CA1187088A - Process of producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds - Google Patents

Abstract

ABSTRACT
A method of producing a 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound represented by formula I
wherein one of R1, R2, and R3 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group and others represent a hydrogen atom, a lower alkyl group, a lower aralkyl group, an aryl group, a lower alkoxy-substituted aryl group, or the group shown by -O-Z, , or -NH-Z (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower aralkyl group, or a aryl group and n represents 0, 1, or 2) and A represents an oxy-gen atom, a sulfur atom, an imino group, a lower alkylimino group, or a 3,5-di-tert-butyl-4-hydroxyphenacylimino group or a salt thereof which comprises reacting the compound repre-sented by formula II
II
and the ?-halocarbonyl compound represented by formula III

III
ABSTRACT:
wherein R1, R2, R3, and A have the same significance as defined concerning formula I; A' represents an oxygen atom, a sulfur atom, an imino group, or a lower alkylimino group; and X repre-sents a halogen atom; and then, if desired, oxidizing, alkylat-ing or desulfurizing the product thus obtained.
The compounds of this invention have an anti-inflammatory, an antipyretic, an analgesic, an anti-arthritic activity, and an immuno regulatory activity. Hence, they are particularly useful as an antirheumatic.

Description

~7~
This invention relates tc a process of producing novel 3,5-di-tert-butyl-4--hydroxyphenyl-substitu~ed heterocyclic compounds.
More particularly, the invention relates to a process of producing the 3,5-di-tert-bu~yl-~-hydroxyphenyl-substi~uted heterocyclic compounds shown by formula I and their salt;

R~ ~ \A ~ R2 [wherein one of Rl ~ R3 represents 3,5-di~tert-butyl-4-hydroxy-phorlyl ~roup, and others represent a hydrogen atom, a lowex alky:l group; a lower aralkyl grou~, an aryl grnup, a lower alkoxy~
sub~3tituted aryl group~ or a group shown by -O-Z, -S~- - Z, or -~NH-Z (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lowex alkyl group~ a lower alkoxycarbonyl lower alkyl group, a lower aralkyl group, or an aryl group and n represents O, l, or 2); A represents an oxygen atom, a sulfur atom, an imino group, a lowex alkylimino group, or a 3,5-di-tert-butyl-4-hydroxy-phenacylimino group C(CH )3 (~ CH2CO - < ~ OH ) C(CH3)3 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 alXyl group"
includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, heptyl group, hexyl group, etc.;
"lower alkyl group" includes benzyl group, phenethyl group, etc.;
"lower alkoxy group" includes methoxy group, ethoxy groupy prOpOxy group, isopropoxy group~ butoxy group, hexyloxy group, etc.;
Furthermore, the term "aryl group" includes phenyl group, naphthyl group, etc., Then, as the salts of the compounds of this invention shown by ormula I, there are pharmaceutically acceptable acid addition ~alts, or example, acid addition salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
The compounds of this invention shown by formula I have an anti-inflammatory, an anti-pyretic, an analgesic, an anti-arthritic and an immuno regulatory activity. Hence they are novel compounds particularly useEul as an antirheumatic.
That is, since the compounds o~ this invention shown by formula I show a therapeutic and prophylactic effect on adjuvant-induced arthritis which is considered to be an animal model ofhuman rheumatism and further have analgesic and anti-inflammatory activities a5 we~l as a prostagrandins formation inhibiting activity 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 ~7~
invention shown hy formula I suppress remarkahly 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 anti-rheumatics repxesented by indome~hacin and diclofenac.
Therefore, the compounds o~ this invention are particularly expected as antirheumatic~ havi.ng new mechanism.
The irst feature of the chemical structure of the compounds of this invention shown by formula I that the compounds belong to a nonsteroidal nonacidic anti-inflammatory agent, and are difforent from (conventional nonsteroidal acidic anti~inflammatory ay~?nts such a.s indomethacin and diclofenac. The 2nd feature is .in the point that the heterocyclic ring of the heterocyclic 15 compound .is directly substituted by a 3,5-di.-tert-butyl-4- hydroxy-ph~nyl ~roup. The third feature is in the point that the substi-tuted heterocyclic ring itself is a specific heterocyclic ring.
Pxactically, the heterocyclic ring in the haterocyclic compound M

o this invention is ~ ~ , i.e., an imidazole ring, a \ A

thiazole ring, or an oxazole, or ~ ~ ~ , i.e., a (2,3-dihydro)imidazo[2~1-b]thiazole ring.
As heterocyclic compounds the heterocyclic ring of which is ~ /

~

~'7~
directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-benzoxazole compounds and 2-(3,5~di-tert-butyl-4-hydroxyphenyl)-benzothiazcle compounds (West German Offenlegungsshrift 2,009,41-4); 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 imidazolidine compounds are used as intermediates for plantpro-tecting agents and dyes. The last acetic acid compound is sug-gested 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 pharmacolog-ical effect of the compound as an anti-inflammatory agent and also the chemical structure of the acetic acid compound is a heterocyclic ring~substituted acetic acid de~ivative, which belongs to a non-~teroi.dal acidic anti-inflammatory agent and hence differs from the compounds of this invention shown by formula 1 in chemical structure.
The particularly preferred compounds ~1) in the foregoing heterocyclic compounds ar~ as ~ollows;
4-t3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imida-zoline, 4-(3,5-di-tert-bu~yl-4-hydroxyphenyl)-5 ethyl-2-oxo-4-imidazoline 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-hydroxypllenyl)-2-mercaptothiazole, '7~
4~(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole, and 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthlo-imidazole.
In addition, there are prototropic isomers on the compounds of this invention shown by formula 1. For example, in the compounds (O)n o this invention shown by formula 1 where.in Rl is ~S Z (where-in n is O and Z is a hydrogen atom) or Rl is -oZ (wherein Z is a hydrogen atom), there are following prototropic isomers;

N ~--- / \~ ( CH3 ) 3 EIN--~ /~ C ( CEI3 ) 3 ~OEI ~ / \ >--OH
HO / ~R2 C (CH3 ) 3 S ~ ~ C (CH3 ) 3 l~j o~ ( 3~3 _~ CUCH3)3 :H A R2 ( 3 ) 3 R2 C (CH3 ) 3 30 ./

~ ~ ~t7~ ~ ~

The compounds of this in~ention shown by formula I can be pre-pared by the following methods:
i). ~irs~ production method:
NH2 O=C-R ~ ~ ~ R
~ l l Rl-C=A' -~ X-CE~2 Rl~ ~ ' ~~"
II III I
wherein A' represents an oxygen atom, a sulfur atom, an imino group or a lower alkylimino group; X represents a halogen atom; and Al, Rl, R2~ and R3 have the same significance as defined above.
That is, the compound of this invention shown by formula I can be prepared by reacting the compound shown by formula II (i.e., urea, thiourea, amidine, amide, thioamide, and amidothiocarbonic acid derivatives) with the a-halocarbonyl compound shown by formula III. This reaction is perormed by heating the compound of formula L5 II artd a corresponding amount of the compound of formula III in situ or in a proper solvent such as methanol, ethanol, toluene, dimethyl~ormamide, acetone, chloroform, methyl ethyl ketone, ethyl acetate, methyl cellosolve, ethyl cellosolve, diyryime, acetonitrile, etc. The react:ion temperature and the reaction tlme are suitablv determined according to the `kinds of starting materials and solvent used. In addition, the compound of formula II may be used for the reactinn as a salt thereof, such asa hydrochloride of an amidine derivative or ammonium amidodithiocarbonate.
Furthermore, when in the method, cyanourea (~H2CONHCN) is reacted with the a-halocarbonyl compound of formula III and then the product is hydrolyzed, the compound of formula I wherein Rl is a hydroxyl group and A is an imino group, i.e., the compound of this invention ~hown by the formula N ~ ~ Rl HO ~ N R2 '7~
wherein R2 and R3 have the same significance as defined above can be produced.
ii). Second production method:

