CA1176260A - Process for production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds - Google Patents
Process for production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compoundsInfo
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Abstract
ABSTRACT
A process of producing novel 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds shown by the formula and the salts thereof.
The compounds of this invention have an anti-inflammatory, an anti-pyretic, an analgesic, an anti-arthritic, and an immuno-regulatory activity. Hence they are particularly useful as an antirheumatic.
A process of producing novel 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds shown by the formula and the salts thereof.
The compounds of this invention have an anti-inflammatory, an anti-pyretic, an analgesic, an anti-arthritic, and an immuno-regulatory activity. Hence they are particularly useful as an antirheumatic.
Description
Tllis invention relates to novel 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds and a process of producing same. More particularly, the invention relates to the 3,5-di-tert-butyl-4-hydroxyphenyl-substituted hetero-cyclic compounds shown by formula I and their salt;
N - 1~ 2 T
[wherein one of Rl and R2 represents 3,5-di-tert-butvl-4-hydroxyphenyl group, others represent a hvdrogen atom, or a 0 lower alkyl group, R3 is a hydrogen atom or a group shown by ()n -O-Z or -S- Z, (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycar-bonyl lower alkyl group, or a lower aralkyl group, and n re-presents O, 1, or 2); R4 represents a hydrogen atom or a 5 lower alkyl group.]
The terminology throughout 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, for 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" in-cludes benzyl group, phenethyl group, etc.; 'llower alkoxy group" includes methoxy group, e-thoxy group, propoxy group, isopropoxy group, butoxy group, hexyloxy group, etc. Further-more, the term "aryl group" includes phenyl group, naphthyl group, etc.
Then, as the salts of the compounds of this invention shown by formula I, there are pharmaceutically acceptable acid addition salts, for example, ac:id addition salts of an inorganic acid such as hydrochloric acid, hydrobro~ic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
~ 7~
1176Z~) The compounds of this invention shown by formula I have an anti-inflammatory, and anti-pyretic, analgesic, an antiarthritic, and an immuno~regulatory activity. Hence they are novel compounds particularly useful as an antirheumatics.
That is, since the compounds of this invention shown by form-ula I show a therapeutic and prophylactic effect on adjuvant-induced a~thritis which is-considered to be an animal model of human rheumatism and further have analgesic and anti-inflammatory activities as well as a prostagrandins formation inhibiting act-ivity as a biochemical 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 suppressing activity and a property as a radical scavenger, which have never been attained by conventional nonsteroidal acidic anti-inflammatory antirheum-atics represented by indomethacin and diclofenac. Therefore, the compounds of this invention are particularly expected as anti-rheumatics having new mechanism.
The 1st feature of the chemical structure of the compounds of this invention sh~wn by formula I is that the compounds belong to a nonsteroidal nonacidic anti-inflammatory and are different from conventional nonsteroidal acidic anti-inflammatory agents such as indometacin and diclofenac. The 2nd feature is in the point that the heterocyclic ring of the heterocyclic compound is directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group. The 3rd feature is in the point that the substituted heterocyclic ring itself is a specific heterocyclic ring that is, imidazole ring.
As heterocyclic compounds the heterocyclic ring of which is ~7~26~
directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-(3,5-di-tert-butyl-4-hydroxyphen-yl)benzoxazole compounds and 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-benzothiazole compounds (West German Offenlegungsshrift 2,008,414);
N - 1~ 2 T
[wherein one of Rl and R2 represents 3,5-di-tert-butvl-4-hydroxyphenyl group, others represent a hvdrogen atom, or a 0 lower alkyl group, R3 is a hydrogen atom or a group shown by ()n -O-Z or -S- Z, (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycar-bonyl lower alkyl group, or a lower aralkyl group, and n re-presents O, 1, or 2); R4 represents a hydrogen atom or a 5 lower alkyl group.]
The terminology throughout 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, for 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" in-cludes benzyl group, phenethyl group, etc.; 'llower alkoxy group" includes methoxy group, e-thoxy group, propoxy group, isopropoxy group, butoxy group, hexyloxy group, etc. Further-more, the term "aryl group" includes phenyl group, naphthyl group, etc.
Then, as the salts of the compounds of this invention shown by formula I, there are pharmaceutically acceptable acid addition salts, for example, ac:id addition salts of an inorganic acid such as hydrochloric acid, hydrobro~ic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
~ 7~
1176Z~) The compounds of this invention shown by formula I have an anti-inflammatory, and anti-pyretic, analgesic, an antiarthritic, and an immuno~regulatory activity. Hence they are novel compounds particularly useful as an antirheumatics.
That is, since the compounds of this invention shown by form-ula I show a therapeutic and prophylactic effect on adjuvant-induced a~thritis which is-considered to be an animal model of human rheumatism and further have analgesic and anti-inflammatory activities as well as a prostagrandins formation inhibiting act-ivity as a biochemical 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 suppressing activity and a property as a radical scavenger, which have never been attained by conventional nonsteroidal acidic anti-inflammatory antirheum-atics represented by indomethacin and diclofenac. Therefore, the compounds of this invention are particularly expected as anti-rheumatics having new mechanism.
The 1st feature of the chemical structure of the compounds of this invention sh~wn by formula I is that the compounds belong to a nonsteroidal nonacidic anti-inflammatory and are different from conventional nonsteroidal acidic anti-inflammatory agents such as indometacin and diclofenac. The 2nd feature is in the point that the heterocyclic ring of the heterocyclic compound is directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group. The 3rd feature is in the point that the substituted heterocyclic ring itself is a specific heterocyclic ring that is, imidazole ring.
As heterocyclic compounds the heterocyclic ring of which is ~7~26~
directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-(3,5-di-tert-butyl-4-hydroxyphen-yl)benzoxazole compounds and 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-benzothiazole compounds (West German Offenlegungsshrift 2,008,414);
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 Open ~o. 7669/'78). The benzoxazole compounds and the benzothiazole compounds are used as an antioxidant and the imidaz-olidine compounds are used as intermediates for 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-inflammatory agent. About the acetic acid compound, the use as an anti-inflammatory agent is suggested as described above but there is no disclosure about the practical pharmacological effect of the compound as an anti-inflammatory agent and also the chemi-cal structure of the acetic acid compound is a heterocyclic ring-substituted acetic acid derivative, which belongs to a nonsteroidal acidic anti-inflammatory agent and hence differs from the com-pounds of this invention shown by formula I in chemical structure.
The particularly preferred compounds in the foregoing heter-ocyclic compounds (I) are as follows, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imida-zoline, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imida-zoline 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole.
4-3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole, 4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole, and 1~'7~2~
4-(3,5-di-tert-butyl-~-hydroxyphenyl)-5-ethyl-2-methylthioimidaz-ole.
In addition, there are prototropic isomers on the compounds of this invention shown by formula I. For example, in the compounds of this invention shown by formula I wherein R3 is -S - Z (wherein n is 0 and Z is a hydrogen atom) or R3 is -oZ (wherein Z is a hydrogen atom), there are following prototropic isomers:
H ~ ` ,S~
0~ \R
The compounds of this invention shown by formula I can be prepared by the following methods;
(i) First production method:
~H2 -CIH-R
R4-N=C-Y + 0=C-R y ~ R
II III Ia wherein Y represents a hydroxyl group or a mercapto group; Y
represents an oxygen atom or a sulfur atom; and Rl, R2, R4 have the same significance as defined above.
That is, the compound of this invention shown by formula I
wherein R3 is a hydroxyl group or a mercapto group, i. e., the compound shown by formula Ia can be prepared by reacting the com-pound shown by formula II (i. e., isocyanic acid, isothiocyanic acid, and the lower alkyl-substituted derivatives of them) or the alkali metal salt thereof with the~c -aminocarbonyl compound shown ~762~i~
by formula III or the salt thereof. In the case of using the alk-ali metal salt of isocyanic acid or isothiocyanic acid, the reac-tion is performed in a solvent such as alcohol, aqueous alcohol, etc., with the addition of an acid such as hydrochloric acid, etc., at room temperature or under heating. In the case of heating, the reaction may be performed under refluxing at about the boiling point of the solvent used.
Also, in the case of using the lower alkyl-substituted deriv-ative of isocyanic acid or isothiocyanic acid, the reaction is per-formed in a basic solvent such as pyridine, etc., at room tempera-ture or under heating.
In addition, the compound of this invention shown by formula Ia wherein Y is a mercapto group, i. e., the compound shown by the formula N ~ - ~ R2 N R
wherein R4, Rl, and R2 have the same significance as defined above can be prepared by reacting the compound shown by the formula R4-NH~NH2 with the compound shown bYH0 CH R
(ii) Second production method:
I~I2 0=C-R2 N ~ ~ R2 R3-C=N-R4 + X-CH-Rl R3 ~N R
I
wherein ~ represents a halogen atom; and Rl-R4 have the same sig-nificance as defined above.
1176Z~O
That is, the compound of this invention shown by formula 1 can be prepared by reacting the compound shown by formula IV with the c~- halocarbonyl compound shown by formula V. This reaction is performed by heating the compound of formula IV and a corr~s-ponding amount o the compound of formula V in situ or in a propersolvent such as methanol, ethanol, toluene, dimethylformamide, ace-tone, chloroform, methyl ethyl ketone, ethyl acetate, methyl cell-osolve, ethyl cellosolve, digrim, acetonitrile, etc. The reaction temperature and the reaction period of time are suitably deter-mined according to the kinds of starting materials and solventused. In addition, the compound of formula IV may be used for the reaction as a salt thereof, such as a hydrochloride of an amidine derivative or ammonium amidodithiocarbonate.
Furthermore, when in the method, cyanourea (NH2CONHCN) is reacted with theo~ -halocarbonyl compound of formula V and then the product is hydrolyzed, the compound of formula I wher~in R3 is a hydroxyl group and -N-R4 is an imino yL'oUp~ i. e., the compound of this invention shown by the formula ~ R2 H0 ~ ~ Rl wherein Rl and R2 have the same significance as defined above can b~ produced.
1176'~60 (iii) Other production methods^
(1) oxidation Ia-2 ~ Xa-3 2-S N 1 Z-S ~
R4 ( )n' 4 (2) alkylation ~ 2 S 1 HS 1 Z-S ~-R
\ R4 4 \ 4 Ia-4 ~ desulfurization Ia-5 Ia-6 wherein n' represents 1 or Z; Z' represents a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group; and Rl, R2, R4 and Z have the same significance as defined above.
The oxidation method (1) is a method of producing the com-pound of this invention shown by formula I wherein R3 is (S)- Z
and n is 1 or 2, i. e., the S-oxide compound shown by formula I 3 The S-oxide compound can be prepared by reacting the corresponding compound of this inven~ion shown by formula I wherein R3 is -S Z
and n is 0, i. e., the thio compound shown by formula I 2 with an oxidizing agent in a solvent such as acetic acid, chloroform, 1,2-dimethoxyethane, etc., according to an ordinary manner. As the oxidizing agent. 10-40% hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc., is usually used. In this case, by ~7~i2~
suitably selecting the reaction conditions such as the reaction time, reaction temperature, the amount of the oxidizing agent, etc., a desired monooxide compound (n' = 1) or dioxide compound (n' = 2) can be obtained.
The alkylation method (2) is a method of producing the com-pound of this invention shown by formula I wherein R3 is -S -Z, n ()n is O, and Z is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group, i. e., the alkylthio compound shown by formula I 5. The alkyl-thio compound can be produced by alkylating the compound of this invention shown by formula I wherein R3 is -S -Z, Z is a hydrogen ()n atom, and n is 0, i. e., the mercapto (or thioxo) compound shown by formula I 4 with an alkylating agent in a solvent such as methanol, acetone, dimethylformamide, etc., by an ordinary manner.
As the alkylating agent used in the reaction, there are alkyl hal-ides or aralkyl halides such as methyl iodide, ethyl bromide,c~-bromopropionic acid,C~-bromoacetic acid, ethylCx-bromopropionate~
benzyl bromide, phenethyl iodide, etc., and dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, etc.
