .: C, 34.64; H, 4.78; N, 14.43%

Found: C, 34.26; H, 4.68; N, 14.28%

Example 11

Gastric acid secretion inhibitory activity

Gastric acid secretion activity of the compounds of the present invention is measured in conscious HEIDENHAIN pouch dogs fasted overnight. A dose of Pentavolon-Aeerst, predicted to stimulate almost maximum acid secretion in the stomach, is continuously injected into the subcutaneous vein of the leg to promote acid secretion. After starting pentagastrin infusion, collect gastric juice at 30-minute intervals and quantify to 0.1 ml. Collect 10 gastric juices from each dog during the test. The acid concentration is measured by titrating 1.0 ml of gastric juice to pH 7.4 with 0.1 N sodium hydroxide using an automatic burette and a glass electrode pH meter (copy system).

90 minutes after initiation of pentagastrin injection, up to 2 mg / kg of drug or carrier is administered intravenously or orally. Gastric acid secretion inhibitory effect is measured by comparing the average amount of gastric acid secretion just before drug administration and the lowest amount of gastric acid secretion after drug administration.

Example 6 Oral administration of the products of f, g, n and o by 2 mg / kg inhibited gastric acid secretion by 24% or more. Preferred compounds of Example 5 ^* and preferred products of Examples 6a ^* , b ^* , c, j, 1 and m inhibited gastric acid secretion of at least 64% at or below these doses. The compound of Example 5 ^* showed 58% inhibition at the 0.1 mg / kg (vein) dose.

^* Test with dihydrobromide salt

Example 12

Histamine-H ₂ antagonist activity

Histamine-H ₂ antagonistic activity of the compounds of the invention is determined by the following method:

Strike the guinea pick's head quickly, remove the heart, and excise the right atrium. The right atrium was suspended in a temperature-controlled (32 ° ± 2 ° C.) homogeneous tissue bath (10 mL) containing oxygenated (95% O ₂ ; 5% CO ₂ ) Krebs-Henslite buffer (pH7.4). Then stabilize for about 1 hour and let the tissue bath blow out several times. Each atrial contraction force is measured with a tension-conversion meter connected to a long-term heart rate monitor and a glass polygraph recorder. After a dose-response curve for histamine is obtained, the bath containing each atrium is ejected several times with freshly made buffer, and then the atrium is equilibrated again at base rate. After reduction at base rate, the test compound is added to a specific final concentration and the histamine dose-response curve is measured again in the presence of the antagonist. The results are expressed in dose-ratio and the ratio of the histamine concentration and the apparent dissociation constant of the H ₂ -receptor antagonist pA ₂ required to represent one-half of the highest response in the presence or absence of the antagonist is determined.

The compound of Example 5 ^* and Example 6 a ^* , b ^* , c, f, g, j and products of l to o had a pA ₂ value of at least 6.9. Preferred compounds of Example 5 and Examples 6 a ^* , b ^* , f, j, l, m and n have preferred pA ₂ values of at least 7.2.

* Tested with dihydrobromide salts.

Example 13

Inhibition of Ethanol-Induced Ulcers in Rats

Ulcer inhibiting activity of the product of the present invention was also determined by ethanol-induced rat ulceration assay. The male rats fasted overnight in this test were dosed orally with drug 30 or 3 mg / kg or water 15 minutes prior to oral administration of 1.0 ml of absolute ethanol. One hour after ethanol administration, test animals (8 / group) are lethal and examined for damage to the stomach. After the test animal is killed and the abdomen is incised, hemostatic potatoes are fixed in the pyloric position. 6 ml of a 4% formaldehyde solution is injected into the stomach via an intragastric filling tube and the other hemostatic potatoes fixed to seal the esophagus. After the stomach is removed and the incision is made along a large direction, the ulcers are examined.

The following grades are used to indicate the degree of ethanol-induced damage.

