KR800001314B1 - Process for preparing imidazol derivatives - Google Patents

Abstract

Title compds. (I,R1,R2,R3,R4 = H, lower alky1; Ar = thienyl, halothienyl or Ph optionally substituted by 1 halo, lower alky1, or lower alkoxy groups; Y = mono- or bicyclic group contg.>=1 heteroatom in a 5- or 6-membered ring and attached to the S bridge by a C atom), useful as fungicides, were prepd. from 1-ary1-2 (imidazoly1)alky1 halide(II) and thiol(III). Thus, 1-[2,4-dichloro-β-(3-chloro-pyridy1-2-thio)phenethy1 imidazoleHCl was prepd. from 1-(β-chloro-2,4-dichlorophenethy1)imidazole by stirring with 3-chloro-2-mercaptopyridine(in DMF, room temp., 2 days.)

Description

Preparation of imidazole derivatives

The present invention relates to imidazole derivatives having an antimicrobial action, in particular 1-aryl-2- (1-imidazolyl) -alkyl sulfides, more particularly novel 1-aryl- represented by the following general formula (1) It relates to 2- (1-imidazolyl) -alkyl-sulfides and pharmacologically acceptable salts thereof.

Wherein R ¹ , R ² , R ³ and R ⁴ are each hydrogen or lower alkyl,

Ar is a phenyl group optionally substituted with one or more halogen atoms, lower alkyl groups or lower alkoxy groups, or is thienyl or halothienyl group

Y is a monocyclic or bicyclic group containing at least one heteroatom in a 5-membered or 6-membered ring and having a 5-membered or 6-membered carbon atom attached to a sulfur atom of the general formula (1).

In the present specification, the halogen atom means fluorine, chlorine, bromine or iodine, and a lower alkyl or alkoxy group means a straight or branched chain alkyl or alkoxy group containing 1-6 carbon atoms and a lower alkanoyl group. A straight or branched group containing 2-6 carbon atoms.

Suitable as lower alkyl and lower alkoxy groups are methyl and methoxy, respectively, and suitable as lower alkanoyl groups are acetyl groups. Suitable as substituents R ¹ , R ² , R ³ and R ⁴ are small atom atoms and suitable as aryl group Ar are dihalophenyl groups, especially 2,4-dichloro-phenyl groups.

Suitable as heterocycle group Y are aromatic or nonaromatic groups, for example thienyl, thiazolyl, thiazolyl, 2- or 4-imidazolyl, 3- (1,2,4) -triazolyl, thidiazolyl, One or more halogen atoms as oxadiazolyl, 5-tetrazolyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2-benzoimidazolyl, or 2-, 3-, or 4-quinolyl groups, Or lower alkyl, lower alkoxy, hydroxy, amino, mercapto, lower alkylthio, phenyl, substituted phenyl, aryl-lower alkyl, carboxy, lower alkoxy carbonyl, mono- or di-lower alkyl amino, lower alkanoyl Amino, lower alkoxycarbonyl-lower alkyl, aryl-lower alkylamino, carbamoyl, C ₃ -C ₆ cycloalkyl, nitro, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxycarbonylamino, lower alkylsulfur May be optionally substituted with a phenylamino, amidino, guanidino or ureido group The. Suitable as heterocycle groups are pyridyls (particularly 2-pyridyls optionally substituted with amino and (or) chloro or bromo, especially 3-chloro-2-pyridyl, 5-chloro- and 5-bromo-2-pyrides). Diyl, 5-amino-3-pyridyl 삔 5-amido-3-chloro-2-pyridyl), thienyl (particularly 2-thienyl), thiazolyl (particularly 2-thiazolyl and 4,5-dimethyl -2-thiazolyl), imidazolyl (especially 1-methyl-2-imidazolyl), 1,2,4-thiadiazolyl (especially 3-methyl-1,2,4-thiadiazol-5- And pyrimidinyl (particularly 2-pyrimidinyl).

Suitable when the aryl substituent is on Y is phenyl and substituted phenyl, suitable as substituents for phenyl are hydroxy and halogen.

Particularly suitable as compounds of the present invention are as follows.