The desulfurization reaction (3) is a method of producing the compound of this invention shown by formula I wherein R3 is a hydrogen atom, i. e., the compound shown by formula I 6. The compound can be produced by desulfurizing the corresponding mer-capto (or thioxo) compound shown by formula I 4 accord~ing to a conventional manner, for example, by treating the compound with a Raney nickel catalyst.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this in-~176ZEiO
vention shown by foxmula I will then be described.
Effect on adjuvant-induced arthrites in rats:
Methods: Male Sprangue Dawley rat aged 7 weeks were used.
Drugs were evaluated by two methods as follows. All test dru~s were suspended in water with 0.5% methylcellulose (0.5% MC) and administered orally once a day.
(1) Therapeutic effect of drugs; arthritis was induced by a single injection of 0.1 ml of sterile suspension of Mycobacterium butyricum (6mg/ml) in liquid paraffin into tail skin of rats (day 0). After about 2 weeks, arthritic rats were selected and alloca-ted into groups. Drugs were given daily following about 10 days.
Thickness 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 thickness (~FT 10 mm) was calculated as a differ-ence between these two values. The results are shown in Table I
(2) Prophylactic effect of drugs: arthritis was induced bysingle subplanter injection-of 0.05 ml of the suspension into the left hind paw of rats. Drugs were given daily for 21 days start-ing from the day (day 0) of injection of the suspension. Thickn-ess of both feet, injected foot (left foot. FTl) and uninjectedfoot (right foot, FTR) were measured with dial thickness gauge on day O and 21. The percent inhibition (1%~) was calculated from difference in increased foot thickness between control and drug-treated group. The results are shown in Table II.
.. . . _ _ 11"~6'~
Table I (Therapeutic effect) Drugs Dose N Day 16-Da~ 17 (mg/kg/day P.O.) ~FT (xlO- mm) .
0.5/~MC - 3 233 ~ 59 Indomethacin 2 3 -173 + 62***
4-(3,5-di-tert-butyl-4~
hydroxyphenyl)-5-methyl-LO 2-oxo-4-imidazoline 25 3 -216 + 30***
. .
Drugs Dose N Day 16-Day 25 (mg/kg/day P.O.) ~FT (10 2mm) 0.50/~C - 3 97 + 91 Indomethacin 2 3 -216 + 30*
~5 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole 25 3 -153 + 56*
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-imidazole 25 3 -122 + 46*
117~2~
Drugs Dose N Day 16-Day 28 (mg/kg/day ~FT (xlO mm) P . O . ) r, 0.5% MC - 6 148 1 37 Indomethacin 2 6 -204 + 33 ***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-thiazole 25 3 -57 + 26***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-thiazole 25 3 -166 + 59***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-L5 2-oxo-4-imida~.oline 25 3 -247 + 49 ***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-imidazole 25 3 -103 + 71 **
Drugs Dose N Day 15-Day 28 (mg/kg/day ~FT (10 mm~
P.O- ) 0.5/~C - 3 96 + 162 Indomethacin 2 3 -161 ~ 137 *
4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-imidazole 25 3 -180 + 241*
u -Drugs Dose N Day 15-Day 29 mg/kgjday ~FT (I%) P.O.) (10 ~m) ' 5 0.5% MC _ 6 280 + 54 Indomethacin 1 6 -243 + 16 ***(69.1) 2 6 -260 t 24***(73.7) 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline 6.25 6 67 + 48**~30.8) L0 do. 12.5 6 -il4 + 33***(53.9) do. 25 6 -194 + 36***(66.7) 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline 6.25 6 -19 + 39***(41.3) do. 12.5 6 -176 + 27***(63.1) do. 25 6 -127 + 38***(54.0) _ _ Significant difference from control (t-test) *P~ 0.05 **P <0.01 ***P<0.001 Table 11 (prophylactic effect) ~76~
Drugs Dose N Day 21 (mg/kg/day L % R %
P . O . ) Indomethacin 1 864.6 81.8 do. 2 859.5 76.9 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole 25 853.1 65.8 L0 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-imidazole 25 868.1 81.3 Drugs Dose N Day 21 (mg/kg/day L R
P . O . ) Indomethacin 1 863.6 68.1 do. 2 863.9 98.0 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline 6.25 838.0 71.7 do. 12.5 830.3 61.6 do. 25 864.4 90.9 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline 6.25 811.6 35.8 do. 12.5 826.3 47.2 do. 25 860.1 70.1 1~'7~Z~
From the above results, it is apparent that the compounds of this invention have excellent pharmacological (therapeutic & pro-phylactic) effects against the adjuvant-induced arthritis.
As the above-described therapeutic and prohylactic test re-sults to adjuvant-induced arthritis, it is clear that the compounds of this invention shown by formula I possess remarkable therapeutic and prohylactic effects to adjuvant-induced arthritis.
Example 1 C~OOH
2S ~ ~ C~CH3 ~ ~ ~~ 2 ~ ~ (CH3)3 H C(CH3)3 1~
In 10 ml of chloroform was dissolved 0.8 g of 2-benzylthio-4-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazole and then 0.35 g of m-chloroperbenzoic acid was added to the solution at room temp-erature. After the reactiOn was over, the reaction mixture was washed with a diluted aqueous alkali solution, dried, and concen-trated under reduced pressure. The residue formed was subjec~ed to silica gel chromatography and eluted with chloroform. The fracti-on thus obtained was concentrated under reduced pressure and the residue was recrystallized from cyclohexane to provide 0.3 g of 2-25 benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole.
Melting point: 189-191C
~lemental analysis for C24 H30 2 6 12 C(%) H(%) ~(%) Calculated: 71.59 7.95 6.19 ~ound: 71.48 8.16 6.19 117~
NH2CH2 C(CH3)~ U~ - 3~ 3 30H~ II ~ C(CH3)3 HC~ (CH3)3 C-HC~ H C(CH3)3 N ~ C(CH3)3 To a mixed solution of 1.2 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride, 10 ml of ethanol, and 0.3 ml of concentrated hydrochloric acid was added a solution of 0.64 g of potassium isocyanate in 3 ml of water at room temperature. After stirring the mixture for 2 hours 0.3 ml of concentrated hydrochlo-ric acid was added thereto and the resultant mixture was refluxed for 2 hours. The reaction mixture thus obtained was poured into water and the precipitates formed were recovered by filtration.
The reaction product was then recrystallized from aqueous ethanol to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline.
Melting point: above 260C (decompd.) Elemental analysis for C17 H24 N2 2 1/2 C2 H5 OH
C(%) H(%) N(%) Calculated: 69.37 8.68 8.99 Found:69.08 9.04 8.84 Example 3 NH CHCH
HC~ (CH3)3 ~ C~CH~)3 ~ (CH3)3 HO ~ ~ H
C(CH3)3 1~7~2~
By following the same procedure as in Example 2 using 1.6 g of 4-(2-aminopropionyl)-2,6-di-tert-butyl-4-hydroxyphenol hydro-chloride, 20 ml of ethanol, 0.5 ml of concentrated hydrochloric acid, 0.8 g of potassium isocyanate, a reaction product thus ob-tained was recrystallized from aqueous isopropanol to provide 0.7 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline.
Melting point: above 270C (decompd.) Elemental analysis for C18 H26 N2 2 C(/~) H1%3 ~(%) Calculated: 71.49 8.67 9.26 Found: 71.47 8.82 9.22 This product was recrystallized from aqueous ethanol to provide the pure product having a melting point of 279-282C
Example 4 H2~C ~ S~ OH ~--OH
HC~ 3 3 C(CH3)3 l l C (CH3)3 HS ~C(CH3)3 To a mixed solution of 4.3 g of 4-(2-aminopropionyl)-2,6-di-tert-butylphenol hydrochloride, 50 ml of ethanol, and 1.2 ml of concentrated hydrochloric acid was added a solution of 2.2g of sodium thiocyanate in 4 ml of water at room temperature. After stirring the mixture for 1.5 hours at room temperature and further refluxing the mixture for 2 hours, the solvent was distilled off under reduced pressure. Then, ~0 ml of acetic acid was added to the residue and the mixture was refluxed for 2-3 hours. The reac tion mixture thus formed poured into in water and the precipitates formed were recovered by filtration. The product was recrystalliz-~L76Z6~
ed from isopropanol to provide 3.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline.
Melting point: 288-290C
Elementa a a y 18 26 2 3 2 C(%) H(%) N(%) Calculated: 66.63 9.05 7.40 Found: 66.519.14 7.43 Example 5 H2NCH2 C(CH3)3 C(CH3) C(CH3) OC ~ SCNNa ~ OH HS ~ ~ ~r~
HC~ (CH3)3 H (CH3)3 C(CH3)3 N ~ oH3)3 (CH3)3 The precipitates obtained by following the same procedure as in Example 4 using 18 g of 4-(2-aminoacetyl)-2,6-di-tert-butyl-phenol; hydrochloride, 150 ml of ethanol, and 5 ml of concentrated hydrochloric acid were subjected to silica gel chromatography and eluted with chloroform. The fraction thus obtained was concentra-ted under reduced pressure and the residue was recrystallized from benzenecyclohexane to provide 12 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)2-thioxo-4-imidazoline.
Melting point: 168-170C
Elemental analysis for C17 H24 N2 OS + 1/2 C6 H12:
C(%) H(%) N(%) Calculated: 69.27 8.06 8.08 Found: 69.33 8.46 7.76 Example 6 C(CH3)3 CH I N ~ H3)~ C(CH3~
17 C~CH¦)3 . _ . ~
1~762~3 To a mixture of 3.18 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-thioxo-4-imidazolineJ 50 ml of dry acetone, and 1.3 g of potassium carbonate was added 1.4 g of methyl iodide at room temperature. After stirring the mixture for one hour, the solvent was distilled off. To the residue thus formed was added water, and the precipitate formed were recovered by filtration and dried to provide 2 g of the product. Then, 0.8 g of the product was re-crystallized from toluene to provide 0,5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole.
Melting point: 249-251C
~lemental analysis for C18 H26 N2 OS:
C(%) H(%) ~(%) Calculated: 67.89 8.23 8.80 Found: 67.62 8.36 8.70 Example 7 (C~3)3 C~3~ ~ C(C~
By following the same procedure as in Example 6 using 0.32 g of 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazolineJ 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizinq the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Melting point: 184-186C
Elemental analysis ror Clg H28 N2 OS:
C(%) H(%) N(%) Calculated: 68.63 8.49 8.43 Found~ 68.42 8.74 8.40 1 76;~
Exam~le 8 C(CH3)3 CH3S ~ (C~3)3 ~ J~C (CH3)3 To a solution of 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylthioimidazole in 5 ml of chloroform was added 0.18 g of m-chloroperbenzoic acid at room temperature and the mixture was stirred for a day. The reaction mixture was washed with a diluted alkali solution, dried, concentrated under reduced pressure, and the residue thus formed was recrystallized from cyclohexane to provide 0.13 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylsulfinylimidazole.
Melting point: 106-108C
Mass spectrum: M+ 334 ~uclear magnetic resonance spectra (in CDCI3):
~(ppm): 1.48~S; 18H), 3.1(S, 3H), 5.3(S; lH), 7.32(S; lH) 7.44(S; 2H).
Example 9 ~ (CH3)3 CH3S~ ~ CH3)3 CH3S02 N -OH
In 10 ml of 1,2-dimethoxyethane was dissolved 0.62 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole and after adding thereto 0.44 g of m-chloroperbenzoic acid, the mixture was refluxed for 3-4 hours. 'rhe reaction mixture was cooled, washed with a diluted alkali solution, dried, and concentrated under re-duced pressure. The residue thus formed was recrystallized from cycloh~xane to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylsulfonylimidazole.
Melting point: 119-120C
. .
il7~Z~
Mass spectrum M+ 350 Nuclear magnetic resonance spectra ~in CDCI3):
~(ppm): 1.4 (S, 18H), 3.06(S, 3H), 5.06 (S, lH), 7.3 (S,-lH), 7.3 (S, lH), 7.48 (S, 2H).