For each group of test animals, the ulcer index is calculated as follows:

Ulcer index = (sum of ulcer grades in group) × (sum of number of ulcers in group) × (percentage of animals that caused ulcers in group)

The ulcer inhibition% is calculated as follows:

Suppression% = 100 × [(ulcer index of control group)-(ulcer index of drug treatment group)] ÷ (ulcer index of control group)

The compound of Example 5 and the products of Examples 6 a to c, f, j, l, m and o inhibited ethanol-induced ulcers by at least 77% at oral doses of 3 mg / kg. At the same dose, the compounds of Example 6 c, f and o showed at least 90% cytoprotective effect. The compound of Example 5 ^* and the product of Examples 6 a ^* , b ^* , f, j and l show at least 40% inhibition at oral doses of 3 mg / kg, and the products of Examples 5 ^* and 6f exhibit 48% The above suppression is shown.

^* Tested with dihydrobromide salts.

Production Example A

General preparation of N-substituted-3-cyanoguanidine of formula (V)

(i) 1-n-hexyl-3-cyanoguanidine (V, R ¹ = nC ₆ H ₁₃ , R ³ = H)

A mixture of 13.8 g (0.10 mole) of n-hexylamine hydrochloride, 8.9 g (0.125 mole) of dicynimide and 75 ml of n-butanol is stirred under heating at reflux for 3 hours. The mixture is then cooled and filtered to remove the precipitated salts and the filtrate is evaporated to give a syrup which is then crystallized with dioxane.

Mass spectrum (m / e): 169 molecular ions

(ii) The process prepares N-substituted-3-cyanoguanidines of the general formula (V) from suitable amines of the general formula R ¹ R ² NH:

Production Example A (continued)

의 화합물이 수득된다.(iii) the reaction is carried out using an appropriate amine of the general formula R ¹ R ² NH and NH (CN) ₂ , which is a dicyanamide, in the above process.

Compounds of are obtained.

Manufacturing Example A (cont.)

Preparation Example B

General preparation method of N-substituted guanylthiourea of general formula (IV).

(i) 1- (n-hexylguanyl) thiourea (IV, R ¹ = nC ₆ H ₁₃ , R ² = H)

This method is Kurzer method for the parent compound (R ¹ = R ² = H). Coll. vol. IV, p.502].

Hydrogen sulfide gas was introduced into a mixture of 4.5 g (0.027 mol) of 1-n-hexyl-3-cyanoguanidine, 75 ml of methanol and 0.5 ml of diethylamine, and the mixture was bubbled for 8 hours. The reaction mixture was stirred overnight at room temperature, then again through H ₂ S for 8 hours and stirred again overnight. At this time, when the reaction mixture is thin layer chromatography, the presence of the starting material is confirmed. The reaction mixture was heated under reflux again for 6 hours through H ₂ S and refluxed overnight. The solvent is evaporated in vacuo and the residue is purified by flash silica gel chromatography and eluted with 9: 1 chloroform / methanol to give 4.49 g of product. Mass spectrum (m / e): 202 (M ⁺ ).

(ii) The compounds of formula (IV) may also be prepared as described below for Curtley and Shalit (US Pat. No. 4,009,163 (Example 17)) as described for 1- (benzylguanyl) -thiourea below. It is prepared by the method.

To a solution of 6.73 g (38.6 mmol) of 1-benzyl-3-cyanoguanidine in 100 ml of methanol, 2 ml of diethylamine was added, and the reaction mixture was cooled to 0 ° C. and saturated with hydrogen sulfide gas. The cold solution is transferred to a stainless steal bomb, sealed and heated at 80 ° C. for 48 hours. The reaction mixture is then transferred to a flask, passed through nitrogen to release excess hydrogen sulfide, and the solvent is evaporated under vacuum. The resulting residual oil was subjected to flash chromatography (silica gel) and eluted with 20: 1 chloroform / methanol to purify to give 3.06 g of the product as a pale yellow oil. Mass spectrum (m / e): 203 (M ⁺ )

(iii) The remaining 1-substituted-3-cyanoguanidine produced in (ii) of Preparation Example A was converted to N-substituted-guanylthiourea of formula (IV) by the method described above. Switch.

