KR830000129B1 - Process for preparing mercaptoimidazole derivatives - Google Patents

Abstract

2-Mercaptoimidazoles I(R1,R2 = heteroaryl, aryl; R3 = H, lower alkyl; R4 = C2 lower alkyl; n = 0, 1, 2), useful as antiinflammatory, anodyne and/or cerebral thrombosis-treating agent, were prepd. by reacting compds. II with epoxy-lower alkane or lower alkene. Thus, 0.8 g Na was dissolved in 200ml EtOH and 8 g 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole added and refluxed, in which EtOH 30ml contg. ethylene oxide 0.84 g was added and refluxed for 16 hr to give 2-(2-hydroxyethylthio)-5(4)-phenyl-4(5)-(3-pyridyl)-imidazole(m.p.128-130≰C).

Description

Method for preparing mercapto imidazole derivatives

The present invention is useful as an anti-inflammatory, analgesic and / or thrombotic agent and is effective for inhibiting prostaglandin synthesis of substituted 2-mercaptoimidazoles of the general formula (I) and their pharmaceutically useful salts, in particular pharmaceutically useful It relates to a process for producing acid addition salts.

In the above general formula

At least one of R ₁ and R ₂ is an unsubstituted or substituted heteroaryl group and the other is an unsubstituted or substituted aryl group

R ₃ is hydrogen or a lower alkyl group

n is 0, 1 or 2

R ₄ represents an unsubstituted or substituted lower alkyl group having 2 or more carbon atoms.

As used herein, "lower" organics and compounds are preferably those having 7 or less carbon atoms, especially 4 or less carbon atoms.

Heteroaryl groups are in particular five-membered heteroaryl groups containing one oxygen or sulfur atom, containing one sulfur and one nitrogen atom, or containing at least two nitrogen atoms, or six-membered containing at least one nitrogen atom. It represents a heteroaryl group, which is bonded through a carbon atom.

For example, in particular furyl (e.g. 2-furyl), thienyl (e.g. 2-thienyl), thiazolyl (e.g. 1,3-thiazol-2 or -4-yl), imidazolyl (e.g. 1,3-imidazol-2 or 4-yl), triazolyl (e.g., 1 H- or 2H-1,2,3-triazol-4- or 5-yl or 1H- or 2H-1,2, 4triazol-3- or -5-yl), tetrazolyl (e.g. 1H-tetrazol-5-yl), pyridyl (e.g. 2-, 3- or 4-pyridyl), pyrimidinyl (e.g. : 2- or 4-pyrimidinyl), or triazinyl (eg, 1,3,5-triazin-2-yl or 1,2,4-triazin-3-yl). Substituents for this heteroaryl group include lower alkyl, lower alkoxy, halogen, unsubstituted or substituted amino, trifluoromethyl and / or halogen on a carbon atom, and on nitrogen atoms, lower alkyl, lower, if necessary. Alkoxy-loweralkyl and / or hydroxy-loweralkyl and oxy and the like.

Unsubstituted or substituted aryl groups, aryloxy groups and arylthio groups include phenyl, phenoxy and unsubstituted or substituted with lower alkyl, lower alkoxy, halogen, unsubstituted or substituted amino, trifluoromethyl and / or nitro; Phenylthio group.

Substituted amino groups are mono- or preferably di-substituted, and the substituents include lower alkyl, or alkylene having 4 to 7 membered ring, nitrogen, oxygen or sulfur atom, for example lower alkylamino, di-lower Alkylamino and 3-aza-, 3-oxa- or 3-thia-alkyleneamino and in each case are 5-6 membered rings. In addition to methylamino and ethylamino, in particular dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino and N'-lower alkyl-piperazino (e.g. N ' Methyl piperazino).

Substituents of lower alkyl groups R ₄ include substituted or unsubstituted-aryl groups (e.g. phenyl) or hydroxyl, lower alkoxy, lower alkylthio or substituted or unsubstituted aryloxy (e.g. phenoxy) or arylthio groups (e.g. Phenylthio), and they are bonded at positions higher than the α-position.

As described above, the substituted or unsubstituted lower alkyl group R ₄ is preferably lower alkyl having 2 or more carbon atoms (eg, C ₂ -C ₇ alkyl), and lower alkyl which may be unsubstituted or substituted with phenyl (which may be substituted). Or a lower alkyl group substituted at a position higher than the α-position with a hydroxyl, lower alkoxy or lower alkylthio, or a substituted or unsubstituted phenoxy or phenylthio group.

Lower alkyl groups R ₄ unsubstituted or substituted with phenyl include phenyl-lower alkyls such as 1- or 2-phenyl-lower alkyls such as 2phenylethyl having 8 to 10 carbon atoms.

Hydroxy-lower alkyls include, in particular, 2-hydroxyethyl, 2- or 3-hydroxypropyl or 2,3-dihydroxypropyl as mono- or di-hydroxy-lower alkyl having from 2 to 4 carbon atoms.

Lower alkoxy-lower alkyl is an alkoxy moiety having 1 to 4 carbon atoms and an alkyl moiety having 2 to 4 carbon atoms, such as 2-methoxyethyl, 2-ethoxyethyl or 2- or 3-methoxypropyl.

Lower alkylthio is one having 3 to 7 carbon atoms and includes 2-methylthioethyl.

Phenoxy-lower alkyl has 2 to 7 carbon atoms in the alkyl moiety and includes 2-phenoxyethyl; The alkyl site has 2 to 4 carbon atoms, and 2-phenylthio-ethyl is used.

