CH637129A5 - 3,5-Bis(tert-butyl)-4-hydroxyphenyl-substituted and 3,5-bis-(tert-butyl)-4-hydroxybenzoyl-substituted thiophenes, and drugs containing these compounds - Google Patents

Description

The invention relates to 3,5-bis (tert-butyl) -4-hydroxy-phenyl and 3,5-bis (tert-butyl) -4-hydroxybenzoyl-substituted thiophenes and anti-inflammatory agents comprising one or more these compounds, optionally together with a suitable pharmaceutical carrier.

Thiophene compounds which are substituted by bis (tert-butyl) phenol groups are not known, with the exception of 2,6-bis (tert-butyl) -4- (2'-thienyl) phenol, which according to J. Med Chem. 21 (1978), 182-188, has already been obtained as an intermediate. Thiophenes substituted by mono-tert-butylphenyl groups are also not known. Compounds such as 4- (2'-thienyl) phenol, 4- (3'-thienyl) phenol, 3- (2'-thienyl) phenol, 3- (3'-thienyl) phenol and 2- (2'-the- noyl) phenol are known, however.

The invention relates to compounds of the formula:

(CH3) 3C

(CH3) 3C

h0- <o> -l-o

• R

(I)

in which L is a carbonyl group or a carbon-carbon bond and R is a hydrogen or halogen (fluorine, chlorine, iodine or bromine) atom or a methyl group, with the exception of 2,6-bis (tert-butyl) -4- (2'-thienyl) phenol.

Because of their easy synthesis and their good therapeutic ratio, compounds of the formula I in which L is a carbonyl group are preferred, especially those in which L is a 2-carbonyl group. Also preferred are compounds in which R is a hydrogen or halogen atom, especially those in which R is a hydrogen or chlorine atom. In the case of the compounds according to the invention in which R is not a hydrogen atom, L and R are preferably not bonded to adjacent carbon atoms of the thiophene ring and R is preferably not an iodine atom.

In addition to their use as effective anti-inflammatory agents, the compounds according to the invention are relatively effective oxidation stabilizers. Some are also analgesics, some antipyretic, and some have mild immunosuppressive activity.

To determine pharmacological activity,

animal experiments were carried out according to various determination procedures, as are known to the person skilled in the art. Thus, the anti-inflammatory activity of the compounds can be conveniently demonstrated with the aid of a determination method which is intended to investigate the ability of these compounds to counteract local edema which is characteristic of an inflammatory (inflammatory) reaction (rat foot edema test). . The compounds (I) have also been shown to inhibit the enzyme prostaglandin synthetase. The determination of prostaglan dinsynthetase inhibition is a general test method for the detection of anti-inflammatory activity and is described by White, H.L. and Glossman, A.T. in "A Simple Radiochemical Assay for Prostaglandin Synthetase". Prostaglandins 7 (2), 123-129 (1974).

The compounds of the invention are effective when administered through the skin (dermally). Such topical activity was measured using the guinea pig erythema test and a contact sensitivity test. The anti-inflammatory effect can also be shown by other known methods of determination, such as the cotton pearl granuloma test and the adjuvant arthritis test. Analgesic efficacy was observed in standard test procedures such as the phenylquinone writhing test (mouse) and the Randall-Selitto test (rat).

40 references for the rat foot edema test are:

1. Adamkiewicz 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 are preferably administered orally as anti-inflammatory agents, but other forms of administration are also contemplated, e.g. through the skin or mucous membrane (e.g. dermal, rectal, etc.) and parenterally, e.g. by subcutaneous, intramuscular, intra-articular, intravenous injection, etc. Administration via the eye is also possible. The doses are usually in the range of approximately 1 to 500 mg / kg body weight of the mammal to be treated, although oral doses are usually not more than 100 mg / kg.

55 The preferred compounds according to the invention due to their anti-inflammatory action are 2,6-bis (tert-butyl) -4- (2 '-thenoyl) phenol, 2,6-bis (tert-butyl) -4- (3' - thenoyl) phenol and 2,6-bis (tert-butyl) -4- (5 'chloro-2' thenoyl) phenol. Preferred compounds due to their 60 dermal activity are 2,6-bis (tert-butyl) -4- (2'-the-noyl) phenol and 2,6-bis (tert-butyl) -4- (5'- chloro-2'-the-noyl) phenol.

The compounds according to the invention, in which L is a carbon-carbon bond, can easily be prepared by reacting 2,6-bis (tert-butyl) benzoquinone with a Grignard reagent which is derived from a corresponding halogenated Thiophene has been obtained. Halogenated thiophenes are known, as are methods of

3rd

637129

their manufacture. Known halogenated thiophenes include 2-iodothiophene, 2-bromothiophene, 2-chlorothiophene, 2-bromothiophene and the like.