Preparation Example C

2-hydroxymethyl-4-bromo-acetylimidazole hydrobromide

(i) 3-bromo-4-ethoxy-3-buten-2-one

A mixture of 400 mL of absolute ethanol and 60 mL of toluene is heated under reflux and 20 mL of the azeotrope is removed via a Dean Stark trap. 33.0 g (0.2 mol) of 3-bromo-4-hydroxy-3-butene-2- was added to the ethanol-toluene solution and the reflux was continued for 3 hours, in which three portions of a 20 ml aliquot of ethanol-toluene were trapped. Remove through. The solution is concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a fluid oil.

¹ H-NMR (DMSO-d ₆ ) ppm (δ): 8.21 (s, 1H), 4.23 (q, 2H), 2.33 (s, 3H), 1.31 (s, 3H).

(ii) 2-hydroxymethyl-4-acetylimidazole

9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-buten-2-one are mixed with 5.53 g (0.05 mol) of hydroxyacet amidine hydrochloride in 100 ml of acetone to form a slurry. To the resulting slurry was added 11.5 g (0.1 mol) of 1,1,3,3-tetramethylguanidine at 25 ° C. over 5 minutes. After stirring for 48 hours, the slurry was filtered and the mother liquor was concentrated in vacuo to give an oil, which was then chromatographed on silica gel 60 (F. Merck) using chloroform as eluent, 2-hydroxymethyl-4-acetyl Yield 1.48 g (21%) of imidazole.

Melting Point: 147 to 148 ° C

¹ H-NMR (DMSO-d ₆ ) ppm (δ): 7.73 (s, 1H), 5.46 (very broad s, 1H), 4.5 (broad s, 2H), 2.4 (s, 3H).

(iii) 1.826 g (0.013 mol) of 2-hydroxymethyl-4-acetylimidazole are dissolved in 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine are added. The reaction is warmed at 80 ° C. for 2 hours and then concentrated in vacuo to give a solid. The product was triturated with isopropyl ether and the resulting solid collected by filtration, washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromo-acetylimidazole hydrobromide. To obtain. Melting point: 183 ° C. (decomposition).

¹ H-NMR (DMSO-d ₆ ) ppm (δ): 8.8 (s, 1H), 4.8 (s, 2 x 2H).

Preparation Example D

4-acetyl-2-methylimidazole

(i) 1,2-dichloro-1-buten-3-one

A mixture of 392 g (5.0 moles) of acetyl chloride and 1,817 g (18.75 moles) of cis, trans-1,2-dichloroethylene is cooled to 0 ° C. under anhydrous conditions (acetone-dry ice bath). While maintaining the temperature at 25 ° C. or lower, 734 g (5.5 mol) of anhydrous aluminum chloride is added to the mixture little by little, and aluminum chloride is washed with 606 g (6.25 mol) of 1,2-dichloroethylene. The cooling bath is removed and the reaction mixture is heated at reflux overnight (50-60 ° C.). The cooled reaction mixture is poured into ice, the organic layer is separated, and the aqueous layer is extracted with methylene chloride. (3 x 500 ml). The combined organic layers were shaken, 450 g sodium chloride was added and the small amount of water separated off was removed. The organic layer was filtered through diatomaceous earth (celite) to remove inorganic salts, and a solution of 748 g (6 mol) of sodium carbonate monohydrate in sufficient water was added to make a 2.5 liter solution. The resulting mixture is stirred for 1.5 hours, the precipitated solid is filtered off and washed with methylene chloride. The organic layer is separated, the aqueous layer is extracted with methylene chloride (2 × 200 mL), and the organic layers are combined and dried (Na ₂ SO ₄ ). The solvent is removed by evaporation in vacuo and the residual oil is distilled to give 517.5 g (74.5%) of the product as a pale yellow liquid.

Boiling point: 40-52 degreeC / 8mmHg.

¹ H-NMR (CDCl ₃ ) ppm (δ): 2.50 (s, 3H), 7.55 (s, 1H).