Example 10 CH3S ~ ~ (C~3)3 ~ (CH3)3 By following the same procedure as in ~xample 9 using 0.9 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole, 10 ml of 1,2-dimethoxyethane, and 0.64 g of m-chloro-perbenzoic acid and recrystallizing the product from toluene, 0.3 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-sulfonylimidazole was obtained.
Melting point: 235-237C
Elemental analysis for Clg H28 N2 3 S:
C(%) H(%) N(%) Calculated: 62.61 7.74 7.69 Found: 62.91 8.01 7.25 Example 11 (CH3~c~H~ooccHBr)cH3 ~ ~ ~
C(CH3) C2H50OCCHS 3 3 C(CH ~
~- C 3~ ~ Co(cHH33~3 By following the same procedure as in Example 6 using 1.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thioxo-4-imidazoline, 30 ml of dry acetone, 0.99 g of potassium carbonate, and 1.3 g of ethyl a-bromopropionate and recrystallizing the product from a mixture of toluene and cyclohexane, 0.95 g of ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolylthio]propionate was obtained.
i~7~2~`~
Melting point: 80-82C
~lemental analysis for C22 H32 N2 3 S:
C(%) H(%) ~(%) Calculated: 65.31 7.97 6.92 Found:65.58 8.19 6.63 Example 12 H2NCH~ C(CH3)3 C(CH3)3 OC ~ OH SCNCH3 ) ~ ~ OH
HCe C(CH3)3 CH3 (CH3)3 After stirring a mixture of 100 ml of pyridine, 6 g of methyl isothiocyanate, and 3 g of 4-(2-aminoacetyl)-2,6-di-tert-butyl-phenol hydrochloride at room temperature for 2 hours, the resulted mixture was maintained at an inside temperature of 80-90C for 1.5 hours. The reaction mixture was concentrated under reduced pres-sure and then the residue was extracted with 100 ml of ethyl ace-tate. The extract was washed with diluted hydrochloric acid, dried, and concentrated under reduced pressure. The residue was recry-stallized from ethanol to provide 0.6 g of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methylimidazole.
Melting point: 288-289C
Nuclear magnetic resonance spectra (in CDCI3):
(ppm): 1.44 (S, 18H), 3.54 (S, 3H), 5.38 (S, lH), 6.64 (S, lH), 7.08 (S, 2H).
Mass spectrum: M+ 318 ~xample 13 HN 3 C(CH3)3 ~ C( 3)3 I CH3 C(CH ) \
51 ~ (CH3)3 N ~ OH ~= ~ ~ C(C~3) z~
A mixture of 1.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 0.5 g of a Raney nickel catalyst, and 50 ml of absolute ethanol was refluxed for one hour and after filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of cyclohexane and n-hexane to provide 1 g of 4-(3,5-di-tert-butyl-4 hydroxyphenyl)-5-methylimidazole.
Melting point: 207-209C
Elemental analysis for C18 H 26 N2 10C(%) H(%) N(%) Calculated: 75.48 9.15 9.78 Found: 75.31 9.40 9.53 Example 14 C(CH3)3 ~ (CH3)3 H S ~ C(CH3)3 CH3~ ¦ C(CH3)3 To a solution of 0.6 g of potassium hydroxide dissolved in 10 ml of ethanol was added 1.6 g of 4-(3,5-di-tert-butyl-4-hydro-xyphenyl)-2-mercapto-1-methylimidazole at a temperature below 10C
and the mixture was stirred for 20 minutes. Thereafter 0.7 g of methyl iodide was added to the mixture and after further stirring the mixture for 3 hours at 10C, the resulted mixture was poured into diluted hydrochloric acid and extracted twice each time with 50 ml of ethyl acetate. The extract was dried, concentrated under reduced pressure, and then the residue was recrystallized from isopropanol to provide 0.75 g of 5-(3,5-di-tert-butyl-4-hydroxy-phenyl)-l-methyl-2-methylthioimidazole hydroiodide.
Melting point: 215-217C
Elemental analysis for Clg H29 N2 OSI:
~7~2~
C(%) H(%) N(%) Calculated: 49.57 6.30 6.08 Found: 49.48 6.33 5.96 Mass spectrum: M+ 332 Example 15 C(CH3)3 C(CH3)3 HS ~ ~ OH CH3I ~ N ~ COHH3)3 In 30 ml of methanol was dissolved 0.18 g of metallic sodium and after adding thereto 2.1 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-mercaptothiazole, 1.15 g of methyl iodide was added drop-wise to the solution at 0-5C. After allowing to stand the mix-ture for 30 minutes at roOm temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated were recovered by filtration and recrystallized from n-hexane to provide 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl~-2-methyl-thiothiazole.
Melting point: 92-93~C
~lemental analysis for C18 H25 ~S2 C(%) H(%) N(%) S(%) Calculated: 64.44 7.51 4.17 19.11 Found: 64.36 7.69 4.23 19.28 Example 16 N~ ~ ~
CH3S S) C(CH3)3 CH302~ S C(CH3)3 ~7~2~`i) In 30 ml of chloroform was dissolved 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and then 1.5 g of m-chloroperbenzoic acid was added portionwise to the solution with s~:irring. After one hour the reaction mixture was washed with a 5% sodium hydrogen carbonate solution, and the chloroform layer was concentrated. The crystals obtained were recrystallized from methanol to provide 0.55 g of 3,5-di-tert-butyl-4~hydroxyphenyl-2-methylsulfonylthioazole.
Melting point: 183-18~C
~lemental analysis for C18 H25 ~3 S2 C(%) H(%) N(%) 3(%~
Calculated: 58.83 6.86 3.81 17.45 Found: 58.72 7.00 3.69 17.66 Example 17 C(CH ) C(CH ) ~ 3 3 ~ 3 3CH grCOOH
N ~ OH ) ~ ~
H S C(CH3)3 HOOCCH2 C(CH3)3 To 20 ml of benzene were added 0.64 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoace-tic acid and then 0.5 g of triethylamine was added dropwise to themixture with stirring. After one hour triethylamine hydrobromide thus precipitated was filtered off and the benzene solution was extracted with 10 ml of a 2% sodium hydroxide solution. The aqu-eous ~xtract was acidified by the addition of hydrochloric acid and extracted with ether. The ether solution was dried over anhy-drous sodium sulfate and concentrated. The crystals thus obtained were recrystallized from benzene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]acetic acid.
Melting point: 158-159C
Elemental analysis ror C19 H25 ~3 S2 ~17~2~i~
C t%) H(%) N (%) S (%) Calculated: 60.13 6.64 3.69 16.89 Found: 60.06 6.62 3.77 16.69 ExamPle 18 2 1 2 ~ C(CH3)3 HN C C(CH3)3 ~ ~ C(CH3)3 HC ~ ( 3)3~ OH --HO ~ CH3)3 _ ~ ~ ( H3)3 C(CH3)3 By following the same procedure as in Example 2 using 3.3 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydro-chloride, 1.62 g of potassium isocyanate, and 1.6 ml of concentrate hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline was obtained.
Melting point: 267-270C
Elemental analysis for Clg H28 N2 2 C(%) H(%) N(%~
Calculated: 72.12 8.92 8.85 Found: 71.83 9.17 8.62 Exam~le 19 CH
H NCHCH ~ 3 2 r CH3 CH ,CH3 Ol ~ OH ~ C(cH3)~rHol ~ o(CH3)3 HC~ C(CH3)3 C(CH3)3 C(CH3)3 1~762C~) By following the same procedure as in Example 2 using 1.7 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 0.8 g of potassium isocyanate, and 1 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 0.35 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl3-5-isopropyl-2-oxo-4-imidazoline was obtained.
Melting point: above 290C (decompd.) Elemental analysis for C20 H30 N2 2 C(%) H(%) N(%) Calculated: 72.69 9.15 8.48 Found: 72.37 9.26 8.47 Example 20 ol~ 3 i~aSCII )~ ~C(CH~ ~CocHH3)3 HCl (CH3)3 (CH3)3 (CH3)3 N ~2 ~ C(CH3) HS ~ N ~ ~ OH
C(CH3)3 By following the same procedure in Example 4 using 13 1 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochlor-ide, 6.5 g of sodium thiocyanate, 3.4 ml of concentrated and 100 ml of acetic acid and recrystallizing the reaction product from iso-propanol, 6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-5 thioxo-4-imidazoline was obtained.
Melting point: 279-281C
Elemental analysis for Clg H28 N2 OS + (CH3)2 CHOH:
C(%) H(%) N(%) Calculated: 67.31 9.24 7.14 -~o Found: 67.17 9.36 7.29 CH 117~2~
~ 3 Example 21 H2NCHCH CH3 CH <CH3 ¦ ~C (CH3~ ~ <~
HS ~ ~ ~ CoCH3)3 H C(CH3) By following the same procedure as in Example 4 using 3.4 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 1.6 g of sodium thiocyanate, 1 ml of concentrated hydrochloric acid, and 31 ml of acetic acid and recrystallizing the reaction product from water-containing isopropanol, 0.8 g of 4-(3,5-di-tert-butyl~4-hydroxyphenyll-5-isopropyl-2-thioxo-4-imidazoline was obtained.
Melting point: above 300C (decompd.) Elemental analysis for C20 H30 N2 OS:
C (%) H (%)N (%) Calculated: 69.32 8.738.08 Found: 69.18 8.95 7.74 Example 22 S ~ ~ oHCH3)3~N ~ CoCH3)3 C(CH3)3C(CH3)3 By following the same procedure as in Example 13 using 2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline, 50 ml of absolute ethanol, and 1 g of a Raney nickel catalyst and recrystallizing the reaction product from toluene, 0.9 g of 4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-5-ethyl-imidazole was obtained.
Melting point: 200-201C
Elemental analysis for Clg H28 N2 = 1/2 C7 H8 117~2Ç~
C(%) H(%) N(%) Calculated: 77.99 9.31 8.08 Found: 77.72 9.53 8.13 Example 23 2 2 (CN3)2 CH2CH(CH3)2 CH2CH(CH3)2 OC~OH ~K ~(~ OH 3 3~rC~CH3)3 .HCe C(CH3)3 CH2CH(CH3)~
~ H3)3 HO N ~ OH
H C(CH3)3 By following the same procedure as in Example 2, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-oxo-4-imidazoline was prod~ed.
Melting point: 286-289~C (benzene-hexane) Elemental analysis for C21 H32 ~2 2 C(%) H(%) N(%) Calculated: 73.22 9.36 8.13 Found:73.43 9.57 8.18 Examples 24-30 HJ~ 3 ) 3_3~_ 3 3( E~CHH) ) 3) By following the same procedure as in Example 6, the follow-ing compounds were produced.
~xample 24 Compoundo 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthio-5-methylimidazole.
Appln. Laid Open ~o. 7669/'78). The benzoxazole compounds and the benzothiazole compounds are used as an antioxidant and the imidaz-olidine compounds are used as intermediates for 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-inflammatory agent. About the acetic acid compound, the use as an anti-inflammatory agent is suggested as described above but there is no disclosure about the practical pharmacological effect of the compound as an anti-inflammatory agent and also the chemi-cal structure of the acetic acid compound is a heterocyclic ring-substituted acetic acid derivative, which belongs to a nonsteroidal acidic anti-inflammatory agent and hence differs from the com-pounds of this invention shown by formula I in chemical structure.
The particularly preferred compounds in the foregoing heter-ocyclic compounds (I) are as follows, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imida-zoline, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imida-zoline 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole.
4-3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole, 4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole, and 1~'7~2~
4-(3,5-di-tert-butyl-~-hydroxyphenyl)-5-ethyl-2-methylthioimidaz-ole.
