KR830000711B1 - Method for preparing 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo- [2, 1-b] thiazole - Google Patents

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Description

Method for preparing 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo- [2,1-b] thiazole

The present invention is directed to 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo [2,1-b], which shows a modulating effect of selmidated immunity and anti-arthritis activity. ] -Thiazole and acid addition salts thereof.

The compound of the present invention has the following formula.

The compounds of the present invention are generally used in free base form, although pharmaceutically suitable acid addition salts or oxide derivatives of N or s atom positions can equally be used.

Pharmaceutically suitable acid addition salts of compounds of formula (I) are formed into strong or usually strong organic or inorganic acids by known methods.

It can be seen that the imidazole ring has one base center and another base center in the 4-pyridyl substituent.

For example, the base is reacted with an organic or inorganic acid in the case of a water-soluble solvent such as ethanol or isopropanol, and then the solvent is removed to separate the salt, and in the case of a water-insoluble solvent in which the acid is an acid such as ethyl ether or chloroform, the desired salt is applied. Is separated directly or by removing the solvent.

Examples of salts included in the present invention include maleate, permarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate Late salts.

As described above, bases have physical properties that are equivalently equilibrated with the salt derivatives.

The sulfoxide derivatives of formula (I) in which sulfinyl groups are present are oxidized to 2,3-dihydroimidazo [2,1-b] thiazoles, preferably in equivalent amounts of m-chloro perbenzoic acid in a solvent such as methylene chloride. Or by oxidizing with sodium or potassium pyriodate, hydrogen peroxide or the same sulfating agent.

The sulfonated moieties of formula (I) in which a 1-sulfonyl group is present can be prepared by the use of 2,3-dihydroimidazo [2,1-b] thiazole or sulfoxide derivatives thereof with one or two equivalents of an oxidizing agent and a suitable organic solvent. Obtained by oxidation in N-oxide derivatives of pyridyl substituents can be prepared using relatively strong oxidation conditions.

The compounds of the present invention are reactive such as urethra, chloro or bromo such as 1-bromo-2-chloroethane, 1,2-dibromoethane or 1-iodo-2-chloroethane in an organic solvent in which the reactant is meltable. It is prepared by alkylating 4- (2-pyridyl) -5- (4-fluorophenyl) -2-mercaptoimidazole with ethylene 1,2-halide having a halo atom.

Alkylation-cyclization proceeds with the use of an acidic solvent to obtain the hydro halide salt form of formula (I).

Other polar solvents may be used in particular in the presence of alkali metal reactants capable of forming alkali metal derivatives of 2-mercaptan groups of starting materials such as sodium or potassium hydrides or lower alkoxides.

Solvents are dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoamide.

The reaction proceeds at an appropriately heated temperature such as room temperature or reflux temperature. Acid addition salt mixtures in the 5,6 position areomers are separated into their respective isomers by known techniques such as fractional recrystallization or chromatography.

This salt is also converted into a freebase mixture which is separated into each isomer, preferably 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo- [2, 1-b] -thiazole.

European Patent Application No. 353, published January 24, 1979, describes a broad group of compounds claimed herein.

The structure closest to this is illustrated in Example 6 of the European Patent and is a mixture of isomers, 5 (6)-(3-pyridyl) -6- (5) -phenyl imidazo [2,1-b] di Hydrothiazole.

The basic structure of the claimed is 4-fluorophenyl, 4-pyridyl and suitable isomeric structures are not described in the European patent.

Useful activity for the treatment of arthritis is determined by the following experiments:

Inhibitory activity of medium-induced polyarthritis measured by the reduction of edema of the foot is generated by oral administration of the compound of the present invention at 3.125-50 mg / kg daily with indomethacin and methotrexate.

In this experiment, mediated arthritis in rats is caused by injecting 0.75 mg of Mycobacterium butyricum suspended in white paraffin oil into the left hind limb.

Infused leg is chlorinated (volume increase) and reaches its maximum size (initial injury) within 3 to 5 days.

Animals lose weight during the initial period. Medium arthritis occurs after 10 days (secondary) and is characterized by weight loss and chlorination of the right hind limb that has not been injected, and the volume of the injected left hind limb is further reduced. The test compound is administered daily for 17 days from the first day of the medium injection and not for 4, 5, 11 and 12 days.

Anticorrosive activity is shown by its ability to protect animals against the development of primary arthritis and secondary injury.

In this study, the oral dose of the active dose of 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo [2,1-b] thiazole was 6.25,12.5 and 50 mg / kg and oral DE ₂₅ is 26.4 (15.6-54.4) mg / kg / day on the left foot on Day 3 and 10.4 (5.3-19.0) mg / kg / day on the left foot on Day 16 and 16 days on the right foot At 7.5 (2.7-15.6) mg / kg / day (ED ₂₅ is the calculated value 25% decrease from the control).

Unlike the displaced isomers, 6- (4-pyridyl) -5- (4-fluorophenyl-2,3-dihydroimidazole [2,1-b] thiazole is completely active at 50 mg / kg / day The same was true for the similar 5,6-bis- (4-pyridyl) -2,3-dihydroimidazo [2,1-b] thiazole (50 mg / kg / day).