(ii) 2-chloro-1,1-dimethoxy-3-butanone

To a solution of 297 g (5.5 mol) of sodium methoxide in 5 liters of methanol was added 695 g (5.0 mol) of 1,2-dichloro-1-buten-3-one at 0 ° C. in a gentle flow. After the addition was completed, the mixture was stirred at 0 ° C. for 1 hour, again 54 g (1.0 mol) of sodium methoxide were added, followed by further stirring at 0 ° C. for 1 hour. The reaction mixture is stirred overnight at room temperature and 1 g of sodium methoxide is added and stirred for 1 hour. The mixture is filtered (filtered) to remove salts and washed with fresh methanol. The filtrate is concentrated in vacuo to give a slurry, which is washed with water in isopropyl ether, washed with sodium bicarbonate solution, washed with brine and dried over anhydrous magnesium sulfate. The extract is concentrated in vacuo to give a residual oil and distilled in vacuo to yield 628 g (74%) of the product in main fractions. Boiling point: 66-75 degreeC / 8mm. ¹ H-NMR (CDCl ₃ ) ppm (δ): 2.33 (s, 3H), 3.43 (s, 3H), 3.47 (s, 3H), 4.23 (d, 1H), 4.63 (d, 1H).

(iiia) 83.5 g (0.50 mole) of 2-chloro-1,1-dimethoxy-3-butanone, 94.5 g (1.0 mole) of acetamidine hydrochloride and 123 g (1.5 mole) of sodium acetate in 500 ml of dioxane After addition, it is heated at reflux overnight. The reaction mixture is cooled, filtered through a pad of silica gel on a sintered glass filtration funnel and washed with 3500 ml of dioxane. The filtrate and washings are combined and then evaporated in vacuo to give a residual oil which is purified by chromatography on silica gel column (600 g) and eluted with ethyl acetate. Collect each 200 ml fraction. Sixteen fractions were collected and eluted with 95: 5 ethyl acetate / methanol. Fractions 18 to 35 are combined and the solvent is evaporated in vacuo to yield 28.82 g (46.4%) of the desired product. Recrystallization with 1: 1 ethyl acetate / isopropyl ether gave 19.27 g (31%) of crystals. Melting point: 132-133 degreeC. The mother liquor was again subjected to the reaction operation to obtain 4.24 g (6.8%) of crystals.

¹ H-NMR (CD ₃ CD) ppm (δ): 2.40 (s, 3H), 2.43 (s, 3H), 7.68 (s, 1H).

(iiib) 1.66 g (10 mmol) 2-chloro-1,1-dimethoxy-3-butanone in 50 ml dioxane, 1.43 g (15 mmol) acet amidine hydrochloride and 2.05 g (25 mmol) sodium acetate ) Is heated at reflux for 24 h. Dioxane is evaporated in vacuo and the residual oil is flash chromatography on silica gel (40:60 ethyl acetate / hexanes, 40 mm) to give three fractions. 1.121 g of the third fraction, white solid, was subjected to rechromatography (40 mm, acetone) to give 933 mg (75.1%) of the product as a white solid, followed by NMR spectrum in CDCl ₃ and TLC on silica gel (monopoly point, 1 : 9 methanol / chloroform) to determine whether it is pure.

Production Example E

4-acetyl-2-methylimidazole

(i) 1-benzyl-2-methylimidazole

To a slurry of 2.4 g (0.1 mol) of sodium hydride in 50 ml of dimethylformamide was added 8.2 g (0.1 mol) of 2-methylimidazole with stirring under nitrogen atmosphere. A gentle exothermic reaction occurs and the temperature rises to 43 ° C. When the exothermic reaction is stopped, the reactant is warmed in a steam bath to 70 to 75 ℃ for 0.5 hours, then warmed at 95 ℃ for 15 minutes to complete the reaction (confirmed by stopping the gas discharge). It is then cooled to 68 ° C. and 12.7 g (0.1 mole) of benzylchloride is added dropwise. An exothermic reaction occurs and the temperature rises to 95 ° C. After completion of the dropwise addition, the mixture was stirred for half an hour, then the reaction was poured into 600 ml of water and extracted with ethyl acetate (2 × 200 ml). The extracts were combined and washed sequentially with water (1 × 400 mL), saturated aqueous sodium chloride solution (1 × 100 mL) and 6N HCl (1 × 50 mL). The HCl washes are extracted with ether (1 × 25 mL) and made basic by addition of sodium hydroxide. The separated yellow oil is extracted with ether and the extract is dried (MgSO ₄ ) and then evaporated under reduced pressure to give a pale yellow oil. Yield: 11.5 g (60.5%), NMR analysis showed that it was monohydrate. The product is used for the hydroxymethylation reaction.