In addition, there are prototropic isomers on the compounds of this invention shown by formula I. For example, in the compounds of this invention shown by formula I wherein R3 is -S - Z (wherein n is 0 and Z is a hydrogen atom) or R3 is -oZ (wherein Z is a hydrogen atom), there are following prototropic isomers:
H ~ ` ,S~
0~ \R
The compounds of this invention shown by formula I can be prepared by the following methods;
(i) First production method:
~H2 -CIH-R
R4-N=C-Y + 0=C-R y ~ R
II III Ia wherein Y represents a hydroxyl group or a mercapto group; Y
represents an oxygen atom or a sulfur atom; and Rl, R2, R4 have the same significance as defined above.
That is, the compound of this invention shown by formula I
wherein R3 is a hydroxyl group or a mercapto group, i. e., the compound shown by formula Ia can be prepared by reacting the com-pound shown by formula II (i. e., isocyanic acid, isothiocyanic acid, and the lower alkyl-substituted derivatives of them) or the alkali metal salt thereof with the~c -aminocarbonyl compound shown ~762~i~
by formula III or the salt thereof. In the case of using the alk-ali metal salt of isocyanic acid or isothiocyanic acid, the reac-tion is performed in a solvent such as alcohol, aqueous alcohol, etc., with the addition of an acid such as hydrochloric acid, etc., at room temperature or under heating. In the case of heating, the reaction may be performed under refluxing at about the boiling point of the solvent used.
Also, in the case of using the lower alkyl-substituted deriv-ative of isocyanic acid or isothiocyanic acid, the reaction is per-formed in a basic solvent such as pyridine, etc., at room tempera-ture or under heating.
In addition, the compound of this invention shown by formula Ia wherein Y is a mercapto group, i. e., the compound shown by the formula N ~ - ~ R2 N R
wherein R4, Rl, and R2 have the same significance as defined above can be prepared by reacting the compound shown by the formula R4-NH~NH2 with the compound shown bYH0 CH R
(ii) Second production method:
I~I2 0=C-R2 N ~ ~ R2 R3-C=N-R4 + X-CH-Rl R3 ~N R
I
wherein ~ represents a halogen atom; and Rl-R4 have the same sig-nificance as defined above.
1176Z~O
That is, the compound of this invention shown by formula 1 can be prepared by reacting the compound shown by formula IV with the c~- halocarbonyl compound shown by formula V. This reaction is performed by heating the compound of formula IV and a corr~s-ponding amount o the compound of formula V in situ or in a propersolvent such as methanol, ethanol, toluene, dimethylformamide, ace-tone, chloroform, methyl ethyl ketone, ethyl acetate, methyl cell-osolve, ethyl cellosolve, digrim, acetonitrile, etc. The reaction temperature and the reaction period of time are suitably deter-mined according to the kinds of starting materials and solventused. In addition, the compound of formula IV may be used for the reaction as a salt thereof, such as a hydrochloride of an amidine derivative or ammonium amidodithiocarbonate.
Furthermore, when in the method, cyanourea (NH2CONHCN) is reacted with theo~ -halocarbonyl compound of formula V and then the product is hydrolyzed, the compound of formula I wher~in R3 is a hydroxyl group and -N-R4 is an imino yL'oUp~ i. e., the compound of this invention shown by the formula ~ R2 H0 ~ ~ Rl wherein Rl and R2 have the same significance as defined above can b~ produced.
1176'~60 (iii) Other production methods^
(1) oxidation Ia-2 ~ Xa-3 2-S N 1 Z-S ~
R4 ( )n' 4 (2) alkylation ~ 2 S 1 HS 1 Z-S ~-R
\ R4 4 \ 4 Ia-4 ~ desulfurization Ia-5 Ia-6 wherein n' represents 1 or Z; Z' represents a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group; and Rl, R2, R4 and Z have the same significance as defined above.
The oxidation method (1) is a method of producing the com-pound of this invention shown by formula I wherein R3 is (S)- Z
and n is 1 or 2, i. e., the S-oxide compound shown by formula I 3 The S-oxide compound can be prepared by reacting the corresponding compound of this inven~ion shown by formula I wherein R3 is -S Z
and n is 0, i. e., the thio compound shown by formula I 2 with an oxidizing agent in a solvent such as acetic acid, chloroform, 1,2-dimethoxyethane, etc., according to an ordinary manner. As the oxidizing agent. 10-40% hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc., is usually used. In this case, by ~7~i2~
suitably selecting the reaction conditions such as the reaction time, reaction temperature, the amount of the oxidizing agent, etc., a desired monooxide compound (n' = 1) or dioxide compound (n' = 2) can be obtained.
The alkylation method (2) is a method of producing the com-pound of this invention shown by formula I wherein R3 is -S -Z, n ()n is O, and Z is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group, i. e., the alkylthio compound shown by formula I 5. The alkyl-thio compound can be produced by alkylating the compound of this invention shown by formula I wherein R3 is -S -Z, Z is a hydrogen ()n atom, and n is 0, i. e., the mercapto (or thioxo) compound shown by formula I 4 with an alkylating agent in a solvent such as methanol, acetone, dimethylformamide, etc., by an ordinary manner.
As the alkylating agent used in the reaction, there are alkyl hal-ides or aralkyl halides such as methyl iodide, ethyl bromide,c~-bromopropionic acid,C~-bromoacetic acid, ethylCx-bromopropionate~
benzyl bromide, phenethyl iodide, etc., and dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, etc.
The desulfurization reaction (3) is a method of producing the compound of this invention shown by formula I wherein R3 is a hydrogen atom, i. e., the compound shown by formula I 6. The compound can be produced by desulfurizing the corresponding mer-capto (or thioxo) compound shown by formula I 4 accord~ing to a conventional manner, for example, by treating the compound with a Raney nickel catalyst.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this in-~176ZEiO
vention shown by foxmula I will then be described.
Effect on adjuvant-induced arthrites in rats:
Methods: Male Sprangue Dawley rat aged 7 weeks were used.
Drugs were evaluated by two methods as follows. All test dru~s were suspended in water with 0.5% methylcellulose (0.5% MC) and administered orally once a day.
(1) Therapeutic effect of drugs; arthritis was induced by a single injection of 0.1 ml of sterile suspension of Mycobacterium butyricum (6mg/ml) in liquid paraffin into tail skin of rats (day 0). After about 2 weeks, arthritic rats were selected and alloca-ted into groups. Drugs were given daily following about 10 days.
Thickness 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 thickness (~FT 10 mm) was calculated as a differ-ence between these two values. The results are shown in Table I
(2) Prophylactic effect of drugs: arthritis was induced bysingle subplanter injection-of 0.05 ml of the suspension into the left hind paw of rats. Drugs were given daily for 21 days start-ing from the day (day 0) of injection of the suspension. Thickn-ess of both feet, injected foot (left foot. FTl) and uninjectedfoot (right foot, FTR) were measured with dial thickness gauge on day O and 21. The percent inhibition (1%~) was calculated from difference in increased foot thickness between control and drug-treated group. The results are shown in Table II.
.. . . _ _ 11"~6'~
Table I (Therapeutic effect) Drugs Dose N Day 16-Da~ 17 (mg/kg/day P.O.) ~FT (xlO- mm) .
0.5/~MC - 3 233 ~ 59 Indomethacin 2 3 -173 + 62***
4-(3,5-di-tert-butyl-4~
hydroxyphenyl)-5-methyl-LO 2-oxo-4-imidazoline 25 3 -216 + 30***
. .
Drugs Dose N Day 16-Day 25 (mg/kg/day P.O.) ~FT (10 2mm) 0.50/~C - 3 97 + 91 Indomethacin 2 3 -216 + 30*
~5 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole 25 3 -153 + 56*
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-imidazole 25 3 -122 + 46*
117~2~
Drugs Dose N Day 16-Day 28 (mg/kg/day ~FT (xlO mm) P . O . ) r, 0.5% MC - 6 148 1 37 Indomethacin 2 6 -204 + 33 ***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-thiazole 25 3 -57 + 26***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-thiazole 25 3 -166 + 59***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-L5 2-oxo-4-imida~.oline 25 3 -247 + 49 ***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-imidazole 25 3 -103 + 71 **
Drugs Dose N Day 15-Day 28 (mg/kg/day ~FT (10 mm~
P.O- ) 0.5/~C - 3 96 + 162 Indomethacin 2 3 -161 ~ 137 *
4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-imidazole 25 3 -180 + 241*
u -Drugs Dose N Day 15-Day 29 mg/kgjday ~FT (I%) P.O.) (10 ~m) ' 5 0.5% MC _ 6 280 + 54 Indomethacin 1 6 -243 + 16 ***(69.1) 2 6 -260 t 24***(73.7) 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline 6.25 6 67 + 48**~30.8) L0 do. 12.5 6 -il4 + 33***(53.9) do. 25 6 -194 + 36***(66.7) 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline 6.25 6 -19 + 39***(41.3) do. 12.5 6 -176 + 27***(63.1) do. 25 6 -127 + 38***(54.0) _ _ Significant difference from control (t-test) *P~ 0.05 **P <0.01 ***P<0.001 Table 11 (prophylactic effect) ~76~
Drugs Dose N Day 21 (mg/kg/day L % R %
P . O . ) Indomethacin 1 864.6 81.8 do. 2 859.5 76.9 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole 25 853.1 65.8 L0 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-imidazole 25 868.1 81.3 Drugs Dose N Day 21 (mg/kg/day L R
P . O . ) Indomethacin 1 863.6 68.1 do. 2 863.9 98.0 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline 6.25 838.0 71.7 do. 12.5 830.3 61.6 do. 25 864.4 90.9 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline 6.25 811.6 35.8 do. 12.5 826.3 47.2 do. 25 860.1 70.1 1~'7~Z~
From the above results, it is apparent that the compounds of this invention have excellent pharmacological (therapeutic & pro-phylactic) effects against the adjuvant-induced arthritis.
As the above-described therapeutic and prohylactic test re-sults to adjuvant-induced arthritis, it is clear that the compounds of this invention shown by formula I possess remarkable therapeutic and prohylactic effects to adjuvant-induced arthritis.
Example 1 C~OOH
2S ~ ~ C~CH3 ~ ~ ~~ 2 ~ ~ (CH3)3 H C(CH3)3 1~
In 10 ml of chloroform was dissolved 0.8 g of 2-benzylthio-4-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazole and then 0.35 g of m-chloroperbenzoic acid was added to the solution at room temp-erature. After the reactiOn was over, the reaction mixture was washed with a diluted aqueous alkali solution, dried, and concen-trated under reduced pressure. The residue formed was subjec~ed to silica gel chromatography and eluted with chloroform. The fracti-on thus obtained was concentrated under reduced pressure and the residue was recrystallized from cyclohexane to provide 0.3 g of 2-25 benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole.
Melting point: 189-191C
~lemental analysis for C24 H30 2 6 12 C(%) H(%) ~(%) Calculated: 71.59 7.95 6.19 ~ound: 71.48 8.16 6.19 117~
NH2CH2 C(CH3)~ U~ - 3~ 3 30H~ II ~ C(CH3)3 HC~ (CH3)3 C-HC~ H C(CH3)3 N ~ C(CH3)3 To a mixed solution of 1.2 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride, 10 ml of ethanol, and 0.3 ml of concentrated hydrochloric acid was added a solution of 0.64 g of potassium isocyanate in 3 ml of water at room temperature. After stirring the mixture for 2 hours 0.3 ml of concentrated hydrochlo-ric acid was added thereto and the resultant mixture was refluxed for 2 hours. The reaction mixture thus obtained was poured into water and the precipitates formed were recovered by filtration.
The reaction product was then recrystallized from aqueous ethanol to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline.
Melting point: above 260C (decompd.) Elemental analysis for C17 H24 N2 2 1/2 C2 H5 OH
C(%) H(%) N(%) Calculated: 69.37 8.68 8.99 Found:69.08 9.04 8.84 Example 3 NH CHCH
HC~ (CH3)3 ~ C~CH~)3 ~ (CH3)3 HO ~ ~ H
C(CH3)3 1~7~2~
By following the same procedure as in Example 2 using 1.6 g of 4-(2-aminopropionyl)-2,6-di-tert-butyl-4-hydroxyphenol hydro-chloride, 20 ml of ethanol, 0.5 ml of concentrated hydrochloric acid, 0.8 g of potassium isocyanate, a reaction product thus ob-tained was recrystallized from aqueous isopropanol to provide 0.7 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline.