In the kerageenan-induced plantar edema test, anti-inflammatory activity is generated by oral administration of Compound 50 and 100 mg / kg of the present invention. In addition, compounds with immunomodulatory activity are useful for the treatment of rheumatoid arthritis.

The compounds of the present invention show that they modulate cell mediated immunity as shown in standard experiments, such as the oxazolone-induced contact sensation experiments shown in the rat experiment.

This is described in Greasebold et al. Cellular Immunology 11: 198-204 (1974).

In the oxazolone sensory test, 5- (4-pyridyl-6- (4-fluorophenyl) -2,3-dihydroimidazo [2,1-b] thiazole has a remarkable effect after oral administration.

The translocated isomers are not as remarkable for oral administration at 25 mg / kg.

In addition, the 5,6-di (2-pyridyl) analog is not remarkable when administered orally at 25 mg / kg.

The compound of the present invention has an oral LD ₅₀ value of 214 · 2mg / kg by oral administration to mice for 14 days.

In addition to its effects on rheumatoid arthritis, immunomodulators have efficacy in other diseases involving cell mediated immunity. These diseases include, for example, systemic lupus erythromatosus and autoimmune thyroiditis. In addition, atopic dermatitis, chronic aphthous ulceration, recurrent upper respiratory tract infections in children, and diseases such as lung and breast cancer are treated with levamisol, which restores an impaired cell mediated immune response.

Pharmaceutically effective compounds of the present invention may be prepared by conventional administration of a compound of formula (I) in admixture with a representative pharmaceutical carrier in an amount sufficient to cause anti-rheumatic activity or control of cell mediated immunity according to conventional methods. Administration in unit form.

That is, mixing, granulation and pressing or dissolving the component in the form of a desired formulation is carried out.

The pharmaceutical carrier used is a solid or liquid, examples of solid carriers are such as lactose, terra alba, sucrose, talc, geladine, agar, pectin, acacia, magnesium stearate, stearic acid, examples of liquid carriers It's like peanut oil, olive oil and water. The diluent or carrier may be mixed with known glyceryl monostearate or glyceryl distearate alone or with wax.

Various pharmaceutical forms may be used, and if solid carriers are used, the preparations may be in tablets, in the form of powders or pellets in hard capsules, or in the form of troches or lozenges.

The amount of solid carrier varies widely but is preferably from 25 mg to 1 g and if liquid carriers are used, the preparation may be in liquid form to which stearyl, such as municipal, emulsion, soft gelatin capsules, ampoules or non-aqueous suspensions can be injected, orally Dosage forms are mainly used.

To obtain a dosage form that is soluble in stable water, an acid addition salt of the pharmaceutically acceptable compound of formula (I), preferably sulmate is an organic, such as 0.3 M solution of succinic acid or preferably citric acid Or in an aqueous solution of an inorganic acid.

Examples of other water soluble salts with sulfates are methanesulfonate, phosphate and hydrochloride.

Preferably, each dosage unit contains about 25 mg to about 100 mg of active ingredient.

The following examples illustrate, but do not limit, the present invention and all temperatures are in degrees Celsius.

Example 1

To an aqueous solution (75 ml) of sodium cyanide (19.6 g; 400 mm) and benzyltriethyl ammonium chloride (3.0 g, 13 mm) isonicotin aldehyde (10 g, 93 mm) in 100 ml of methylene chloride is added at 0 ° C.

Stir vigorously for 15 minutes and slowly add a solution of methylene chloride of benzoyl chloride (14.0 g, 100 mm 50 ml). Cooling stops after half the reaction and the mixture is left until ambient temperature is reached.

The organic layer is separated, washed with 5% sodium carbonate and brine, dried and the oil is evaporated and extracted with ether (4 L).

The ethereal solution was concentrated to 500 ml and left to crystallize to obtain 5.0 g of isnicotinaldehyde-0-benzoylcyanohydrin. Stir cyanohydrin (3.0 g, 12 mm) in 50 ml of p-fluoro benzaldehyde (12 mm) and tert-butyl alcohol, add sodium hydride (12 mm) and continue stirring at room temperature for 1- 1/2 hours. .

Thin layer chromatography analysis of the reaction mixture with the oil mixture of potassium hydride (24% suspension, 4 ml, 23 mm) and after 1-1 / 2 hours shows formation of single products.

The material is cooled in 200 ml of an ice-water mixture and the cooling material is extracted with chloroform.

The chloroform extract is evaporated to a crystalline residue which is further crystallized by ether addition.

The crystalline product obtained is partially purified by crystallization from methylene chloride-ether mixture.

9.0 g (37 mm) of hydroxy ketone was refluxed in 5.3 g (70 mm) of thiourea and 140 ml of dimethylformamide, and the starting material was not detected until after 4 hours of reaction.

The solvent is concentrated to half of the initial amount by initial precipitation of crystalline 2-mercapto imidazole;

Crystallization completes overnight in the freezer and the compound is purified by crystallization from ethanol.