Grignard reactions between the Grignard reagent made from halogenated thiophene and 2,6-bis (tert-butyl) benzoquinone give the optionally substituted intermediates 2,6-bis (tert-butyl) -4-hydroxy-4- ( thienyl) -2,5-cyclohexadien-l-one of the formula:

(a'3) OH

• -pHöh (»)

in which R has the meaning given above (i.e. is a hydrogen or halogen atom or a methyl group). These compounds (II) are also new. They are reduced (with the aid of hydrogen gas and a catalyst, such as palladium on activated carbon or Raney nickel, a metal hydride, such as lithium aluminum hydride, or hydrogen iodide) to the compound of the formula I according to the invention. As an alternative to using a Grignard reagent in the above reaction, known reaction equivalents such as lithium compounds can also be used.

The compounds of the invention in which L is a carbonyl group can be easily prepared by various methods. The reaction of 3,5-bis (tert-butyl) -4-hydroxybenzoyl chloride with optionally substituted thiophenes in the presence of Friedel-Crafts catalysts is suitable for the synthesis of compounds in which L is a carbonyl group in the 2-position on the Is thiophenring and R is in the 3- or 5-position. Friedel-Crafts catalysts that are suitable for this include aluminum chloride, titanium tetrachloride, zinc chloride and the like. The reaction is generally carried out by dissolving the benzoyl chloride in an inert solvent, such as carbon disulfide, dichloroethane, dichloromethane and others, optionally under a protective atmosphere from an inert gas, such as nitrogen, adding the Friedel-Crafts catalyst at room temperature and then adding the The thiophene component was added dropwise and the reaction was allowed to proceed to completion (as can be seen from the end of the evolution of hydrogen chloride). Heating or heating can sometimes be beneficial to accelerate the reaction.

Optionally, 2,6-bis (tert-butyl) phenol can be reacted in the Friedel-Crafts reaction with an appropriate thiophenecarbonyl chloride. The procedure is essentially as given above using standard Friedel-Crafts procedures. A weaker catalyst such as titanium tetrachloride is preferred when the reaction rate with aluminum chloride becomes too fast. Another alternative is the direct introduction of one or two tert-butyl groups on the 4'-thienylphenylphenol or 4'-thenoylphenol nucleus by Friedel-Crafts reaction.

The preparation of the compounds of the formula I is described in the following examples using the processes described above.

example 1

13.5 g of aluminum chloride were added to a solution of 26.9 g (0.10 mol) of 3,5-bis (tert-butyl) -4-hydroxybenzoyl chloride in 300 ml of carbon disulfide. After stirring for 15 min and warming slightly, 17 g (0.104

Mol) 2-bromothiophene added. The reaction mixture gradually changed its color from green to red-brown. It was then poured into 10% hydrochloric acid and extracted with dichloromethane. The extracts were dried, the solvent evaporated to give an oil which crystallized easily. Recrystallization from hexane with treatment with activated carbon gave 2,6-bis (tert-butyl) -4- (5'-bromo-2-'thenoyl) phenol, mp. 126-127.5 ° C.

Analysis for Ci9H23BrChS:

Calc .: C 57.7; H 5.9%

Found: C 57.6; H 5.9%

Using essentially the same procedure as in Example 1 and using appropriate thiophene starting substances, the following compounds were obtained:

example

connection

Mp ° C

2nd

2,6-bis (tert-butyl) -4- (5'-methyl-2 '-

thenoyl) phenol

126-127.5

3rd

2,6-bis (tert-butyl) -4- (5'-chloro-2 '-the-

noyl) phenol

114.5-115.5

4th

2,6-bis (tert-butyl) -4- (2 '-the-

noyl) phenol

129-130.5

5

2,6-bis (tert-butyl) -4- (5 '-fluoro-2' -the-

noyl) phenol

-

6

2,6-bis (tert-butyl) -4- (3'-methyl-2 '-

thenoyl) phenol

105.5-107.5

7

2,6-bis (tert-butyl) -4- (3'-bromo-2 '-

thenoyl) phenol

116-118

Preparation 8 (known compound)

A Grignard reagent made from 0.0181 mol of 2-bromothiophene was prepared by reaction with 0.45 g of magnesium in diethyl ether. This reagent was added to a solution of 4.0 g (0.018 mol) of 2,6-bis (tert-butyl) benzoquinone in 75 ml of diethyl ether. The mixture was heated to reflux temperature and kept at this temperature for 5 hours. The product obtained was 2,6-bis (tert-butyl) -4-hydroxy-4- (2'-thienyl) -2,5-cyclohexadien-l-one. It was used in the next step in the mixture obtained. A slight excess of lithium aluminum hydride was carefully added to this mixture. After stirring for about 16 hours at room temperature, water was carefully added, followed by 10% hydrochloric acid. The mixture was extracted with dichloromethane, the extracts dried and evaporated to an oil. The oil was extracted with petroleum ether and the extracts cooled to -20 ° C for about 16 hours. The product was filtered off and then sublimed at 80 to 82 ° C / 0.1 mm Hg. Recrystallization from hexane gave 2,6-bis (tert-butyl) -4- (2'-thienyl) phenol, mp. 93-94 ° C.

