CA1181074A - Process for producing 3,5-di-tert-butyl-4- hydroxyphenyl-substituted heterocyclic compounds - Google Patents

Abstract

ABSTRACT
A process for producing novel 3,5-di-tert-butyl-4-hydroxyphen-yl-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 immunoreg-ulatory activity. Hence they are particularly useful as an anti-rheumatic.

Description

This invention relates -to a process of producing novel 3,5-di-te~t-butyl-~-hydroxyphenyl-substituted heterocyclic compounds.
More particularly, the invention relates to a process of produc-ing the 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocy-clic compounds shown by formula l and their salt;

~ ~ R2 ( ~, wherein one of Rl, R2, R3 and R4 represents 3,5-di-tert-bu-tyl-4-hydroxyphenyl group, and others represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, a lower alkoxy-substituted aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group, or a thiocyanato group; m represents 0, l or 2;
and the dotted line means the presence or absence of a double bond).
The terminology throughout the speciEication and the claims oE
this invention is as follows:
The term "lower" means a straight or branched carbon chain of 1-6 carbon a-toms. ThereEore, ~or example, "lower alkyl group"
includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, heptyl group, hexyl group, etc.; "lower aralkyl group" includes benzyl group, phene-thyl ~roup, etc.' "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, hexy-loxy group, etc.; "lower alkylthio group" includes methylthiogroup, ethylthio group, propylthio group, isopropythio group, etc.;
and "lower alkanoyl group" includes formyl group, acetyl group, propionyl group, isopropionyl group, butyryl group, hexanoyl group, etc. Also, the term "amino" in "amino lower alkyl group" means not only amino group but also mono~ or di-alkylamino group such as methylamino group, dimethylamino group, diethylamino group, etc., and cyclic amino group such as morpholino group, pyrnolidino group, piperidino group, piperazino group, 4-lower alkylpiperazino group, etc. Furthermore, the term "aryl group" includes phenyl group, naphthyl group, etc., and the term "halogan atom" includes chlorine atom, bromine atom, iodine atom, fluorine atom, etc.
Then, as the salts of the compounds of this invention shown by formula l, there are pharmaceutically acceptable acid addition salts, for 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 1 have an anti-inflammatory, and anti-pyretic, an analgesic, an anti-arthri-tic and an immuno regulatory activity.
Hence they are novel compounds particularly useful as an anti-rheumatic.
That is, Cince the compounds of this invention shown by form-ula l show a therapeutic and prophylactic effect on adjuvant-indu-ced arthritis which is considered to be an animal model of human rheumatism and further have analgesic and anti-inflammatory act-ivities as well as a prostagrandins formation inhibiting activityas a biochemical activity, the compounds oE 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 1 suppress remarkably Coomb's type 111 (Arthus reaction) and type lV (delayed type hypersensitivity) allergic reactions as well as have a lipoxygenase suppressing activity and a property as a radical scavenger, whlch have never been attained by conventional nonsteroidal acidic anti-inflammatory anti-rheum-atics represented by indomethacin and diclofenac. Therefore, thecompounds 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 shown by formula 1 is that the compounds belong to a nonsteroidal nonacidic anti-inflammatory agent and are different from conventional nonsteroidal acidic anti-inflammatory agents represented by indomethacin 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 heter-ocyclic ring itself is a specific heterocyclic ring (Practically, S~ ~ , i. e., a (2,3-dihydro)imidazo[2.1-b]thiazole ring.) As heterocyclic compounds the heterocyclic ring of which is directly substituted by a 3,5-di-tert-butyl-4-hydroxyphenyl group, there are known, for example, 2-(3,5-di-tert-butyl-4~hydroxypheny-l)-benzoxazole compounds and 2-(3,5-di-ter~-butyl-4-hydroxyphenyl)-benzothiazole compounds (West German Offenlegungsshrift 27008,414);

2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-diphenylimidazolidine compounds (Belgian Pak. Mo. 807,140); and 2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethoxy-4-thiazolyl]acetic acid (Japanese Pat.