Melting point: above 270C (decompd.) Elemental analysis for C18 H26 N2 2 C(/~) H1%3 ~(%) Calculated: 71.49 8.67 9.26 Found: 71.47 8.82 9.22 This product was recrystallized from aqueous ethanol to provide the pure product having a melting point of 279-282C
Example 4 H2~C ~ S~ OH ~--OH
HC~ 3 3 C(CH3)3 l l C (CH3)3 HS ~C(CH3)3 To a mixed solution of 4.3 g of 4-(2-aminopropionyl)-2,6-di-tert-butylphenol hydrochloride, 50 ml of ethanol, and 1.2 ml of concentrated hydrochloric acid was added a solution of 2.2g of sodium thiocyanate in 4 ml of water at room temperature. After stirring the mixture for 1.5 hours at room temperature and further refluxing the mixture for 2 hours, the solvent was distilled off under reduced pressure. Then, ~0 ml of acetic acid was added to the residue and the mixture was refluxed for 2-3 hours. The reac tion mixture thus formed poured into in water and the precipitates formed were recovered by filtration. The product was recrystalliz-~L76Z6~
ed from isopropanol to provide 3.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline.
Melting point: 288-290C
Elementa a a y 18 26 2 3 2 C(%) H(%) N(%) Calculated: 66.63 9.05 7.40 Found: 66.519.14 7.43 Example 5 H2NCH2 C(CH3)3 C(CH3) C(CH3) OC ~ SCNNa ~ OH HS ~ ~ ~r~
HC~ (CH3)3 H (CH3)3 C(CH3)3 N ~ oH3)3 (CH3)3 The precipitates obtained by following the same procedure as in Example 4 using 18 g of 4-(2-aminoacetyl)-2,6-di-tert-butyl-phenol; hydrochloride, 150 ml of ethanol, and 5 ml of concentrated hydrochloric acid were subjected to silica gel chromatography and eluted with chloroform. The fraction thus obtained was concentra-ted under reduced pressure and the residue was recrystallized from benzenecyclohexane to provide 12 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)2-thioxo-4-imidazoline.
Melting point: 168-170C
Elemental analysis for C17 H24 N2 OS + 1/2 C6 H12:
C(%) H(%) N(%) Calculated: 69.27 8.06 8.08 Found: 69.33 8.46 7.76 Example 6 C(CH3)3 CH I N ~ H3)~ C(CH3~
17 C~CH¦)3 . _ . ~
1~762~3 To a mixture of 3.18 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-thioxo-4-imidazolineJ 50 ml of dry acetone, and 1.3 g of potassium carbonate was added 1.4 g of methyl iodide at room temperature. After stirring the mixture for one hour, the solvent was distilled off. To the residue thus formed was added water, and the precipitate formed were recovered by filtration and dried to provide 2 g of the product. Then, 0.8 g of the product was re-crystallized from toluene to provide 0,5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole.
Melting point: 249-251C
~lemental analysis for C18 H26 N2 OS:
C(%) H(%) ~(%) Calculated: 67.89 8.23 8.80 Found: 67.62 8.36 8.70 Example 7 (C~3)3 C~3~ ~ C(C~
By following the same procedure as in Example 6 using 0.32 g of 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazolineJ 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizinq the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Melting point: 184-186C
Elemental analysis ror Clg H28 N2 OS:
C(%) H(%) N(%) Calculated: 68.63 8.49 8.43 Found~ 68.42 8.74 8.40 1 76;~
Exam~le 8 C(CH3)3 CH3S ~ (C~3)3 ~ J~C (CH3)3 To a solution of 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylthioimidazole in 5 ml of chloroform was added 0.18 g of m-chloroperbenzoic acid at room temperature and the mixture was stirred for a day. The reaction mixture was washed with a diluted alkali solution, dried, concentrated under reduced pressure, and the residue thus formed was recrystallized from cyclohexane to provide 0.13 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylsulfinylimidazole.
Melting point: 106-108C
Mass spectrum: M+ 334 ~uclear magnetic resonance spectra (in CDCI3):
~(ppm): 1.48~S; 18H), 3.1(S, 3H), 5.3(S; lH), 7.32(S; lH) 7.44(S; 2H).
Example 9 ~ (CH3)3 CH3S~ ~ CH3)3 CH3S02 N -OH
In 10 ml of 1,2-dimethoxyethane was dissolved 0.62 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole and after adding thereto 0.44 g of m-chloroperbenzoic acid, the mixture was refluxed for 3-4 hours. 'rhe reaction mixture was cooled, washed with a diluted alkali solution, dried, and concentrated under re-duced pressure. The residue thus formed was recrystallized from cycloh~xane to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylsulfonylimidazole.
Melting point: 119-120C
. .
il7~Z~
Mass spectrum M+ 350 Nuclear magnetic resonance spectra ~in CDCI3):
~(ppm): 1.4 (S, 18H), 3.06(S, 3H), 5.06 (S, lH), 7.3 (S,-lH), 7.3 (S, lH), 7.48 (S, 2H).
Example 10 CH3S ~ ~ (C~3)3 ~ (CH3)3 By following the same procedure as in ~xample 9 using 0.9 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole, 10 ml of 1,2-dimethoxyethane, and 0.64 g of m-chloro-perbenzoic acid and recrystallizing the product from toluene, 0.3 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-sulfonylimidazole was obtained.
Melting point: 235-237C
Elemental analysis for Clg H28 N2 3 S:
C(%) H(%) N(%) Calculated: 62.61 7.74 7.69 Found: 62.91 8.01 7.25 Example 11 (CH3~c~H~ooccHBr)cH3 ~ ~ ~
C(CH3) C2H50OCCHS 3 3 C(CH ~
~- C 3~ ~ Co(cHH33~3 By following the same procedure as in Example 6 using 1.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thioxo-4-imidazoline, 30 ml of dry acetone, 0.99 g of potassium carbonate, and 1.3 g of ethyl a-bromopropionate and recrystallizing the product from a mixture of toluene and cyclohexane, 0.95 g of ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolylthio]propionate was obtained.
i~7~2~`~
Melting point: 80-82C
~lemental analysis for C22 H32 N2 3 S:
C(%) H(%) ~(%) Calculated: 65.31 7.97 6.92 Found:65.58 8.19 6.63 Example 12 H2NCH~ C(CH3)3 C(CH3)3 OC ~ OH SCNCH3 ) ~ ~ OH
HCe C(CH3)3 CH3 (CH3)3 After stirring a mixture of 100 ml of pyridine, 6 g of methyl isothiocyanate, and 3 g of 4-(2-aminoacetyl)-2,6-di-tert-butyl-phenol hydrochloride at room temperature for 2 hours, the resulted mixture was maintained at an inside temperature of 80-90C for 1.5 hours. The reaction mixture was concentrated under reduced pres-sure and then the residue was extracted with 100 ml of ethyl ace-tate. The extract was washed with diluted hydrochloric acid, dried, and concentrated under reduced pressure. The residue was recry-stallized from ethanol to provide 0.6 g of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methylimidazole.
Melting point: 288-289C
Nuclear magnetic resonance spectra (in CDCI3):
(ppm): 1.44 (S, 18H), 3.54 (S, 3H), 5.38 (S, lH), 6.64 (S, lH), 7.08 (S, 2H).
Mass spectrum: M+ 318 ~xample 13 HN 3 C(CH3)3 ~ C( 3)3 I CH3 C(CH ) \
51 ~ (CH3)3 N ~ OH ~= ~ ~ C(C~3) z~
A mixture of 1.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 0.5 g of a Raney nickel catalyst, and 50 ml of absolute ethanol was refluxed for one hour and after filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of cyclohexane and n-hexane to provide 1 g of 4-(3,5-di-tert-butyl-4 hydroxyphenyl)-5-methylimidazole.
Melting point: 207-209C
Elemental analysis for C18 H 26 N2 10C(%) H(%) N(%) Calculated: 75.48 9.15 9.78 Found: 75.31 9.40 9.53 Example 14 C(CH3)3 ~ (CH3)3 H S ~ C(CH3)3 CH3~ ¦ C(CH3)3 To a solution of 0.6 g of potassium hydroxide dissolved in 10 ml of ethanol was added 1.6 g of 4-(3,5-di-tert-butyl-4-hydro-xyphenyl)-2-mercapto-1-methylimidazole at a temperature below 10C
and the mixture was stirred for 20 minutes. Thereafter 0.7 g of methyl iodide was added to the mixture and after further stirring the mixture for 3 hours at 10C, the resulted mixture was poured into diluted hydrochloric acid and extracted twice each time with 50 ml of ethyl acetate. The extract was dried, concentrated under reduced pressure, and then the residue was recrystallized from isopropanol to provide 0.75 g of 5-(3,5-di-tert-butyl-4-hydroxy-phenyl)-l-methyl-2-methylthioimidazole hydroiodide.
Melting point: 215-217C
Elemental analysis for Clg H29 N2 OSI:
~7~2~
C(%) H(%) N(%) Calculated: 49.57 6.30 6.08 Found: 49.48 6.33 5.96 Mass spectrum: M+ 332 Example 15 C(CH3)3 C(CH3)3 HS ~ ~ OH CH3I ~ N ~ COHH3)3 In 30 ml of methanol was dissolved 0.18 g of metallic sodium and after adding thereto 2.1 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-mercaptothiazole, 1.15 g of methyl iodide was added drop-wise to the solution at 0-5C. After allowing to stand the mix-ture for 30 minutes at roOm temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated were recovered by filtration and recrystallized from n-hexane to provide 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl~-2-methyl-thiothiazole.
Melting point: 92-93~C
~lemental analysis for C18 H25 ~S2 C(%) H(%) N(%) S(%) Calculated: 64.44 7.51 4.17 19.11 Found: 64.36 7.69 4.23 19.28 Example 16 N~ ~ ~
CH3S S) C(CH3)3 CH302~ S C(CH3)3 ~7~2~`i) In 30 ml of chloroform was dissolved 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and then 1.5 g of m-chloroperbenzoic acid was added portionwise to the solution with s~:irring. After one hour the reaction mixture was washed with a 5% sodium hydrogen carbonate solution, and the chloroform layer was concentrated. The crystals obtained were recrystallized from methanol to provide 0.55 g of 3,5-di-tert-butyl-4~hydroxyphenyl-2-methylsulfonylthioazole.
Melting point: 183-18~C
~lemental analysis for C18 H25 ~3 S2 C(%) H(%) N(%) 3(%~
Calculated: 58.83 6.86 3.81 17.45 Found: 58.72 7.00 3.69 17.66 Example 17 C(CH ) C(CH ) ~ 3 3 ~ 3 3CH grCOOH
N ~ OH ) ~ ~
H S C(CH3)3 HOOCCH2 C(CH3)3 To 20 ml of benzene were added 0.64 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoace-tic acid and then 0.5 g of triethylamine was added dropwise to themixture with stirring. After one hour triethylamine hydrobromide thus precipitated was filtered off and the benzene solution was extracted with 10 ml of a 2% sodium hydroxide solution. The aqu-eous ~xtract was acidified by the addition of hydrochloric acid and extracted with ether. The ether solution was dried over anhy-drous sodium sulfate and concentrated. The crystals thus obtained were recrystallized from benzene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]acetic acid.
Melting point: 158-159C
Elemental analysis ror C19 H25 ~3 S2 ~17~2~i~
C t%) H(%) N (%) S (%) Calculated: 60.13 6.64 3.69 16.89 Found: 60.06 6.62 3.77 16.69 ExamPle 18 2 1 2 ~ C(CH3)3 HN C C(CH3)3 ~ ~ C(CH3)3 HC ~ ( 3)3~ OH --HO ~ CH3)3 _ ~ ~ ( H3)3 C(CH3)3 By following the same procedure as in Example 2 using 3.3 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydro-chloride, 1.62 g of potassium isocyanate, and 1.6 ml of concentrate hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline was obtained.
