JPS6113715B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 3,5-bis(t-butyl)-4-
Hydroxyphenyl-substituted thiophene and 3.
5-bis(t-butyl)-4-hydroxybenzoyl-substituted thiophenes, the use of such compounds as anti-inflammatory agents, the combination of one or more such compounds with suitable pharmaceutical bulking vehicles; The present invention relates to novel intermediates useful in the preparation of combination anti-inflammatory compositions and final product compounds of the present invention. A thiophene compound substituted with a bis(t-butyl)phenol group has not been known so far. To the best of the inventor's knowledge, even thiophenes substituted with mono-t-butylphenol groups are unknown. However, 4
-(2'-thienyl)phenol, 4-(3'-thienyl)phenol, 3-(2'-thienyl)phenol, 3-(3'-thienyl)phenol and 2-
Compounds such as (2'-thenoyl)phenol are known. The invention particularly relates to compounds of the formula: [wherein L is carbonyl or a carbon-carbon bond, and R is hydrogen, methyl or halogen (fluorine, chlorine, iodine or bromine)].
Compounds of the formula in which L is carbonyl, especially L is 2-carbonyl, are presently preferred because of their ease of synthesis and high therapeutic index. Also,
Preference is given to compounds according to the invention in which R is hydrogen or halogen, especially R is hydrogen or chlorine. In compounds of the invention where R is hydrogen, it is preferred that L and R are not bonded to adjacent carbon atoms of the thiophene ring and that R is not iodine. In addition to being used as effective anti-inflammatory agents, the compounds of the present invention are also relatively active as stabilizers to prevent oxidation. Also, some compounds are analgesics, some are antipyretics, and some have mild immunosuppressive activity. For the purpose of measuring and evaluating pharmacological activity,
Animal testing was performed using various tests known to those skilled in the art. The anti-inflammatory activity of the compounds of the invention is conveniently demonstrated using a test method (rat paw edema test) designed to test the ability of this compound to ameliorate the local edema that is characteristic of inflammatory responses. can do. The above compound () is the enzyme prostaglandin synthetase (synthelase).
It was also found that it suppresses This prostaglandin synthetase inhibition test is a broad screening method for the detection of anti-inflammatory activity, which was described by HL White and AT Grossman in Prostaglandins 7(2):123-129.
(1974) “A Simple Radiochemical Assay for Prostaglandin Synthetase”
Prostaglandin Synthetase). The compounds of this invention are highly active when administered to the skin. Such local activity was determined using the guinea pig erythema test and by the contact sensitivity test. Anti-inflammatory activity may also be detected by other test methods known to those skilled in the art, such as the cotton pellet granuloma test or the adjuvant arthritis test. Its analgesic activity was also observed in standard tests such as the phenylquinone pain (mice) and Randall-Selitto (rats) tests. Literature on rat paw edema methods includes: (1) Adamk iewicz et al.
Canad, J.Biochem.Physio.33:332, 1955: (2) Selye, Brit.Med.J.2:1129,
1949: and (3) Winter, Proc.Exper.Biol.
Med.111:544, 1962. The compounds of the invention are preferably administered orally as anti-inflammatory agents, although other known methods of dosing may be used, such as mucocutaneous administration (e.g. dermal administration, rectal administration, etc.) as well as e.g. subcutaneous injection, intramuscular injection, etc. Parenteral administration by intra-articular injection, intravenous injection, etc. is also contemplated. This includes eye medications. Dosages are usually in the range of about 1 to 500 mg/kg of body weight of the mammal being treated, although oral doses are usually about 100 mg/kg body weight of the mammal being treated.
Do not exceed mg/Kg. Presently preferred compounds of the invention with respect to anti-inflammatory activity include 2,6-bis(t-butyl)-4-(2'-thenoyl)phenol, 2,6-
Bis(t-butyl)-4-(2'-thienyl)phenol, 2,6-bis(t-butyl)-4-(3'-thenoyl)phenol and 2,6-bis(t-butyl)-4 -(5'-chloro-2'-thenoyl)phenol. Presently preferred compounds of the invention with respect to skin activity are 2,6-bis(t-
butyl)-4-(2'-thenoyl)phenol and 2,6-bis(t-butyl)-4-(5'-chloro-
2′-Thenoyl)phenol. Compounds of the present invention in which L is a carbon-carbon bond,
It is easily prepared by reacting 2,6-bis(t-butyl)benzoquinone with a Grignard reagent prepared from the appropriate halogenated thiophene. Halogenated thiophenes and methods of their preparation are well known in the art. Known halogenated thiophenes include 2-iodothiophene, 2-bromothiophene, 2-chlorothiophene, and 2-fluorothiophene. By the Grignard reaction between the Grignard reagent of halogenated thiophene and 2,6-bis(t-butyl)benzoquinone, the intermediate 2,6-bis(t- butyl)-4-hydroxy-4-(thienyl)-2.