(ii) 1-benzyl-4-hydroxymethyl-2-methylimidazole

A mixture of 8.5 g (0.05 mol) of 1-benzyl-2-methyl-imidazole monohydrate, 50 ml of 36% formaldehyde, 6 ml of acetic acid and 8.0 g (0.098 mol) of sodium acetate is stirred and heated at reflux for 26 hours. do. It is then stirred at room temperature for one week (about 65 hours) and then neutralized with sodium carbonate solid. The neutral solution is extracted with ethyl acetate and the extract is dried (MgSO ₄ ) and then evaporated under reduced pressure to give an oil. 10 ml of water and 50 ml of isopropanol are added to the oil, stirred overnight and then evaporated under reduced pressure. The oily residue obtained is added in water, and then made solid by addition of solid sodium hydroxide. The product is cooled, the layers are separated with diethyl ether, and the resulting white solid is removed by filtration and air dried.

Yield: 1.8 g (18%), Melting point: 140 to 146 DEG C The product was dissolved in 30 ml of hot (50 DEG C) ethyl acetate and then purified by filtration. The filtrate is concentrated to about 2/3 volume and cooled to yield 1.3 g of white solid. Melting point: 147-151 degreeC.

Ethyl acetate: Methanol: Diethylamine (80:10: 10) Based on thin layer chromatography, single spots are formed.

(iii) 1-benzyl-2-methylimidazole-4-carboxaldehyde

A slurry of 9.0 g (0.446 mol) of 1-benzyl-4-hydroxymethyl-2-methylimidazole, 750 ml of methylene chloride and 50.0 g (0.575 mol) of manganese dioxide was stirred at room temperature for 2 hours. The product is then filtered and the filter cake is washed with methylene chloride, the filtrate and wash solution are combined and evaporated under reduced pressure to give an oil. This oil is poured into 10 ml of diethyl ether, 100 ml of hexane is added, and a little of the title compound crystals are added as crystal nuclei. Concentrate the solution while converting hexane to periodic acid in a nitrogen emitter to yield 7.2 g (81%) of crystalline product and to separate by filtration: Melting point: 57-60 ° C.

The filtrate is concentrated to a second yield 0.75 g of product.

Melting Point: 57 to 59.5 ° C

Total yield: 89.4%

(Iii) 1-benzyl-4- (1-hydroxyethyl) -2-methylimidazole

To a solution of 7.2 g (0.306 mole) of 1-benzyl-2-methylimidazole-4-carboxaldehyde in 100 mL of tetrahydrofuran is added 15 mL (0.044 mole) of 2.9 M methylmagnesium chloride in tetrahydrofuran. White precipitates are produced immediately. The mixture was stirred at room temperature for 30 minutes, and then heated by adding 50 ml of 25% aqueous ammonium chloride solution. The precipitate is filtered off, washed with tetrahydrofuran and dried. The combined filtrate and washings are dried (Ma ₂ SO ₄ ) and then concentrated in vacuo to give a solid residue. The obtained residue was dissolved in 300 ml of boiling ethyl acetate, and concentrated to dryness (Na ₂ SO ₄ ) under reduced pressure to a volume of 1/2. The solid which separates on cooling is filtered off and dried.

Total yield: 7.1g (90%)

Melting Point: 162.5 ~ 167.5 ℃

(V) 4- (1-hydroxyethyl) -2-methylimidazole

Fill the Parr stirrer with 10.0 g (46.23 mmol) of 1-benzyl-4- (1-hydroxyethyl) -2-methylimidazole, 60 ml of methanol and 2.0 g (50% mol) of 5% pd / c. . Hydrogen gas is introduced to 30 psi (2.04 atm) and the mixture is heated to 50 ° C. and stirred for 16 hours. After cooling to 30 ° C. and filtering through diatomaceous earth, the filter cake is washed with 10 ml of methanol. The filtrate and washes were combined and evaporated under reduced pressure to give 6.44 g (97% yield) of the title product as an oil.