Melting point: 267-270C
Elemental analysis for Clg H28 N2 2 C(%) H(%) N(%~
Calculated: 72.12 8.92 8.85 Found: 71.83 9.17 8.62 Exam~le 19 CH
H NCHCH ~ 3 2 r CH3 CH ,CH3 Ol ~ OH ~ C(cH3)~rHol ~ o(CH3)3 HC~ C(CH3)3 C(CH3)3 C(CH3)3 1~762C~) By following the same procedure as in Example 2 using 1.7 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 0.8 g of potassium isocyanate, and 1 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 0.35 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl3-5-isopropyl-2-oxo-4-imidazoline was obtained.
Melting point: above 290C (decompd.) Elemental analysis for C20 H30 N2 2 C(%) H(%) N(%) Calculated: 72.69 9.15 8.48 Found: 72.37 9.26 8.47 Example 20 ol~ 3 i~aSCII )~ ~C(CH~ ~CocHH3)3 HCl (CH3)3 (CH3)3 (CH3)3 N ~2 ~ C(CH3) HS ~ N ~ ~ OH
C(CH3)3 By following the same procedure in Example 4 using 13 1 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochlor-ide, 6.5 g of sodium thiocyanate, 3.4 ml of concentrated and 100 ml of acetic acid and recrystallizing the reaction product from iso-propanol, 6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-5 thioxo-4-imidazoline was obtained.
Melting point: 279-281C
Elemental analysis for Clg H28 N2 OS + (CH3)2 CHOH:
C(%) H(%) N(%) Calculated: 67.31 9.24 7.14 -~o Found: 67.17 9.36 7.29 CH 117~2~
~ 3 Example 21 H2NCHCH CH3 CH <CH3 ¦ ~C (CH3~ ~ <~
HS ~ ~ ~ CoCH3)3 H C(CH3) By following the same procedure as in Example 4 using 3.4 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 1.6 g of sodium thiocyanate, 1 ml of concentrated hydrochloric acid, and 31 ml of acetic acid and recrystallizing the reaction product from water-containing isopropanol, 0.8 g of 4-(3,5-di-tert-butyl~4-hydroxyphenyll-5-isopropyl-2-thioxo-4-imidazoline was obtained.
Melting point: above 300C (decompd.) Elemental analysis for C20 H30 N2 OS:
C (%) H (%)N (%) Calculated: 69.32 8.738.08 Found: 69.18 8.95 7.74 Example 22 S ~ ~ oHCH3)3~N ~ CoCH3)3 C(CH3)3C(CH3)3 By following the same procedure as in Example 13 using 2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline, 50 ml of absolute ethanol, and 1 g of a Raney nickel catalyst and recrystallizing the reaction product from toluene, 0.9 g of 4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-5-ethyl-imidazole was obtained.
Melting point: 200-201C
Elemental analysis for Clg H28 N2 = 1/2 C7 H8 117~2Ç~
C(%) H(%) N(%) Calculated: 77.99 9.31 8.08 Found: 77.72 9.53 8.13 Example 23 2 2 (CN3)2 CH2CH(CH3)2 CH2CH(CH3)2 OC~OH ~K ~(~ OH 3 3~rC~CH3)3 .HCe C(CH3)3 CH2CH(CH3)~
~ H3)3 HO N ~ OH
H C(CH3)3 By following the same procedure as in Example 2, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-oxo-4-imidazoline was prod~ed.
Melting point: 286-289~C (benzene-hexane) Elemental analysis for C21 H32 ~2 2 C(%) H(%) N(%) Calculated: 73.22 9.36 8.13 Found:73.43 9.57 8.18 Examples 24-30 HJ~ 3 ) 3_3~_ 3 3( E~CHH) ) 3) By following the same procedure as in Example 6, the follow-ing compounds were produced.
~xample 24 Compoundo 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthio-5-methylimidazole.
3~ ~ = CH2 CH3) ~7~i2~
Melting point: 245-250C (toluene) Elemental analysis for C20 H30 N2 OS:
C(/O) H(%) N(%) S(%) Calculated: 69.32 8.73 8.08 9.25 Found: 69.38 8.70 8.00 9.47 ExamPle 25 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methylimidazole.
( ~ = CH3, ~ = CH /CH
Melting point: 250-258C (toluene) Elemental analysis for C21 H32 N2 OS:
C(%) H(%) N(%) S(%) Calculated: 69.96 8.95 7.77 8.89 Found: 69.74 9.02 7.61 8.63 Example 26 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthioimidazole.
( ~ = CH2CH3, ~ 3 Melting point: 210-211C (toluene) Elemental analysis for C20 H30 ~2 OS:
C(%) H(%) N(%) Calculated: 69.32 8.73 8.08 Found: 69.05 8.68 7.48 Bxample 27 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthioimidazole.
( ~)= C~2CH3~ (~) = CH2CH3) Melting point: 226-228C (toluene) Elemental analysis for C21 H32 N2 OS
~17~
C(%) H(%) N(%) Calculated 69.96 8.95 7.74 Found: 70.18 8.97 7.63 Example 28 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl -2-isopropylthioimidazole.
( ~ CH2CH3, ~ = CH ~ 3 Melting point: 247-248C (toluene) Elemental analysis for C22H34N20S:
~ ~7~2~
C(%) H(%) N(%) Calculated: 70.54 9.15 7.48 Found: 70.32 9.27 7.37 Exam~le 29 Compound: 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-- ethyl-2-ethylthioimidazole.
( (~ = CH2CH3J (~ = CH~CH
Melting point: 222-223C (ethyl acetate-hexane) Elemental analysis for C21 H32 N2 OS:
C(%) H(%) N(%) Calculated: 69.96 8.95 7.77 Found: 69.78 9.01 7.65 Example 30 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methylthioimidazole.
~ = CH2CH~CH , ~ = CH3 ) Melting point: 210-212C (benzene-hexane) Elemental analysis for C22 H3~ N2 OS:
C(%) H(%) N(%) Calculated: 70.54 9.15 7.48 Found: 70.45 9.24 7.07 Example 31 ~ OH BrCH2CooH ~ ~ C(HH3)3 HS ~ CH C(CH3)3 CH2S ~ H3 C(CH3)3 ~17~
In 30 ml of toluene were dissolved 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline and 0.7 g of bromoacetic acid and after adding thereto 1 g of triethylamine at room temperature, the mixture was refluxed for 4 hours. After cooling, the reaction mixture was filtrated and the filtrate was extracted with an a~ueous sodium carbonate solution and the alkali solution was acidified with diluted hydrochloric acid. The precip-itates thus formed were recovered b~ filtration and recrystallized from aqueous isopropanol to provide 0.5 g of [4-(3,5-di-tert-butyl-0 4-hydroxyphenyl)-5-methyl-2-imidazoylthio]acetic acid.
Melting point: 252-254C
Elemental analysis for C20 H28 N2 3 S:
C(%) H(%) N(%) Calculated: 63.80 7.50 7.44 Found: 63.53 7.74 7.26 Example 32 H2NC~CH ~ C(CH3)3 oC~CH N ~ ~ C(CH3)3 20 OC ~ OH ~ HO ~ ~ ~ OH
C(CH3)3 CH3 By following the same procedure as in Example 16, 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-dimethyl-2-oxo-4-imidazoline was produced.
Melting point: 285-286C
Elemental analysis for Clg H28 N2 2 C(%) H(%) N(%) Calculated: 72.12 8.92 8.85 Found:72.18 9.18 8.57 ~7~2~3 xample 33-34 ~ C _ ~ C(CH3)3~
By following the same procedure as in Example 13, the follow-ing compounds were produced.
Example 33 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-i~Oporpy~limidazole. 1/2CH30H:
( (~) = CH~CH
Melting point: 208-210C (methanol) Elemental analysis for C20 H30 N2 0.1/2CH30H:
C(%) H(%) N(%) Calculated: 74.50 9.76 8.48 Found: 74.23 10.08 8.43 ExamPle 34 Compound: 4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimidazole.
( ~ = CH2CH~CH
Melting point: 202-203C (benzene) Elemental analysis for C21 H32 N2 C(%) H(%) N(%) Calculated: 76.78 9.82 8.53 Found: 76.64 9.95 8.45 Example 35-40 HS ~ ~ C(CH 3~ ~ C(HH3))3 ~76Z~) By following the same procedure as in Example 15, the follow-ing compounds were produced.
Example 35 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthiothiazole:
( ~ = H, ~ = CH2CH3) Melting point: 130-131C (methanol) Elemental analysis for ClgH27~OS2:
C (%) E~ (%) ~ (%) S (%) Calculated: 65.29 7.79 4.01 18.34 Found: 64.97 7.99 4.01 18.38 ExamPle 36 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthiothiazole.
( ~ = H, ~ = CH \
Melting point: 173-174C (hexane) 3 Elemental analysis for C20H29NOS2:
C(%) H(%) ~(%) S(%) Calculated: 66.07 8.04 3.85 17.64 Found: 66.20 7.84 3.67 17.80 Example 37 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthiothiazole.
( ~ = CH3, ~ = CH3) Melting point: 118-119C (hexane) Elemental analysis ~or ClgH27NOS2:
C(%) H(%) ~(%) S(%) Calculated: 65.29 7.79 4.01 18.34 Found: 65.41 7.96 4.01 18.60 Example 38 ~ l762~
Compound: 4~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthiothiazole.
( ~ = CH2CH3, ~ 3 Melting point: 115~116C (he~ane) Elemental ana ly5 i s for C20H29NOS2:
C(%) H(%) N(%) S(%) Calculated: 66.07 8.04 3.85 17.64 Found: 66.17 8.18 4.11 17.60 Example 39 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2~methylthiothazole.
( ~ = CH \ , ~ = CH3) Melting point: 135-137C (methanol) Elemental analysis for C21H31Nos2:
C(%) H(%) N(%) S(%) Calculated: 66.80 8.27 3.7116.98 Found: 66.70 8.37 3.7717.20 Example 40 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methylthiothiazole.
( ~ = CH2CH ~CH ~ ~ = CH3) Melting point: 96-97C (methanol) Elemental analysis for C22H33NOS2:
C(%) H(%) N(%)S(%) Calculated: 67.42 8.49 3.5816.37 Found: 67.12 8.71 3.5816.59 Example 41 COOOH
N ~ OHC~ ~ ~ ~ (CH3)3 3 S C(CH3)3 C(CH3)3 ~ ~7~Z~) In 5 ml of chloroform was dissolved 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and then 0.4 g of m-chloroperbenzoic acid (80%) was added portionwise to the solution with stirring. ~fter 30 minutes since then, the reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution and the chloroform layer was concentrated. The crystals thus obtained were recrystallized from hexane to provide 0.45 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylthiazole.
Melting point: 124-125C
Elemental analysis for C18H25NO2S2:
C(%) H(%) N(%) S(%) Calculated: 61.50 7.17 3.98 18.24 Found: 61.41 7.32 4.05 18.56 Example 42 2 (CH3)3 ~ C CH H ~ C(CH ) 1 ~ H ~ O 1 ~ ( 3 ~ ~ ~ OH 3 3 HC~ (cH3~c-Hc H C(CH3)3 ll C(CH3)3 ~O ~ C(CH )3 By following the same procedure as in Example 2, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-oxo-imidazoline was produced.
Melting point: > 300C (DMF-water) Elemental analysis for C23H28N2O2:
C(%) H~%)N(%) Calculated: 75.79 7.74 7.69' Found: 75.70 7.97 7.85 30 Example 43 117g~2~) N
2J ~ CH3)3 ~ O3 H ~ ~ ~ ~
HC~ (CH3)3 (CH3)3 ¦¦ ~ ( 3)3 N ~ ~ (CH3)3 C(CH3)3 By following the same procedure as in Example 4, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-thioxo-4-imidazoline was produced.