7~
Appln. Laid Open No. 1669/'-1~3). llle ~enzoxa~.olc colllpounds ancl the benæothiazole compounds are used as an anLioxidant and the imidaz-olidine compounds are used as intermediates for plant pro-tecting agents and dyes. ~he last ace-tic acid compound is sugyested to be used as an anti-thrombotic ayent. a hypolipaemic agent, and an anti-inflamma-tory agent. About the acetic acide compound, the use as an anti-inflamma-tory agen-t is suggested as described above but there is no disclosure about the practical pharmacological effect of the compound as an an-ti-inflammatory agent and also the chemical structure of the acetic acid compound is a heterocyclic riny-sub-stituted acetic acid derivative, which belongs to a non-steroidal acidic anti-inflammatory agent and hence differs from the compounds of this invention shown by formula 1 in chemical structure.
The particularly preferred compounds in the Eoregoing hetero-cyclic compounds (1) are as follows;
6-(3,5-di-tert-bu-tyl-4-hydroxyphenyl)5-methyl-2,3-dihydro-imidazo[2,1-b]thiazole, 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole l-oxide, 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole l,l-dioxide, and 6-(3,5-di-te.rt-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
The compounds of this invention can be prepared by -the Eollowing methods.
i). First production method:

R~ H2 R4 ~ 5 II III a ~8~
wherein X represents a haloycn atom ancl R~ 2~ ~3 and R~ and the dotted line have -the same significance as clefined above.

The compound of this invention shown by formula l wherein m is 0, i. e., the compound shown by forrnula l can be prepared by react-ing the 2-aminothiazoline derivative or 2-aminothiazoIe derivative shown by formula 11 with the c~-halocarbonyl compound shown by formula 111. The reac-tion is performed by heating -the compound of formula 11 and the correspondiny amount of the compound of formula 111 in si-tu or in a proper solvent such as me-thanol, ethanol, tol-uene, dimethylformamide, acetone, chloroform, methyl ethyl ketone,ethyl acetate, methyl cellosolve* ethyl cellosolve*, digryme, ace~
tonitrile, etc. The reaction temperature and the reaction time are properly selected according to the kinds of the solvent and the starting materials used, but the reaction is advantageously perfor-med under refluxing.

ii). Second production method R -C-0 HN ~ R R

IV V

wherein Rl, R2, R3 and R4, ~ and the dotted line have the same signiEi-cance as defined above.
The compound shown by formula l can be also prepared by reacting the G~ -halocarbonyl compound showll by form~la lV and the 2-mercaptoimidazole derivative shown by -Eormula V or a sal-t there-of, e g., an alkali metal salt thereof. The reactiOn is per-formed by reacting the compound of formula IV with the correspond-ing amount of the compound of forrnula V or an alkali metal salt thereof in situ or in a proper solvent such as methanol, ethanol, *trade mark 5 79~
toluene~ dimethylformamide~ acetollc!, chlnro:Eorm, metl-yl ethyl ke-tone ethyl acetate, methyl cellosolve* ethy:L cellosolve* dicJryme, acetonitrile, etc. The reac-tion usually proceeds at room -temper-ature but may be performed under heating. The reaction time is properly determined according to the kinds of the solvent and the starting materials used. When the compound of formula V is used as it is, i. e., not as an alkali metal sal-t thereof, i.t is pref-erred that the compound is previously reac-ted with a alkali metal alcoholate to form a corresponding alkali metal salt and then the alkali metal salt is reacted with the compound of formula IV.
This reaction is considered to proceed via an intermediate shown by formula VI

R -C=O El~ VI

. R4-cH-s ~ N R

wherein Rl, R2, R3 and R4 have the same significance as defined above and,if necessary, the intermediate can be isolated. The intermed-iate of formula VI can be converted into the compound of formula I by the treatment with an acid such as hydrochloric acid, acetic acid, etc., Or phosphorus oxychloride.
In addition, by using the dihalogenoethane derivative shown by formula IV R3 1l IV
R~ ~

wherein R3, R4, and X have -the same significance as defined above, in place of the o~ -halocarbonyl compound used in the star-ting material in the production method, the compound of formula I
can be prepared.
* trade mark 6 iii). O-ther production method:

R3.~Rl (1) oxidation> R ~R
(O)m c~ Iu_l R ~ ~ / Rl (2) a.minomethylati ~ (O)m C 2N ~5 (O) . I~-2\ ~ lower alkanoylation I 3 \ R4 ~S ~ $ R
\ (O)m a-4 (4) for~ lation R3 ~ CHO 3 N _ CH20H
(O)m reductio.n ~ ~ R]

a-5 N ,CN

~S 1~ ~ R
4 (O)m Ic~-7 .~ , --S ~NIR 1 4 (O)m ~-8 (8 ~ ower alkylation \ R S-lower alkyl N~ R
4 (O)m o~

~r ,. ...