5-cyclohexadien-1-one is obtained. (wherein R has the same meaning as above, ie hydrogen, methyl or halogen). These compounds () are new and within the scope of the present invention. These compounds are reduced using a combination of hydrogen gas and a catalyst such as palladium on charcoal or Raney nickel, a metal hydride reducing agent such as lithium aluminum hydride, or hydrogen iodide to form the present invention of formula (). Forms a compound of Instead of using the Grignard test in the reactions described above, known reactive equivalents such as lithium compounds are also useful. Compounds of the invention in which L is a carbonyl group are readily prepared in several ways. The reaction of 3,5-bis(t-butyl)-4-hydroxybenzoyl chloride with optionally substituted thiophene in the presence of a Friedel-Crafts catalyst is
is a carbonyl attached to the 2-position of the thiophene, and R is useful in the synthesis of compounds in the 3- or 5-position. Useful Friederu-Crafts catalysts include aluminum chloride, titanium tetrachloride,
These include zinc chloride. This reaction generally involves dissolving the benzoyl chloride described above in an inert solvent such as carbon disulfide, dichloroethane, dichloromethane, optionally under an inert gas atmosphere such as nitrogen, adding a Friederu-Crafts catalyst at room temperature, and The thiophene component is then added dropwise and the reaction is allowed to proceed to completion, as indicated by the end of hydrogen chloride evolution. Heating or warming is sometimes beneficial to accelerate the reaction. On the other hand, 2,6-bis(t-butyl)phenol can be reacted with a suitable thiophene carbonyl chloride in a Friedel-Crafts reaction. The method is essentially as described above using standard Friederu-Craft techniques. If the reaction rate is too fast for aluminum chloride, it is preferred to use a weaker catalyst such as titanium tetrachloride. Another alternative is to convert one or more tertiary butyl groups to a 4'-thienylphenol nucleus or
There is a method of directly introducing it into the 4'-tenoylphenol nucleus. The following examples illustrate how to prepare compounds of the invention using the methods described above. Example 1 3,5-bis(t-butyl)-4-hydroxybenzoyl chloride in 300 ml of carbon disulfide 26.9
g (0.10 mol) of solution, 13.5 g of aluminum chloride was added. After stirring for 15 minutes and warming slightly, 17 g (0.104 mol) of 2-bromothiophene was added. The reaction mixture gradually turned from green to amber. This was then poured into 10% hydrochloric acid and extracted with dichloromethane. The extract was dried and then the solvent was evaporated to give an oil that crystallized easily. 2,6-bis(t-butyl)-4 was recrystallized from hexane while being treated with decolorizing charcoal.
-(5′-bromo-2′-thenoyl)phenol (m.
p.126-127.5℃) was obtained. Analysis: %C as C ₁₉ H ₂₃ BrO ₂ S %H Calculated: 57.7:5.9 Found: 57.6:5.9 Using substantially the method of Example 1 (and replacing the thiophene starting material with the appropriate material) ) obtained the following compound:

[Table] Tenoyl) Phenol

[Table] Thenoyl) Phenol Example 8 0.0181 mol of 2-bromothiophene was added to magnesium in diethyl ether.
It was prepared by reacting with 0.45g. This reagent was dissolved as 2,6-bis(t-butyl) in 75 ml of diethyl ether.
Added to a solution of 4.0 g (0.018 mol) of benzoquinone. The mixture is heated to reflux temperature and about 5
Keep at reflux for an hour. The product obtained is 2.6
-bis(t-butyl)-4-hydroxy-4-
(2'-thienyl)-2,5-cyclohexadiene-
It was 1-on. This mixture was used as it was in the next step. A slight excess of lithium aluminum hydride was carefully added to the mixture. After stirring at room temperature for about 16 hours, water was carefully added followed by 10% hydrochloric acid. The mixture was extracted with dichloromethane, the extract was dried and the solvent was evaporated to give an oil. This oil was extracted with petroleum ether and the extract was then heated to -20
Cooled at °C for approximately 16 hours. The product was overseparated and then sublimed at 80-82°C/0.1 mmHg. 2,6-bis(t-butyl) by recrystallization from hexane
-4-(2'-thienyl)phenol (mp93~94
°C) was obtained. Analysis: %C as C ₁₈ H ₂₄ OS %H Calculated 74.9:8.4 Actual 75.2:8.6 Example 9 Using the method of Example 8, the Grignard reagent of 4-bromo-2-fluorothiophene was reacted with 2,6-bis By reacting with (t-butyl)benzoquinone, 2.