1- [2,4-dichloro-β- (1-methyl-imidazolyl-2-thio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4,5-dimethylthiazolyl-2-thio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2-pyrimidinylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2-pyridylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2-thienylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (5-bromopyridyl-2-thio) phenethyl) imidazole,

1- [2,4-dichloro-β- (3-methyl-1,2,4-thiazolyl-5-thio) phenethyl) imidazole,

1- [2,4-dichloro-β- (2-thiazolinylthio) phenethyl) imidazole,

1- [2,4-dichloro-β- (5-chloro-pyridyl-2-thio) phenethyl) imidazole,

1- [2,4-dichloro-β- (3-chloro-pyridyl-2-thio) phenethyl] imidazole,

1- [β- (2-pyridylthio) -5-chloro-2-thienyl-ethyl] imidazole,

1- [2,4-dichloro-β- (5-aminopyridyl-2-thio) phenethyl] imidazole,

1- [2,4-dichloro-β- (5-amino-3-chloro-pyridyl-2-thio) phenethyl] imidazole,

And their pharmacologically acceptable acid addition salts, in particular hydrochloride.

(1) The compounds of the present invention can be prepared by reacting a suitable 1-aryl-2- (imidazolyl) alkyl halide of the general formula (II) with a thiol of the general formula (III).

Wherein Ar and R ¹ -R ⁴ are as described above

X is a halogen atom, in particular chlorine,

Y is as described above.

However, when Y is a compound containing a lower alkanoylylamino, lower alkoxycarbonylamino or lower alkylsulfonylamino substituent, it is suitable to prepare by the modification method indicated by the method (2) mentioned later.

The reaction is generally carried out in an aqueous organic solvent, suitably aqueous dimethylformamide, in the presence of an acid binder such as sodium carbonate, sodium bicarbonate or triethylamine. Typically thiol is used in a slight excess. In addition, the reaction is carried out at a temperature ranging from room temperature to reflux temperature of the solvent and takes 1-48 hours depending on the nature and temperature of the reactants used. Rod inventors have generally found that the reaction is virtually complete in 3-4 hours at 100 ° C. and takes 48 hours at room temperature. For convenience, the product may be separated from the reaction mixture by injecting the reaction mixture into water, extracting the product with an organic solvent, such as diethyl ether, which is not mixed with water, and then evaporating the organic solvent to obtain the product as an oily or chewing substance. .

Alternatively, the reaction mixture may be evaporated and the product may be extracted with an organic solvent, ie ethyl acetate or ether. In either case, the preparation can be purified as free base or converted to acid addition salts as needed. For example, hydrochloride can be obtained by treatment with a solution of hydrogen chloride, or a hydroxide can be obtained by treatment with an aqueous solution. The solid product can then be purified by conventional methods, such as by recrystallization, if necessary. The oxalate can be converted to a pharmacologically acceptable acid addition salt by, for example, conventional ion-exchange methods.

Halides of formula (II) are known compounds disclosed in US Pat. No. 3,679,697. Compounds of formula (III) are generally known compounds that can be readily obtained or can be prepared by known methods.

(2) Certain compounds of the present invention can also be prepared by converting a substituent of the Y group to another substituent according to the following method.

(a) A compound in which Y contains a lower alkanoylamino substituent may be substituted with an appropriate amino substituted compound with a suitable C ₂ to C ₆ acid chloride or bromide (ie CH ₃ COCl or CH ₃ COBr) or C _{4 to} C ₁₂ acid anhydride. (I.e., [CH ₃ CO] ₂ O).

(b) A compound in which Y contains a lower alkoxycarbonylamino substituent can be prepared by reacting the corresponding amino substituted compound with a suitable lower alkylchloroformate or bromoformate.

(c) A compound in which Y contains a lower alkylsulfonylamino substituent may be substituted with an appropriate amino substituted compound with a suitable C ₂ -C ₁₂ alkylsulfonic anhydride (ie [CH ₃ SO ₂ ] ₂ O) or C ₁ -C ₆ It can be prepared by reaction with alkanesulfonylchloride or bromide (ie CH ₃ SO ₂ Cl).

(d) A compound in which Y contains an amino substituent can be prepared by reducing a compound substituted with a corresponding nitrile with ferrous sulfate and ammonia.

(e) Compounds in which Y contains a primary loweralkyl-amino substituent can be prepared by reacting the corresponding amino substituted compound with a suitable C ₁ -C ₆ aldehyde followed by reduction with sodium borohydride.

This method is expressed in the following scheme.

(f) A compound in which Y contains a ureido substituent can be prepared by reacting the corresponding amino-substituted compound with sodium or carlium cyanate in the presence of an acid.

The compounds of the present invention exist in D- and L-photoactive isoforms so that the present invention includes not only these isoforms but also racemic mixtures. The racemic product can be divided by known methods such as the fractional determination method of acid addition salts formed with photoactive acids.