NH 2 -CH -R 3 :e~--~ 1~ R3 R '--~=C=Y ~
O=C~R2 y,1 2 IV V I~
wherein R' represents a hydrogen atom or a low~r alkyl group' Y' xepresents a hydroxyl group or a mercapto group; Y represents an oxygen atom or a sulfur atom; and R2 and R3 have the same signif-icance as deEined above.
That is, the compound of this invention shown by formula 1 wherein A is an imino group or a lower alkylimino group and Rl is 15 a hydroxyl group or a mercapto group, i.e., the compound shown by Eormula 1~ can be prepared by reacting the compound shown by for~ula lV (i. e., isocyanic acid, isothiocyanic acid, and the lower alkyl substituted derivatives of them) or the alkali metal salt thereo with thec~-aminocarbonyl compound shown by formula V
or the salt thereof. In the case of using the alkali metal salt of isocyanic acid or isothiocyanic acid, the reaction is perform-ed in a solvent such as alcohol, aqueous alcohol, etc., with the addition oE an acid such as hydrochloric acid, etc., ak room temp-erature or under heating. In the case of heating~ the reaction may be perEormed under refluxing at about the boiling point of the solvent used.
Also, in the case of using the lower alkyl-substituted der-ivative of isocyanic acid or isothiocyanic acid, the reaction is performed in a basic solvent such as pyridine, etc., at Lsom temperature or under heating.

In addition, the cornpound of this invention shown by ~ormula 7~
I wherein Y~ is a mercapto group5 i.e., the compound shown by the formula N ___~_~ 3 )I i~
HS ~ / R2 R' wherein R', R2, and R3 have the same significance as defined above can be prepared by reacting the compound shown by -the formula R' -NH~NH2 with the compound shown by HO-CH-R2 iii). Other production methods:
(1) oxidation R3 Ia-I ~ E2 Z S ~ ~ 2 Ia-2 ( H N ~ ~ ~ (2) alkylation ~ (3) desulfurization a a-3 ~ ~ R3 A
Ia_5 wherein n' represents 1 or 2; Z' represents a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a lower aralkyl group, and R2, R3, A, and Z have the same significance as defined above.
The oxi~ation method (1) is a method of producing the compound of this invention shown by formula 1 wherein Rl is -S -Z and ()n n is 1 or 2, i.e., the S-oxide compound shown by formula la-2 Th~ S-oxide compound can be pxepared by reacting tha corresponding compound o~ this invention shown by formula .L wherain Rl is 7~
()n -~ ~ and n is o, i.e., the thio compount shown by formula I
with an oxidizing agent in a solvent such as acetic acid, chloro-form, l,2-dimethoxyethane, etc., according to an ordinary manner.
As 'he oxidizing agent, 10 40% hydrogen peroxide, perbenzoic acid, m chloroperbenzoic acid, etc., is usually used. In this case, by suitably selecting the reaction conditlons such as the reaction tlme, reaction temperature, the amount or the o~idizing 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 1 wherein R~ is -~O) Z, n i$ O, and Z is a lower al~yl 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 la_4. The alkyl-thio compound can be produced by alkylating the compound of this invention shown by formula 1 wherein Rl is (~) Z, Z is a hydrogen atom, and n is O, i. e., the mercapto (or thioxo) compound shown by formula 1(~ 3 with an alXylating 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 halides or aralkyl halides such as methyl iodide, ethyl bromide, c~-bromopropionic acid,~-bromoacetic acid, ethylc~-bromopropi-onate, benzyl bromide, phenethyl iodide, etc., and dialXyl sul-fates such as dimethyl sulfate, diethyl sulfate, etc.
The desulfurization reaction (3) is a method of producing the compound of this invention shown by formula 1 wherein Rl is a hydrogen atom, i. e., the compound shown by formula la 5. The compound can be produced by ~esulfurizing the corresponding mercapto (or thio~o) compound shown by fo:rmula la 3 according g 7~
to a c~nventional manner, for example, by treating the compound with a ~aney nickel catalyst.
Typical methods of produc.ing the compounds of this invention shown by formula 1 were expl~:~ned above and the compounds of this invention and the methods of producing them will be further expl-ained more practically and in more detail by the following examples.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this invention shown by formula 1 will then be described.
Effect on adjuvant-induced arthrites in rats:
~ thods: Male Sprangue Dawley rat aged 7 weeks were used.
Drugs were evaluated by two methods as follows. All test drugs 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 o 0~1 rnl of sterile suspension of Mycobacterium ~y_icum (6mg/ml) in liquid paraffin into tail skin of rats (day 0). After about 2 weeks, arthritic rats were selected and allocated into groups. Drugs were given daily following about 10 days. Thickness of the foot was measured with dlal thick-ness gauge both on the day of initial dosing and on the next day of final dosing, change of foot thickness (~FT 10 mm) was cal-culated as a difference between these two values. The results are shown in Table 1.

(2) Prophylactic ~ffect.of drugs: arthritis was induced by single subplanter injection of 0.05 ml of the suspension into the left hind paw of rats. Drugs were gi~en daily ~or 21 days star~i.ng from the day (day 0) of injection of the suspension.
Thickness of both feet, injected foot (left foot, FT~ ) and uninjected foot (right foot, FTR) were measured wlth dial -thick~

ness gauge on day 0 and 21. The percent inhibition (~C%) was '7~
calculated from difference in increased foot thickness between control and drug~treated group.
The results are shown in Table 11.