Lower alkyl has 2 to 7 carbon atoms, 1 to 7 carbon atoms for R ₃ , and includes ethyl, propyl, isopropyl or n-, iso, secondary- or tertiary butyl, and is not preferred but iso-pentyl. , -Hexyl, or -heprene group, and methyl for R ₃ .

Lower alkoxy, having 1 to 7 carbon atoms, includes methoxy, ethoxy, propoxy, isopropoxy or n-, secondary-, iso, or tert-butoxy, and is not preferred but iso-pentyloxy , -Hexyloxy or -heptyloxy.

Lower alkylthio has 2 to 7 carbon atoms, and includes methylthio, ethylthio, propylthio, isopropylthio or butylthio, and although not particularly preferred, pentylthio, hexylthio, or heptylthio.

Halogen has an atomic number of 35 or less, preferably fluorine, chlorine or bromine.

Salts of the compounds of formula (I) are in particular pharmaceutically useful acid addition salts with mineral acids such as inorganic acids, for example salts with halogenated acids, in particular hydrochloric acid, bromic acid, etc., in particular hydrochlorides or bromates such as hydrochlorides, bromates , Bisulfate and sulfate.

Compounds of general formula (I) have pharmaceutically useful properties and exhibit exceptional anti-inflammatory, analgesic and / or thrombolytic and prostaglandin synthesis. These effects were measured in the kaolin plantar edema test in rats at doses of 15 to 150 mg / kg. Helv. Phydiol Acta. 25,156 (1967)], oral administration of 20 to 200 mg / kg once oral Carrageenen plantar edema test (Refer to Agents and Actions 5,256 (1975) by Di Pasquale et al.) Four doses of 10 to 60 mg / kg (oral) to arthritic mice were administered to mice with torsion syndrome induced by phenyl-p-benzoquinone at a dose of 30 to 300 mg / kg (oral). J. Pharma lo.exp Therap. 125,237 (1959)] and when administered at a dose of 0.1-3 mg / kg (oral) to embolism of rabbit lung induced by arachidonic acid.

Moreover, at concentrations of 10 to 30 ml / l, in vitro prostaglandin synthesis from arachidonic acid is inhibited. [Prostaglandins 7, 123 (1974)].

Therefore, the compound of general formula (I) has excellent suitability as an active ingredient of a medicament for treating inflammation, especially rheumatoid chronic inflammation such as chronic arthritis.

The present invention provides that at least one of R ₁ and R ₂ is substituted or unsubstituted furyl, thienyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or triazinyl and the other is substituted or Unsubstituted phenyl, R ₃ is hydrogen or lower alkyl, n is 0,1 or 2, and R ₄ is unsubstituted or substituted with phenyl or hydroxyl, lower alkoxy (e.g. Methoxy or ethoxy), lower alkylthio (e.g. methylthio) or an unsubstituted or substituted phenoxy or phenylthio group alkyl group having 2 to 7 carbon atoms, wherein R ₁ and R ₂ and phenyl, phenoxy and The ring carbon atoms in the phenylthio group may be selected from lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy, ethoxy), halogens (e.g. chlorine) up to and including atomic number 35, trifluoromethyl, nitro and / or amino [ It is either unsubstituted or substituted as lower alkyl (e.g. methyl ) Or 4- to 7-membered alkylene (e.g., trimethylene or tetramethylene; which may contain nitrogen, oxygen or sulfur), and may also be pyrimidinyl, triazinyl or especially pyri It relates to the preparation of compounds of formula (I) in which the nitrogen atom of the dill group can be substituted with oxy and acid addition salts thereof, in particular pharmaceutically useful acid addition salts.

The present invention particularly relates to one of R ₁ and R ₂ is a substituted or unsubstituted pyridyl group and the other is a substituted or unsubstituted phenyl or pyridyl group, R ₃ is hydrogen or lower alkyl having 1 to 4 carbon atoms (eg : Methyl), n is 0, R ₄ is unsubstituted, substituted with phenyl or hydroxyl at a position higher than the α-position; lower alkoxy having 1 to 4 carbon atoms, lower alkylthio having 1 to 4 carbon atoms, phenoxy Or lower alkyl of 2 to 7 carbon atoms substituted with phenylthio, wherein pyridyl, phenyl, phenoxy or phenylthio group is lower alkyl of 1 to 4 carbon atoms (e.g. methyl), alkoxy of 1 to 4 carbon atoms (e.g. Oxy or ethoxy), halogen (e.g. chlorine) having an atomic number of 35 or less, nitro, amino or each alkyl moiety may be substituted with N, N-di-loweralkylamino (e.g. dimethylamino) having 1 to 4 carbon atoms. Regarding the preparation of a compound of formula (I) and salts thereof will be.

In the present invention, preferably, one of R ₁ or R ₂ is pyridyl and the other is phenyl, and each of these groups is independently a lower alkyl having 1 to 4 carbon atoms (eg methyl), lower alkoxy having 1 to 4 carbon atoms (eg Methoxy or ethoxy), halogen with an atomic number of 35 or less (e.g. chlorine) and / or each alkyl group may be substituted with N, N-di-lower alkylamino (e.g. dimethylamino) having 1 to 4 carbon atoms, Preferably unsubstituted, R ₃ is hydrogen or lower alkyl of 1 to 4 carbon atoms (e.g. methyl), n is 0 and R ₄ is lower alkyl of 1 to 4 carbon atoms (e.g. ethyl, propyl, isopropyl Or butyl); Lower alkyl having 2 to 4 carbon atoms and unsubstituted or having 1 to 4 carbon atoms (e.g. methyl), lower alkoxy having 1 to 4 carbon atoms (e.g. methoxy or ethoxy) and / or halogen having an atomic number of 35 or less Phenyl-loweralkyl substituted with (eg chlorine); Hydroxy-lower alkyl having 2 to 4 carbon atoms (eg, 2-hydroxyethyl) substituted at a position where the hydroxy group (s) is higher than the α-position; Or lower alkoxy- or lower alkylthio-lower alkyl wherein the alkyl moiety has 2 to 4 carbon atoms and the alkoxy or alkylthio group moiety has 1 to 4 carbon atoms and the alkoxy or alkylthio group is substituted at the α-position. Methoxyethyl or 2-methylthioethyl), and a method for producing an acid addition salt thereof.