'7~
wherein m' represents 1 or 2; R5 and R~ each represents a hydrogen atom, a lower alkyl group, or they may combine with each other to form a cyclic amino group; and R1, R2, R3 and R4 m, and the dotted line have the same significance as deflned above.

The oxidation method (1) is a method of producing the compound of this invention shown by formula I wherein m is 1 or 2, i.e., the S-oxide compound shown by formula I 1 The S-oxide compound can be prepared by reacting the corresponding thio compound of foregoing formula 1 with an oxidizing agent in a solvent such as chloroform, 1,2-dimeth-oxyethane, acetic acid, etc., according to a conventional method. As the oxidizing agent, 10-40% hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc., is usually used. In this case, by properly selecting the xeaction conditions such as the reaction period of time, the reaction temperature, the amount of the oxidizing agent, etc., the desired mono-oxide compound (m' = 1) or dioxide compound (m' = 2) can be obtained.

The aminomethylation method (2) is a method of producing the compound of this invention shown by formula ~ wherein R2 is an aminomethyl group, i.e., the aminomethyl compound shown by formula I 3. The aminomethyla-tion is performed by reacting the compound shown by formula I wherein R2 is a hydrogen atom, i.e., the compound shown by formula I 2 with -formaldehyde and the amine shown by H ~ according to a Mannich reaction.

The lower alkanoylation method (3) is a method of producing the compound of this invention shown by formul-a I
wherein R2 is a lower alkanoyl group, i.e., the lower alkanoyl f7~
compound shown by formula I _~. The lower alkanoyl compound can be prepared by reacting the compound shown by formula I
with a lower alkanoyl halide such as acetyl chloride, etc., and an acid anhydride such 8(a) :, as acetic anhydride, etc., according to a conventional method.
In addition, the lower alkanoyl compound shown by formula I wherein the lower alkanoyl group is a formyl group, i. e., a-4 the formyl compound shown by formula I 5 can be also prepared by reacting the compound shown by formula I accordiny to an ordinaxy manner with a complex (Vilsmeie reagent) of dimethylformamide (DM~
and phosphorus oxychloride or oxalyl chloride and then hydrolyzing the reaction product. This method is the foregoing formylation method.(4) The reduction method (5) is a method of producing the compound of this invention shown by formula I wherein R2 is a hydroxymethyl group, i. e., the hydroxymethyl compound shown by formula I 6.
The hydroxymethyl compound can be produced by reduc~ng th~ fore-going formyl compound of formula I 5 with a reducing agent such as sodium borohydride.
The cyanation method (6) is a method of producing the compound of this invention shown by formula I wherein R2 is a cyano group, i. e., the nitrile compound shown by formula I 7.
The nitrile compound can be produced by reacting the compound shown by formula I~w~th a Vilsmeier reagent as in the foregoing formylation method (4) according to a conventional method and then reacting the reaction product with hydroxyamine.
The thiocyanation method (7) is a method of producing the compound o-f this invention shown by formula I wherein R2 is a thiocyante (-SC~) group, i. e., the thiocyanate compound shown by formula Ia_8. The thiocyanate compound can be produced by react-ing the compound shown by formula I 2 with a thiocyanate such as sodium thiocyanate, etc., and bromine.
The lower alkylation method (8) is a method of producing the compound of this invention shown by formula I wherein R2 is a lower alkyl thio group, i. e., the lower alkylthio compound shown by formula I 9- The lower alkylthio compound can be produced by reacting the thiocyanate compound shown by formula I 8 with a lower alkylating agent according to a conventional method. As the lower alkylating agent, a lower alkyl halide such as methyl iodide, ethyl iodide, etc., is used.
The compound of this invention shown by formula I thus prod-uced is isolated and purified by a conventional chemical operation such as concentration, recrystallization, column choromatography, etc.
Typical methods of producinq the compounds of this invention shown by formula I were explained above, and the compounds of this invention and the methods of producing them will be further expl-ained more practically and in ~ore detail by the following examples.
In addition, the results of pharmacological tests for showing the excellent pharmacological effects of the compounds of this invention shown by formula I will then be described.
Effect on adjuvant-induced arthrites in rats:
Methods: Male ~prangue 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/~C) and administered orally once a day.
(I) Therapeutic effect o drugs; arthritis was induced by a single injection of 0.1 ml of sterile suspension of My~
b tyricum (6mg/ml) in liquid paraffin into tail skin of rats (dayO).
After about 2 weeks, arthritic rats were selected and allocated in-to groups. Drugs were given daily following about 10 days. Thick-ness 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-7~
ence between these two values. The results are shown in Table I.
Table I (Therapeutic effect) Drugs Dose ~ Day 16 - Day 28 (mg/kg/day ~FT (X10 mm) PØ) 0.5% MC _ 3 210 1 91 Indomethacin 2 3 -177 + 41**
6-(3,5-di-tert-butyl-4-hydroxyphenyl-5-methyl-2,3-dihydroimidazo(2,1-b)-thiazole 2S 3 -16 + 27*
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo(2,1-b)thiazole 1-oxide 25 3 -245 + 57**
6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo~2,1-b)thiazQle l~-dinxld~ 25_ 3 -141 + 60**