The compounds of the present invention are pharmacologically acceptable acid addition salts such as hydrochloride, bromate, iodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, nitrate, lactate, tartarate, citrate, gluconate. , Saccharate and P-toluenesulfonate.

Compounds of the invention and pharmacologically acceptable acid addition salts are antifungal agents useful for treating fungal infections in animals such as humans.

In vitro evaluation of the antifungal action of a compound is made by measuring the minimum inhibitory concentration (m.i.c) of the test compound in a suitable medium in which the growth of a particular microorganism may occur.

In fact, inoculate standard cultures of Candida albicans on agar plates containing a specific concentration of the test compound, and incubate each plate for 24 hours at 37 ° C, and examine each plate for fungal growth. Find the appropriate mic value. Other microorganisms used in these tests include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Epidermophyton floccosum, Blastomyces dermatitidis and Torulopsis glabrata.

In vivo evaluation of the compounds is also performed at multiple dose levels in mice inoculated with strains of Candida albicans, either by intraperitoneal injection or intravenous injection. Antifungal action is assessed based on the survival of the post-treated mice group in the untreated group of mice followed by a 48-hour observation to determine the compound at a dose level that provides 50% protection against the bactericidal effect of the infection.

The antifungal compound of the present invention may be administered alone when used in the body, but is generally used in combination with a pharmaceutical carrier selected in association with the intended route of administration and standard pharmaceutical form. For example, the antifungal compounds of the present invention may be administered orally in the form of tablets containing excipients such as starch or lactose, alone or in admixture with excipients, or in the form of erics or suspensions containing flavoring and coloring agents. It can be administered orally.

The compounds of the invention may also be administered parenterally, such as intravenous, intramuscular or subcutaneous injection. For parenteral administration, it is best to use in the form of sterile infusions containing saline or glucose suitable for forming other solutes such as isotonic solution.

When administered orally and parenterally to a patient, the daily dose level of the antifungal compound of the present invention is comparable to that of antifungal agents currently in use, i.e., 0.5 to 50 mg / kg (in divided doses), orally when administered parenterally. It is expected to be between 2 and 200 mg / kg (in aliquots). Therefore, tablets or capsules of the compound may contain 30 mg to 3 g of active ingredient when administered orally up to four times a day, while parenteral administration may be expected to contain 10 mg to 1 g of active ingredient. In some cases, the physician will determine the actual dose based on the age, weight, and sensitivity of the patient as best suited to the individual patient. The dosage range may, of course, be high or low depending on the patient and this is within the scope of the present invention.

Accordingly, the present invention provides a pharmaceutical composition containing a compound of formula (1) and a pharmacologically acceptable diluent or carrier.

In contrast, the antifungal compound of formula (1) can be used topically, that is, in the form of a cream or ointment. For example, the antifungal compound of the formula (1) may be blended into a cream formed of an aqueous emulsion of polyethylene glycol or a liquid paraline, or a white wax or soft paraffin base with a stabilizer and a preservative as necessary in a concentration ranging from 1 to 10%. It can be blended into the ointment formed.

The present invention also provides an antifungal composition for topical administration containing a compound of formula (1) and a locally acceptable diluent or carrier.

Hereinafter, the present invention will be described in detail with reference to the following examples.

Example 1

1- (β-3-chloro-2,4-dichloro-phenedil) imidazole salt mill (0.82 g) in which a solution of sodium carbonate (0.85 g, 8.0 mmol) dissolved in water (10 ml) was dissolved in water (5 ml). , 2.6 mmol) and a sufficient amount of salt dimethylformamide were added to give a clear solution (25 ml). 3-chloro-2-mercapto-pyridine (0.46 g, 3.1 mmol) dissolved in dimethylformamide (5 ml) was added to the solution, the mixture was stirred at room temperature for 2 days, the solvent was removed in vacuo, and the residue was washed with water ( 50 ml), extracted with ether (3 x 50 ml), the combined ether extracts are dried over magnesium sulfate, evaporated, and the oily residue is dissolved in dry ether (25 ml) and hydrochloric acid in ether is added to precipitate the hydrochloride. The precipitate was collected and filtered and recrystallized from a mixture of methanol and di-isopropylether to yield 1- (2,4-dichloro-β- (3-chloro-pyridyl-2-thio) phenethyl] imidazole hydrochloride (0.4 g, 36%), melting point 225-226 ° C.