The present invention particularly relates to unsubstituted pyridyl (e.g. 3-pyridyl) or thienyl (e.g. 2-thienyl), wherein one of R ₁ and R ₂ is unsubstituted phenyl or 1 to 4 carbon atoms. Phenyl substituted by lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy) having 1 to 4 carbon atoms, and / or halogen (e.g. chlorine, in particular fluorine) having up to 35 atomic atoms, and R ₃ is hydrogen Less preferred, but are compounds of formula (I) wherein lower alkyl (e.g. methyl) of 1 to 4 carbon atoms, n is 0, 1 or 2, and R ₄ is lower alkyl (e.g. ethyl) of 2 to 4 carbon atoms, and compounds thereof It is about the manufacturing method of a salt.

The present invention, in particular R ₁ and R ₂ is one of an unsubstituted pyridyl (such as 3-pyridyl) and the other is unsubstituted phenyl, or less desirable, lower alkyl (e.g. of 1 to 4 carbon atoms: methyl ), Phenyl substituted with lower alkoxy (e.g. methoxy) or halogen (e.g. chlorine or bromine) with 1 to 4 carbon atoms, R ₃ is hydrogen or lower alkyl (e.g. methyl or ethyl) with 1 to 4 carbon atoms , n is 0, R ₄ is lower alkyl having 2 to 4 carbon atoms (e.g. ethyl) or hydroxy-lower alkyl having 2 to 4 carbon atoms and hydroxyl group is substituted at the α-position. Hydroxyethyl) and a process for producing acid addition salts thereof.

In the present invention, in particular, one of R ₁ and R ₂ is pyridyl (e.g. 3-pyridyl) and the other is phenyl, R ₃ is hydrogen, n is 0 or 1 and R ₄ is 2 to 4 carbon atoms. It relates to a general formula (I) compound which is a lower alkyl of (eg ethyl) and a process for acid addition salts thereof.

The compound of formula (I) and salts thereof react the compound of formula (II) with epoxy-lower alkanes or lower alkenes, which are substituted or unsubstituted as described above, and the resulting compounds, if necessary, (I) prepared by converting into a compound and / or by converting the resulting free compound into acid addition salts or by converting the resulting acid addition salts into free compounds or other salts.

In the above general formula

R, R ₂ and R ₃ are as described above,

X is mercapto and it may exist in the form of a salt.

The mercapto group in salt form is a mercapto group in the form of an alkali metal salt or ammonium salt, for example in the form of a sodium, potassium or ammonium salt.

The reaction is a reaction similar to the methods known in the literature, and if necessary, is carried out in the presence of a catalyst, and when the mercapto compound of formula (II) is reacted with an alkene or phenylalkene, a Lewis acid (eg iron-II salt Or in the presence of an acidic reagent such as boron trifluoride) or a peroxide (e.g., di-tert-butyl peroxide), or under UV light action having a wavelength of about 200-350 μm. When carrying out the above reaction, the reaction is preferably carried out in each case in a solvent. When the mercapto compound of formula (II) is reacted with alkene or phenylalkene, it is carried out in ether, tetrahydrofuran, dioxane or alcohol (e.g. methanol, ethanol, ethylene glycol or ethylene glycol monomethyl ether) and the reaction is It is advantageous to carry out at elevated temperatures (eg boiling points) under an inert gas (eg nitrogen) atmosphere if necessary.

Some starting materials are known compounds and new starting materials can be prepared by known methods.

The X used as starting materials mercapto toe general formula (I) compound, that is _{1-R 3 -4-R 1} -5-R 2 -2- mercapto-imidazole and _{1-R 3} -4-R 1 -5-R ₂ -imidazoline-thione, wherein R ₁ , R ₂ and R ₃ are as defined in formula (I) above is a compound of formula (IV) or a tautomer thereof Can be in dehydrated form).

In the above general formula

X ₁ is a group of the formula-NH-C-(= S) -NHR ₃ and X ₂ is hydroxyl

X ₂ is a group of the formula —NR ₃ C (═S) —NH ₂ and X ₁ is hydroxyl.

The tautomer of the general formula (IV) compound is preferably a tautomeric ketone for the general formula (IV) enol. Such enols may be ketalized with lower alkanols or lower alkanediols such as methanol, ethanol, ethylene glycol or 1,3-propylene glycol.

Intramolecular ring-closure reactions are carried out by conventional methods, in particular solvents such as water or alcohols (e.g. methanol, butanol, ethylglycol or ethylene glycol monomethyl ether), acid condensing agents such as inorganic acids (e.g. hydrochloric acid), if necessary, and / or Can be performed at elevated temperatures (e.g. boiling).

Starting materials of the general formula (IV) can be obtained by known methods, but are preferably prepared in situ and ring-closed without separation. For this purpose, the starting materials used are preferably compounds of formula R ₁ -CO-CH (NHR ₃ ) -R ₂ (IV _a ) or acid addition salts thereof, which react with thiocyanic acid or metal thiocyanate Let's do it. Compounds of formula (IV) are formed as intermediates and are ring-closed according to the invention. Particularly preferred reactions are hydrohalides of compounds of formula (IV _a ) (eg hydrochloride) in aqueous solution, if necessary Reacting with an alkali metal thiocyanate (eg sodium thiocyanate or potassium thiocyanate) or ammonium thiocyanate while warming to 100 ° C.