Drugs Dose ~ Day 17 - Day 27 (mg/kg/day ~FT (10 mm) P . O . ) 0.5%MC _ 3 181 + 7 Indomethacin 2 3 -225 + 61**

Diclofenac EICI 2 3 -83 + 49*
6-(3,5-di-tert-butyl-4-hydroxyphenyl)2,3-dihydro-imidazo(2,1-b)thiazole 25 3 -177 + 36***

Significant difference from control (t-test) * P ~.05 ** P~0.01 *** P6 o l From the abo~e results, it is apparent that the compounds of this invention have excellent pharmacological (therapeutic & proph-ylactic) effects against the adjuvant~induced arthritis.xample 1

3 3 ~ 1 ~ ~ (HH3)3 C(CH3)3 C(CH3)3 In 300 ml of methyl ethyl ketone was dissolved 10.2 g of 2-amino-2-thiazoline and after adding 32.7 g of 3,5-di-tert-butyl-

4-hydroxyphenacyl bromide was added portionwise to the solution followed by stirring for 30 minutes at room temperature, the re-sultant mixture was refluxed for one hour. Then, the solvent was distilled o-ff under reduced pressure, the crystals thus formed were dissolved in 200 ml of ethanol, and the solution was refluxed for 4 hours. The reaction mixture was basified by the addition of aqueous ammonia and then 200 ml of water was added to the reaction mixture to precipitate crude crystals, which were recovered by filtration and recrystallized from ethanol to provide 23.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b~
thiazole.
Melting pointo 212-214C.
Elemental analysis for Clg H26 N2 OS:

C(%) El(%) N(%) Calculated: 6~.11 8.0~ 8.~3 Found: 69.05 7.93 8.48 Example 2 cH3 -c ll -c ~)-o}

By followiny the same procedure as in Example 1, 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydroimidazo[2,1-b]-thiazole was produced.
Melting point: 258-261C
Elemerltal analysis for C20 H28 N2 oS:
C(%) H(%) N(%) Calculated: 69.62 8.22 8.11 Found: 69.73 8.19 8.13 Example 3 C(CH3)3 N C(C~
Brcl-l2-c ~ OH ~ ~ ~ N ~ ~ ~ Oll 2 C(CH3)3 ( 3)3 In 20 ml of ethanol were dissolved 1.2 g of 2-aminothiazole and 3.9 g of 3,5-di-tert-butyl-4-hydroxyphenacyl brornide~ and t:he solution was refluxed for 2 hours. The reaction mixtur-e was ~' neutralized by the addit.ion of aqueous ammonia and after adding thereto 30 ml oE water, the crys-tals thus precipitated were re-covered by filtration and recrys-tallized from ethanol to provide 1.5 g of 6-(3,5-di-ter-t-bu-tyl-4-hydroxyphenyl)imidazo[2,1-b]-thi-azole.
Melting point: 184-185c Elemen-tal analysis for Clg H24 N2 OS:
C(%) H(%) N(%) Calculated: 69.31 7.65 8.38 10 Found: 69.48 7.36 8.53 Examples 4-8 C(CH3)3 By following the sampe procedure as in Example 3, the follow-ing compounds were produced.
Exam~le 4 Compound: The compound of the above formula wherein Rg is CH3~ 11 3 12 Melting point (n-hexane-cyclohexane): 188-190C
Elemental analysis for C21 112~3 ~2 OS:
C(%) H(%j N(%) Calculated: 70.56 8.03 7.64 Found: 70.75 7.92 7.86 Example 5 Compound: The compound of the above formula wherein Rg is CH3, Rll is CH3, and R12 is CH3-Melting point: 208-210C (n-hexane) ~lemental analysis for C22 1130 2 2 7~