Table 1 (Therapeutic effect) ~___ _ _ _ DRUGS DOSE N Day 16 - Day 17 (mg~kg/day PØ) ~FT (10 mm) 0.5% MC - 3 233 ~ 59 1~Indomethacin 2 3 -173 + J~2***
4-(3,5-di~tert-butyl-4-hydroxyphenyl)-5~methyl-2-oxo-4-imidazoline 25 3 -216 + 30***

DRUGS DOSE ~ Day 16 - Day 17 (mg/kg/day PØ) ~FT (10-2 mm) _ _ . .
0.5% Mc - 3 97+~1 Indomethacin 2 3 -216 + 30*
20 4~(3,5-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*

_ DRUGS Dose N Day 16-Day 28 (mg/kg,~day ~FT (10 2 mm) P . O . ) 0~5O/o Mc - 6 148~ 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-(3J 5-di-tert~hutyl-4-hydroxyphenyl) -5-ethyl-2-oxo-4-imi.dazoline 25 3 -247 ~ 49 ***
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-imidazole 25 3 -103 + 71 **

DRUGS DOSE N DAY 16 - D~ 28 ~mg/kg/day ~FT (10-2 mm) ' P.O.) ... . _ _ _ _ _ 0.5% Mc - 3 96 + 162 Indomethacin 2 3 -161 ~ 137 *
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylth.io imidazole 25 3 -180 -~ 241 *

'7~

DRUGS DOSE N DAY 15- Day 29 (mg/kg/day ~FT (1%) PØ) 10~2 mm) 0.5% MC - 6 280 ~ 54 5Indomethacin 1 6 -243 + 16 ***(691) 2 6 -260 _ 17 ***(73.7) 4-(3,5~di-ter-t-butyl-4~
hyclroxyphenyl)-5-methyl- 6.25 6 67 + 48 ** (30.8) do. 12.5 6 -Jl~ + 3~ ***(53.9) 10 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) 15 do. 25 6 -127 ~ 38 ***(54.0) SicJnificant diffexerlce from control (t~test) * P 0.05 ** P 0.01 *** P 0.001 Table 11 (Prophylactic effect) ~
~ Drugs DOSE ~ ~ Day 21 p. o . ) E~TL l~.>/o FrR 1%
~ ~ _ _ Indomethacin 1 8 64.6 81.8 do. 2 8 59.5 76.9 4-(3,5-di-ter-t-butyl-4-25 hydroxyphenyl)-5-methyl-2 methylthiomidazole 25 8 53.1 65.8 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-imidazole 25 8 68.1 81.3 (~/kg/day L % R
P. O . ) Indome-thacin 1 8 63O6 68.1 do. 2 8 63.9 98.0 4-(3,5-di~-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline 6.25 8 38.0 71.7 do. 12.5 8 30.3 61.6 do. 25 8 64.4 9Q.0 4~(3,5-di-tert-butyl~
4-hydroxyphenyl~-5-ethyl--2-oxo-4-imidazollne 6.25 8 11.6 35.8 do. 12.5 8 26.3 47~2 do. 25 8 60.1 70.1 . . .. .. _ . _ . . A . ~ .. ..
From the above results, i-t is apparent -that the compounds o this invention have excellent pharmacoloyical therapeutic &
prophylactic effects against the adjuvan-t-induced arthriti~.
~ s the above-de3cribed -therapeutic and prohylactic test results to adjuvant-induced arthritis, it is clear that the compounds of this invention shown by formula 1 possess remarkable therap-eutic and prohylactic effects to adjuvant-induced arthritis~
Example 1 A mixture of 2.4 g of N-(2-phenylethyl)-thiourea, 5 g of 4-(2~bromoacetyl)-2,6-di-tert-butylphenol, and 25 ml of absolute ethanol was refluxed for 3 hours and then cooled. The precip-itates thus formed were recovered by filtration and recrystallized from ethanol to provide 2.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphe-nyl)-2-(CX-phenethylamino) thiazole hydrobromide.
Melting point- 228-230C
Elemental analysis for C25 H33 N2 OSBr:

C(%)H(%) N(%) Calculated: 61.346.7g 5.72 Found: 61.656.96 5.63 Example 2 ( 3 3 ~H2 ~ ~(CH3)3 BrCHCH3 c(cH3)3 ~I3 A mixture of 4.5 g of formamide and 2.25 g of 4-(2--bromo~
propionyl)-2,6-di-tert-butylphenol was heated to 150C for 1.5 hours. The reac~ion mixture was poured into water after cooling and then extracted twice each time with 30 ml of toluene. The extract was dried over anhydrous magnesium .sulfate and concent-rated under reduced pressure and the residue was recrystallized Erom aqueous methanol to provide 1.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazo]e.
~elting point: 105-107C
Elemental analysis for C18 H25 N2 C(%) H(%) ~(%) Calculated: 75.23 8.77 4.87 Found~ 75.07 8.91 4.68 Example 3 C(CH3)3 lH2 C(CH3)3 OC ~ OH HCS
Br~C~ C(CH3)3 ~ ~CH3 (C~3)3 :~ 8'7~
A mixture of 0.7 g of thioformamide, 3.4 g of 4-(2-bromo-propionyl)-2,6-di-tert-butylphenol, and 1~ ml of absolute ethanol was heated to 50-60C for 2-3 hours. After cooling, th~ reaction mi~ture was dispersed in a diluteda~ueous solution of potassium carbonate. The precipitates thus formed were recovered by filtratlon and recrystallized from a mixture of cyclohexane and hexane to provide 1.2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthiazole.
Melting point: 128 130C
Elemental analysis for C18 H~5NOS:

C(%) H(%) N(%) Calculated: 71.24 8.30 4.62 Found: 71.39 8.53 4.38 Example 4 ( 3~3 ~ CH SC--NH F~C~ ~ C(CH3)3 OC~ ~ OH ~ r OH
B~CF~2 ~ C(CF~3)3 ~ + ~ ~ ~ '-J~' C(OEI ) (a) C(CH3)3 N. ~ OH
and ~ CEI2 ~ ~ C(C 3 3 1H CO~ CO (CH3)3 C(CH3)3 (b) A mixture of 4 g of benzylthioformamidine hydrochloride, 6.4 g of 4-(2-bromoacetyl)-2,6-di-tert-butylphenol, 20ml of chloroform, and 48 ml of 84% aqueous ethanol was vigorou91y stirred and -then 6.6 g of sodium hydrogen carbonate was added to -the mixture at room temperature. The~eafter, the resultant mixture was refluxed '7~
,.,`, ~
for 3 hours. The reaction mixture thus obtained was poured into water and extracted twice each time with 100 ml of benzene. The extract was dried and then concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography and by eluting with chloroform, two fractions were obtained. Each fraction was concentrated and recrystallized from cyclohexane to provide 1.2 g of (a) 2-benzylthio-4-(3,5~ tert-butyl-4-hydroxy-phenyl) imidazole and 0.6 g of (b) 2-benzylthio-1-(3,5-di-tert-butyl-4-hydroxyphenacyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole respec~ively.
~a~ Melting point: 92-94C
Elemental analysis for C24 H30 N2 OS + 1/2 C6 H12 C(%) H(%) N(%) Calculated: 74.21 8.25 6.41 Found: 73.83 8O43 6~36 (b) Melting point: 99-102C
Elemental analysis for C40 H52 N2 3 S:

C (%) H(%) N(%) Calculated: 74.96 8.18 4.37 Found: 74.78 8.58 4.05 Example 5 ( 3 3 1 N ~J ~OH (~3~ C ( CH2 ) 2 2S -~ C(CH ) ~=~ N 3 3 0 N ~ ~ OH
H ~ CH2S ~ NY ( 2)2 ~'7~
In 10 ml of chloroform was dissolved 0.8 g of 2-benzylthio-~-(3,5-di-tert-butyl~4-hydroxyphenyl)-imidazole and then 0.35 g uf m-chloroperbenzoic acid was added to the solu~ at -oom temperature. After the reactlon was over, the reaction mixture was washed with a diluted aqueous alkali solution, dried, and con-centrated under reduced pressure. The residue formed was sub-jected to silica gel chromatography and eluted with chloroform.
The fraction thus obtained was concentrated under reduced pres-sure and the residue was recrystallized from cyclohexane to i~ provide 0.3 g of 2-benzylsulfinyl-4-(3~5-di-tert~butyl-4-hydro-xyphenyl) imidazole.
M~lting po nt: 189-191C
Y 2~30 2 2 / 6 12 C(%) H(%) N(%) Calculat~d: 71.5g 7.95 6.19 ~ound: 71.48 8.16 6.19 Example 6 HN C(CH3)3 ~ ( 3 ~ _HN ( 33\
~CH~I ~ ~ j ~ HH \ ~ ~ OH
C(CH3~ 3 H 3 3 3 C(OEI3 3 .