The product is crystallized by sufficient addition of tetrahydrofuran to dissolve the oil and stirring at ambient temperature for 2 hours. Filter to combine white crystalline solid and dry.

Melting point: 107-111 degreeC.

(Iii) A mixture of 1240 g (9.989 moles) of 4 (5)-(1-hydroxyethyl) -2-methylimidazole in 10 L of tetrahydrofuran was refluxed, and 22200 g (25.2 93 moles) of manganese dioxide was charged over 10 minutes. Ha ha. The mixture is refluxed overnight (18 hours) and then heat filtered through diatomaceous earth. The filter cake is washed with 4 liters of tetrahydrofuran.

The combined filtrate and washings from the two reactions were combined, stirred and concentrated to about 6 liters under atmospheric pressure, whereupon the reaction mixture became a solid. Ethyl acetate (2 L) is added and the mixture is heated to form a solution, followed by further removal of tetrahydrofuran. Once the reaction mixture is solid, 2 liters more ethyl acetate is added and heated again. Once the mixture is solid, heating and stirring are stopped and the mixture is cooled overnight. Ethyl acetate (3.8 L) is added and the solid mass is broken up with a spatula. When allowed to stir, the slurry is heated at 50 ° C. for 3 hours, then cooled at 5 ° C. for 1 hour and suction filtered. The yellow filter cake is washed with 1.5 L of ethyl acetate at 5 ° C. and then dried.

Yield: 1887 g (76.08%)

Melting point: 128-130 ° C.

Production Example F

4-chloroacetyl-2-methylimidazole and its hydrochloride salt

A solution of 248 mg (2.0 mmol) of 4-acetyl-2-methylimidazole in 20 ml of methylene chloride was supplied with anhydrous hydrogen chloride gas for 5 minutes, followed by addition of 192 mg (6 mmol) of anhydrous methanol. To the resulting solution was added 297 mg (2.2 mmol) of sulfuryl chloride and then the reaction mixture was stirred for 1 hour at room temperature. 155 mg of each sulfuryl chloride was added twice at 10 minute intervals to complete the reaction. A few ml of methanol is added and the reaction mixture is concentrated to dryness in vacuo. The resulting colorless oil is basified with sodium bicarbonate solid. The precipitated solids were combined, washed with water and dried under high vacuum to yield 167 mg (53%) of fine white solids.

¹ H-NMR (DMSO-d ₆ ) ppm (δ): 2.25 (s, 3H), 4.75 (s, 2H), 7.8 (s, 1H). Mass spectrum (m / e): 158 (M ⁺ ), 109 (M-CH ₂ Cl).

The above process was repeated, except that, on the same scale, without adding sulfuryl chloride in the absence of methanol and stirring at room temperature for 2 hours, 395 mg (10%) of a hydrochloride salt were obtained.

Melting point: 159-166 degreeC (decomposition).

Production Example G

2-aminomethylnaphthalene

A mixture of 10.0 g (65.3 mmol) 2-cyano naphthalene, 2.0 g Raney nickel, 100 ml ethanol and 9 ml concentrated ammonium hydroxide is hydrogenated at 36 psi (2.53 kg / cm 2) for 4.5 days. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give an oil. The oil obtained is distilled under vacuum to give the desired amine as a colorless liquid which solidifies upon standing. Yield: 2.02 g. TLC results on the run car gel plate When developed with 19: 1 chloroform / methanol, a single spot appeared at the point where R _f = 0.1.

Production Example H

2- (3-trifluoromethylphenyl) ethylamine

(i) 2- (3-trifluoromethylphenyl) acetonitrile

A mixture of 12.0 g (61.5 mmol) of m-trifluoromethylbenzyl chloride, 9.56 g (195 mmol) of sodium cyanide and 60 ml of dimethyl sulfoxide is heated at 50 to 80 ° C. for 4 hours and then poured into water. After the aqueous mixture is extracted with methylene chloride, the extract is dried over sodium sulfate and the solvent is evaporated under vacuum to give 12.2 g of yellow oil which is used in the next step.

¹ H-NMR (CDCl ₃ ) ppm (δ): 3.80 (s, 2H), 7.60 (s, 4H).