Analysis: for C18H24OS:

Calc .: C 74.9; H 8.4%

Found: C 75.2; H 8.6%

Example 9

According to the method of preparation 8, the Grignard reagent from 4-bromo-2-fluorothiophene was reacted with

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

637 129

4th

2,6-bis (tert-butyl) benzoquinone to form 2,6-bis (tert-butyl) -4- (5'-fluoro-3'-thienyl) phenol.

Example 10

Thiophene-3-carboxylic acid was converted to the acid chloride by reaction with thionyl chloride. Thiophene-3-carbonyl chloride was isolated by distillation at 80 to 85 ° C / 0.25 mm Hg.

A solution of 14.66 g (0.10 mol) of thiophene-3-carbonyl chloride in 100 mg of dichloroethane was added to 20.87 g (0.1 mol) of titanium tetrachloride. 0.10 mol of 2,6-bis (tert-butyl) phenol was added to this solution in the smallest possible amount of dichloroethane. The mixture was stirred for approximately 16 hours, then poured into 500 ml of 10% hydrochloric acid. The organic layer was separated, 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. This gave 2,6-bis (tert-butyl) -4- (3'-thenoyl) phenol, mp. 101-102 ° C, then 127-218 ° C with a change in the crystal structure.

Analysis for C19H24O2S:

Calculated: C 72.1; H 7.7%

Found: C 72.0; H 7.8%

Example 11

Following the procedure of Example 10, 5-chlorothiophen-3-carbonyl chloride was reacted with 2,6-bis (tert-butyl) phenol to form 2,6-bis (tert-butyl) -4- (5th '-chlor-3'-thenoyl) phenol.

Example 12

Using the procedure of Example 10, 5-fluorothiophene-3-carbonyl chloride was reacted with 2,6-bis (tert-butyl) phenol to form 2,6-bis (tert-butyl) -4- (5 '- fluoro-3'-thenoyl) phenol.

Example 13

42 g (0.20 mol) of 2-iodothiophene were added to a solution of 0.2 mol of 3,5-bis (tert-butyl) -4-hydro-xybenzoyl chloride in dichloroethane.

s This solution was added dropwise to 37.9 g (0.20 mol) of titanium tetrachloride in 200 ml of dichloroethane at about 5 ° C in about 30 minutes. The solution was allowed to warm to 20 ° C and was stirred for 48 hours. It was then poured into 10% hydrochloric acid and the organic layer separated, 10 washed with water, dried and evaporated to dryness. The residue obtained was washed with hexane and recrystallized from methanol. The product was extracted again and washed with a hot hexane / toluene mixture (90:10). The pale yellow solid was recrystallized from methanol again. This gave 2,6-bis (tert-butyl) -4- (5'-iodo-2'-thenoyl) phenol, mp. 145.5-147 ° C.

Analysis for C19H23JO2S:

20th

Calc .: C 51.8; H 5.3%

Found: C 51.7; H 5.4%

Example 14

25 To a solution of 3.8 g (0.02 mol) of titanium tetrachloride in 50 ml of dichloroethane was added a solution of 3.21 g (0.02 mol) of 4-methylthiophene-2-carbonyl chloride in dichloroethane under nitrogen. The solution was then cooled in an ice bath and 4.12 g (0.02 mol) of 3,5-di (tert-butyl) phenol in 30 dichloroethane were added dropwise over the course of 30 minutes. The mixture was stirred for approximately 20 h, then filtered through silica gel and eluted with a mixture of hexane and chloroform (20:80). Recrystallization from hexane gave a white solid 2,6-bis (tert-butyl) -4- (4'-methyl-2'-the-3s noyl) phenol, mp 111.5-113 ° C.

Analysis: for C20H26O2S:

Calc .: C 72.7; H 7.9%

40 Found: C 73.3; H 7.9%

B

Claims (6)

637 129 PATENT CLAIMS 1. Medicinal product, characterized in that it contains one or more thiophene derivatives of the formula: (CH3) 3CN. HO— ^ Oy ~ L {ch3) 3C ^ O R (I) in which L represents a carbonyl group or a carbon-carbon bond and R represents a hydrogen or halogen atom or a methyl group, alone or in a mixture with a carrier and / or additive. 2. Medicament according to claim 1, characterized in that in the formula of the active ingredient R represents a hydrogen atom. 3. Medicament according to claim 1 or 2, characterized in that in the formula of the active ingredient L represents a carbonyl group. 4. thiophene derivatives of formula I given in claim 1, with the exception of 2,6-bis (tert-butyl) -4- (2'-thienyl) phe-nol. 5. thiophene derivatives according to claim 4, characterized in that in the given formula R represents a hydrogen atom. 6. thiophene derivatives according to claim 4 or 5, characterized in that in the given formula L represents a carbonyl group.