C(%) H(%) N(%) Calculated: 70.67 8.27 7.39 Found: 71.31 8.16 7.56 Example 6 Compound: The compound of the above formula wherein R is H, Rll is H, and R12 is Br.
Melting point: 174-176C (n-hexane-cyclohexane) Elemental analysis for C19 H23 BrN2 OS:
C(%) H(%) N(%) 10 Calculated: 56.40 5.92 6.55 Found: 56.02 5.69 6.88 Example 7 Compound: The compound of the above formula wherein Rg is H, Rll is H, and R12 is CH3S.
Melting point: 131-132C (n-hexane-cyclohexane) Elemental analysis for C20 H26 N2 S2 C(%) EI(%) N(%) Calculated: 63.95 7.09 7.62 Found: 64.14 7.00 7.48 Exam~le 8 Compound: The compound of the above formula wherein Rg is H, Rll is a phenyl group, and R~2 is CH3.
Melting point: 229-231C (n-hexane) Elemental analysis for C26 H30 2 C(%) H(%) N(%) Calculated: 74.34 7.60 6.49 Found: 74.60 7.22 6.69 Example 9 ~S ~ ~ -OH ~ ~ ~ ~ OH
(CH3)3 C(CEI3)3 7~
In 10 ml of chloroform was dissolved 1.6 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and after adding thereto 1 g of m-chloroperbenzoic acid, the mixture was stir-red for 10 minutes. The reaction mixture was washed with an a~u-eous 5% sodium hydrogen carbonate solution, dried, and then thesolvent was distilled off. The crystals thus formed were recryst-allized from ethanol to provide 1.3 g of 6-(3,5-di-tert-butyl-4-hydroxphenyl)-2,3-dihydroimidazo[2,1-b]thiazole l-oxide as the 1/2 ethanol addition product.
Melting point: 211-212C
Mass spectrum: m/e: 346(M+) Elemental analysis for Clg H26 N2 2 S-1/2 C2 Hs OH
C (%) ~I (%) ~1 (%) Calculated: 65.11 7.78 7.82 Found: 65.01 7.91 7.58 ~5 ~ 0~1 ~~~~~~~ / ~ ~ _O

In 10 ml of chloroform was dissolved 0.6 g of 6~(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiaæole l-oxide and then 0.4 g of m-chloroperbenzoic acid was added to the solut-ion. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was fur-ther added to the mixture and the resultant mixture was allowed tostand for one hour. The reaction mixture was washed with an a~u-eous 5% sodium hydrogen caxbonate solution, dried, and then the solvent thereof was distilled off. The residue was purified by silica gel chromatography using chloroform as the eluent and fur-ther recrystallized from a~ueous ethanol to provide 0.2 g of 6-(3~-o~

5-di-tert-butyl-4-llydroxyphenyl)-2~3-dil-~yclroLmidazo[2,1-b] thia7,01e l,l-ciioxide.

Melting point: 267-269C

Flemental analysis for Clg H26 2 3 C(%) E~(%) N(%) Calculated: 62.77 7.35 7.60 Found: 62.96 7.23 7.73 Example ll 10 ~(CIf3) 3~~ ~H

To a solution of 1.5 ml o dimethylformamide in 10 ml of chloroform was added 1.1 g of phosphorus oxychloride under i~e-cooling and the mixture was allowed to stand for one hour. To the 15 reaction mixture was added 1.5 g oE 6-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2.3-dihydroimidazo[2,1-b]thiazole and the mixturé was re-fluxed for 4 hours. To the reac-tion mixture was added 20 ml of an aqueous 10% potassium carbonate solu-tion and the mixture was stir-red for 15 minutes. The chloroform layer was dried and concentra-ted. The crystals thus obtained were recrys-tallized from ethanol to provide l.0 g of 6-(3,$-di--tert-butyl-4-hydroxyphenyl)-S-Eormyl-2,3-dihydroimidazo[2,1-b]thiazole.
Melting point: 210-212C