As a conversion method of this step, the compound (IV _b ) of the general formula R ₁ -CN (NH ₂ ) -CO-R ₂ or an acid addition salt thereof is converted to isothiocyanate of the general formula R ₃ -N = C = S ( With IV _c ).

In addition, the starting material of formula (IV) is a compound of formula Ro-Co-CHOH-Ro (IV _d ) or a compound of formula Ro-CO-CH ₂ -Ro (IV _e ) as bromine in acetic acid. Compound (IV _f ) of the general formula Ro-CO-CH (halogen) -R ₁ , which can be obtained by α-halogenation, wherein one of Ro is R ₁ and the other is R ₂ in a conventional manner It may also be prepared by reacting a thiourea compound (IV _g ) or a thiourea compound of R ₃ NH-CS-NH ₂ with a compound (eg R ₃ -ammoniumthiocyanate) produced in the same reactor. The compound of formula (IV) formed in the first step at the corresponding temperature (eg 100-250 ° C.) is closed in accordance with the invention. If R ₁ and R ₂ are different and R ₃ is not hydrogen, one or two isomers are possible depending on the reactivity and / or reaction conditions of each component of general formula (IV _c ), for example 1-R ₃ -4-R _1- 5-R ₂ -2 (3H) -imidazoline-2-thione and / or 1-R ₃ -4-R ₂ -5-R ₁ -2 (3H) -imidazolyl-2-thione can be obtained These isomers may be separated by conventional methods, that is, by fractional crystallization or chromatography, if necessary.

The starting material of formula (IV _a ) converts a compound of formula R ₁ -CO-CH ₂ -R ₂ to oxime and treats the oxime with toluene sulfonylchloride in pyridine to give oxime ester (Neber's) oxime / amine-kerone potential reactions and, if necessary, introducing R ₃ into the resulting general formula R ₁ -CO-CH (NH ₂ ) -R ₂ compound (eg lower alkyl bromide or lower alkyl iodide And react with).

Starting materials of formula (IV _b ) can be prepared in a similar manner using compounds of the general formula R ₁ -CH ₂ -CO-R ₂ as starting materials.

Starting materials of the general formula (IV _d ), in which R ₁ -R ₂ are the same R _0, may self-condense the aldehydes of the general formula R ₀ -CHO (IV _h ) with potassium cyanide in ethanol / water or tetrabutyl-ammonium in water. It can be prepared by self-condensation with cyanide.

Compound of formula (II), wherein X is mercapto, is unsubstituted in the 2-position and then heated the corresponding imidazole derivative of formula to 150-250 ° C. (preferably 200 ° C.) in tetramethylenesulfone with sulfur. Can be prepared.

Substituents may be introduced, converted or separated in the resulting compound of formula (I).

Thus, the organic group R ₃ is, by reacting a reagent capable of introducing a R ₃ may be introduced into R ₃ group instead of hydrogen, such reagents are hydrohalic acid esters (e.g., hydrochloric acid esters, boric acid esters or iodine ester ), Active sulfoic acid esters such as methane-, ethane-, benzene-, p-bromobenzene, or p-toluenesulfonic acid esters or sulfuric acid esters of the corresponding alcohols R ₃ OH. The reaction with these reagents is conventionally carried out by alkali metal hydroxides or alkali metal carbonates (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate), alcoholates (e.g. alkali metal lower alkanolates such as sodium methanolate). Or in the presence of a basic condensing agent such as sodium hydride, preferably in an inert solvent such as dimethylformamide, N-methylpyrrolidone.

를 갖는 헤테로아릴기 R₁및/또는 R₂(예 : 피리딜기)를 N-산화시킨다. 산화반응은 적합한 산화제 존재하에, 바람직하게는 이 시약에 불활성인 용매 내에서, 필요한 경우 과열 또는 냉각시키면서(예 : -30°내지 +100℃, 바람직하게는 0°내지 60℃), 밀폐용기 중에서 필요한 경우 불활성 기체(예 : 질소) 대기하에 수행하는 것이 바람직하다.Furthermore, in compounds of formula (I), the -S (O) _n -R ₄ group with n of 0 can be S-oxidized to convert to the corresponding sulfinyl or sulfonyl groups with n = 1 or 2, with n = A -S (O) _n -R ₄ group of 1 is S-oxidized to convert to the corresponding sulfonyl group with n = 2 and / or at least one free ring nitrogen atom

N-oxidize heteroaryl groups R ₁ and / or R ₂ (eg pyridyl groups) having The oxidation reaction is carried out in a closed container in the presence of a suitable oxidizing agent, preferably in a solvent inert to the reagent, with overheating or cooling if necessary (eg -30 ° to + 100 ° C., preferably 0 ° to 60 ° C.). If necessary, it is preferably carried out under an inert gas (eg nitrogen) atmosphere.

Suitable oxidizing agents include peroxy compounds such as hydrogen peroxide, organic hydroperoxides such as tert-butylhydroperoxide, aromatic or aliphatic percarboxylic acids such as m-chloroperoxybenzoic acid, peroxyacetic acid or permonophthalic acid, and the like. Heavy metal oxide compounds such as organic peracids, chromium-VI compounds or manganese-VI or manganese-VII compounds (e.g. chromium trioxide, chromic acid, manganese dioxide, potassium permanganate) or inorganic oxide oxy acids (e.g. nitrogen, halogens or chalcogens) oxyacids of n) or anhydrides or salts thereof (such as nitric acid, N ₂ O ₂ , selenium dioxide or sodium metaperiodate) and azone. Suitable solvents include halogenated hydrocarbons such as halogenoalkanes such as carbon tetrachloride, chloroform or methylene chloride or carboxylic acids such as alkanoic acids such as acetic acid or their anhydrides.

을 갖는 일반식(I)의 티오에테르를 클로로포름 등의 할로게노알칸중에서 필요한 경우 질소 원자

에서 m-클로로퍼벤조산 등의 유기과산으로 산화시킴으로써 n=1 또는 2인 상응하는 설피닐 또는 설포닐 화합물로 전환시킬 수 있다.In a preferred embodiment of the oxidation process, n is 0 and / or one of R ₁ and / or R ₂ is an unsaturated ring nitrogen atom

Thioether of formula (I) having a nitrogen atom when necessary in halogenoalkanes such as chloroform

By oxidation with an organic peracid, such as m-chloroperbenzoic acid, to a corresponding sulfinyl or sulfonyl compound with n = 1 or 2.

Alternatively, thioethers of general formula (I) with n = 0 are optionally oxidized by treatment with sodium metaperiodate in halogenoalkanes such as carbon tetrachloride or chloroform to the corresponding sulfoxides with n = 1. The sulfone with n = 2 can be obtained by conversion or by oxidizing this sulfoxide with hydrogen peroxide in acetic acid.

-O를

로 환원시킬 수 있다. 이 환원반응은 통상의 환원제, 예를 들어 철 또는 아연 및 산(예 : 염산)과 같은 발생기 또는 촉매적 활성화수소로 처리하거나, 라니니켈 존재하에, 바람직하게는 저급알칸올 같은 불활성 용매 내에서 수소로 처리하거나, 에테르류(예 : 디에틸에테르 또는 테트라하이드로푸란)와 같은 불활성용매 중에서 알칼리금속 알루미늄 하이드라이드 또는 알칼리금속보로하이드라이드(예 : 수소화붕소나트륨 또는 수소화알루미늄 리듐) 같은 경금속 하이드라이드 또는 디-경금속 하이드라이드로 처리하거나, 또는

-O기를 선택적으로 환원시키기 위해서는, 포스핀(예 : 트리페닐포스핀 또는 트리-n-부틸포스핀) 또는 아인산에스테르(예 : 트리메틸포스파이트 또는 트리에틸포스파이트 같은 트리-저급알킬포스파이트) 같은 포스포러스-III 화합물로 처리하는 것이 효과적이다.Conversely, in compounds of general formula (I) wherein n = 1 or 2 and / or heteroaryl groups R ₁ and / or R ₂ are N-oxidized, -S (O) -R ₄ or -S (O) ₂ -R ₄ groups are reduced to the corresponding S (O) ₀ -R ₄ groups and / or N-oxidized ring nitrogen

-O

Can be reduced. This reduction reaction is treated with conventional reducing agents such as iron or zinc and generators such as acids (e.g. hydrochloric acid) or catalytically activated hydrogen, or in the presence of Ranickel, preferably hydrogen in an inert solvent such as lower alkanols. Or light metal hydrides such as alkali metal aluminum hydrides or alkali metal borohydrides (e.g. sodium borohydride or aluminum hydride aluminum) in an inert solvent such as ethers (e.g. diethyl ether or tetrahydrofuran) or Treatment with di-light metal hydride, or

To selectively reduce -O groups, such as phosphines (e.g. triphenylphosphine or tri-n-butylphosphine) or phosphite esters (e.g. tri-lower alkylphosphites such as trimethylphosphite or triethylphosphite) Treatment with phosphorus-III compounds is effective.

Furthermore, if desired, additional C substituents can be introduced in the R ₁ and R ₂ groups and introduced as constituents of R ₄ in the aryl, aryloxy and arylthio groups. The halogenation reaction can be carried out using chlorine or bromine in the presence of iron or by conventional methods using N-chlorosuccinimide. Moreover, the alkylation reaction can be carried out by conventional methods such as reacting with alkyl halides, alkanols or alkenes in the presence of aluminum trichloride. The nitration reaction can also be carried out according to conventional methods using nitric acid / sulfuric acid.

The nitro group can be conventionally reduced to an amino group using generator hydrogen such as iron / hydrochloric acid.

Amino groups can be substituted according to conventional methods by alkylating with alkylating agents as mentioned above in the presence of a basic condensing agent.

The resulting free compound can be converted into an acid addition salt by reacting the free compound solution with a suitable solvent or solvent mixture with the above-mentioned acids or their solutions or with suitable anion exchange resins.

The resulting acid addition salt can be converted to the free compound by treatment with a base such as an alkali metal hydroxide, metal carbonate or metal bicarbonate or ammonia salt or by treatment with a suitable anion exchange resin.

The resulting acid addition salts can be converted to other acid addition salts by treatment with anion exchange resins or by treating the inorganic acid salts with acid metal salts (e.g. sodium, barium or mercury salts) in a suitable solvent, and the inorganic salts formed are insoluble Thus precipitates from the reaction mixture.

The compound or salt thereof can be obtained in the form of a hydrate and the solvent used for crystallization can be added.

Due to the close relationship between the free and salt forms of the novel compounds, the free compounds or salts thereof can be used accordingly from time to time.

The present invention uses a compound obtainable as an intermediate at any stage of the preparation as a starting material and proceeds with the remaining steps, or to obtain a starting material under reaction conditions or to obtain a starting material in the form of a derivative thereof (in the form of a salt if necessary). It is also about how to use.

Pharmaceutical formulations containing a compound of formula (I) or (II) or a pharmaceutically useful salt thereof may be administered orally or gall or parenterally or topically to warm-blooded animals, which are pharmacologically active Or in combination with a pharmaceutically useful carrier.

The dosage of active ingredient depends on the type, age, individual condition and dosage form of the warm-blooded animal. In normal cases, for example, it is preferable to administer a daily dose of 30 to 300 mg in several equal doses to a temperate animal of 75 kg in weight.

The pharmaceutical preparations contain 10 to 80%, preferably 20 to 60% of active ingredient. Pharmaceutical preparations for enteral and parenteral administration include epidermal tablets, tablets, capsules, suppositories, and ampoules. They are prepared according to known methods such as conventional mixing, granulation, coating, dissolving or lyophilization.

Thus, oral pharmaceuticals are prepared into tablets or coated tablets by mixing the active ingredient with a solid carrier, granulating the resulting mixture as necessary, and adding appropriate auxiliaries as necessary.

Suitable carriers, especially fillers, include sugars such as lactose, sucrose, mannitol, sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate; Binders include rice, wheat, corn, potato starch, gelatin, tragacanth, methylcellulose and / or starch paste such as polyvinylpyrrolidone; If necessary, disintegrants such as starch and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or salts thereof (eg sodium alginate) are also used. As auxiliaries, lubricants and lubricants such as silicic acid, talc, stearic acid or salts thereof (eg magnesium stearate or calcium stearate) and / or polyethylene glycols are used. The epidermal nucleus is coated with a suitable coating that is resistant to gastric juice, in particular sucrose solution, which comprises arabic gum, chalcopyrite, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, shellac in a suitable organic solvent or solvent mixture. Suitable coatings such as acetyl cellulose phthalate or hydroxypropylmethylcellulose phthalate are used for coatings that contain (She llac) and are resistant to gastric juice.

Dyestuffs or pigments may be added to the coatings of tablets or coatings to indicate or identify differences in active ingredient content.

Furthermore, pharmaceuticals used for oral administration include anhydrous-filled capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers (eg glycerol or sorbitol). Anhydrous-filled capsules may contain the active ingredient in the form of granules, for example in the form of granules mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate and a stabilizer if necessary and the like. . In soft capsules, it is preferable to dissolve or suspend the main component in fatty oil, paraffin oil, liquid polyethylene glycol or the like and to add a stabilizer.

Formulations for intraocular administration, such as suppositories, are prepared by mixing the active ingredient with the suppository base. Suitable suppository bases include natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols.

Gelatin rectal capsules in which the active ingredient is mixed with a substrate may also be used. As the substrate, liquid triglyceride, polyethylene glycol or paraffin hydrocarbon may be used.

Formulations for parenteral administration include, in particular, aqueous solutions containing the active ingredients in water-soluble form, ie in the form of water-soluble salts, and suspensions of the active ingredients (e.g., corresponding oily suspensions). Or synthetic fatty acid esters, such as ethyloleate or triglycerides. There are also aqueous injection suspensions containing stabilizers and substances which increase the viscosity (eg sodium carboxymethylcellulose, sorbitol and / or dextrin).

Topical preparations include creams, ointments, pastes, foaming agents, tinctures and solvents containing about 0.5 to 20% of the active ingredient.

Creams are water-in-oil emulsions containing more than 50% water. Emulsifying base materials include fatty alcohols such as lauryl alcohol, cetyl alcohol or stearyl alcohol or fatty acids such as palmitic or stearic acid, isopropyl myristate, liquid and solid waxes such as wool or beeswax and / or petroleum jelly hydrocarbons such as petrolatum or paraffin oil and the like. Suitable emulsifiers include hydrophilic surfactants, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof (e.g. polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens) and polyoxyethylene fatty acids). Alkalis of nonionic emulsifiers such as esters or fatty acid esters, or fatty acid alcohol sulfates such as sodium lauryl-sulfate, sodium cetyl-sulfate or sodium stearyl-sulfate, usually used in the presence of fatty alcohols such as cetyl alcohol or stearyl alcohol There is a corresponding ionic emulsifier, such as metal salts, as substances which can be added to the aqueous phase, in particular compounds which can reduce the extent to which the cream dries, such as glocerol, sorbitol, propylene glycol and / or polyethylene Same as glycol Silver, polyalcohol, preservatives, and pharmaceuticals.

Ointments are oil emulsions containing up to 70% water, preferably 20% to 50% water or aqueous phase. The oil phase consists of hydrocarbons such as petroleum jelly, paraffin oil, and / or light paraffin, and contains hydroxy compounds suitable for enhancing water binding, such as fatty alcohols such as cetyl alcohol, wool lead, and alcohols or their esters. It is preferable. Emulsifiers include the corresponding lipophilic substances, such as sorbitan fatty acid esters (eg sorbitan oleate and / or sorbitan isostearate). Substances which can be added to the aqueous phase include moisturizing agents such as glycerol, propylene glycol, sorbitol and / or polyethylene glycol, preservatives, and pharmaceuticals.

Oily ointments are anhydrous and are used as substrates, in particular hydrocarbons such as paraffin, petroleum jelly and / or liquid paraffin, natural and partially synthetic fats (such as palm fatty acid triglycerides) or preferably hydrogenated oils such as hydrogenated peanut oil or castor oil and Fatty acid partial esters of glycerol (such as glycerol mono- and di-stearate) and fatty alcohols and additives and / or emulsifiers to increase water absorption.

Pastes include creams and ointments that contain a secretion-absorbing powder that is capable of combining moisture or secretions, such as talc and / or aluminum silicates, with metal oxides such as titanium oxide or zinc oxide.

Foaming agents are liquid emulsified emulsions in the form of aerosols, which are administered as pressurized dispersers and contain halogenated hydrocarbons such as chlorofluorolower alkanes (e.g., dichlorodifluoromethane and dichlorotetrafluoroethane) as propellants.

Substances used in the oil phase include paraffin oil, fatty alcohols such as cetyl alcohol, fatty acid esters such as isopropyl myristate, and hydrocarbons such as other waxes. The emulsifier used consists of a mixture of hydrophilic compounds such as polyoxyethylene sorbitan fatty acid esters (Tween) and lipophilic compounds such as sorbitan fatty acid esters (Spans).

In addition, conventional additives such as preservatives and the like are used.

In most cases the tinctures and solvents contain an aqueous-ethanol base, to which the following substances can be added:

As a moisturizer to reduce evaporation, a polyalcohol such as glycerol, glycol and / or polyethylene glycol, a substitute for fatty acids removed from the skin by ethanol, a fat recovery material consisting of lower polyethylene glycols and fatty acid esters, ie lipophilic substances soluble in aqueous mixtures .

Topical pharmaceutical preparations are prepared by known methods for dissolving or suspending the active ingredient in a substrate or, if necessary, a portion of the substrate. If the active ingredient is in solution form it is usually dissolved in one of two phases before emulsification, if it is a suspension it is emulsified and then mixed with a portion of the substrate and added to the rest.

The present invention also refers to the use of compounds of formula (I) and (II) and salts thereof, ie for the treatment of inflammation, in particular for rheumatoid chronic inflammatory diseases such as chronic arthritis.

The following examples illustrate the invention without limiting the scope and the temperature represents ° C.

Example 1

0.8 g of sodium is dissolved in 200 ml of ethanol and 8 g of 2-mercapto-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole is added to this solution and the mixture is heated to reflux. After the clear solution was formed, a solution of 0.84 g of ethylene oxide dissolved in 30 ml of ethanol was added dropwise and the reaction mixture was heated under reflux for 16 hours. The solvent is evaporated in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride solution, dehydrated over sodium sulfate, evaporated and recrystallized with ethyl acetate / petroleum ether to give 2- (2-hydroxyethylthio) -5 (4) -phenyl-4 (5). -(3-pyridyl) -imidazole crystals are obtained (melting point: 128 to 130 ° C).

Starting materials are prepared as follows:

10.8 g of benzyl 3-pyridylketone is stirred at 100 ° C. for 6 hours with a solution of 40 ml of pyridine and 8 g of hydroxylamine hydrochloride in 15 ml of pyridine. The reaction mixture is poured into ice water and the resulting mixture is stirred for another 15 minutes. The precipitated crystals are suction filtered, washed with water and dried under high vacuum to yield benzyl 3-pyridyl ketone oxime (melting point 122-126 ° C.).

A solution of 7.7 g of p-toluenesulfonyl chloride in 15 ml of pyridine was added dropwise to the solution of 8.5 g of benzyl 3-pyridyl ketone oxime in 20 ml of pyridine with stirring at −10 ° C. for 5 minutes. The reaction mixture is placed in the refrigerator for 24 hours and then poured into ice water. After stirring and grinding, the separated oil solidifies into crystals. It was suction filtered, washed with water and dried under high vacuum to yield benzyl 3-pyridylketone oxime p-toluenesulfonate which was used for the next step without further purification.

11.6 g of crude benzyl 3-pyridyl ketone oxime p-toluene sulfonate is suspended in 90 ml of anhydrous ethanol. A solution of 3.7 g of sodium tert-butylate in 30 ml of anhydrous ethanol was added dropwise while stirring at 0 ° C. The reaction mixture is stirred at 0 ° C. for 2 hours, the suspension is filtered off with suction and the filtrate containing the desired α-amino-benzyl-3-pyridylketone is immediately reacted in the next step.

3.6 g of sodium thiocyanate is dissolved in 60 ml of ethanol and 4.5 ml of concentrated hydrochloric acid is added to the solution. This suspension is suction filtered and the filtrate is heated with an alcoholic solution of α-amino-benzyl 3-pyridineketone under limiting for 18 hours. After cooling, the crude 2-mercapto-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole is suction filtered from the reaction mixture. The crude product contained in the filtrate is recrystallized from dimethylformamide / water (melting point 290-300 ° C.).

Example 2

25 g of ethylene is passed through a solution dissolved in 90 ml of 4-phenyl-5- (3-pyridyl) -imidazolin-2-one 10 g dimethylformamide and 5 ml of diisopropylamine over 75 minutes. One half of the solvent is distilled under vacuum and the reaction mixture is poured onto ice and stirred until settled (3 hours). The crystalline precipitate is filtered and recrystallized with ether / petroleum ether to give 2-ethylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole (melting point: 195-198 ° C.). .

Example 3

The following compounds can also be prepared by methods analogous to those described in Examples 1-2. 2- (2-hydroxyethylthio) -1-methyl-4-phenyl-5- (3-pyridyl) -imidazole, 2- (2-hydroxyethylthio) -1-methyl-5-phenyl- 4- (3-pyridyl) -imidazole, 2- (2-methoxyethylthio) -4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole (melting point: 118 to 120 ° C), 2- (2-methoxyethylthio) -1-methyl-4-phenyl-4- (3-pyridyl) -imidazole, 2- (2-methoxyethylthio) -1-methyl-5 -Phenyl-5- (3-pyridyl) -imidazole, 2- (2-methylthioethylthio) -4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole, 1- Methyl-2- (2-methylthioethylthio) -4-phenyl-5- (3-pyridyl) -imidazole (melting point: 164 ° C to 168 ° C), 1-methyl2- (2-methylthioethylthio ) -5-phenyl-4- (3-pyridyl) -imidazole, 2-propylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole (melting point: 143 to 144) ° C), 2-propylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole and 2-ethylthio-4,5-bis- (2-thienyl) -imidazole (Melting point: 209 ° to 210 ° C.).

Example 4

A solution of 6.3 g of 85% m-chloroperbenzoic acid dissolved in 70 ml of chloroform, and 8 g of 2-methylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole in 400 ml of chloroform. It is added dropwise while stirring. The resulting solution is left overnight, washed with sodium bicarbonate solution and water, dehydrated over sodium sulfate and evaporated to dryness. The residue is recrystallized twice with isopropanol / petroleum ether to give 2-methanesulfinyl-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole (melting point: 166-169 ° C.).

2-ethanesulfinyl-4 (5) -phenyl-5 in a similar manner using 2-ethylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole as starting material 4)-(3-pyridyl) -imidazole (melting point: 162 to 164 ° C.) is obtained.

Example 5

8 ml of acetic acid and 0.38 ml of 30% hydrogen peroxide are added to 1.0 g of 2-ethanesulfinyl-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole and the mixture is stirred overnight at 70 ° C. Cool, neutralize with sodium hydroxide solution, and then filter by suction with 2-ethanesulfonyl-4 (5) -phenyl-5 (4)-[3- (1-oxidopyridinio)]-imidazole (melting point: 208 to 210 ° C.).

Example 6

The following compounds can also be prepared by methods similar to those described in Examples 1-5. 2-ethylthio-4 (5)-(p-fluorophenyl) -5 (4)-(2-thienyl) -imidazole (melting point: 160 ° to 1 63 ° C.) and 2-propylthio-4 ( 5)-(p-fluorophenyl) -5 (4)-(2-thienyl) -imidazole.

Example 7

Tablets containing 25 mg of the active ingredient, such as 2-methylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole, are prepared as follows.

Composition (1000 tablets)

Manufacturing method

The solid components are first passed through a 0.6 mm human body. Half of the active ingredient, lactose, boehmite, magnesium stearate and starch are mixed. Half of the remaining starch is suspended in 40 ml of water and the suspension is added to a solution which has been dissolved in 100 ml of water with polyethylene glycol. The resulting starch paste is added to the population of ingredients and the mixture is granulated (water is added if necessary). The granules are dried overnight at 35 ° C. and passed through a 1.2 mm human body with a mesh width and compressed into stagnant bodies (both concave and 6 mm in diameter).

Tablets containing 25 mg of a compound, which is one of the other compounds of the general formula (1) named in Examples 1-6, can be prepared by a similar method.

Example 8

A slow acting tablet containing 30 mg of the active ingredient such as 2-methylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazoline can be prepared as follows.

Composition (1000 tablets)

All solid components are first passed through a 0.25 mm mesh body. Mannitol and lactose are mixed and granulated under the addition of gelatin solution. The two granules are passed through a 2 mm mesh body, dried at 50 ° C., and then passed through a 1.7 mm mesh body again.

Carefully mix the active ingredient, glycine and saccharin, add mannitol, lactose granules, stearic acid and talc, mix thoroughly and compress into tablets approximately 10 mm in diameter with concave sides and cutting grooves on top.

In each case, a low-acting tablet containing 30 mg of one of the other compounds of formula (i) shown in Examples 1 to 6 can also be prepared in a similar manner.

Example 9

Tablets containing 100 mg of active ingredient, for example 2-methylthio-4 (5) -phenyl-5 (4)-(3-pyridyl) -imidazole, are prepared as follows.

Composition (for 1,000 tablets)

Produce

The solid components are first passed through a 0.6 mm mesh body. Mix half the active ingredient, lactose, talc, magnesium stearate and starch immediately. Half of the other starch is suspended in 65 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the powdery substance, mixed in its entirety and granulated by addition of water if necessary. The granules are dried overnight at 35 ° C. and passed through a 1.2 mm mesh sieve and then compressed into tablets of about 10 mm in diameter with concave sides and cutting grooves in the upper layer.

Tablets containing 100 mg of the other compound of general formula (I) according to Examples 1 to 6 can also be prepared by a similar method.

Example 10

In a manner similar to that described in Examples 1-6, 2-ethane sulfinyl-4 (5)-(4-fluorophenyl) -5 (4)-(2-thienyl) -imidazole (melting point: 143) ° to 145 ° C.), 2-ethanesulfonyl-4 (5)-(4-fluorophenyl) -5 (4)-(2thienylimidazole (melting point: 180 ° to 182 ° C.), 2-ethane Sulfonyl-4 (5) -phenyl-5 (4)-(3-pyridyl) imidazole (melting point: 190 ° to 192 ° C.) and 2- (2-ethoxyethylthio) -4 (5) -phenyl -5 (4)-(3-pyridyl) -imidazole (melting point 100 ° to 102 ° C.) can be prepared.

Claims (1)

A method for preparing a mercaptoimidazole derivative of the following general formula (I) by reacting a compound of the following general formula (II) with an epoxy-lower alkane or a lower alkene (substituted or unsubstituted).

In the above general formula At least one of R ₁ and R ₂ is an unsubstituted or substituted heteroaryl group and the other is an unsubstituted or substituted aryl group R ₃ is hydrogen or lower alkyl, n is 0, 1 or 2 R ₄ is an unsubstituted or substituted lower alkyl group of 2 or more carbon atoms X is mercapto, which may exist in the form of a salt.