Melting point: 258-262C (toluene) Elemental analysis for C23H28N2OS:
C(%)H(%) N(%) S(%) Calculated: 72.597.42 7.36 8.42 Found: 72.707.52 7.49 8.28 ] Example 44 C(CH ) HN ~ ~ N ~ OH 3~` HN 1 C(CH3)3 S 1NH ~ C(CCH3)3 CH ~SI~ ~ \ ~ (CH3)3 /
By following the same procedure as in Example 6, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenylimida~ole was produced.
Melting point: 129-131C (toluene-hexane) Elemental analysis for C24H30N2OS.1/4C7H8:
1176Z~
C(%) H(%) N(%) S(%) Calculated: 74.10 7.67 6.71 7.67 Found: 73.64 7.86 6.42 7.46 Example 45 ~(CH3)3 ~(CH~ OH
HJ~OH (CH3)3 (CH3)3 By following the same procedure as in Example 13, 4-(3,5-di-tert-butyl-hydroxyphenyl)-5-phenylimidazole was produced.
Melting point: 170-171C (toluene) Elemental analysis for C23H28N20:
C(%) H(%) ~(%) Calculated: 79.27 8.10 8.04 Found: 79.16 8.28 8.06 Example 46 C(CH3)3 ¦ ~C(CH ) > ~(CH3)3 BrCH ~
By following the same procedure as in Example 12, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-phenylthiazole was pro-duced.
Melting point: 168-171C (tetrahydrofuran-hexane) Elemental analysis for C23H27NOS2:
C(%) H(%) N(%) S(%) Calculated: 69.48 6.84 3.52 16.13 Found: 69.80 7.10 3.43 16.22 ~ 7~
Example 47 N ~ (CH3)3 N C OH
HSJ~S ~ C(CH3)3 CH3I ~ )~S ~1~ C~CH3)3 \~ CH3S \~
By following the same procedure as in Example 15, 4-(3,5-di-tert-butyl-4-hydroxypheny~) -2-methylthio-5-phenylthiazole.
Melting point: 135-137C (hexane) Elemental analysis for C24H29NOS2:
C(%) H(%) N(%) S(%) Calculated:70.03 7.10 3.40 15.58 Found: 70.30 7.37 3.44 15.61
Melting point: 245-250C (toluene) Elemental analysis for C20 H30 N2 OS:
C(/O) H(%) N(%) S(%) Calculated: 69.32 8.73 8.08 9.25 Found: 69.38 8.70 8.00 9.47 ExamPle 25 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methylimidazole.
( ~ = CH3, ~ = CH /CH
Melting point: 250-258C (toluene) Elemental analysis for C21 H32 N2 OS:
C(%) H(%) N(%) S(%) Calculated: 69.96 8.95 7.77 8.89 Found: 69.74 9.02 7.61 8.63 Example 26 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthioimidazole.
( ~ = CH2CH3, ~ 3 Melting point: 210-211C (toluene) Elemental analysis for C20 H30 ~2 OS:
C(%) H(%) N(%) Calculated: 69.32 8.73 8.08 Found: 69.05 8.68 7.48 Bxample 27 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthioimidazole.
( ~)= C~2CH3~ (~) = CH2CH3) Melting point: 226-228C (toluene) Elemental analysis for C21 H32 N2 OS
~17~
C(%) H(%) N(%) Calculated 69.96 8.95 7.74 Found: 70.18 8.97 7.63 Example 28 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl -2-isopropylthioimidazole.
( ~ CH2CH3, ~ = CH ~ 3 Melting point: 247-248C (toluene) Elemental analysis for C22H34N20S:
~ ~7~2~
C(%) H(%) N(%) Calculated: 70.54 9.15 7.48 Found: 70.32 9.27 7.37 Exam~le 29 Compound: 4-(3J5-di-tert-butyl-4-hydroxyphenyl)-5-- ethyl-2-ethylthioimidazole.
( (~ = CH2CH3J (~ = CH~CH
Melting point: 222-223C (ethyl acetate-hexane) Elemental analysis for C21 H32 N2 OS:
C(%) H(%) N(%) Calculated: 69.96 8.95 7.77 Found: 69.78 9.01 7.65 Example 30 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methylthioimidazole.
~ = CH2CH~CH , ~ = CH3 ) Melting point: 210-212C (benzene-hexane) Elemental analysis for C22 H3~ N2 OS:
C(%) H(%) N(%) Calculated: 70.54 9.15 7.48 Found: 70.45 9.24 7.07 Example 31 ~ OH BrCH2CooH ~ ~ C(HH3)3 HS ~ CH C(CH3)3 CH2S ~ H3 C(CH3)3 ~17~
In 30 ml of toluene were dissolved 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline and 0.7 g of bromoacetic acid and after adding thereto 1 g of triethylamine at room temperature, the mixture was refluxed for 4 hours. After cooling, the reaction mixture was filtrated and the filtrate was extracted with an a~ueous sodium carbonate solution and the alkali solution was acidified with diluted hydrochloric acid. The precip-itates thus formed were recovered b~ filtration and recrystallized from aqueous isopropanol to provide 0.5 g of [4-(3,5-di-tert-butyl-0 4-hydroxyphenyl)-5-methyl-2-imidazoylthio]acetic acid.
Melting point: 252-254C
Elemental analysis for C20 H28 N2 3 S:
C(%) H(%) N(%) Calculated: 63.80 7.50 7.44 Found: 63.53 7.74 7.26 Example 32 H2NC~CH ~ C(CH3)3 oC~CH N ~ ~ C(CH3)3 20 OC ~ OH ~ HO ~ ~ ~ OH
C(CH3)3 CH3 By following the same procedure as in Example 16, 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-dimethyl-2-oxo-4-imidazoline was produced.
Melting point: 285-286C
Elemental analysis for Clg H28 N2 2 C(%) H(%) N(%) Calculated: 72.12 8.92 8.85 Found:72.18 9.18 8.57 ~7~2~3 xample 33-34 ~ C _ ~ C(CH3)3~
By following the same procedure as in Example 13, the follow-ing compounds were produced.
Example 33 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-i~Oporpy~limidazole. 1/2CH30H:
( (~) = CH~CH
Melting point: 208-210C (methanol) Elemental analysis for C20 H30 N2 0.1/2CH30H:
C(%) H(%) N(%) Calculated: 74.50 9.76 8.48 Found: 74.23 10.08 8.43 ExamPle 34 Compound: 4-~3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimidazole.
( ~ = CH2CH~CH
Melting point: 202-203C (benzene) Elemental analysis for C21 H32 N2 C(%) H(%) N(%) Calculated: 76.78 9.82 8.53 Found: 76.64 9.95 8.45 Example 35-40 HS ~ ~ C(CH 3~ ~ C(HH3))3 ~76Z~) By following the same procedure as in Example 15, the follow-ing compounds were produced.
Example 35 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthiothiazole:
( ~ = H, ~ = CH2CH3) Melting point: 130-131C (methanol) Elemental analysis for ClgH27~OS2:
C (%) E~ (%) ~ (%) S (%) Calculated: 65.29 7.79 4.01 18.34 Found: 64.97 7.99 4.01 18.38 ExamPle 36 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthiothiazole.
( ~ = H, ~ = CH \
Melting point: 173-174C (hexane) 3 Elemental analysis for C20H29NOS2:
C(%) H(%) ~(%) S(%) Calculated: 66.07 8.04 3.85 17.64 Found: 66.20 7.84 3.67 17.80 Example 37 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthiothiazole.
( ~ = CH3, ~ = CH3) Melting point: 118-119C (hexane) Elemental analysis ~or ClgH27NOS2:
C(%) H(%) ~(%) S(%) Calculated: 65.29 7.79 4.01 18.34 Found: 65.41 7.96 4.01 18.60 Example 38 ~ l762~
Compound: 4~3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthiothiazole.
( ~ = CH2CH3, ~ 3 Melting point: 115~116C (he~ane) Elemental ana ly5 i s for C20H29NOS2:
C(%) H(%) N(%) S(%) Calculated: 66.07 8.04 3.85 17.64 Found: 66.17 8.18 4.11 17.60 Example 39 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2~methylthiothazole.
( ~ = CH \ , ~ = CH3) Melting point: 135-137C (methanol) Elemental analysis for C21H31Nos2:
C(%) H(%) N(%) S(%) Calculated: 66.80 8.27 3.7116.98 Found: 66.70 8.37 3.7717.20 Example 40 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methylthiothiazole.
( ~ = CH2CH ~CH ~ ~ = CH3) Melting point: 96-97C (methanol) Elemental analysis for C22H33NOS2:
C(%) H(%) N(%)S(%) Calculated: 67.42 8.49 3.5816.37 Found: 67.12 8.71 3.5816.59 Example 41 COOOH
N ~ OHC~ ~ ~ ~ (CH3)3 3 S C(CH3)3 C(CH3)3 ~ ~7~Z~) In 5 ml of chloroform was dissolved 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and then 0.4 g of m-chloroperbenzoic acid (80%) was added portionwise to the solution with stirring. ~fter 30 minutes since then, the reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution and the chloroform layer was concentrated. The crystals thus obtained were recrystallized from hexane to provide 0.45 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylthiazole.
Melting point: 124-125C
Elemental analysis for C18H25NO2S2:
C(%) H(%) N(%) S(%) Calculated: 61.50 7.17 3.98 18.24 Found: 61.41 7.32 4.05 18.56 Example 42 2 (CH3)3 ~ C CH H ~ C(CH ) 1 ~ H ~ O 1 ~ ( 3 ~ ~ ~ OH 3 3 HC~ (cH3~c-Hc H C(CH3)3 ll C(CH3)3 ~O ~ C(CH )3 By following the same procedure as in Example 2, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-oxo-imidazoline was produced.
Melting point: > 300C (DMF-water) Elemental analysis for C23H28N2O2:
C(%) H~%)N(%) Calculated: 75.79 7.74 7.69' Found: 75.70 7.97 7.85 30 Example 43 117g~2~) N
2J ~ CH3)3 ~ O3 H ~ ~ ~ ~
HC~ (CH3)3 (CH3)3 ¦¦ ~ ( 3)3 N ~ ~ (CH3)3 C(CH3)3 By following the same procedure as in Example 4, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-thioxo-4-imidazoline was produced.
Melting point: 258-262C (toluene) Elemental analysis for C23H28N2OS:
C(%)H(%) N(%) S(%) Calculated: 72.597.42 7.36 8.42 Found: 72.707.52 7.49 8.28 ] Example 44 C(CH ) HN ~ ~ N ~ OH 3~` HN 1 C(CH3)3 S 1NH ~ C(CCH3)3 CH ~SI~ ~ \ ~ (CH3)3 /
By following the same procedure as in Example 6, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenylimida~ole was produced.
Melting point: 129-131C (toluene-hexane) Elemental analysis for C24H30N2OS.1/4C7H8:
1176Z~
C(%) H(%) N(%) S(%) Calculated: 74.10 7.67 6.71 7.67 Found: 73.64 7.86 6.42 7.46 Example 45 ~(CH3)3 ~(CH~ OH
HJ~OH (CH3)3 (CH3)3 By following the same procedure as in Example 13, 4-(3,5-di-tert-butyl-hydroxyphenyl)-5-phenylimidazole was produced.
Melting point: 170-171C (toluene) Elemental analysis for C23H28N20:
C(%) H(%) ~(%) Calculated: 79.27 8.10 8.04 Found: 79.16 8.28 8.06 Example 46 C(CH3)3 ¦ ~C(CH ) > ~(CH3)3 BrCH ~
By following the same procedure as in Example 12, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-phenylthiazole was pro-duced.
Melting point: 168-171C (tetrahydrofuran-hexane) Elemental analysis for C23H27NOS2:
C(%) H(%) N(%) S(%) Calculated: 69.48 6.84 3.52 16.13 Found: 69.80 7.10 3.43 16.22 ~ 7~
Example 47 N ~ (CH3)3 N C OH
HSJ~S ~ C(CH3)3 CH3I ~ )~S ~1~ C~CH3)3 \~ CH3S \~
By following the same procedure as in Example 15, 4-(3,5-di-tert-butyl-4-hydroxypheny~) -2-methylthio-5-phenylthiazole.