Elemental analysis or C20 H26 N2 2 25C(%) EI(%) N(%) Galculated: 66.82 7.20 7.80 Found: 67.01 7.31 7.81 ~xample 12 CH0 C(C1-13)3 ~ N ~ 2 C(CH3)3 N~C ( C~13 ) 3 C ( C 113 ~ 3 In 10 ml of ethanol was dissolved 0.4 g o~ 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-~ormyl-2,3-dihydroimidazo[2,1-~]thiazole and after adding 40 my of sodium borohydride to the solution, the mixture was stirred for 10 minutes. To the reaction mixture were added 0.3 ml of acetic acid and 30 ml of water, and the crystals thus precipitated were recovered by filtration and recrystallized from aqueous ethanol to provide 0.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole.
Melting point: 227-229C
Elemental analysis -for C20 ~28 N2 2 S:
C~%) H(%) ~(%) Calculated: 66.55 8.04 7.73 Found: 66.63 7.80 7.77 / H3 Example 13 C(CH3)3 _ N CH2N\ CH
~ (CH3) ~ ~C(CH3)3 To a mixed solution of 0.9 g of an aqueous 40/0 dimethylamine solution, 0.6 g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 5 ml of dioæane was added 0.66 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2~1-b]thi~zole and the resultant mixture was refluxed for 6 hours. The reaction mix-ture was concentrated under reduced pressure and the residue was mixed with 20 ml o-f an aqueous 10% potassium carbonate solution and extracted with chloroform. The extract was dried and concentrated, and the residue thus formed was purified by silica gel chromato-graphy using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.3 g o-f 5-dimethylaminomethyl-

6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]-thiazole.l/4H20.
Melting point: 188-191C

0~
Mass spectrum: m/e: 387(M+) Elemental analysis for C22 H33 N3 OS.1/4H20:

C(%) H(%) ~(%) Calculated: 67.49 8.70 10.48 Found:67.39 8.61 10.72 Example 14 NC(CH3)3HN~O+HCHO N CH2N O
1 r~ OH ~ ~ (ECIH3)3 C(CH3)3 A mixture of 1.65 g of 6-(3,5-di-tert-butyl-~-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole of 1.8 g of morpholine, 1.7 g of an aqueous 35% formaldehyde solution~ 1.5 ml of acetic acid, and 10 ml of dioxane was refluxed for 6 hoursO The reaction mixture was concentrated under reduced pressure and to the residue was added 20 ml of an aqueous 10% potassium carbonate to precipitate crystals, which were recovered by filtration and recrystallized from methanol to provide 0.85 g of 6-(3,5-di-tert~butyl-4-hydroxy-phenyl)-5-morpholinomethyl-2,3-dihydroimidazo[2,1-b]thiazole.
Melting point: 231-233C
Elemental analysis for C24 H35 ~3 2 S:
C(%) H(%) N(%) S(%) Calculated: 67.08 8.32 9.67 7.35 Found: 67.10 8.21 9.78 7.46 Example 15 C(CH3)~ ~2N NCEI
~r~ ~ OEI ~ -~ (CI33)3 C(CEI3)3 ~ By following the same procedure as in Example 14) 6-(3,5-di-tert~butyl-4-hydroxyphenyl)-5-(4-methylpiperazinomethyl)-2,3-dihydroimidazo[2,1-b]thiazole was produced.

7~

Melting point: 211-212C
~lemental analysis for C25 H38 ~4 OS.H20:
C(%) H~%) ~(%) S(%) Calculated: 65.28 8.61 12.00 7.06 Found: 65.18 8.75 12.16 6.96 Example 16 C(CH~ ~ (CH3~3 In 10 ml of acetic acid was dissolved 1.35 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and afker adding thereto 0.64 g of sodium thiocyanate, 0.7 g of bromine was added dropwise to the solution u~der ice-cooling. After per-forming the reaction for one hour at room temperature, 30 ml of water was added to the reaction mixture to precipitate crystals, which were recovered by filtration. The crystals were added to a mixture of 20 ml of chloroEorm and 10 ml oE an aqueous 10% potas-sium carbonate solution followed by stirring. The chloroform layer thus formed was dried and concentrated, and the residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.6 g of 6-(3,5-di-text-butyl-4-hydroxyphenyl~-5-thio-cyanato-2,3-dihydroimidazo[2,1-b]thiazole.
Melting point: 178-179C
Elemental analysis for C20 H25 ~3 S2 C(%) H(%) ~(%) S(%) Calculated: 62.05 6.50 10.66 16.84 Found: 61.98 6.50 10.84 16.54 Example 17 OH - ~ ~ (Co~I3)3 C(CH3)3 C(CH3)3 In 10 ml of methanol was dissolved 1.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]-thiazole and after cooling the solution to 0C, 0.65 g of methyl iodide was added dropwise to the solution with stirring and fur-ther a solution of 0.2 g of potassium hydroxide dissolved in a mixture of 2 ml of water and 2 ml of methanol was added dropwise to the solution. After 30 minutes, the reaction mixture was con-centrated and the residue was purified by silica gel column chrom-atography using chloroform as the eluent and further recrystalli-zed from ethanol to provide 0.18 g of 6-(3,5-di-tert-butyl-4-hydro-xyphenyl)-5-methylthio-2,3-dihydroimidazo[2,1-b]thiazoleO
Melting point: 170-171~C
Elemental analysis for C20 H28 ~2 S2 C(%) EI(%) ~(%) S(%) Calculated: 63.49 7.60 7.36 16.85 Found: 63.49 7.49 7.44 17.03 Example 18 OEI DMF~(COC )~ -OH
( 3~3 C(CH3)3 To a mixed solution of 0.5 g o-f dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of et~ylene dichloride under ice-cooling.
~fter allowlng to stand the mixture for 15 minutes at room temp-erature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole dissolved in a mixture of 3 ml 7g~
of diMethylLormamide and L0 ml oE otl-lylelle dicllloride was added dropwise to the solution ancl the resultant mixture was s-tlrred Eor 2 hours. Then, a solution of 0.5 g of hydroxylamine hydrochloride dissolved in a mixture of l.5 mL of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mix-ture was refluxed overnight. The reac-tion mixture was washed with 30 ml of an aqueous 5% sodium hydrogen carbona-te solu-tion, dried, and then concentrated. The residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-ter~-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,l-b]thiazole.
Melting point: 207-208C
Elemen-tal analysis Eor C20 EI25 N3 OS:
lS C(%) H(%) N(%) Calculated: 67.52 6.92 ll.74 Found: 67.57 7.09 ll.82 By following the same procedure as in Example l, the fol]ow-ing compounds were produced.
Example l9.

3 El ~ l M ~
( 3)3 ~ S ~ ~ ) ~ mp. 237-8C

E~ample 20.

(CH3)3c ~ M ~ -OC113 (CH3)3 ~ / ~ N ~ mp. 236-7C

. .
, ~ ` J .:
., ~,..

Claims (42)

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

1. A method of producing a 3,5-ditert-butyl-4-hydroxy-phenyl-substituted heterocyclic compound represented by formula I

I

wherein one of R1, R2, R3, and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group and the others repre-sent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, a lower alkoxy-substituted aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group, or a thiocyanato group; m repre-sents 0, 1, or 2; and the dotted line means the presence or absence of a double bond or a pharmaceutically acceptable acid addition salt thereof which comprises selecting a process from the group of processes consisting of:
(a) reacting the 2-aminothiazoline or 2-aminothiazole derivative represented by formula II

II

and the .alpha.-halocarbonyl compound represented by formula III

III

wherein R1, R2, R3, R4, and the dotted line have the same significance as defined concerning formula I and X repre-sents a halogen atom;

(b) oxidizing a compound of formula I wherein m is 0 to obtaln the corresponding compound of formula I
wherein m is 1 or 2;
(c) reacting the compound of formula I wherein R2 is a hydrogen atom with formaldehyde and the amine repre-sented by the formula wherein R5 and R6 each represent a hydrogen atom, a lower alkyl group or they may combine with each other to form a cyclic amino group, to obtain the corresponding com-pound of formula I wherein R2 is an amino-methyl group;
(d) reacting a compound of formula I wherein R2 is a hydrogen atom with a lower alkanoyl halide to obtain the corresponding compound of formula I wherein R2 is a lower alkanoyl group;
(e) reacting a compound of formula I wherein R2 is a hydrogen atom with a complex of dimethylformamide and phosphorus oxychloride or oxalyl chloride and then hydrolizing the reaction product to obtain the compound of formula I wherein R2 is a formyl group;
(f) reducing a compound of formula I wherein R2 is a formyl group to obtain the corresponding compound of formula I wherein R2 is a hydroxymethyl group;
(g) cyanating a compound of formula I wherein R2 is a hydrogen atom to obtain the corresponding compound of formula I wherein R2 is a cyano group;
(h) reacting a compound of formula I wherein R2 is a hydrogen atom with a thiocyanate to obtain the corres-ponding compound of formula I wherein R2 is a thiocyanate group;

(i) reacting a compound of formula I wherein R2 is a thiocyanate group with a lower alkylating agent to obtain the corresponding compound of formula I wherein R2 is a lower alkylthio group; and, (j) converting a compound of formula I into its corres-ponding pharmaceutically acceptable acid addition salt.

2. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addi-tion salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, R2, R3 and R4 are each a hydrogen atom and m is 0.

3. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a methyl group, R3 and R4 are each a hydrogen atom and m is 0.

4. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 are each a hydrogen atom and m is 0.

5. A process according to claim 1 for the preparation of 3-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a methyl group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a methyl group, R4 is a hydrogen atom and m is 0.

6. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-2,3-dimethyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1, R3 and R4 are each a methyl group, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and m is 0.

7. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-bromoimidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R3 are each a hydrogen atom, R4 is a bromine atom and R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group and m is 0.

8. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio group-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R1 and R3 are each a hydrogen atom, R4 is a methylthio group and m is 0.

9. A process according to claim 1 for the preparation of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methyl-3-phenyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a hydrogen atom, R2 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R3 is a phenyl group, R4 is a methyl group and m is 0.

10. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1-oxide, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 are each a hydrogen atom and m is 1.

11. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole 1,1-dioxide, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2, R3 and R4 are each a hydrogen atom and m is 2.

12. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a formyl group, R3 and R4 are each a hydrogen atom and m is 0.

13. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a hydroxymethyl group, R3 and R4 are each a hydrogen atom and m is 0.

14. A process according to claim 1 for the preparation of 5-dimethylaminomethyl-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a dimethylaminomethyl group, R3 and R4 are each a hydrogen atom and m is 0.

15. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a morpholinomethyl group, R3 and R4 are each a hydrogen atom and m is 0.

16. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(4-methylpiperazino-methyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceuti-cally acceptable acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a 4-methylpiper-azinomethyl group, R3 and R4 are each a hydrogen atom and m is 0.

17. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addltion salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a thiocyanato group, R3 and R4 are each a hydrogen atom and m is 0.

18. A process according to claim 1 for the preparation of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a methylthio group, R3 and R4 are each a hydrogen atom and m is 0.

19. A process according to claim 1 for the preparation of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid additlon salt thereof, wherein R1 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R2 is a cyano group, R3 and R4 are each a hydrogen atom and m is 0.

20. A process according to claim 1 for the preparation of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenylimidazo-[2,1-b]thiazole,or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R2 are each a phenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxyphenyl group, R4 is a hydro-gen atom and m is 0.

21. A process according to claim 1 for the preparation of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-methoxy-phenyl)-imidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, wherein R1 and R2 are each a p-methoxyphenyl group, R3 is a 3,5-di-tert-butyl-4-hydroxy-phenyl group, R4 is a hydrogen atom and m is 0.

22. A 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compound represented by formula I

I

wherein one of R1, R2, R3 and R4 represents a 3,5-di-tert-butyl-4-hydroxyphenyl group and the others repre-sent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, a lower alkoxy-substituted aryl group, a lower alkanoyl group, a lower alkylthio group, a lower alkoxy group, a lower aralkyl group, a cyano group, or a thiocyanato group; m repre-sents 0, 1 or 2 and the dotted line means the presence or ab-sence of a double bond or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of claim 1.

23. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 2.

24. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 3.

25. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]-thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 4.

26. 3-methyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 5.

27. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-2,3-dimethylimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 6.

28. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-bromoimidazo-[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 7.

29. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthio group-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 8.

30. 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methyl-3-phenylimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 9.

31. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]-thiazole 1-oxide, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 10.

32. 6-(3,5-di-ter-t-butyl-4-hydroxyphenyl)-2,3-dihydro-imidazo[2,1-b]thiazole 1,1-dioxide, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 11.

33. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 12.

34. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 13.

35. 5-dimethylaminomethyl-6-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutical-ly acceptable acid addition salt thereof, when prepared by the process of claim 14.

36. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholino-methyl-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 15.

37. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(4-methyl-piperazinomethyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharma-ceutically acceptable acid addition salt thereof, when prepared by the process of claim 16.

38. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 17.

39. 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 18.

40. 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole, or a pharmaceutically accept-able acid addition salt thereof, when prepared by the process of claim 19.

41. 3-(3,5 di-tert-butyl-4-hydroxyphenyl)-5,6-diphenyl-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 20.

42. 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-bis(p-methoxyphenyl)-imidazo[2,1-b]thiazole, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 21.