6-bis(t-butyl)-4-(5'-fluoro-3'-
Thienyl) phenol was obtained. Example 10 Thiophene-3-carboxylic acid was converted to its acid chloride by reacting with thionyl chloride. Thiophene-3-carbonyl chloride at 80-85℃/
It was isolated by distillation at 0.25 mmHg. A solution of 14.66 g (0.10 mol) of thiophene-3-carbonyl chloride in 100 ml of dichloroethane was added to 20.87 g (0.1 mol) of titanium tetrachloride. To this solution was added a minimum amount of 0.10 moles of 2,6-bis(t-butyl)phenol in dichloroethane. This mixture was stirred for about 16 hours, then 500ml
injected into 10% hydrochloric acid. Separate the organic layer,
Washed with water and dried. The solvent was evaporated to give an oil, which was mixed with hexane and cooled.
The product was separated and recrystallized from hexane to give 2,6-bis(t-butyl)-4-(3'-thenoyl)phenol (mp 101-102°C). Next, the melting point is 127 ~
The temperature reached 218℃. Analysis: %C as C ₁₉ H ₂₄ O ₂ S %H Calculated 72.1:7.7 Found 72.0:7.8 Example 11 Using the method of Example 10, 5-chlorothiophene-3-carbonyl chloride was converted to 2.6 -2,6- by reacting with bis(t-butyl)phenol
Bis(t-butyl)-4-(5'-chloro-3'-thenoyl)phenol was obtained. Example 12 Using the method of Example 10, 5-fluorothiophene-3-carbonyl chloride was reacted with 2,6-bis(t-butyl)phenol to give 2,6
-bis(t-butyl)-4-(5'-chloro-3'-thenoyl)phenol was obtained. Example 13 To a solution of 0.2 moles of 3,5-bis(t-butyl)-4-hydroxybenzoyl chloride in dichloroethane was added 42 g (0.20 moles) of 2-iodothiophene. 37.9 g of this solution in 200 ml of dichloroethane
(0.20 mol) of titanium tetrachloride at about 5° C. over a period of about 30 minutes. The solution was warmed to 20°C and stirred for 48 hours. This was then poured into 10% hydrochloric acid and the organic layer was separated, washed with water, dried and evaporated to dryness. The resulting residue was washed with hexane and then recrystallized from methanol. The product was extracted and washed again with a hot (90/10) hexane/toluene mixture. The pale blue-yellow solid was recrystallized again from methanol to give 2,6-bis(t-butyl)-4-(5'-iodo-2'-thenoyl)phenol (mp145.5~
147°C). Analysis: %C as C ₁₉ H ₂₃ lO ₂ S %H Calculated 51.8:5.3 Found 51.7:5.4 Example 14 A solution of 3.8 g (0.02 mol) of titanium tetrachloride in 50 ml of dichloroethane was dissolved in a nitrogen atmosphere at 3.21 g
(0.02 mol) of 4-methylthiophene-2-carbonyl chloride in dichloroethane was added. The solution was then cooled in an ice bath and 4.12 g (0.02 mol) of 3,5-di(t-butyl)phenol in dichloroethane was added dropwise over a period of 30 minutes. The mixture was stirred for about 20 hours and then filtered through silica gel, eluting with a mixture of hexane/chloroform (20/80). Recrystallized from hexane to form a white solid, 2,6-bis(t-
Butyl)-4-(4'-methyl-2'-thenoyl)phenol (mp 111.5-113°C) was obtained. Analysis _: %C %H _{as C20H26O2S} Calculated value 72.7:7.9 Actual value 73.3:7.9

Claims (1)

[Claims] 1. General formula wherein L is carbonyl or a carbon-carbon bond and R is hydrogen, methyl or halogen. 2. The compound according to claim 1, wherein R is hydrogen. 3. The compound according to claim 1, wherein L is carbonyl. 4. The compound according to claim 1, which is 2,6-di(t-butyl)-4-(2'-thenoyl)phenol. 5. The compound according to claim 1, which is 2,6-di(t-butyl)-4-(3'-thenoyl)phenol. 6 4-(5'-chloro-2'-thenoyl)-2,6-
The compound according to claim 1, which is di(t-butyl)phenol. 7. The compound according to claim 1, which is 2,6-di(t-butyl)-4-(2'-thienyl)phenol.