(ii) a mixture of 7.20 g (38.9 mmol) of 2- (3-trifluoromethylphenyl) acetonitrile, 0.75 g of Raney nickel, 30 ml of ethanol and 4.0 ml of concentrated ammonium hydroxide, was passed through nitrogen and 3.5 kg for 18 hours. Hydrogenation under / cm 2. The catalyst is removed by filtration under nitrogen atmosphere and the filtrate is evaporated under vacuum to give 6.86 g (93%) of the title amine as a red oil.

¹ H-NMR (CDCl ₃ ) ppm (δ): 0.65-4.10 (bs, 2H), 2.65-3.40 (m, 4H), 7.3 0-7.60 (m, 4H).

Preparation Example I

General preparation of ^3- arylpropylamine of the general formula (R ³ ) ₂ Ar (CH ₂ ) ₃ NH ₂ is as described below:

3- (4-n-propylphenyl) propylamine

(i) ethyl 2-cyano-3- (4-n-propylphenyl) acrylate

A mixture of 20.0 g (90 mmol) of 4-n-propylbenzaldehyde diethylacetal, 20.4 g (180 mmol) of ethyl cyano acetate, 7.2 g (93.4 mmol) of ammonium acetate and 60 mL of toluene was heated under reflux for 6 hours. , Cool and pour in water. The resulting mixture was extracted with ethyl ether, dried (MgSO ₄ ), and the volatiles were evaporated in vacuo to give 23.0 g of crude yellow oil which was then chromatographed on silica gel column (eluant 2: 1 methylene chloride / hexane). To give 20.5 g (94%) of the desired product.

¹ H-NMR (CDCl ₃ ) ppm (δ): 0.85-1.95 (m, 8H), 2.45-2.70 (t, 2H), 4.15-4.60 (q, 2H), 7.15-8.05 (q, 4H), 8.25 (s, 1 H).

(ii) 3- (4-n-propylphenyl) propionitrile

A mixture of 20.50 g (84.3 mmol) of the product of (i), 8.75 g of magnesium turning and 200 ml of methanol is sometimes cooled under a nitrogen atmosphere and stirred for 6 hours while maintaining the temperature at about 30 ° C. The reaction mixture is acidified with hydrochloric acid, extracted with ethyl ether and the extract is washed with sodium bicarbonate, water, brine and dried over MgSO 4. The solvent was evaporated to give 23.8 g of crude product, followed by column chromatography on silica gel (eluant: methylene chloride) to give 11.55 g of purified methyl 2-cyano-3- (4-n-propylphenyl) propionate. (59%) is obtained. The product is combined with 4.17 g of sodium chloride, 175 ml of dimethylsulfoxide and 5 ml of molar under nitrogen atmosphere, and then the mixture is heated at 150 ° C. for 5 hours. The reaction mixture is cooled, poured into 700 mL of water and extracted with ethyl acetate (2 x 500 mL). The extracts are combined, washed with 300 ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to yield 12.5 g of the desired nitrile, which is purified by distillation. Boiling point: 124-128 degreeC / 1.0 mm.

¹ H-NMR (CDCl ₃ ) ppm (δ): 0.75-1.15 (t, 3H), 1.30-2.00 (m, 2H), 2.40-3.10 (m, 6H), 7.15 (s, 4H).

(iii) A mixture of 14.13 g (81.6 mmol) of nitrile (distilled), 1.5 g Raney nickel, 60 ml ethanol and 8 ml concentrated ammonium hydroxide is hydrogenated for 18 hours under hydrogen pressure of 3.5 kg / cm 2. The mixture was passed through nitrogen, filtered to remove the catalyst and the filtrate was concentrated in vacuo to give 12.3 g (84.8%) of a clear oil. The resulting oil is distilled to yield 8.60 g (59%) of pure amine as a colorless oil.

¹ H-NMR (CDCl ₃ ) ppm (δ): 0.75-1.05 (t, 3H), 1.05 (s, 3H), 1.15-1.75 (m, 4H), 2.30-2.85 (m, 6H), 6.95-7.10 (m, 4 H).