4- (4-pyridyl) -5- (4-fluorophenyl) -2-mercaptoimidazole is formed at a yield of 40% of the residue based on benzoyl cyanohydrin concentration having a melting point of 386-388 ° C.

analysis:

Calculated Value: 1 / 8H ₂ O: C, 61.46 H, 3.78 N, 15.39

Found: C, 61.58 H, 3.21 N, 15.11

100 ml of dimethylformamide and 2-mercaptomidazole (12.5 mm) suspended in sodium hydride (13.0 mm) are added. Salt formation proceeds at room temperature for 1/2 hour, at which time 1-bromo-2-chloroethane is added from the syringe and the solution is stirred overnight under argon pressure.

Solid anhydrous potassium carbonate (20.0 mm) is added to the reaction mixture and reflux is continued for 2-1 / 2 hours.

Dilution of dimethylformamide to 300 ml of ice-water mixture precipitates an oily product.

The oily residue is chromatographed on silica gel with 1: 1 ethyl acetate / ether using dry column technology.

This operation separates the isomer mixture from all impurities. Isomers are separated by isopropanol / ether (1: 2) by medium pressure liquid chromatography on silica, and after elution the fast moving spot (Rf: 55, silica / isopropanol) is further purified by crystallization from isopropanol. Melting point of 5- (4-fluorophenyl) -6- (4-pyridyl) isomer 165-167 ° C yield 0.75 g

analysis:

Calculated Value: C, 64.63 H, 4.07 N, 14.13

Found: C, 64.85 H, 4.12 N, 14.12

Slow transfer spot, after elution The preferred 5- (4-pyridyl) -6- (4-fluorophenyl) isomer (Rf, .25, silica / isopropanol) is recrystallized from isopropanol. Melting Point 186-189 ℃, Yield 0.62g

analysis:

Calculated Value: C, 64.63 H, 4.07 N, 14.13

Found: C, 64.27 H, 4.10 N, 14.05

The compound is converted from one of the pharmaceutically acceptable acid addition salts such as dihydrochloride, sulphate, methanesulfate to the other by the reaction of the base with the excess acid in a pharmaceutically acceptable acid addition salt such as isopropanol and an organic solvent such as isopropanol. do.

Example 2

To 6- (4-fluororectyl) -5- (4-pyridyl) -2,3-dihydroimidazo [2,1-b] thiazole 1.9 in 25 ml of methylene chloride cooled to ice-bath temperature -Add 1.36 g of chloro perbenzoic acid.

After stirring is continued for 1 hour, the solution is diluted with methylene chloride and washed with a 1: 1 mixture of 5% sodium carbonate and brine.

Treatment with magnesium sulfate, filtration and separation yielded 6- (4-fluorophenyl) -5- (4-pyridyl-2,3-dihydroimidazo [2,1-b] thiazole-1-oxide 2.1. 1.8 g is obtained by treatment with ether, filtration and drying.

Melting Point 229-231 ℃

analysis:

Calculated Value: C, 61.33 H, 3.86 N, 13.41

Calculated Value: C, 61.61 H, 4.18 N, 13.46

The starting material is treated with 2.72 g of m-chloroperbenzoic acid to give the 1-dioxide derivative.

Example 3

To 50 ml of glacial acetic acid, 1.0 g of 4- (4-pyridyl) -5- (4-fluorophenyl) -2-mercaptoimidazole and 1.0 g of dibromoethane are added. The milky solution is cleared after reflux for 1 hour.

At this point additional 2.1 g of dibromoethane are added and reflux is continued for 3 hours.

Acetic acid is separated in vacuo and the residue is partitioned between methylene chloride and 5N sodium carbonate solution. The organic extract is washed with 5N sodium carbonate solution and brine and treated with magnesium sulfate.

Evaporation of the solvent gave 6- (4-fluorophenyl) -5- (4-pyridyl) -2,3-dihydroimidazo [2,1-b] thiazole and 5- (4-fluorophenyl ( A mixture of -6- (4-pyridyl) -2,3-dihydro-imidazo [2,1-b] -thiazole remains and is separated as described above.

Example 4

The ingredients are filtered, mixed and filled into hard gelatin capsules. Capsules are administered to patients in need of arthritis treatment or orally administered 1-6 times daily to modulate cell mediated immunity.

Claims (1)

4- (4-pyridyl) -5- (4-fluorophenyl) -2-mercapto imidazole is reacted with 1,2-dihaloethane (where halo is chloro, bromo or urethra) 5- (4-pyridyl) -6- (4-fluorophenyl) -2,3-dihydroimidazo [2,1-b] thiazole and 5- (4-fluorophenyl) -6- (4- 5- (4-pyridyl) -6 characterized by obtaining a mixture of pyridyl) -2,3-dihydroimidazo [2,1-b) thiazole and then subjecting the mixture to fractional crystallization or chromatography. A process for preparing-(4-fluorophenyl) -2,3-dihydroimidazo [2,1-b] thiazole or a salt thereof or an oxide derivative thereof.