GB1600704A

GB1600704A - Substituted thiophenes

Info

Publication number: GB1600704A
Application number: GB19649/78A
Authority: GB
Original assignee: Riker Laboratories Inc
Current assignee: Riker Laboratories Inc
Priority date: 1977-05-16
Filing date: 1978-05-15
Publication date: 1981-10-21
Also published as: JPS6113715B2; BE867067A; HK11682A; NL7805226A; ZA782765B; SE7811478L; DE2821391C2; FR2391208B1; FR2391208A1; CA1113103A; DE2821391A1; JPS53141265A; AU518109B2; SE442509B; AT361467B; ATA783578A; AU3612978A; CH637129A5

Abstract

Compounds of formula: <IMAGE> in which L denotes a carbonyl group, or a C/C bond, and R denotes a hydrogen or halogen atom, or a methyl group, have antiinflammatory, and in some cases also analgesic, antipyretic and/or immunosuppressive, properties; they are particularly suitable for use as antiinflammatory agents, as well as oxidation stabilisers. Compounds are preferred in which L denotes a carbonyl group and R denotes a hydrogen or chlorine atom.

Description

(54) SUBSTITUTED THIOPHENES (71) We, RIKER LABORATORIES INC, a corporation organised under the laws of the State of Delaware, United States of America, of 19901 Nordhoff Street, Northridge, California 91324, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to substituted thiophenes, to the use of such compounds as antiinflammatory agents, and to antiinflammatory compositions comprising one or more such compounds together with a suitable pharmaceutical extending medium.

Thiophene compounds substituted by bis(t-butyl)phenol groups have not been known previously. Insofar as applicant is aware, even thiophenes substituted by mono-t-butylphenol groups are not known. Compounds such as 4-(2'thienyl)phenyl, 4-(3'-thienyl)phenol, 3'(2'-thienyl)phenol, 3-(3'-thienyl)phenol and 2-(2'-thenoyl)phenyl are known, however.

The present invention provides 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). Presently preferred, due to their ease of synthesis and their therapeutic ratio, are the compounds of formula I in which L is carbonyl, particularly those in which L is 2-carbonyl. Also, compounds of the invention wherein R is hydrogen or halogen are preferred, particularly those compounds wherein R is hydrogen or chlorine. In the compounds of the invention in which R is not 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 their use as antiinflammatory agents, compounds of the invention can act as stabilizers to prevent oxidation. Some also are analgesics, some are antipyretic agents, and some have mild immunosuppressant activity.

In order to determine and assess pharmacological activity, testing in animals is carried out using various assays known to those skilled in the art. Thus, the antiflammatory activity of the compounds can be conveniently demonstrated using an assay designed to test the ability of these compounds to antagonize the local edema which is characteristic of the inflammatory response (the rat foot edema test). The compounds (I above) have also been found to inhibit the enzyme prostaglandin synthetase. The prostaglandin synthetase inhibition assay is a broad screen for the detection of antiinflammatory 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 quite active when administered dermally.

Such topical activity has been measured by means of the guinea pig erythema test and by a contact sensitivity test. Antiinflammatory activity may also be detected by other assays known to the art such as the cotton pellet granuloma test and the adjuvant arthritis test. The analgesic activity has been observed in standard test methods such as the phenylquinone writhing (mouse) and Randall-Selitto (rat) tests.

Leading references to the rat foot edema method 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 antiinflammatory agents but other known methods of administration are contemplated as well, e.g.

dermatomucosally (for example dermally, rectally) and parenterally, for example by subcutaneous injection, intramuscular injection, intra-articular injection, and intravenous injection. Ocular administration is also included. Dosages ordinarily fall within the range of I to 500 mg/kg of body weight of the mammal to be treated although oral dosages are not usually above 100 mg/kg.

Compounds of the invention prepared because of their antiinflammatory 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. Compounds of the invention preferred because of their dermal activity are 2,6 - bis(t - butyl) - 4 - (2' thenoyl)phenol and 2,6 - bis(t - butyl) - 4 - (5' - chloro - 2' - thenoyl)phenol.

The compounds of the invention wherein L is a carbon-carbon bond are prepared readily by the reaction of 2,6 - bis(t - butyl)benzoquinone with a Grignard reagent prepared from an appropriate halogenated thiophene.

.Halogenated thiophenes are well known to the art, as are procedures for their preparation. Among the known halogenated thiophenes are 2-iodothiophene, 2bromothiophene, 2-chlorothiophene, and 2-bromothiophene.

Grignard reactions between the Grignard reagents of halogenated thiophenes and 2,6- bis(t- butyl)benzoquinone provide the intermediate optionally substituted 2,6 - bis(t - butyl)- 4- hydroxy - 4- (thienyl) - 2,5 cyclohexadiene - 1 - ones having the formula:

wherein R is as previously defined (i.e. hydrogen, methyl or halogen). These compounds are reduced (using 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 compounds of the invention of Formula I. As an alternative to using a Grignard reagent in the above reaction, known reactive equivalents such as lithium compounds are useful.

The compounds of the invention wherein L is a carbonyl group are prepared readily by several methods. The reaction of 3,5 - bis(t- butyl)- 4hydroxybenzoyl chloride with optionally substituted thiophenes in the presence of Friedel-Crafts catalysts is useful for the synthesis of compounds wherein L is carbonyl bonded to the 2-position of thiophene and R is in the 3- or 5-position.

Friedel-Crafts catalysts which are useful include aluminum chloride, titanium tetra-chloride, and zinc chloride. The reactions are generally carried out by dissolving the benzoyl chloride in an inert solvent such as carbon disulfide, dichloroethane, or dichloromethane, optionally under an inert gas atmosphere such as nitrogen, adding the Friedel-Crafts catalyst at room temperature, and then adding the thiophene component dropwise, and allowing the reaction to progress to completion (s shown by completion of hydrogen chloride evolution). Heating or warming may sometimes be useful to promote the reaction.

Alternatively 2,6-bis(t-butyl)phenol can be reacted in the Friedel-Crafts reaction with an appropriate thiophenecarbonyl chloride. The procedure is essentially as above, using standard Friedel-Crafts techniques. A weaker catalyst such as titanium tetrachloride will be preferred if the reaction rate is too rapid with aluminum chloride. