CA1181751A - Process of production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds - Google Patents
Process of production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compoundsInfo
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- CA1181751A CA1181751A CA000396501A CA396501A CA1181751A CA 1181751 A CA1181751 A CA 1181751A CA 000396501 A CA000396501 A CA 000396501A CA 396501 A CA396501 A CA 396501A CA 1181751 A CA1181751 A CA 1181751A
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Abstract
ABSTRACT
A process of producing novel 3,5-di-tert-butyl-4-hydroxy-phenyl-substituted heterocyclic compounds shown by the formula and the salts thereof.
The compounds of this invention have an anti-inflammatory, an anti-pyretic, analgestic, an antiarthritic, and an immuno regula-tory activity. Hence they are particularly useful as an anti-rheumatic.
A process of producing novel 3,5-di-tert-butyl-4-hydroxy-phenyl-substituted heterocyclic compounds shown by the formula and the salts thereof.
The compounds of this invention have an anti-inflammatory, an anti-pyretic, analgestic, an antiarthritic, and an immuno regula-tory activity. Hence they are particularly useful as an anti-rheumatic.
Description
s~
This invention ~elates to a process oE produciny novel 3,5 c1i--tert-butyl-4-hydroxy-phenyl-substituted heterocyclic compounds.
More particularly, the invention relates to a process for producing the 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic com-pounds shown by formula I and their salt;
R3 ~ N~ ~ R2 R4 - S ~ ~ R
(O) m wherein one of Rl - R4 represents 3,5~di-tert-butyl-4-hydroxyphenyl group) and others represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, a lower alkoxy-substituted aryl group, a lower alkanoyl group, a lower al~ylthio group, a low~r alkoxy group, a lower aralkyl group, a cyano group, or thiocyanato group; m re-presents 0, 1, or 2; and the dotted line means the presence or absence of a double bond.
The terminology throughouk the specification and the claims of this invention is as follows:
The term "lower" means a straight or branched carbon chain of 1-6 carbon atoms. Therefore, ~or example "lower alkyl group"
includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, heptyl group, hexyl group, etc.; "lower aralkyl group" includes benzyl group, phenethyl group, etc.; "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group~ hexyloxy group, etc.; "lower alkylthio group" includes methylthio qroup, ethylthio group, propylthio group, isopropylthio group, etc.; and "lower al~anoyl group" include~ ~ormyl group, acetyl group~ propionyl qroup~
~L81~'7~
isopropionyl group, bu-tyryl group, hexanoyl group, etc. ~lso, the term "amino" in "amino lower alkyl group" means not only amino group but also mono- or di-alkylamino group such as methylamino ~roup, dimethylamino group, diethylamino ~roup~ etc., and cyclic amino group such as morpholino group, pyrrolidino group, piperidino group, piperaæino group, 4-lower alkylpipera~ino group, etc.
~u~thermore, the term "aryl group" includes phenyl group, naphthyl group, etc., and the term "halogen atom" includes chlorine atom~
bromine atom~ iodine atom, fluorine atom, etc.
Then, as the salts o~ the compounds o~ this invention shown by formula I, there are pharmaceutically acceptable acid addition salts, for example, acid addition salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nltric acid, phosphoxic acid, etc.
The compounds of this invention shown by formula I have an anti-in~lammatory, an anti-pyretic, an antiarthritic, and an immuno regulatory activity. EIence they are novel compounds particularly useful as an antirheumatic.
That is, since the compounds of this invention shown by ~ormula I show a therapeutic and prophylactic effect on adjuvant-induced arthritis which is considered to be an animal model of human rheu-matisim and further have analgesic and anti-inflammatory activities as well as a prostagrandins formation inhibiting activity as a bio-chemical activity, the compounds of this invention are considered to be useful for the therapeutic and prophylaxis of human rheumatic disease. Moreover, the compounds of this invention shown by formula I suppress remarkably Coomb's type III (Arthus reaction) and type IV
(delayed type hypersensitivity) allergic reactions as well as have a lipoxygenase s~ppressing activity, and a property as a radical scavenyer, which have never been attainecl by conventional non-.
, ~ . .
7~i~
steroidal acidic anti-inflammatory ant:irheumatic5 represented by in-domethacin and diclofenac. Therefore, the compounds o~ this inven-tion are particularly expected as an-tirheumatics having new activi-ty mechanism.
The 1st feature o~ the chemical structure o~ th~ compound o-f this invention shown by ~ormula I is that the compounds belong to a nonsteroidal nonacidic anti-inflammatory agent and are dif~erent ~rom conventional nonsteroidal acidic anti-in~lammatory agents such as indomethacin and diclofenac. The 2nd ~eature is in the point that the heterocyclic ring o~ the heterocyclic compound is directly sub-stituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group. The 3rd ~ea-ture is in the point that the substituted heterocyclic ring itsel~
is a speci~ic heterocyclic ring. Practically, the h~terocyclic ring in the heterocyclic compound o~ this invention is i.a., a (2,3-dihydro)imidazo[2.1-b]thiazole ring.
As heterocycli.c compounds the heterocyclic ring o~ which is directly substituted by a 3,5 di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-~3,5-di-tert-butyl-4-hydroxyphenyl)-benzoxazole compounds and 2-(3,5-di-tert-butyl-~-hydroxyphenyl)-benzothiazole compounds (West German O-fenlegungsshrift 2,008,41~),
This invention ~elates to a process oE produciny novel 3,5 c1i--tert-butyl-4-hydroxy-phenyl-substituted heterocyclic compounds.
More particularly, the invention relates to a process for producing the 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic com-pounds shown by formula I and their salt;
R3 ~ N~ ~ R2 R4 - S ~ ~ R
(O) m wherein one of Rl - R4 represents 3,5~di-tert-butyl-4-hydroxyphenyl group) and others represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, a lower alkoxy-substituted aryl group, a lower alkanoyl group, a lower al~ylthio group, a low~r alkoxy group, a lower aralkyl group, a cyano group, or thiocyanato group; m re-presents 0, 1, or 2; and the dotted line means the presence or absence of a double bond.
The terminology throughouk the specification and the claims of this invention is as follows:
The term "lower" means a straight or branched carbon chain of 1-6 carbon atoms. Therefore, ~or example "lower alkyl group"
includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, heptyl group, hexyl group, etc.; "lower aralkyl group" includes benzyl group, phenethyl group, etc.; "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group~ hexyloxy group, etc.; "lower alkylthio group" includes methylthio qroup, ethylthio group, propylthio group, isopropylthio group, etc.; and "lower al~anoyl group" include~ ~ormyl group, acetyl group~ propionyl qroup~
~L81~'7~
isopropionyl group, bu-tyryl group, hexanoyl group, etc. ~lso, the term "amino" in "amino lower alkyl group" means not only amino group but also mono- or di-alkylamino group such as methylamino ~roup, dimethylamino group, diethylamino ~roup~ etc., and cyclic amino group such as morpholino group, pyrrolidino group, piperidino group, piperaæino group, 4-lower alkylpipera~ino group, etc.
~u~thermore, the term "aryl group" includes phenyl group, naphthyl group, etc., and the term "halogen atom" includes chlorine atom~
bromine atom~ iodine atom, fluorine atom, etc.
Then, as the salts o~ the compounds o~ this invention shown by formula I, there are pharmaceutically acceptable acid addition salts, for example, acid addition salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nltric acid, phosphoxic acid, etc.
The compounds of this invention shown by formula I have an anti-in~lammatory, an anti-pyretic, an antiarthritic, and an immuno regulatory activity. EIence they are novel compounds particularly useful as an antirheumatic.
That is, since the compounds of this invention shown by ~ormula I show a therapeutic and prophylactic effect on adjuvant-induced arthritis which is considered to be an animal model of human rheu-matisim and further have analgesic and anti-inflammatory activities as well as a prostagrandins formation inhibiting activity as a bio-chemical activity, the compounds of this invention are considered to be useful for the therapeutic and prophylaxis of human rheumatic disease. Moreover, the compounds of this invention shown by formula I suppress remarkably Coomb's type III (Arthus reaction) and type IV
(delayed type hypersensitivity) allergic reactions as well as have a lipoxygenase s~ppressing activity, and a property as a radical scavenyer, which have never been attainecl by conventional non-.
, ~ . .
7~i~
steroidal acidic anti-inflammatory ant:irheumatic5 represented by in-domethacin and diclofenac. Therefore, the compounds o~ this inven-tion are particularly expected as an-tirheumatics having new activi-ty mechanism.
The 1st feature o~ the chemical structure o~ th~ compound o-f this invention shown by ~ormula I is that the compounds belong to a nonsteroidal nonacidic anti-inflammatory agent and are dif~erent ~rom conventional nonsteroidal acidic anti-in~lammatory agents such as indomethacin and diclofenac. The 2nd ~eature is in the point that the heterocyclic ring o~ the heterocyclic compound is directly sub-stituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group. The 3rd ~ea-ture is in the point that the substituted heterocyclic ring itsel~
is a speci~ic heterocyclic ring. Practically, the h~terocyclic ring in the heterocyclic compound o~ this invention is i.a., a (2,3-dihydro)imidazo[2.1-b]thiazole ring.
As heterocycli.c compounds the heterocyclic ring o~ which is directly substituted by a 3,5 di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-~3,5-di-tert-butyl-4-hydroxyphenyl)-benzoxazole compounds and 2-(3,5-di-tert-butyl-~-hydroxyphenyl)-benzothiazole compounds (West German O-fenlegungsshrift 2,008,41~),
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-diphenylimidazolidine compounds (Belgian Pat. No. 807,140); and 2-[2-(3.5-di-tert-butyl-4-hydroxyphenyl)-5-ethoxy-4-thiazolyl]acetic acid (Japanese Pat.
Appln. Laid Ooen ~o. 7669/'78). The benzoxazole compounds and the benzothiazole compounds are used as an antioxidant and the imida-zolidine compounds are usad as intermediates ~or plant protecting agents and dyes. The last acetic acid compound is suggested -to be used as an anti-thrombotic agent, a hypolipaemic agent, and an anti-in~lammatory agent. About the acetic acid compound, the usa as an anti-inflammatory agent i9 ~ugge~ted a9 describad above but there is no disclo~ure about the practical pharmacolocJical e~ect of the compound ~L8~
as an antl-inflammatory acJent and also the chemlcal structure o~ the acetic acid compound is a he-terocyclic ring-substituted acetic acid derivative, which belongs to a nonsteroidal acidic anti-inflammatory agent and hence differs from the compounds of this invention shown by formula I in chemical structure.
The particularly preferred compounds in the Eoregoing heterocyclic compounds (I) are as ollows:
6-(3,5-di--tert-butyl-4-hydroxyphenyl)5-methyl-2,3-dihydroimidazo[2,1-b]-thiazole, 6-(3,5-di-tert-butyl-~-hydrox~,~phenyl)-2,3-dihydroimidazo [2,1-b]thiazole l-oxide, 6-~3,5-di-tert-butyl-4-hydxoxyphenyl)-2,3-dihydroimidazo [2,1-bJthiazole 1,1-dioxide, and 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b]thiazole.
The compounds of -this invention shown by formula I can be prepared by the following methods:
i). First production method R -CH-X ~ ~ 1 3 IV V Ia wherein Rl, R2, R3, R4 and the dotted line have the same significance as defined above. X is a halogen atom.
The compound shown by formula I2 can be also prepared by reacting the a~-halocarhonyl compound shown by formula IV and the 2-mercaptoimidazole derivati~e shown by formul~ V or a salt thereof, e.g., an alkali me-tal salt -thereof. The reaction is performed by reacting the compound of formula IV with the '7~
correspondin~ amoun-t of -the compouncl o:E formula V or an alkali metal salt -thereof in situ or in a proper solvent such as methanol, ethanol, toluene, dimethylEormamide, acetone, chloroform, methyl e-thyl ke-tone, ethyl acetate, 4(a) * *
methyl cellosolve, ethyl cellosolve, digryme, ace-tonitri.le, etc. The reac-tion usually proceeds at room tempera-ture bu-t may be performed under heatinq. The reaction time is properly determined according to the kinds of the solvent and the starting materials used. When the compound o:E formula V i5 used as it is, ie., not as an alkali metal sal-t thereof, it i5 preferred that the compound is previously reacted with an alkali metal alcoholate to form a corresponding alkali metal salt and then the alkali metaL salt is reacted with the compound of formula IV.
This reaction is considered to proceed via an intermediate shown by formula VI
R3- T = H~ ~ 2 R4-CH-S N Rl wherein Rl, R2, R~, R4 have the same significance as defined above, and, if necessary, the intermediate can be isolated.
The intermediate of formula VI can be converted into the compound of formu:La Ia by the treatment with an acid such as hydrochloric acid, acetic acid, etc., or phosphorus oxychloride.
~0 In addition, by using the dihalogenoethane derivati.ve shown by formula IV
Appln. Laid Ooen ~o. 7669/'78). The benzoxazole compounds and the benzothiazole compounds are used as an antioxidant and the imida-zolidine compounds are usad as intermediates ~or plant protecting agents and dyes. The last acetic acid compound is suggested -to be used as an anti-thrombotic agent, a hypolipaemic agent, and an anti-in~lammatory agent. About the acetic acid compound, the usa as an anti-inflammatory agent i9 ~ugge~ted a9 describad above but there is no disclo~ure about the practical pharmacolocJical e~ect of the compound ~L8~
as an antl-inflammatory acJent and also the chemlcal structure o~ the acetic acid compound is a he-terocyclic ring-substituted acetic acid derivative, which belongs to a nonsteroidal acidic anti-inflammatory agent and hence differs from the compounds of this invention shown by formula I in chemical structure.
The particularly preferred compounds in the Eoregoing heterocyclic compounds (I) are as ollows:
6-(3,5-di--tert-butyl-4-hydroxyphenyl)5-methyl-2,3-dihydroimidazo[2,1-b]-thiazole, 6-(3,5-di-tert-butyl-~-hydrox~,~phenyl)-2,3-dihydroimidazo [2,1-b]thiazole l-oxide, 6-~3,5-di-tert-butyl-4-hydxoxyphenyl)-2,3-dihydroimidazo [2,1-bJthiazole 1,1-dioxide, and 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b]thiazole.
The compounds of -this invention shown by formula I can be prepared by the following methods:
i). First production method R -CH-X ~ ~ 1 3 IV V Ia wherein Rl, R2, R3, R4 and the dotted line have the same significance as defined above. X is a halogen atom.
The compound shown by formula I2 can be also prepared by reacting the a~-halocarhonyl compound shown by formula IV and the 2-mercaptoimidazole derivati~e shown by formul~ V or a salt thereof, e.g., an alkali me-tal salt -thereof. The reaction is performed by reacting the compound of formula IV with the '7~
correspondin~ amoun-t of -the compouncl o:E formula V or an alkali metal salt -thereof in situ or in a proper solvent such as methanol, ethanol, toluene, dimethylEormamide, acetone, chloroform, methyl e-thyl ke-tone, ethyl acetate, 4(a) * *
methyl cellosolve, ethyl cellosolve, digryme, ace-tonitri.le, etc. The reac-tion usually proceeds at room tempera-ture bu-t may be performed under heatinq. The reaction time is properly determined according to the kinds of the solvent and the starting materials used. When the compound o:E formula V i5 used as it is, ie., not as an alkali metal sal-t thereof, it i5 preferred that the compound is previously reacted with an alkali metal alcoholate to form a corresponding alkali metal salt and then the alkali metaL salt is reacted with the compound of formula IV.
This reaction is considered to proceed via an intermediate shown by formula VI
R3- T = H~ ~ 2 R4-CH-S N Rl wherein Rl, R2, R~, R4 have the same significance as defined above, and, if necessary, the intermediate can be isolated.
The intermediate of formula VI can be converted into the compound of formu:La Ia by the treatment with an acid such as hydrochloric acid, acetic acid, etc., or phosphorus oxychloride.
~0 In addition, by using the dihalogenoethane derivati.ve shown by formula IV
3 ~ IVa
4 ~ X
wherein R3, R4 and X have the same significance as defined above, in place of the o~-halocarbonyl compound used in the starting material in the producti.on method, the compound of formula Ia can be prepared.
~!
ii ) . Second produc-tion m~ thod:
3 ~ X-fEI-R2 ~ 3~¢R2 R4 S NH2 O=C -R R~ S N R
II III Ia
wherein R3, R4 and X have the same significance as defined above, in place of the o~-halocarbonyl compound used in the starting material in the producti.on method, the compound of formula Ia can be prepared.
~!
ii ) . Second produc-tion m~ thod:
3 ~ X-fEI-R2 ~ 3~¢R2 R4 S NH2 O=C -R R~ S N R
II III Ia
5 (a) wherein X, Rl, R2, R3, R~ ancl the dotted line have the same signif.icance as defined above.
The compound (I) of this invention wherein m is O, ie., the compound shown by formula I can be prepared by reacting 2-aminothiazoline derivative or 2-am.inothiazole derivative shown by formula II and the ~ halocarbonyl compound shown by formula III. The reaction is performed by heating the compound of formula II and the corresponding amount of the compound of formula III in situ or in a proper solven-t such as methanol, ethanol, toluene, dimethylformamide, acetone, chloroform, methyl ethyl ketone, ethyl acetate, methyl cellosolve*, ethyl cellosolve*,.digrim, acetonitrile, etc. The xeaction temperature and the reaction period of -time are properly selected according to the kinds of the solvent and the starting materials used but the reaction is advantageously performed under refluxing.
iii). Other production method:
/
l~ *tradt-3 m~rk 6 L'i'53L
~L~
4 2 (1) oxidation 4 (O)m Ia Ia-l ~ ~ (2) aminomethyl 3 ~ CH N ~ 5 R S N R R S N R
4 (,O)m L 4 (O)m \ (3) 1 ~ anoylation \ \ lower \ \ R3 ~ ~ alkanoyl \(4) formylation ( 7) th ocyanation \R3 CHO
. ~ ~ ~ re~uckion - \(O)m
The compound (I) of this invention wherein m is O, ie., the compound shown by formula I can be prepared by reacting 2-aminothiazoline derivative or 2-am.inothiazole derivative shown by formula II and the ~ halocarbonyl compound shown by formula III. The reaction is performed by heating the compound of formula II and the corresponding amount of the compound of formula III in situ or in a proper solven-t such as methanol, ethanol, toluene, dimethylformamide, acetone, chloroform, methyl ethyl ketone, ethyl acetate, methyl cellosolve*, ethyl cellosolve*,.digrim, acetonitrile, etc. The xeaction temperature and the reaction period of -time are properly selected according to the kinds of the solvent and the starting materials used but the reaction is advantageously performed under refluxing.
iii). Other production method:
/
l~ *tradt-3 m~rk 6 L'i'53L
~L~
4 2 (1) oxidation 4 (O)m Ia Ia-l ~ ~ (2) aminomethyl 3 ~ CH N ~ 5 R S N R R S N R
4 (,O)m L 4 (O)m \ (3) 1 ~ anoylation \ \ lower \ \ R3 ~ ~ alkanoyl \(4) formylation ( 7) th ocyanation \R3 CHO
. ~ ~ ~ re~uckion - \(O)m
(6) cyanation~
I Ia-6 a-5 R3 ~ ~ S N R ~ CN
(O)m \ (O)m Ia-8 \ Ia-7 (8) lo~ alkylation S-lower alkyl R~ ~ U~
R~ S N R
(O)m Ia 9 . 7 17~:~
wherein m' represen-ts 1 or 2; R5 and R6 each represents a hydroyen atom, a lower alkyl group, or they may combine wi-th each other to form a cyclic amlno group, and Rl, R , R3, R4, m, and the dotted line have the same significance as defined above.
The oxidation method (I) is a method of producing the compound of this invention shown by formula I wherein m is 1 or 2, ie., the S-oxide compound shown by formula I 1 The S-oxide compound can be prepared by reacting the corresponding thio compound of fore-going formula I wit ~n oxidizing agent in a solvent such as chloro-form, 1,2-dimethoxyethane, acetic acid, etc., according to a con-ventional method. As the oxidizing agent, 10-~/o hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc., is usually used.
In this case, by properly selecting the reaction conditions such as the reaction period of time, the reaction temperature, the amount of the oxidizing agent, etc., the desired mono-oxide compound (m' =
1) or dioxide compound (m' = 2) can be obtained.
The aminomethylation method (2) is a mthod of producing the compound of this invention shown by formula wherein R2 is an amino-methyl group, ie.~ the aminomethyl compound shown by formula I 3.
The aminomethylation is performed by reacting the compound shown by formula I wherein R2 is a hydrogen atom, ie., the compound shown by ~ R5 formula I 2with formaldehyde and the amine shown by ~ ~ ac-cording to a Mannich reaction. ,~
/~ -, /
/
''~
ji~
, ,, ~3 l'7~
The lower alkanoylation mathod (3) is a mathod of producing the compound of this inVQntion shown by ormula I wherein R2 is a lower alkanoyl group, i.e., the lower alkanoyl compound shown by formula I 4. The lower alkanoyl compound can be prepared by reacting the compoun~ shown by formula I 2 with a lowar alXanoyl halide such as acetyl chloride, etc., and an acid anhydride such as acetic anhydride, etc., according to a conventional method.
In addition, the lower alkanoyl compound shown by formula I 4 wherein the lower alkanoyl group i5 a formyl group, i.e., the formyl compound shown by formula I 5 can be also prepared by reac-ting the compound shown by formula I 2 by an ordinary manner with a complex (Vilsmeier reagent) of dimethylformamide (D~') and phos-phorus oxychloride or oxalyl chloride and then hydrolyzing the reac-tion product. This method is the foregoing formylation method (4).
The reduction method (5) is a method of producing the compound o this invention shown by formula I wherein R2 is a hydroxymethyl group, i.e., the hydroxymethyl compound shown by formula I 6 The hydroxymethyl compound can be produced by reducing the fore-going formyl compound of formula I 5 with a reducing agent such as sodium borohydride.
The cyanation method (6) is a method of producing the compound of this invention shown by formula I wherein R2 is a cyano group, i.e., the nitrile cornpound shown by formula I 7. The nitrile compound can be procluced by reacting the compound shown by formula I 2 with a Vilsmeire reagent as in the foregoing formylation method (4) according to a conventional method and then reacting the reaction product with hydroxyamina.
The thiocyanation method (7) is a metho~ of producing the compound of thi~ invention shown by formula I wherein R2 is a thiocyanate (-SCM) group, i.e., the thiocyanate compouncl shown , ~
by formula I 8. The thiocyanate compound can be produced by reacting the compound shown by formula I 2 with a -thiocyanate such as sodium thiocyanate, etc., and bromine.
The lower alkylation method (8) is a method of producing the compound of this invention shown by formula I whe~ein R2 is a lower alkylthio group, 1~ e., the lower alkylthio compound shown by formula I 9. ~he lower alkylthio compound can be produced by reacting the thiocyanate compound shown by formula I ~ with a lower alkylating agent according to a conventional method. As the lower alkylating agent, a lower alkyl halide such as methyl iodide, ethyl iodide, etc., is used.
The compound of this invention shown by formula I thus pro-duced is isolated and purified by a conventional chemical oper-ation such as concentration, recrystallization, column chromato-graphy, etc.
Typical methods of producing the compounds of this inventionshown by formula I were explained above and the compounds of this invention and the melhods of producing them will be Eurther ex-plained more practically and in more detail by the following examples.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this invention shown by formula I will then be described.
Effect on adjuvant~incluced arthrites in rats:
Methods: Male Sprangue Dawley rat aged 7 weeks were used.
Drugs were evaluated by two methods as follows. All tes-t drugs were suspended in water with 0~5% methylcellulose (0.5% MC) and administered orally once a day.
(l) Therapeutic effect of drugs; arthritis was induced by a sinyle injection of 0.1 ml of st.erile suspension of M~co cterlum t~icum (6my/ml) in li~uid para-ffLn into tail skin of ra-ts 5~
(day 0). After about 2 weeks, arthrit.ic rat~ wexe selectecl ancl allocated into groups. Drugs wexe given daily following about 10 days. Thi.ckrless of the foot was measured with dial thickness gauge both on the day of initial dosing and on the next day of final dosing, change of foot thickne6s (~FT 10 mm) was calcu-lated as a di~ference between these two values. The results are shown in Table I.
Table I (Therapeutic effect) Drugs Dose ~ Day 16-Da~ 28 (mg/kg/day) ~FT (X10 mm) P . O . ) ~ - :. __ __.________ r -- . : . .. _ 0.5% MC - 3 210 ~ 91 Indomethacin 2 3 -177 + 41**
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydroimidazo (2~1-b)-thiazole 25 3 -16 + 27*
6-(3,5-di-tert-bu-tyl-4-hydroxyphenyl)-2,3--dihydro-imida7.0 (2,1-b) thiazole 1-20 oxide 25 3 -245 + 57**
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo (2,1-b) thiazole 1,1 dioxide 25 3 -141 + 60**
Drugs Dose~ay 17-~ay 27 (mg~kg/day N ~T
P.O.) (10 mm) _ _ _ 0.5% Mc - 3181~ 7 Indomethacin 2 3-225 -~ 61**
Diclofenac HCI 2 3 -83 ~ 49*
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-lmidazo ~2,1-b) thiazole 25 3 -177 -~ 36***
Significant diEference rom con-trol (t-test) * P~0.05 **P ~ .01 *** P<0.001 From the above results, it is apparent that the compounds ; of this invention have excellent pharmacological (therapeutic) effects against the adjuvant-induced arthrites.
Example 1 ._ (C~l ) C HS N ~ (CH C~
In 20 ml of ethanol was dissolved 0.11 g of metallic sodium and after adding lg of 4,5-diphenyl-2-mercaptoimidazole to the solution followed by stirring several minutes, lg~lof 3,5-di-tert-butylphenacyl bromide was added there-to followed by s-tir-ring for one hour at room tempera-ture. The reaction mixture was concentrated under reduced pressure and -then wa-ter was added 0 to l2 the residue. rl~he crystal.s Lhus ~ornlccl wer~ recoverecli~y f:iL~-:c,-tion, dried, tllssolvecl in 20ml of phospllorus oxychloride, and the solution was refluxed Eor 14 hours. The reactiOn mixture was concentrated under reduced pressure and after adding water to the residue followed by neutralization with potassium carbonate, the product was extracted wi.th chloroform. The extrac~ was dried and concen-trated. The residue was subjected to si].ica gel column ~hromatography and the product was eluted with chloroform. The crude crystals -thus obtained were recrystallized from ethanol -to provide 0.8 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenyl-imidazo [2,1-b] thiazole.
Melting point: 237-238C
Elemental analysis for C31H32N2 OS:
C(%) H(%) N(%) S(%) 15 Calculated: 77.47 6.57 5.70 6.48 Found: 77.46 6.71 5.83 6.67 Example 2 20 (CH3)3c ~ 3 ~ OCH
HO ~ C-CH2Br + N ~ > Ho4 ~ ___N ~
(CH3)3c Y HS ~ N ~ ~ OCH3( ~ C ~ N ~ OCH3 By following the same procedure as in Example 1, 3-(3J5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-me-thoxyphenyl)-imidazo[2Jl-b] thiazole was produced.
Melting point: 236-237C
El.emental analy.sis ~or'C33 1~3~ N2 S3 s 13 75~
C(%~ H(%) M(%) S(%) Calculated: 72.92 6.53 5.32 6.42 Found: 73.30 6.71 5.18 5.93 Example 3 (C~3)3~ ~ ~ C(C~3)3 (CH ) 3 3 C(CH3)3 In 10 ml of chloroform wa.s dissolved 1.6 g of 6-(3,5-di-tert-15 butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole and after adding thereto 1 g of m-chloroperbenzoic acid, the mixture was stirred for 10 minutes. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent was distilled off. The cry~tals thus formed were re-20 crystallized from ethanol to provide 1~3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole l-oxide as the 1/2 ethanol addition product.
Melting point: 211-212C
Mass spectrum: m/e: 346(M~) Elemental 3nalysis for Clg H26 N2 2 S 1/2C2 H5 OH
C(%) ~(%) N(%) Calculated: 65.11 7.78 7.82 Found: 65.01 7.91 7.58 75~
` Fx mple 4 ~ ~ c(cH3)3 ~ ~ C(C33)3 In 10 ml of chloroform was dissolved 0.6 g of 6-(3,5~di-tert-butyl-4-hydroxyphenyl)-2,3 dihydroimidazo [2Jl-b~thia2ole l-oxide and then 0.4 g of m-chloroperbenzoic acid was added to the solu-tion. After 30 minutes, 0.4 g of m-chloroperbenæoic acid was fur-ther added to the mixture and the resultant mixture was allowed to stand for one hour. Th~ reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent thereof was distilled off. The residue was purified by silica gel chromatography using chloroform as the eluent and further recrystalllzed from aqueous ethanol to provide 0.2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b]-thiazole l,l-dioxide.
Melting point: 267-269C
Elemental analysis for Clg H26 ~2 3 S:
C(%) H(%) N(%) Calculated: 62.77 7.35 7.60 25 Found: 62~96 7.23 7.73 _,......
, --~
J~
Example 5 3 $OEI3, 3 To a solution of 1.5 ml of dimethylformamide in 10 ml of chloroform was added l.lg oE phosphorus oxychloride under ice-lO cooling and the mixture was allowed to stand for one hour. Tothe reaction mixture was added 1.5 g of 6-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrolmidazo [2, l-b~ thiazole and the mixture was refluxed for 4 hours. To the reaction mixture was added 20 ml of an aqueous 10% potassium carbonate solution and 15 the mixture was stirred for 15 minutes. The chloroform layer was dried and concentrated. The crystals thus obtained were recrystallized from ethanol to provide 1.0 g of 6-(3,5-di-tert-butyl-4-hydroxyphe~nyl~ -5-formyl-2,3-dihydroimidazo [2, l-b]
thiazole.
Melting point: 210-212C
Elemental analysis for C20 H26 ~2 2 S:
C(%) H(%) M(%) Calculated: 66.82 7.20 7.80 Found 67.01 7.31 7.81 _-_ ,,,- -~
30 ~
,, ~ ~ . .
I Ia-6 a-5 R3 ~ ~ S N R ~ CN
(O)m \ (O)m Ia-8 \ Ia-7 (8) lo~ alkylation S-lower alkyl R~ ~ U~
R~ S N R
(O)m Ia 9 . 7 17~:~
wherein m' represen-ts 1 or 2; R5 and R6 each represents a hydroyen atom, a lower alkyl group, or they may combine wi-th each other to form a cyclic amlno group, and Rl, R , R3, R4, m, and the dotted line have the same significance as defined above.
The oxidation method (I) is a method of producing the compound of this invention shown by formula I wherein m is 1 or 2, ie., the S-oxide compound shown by formula I 1 The S-oxide compound can be prepared by reacting the corresponding thio compound of fore-going formula I wit ~n oxidizing agent in a solvent such as chloro-form, 1,2-dimethoxyethane, acetic acid, etc., according to a con-ventional method. As the oxidizing agent, 10-~/o hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc., is usually used.
In this case, by properly selecting the reaction conditions such as the reaction period of time, the reaction temperature, the amount of the oxidizing agent, etc., the desired mono-oxide compound (m' =
1) or dioxide compound (m' = 2) can be obtained.
The aminomethylation method (2) is a mthod of producing the compound of this invention shown by formula wherein R2 is an amino-methyl group, ie.~ the aminomethyl compound shown by formula I 3.
The aminomethylation is performed by reacting the compound shown by formula I wherein R2 is a hydrogen atom, ie., the compound shown by ~ R5 formula I 2with formaldehyde and the amine shown by ~ ~ ac-cording to a Mannich reaction. ,~
/~ -, /
/
''~
ji~
, ,, ~3 l'7~
The lower alkanoylation mathod (3) is a mathod of producing the compound of this inVQntion shown by ormula I wherein R2 is a lower alkanoyl group, i.e., the lower alkanoyl compound shown by formula I 4. The lower alkanoyl compound can be prepared by reacting the compoun~ shown by formula I 2 with a lowar alXanoyl halide such as acetyl chloride, etc., and an acid anhydride such as acetic anhydride, etc., according to a conventional method.
In addition, the lower alkanoyl compound shown by formula I 4 wherein the lower alkanoyl group i5 a formyl group, i.e., the formyl compound shown by formula I 5 can be also prepared by reac-ting the compound shown by formula I 2 by an ordinary manner with a complex (Vilsmeier reagent) of dimethylformamide (D~') and phos-phorus oxychloride or oxalyl chloride and then hydrolyzing the reac-tion product. This method is the foregoing formylation method (4).
The reduction method (5) is a method of producing the compound o this invention shown by formula I wherein R2 is a hydroxymethyl group, i.e., the hydroxymethyl compound shown by formula I 6 The hydroxymethyl compound can be produced by reducing the fore-going formyl compound of formula I 5 with a reducing agent such as sodium borohydride.
The cyanation method (6) is a method of producing the compound of this invention shown by formula I wherein R2 is a cyano group, i.e., the nitrile cornpound shown by formula I 7. The nitrile compound can be procluced by reacting the compound shown by formula I 2 with a Vilsmeire reagent as in the foregoing formylation method (4) according to a conventional method and then reacting the reaction product with hydroxyamina.
The thiocyanation method (7) is a metho~ of producing the compound of thi~ invention shown by formula I wherein R2 is a thiocyanate (-SCM) group, i.e., the thiocyanate compouncl shown , ~
by formula I 8. The thiocyanate compound can be produced by reacting the compound shown by formula I 2 with a -thiocyanate such as sodium thiocyanate, etc., and bromine.
The lower alkylation method (8) is a method of producing the compound of this invention shown by formula I whe~ein R2 is a lower alkylthio group, 1~ e., the lower alkylthio compound shown by formula I 9. ~he lower alkylthio compound can be produced by reacting the thiocyanate compound shown by formula I ~ with a lower alkylating agent according to a conventional method. As the lower alkylating agent, a lower alkyl halide such as methyl iodide, ethyl iodide, etc., is used.
The compound of this invention shown by formula I thus pro-duced is isolated and purified by a conventional chemical oper-ation such as concentration, recrystallization, column chromato-graphy, etc.
Typical methods of producing the compounds of this inventionshown by formula I were explained above and the compounds of this invention and the melhods of producing them will be Eurther ex-plained more practically and in more detail by the following examples.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this invention shown by formula I will then be described.
Effect on adjuvant~incluced arthrites in rats:
Methods: Male Sprangue Dawley rat aged 7 weeks were used.
Drugs were evaluated by two methods as follows. All tes-t drugs were suspended in water with 0~5% methylcellulose (0.5% MC) and administered orally once a day.
(l) Therapeutic effect of drugs; arthritis was induced by a sinyle injection of 0.1 ml of st.erile suspension of M~co cterlum t~icum (6my/ml) in li~uid para-ffLn into tail skin of ra-ts 5~
(day 0). After about 2 weeks, arthrit.ic rat~ wexe selectecl ancl allocated into groups. Drugs wexe given daily following about 10 days. Thi.ckrless of the foot was measured with dial thickness gauge both on the day of initial dosing and on the next day of final dosing, change of foot thickne6s (~FT 10 mm) was calcu-lated as a di~ference between these two values. The results are shown in Table I.
Table I (Therapeutic effect) Drugs Dose ~ Day 16-Da~ 28 (mg/kg/day) ~FT (X10 mm) P . O . ) ~ - :. __ __.________ r -- . : . .. _ 0.5% MC - 3 210 ~ 91 Indomethacin 2 3 -177 + 41**
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydroimidazo (2~1-b)-thiazole 25 3 -16 + 27*
6-(3,5-di-tert-bu-tyl-4-hydroxyphenyl)-2,3--dihydro-imida7.0 (2,1-b) thiazole 1-20 oxide 25 3 -245 + 57**
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo (2,1-b) thiazole 1,1 dioxide 25 3 -141 + 60**
Drugs Dose~ay 17-~ay 27 (mg~kg/day N ~T
P.O.) (10 mm) _ _ _ 0.5% Mc - 3181~ 7 Indomethacin 2 3-225 -~ 61**
Diclofenac HCI 2 3 -83 ~ 49*
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-lmidazo ~2,1-b) thiazole 25 3 -177 -~ 36***
Significant diEference rom con-trol (t-test) * P~0.05 **P ~ .01 *** P<0.001 From the above results, it is apparent that the compounds ; of this invention have excellent pharmacological (therapeutic) effects against the adjuvant-induced arthrites.
Example 1 ._ (C~l ) C HS N ~ (CH C~
In 20 ml of ethanol was dissolved 0.11 g of metallic sodium and after adding lg of 4,5-diphenyl-2-mercaptoimidazole to the solution followed by stirring several minutes, lg~lof 3,5-di-tert-butylphenacyl bromide was added there-to followed by s-tir-ring for one hour at room tempera-ture. The reaction mixture was concentrated under reduced pressure and -then wa-ter was added 0 to l2 the residue. rl~he crystal.s Lhus ~ornlccl wer~ recoverecli~y f:iL~-:c,-tion, dried, tllssolvecl in 20ml of phospllorus oxychloride, and the solution was refluxed Eor 14 hours. The reactiOn mixture was concentrated under reduced pressure and after adding water to the residue followed by neutralization with potassium carbonate, the product was extracted wi.th chloroform. The extrac~ was dried and concen-trated. The residue was subjected to si].ica gel column ~hromatography and the product was eluted with chloroform. The crude crystals -thus obtained were recrystallized from ethanol -to provide 0.8 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenyl-imidazo [2,1-b] thiazole.
Melting point: 237-238C
Elemental analysis for C31H32N2 OS:
C(%) H(%) N(%) S(%) 15 Calculated: 77.47 6.57 5.70 6.48 Found: 77.46 6.71 5.83 6.67 Example 2 20 (CH3)3c ~ 3 ~ OCH
HO ~ C-CH2Br + N ~ > Ho4 ~ ___N ~
(CH3)3c Y HS ~ N ~ ~ OCH3( ~ C ~ N ~ OCH3 By following the same procedure as in Example 1, 3-(3J5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-me-thoxyphenyl)-imidazo[2Jl-b] thiazole was produced.
Melting point: 236-237C
El.emental analy.sis ~or'C33 1~3~ N2 S3 s 13 75~
C(%~ H(%) M(%) S(%) Calculated: 72.92 6.53 5.32 6.42 Found: 73.30 6.71 5.18 5.93 Example 3 (C~3)3~ ~ ~ C(C~3)3 (CH ) 3 3 C(CH3)3 In 10 ml of chloroform wa.s dissolved 1.6 g of 6-(3,5-di-tert-15 butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole and after adding thereto 1 g of m-chloroperbenzoic acid, the mixture was stirred for 10 minutes. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent was distilled off. The cry~tals thus formed were re-20 crystallized from ethanol to provide 1~3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole l-oxide as the 1/2 ethanol addition product.
Melting point: 211-212C
Mass spectrum: m/e: 346(M~) Elemental 3nalysis for Clg H26 N2 2 S 1/2C2 H5 OH
C(%) ~(%) N(%) Calculated: 65.11 7.78 7.82 Found: 65.01 7.91 7.58 75~
` Fx mple 4 ~ ~ c(cH3)3 ~ ~ C(C33)3 In 10 ml of chloroform was dissolved 0.6 g of 6-(3,5~di-tert-butyl-4-hydroxyphenyl)-2,3 dihydroimidazo [2Jl-b~thia2ole l-oxide and then 0.4 g of m-chloroperbenzoic acid was added to the solu-tion. After 30 minutes, 0.4 g of m-chloroperbenæoic acid was fur-ther added to the mixture and the resultant mixture was allowed to stand for one hour. Th~ reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent thereof was distilled off. The residue was purified by silica gel chromatography using chloroform as the eluent and further recrystalllzed from aqueous ethanol to provide 0.2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b]-thiazole l,l-dioxide.
Melting point: 267-269C
Elemental analysis for Clg H26 ~2 3 S:
C(%) H(%) N(%) Calculated: 62.77 7.35 7.60 25 Found: 62~96 7.23 7.73 _,......
, --~
J~
Example 5 3 $OEI3, 3 To a solution of 1.5 ml of dimethylformamide in 10 ml of chloroform was added l.lg oE phosphorus oxychloride under ice-lO cooling and the mixture was allowed to stand for one hour. Tothe reaction mixture was added 1.5 g of 6-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrolmidazo [2, l-b~ thiazole and the mixture was refluxed for 4 hours. To the reaction mixture was added 20 ml of an aqueous 10% potassium carbonate solution and 15 the mixture was stirred for 15 minutes. The chloroform layer was dried and concentrated. The crystals thus obtained were recrystallized from ethanol to provide 1.0 g of 6-(3,5-di-tert-butyl-4-hydroxyphe~nyl~ -5-formyl-2,3-dihydroimidazo [2, l-b]
thiazole.
Melting point: 210-212C
Elemental analysis for C20 H26 ~2 2 S:
C(%) H(%) M(%) Calculated: 66.82 7.20 7.80 Found 67.01 7.31 7.81 _-_ ,,,- -~
30 ~
,, ~ ~ . .
7~i~
Example 6 CHO C(C~)3 CH OH
~ C( 3)3 C(CH )3 In 10 ml of ethanol was dissolved 0.4 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo [2,1-b~ thia-zole and after adding 40 mg o sodium borohydride to the solution, the mixture was stirred for 10 minutes. To the reaction mixture were added 0.3 ml of acetic acid and 30 ml of water, and the crystals thus precipitated were recovered by filtration and re-crystallized from aqueous ethanol to provide 0.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo [2,1-b]-thiazole.
M~elting point: 227-229C
Elemental analysis for C20 ~I28 N2 2 S:
C(%) H(%) ~(%) Calculated: 66.55 8.047.73 Found: 66.63 7.80 7.77 Example 7 N C(CH3)3 CH2N /CH3 ~S ~ ~ OH NEI(C~12-~HCHO ~ OH
(C~3)3 ~ C(CH3)3 rJ, "
1:~8~
To a mixed solution of 0.9g oE an aqueous 40O/o dimethylamine solution, 0.6 g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 5 ml of dioxane was added 0.66 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole and the resultant mixture was refluxed for 6 hours. The reaction mixture was concentrat~d under reduced pressure and -the residue was mixed with 20 ml of an aqueous 10~/o potassium carbonate solu-tion and extracted with chloroform. The extract was dried and concentrated, and the residue thus formed was purified by silica gel chromatography using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.3 g of 5-dlmethy-laminomethyl-6-(3,5-di-tert-butyl-4~hydroxyphenyl)-2,3-dihydroimid-azo [2,1-b] thiazole~l/4 H20.
Melting point: 188-191C
Mass spectrum: m/e: 387(M+) Elemental analysis for C22 H33 N3 OS.1/4 H20:
C(%) H(%) N(%) Calculated: 67.49 8.70 10.48 Found: 67.39 8.61 10.72 Example 8 N ~_~ ( 3)3 ~, HCH0 ~ CH2N
( 3)3 ~ oHH3)3 (CH3)3 5~
A mixture of 1.65g of 6-(3,5-dl-ter-t-buty:l-4-hydroxyphenyl-2,3-dihydroimidazo [2J l-b~ thiazole of 1.8g of morpholin~, 1.7g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 10 ml of dioxane was refluxed for 6 hours. The reaction mix-ture was concentrated under reduced pressure and to the residuewas added 20 ml of an aqueous 10% potassium carbonate to precip-itate crystals, which were recovered ~y filtration and recrystall-ized from methanol to provide 0.85g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo [2,1-b]-thiazole.
Melting point: 231-233C
Elemental analysis for C2~ H 35 ~3 2 S:
C(%) H(%) N(%) ~(%) Calculated: 67O08 8.32 9.67 7.35 Found: 67.10 8.21 9.78 7.46 Example 9 rS ~ o~ N~N CH3+HCHO ~ ~ ~ H2N~,NCH3 ~ OH
C(CH3)3 ~ (CH3)3 i .
'7S~L
By followincJ the same procedure as in Example 8, 6-(3,5-cli-tert-butyl-4-hydroxyphenyl)-5-(4-methylpiperazinomethyl)-2,3-dihydroimidazo [2,1-b] thiazole was produced.
Melting point: 211-212C
Elemental analysis for C25 H3~3 N~ OS.EI~O:
C(%) H(%) ~(%) S(%) Calculated:65.28 8.61 12.00 7.06 Found: 65.18 8.7S 12.16 6.96 E3~e~
N C(CH3)3 N C(CH3)3 ~ ~ ~ ~ OH Br2 ~ ~ (CH3)3 In 10 ml of acetic acid was dissolved 1.35g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2~3-dihydroimidazo [2,1-b] thiazole and after adding thereto 0.64g of sodium thiocyanate, 0.7g of bromine was added dropwise to the solution under ice-cooling.
After performing the reaction for one hour at room temperature, 30ml of water was added to the reaction mixture to precipitate crystals, which were recovered by filtration. The crystals wer~
added to a mixture of 20 ml of chloroform and 10 ml of an aqueous 10% potassium carbonate solution followed by stirriny. The chloroform layer thus formed was dried and concentrated, and the residue thus formed was purified by silica yel column chromato-yraphy usiny chloroform as the eluent and further recrys-tallized from ethanol to provide 0.6 g of 6-t3~5-di-tert-butyl-4-hydroxy-phenyl)-5-thiocyanato-2,3-dihydroimidazo [2,1-b] thiazoLe.
Melting point: 178-179C
Elemental analysis for C20 H25 N3 S2 Ct%) Ht%) Nt%) S(%) Calculated: 62.05 6.50 10.66 16.84 Found: 61.98 6.50 10.84 16.54 Example 11 lO ~ ~ ¦ ~ ~ 3 3 C~3I SC ~ C(CH3)3 In lO ml of methanol was dissolved 1.3g of 6-t3,5-di-tert-butyl-4-hydroxyphenyL)-5-thiocyanato-2,3-dihydroimidazo [2,1-b]-thiazole and after cooling the soluf ion to oC, 0.65 g of methyl iodide was added dropwise to the solution with stirring and fur-ther a solution of 0.2g of potassium hydroxide dissolved in a mixture of 2ml of water and 2 ml of methanol was added dropwise to the solution. After 30 minutes, the reaction mixture was concentrated and the r0sidue was purified by silica gel column chromatography using chloroform as the eluent and further recry-stallized from ethanol to provide 0.18 g of ~-t3,5-di-ter-t-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo [2,1-bl thiazole.
2:L
J', 75~
Meltiny point: 170-171C
Elemental analysis for C20 H28 N2 OS~:
C(%) H(%) ~(%) S(%) CalcuLated: 63.49 7.60 7.36 16.85 5 Found: 63.79 7.49 7.44 17.03 Example 12 N ~ - ( 3)3 DMF~(COC~ N CN C(CH3)3 =~CH3)3 ~(CH3)3 To a mixed so:Lution of 0.5 y of dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of ethylene dichloride under ice-cooling.
After allowing to stand the mixture for 15 minutes at room temp-erature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphen-yl)-3,4-dihydroimidazo [2,1-b] thiazole dissolved in a mixture of 3 ml of dimethylformamide and 10 ml of ethylene dichloride was : added dropwise to the solution and the resultant mixture was stir-red for 2 hours. Then, a solution of 0.5 g of hydroxylamine hy-drochloride dissolved in a mixture of 1.5 ml of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mixture was refluxed overniyht. ~he reaction mixture was washed with 30 ml of an aqueous S% sodium hydrocJen carbonate solution, dried, and then concentrated. The residue thus formed was purifiod by silica yel column chromatography using chloroform " . ~, , :~8~
as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole.
Melting point: 207-208C
Elemental analysis for C20 ~I25 N3 OS:
C(%) H(%) N(%) Calculated: 67.52 6.92 11.74 Found: 67.57 7.09 11.82 By following the same procedure as in Example l, the follow-ing compounds were prepared.
Example 13.
~ ~ N~ (CoH3~3 mp. 212 -4C
(CH3)3 ExamPle 14.
OH mp. 258 - 261C
(CH3)3 Example 15.
~ S ~N ) ~ (CH3)3 mp. 184 - 5C
~,, "
75~L
E~ample 16.
C ( CH3 ) 3 3 ~ =~ mp . 18 8 - 19 0 C
:ESxample 17.
1~ SJ~ ( CN3 ) 3 mp. 208 - 210~c Exampl~ 18 3 ~ C(CH3)3 mp. Z29 - 231C
~/; 2
Example 6 CHO C(C~)3 CH OH
~ C( 3)3 C(CH )3 In 10 ml of ethanol was dissolved 0.4 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo [2,1-b~ thia-zole and after adding 40 mg o sodium borohydride to the solution, the mixture was stirred for 10 minutes. To the reaction mixture were added 0.3 ml of acetic acid and 30 ml of water, and the crystals thus precipitated were recovered by filtration and re-crystallized from aqueous ethanol to provide 0.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo [2,1-b]-thiazole.
M~elting point: 227-229C
Elemental analysis for C20 ~I28 N2 2 S:
C(%) H(%) ~(%) Calculated: 66.55 8.047.73 Found: 66.63 7.80 7.77 Example 7 N C(CH3)3 CH2N /CH3 ~S ~ ~ OH NEI(C~12-~HCHO ~ OH
(C~3)3 ~ C(CH3)3 rJ, "
1:~8~
To a mixed solution of 0.9g oE an aqueous 40O/o dimethylamine solution, 0.6 g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 5 ml of dioxane was added 0.66 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole and the resultant mixture was refluxed for 6 hours. The reaction mixture was concentrat~d under reduced pressure and -the residue was mixed with 20 ml of an aqueous 10~/o potassium carbonate solu-tion and extracted with chloroform. The extract was dried and concentrated, and the residue thus formed was purified by silica gel chromatography using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.3 g of 5-dlmethy-laminomethyl-6-(3,5-di-tert-butyl-4~hydroxyphenyl)-2,3-dihydroimid-azo [2,1-b] thiazole~l/4 H20.
Melting point: 188-191C
Mass spectrum: m/e: 387(M+) Elemental analysis for C22 H33 N3 OS.1/4 H20:
C(%) H(%) N(%) Calculated: 67.49 8.70 10.48 Found: 67.39 8.61 10.72 Example 8 N ~_~ ( 3)3 ~, HCH0 ~ CH2N
( 3)3 ~ oHH3)3 (CH3)3 5~
A mixture of 1.65g of 6-(3,5-dl-ter-t-buty:l-4-hydroxyphenyl-2,3-dihydroimidazo [2J l-b~ thiazole of 1.8g of morpholin~, 1.7g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 10 ml of dioxane was refluxed for 6 hours. The reaction mix-ture was concentrated under reduced pressure and to the residuewas added 20 ml of an aqueous 10% potassium carbonate to precip-itate crystals, which were recovered ~y filtration and recrystall-ized from methanol to provide 0.85g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo [2,1-b]-thiazole.
Melting point: 231-233C
Elemental analysis for C2~ H 35 ~3 2 S:
C(%) H(%) N(%) ~(%) Calculated: 67O08 8.32 9.67 7.35 Found: 67.10 8.21 9.78 7.46 Example 9 rS ~ o~ N~N CH3+HCHO ~ ~ ~ H2N~,NCH3 ~ OH
C(CH3)3 ~ (CH3)3 i .
'7S~L
By followincJ the same procedure as in Example 8, 6-(3,5-cli-tert-butyl-4-hydroxyphenyl)-5-(4-methylpiperazinomethyl)-2,3-dihydroimidazo [2,1-b] thiazole was produced.
Melting point: 211-212C
Elemental analysis for C25 H3~3 N~ OS.EI~O:
C(%) H(%) ~(%) S(%) Calculated:65.28 8.61 12.00 7.06 Found: 65.18 8.7S 12.16 6.96 E3~e~
N C(CH3)3 N C(CH3)3 ~ ~ ~ ~ OH Br2 ~ ~ (CH3)3 In 10 ml of acetic acid was dissolved 1.35g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2~3-dihydroimidazo [2,1-b] thiazole and after adding thereto 0.64g of sodium thiocyanate, 0.7g of bromine was added dropwise to the solution under ice-cooling.
After performing the reaction for one hour at room temperature, 30ml of water was added to the reaction mixture to precipitate crystals, which were recovered by filtration. The crystals wer~
added to a mixture of 20 ml of chloroform and 10 ml of an aqueous 10% potassium carbonate solution followed by stirriny. The chloroform layer thus formed was dried and concentrated, and the residue thus formed was purified by silica yel column chromato-yraphy usiny chloroform as the eluent and further recrys-tallized from ethanol to provide 0.6 g of 6-t3~5-di-tert-butyl-4-hydroxy-phenyl)-5-thiocyanato-2,3-dihydroimidazo [2,1-b] thiazoLe.
Melting point: 178-179C
Elemental analysis for C20 H25 N3 S2 Ct%) Ht%) Nt%) S(%) Calculated: 62.05 6.50 10.66 16.84 Found: 61.98 6.50 10.84 16.54 Example 11 lO ~ ~ ¦ ~ ~ 3 3 C~3I SC ~ C(CH3)3 In lO ml of methanol was dissolved 1.3g of 6-t3,5-di-tert-butyl-4-hydroxyphenyL)-5-thiocyanato-2,3-dihydroimidazo [2,1-b]-thiazole and after cooling the soluf ion to oC, 0.65 g of methyl iodide was added dropwise to the solution with stirring and fur-ther a solution of 0.2g of potassium hydroxide dissolved in a mixture of 2ml of water and 2 ml of methanol was added dropwise to the solution. After 30 minutes, the reaction mixture was concentrated and the r0sidue was purified by silica gel column chromatography using chloroform as the eluent and further recry-stallized from ethanol to provide 0.18 g of ~-t3,5-di-ter-t-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo [2,1-bl thiazole.
2:L
J', 75~
Meltiny point: 170-171C
Elemental analysis for C20 H28 N2 OS~:
C(%) H(%) ~(%) S(%) CalcuLated: 63.49 7.60 7.36 16.85 5 Found: 63.79 7.49 7.44 17.03 Example 12 N ~ - ( 3)3 DMF~(COC~ N CN C(CH3)3 =~CH3)3 ~(CH3)3 To a mixed so:Lution of 0.5 y of dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of ethylene dichloride under ice-cooling.
After allowing to stand the mixture for 15 minutes at room temp-erature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphen-yl)-3,4-dihydroimidazo [2,1-b] thiazole dissolved in a mixture of 3 ml of dimethylformamide and 10 ml of ethylene dichloride was : added dropwise to the solution and the resultant mixture was stir-red for 2 hours. Then, a solution of 0.5 g of hydroxylamine hy-drochloride dissolved in a mixture of 1.5 ml of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mixture was refluxed overniyht. ~he reaction mixture was washed with 30 ml of an aqueous S% sodium hydrocJen carbonate solution, dried, and then concentrated. The residue thus formed was purifiod by silica yel column chromatography using chloroform " . ~, , :~8~
as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo [2,1-b] thiazole.
Melting point: 207-208C
Elemental analysis for C20 ~I25 N3 OS:
C(%) H(%) N(%) Calculated: 67.52 6.92 11.74 Found: 67.57 7.09 11.82 By following the same procedure as in Example l, the follow-ing compounds were prepared.
Example 13.
~ ~ N~ (CoH3~3 mp. 212 -4C
(CH3)3 ExamPle 14.
OH mp. 258 - 261C
(CH3)3 Example 15.
~ S ~N ) ~ (CH3)3 mp. 184 - 5C
~,, "
75~L
E~ample 16.
C ( CH3 ) 3 3 ~ =~ mp . 18 8 - 19 0 C
:ESxample 17.
1~ SJ~ ( CN3 ) 3 mp. 208 - 210~c Exampl~ 18 3 ~ C(CH3)3 mp. Z29 - 231C
~/; 2
Claims (38)
1. A method of producing a 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound represented by the formula I
I
wherein one of R1, R2, R3 and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and others represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy-lower-alkyl group, an amino-lower-alkyl group, an aryl group, a lower-alkoxy-substituted-aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group or an thiocyanato group and m re-presents 0, 1 or 2, and the dotted line represents the absence or the presence of a double bond; or a pharmaceutically accept-able acid addition salt thereof, which comprises selecting a process from the group of processes consisting of:
(a) reacting the compound represented by formula II
II
and the compound of the formula III
III
or a salt thereof wherein R1, R2, R3, R4 have the same significance as defined concerning formula I and X re-presents a halogen atom;
(b) reacting a compound of formula I wherein m repre-sents 0 with an oxidizing agent to obtain the corres-ponding compound of formula I wherein m is 1 or 2;
(c) reacting a compound of formula I wherein R2 is a hydrogen atom with formaldehyde and an amino group of the formula:
according to a Mannich reaction where R5 and R6 each represent a hydrogen atom, a lower alkyl group or combine with each other to form a cyclic amino group to obtain the compound of formula I wherein R2 is an amino methyl group of the formula (d) reacting a compound of formula I wherein R2 is a hydrogen atom with a lower alkanoyl halide and an acid anhydride to obtain the corresponding compound of formula I wherein R2 is a lower alkanoyl group;
(e) reacting a compound of formula I wherein R2 is a hy-drogen atom with a complex of dimethylformamide and phosphorus oxychloride or oxalyl chloride, then hydro-lizing the reaction product to obtain the corresponding compound of formula I wherein R2 is a formyl group;
(f) reducing a compound of formula I wherein R2 is a formyl group to obtain the corresponding compound of formula I wherein R2 is a hydroxy methyl group;
(g) cyanating a compound of formula I wherein R2 is a hydrogen atom to obtain the corresponding compound of formula I wherein R2 is a cyano group;
(h) thiocyanating a compound of formula I wherein R2 is a hydrogen atom to obtain the corresponding compound of formula I wherein R2 is a thiocyanate group;
(i) alkaylating the compound of formula I wherein R2 is a thiocyanate group to obtain a corresponding compound of formula I wherein R2 is a lower alkylthio group; and, (j) converting a compound of formula I to the corres-ponding pharmaceutically acceptable acid addition salt.