Elemental analysis for C ₁₆ H ₁₂ Cl ₃ N ₃ S.HCl;

Theoretical value; C, 45.6; H, 3.1; N, 10.0%

Anal: C, 45.4; H, 3.2; N, 9.8%

Example 2-49

Treatment with 1- (β-chloro-2,4-dichlorophenethyl) imidazole and a suitable heterocycle-thiol as starting material according to the method described in Example 1 above resulted in 1- ( 2,4-dichlorophenyl) -2- (1-imidazolyl) ethyl sulfide derivative was obtained. Table 1 below shows the heterocycle group Y and its melting point and analysis data.

The structure of the compound for which melting point and analytical data were not obtained is i.r. And n.m.r.

TABLE 1

Example 50

1- (β-chloro-phenethyl) imidazole hydrochloride dissolved 2-mercapto-pyridine (0.77 g, 7,0 mmol) in aqueous sodium bicarbonate solution (1.5 g in 70 ml) and dissolved in dimethylformamide (70 ml) (1.5 g, 6.0 mmol) was added, the mixture was stirred overnight at room temperature, poured into water (300 ml), extracted with ether (4 x 100 ml), and the combined ether extracts were washed with water and brine, and then magnesium sulfate phase. After drying by evaporation, the oily residue was dissolved in dry ether, and saturated solution dissolved in ether was added to precipitate the hydroxide as a gum-like substance. The precipitate was kneaded with dry ether to solidify and recrystallized from methanol and ether. Results 1-β- (2-pyridyl-thio) phenethyl] imidazole dihydrate (0.38 g, 14%) was obtained. Melting point 128 ℃

Elemental Analysis for C ₁₆ H ₁₅ N ₈ S (C ₂ H ₂ O ₄ ) ₂ ;

Theoretical value; C, 54.8; H, 4.3; N, 10.1%

Analysis value; C, 54.9; H, 4.55; N, 9.6%

Example 51

1- (2-Chloro-5-thienyl) -2- (1-imidazolyl) -ethyl chloride (1.5 g, 5.3 mmol) dissolved in dimethylformamide (100 ml), 2-mercapto-pyridine (0.75 g, 6.7 mmol) and a mixture of sodium carbonate (2 g, 19 mmol) were stirred at room temperature for 5 hours, and then the solution was filtered to remove the organic solvent in vacuo, and the remaining oil was dissolved in ethyl acetate and filtered. The precipitated oxalate was added by saturation of the dissolved oxalic acid, washed with ether, and then recrystallized from a mixture of acetone, methanol and di-isopropyl ether to obtain 1- [β- (2-pyridylthio) -5-chloro 2-thienyl-ethyl] imidazole hydrate was obtained (0.98 g, 46%). Melting Point 190 ~ 191 ℃

Elemental Analysis for C ₁₆ H ₁₂ ClN ₃ SC ₂ H ₂ O ₄ ;

Theoretical value; C, 46.7; H, 3.4; N, 10.2%

Analysis value; C, 46.6; H, 3.5; N, 10.1%

Example 52

Ferrous sulfate (240 g) was dissolved in water (600 ml) and concentrated hydrochloric acid (1 ml) and 1- (2,4-dichloro-β- (5-nitropyridyl-2-thio) phenethyl] The mixture was stirred vigorously by addition of imidazole (22.5 g-compound of Example 42), then heated at 90 ° C. and ″ 0.88 ″ ammonia (100 ml, added 3 × 50 ml every two minutes) was added to the mixture for 90 minutes. After heating at 占 폚, the reaction mixture was cooled, diluted with water, the iron residue was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried and treated with a saturated solution of d-tin acid in methanol, and the resulting precipitate was filtered. Isolate to give 1- (2,4-dichloro-β- (5-aminopyridyl-2-thio) phenethyl] imidazole distannate (1.5 g) as a precipitate, and then the iron-containing residue was stirred in methyl acetate , Ethyl acetate layer was raced to dryness and treated with a solution of d-tartrate in methanol As a result, the desired product (22 g) was further precipitated, and the iron residue was then treated once more with ethyl acetate / d-tartrate in methanol to give the desired product (3 g). Fine hygroscopic powder (26 g, 68%) was obtained.