, ....

,..._ _---_- ~

1~3 To a mixture of 3.18 g of 4-(3,5-di-tert-butyl-4-hydroxyphen-yl)-2-thioxo-4-imidazollne, 50 ml of dry acetone, and 1.3 g of potassium carbonate was added 1.4 g of methyl iodide at room temp-erature. 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.~ g of the product was re-crystallized from toluene to provide 0.5 g of 4-(3,5-di-tert-butyl-4~hydroxyphenyl)-2-methyl-thioimidazole.
Melting point: 249-251C
Elemental analysis for C18 ~26 ~ OS:
C(%) H(%) N(%) Calculated: 67.89 8.23 8.80 Found: 67.62 8.36 8.70 Example 7

3 3 F~- ~ CH2 C(CH3)3 C~ I N ~ OH ~ C(CH3) \
S~ OH ~N~ C~ 3 3 ~l ~ ~ OH
H (CH3)3 H 3 C(CH3)3t By following the same procedure as in Example 6 using 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl 2-thioxo-4-im-idazoline, 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizing 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 Eor C19 H28 N2OS
, 19 7~
.,. ~
C(%)H(%) N(%) Calculated: 68.63 8.49 8.43 Found: 68.42 8.74 8.40 Example 8 C(CH3)3 C(CH3)3 ~ ~ ~ OH ~ ~ ~ (CH~3)3 C~3S N ( 3 3 H

To a solution o~ 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylthioimidazole in 5 ml of chloroform was added 0~1~ g of m-chloroperbenzoic acid at room temperature and the mlxture was stirred for a day. The reaction mixture was washed wi.t:h a diluted alkali solution, dried, concentrated under reduc-ed pressure, and khe residue thus formed was:rec~ystallized from cyclohexane to provide 0.13 g of 4 (3,5-di-tert-butyl-4-hydroxy-0 phenyl)-2-methylsulfinylimidazole.

Melting poi~t- 106-108C
Mass spectrum: M-~ 334 ~uclear magnetic resonance spectra ~in CDCI3):
~(ppm): 1.48~S; ls3H), 3.1(S; 3~, 7.32(S; lH)~ 7.44(S,2H).

Exa~le 9 C(C~3)3 CH~SJ~ ~C(CE13)3 CH2SO~ ~ ;~C(CE13)3 7~8 In 10 ml of l,2-dimethoxyethane was dissolved 0.62 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methyl~hioimidazole and after adding thereto 0.44 g of m-chloroperbenxoic acid~ the mixture was refluxed for 3-4 hours. The reaction mixture was cooled, washed with a diluted alkali solution, dried, and concentrated under reduced pressure. The residue thus formed was recrystallized from cyclohexane to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-methylsulfonylimidazole.
Melting point: 119-120C
1~0 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 C(CH3)3 C(CH3)3 OH _ ~ 11 ~H
~ CH3 2 ~ 3 C(CH ) By following the same procedure as in Example 9 using 0O9 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-sulfonylimid~zole was obtained.
Melting point: 235-237C
Elemental analysis for Clg H28 N2 Cl3 S:

7~
C(%) H(%) M(%) Calculated: 62.61 7.74 7.69 Found: 62.91 8.01 7.25 HN C(CH3)3 C H OOCCHBr C( CH3 ) 3 ~ ~ 2 5 ~ CH N l~
S~ ~ OH ~ (CH3)3 ~ (CH3)3 C2H500CCES H

CIH3 ~ C(CH3) H500CHS C(CH3) 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 dxy acetone, 0.99 g of potassium carbonate, and 1.3 y of ekhyl cx~bromopropionate and recrystallizing the product from a mixture of toluelle and cyclohexane, 0.95 g of ethyl. 2~[4-(3~5-di-tert butyl-4-hydroxyphenyl)-2-imidazolylthio~propionate was obtained.
Melting point: 80-82C
~lemental analysis for C22H32N203S:
C(%) H(%) ~(%) Calculated: 65.31 7.97 6.92 Found: 65.58 8.19 6.63 Example 12 ~C(CH3)3 ~CH3 ( 3)3~ ~C(CH~

~7~
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 xefluxed for one hour and after filtering the reaction mixture9 the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of cyclohexane and n-hexane to provide lg of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole.
Melting point: 207 - 209C
~lemental analysis for C18H26~2 0.
iO C(%) H(%) N(%) Calculated: 75.48 9.15 9.78 Found: 75.31 9.40 9.53 ~xam~le 13 C(CH3)3 \ ~ CH ~ N 3 3 H C(CH3)3 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-hydroxy-phenyl)-2-mercapto-1-methylimidazole at a temperature below 10C
and the mixture was stirred for 20 minutes. Thereafter, 0.7g of methyl iodide was added to the mixture and after fuxther stirring tha mixture for 3 hours at 10C, the resultant mixture was poured into diluted hydrochloric acid and extracted twice each tima 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-4-0 hydroxyphenyl)~l-methyl-2-methylthioimidazole hydroiodide.

Melting point: 215-217C
Elemental analysis for C19 H29 N2 OSI:
C(%) H(%) N(%) Calculated: 49.57 6.30 6.08 Found: 49.48 6.33 5.96 Mass ~pectrum: M~ 332 Example 14 In 60 ml of ethanol was suspended 10 g of ammonium amidodi-thiocarbonate and 15 g of a-bromo-3,5-di-tert-butyl-4-hydroxy-acetophenone was ad~ed portionwise to the suspension under stirring at 0-5C. Then, after stirring the mixture overnlght at room temperature, 200 ml of water was added to the reaction mixture and the product was extracted with benzene. The extract was concen-trated and the residue was dissolved in 50 ml of acetic acid and re1uxed for 4 hours. To the reaction mixture were added 150 ml oE water and 50 ml of ethyl acetate and then the mixture was stirred. The crystal~ thus precipitated were xecovered by fil-tration and recrystallized from dioxane to provide 9.5 g of 4-(3,5-di~tert-butyl-4~hydroxyph~nyl)-2-mercaptothiazole as the 1/2 dioxane addition product thereof.
Melting point: 285-288C
Elemental analysis for C19 H27 NS2:
C(%) H(%) N(%) Calculated~ 62.43 7.44 3.83 Found: 62.31 7.47 3.96 . .

~'7~

~ ~ 2 4 H ~ ~ r C~CH ) Br CH3 C(CH3)3 3 3 Example 15 C(CH ) 3 3 C(CEI3)3 ~ ~ CH3l ~ H
HS S C(CH3)3 CH3S S C(CH3)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 dropwise to the solution at 0-5C. After allowing to stand the mixture for 30 minutes at room temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated wexe recovexed by filtration and recrystallized Erom n-hexane to provide 1.6 g of 4--(3,5-di-tert-butyl-~-hydroxyphenyl)-2-methyl-thiothiazole.
Melting point: 92-93C
Elemental analysis Eor C18 H~5 ~OS2:

~37~
C(%) H(%) N(%) S(%) Calculated: 64.44 7.51 4.17 19.11 Found~64.36 7069 4.23 19.28 Example 16 C(CH3)3 C(CH3)3 N ~ CEI o ~ ' ~
3 S C(CH3)3 3 2 S C(CH3)3 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 stirring. After one hour the reaction mixture was washed with a 5% sodium hydrogen carbonate solution, and the chloroform layer was concentrated. llhe crystals obtained were recrystallized from methanol to provide 0.55 g of 3,5-di-tert-butyl-4-hydroxy-phenyl-2-methylsulfonylthiazole.
Melting point: 183-184C
Elemental analysis for C18 H25 N3 S2 C(%) H(%) N(%) S(%) Calculated: S8.83 6.86 3.81 17.45 E'ound: 58.72 7.00 3.69 17.66 Example 17 3 3 _ 2 _ ~ ~ oHH3)3 ~ ~ OH HOOCCH2s ~ ~ C(CH3)3 HS J~ y C(CH3)3 To 20 ml of benzene were added 0.64 g of A-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoacetic acid and then 0.5 g of triethylamine was added dropwise to the mixture 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 a~ueous extract was acidified by the addition of hydrochlori~
aci.d and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The crystals lQ thus obtained were recrystallized from benezene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio] acetic acid.
Melting point: 158-159C
Elemental analysis for Clg H25 ~3S2 C(%) H(%) ~(%) S(%) Calculated: 60.13 6.64 3.69 16.89 Found: 60.06 6.62 3.77 16.69 ~ y~ 8 S ~ (C~3)3 ~ c(c~3)3 By ~ollowing the same procedure as in Example 12 using 2 g o~ ~-(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-butyl-4-hydroxyphenyl)-5-ethyl-imidazole was obtained.

~7 Melting point: 200-201C
Elemental analysis for Clg H28 N2 ~ l/2 C7 H8:

~(/O) H(%) ~(%) Calculated: 77.99 9.31 8008 Found: 77.72 9.53 8.13 _amples 19-25 0 EIN ~(CH3)~ N~O~l ~(CH3) 3) By Eollowing the same procedure as in Example 6, the follow~
ing compounds were produced~
Example l9 Compound: 4-(3,5-di~tert-butyl-4-hydroxyphenyl) 2-ethylthio-5-methylimidazole.

( ~ - CH3, ~ 2 3 Meltir-g point: 245-250C (to~'uene) Eleme~tal analysis or ~20 H30 2 C(%) H(%) N(%) S(%) Calculated: 69.32 8.73 8.08 9.25 Found~ 69.38 8070 8.00 9.47 Example 20 25Compound: 4-(3,5-di tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methylimidazole.
,CH3 ( ~ ~ CH3, ~ C ~CE3 Melting point; 250-258C (toluene) 30~lemental analysis ~or C21 H32 N2 OS:

~t7~

C(%) H(%) N(%) S(%) Calculated: 69.96 8.95 7.77 8.~9 Found: 69.74 9.02 7.61 8.63 Example 21 Compound: 4-(3,5~di-tert-butyl~4-hydroxyphenyl)-5-ethyl-2-methylthioimidazole.
( ~ = CH2 CH3, ~ 3 Melt.ing point: 210-211C (toluene) El mental analysis for C20 30 2 C(%) H(%) N(%) Calculated~ 69.32 8.73 8.08 Found: 69.05 8.68 7.48 ExamPle 22 Compound; 4-(3,5-di-tert-butyl 4-hydroxyphenyl)-5-ethyl-2-ethylthioimidazole.
( ~ - CEI2 CH3, ~ CH2 3 Melting point: 226-228~C (toluene) Elemental analysis for C21 H32 N2 OS:

C(%) H(%)N(%) Calculated: 69.96 8.95 7.74 Found: 70.1~3 8.97 7.63 Example 23 Compound: 4-(3,5~di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-isopropylthioimidazole.
( ~ = CII2 CH3, ~ = CH~CH

Melting point: 247-248~C (toluene) Elemental analysis for C22 H34 N2 OS

C~%) H(%)~(%) Calculated: 70.54 9.15 7.4 Found: 70.32 9.27 7.37 Compound: 4-(3,5-di-tert-butyl 4-hydroxyphenyl)-5-isopropyl-2-methylthioimidazole.
( ~ = CH ~ CH ~ ~ = CH3 Melting point: 222-223C (ethyl acetate-hexane) Elemental analysis for C21 H32 N2 OS:

C(%) H(%) ~(%) Calculated: 69.96 8.95 7.77 Found: 69.78 9.01 7.65 Example 25 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)~5-isobutyl-2-methylthioimida~ole.

~ CH2 CH~C~ , ~ = CE13 ) Melting point: 210-212C (benzene-hexane) Elemental analysis for C22 H34 N2 OS:

C (%) '.EI (%) ~ (%) Calculated: 70.54 9.15 7.48 Found: 70.45 9.24 7.07 C(CH3)3 ~ 0~ BrCEI2COOH~ ~l ~ C(CH3)3 HS _~_ (CH3)3 3 ~T

'7~
In 30 ml of toluene were dissolved 1.6 g of 4-(3,5-di-tert-butyl-4-hydro~yphenyl)-5~methyl-2-thioxo-4-imidazoline and 0.7 y oE bromoacetic acid and after adding thereto l g of triethylamine at room temperature, the mixture was refluxed for 4 ~lours. After cooling, the reaction mixture was filtrated and the filtrate was extracted with an aqueous sodium carbonate solution and the alkali solution was acidified with diluted hydrochloric acidO The precipitates thus formed were recovered by filtration and recrys-tallized from aqueolls isopropanol to provide 0.5 g of [4-(3,5-di-tert-butyl-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 E.xamples 27-28 HN ~ ~ C(CH3)3 ~ OH ~ ~ r~
S ~ N ~ OH N ~ ~ ~ OH
H ~ ~N ~ C(CH3)3 C(CH3)3 , C(CH3)3 H

By following the same procedure as in Example 12, the following compounds were produced.

;~ 31 , ... .

7~

Example 2 7 Compound: 4- (3 ,5-di~tert-butyl-4-hydroxyphenyl) -5-isopropylimidazole. 1/2 CH3 OH

~ ~C 3 ) /

/

/

31 ( a) ;~

~7~
Melting point: 208-210C (methanol) Elemental analysis for C20 H30 M2 0.1/2 CH3OH:

C(%) ~(%) N(%) Calculated: 74,50 9.76 8.4B
Found: 74.23 10.08 8.43 _a~ple 28 Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyL)-5-isobutylimidazole.

( (~ - CH2 CH~CH
Melting point: 202-203C (benzene) Elemental analysis for C l H32 N2 C(%) ~(%) N(%) Calculated:76.78 9.82 8.53 Found:76.64 9.95 8.45 lS Example 29 OC ~ OH ~ ~ oH
Brc~cH3 C(CH3)3 NH2CSSNH4 HS ~ ~ C(CH3)3 By following the same procedure as in Example 14, 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-methylthiazole was pro-duced.
Melting point: 267-269C (tetrahydrofuran-hexane) Elemental analysis for Cl8 H25 ~S2 C(%) H(%) ~%) Calculated: 64~44 7.51 '}~17 Found: 64.29 7.50 4.16 ~3'7~
Example 30-35 C(C~I3) H~ ~ ~ (CH ~ H3)3 3 3 ~ S S ~ C(C~3)3 By following the same p~ocedure as in Example 15, the follow-ing compourLds were produced.
ExamE~
Compound: 4-(3,5-di-kert-butyl-4-hydro~yphenyl)-2-ethylthiothiazole.
( ~ = H, ~ = CEI2 CF~3) Melting point: :L30-131C (methanol) Elemental analysis for Clg H27 NOS2:

C(%) H(%) N(%) S(%) Calculated: 65.29 7.79 4.01 18.34 Found: 64.97 7.99 4.01 18.38 Example 31 ~ Compound: 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthiothiazole.
( ~ = H, ~ ~ CH~ 3 ) Melting point: 173-174C (hexane) Elemental analysis for C~0 H29 NOS2:

C(%) H(%) N(%) S(%) Calculated: 66.07 8.04 3.85 17.64 Found: 66.20 7.84 3.67 17.80 Example 32 Compound: 4~(3,5-di-te~t-butyl-4-hydroxyphenyl)-5-methyl-2-methylthiothiazole.

((~) (~
Melting polnt: 118-119C (hexane) Elemental analysis for C g H27 ~S2 C(%) ~(%) N(%) S(%) Calculated: 65.29 7.79 4.01 18.34 E'ound: 65,41 7.96 4~01 18~60 Example 33 Compound: 4-(3,5-dl-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthiothiazole.
( ~ = CH2 CH3, ~ 3 ~ . Melting polnt: 115-116C (hexane) ~lemental analysis for C20 H29 NOS2:

C(%) E-I(%) N(%) S(%) Calculated: 66.07 8.04 3.85 17.G4 Found: 66.17 8.18 4.11 17.60 Example 3 Compound: 4-(3~5-di-tert-butyl-4-hydroxyphenyl)-5 isopropyl-2-methylthiothi.azole.

~ CH3 Melting point: 135-137C (methanol) ~lemental analysis for C21 ~3l NOS2:

C(%) H(%) N(%) S(%) Calculated: 66.80 8.27 3.71 16.98 ~ound: 66.70 8.37 3.77 17.20 3J~, 3~

7~
Example 35 Compound: 4-(3 9 5-di tert-butyl-4-hydroxyphenyl)-5 isobutyl-2-methylthiothiazole.
( ~ - CH2 CII~ CH3 Melting point: 96-97C (methanol) Elemental analys i5 for C22 H33 NOS2:

C(%) E(%) ~(%) S(%) Calculated: 67.42 8.49 3.58 16.37 Found: 67.12 8.71 3.58 16.59 Example 36 c(cH3~3 ~OOOH / C(CH3)3 15N ~ OEI ~ C~ N ~ OH

C~ S~lS~ ~ (C ) ~ C(CH3)3 In S 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. After 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-meth~rlsulfinylthiazole.
~elting point: 124-125C
Elemental analysis fox C18 H25 N02 S2:

t~

C(o/o) H(%) N(%) S(%) Calculated:61.50 7.17 3.98 18.24 Found: 61.41 7.32 4.05 18.56 Example 37 S~OH CH35~ ~3 ~ 3 C(CH3~ ~

By following the same procedure as in Example 6, 4-(3~5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenylimidazole was 15 produced.
Melting point: 129-131C (toluene-hexane) ~lemental arlalysis for C24 H30 2 7 C(%) Il(%) N(%) S(%) Calculated: 74.10 7.676.71 7.67 Found: 73.64 7.866.42 7.46 Example 38 __ J~ (CH3 ) 3 ~ 3 3( ~ OH

7q~
By following the same procedure as in Example 12, ~-(3,5-di-tert-butyl-hydroxyphenyl)-5-phenyllmidazole ~as produced.
Meltiny point: 170-171C (toluene) Elemental analysis for C23 H28 N2 C(%) H(%) N(%) Calculated: 79.27 8.10 8.04 Found: 79.16 8.28 8.06 Example 39 C(CEI )3 C(CH ) 1 ~ C(C~13) Nfl~CSSN~I4 HS ~ ( 3 3 By following the same procedure as in Example 14, 4-(3,5-di-terk-butyl-4-hydroxyphenyl)~2-mercapko-5-phenylthiazole was pro-duced.
Melt.ing point: 168-171C (tetrahydrofuran-hexane) EL mental analysis for C23 27 2 C(%) H(%) N(%) S(%) Calculated: 69.48 6.84 3.52 16.13 Found: 69.80 7~10 3.43 16.22 Following the same procedure as in Example 1, the following compounds were prepared.

1~8 7~
E'ollowing the same procedure a~ in Example l, the following compounds were prepared.

Æxample Mo. The Chemical Formula mp.
IIN ~ ~ ( 3)3 above 260C (decomp ) C~CH3)3 . . _ _ 41 above 270C L~ I
HN f H3 C(CH3)3 (decomp.) Thi~ produc-t I Il ~ was recrystalll~ed from 0~ ~ / \~ OH aqueous ethanol to pro-H ~ vide the pure produc-t ~(CE3)3 having a melting point o~ 279-282C.
_ . . . _ . . _ _ L5 42 ~ C(CH3)3 288-290C
S ~ NH J~OH
(CI-I3)3 _ _ _ _ C(CH3)3 S ~ ~ 168-170C
(CH3)3 . . . ~
C(CH3)3 HS ~ ~ OH 288-289C
CH3 C(CE3)3 2.5 _ _ _ ~ ~ 2 5 C(CH3)3 H ~ OH 267-270C
~=~`C(C~I3)3 >7~3~
Example No.The Chemical Formula mp.

HN 3" C ~ CH3 ) 3 O ~ ~1 ~ OH above 290C (decomp.) C (C:H3 ) 3 C H
47 ~L ~ 2 ~ C (CH3) 3 279-281C
H --~( CHH3 ) 3 ~CH3 48 S ~ ~ J~CH3) 3 above 300C (decomp.) C ( CH3 ) 3 ~C~I3 49 HN CH2CH~CH 286-289C
J~C(CH3)3 C (CH3 ) 3 c _r ( CH3 ) 3 2 0 HO ~ N ~ ~ H
1I~ \~c ( CH3 ) 3 51 HN_~J 300C

O ~L N ~ - c (HH3 ) 3 C(CH3) 52 ,lJ 258-262C
HN ~ C (CH
S ~ N ~ ~ OH 3 3 H \ ~ C(CH3)3 7~
Example No ~ The Chemica 1 Formula mp .

( CH ) C N --~3 53 3 3~ ll ~ 185-186C
H0--~ \7- ~ o ~u 3 ) 3 \.~
_ _ __ __ _ _ (CH3) ~ 3 . _ _ 3) 3 ~ ~ _ above 300C

(CH3) C ~3 N~

..... .. .. _ _ , ,, , , , , _ _ _ _ _ _ _ 56 ~ ~ 2.98-300C

.0 _ .

, ,/

,/

~' ,.,--SUPPLEMENTARY DISCLOSURE
Ex mple 57 C (CH3)3 C(CH3)3 HS~C(CH3) 3 3 1~ J~ C(CH3)3 By following the same procedure as in Example 15, 4-10 (3,5-di-tert-butyl-4~hydroxyphenyl)-2-methylthio-5-phenyl-thiazole is produced.
Melting point: 135-137C (hexane) Elemental analysls for C24H29NOS2:

C(%) H (%) N(%) S(%) 15 Calculated:70.03 7.10 3.4015.58 Found: 70.30 7.37 3.4415.61 Fxample 58 C(C~13)3 C(CEI3)3 EIO-~ COCH23r 2)HCL HO ~O

C(CH3) 3 3 3 3.27 g oE 4 (2-bromoacetyl)-2,6-di-tert-butylphenol is dissolved in 20 ml of ethanol. To the solutionl a solution of 0.81 g of sodium thiocyante in 1 ml oE water is added 25 portionwise. After stirring, the reaction mixture is heated, and 2 ml of conc. hydrochloric acid is added to the mixture at 50C followed by refluxing under heating Eor 1.5~2 hours.
After cooling, the reaction mixture is poured into 100 ml of water, and the resultan-t precipitates are collec-ted by filtra-~ 1.' ' ~7~
tion to provide 1.6 g of crude 4-(3,5-di-tert-butyl-4-hydroxy-phen-yl)-2-oxo-4-thiazoline. 1.2 g of crude product is recrystallized from iso-propanol to provide 0.7 g of pure product showing a melting point of 279^~281C. ~ - .
S

/

41(a) Example 59 R - COfH - Br NaSCN ~ NH

CH3 H3 ~

3.41 g of 4-(2 bromopropionyl)-2t6-di-tert-butylphenol is d:issolved in 20 ml of acetone. To the solution, a solution of 0.81 g of sodium thiocyanate in 2 ml of water is added at room temperature. After stirring for 3 hours, the solvent is dis-tilled away under reduced pressure. To the residue, 40 ml of ethanol and 2 ml of conc. hydrochloric acid are added followed by refluxing for 5 hours under heating. After cooling, the reacti.on mixture is poured into 100 ml'of water. The resultant precipitates are co].lected by fi].tration to provide 3.0 g of crude 4~(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-thlazoline. 0.~ g of crude product is recrystallized from lso-propanol to provide 0.27 g of pure product showing a melt-inrJ point of 255~257 C.

. .
j~ ,.

Claims (122)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of producing a 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound represented by formula I
I

wherein one of R1, R2, and R3 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group and others repre-sent a hydrogen atom, a lower alkyl group, a lower aralkyl group, an aryl group, a lower alkoxy-substituted aryl group, or the group shown by -O-Z, or -NH-Z (wherein Z repre-sents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower aralkyl group, or a aryl group and n represents 0, 1, or 2) and A represents an oxygen atom, a sulfur atom, an imino group, a lower alkylimino group, or a 3,5-di-tert-butyl-4-hydroxy-phenacylimino group or a pharmaceutically acceptable acid addition salt thereof which comprises selecting a process from the group of pro-cesses consisting of:
(a) reacting the compound represented by formula II
II

and the ?-halocarbonyl compound represented by formula III
III

wherein R1, R2, R3, and A have the same significance as defined concerning formula I; A' represents an oxygen atom, a sulfur atom, an imino group, or a lower alkyl-imino group; and X represents a halogen atom;
(b) reacting a compound of formula I wherein R1 is -S-Z with an oxidizing agent to obtain the correspond-ing compound of formula I wherein R1 represents wherein n is 1 or 2;
(c) reacting a compound of the formula:
wherein R2, R3 and A are as defined above with an alkylat-ing agent to obtain the corresponding compound of formula I wherein R1 represents -S-Z wherein Z is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxy car-bonyl lower alkyl group or a lower aralkyl group;
(d) desulfurizing a compound of the formula:
wherein R2, R3 and A are as defined above to obtain the corresponding compound of formula I wherein R1 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 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(?-phenethylamino) thiazole hydrobromide and its pharmaceutically acceptable acid addition salt, wherein R1 is a ?-phenethylamino group, R2 is a hydrogen atom, R3 is a 3-5-di-tert-butyl-4-hydroxy-phenyl group and A is a sulfur atom.

3. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydrogen atom, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an oxygen atom.

4. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydrogen atom, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

5. A process according to claim 1 for the preparation of 2-benzylthio-4-(3,5-di-tert-butyl-4-hydroxyphenyl)) imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a benzylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

6. A process according to claim 1 for the preparation of 2-benzylthio-1-(3,5-di-tert-butyl-4-hydroxyphenacyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole and its pharma-ceutically acceptable acid addition salt, wherein R1 is a benzylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a 4-hydroxyphenacyl imino group.

7. A process according to claim 1 for the preparation of 2-benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a benzylsulfinyl group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

8. 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 salt, wherein R1 is a methylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

9. 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 salt, wherein R1 is a methylthio group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

10. 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 salt, wherein R1 is a methylsulfinyl group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

11. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfonylimida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylsulfonyl group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

12. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylsulfonyl-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylsulfonyl group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

13. 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 salt, wherein R1 is an ethoxyisopropylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group and A is an imino 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 salt, wherein R1 is a hydrogen atom, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

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 salt, wherein R1 is a methylthio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and A is a methylimino group.

16. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a mercapto group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

17. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and its pharmaceutically acceptable acid addition salt, where-in R1 is a methylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

18. A process according to claim 1 for the preparation of 3,5-di-tert-butyl-4-hydroxyphenyl-2-methylsulfonylthiazole and its pharmaceutically acceptable acid addition salt, where-in R1 is a methylsulfonyl group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

19. A process according to claim 1 for the preparation of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio] acetic acid and its pharmaceutically acceptable acid addition salt, wherein R1 is an acetic acid thio, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

20. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydrogen atom, R2 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, R3 is an ethyl group and A is an imino group.

21. 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 salt, wherein R1 is an ethylthio group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

22. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methyl-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an isopropylthio group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

23. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylthio group, R2 is an ethyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

24. 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 addi-tion salt, wherein R1 is an ethylthio group, R2 is an ethyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

25. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-isopropylthio-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an isopropylthio group, R2 is an ethyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, and A is an imino group.

26. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-methyl-thioimidazole and its pharmaceutically acceptable acid addi-tion salt, wherein R1 is a methylthio group, R2 is an isopropyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

27. 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 addition salt, wherein R1 is a methylthio group, R2 is an isobutyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A
is an imino group.

28. 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 salt, wherein R1 is an acetic acid thio group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

29. 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 salt, wherein R1 is a hydrogen atom, R2 is an isopropyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

30. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydrogen atom, R2 is an isobutyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

31. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-methylthia-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a mercapto group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

32. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthiothiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an ethylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

33. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthiothiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an isopropylthio group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

34. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-thiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylthio group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

35. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-thiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methyl-thio group, R2 is an ethyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

36. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-methylthio-thiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylthio group, R2 is an isopropyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

37. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxypheny])-5-isobutyl-2-methyl-thiothiazole and its pharmaceutically acceptable acid addi-tlon salt, wherein R1 is a methylthio group, R2 is a iso-butyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

38. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylthia-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylsulfinyl group, R2 is a hydrogen atom, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

39. 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 salt, wherein R1 is a methylthio group, R2 is a phenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

40. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-A-hydroxyphenyl)-5-phenylimidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydrogen atom, R2 is a phenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

41. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-phenylthia-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a mercapto group, R2 is a phenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

42. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an oxo group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and A is an imino group.

43. A process according to claim 1 for the preparation of 4-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an oxo group, R2 is a 3,5 di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl group and A is an imino group.

44. A process according to claim 1 for the preparation of 4-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thio-imida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a thio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl group and A is an imino group.

45. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thio-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a thio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and A is an imino group.

46. 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 salt, wherein R1 is a mercapto group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a hydrogen atom and A
is a methylimino group.

47. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-5-ethyl-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an oxo group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is an ethyl group and A is an imino group.

48. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isopropyl-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an oxo group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is an isopropyl group and A is an imino group.

49. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-ethyl-2-thio-imida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a thio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is an ethyl group and A is an imino group.

50. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isoprophyl-thio-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a thio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is an isopropyl group and A is an imino group.

51. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isobutyl-2-oxo-imi-dazole and its pharmaceutically acceptable acid addition salt, wherein R1 is an oxo group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is an isobutyl group and A is an imino group.

52. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-methyl-2-hydroxy-1-methyl-imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a hydroxy group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl group and A is a methylimino group.

53. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-phenyl-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt, where-in R1 is an oxo group, R2 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, R3 is a phenyl group and A is an imino group.

54. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-phenyl-2-thio-imida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a thio group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a phenyl group and A is an imino group.

55. A process according to claim 1 for the preparation of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-diphenyl-oxazole and its pharmaceutically acceptable acid addition salt, where-in R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a phenyl group, R3 is a phenyl group and A is an oxygen atom.

56. A process according to claim 1 for the preparation of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-bis(p-methoxyphenyl) imidazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a p-methoxyphenyl group, R3 is a p-methoxyphenyl group and A is an imino group.

57. A process according to claim 1 for the preparation of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-diphenyl-imidazole and its pharmaceutically acceptable acid addition salt, where-in R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a phenyl group, R3 is a phenyl group and A is an imino group.

58. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-phenyl-imida-zole and its pharmaceutically acceptable acid addition salt, wherein R1 is a phenyl group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is an imino group.

59. A 3,5-di-tert-butyl-4-hydroxyphenyl-substituted hetero-cyclic compound represented by formula I

I

wherein one of R1, R2, and R3 represents a 3,5-di-tert-butyl-4-hydroxyphenyl yroup and others repre-sent a hydrogen atom, a lower alkyl group, a lower aralkyl group, an aryl group, a lower alkoxy-substituted aryl group, or the group shown by -O-Z, or -NH-Z (wherein Z represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower aralkyl group, or a aryl group and n represents 0, 1, or 2) and A represents an oxygen atom, a sulfur atom, an imino group, a lower alkyl-imino group, or a 3,5-di-tert-butyl-4-hydroxyphenylimino group or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of claim 1.

60. 4-(3,5-di-tert-butyl-4-hydroxyphenyl1)-2-(?-phenethyl-amino) thiazole hydrobromide and its pharmaceutically accept-able acid addition salt when prepared by the process of claim 2.

61. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 3.

62. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 4.

63. 2-benzylthio-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imi-dazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 5.

64. 2-benzylthio-1-(3,5-di-tert-butyl-4-hydroxyphenacyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole and its pharma-ceutically acceptable acid addition salt when prepared by the process of claim 6.

65. 2-benzylsulfinyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl) imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 7.

66. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methyl-thioimida-zole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 8.

67. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-thio-imidazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 9.

68. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 10.

69. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfonyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 11.

70. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methyl-sulfonyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 12.

71. ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imida-zolyl-thio]propionate and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 13.

72. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 14.

73. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-methyl-thio-imidazole hydroiodide and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 15.

74. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 16.

75. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 17.

76. 3,5-di-tert-butyl-4-hydroxyphenyl-2-methylsulfonylthiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 18.

77. [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]
acetlc acid and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 19.

78. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 20.

79. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthio-5-methyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 21.

80. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-5-methyl-imidazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 22.

81. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 23.

82. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-ethylthio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 24.

83. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-isopropyl-thio-imidazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 25.

84. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-methyl-thioimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 26.

85. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methyl-thioimidazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 27.

86. [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-imidazoyl-thio]acetic acid and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 28.

87. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropylimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 29.

88. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutylimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 30.

89. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-methyl-thiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 31.

90. A (3,5-di-tert-butyl-4-hydroxyphenyl)-2-ethylthiothiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 32.

91. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-isopropylthio-thiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 33.

92. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthio-thiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 34.

93. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-methylthio-thiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 35.

94. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-methyl-thio-thiazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 36.

95. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isobutyl-2-methyl-thiothiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 37.

96. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinyl-thiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 38.

97. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 39.

93. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-phenylimidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 40.

99. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-5-phenylthiazole and its pharmaceutically acceptable acid addi-tion salt when prepared by the process of claim 41.

100. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt when pre-pared by the process of claim 42.

101.4-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 43.

102. 4-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 44.

103. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 45.

104. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methyl imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 46.

105. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-5-ethyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 47.

106. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isopropyl-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 48.

107. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-ethyl-2-thio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 49.

108. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isoprophyl-thio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 50.

109. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-isobutyl-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 51.

110. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-methyl-2-hydroxy-l-methyl imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 52.

111. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-phenyl-2-oxo-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 53.

112. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-phenyl-2-thio-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 54.

113. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-diphenyl-oxazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 55.

114. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-bis(p-methoxy-phenyl) imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 56.

115. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-diphenyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 57.

116. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-phenyl-imidazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 58.

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE

117. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenyl-thiazole and its pharmaceutically acceptable acid addition salt, wherein R1 is a methylthio group, R2 is a phenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

118. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio-5-phenylthiazole and its pharmaceutically acceptable acid addition salt when prepared by the process of claim 117.

119. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-thiazoline and its pharmaceutically acceptable acid addition salts, wherein R1 is an oxo group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a hydrogen atom and A is a sulfur atom.

120. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-thiazoline and its pharmaceutically acceptable acid addition salts when prepared by the process of claim 119.

121. A process according to claim 1 for the preparation of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-thiazoline and its pharmaceutically acceptable acid addition salts, wherein R1 is an oxo group, R2 is a methyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and A is a sulfur atom.

122. 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-thiazoline and its pharmaceutically acceptable acid addition salts when prepared by the process of claim 121.