I
wherein one of R1, R2, R3 and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and others represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy-lower-alkyl group, an amino-lower-alkyl group, an aryl group, a lower-alkoxy-substituted-aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group or an thiocyanato group and m re-presents 0, 1 or 2, and the dotted line represents the absence or the presence of a double bond; or a pharmaceutically accept-able acid addition salt thereof, which comprises selecting a process from the group of processes consisting of:
(a) reacting the compound represented by formula II
II
and the compound of the formula III
III
or a salt thereof wherein R1, R2, R3, R4 have the same significance as defined concerning formula I and X re-presents a halogen atom;
(b) reacting a compound of formula I wherein m repre-sents 0 with an oxidizing agent to obtain the corres-ponding compound of formula I wherein m is 1 or 2;
(c) reacting a compound of formula I wherein R2 is a hydrogen atom with formaldehyde and an amino group of the formula:
according to a Mannich reaction where R5 and R6 each represent a hydrogen atom, a lower alkyl group or combine with each other to form a cyclic amino group to obtain the compound of formula I wherein R2 is an amino methyl group of the formula (d) reacting a compound of formula I wherein R2 is a hydrogen atom with a lower alkanoyl halide and an acid anhydride to obtain the corresponding compound of formula I wherein R2 is a lower alkanoyl group;
(e) reacting a compound of formula I wherein R2 is a hy-drogen atom with a complex of dimethylformamide and phosphorus oxychloride or oxalyl chloride, then hydro-lizing the reaction product to obtain the corresponding compound of formula I wherein R2 is a formyl group;
(f) reducing a compound of formula I wherein R2 is a formyl group to obtain the corresponding compound of formula I wherein R2 is a hydroxy methyl group;
(g) cyanating a compound of formula I wherein R2 is a hydrogen atom to obtain the corresponding compound of formula I wherein R2 is a cyano group;
(h) thiocyanating a compound of formula I wherein R2 is a hydrogen atom to obtain the corresponding compound of formula I wherein R2 is a thiocyanate group;
(i) alkaylating the compound of formula I wherein R2 is a thiocyanate group to obtain a corresponding compound of formula I wherein R2 is a lower alkylthio group; and, (j) converting a compound of formula I to the corres-ponding pharmaceutically acceptable acid addition salt.
2. A process according to claim 1 for the preparation of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenylimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addi-tion salt thereof, wherein R3 is a 3,5-di-ter-t-butyl-4-hydroxyphenyl group, R4 is a hydrogen atom, R1 and R2 are each a phenyl group and m is 0.
3. A process according to claim 1 for the preparation of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-methoxyphenyl)-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R3 is 3,5-di-tert-butyl-4-hydroxyphenyl group, R4 is a hydrogen atom, R2 and R1 are each a p-methoxyphenyl group and m is 0.
4. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1-oxide, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3, and R4 each are a hy-drogen atom and m is 1.
5. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1,1-dioxide, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 each are a hydro-gen atom and m is 2.
6. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a formyl group, R3 and R4 are each a hydrogen atom and m is 0.
7. A process according to claim 1 for the preparation of 6-(3,5-di-ter-t-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]-thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a hydroxymethyl group, R3 and R4 are each a hydrogen atom and m is 0.
8. A process according to claim 1 for the preparation of 5-dimethylaminomethyl-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a dimethylamino-methyl group, R3 and R4 are each a hydrogen atom and m is 0.
9. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a morpholinomethyl group, R3 and R4 are each a hydrogen atom and m is 0.
10. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(4-methylpiperazino-methyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceuti-cally acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a 4-methyl-piperazinomethyl group, R3 and R4 are each a hydrogen atom and m is 0.
11. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a thiocyanato group, R3 and R4 are each a hydrogen atom and m is 0.
12. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-thio-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a methylthio group, R3 and R4 are each a hydrogen atom and m is 0.
13. A process according to claim 1 for the preparation of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a cyano group, R3 and R4 are each a hydrogen atom and m is 0.
14. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addi-tion salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 are each a hydrogen atom and m is 0.
15. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a methyl group, R3 and R4 are each a hydrogen atom and m is 0.
16. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 are each a hydrogen atom and m is 0.
17. A process according to claim 1 for the preparation of 3-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a methyl group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl group, R4 is a hydrogen atom and m is 0.
18. A process according to claim 1 for the preparation of 2,3-dimethyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a methyl group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 and R4 are each a methyl group and m is 0.
19. A process according to claim 1 for the preparation of 2-methyl-3-phenyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-imidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a hydrogen atom, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a phenyl group, R4 is a methyl group and m is 0.
20. A 3,5-di-tert-butyl-4-hydroxyphenyl-substituted hetero-cyclic compound represented by the formula I
I
wherein one of R1, R2, R3 and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ) and others represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy-lower-alkyl group, an amino-lower-alkyl group, an aryl group, a lower-alkoxy-substituted-aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group or a thiocyanato group and m represents 0, 1 or 2, and the dotted line represents the absence or the presence of a double bond; or a pharma-ceutically acceptable acid addition salt thereof, when pre-pared according to the process of claim 1.
I
wherein one of R1, R2, R3 and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ) and others represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy-lower-alkyl group, an amino-lower-alkyl group, an aryl group, a lower-alkoxy-substituted-aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group or a thiocyanato group and m represents 0, 1 or 2, and the dotted line represents the absence or the presence of a double bond; or a pharma-ceutically acceptable acid addition salt thereof, when pre-pared according to the process of claim 1.
21. 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenylimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addi-tion salt thereof, when prepared by the process of claim 2.
22. 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-methoxy-phenyl)imidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 3.
23. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1-oxide, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 4.
24. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1,1-dioxide, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 5.
25. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-di-hydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 6.
26. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 7.
27. 5-dimethylaminomethyl-6-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceuti-cally acceptable acid addition salt thereof, when prepared by the process of claim 8.
28. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 9.
29. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(4-methylpiper-azinomethyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharma-ceutically acceptable acid addition salt thereof, when pre-pared by the process of claim 10.
30. 6-(3,5-di-tert-butyl-4-hydroxphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 11.
31. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 12.
32. 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 13.
33. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 14.
34. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 15.
35. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]thia-zole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 16.
36. 3-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 17.
37. 2,3-dimethyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 18.
38. 2-methyl-3-phenyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 19.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56023515A JPS57150692A (en) | 1981-02-19 | 1981-02-19 | 4-hetero ring-substituted-2,6-di-tert-butyl-phenol derivative |
| JP23515/1981 | 1981-02-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1181751A true CA1181751A (en) | 1985-01-29 |
Family
ID=12112578
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396501A Expired CA1181751A (en) | 1981-02-19 | 1982-02-17 | Process of production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
| CA000396500A Expired CA1181074A (en) | 1981-02-19 | 1982-02-17 | Process for producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396500A Expired CA1181074A (en) | 1981-02-19 | 1982-02-17 | Process for producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS57150692A (en) |
| CA (2) | CA1181751A (en) |
| ES (2) | ES509780A0 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868183A (en) * | 1986-07-21 | 1989-09-19 | Otsuka Pharmaceutical Factory, Inc. | N-pyrazinyl substituted P-aminophenols |
-
1981
- 1981-02-19 JP JP56023515A patent/JPS57150692A/en active Granted
-
1982
- 1982-02-17 CA CA000396501A patent/CA1181751A/en not_active Expired
- 1982-02-17 CA CA000396500A patent/CA1181074A/en not_active Expired
- 1982-02-19 ES ES509780A patent/ES509780A0/en active Granted
- 1982-02-19 ES ES509781A patent/ES8304144A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1181074A (en) | 1985-01-15 |
| ES509781A0 (en) | 1983-02-16 |
| ES8302722A1 (en) | 1983-01-16 |
| JPS57150692A (en) | 1982-09-17 |
| ES509780A0 (en) | 1983-01-16 |
| JPH0139434B2 (en) | 1989-08-21 |
| ES8304144A1 (en) | 1983-02-16 |
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