C ₁₆ H ₁₄ N ₄ SCl ₂ .HOHO. Elemental analysis for (CHOH) ₂ COOH;

Theory; C, 43, 32; H, 3.94; N, 8.42%

Analysis value; C, 44.40; H, 4. 34; N, 8.15%

A solution of 1- [2,4-dichloro-β- (5-aminopyridyl-2-thio) phenethyl] imidazole mono oxal as a result of using an aqueous solution in ether instead of a solution of d-tartrate in methanol according to a similar method as above. The rate was obtained. Melting point 105-125 ℃

Elemental Analysis for C ₁₆ H ₁₄ N ₄ Cl ₂ SC ₂ H ₂ O ₄ ;

Theory; C, 47.49; H, 3.54; N, 12.31%

Analysis value; C, 47.83; H, 3.71; N, 11.63%

Example 53

Preparation of 1- [2,4-dichloro-β- (3-chloro-5-aminopyridyl-2-thio) phenethyl] imidazole monohydrochloride (melting point 222-224 ° C.)

The subject compound was obtained by following the method of Example 52 using the corresponding 3-chloro-5-nitropyridyl imidazole as starting material and hydrochloric acid in ether instead of tartaric acid in methanol.

Elemental analysis for C ₁₆ H ₁₃ N ₄ SCl ₃ .HCl;

Theory; C, 44.0; H, 3.2; N, 12.5%

Analysis value; C, 44.1; H, 3.2; N, 12.8%

Example 54

An aqueous solution of 1- [2,4-dichloro-β- (5-aminopyridyl-2-thio) phenethyl imidazole distannate (2.5 g, compound of Example 52) was treated with aqueous sodium carbonate solution and treated with methylene chloride After treatment and separation, the organic layer is dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue of the free base was dissolved in 30% aqueous acetic acid solution, and an aqueous sodium cyanate solution (containing 0.5 g of cyanate) was added dropwise, and the mixture was left overnight at room temperature to give sodium cyanate (0.25 g). ) And the reaction mixture was stirred overnight at room temperature, followed by further addition of sodium cyanate (0.25 g), and the reaction mixture was left for 24 hours to be alkaline with an aqueous sodium carbonate solution, followed by extraction and separation with ethyl acetate, and then an organic layer of anhydrous sulfuric acid. After drying over magnesium, the solvent was distilled off under reduced pressure, and the residue was dissolved in a small amount of methanol. The residue was chromatographed on silica gel using ethyl acetate / methanol as eluent. The result was 1- [2,4-dichloro-β- (5-urea). Imidopyridyl-2-thio) phenethyl] imidazole (225 mg) was obtained. Melting point 106-110 ℃

The product was confirmed by n.m.r.i.r and mass spectrometry data.

Example 55

Aqueous solution of 1- [2,4-dichloro-β- (5-aminopyridyl-2-thio) phenethyl] imidazole distannate (1.5 g, compound of Example 52) was extracted with an aqueous solution of sodium carbonate and methylene chloride After extraction and separation, the organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue of the free base was dissolved in tetrahydrofuran, triethylamine (0.5 ml) and methanesulfonic anhydride (0.44 g) were added thereto. The reaction mixture was stirred overnight at room temperature, anhydrous (80 mg) was further added, the mixture was stirred overnight at room temperature, the reaction mixture was evaporated to dryness under reduced pressure, water and a small amount of aqueous sodium carbonate solution were added to dissolve the residue, and the mixture was then diluted with ethyl acetate. Extraction and drying over magnesium sulfate and removal of the solvent under reduced pressure, the residue was dissolved in a small amount of ethyl acetate and the solution was saturated with an aqueous solution of ether in ether. Result of applying the formed precipitate was filtered and recrystallized from _{Me OH / H 2 O 1- [} 2,4- dichloro -β- (5- methylsulfonyl-amino-pyridyl-2-thio) phenethyl] imidazole mono-oxalate A rate (270 mg) was obtained. Melting Point 141-143 ℃

Elemental analysis for C ₁₇ H ₁₆ N ₄ O ₂ S ₂ Cl ₂ (COOH) ₂ ;

Theory; Ci 42.78; H, 3.38; N, 10.50

Analysis value; C, 43.52; H, 3.53; N, 10.62

In vitro mic values for Candida Albicans C ₆₆ were tested for antifungal action by the above-described methods of a plurality of compounds prepared in the above examples.

TABLE 2

Claims (1)

A compound represented by the following general formula (I) characterized by reacting a halide of the following general formula (II) with a thiol of the following general formula (III), and a method for preparing an acid addition salt thereof.

Wherein R ¹ , R ² , R ³ and R ⁴ are each a hydrogen atom or a lower alkyl group, and Ar is a phenyl group optionally substituted with one or more halogen atoms, lower alkyl or lower alkoxy groups; Thienyl or halothienyl, Y is a monocyclic or bicyclic group in which a 5- or 6-membered carbon atom is attached to a sulfur atom of general formula (I), and X is a halogen atom.