Production Example J

4- (4-chlorophenyl) butylamine

General preparation of _4- arylbutylamine of formula (R ³ ) ₂ Ar (CH ₂ ) ₄ NH ₂ is as described below:

(i) 4- (4-chlorophenyl) -3-butenoic acid

10.0 g (68.2 mmol) of 4-chlorobenzaldehyde, 3- (triphenylphosphonium) propionate bromide (prepared by reacting triphenylphosphine and 3-bromopropionic acid in xylene) 34.0 g (81.9 mmol), sodium hydride (mineral oil) 50%) 12.5 g and 200 ml of dimethylsulfoxide are heated at 120 ° C. for 5 hours, then cooled and poured into ice water. Sodium carbonate is added to the reaction mixture to make it alkaline, then extracted with ethyl ether and discarded. The aqueous layer is acidified and extracted again with ethyl ether, then dried (MgSO ₄ ) and the ether is evaporated in vacuo to give 6.9 g (51%) of the desired acid.

¹ H-NMR (CDCl ₃ ) ppm (δ): 3.30-3.10 (d, 2H), 6.10-6.35 (m, 2H), 7.20 (s, 4H), 11.55-11.75 (bs, 1H).

(ii) 4- (4-chlorophenyl) butanoic acid

A mixture of 19.5 g (98.2 mmol) of unsaturated acid in (i), 1.95 g of pd / c catalyst, and 200 ml of ethyl acetate was hydrogenated under 3.5 kg / cm 2 of hydrogen pressure, and the reaction structure was completed in a conventional manner. A saturated acid is obtained (yield 91%).

¹ H-NMR (CDCl ₃ ) ppm (δ): 1.75-2.80 (m, 6H), 6.95-7.40 (q, 4H), 9.15 -10.25 (bs, 1H).

(iii) 4- (4-chlorophenyl) butyric acid amide

The mixture of 8.8 g (44.3 mmol) of saturated acid of (ii) and 45 ml of thionyl chloride is heated under reflux for 3 hours. The reaction mixture is cooled and evaporated in vacuo to remove excess thionyl chlorides. The crude acid chloride is dissolved in 20 ml of ethyl ether, and the resulting solution is added dropwise to 67 ml of ammonium hydroxide over 20 minutes at 0 ° C. An instant tan solid is produced. The reaction mixture is stirred at 0 ° C. for 1 h, then 80 ml of water are added and extracted with ethyl ether (3 × 100 ml). The combined ether layers are washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to yield 8.70 g (97%) of amide.

¹ H-NMR (CDCl ₃ ) ppm (δ): 1.60-2.40 (m, 4H), 2.45-2.85 (t, 2H), 5.25-6.10 (bs, 2H), 6.90-7.30 (q, 4H).

(Iii) A mixture of 8.70 g (44 mmol) of the amide of (iii) and 71 ml of 1.0 M bron hydride / tetrahydrofuran in 60 ml of tetrahydrofuran was stirred for 4 hours, followed by quenching the reaction with 36 ml of 6N hydrochloric acid. Let's do it. The reaction mixture is extracted with ethyl ether, and the extract is dried (Na ₂ SO ₄ ) and then concentrated in vacuo. The residual oil is stirred with isopropyl ether, filtered and the filtrate is evaporated under vacuum to give 2.08 g of product. The mother liquor is extracted with ethyl acetate to give 2.4 g of additional product.

¹ H-NMR (CDCl ₃ ) ppm (δ): 1.15 (s, 2H), 1.30-1.90 (m, 4H), 2.40-2.90 (q, 4H), 6.90-7.35 (q, 4H).

Claims (4)

The acid hydrazide compound of formula (II) is reacted with at least a molar equivalent of thioamide of formula (XIII) at 50 to 150 캜 in the presence of a reaction-inert organic solvent. A method of making a compound or a pharmaceutically inadequate acid addition salt thereof.

In the above formula Y is N and X is NH: R ⁴ is CH ₃ or NH ₂ . The method of claim 1 wherein the solvent described above is butanol. The process of claim 1 or 2, wherein the reaction is carried out at reflux temperature of the solvent. The method of claim 1 wherein the compound prepared is separated in the form of a hydrobromide salt.