Melting point: 135-137C (hexane) Elemental analysis for C24H29NOS2:
C(%) H(%) N(%) S(%) Calculated:70.03 7.10 3.40 15.58 Found: 70.30 7.37 3.44 15.61
Claims (72)
1. A method of producing 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound represented by formula I
I
wherein one of R1 and R2 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and the other represents a hydrogen atom or a lower alkyl group; R3 re-presents a hydrogen atom or a group shown by -O-Z or (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group and n represents 0, 1 or 2); and R4 represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable acid addition salt thereof which comprises selecting a process from the group of processes consisting of:
(a) reacting the compound represented by formula II
R4 - N = C = Y II
and the .alpha.-aminocarbonyl compound represented by formula III
III
wherein R1, R2, and R4 have the same significance as defined concerning formula I and Y represents an oxygen atom or a sulfur atom;
(b) reacting a compound of formula I wherein R3 is -S-Z with an oxidizing agent to obtain the corresponding compound of formula I wherein R3 represents wherein n is 1 or 2;
(c) reacting a compound of formula I wherein R3 is -S-H with an alkylating agent to obtain the corresponding-compound of formula I wherein R3 represents -S-Z wherein Z is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy carbonyl lower alkyl group or a lower aralkyl group;
(d) desulfurizing a compound of the formula:
or wherein R1, R2 and R4 are as defined above to obtain the corresponding compound of formula I wherein R3 represents a hydrogen atom; and, (e) converting a compound of formula I to its pharma-ceutically acceptable acid addition salt.
I
wherein one of R1 and R2 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and the other represents a hydrogen atom or a lower alkyl group; R3 re-presents a hydrogen atom or a group shown by -O-Z or (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group and n represents 0, 1 or 2); and R4 represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable acid addition salt thereof which comprises selecting a process from the group of processes consisting of:
(a) reacting the compound represented by formula II
R4 - N = C = Y II
and the .alpha.-aminocarbonyl compound represented by formula III
III
wherein R1, R2, and R4 have the same significance as defined concerning formula I and Y represents an oxygen atom or a sulfur atom;
(b) reacting a compound of formula I wherein R3 is -S-Z with an oxidizing agent to obtain the corresponding compound of formula I wherein R3 represents wherein n is 1 or 2;
(c) reacting a compound of formula I wherein R3 is -S-H with an alkylating agent to obtain the corresponding-compound of formula I wherein R3 represents -S-Z wherein Z is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy carbonyl lower alkyl group or a lower aralkyl group;
(d) desulfurizing a compound of the formula:
or wherein R1, R2 and R4 are as defined above to obtain the corresponding compound of formula I wherein R3 represents a hydrogen atom; and, (e) converting a compound of formula I to its pharma-ceutically acceptable acid addition salt.
2. A process according to claim 1 for the preparation of 2-benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein R1 or R2 is a hydrogen atom, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a benzylsulfinyl group and R4 is a hydrogen atom.
3. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline and its pharmaceutically acceptable acid addition salts there-of, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, the other is a hydrogen atom, R3 is a oxo group and R4 is a hydrogen atom.
4. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imi-dazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a methyl group, R3 is an oxo group and R4 is a hydrogen atom.
5. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline and its pharmaceutically acceptable acid addi-tion salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a methyl group, R3 is a thioxo group and R4 is a hydrogen atom.
6. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)2-thioxo-4-imidazoline and its pharmaceutically acceptable acid addition salts there-of, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, the other is a hydrogen atom, R3 is a thioxo group and R4 is a hydrogen atom.
7. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methyl-thioimidazole and its pharmaceutically acceptable acid addition salts there-of, wherein one of R1 or R2 is a hydrogen atom, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methylthio group and R4 is a hydrogen atom.
8. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a methyl group, the other is a 4-(3,5-di-tert-butyl-4-hydroxyphenyl) group, R3 is a methylthio group and R4 is a hydrogen atom.
9. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylimida-zole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a hydrogen atom, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methylsulfinyl group and R4 is a hydrogen atom.
10. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfonylimi-dazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a hydrogen atom, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methylsulfonyl group and R4 is a hydrogen atom.
11. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-sulfonylimidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a methyl group, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl-sulfonyl group and R4 is a hydrogen atom.
12. A process according to claim 1 for the preparation of ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolyl-thio]propionate and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a hydrogen atom, R3 is a ethyl 2-thio propionate group and R4 is a hy-drogen atom.
13. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methyl-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a hydrogen atom, R3 is a mercapto group and R4 is a methyl group.
14. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a methyl group, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and R4 is a hydrogen atom.
15. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-methylthio-imidazole hydroiodide and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a hy-drogen atom, R3 is a methylthio group and R4 is a methyl group.
16. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazo-line and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is an oxo group and R4 is a hydrogen atom.
17. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-oxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a isopropyl group, R3 is an oxo group and R4 is a hydrogen atom.
18. A process according to claim 1 for the preparation of 4-(3,5 di-tert-buty1-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is a thioxo group and R4 is a hydrogen atom.
19. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-thioxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a isopropyl group, R3 is a thioxo group and R4 is a hydrogen atom.
20. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-imiddazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is a hydrogen atom and R4 is a hydrogen atom.
21. A process according to claim 1 for the preparation of 4-(3,5-di-tert-buty1-4-hydroxyphenyl)-5-isobutyl-2-oxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a isobutyl group, R3 is an oxo group and R4 is a hydrogen atom.
22. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthio--5-methyl-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a methyl group, R3 is an ethylthio group and R4 is a hydrogen atom.
23. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropyltthio-5-methylimidazole and its pharmaceutically acceptable acid addi-tion salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a methyl group, R3 is a isopropylthio group and R4 is a hydrogen atom.
24. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-meethylthio-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is a methylthio group and R4 is a hydrogen atom.
25. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthio-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is an ethylthio group and R4 is a hydrogen atom.
26. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-issopropyl-thioimidazole and its pharmaceutically acceptable acid addi-tion salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is an isopropylthio group and R4 is a hydrogen atom.
27. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthio-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an ethyl group, R3 is an ethylthio group and R4 is a hydrogen atom.
28. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methyl-thioimidazole and its pharmaceutically acceptable acid addi-tion salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is an isobutyl group, R3 is a methylthio group and R4 is a hydrogen atom.
29. A process according to claim 1 for the preparation of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-imidazoyl-thio]acetic acid and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a methyl group, the other is a [4-(3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a thioacetyloxy group, and R4 is a hydrogen atom.
30. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-dimethyl-2-oxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a methyl group, R3 is an oxo group and R4 is a methyl group.
31. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropylimidazole and its pharmaceutically acceptable acid addition salts there-of, wherein one of R1 or R2 is an isopropyl group, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydro-gen atom and R4 is a hydrogen atom.
32. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimmidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is an isobutyl group, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and R4 is a hydrogen atom.
33. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-oxo-imida-zoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a phenyl group, R3 is an oxo group and R4 is a hydrogen atom.
34. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-thioxo-4-imidazoline and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a phenyl group, R3 is a thioxo group and R4 is a hydrogen atom.
35. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenyl-imidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, the other is a phenyl group, R3 is a methylthio group and R4 is a hydrogen atom.
36. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-hydroxyphenyl)-5-phenylimidazole and its pharmaceutically acceptable acid addition salts thereof, wherein one of R1 or R2 is a phenyl group, the other is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and R4 is a hydrogen atom.
37. A 3,5-di-tert-butyl-4-hydroxyphenyl-substituted hetero-cyclic compound represented by formula I
I
wherein one of R1 and R2 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and the other represents a hydrogen atom or a lower alkyl group; R3 repre-sents a hydrogen atom or a group shown by -O-Z or (where-in Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group and n represents 0, 1 or 2); and R4 represents a hydrogen atom or a lower alkyl group or the pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 1.
I
wherein one of R1 and R2 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group ( ) and the other represents a hydrogen atom or a lower alkyl group; R3 repre-sents a hydrogen atom or a group shown by -O-Z or (where-in Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group and n represents 0, 1 or 2); and R4 represents a hydrogen atom or a lower alkyl group or the pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 1.
38. A compound of claim 37, namely 2-benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole, and its pharmaceuti-cally acceptable acid addition salts thereof when prepared by the process of claim 2.
39. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 3.
40. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 4.
41. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 5.
42. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)2-thioxo-4-imidazoline, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 6.
43. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 7.
44. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-imidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 8.
45. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylimidazole, and its pharmaceuti-cally acceptable acid addition salts thereof when prepared by the process of claim 9.
46. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfonylimidazole, and its pharmaceuti-cally acceptable acid addition salts thereof when prepared by the process of claim 10.
47. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-sulfonylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 11.
48. A compound of claim 37, namely ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolylthio]propionate, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 12.
49. A compound of claim 37, namely 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methyl-imidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 13.
50. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 14.
51. A compound of claim 37, namely 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-methyl-thio-imidazole hydroiodide, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 15.
52. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline, and its pharmaceuti-cally acceptable acid addition salts thereof when prepared by the process of claim 16.
53. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-oxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when prepared by the process of claim 17.
54. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when prepared by the process of claim 18.
55. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-thioxo-4-imidazoline, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 19.
56. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-imidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 20.
57. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-oxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when prepared by the process of claim 21.
58. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthio-5-methylimidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 22.
59. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 23.
60. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-imidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 24.
61. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthio-imidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 25.
62. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-isopropyl-thioimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 26.
63. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthio-imidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 27.
64. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methyl-thioimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 28.
65. A compound of claim 37, namely [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-imidazoylthio]acetic acid, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 29.
66. A compound of claim 37, namely 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-dimethyl-2-oxo-4-imidazoline, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 30.
67. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 31.
68. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 32.
69. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-oxo-imidazoline, and its pharmaceuti-cally acceptable acid addition salts thereof when prepared by the process of claim 33.
70. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenyl-2-thioxo-4-imidazoline, and its pharma-ceutically acceptable acid addition salts thereof when prepared by the process of claim 34.
71. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenylimidazole, and its pharma-ceutically acceptable acid addition salts thereof when pre-pared by the process of claim 35.
72. A compound of claim 37, namely 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenylimidazole, and its pharmaceutically acceptable acid addition salts thereof when prepared by the process of claim 36.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56059990A JPS57175171A (en) | 1981-04-21 | 1981-04-21 | 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound |
| JP59990/1981 | 1981-04-21 | ||
| JP157010/1981 | 1981-10-02 | ||
| JP56157010A JPS5857366A (en) | 1981-10-02 | 1981-10-02 | 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1176260A true CA1176260A (en) | 1984-10-16 |
Family
ID=26401054
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396507A Expired CA1187088A (en) | 1981-04-21 | 1982-02-17 | Process of producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
| CA000396506A Expired CA1176260A (en) | 1981-04-21 | 1982-02-17 | Process for production for 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396507A Expired CA1187088A (en) | 1981-04-21 | 1982-02-17 | Process of producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds |
Country Status (3)
| Country | Link |
|---|---|
| CA (2) | CA1187088A (en) |
| ES (2) | ES509779A0 (en) |
| MX (1) | MX7156E (en) |
-
1982
- 1982-02-17 CA CA000396507A patent/CA1187088A/en not_active Expired
- 1982-02-17 CA CA000396506A patent/CA1176260A/en not_active Expired
- 1982-02-19 ES ES509779A patent/ES509779A0/en active Granted
- 1982-02-19 ES ES509778A patent/ES509778A0/en active Granted
- 1982-02-19 MX MX992782U patent/MX7156E/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES8302667A1 (en) | 1983-01-16 |
| ES509778A0 (en) | 1983-01-16 |
| CA1187088A (en) | 1985-05-14 |
| MX7156E (en) | 1987-11-27 |
| ES8302668A1 (en) | 1983-01-16 |
| ES509779A0 (en) | 1983-01-16 |
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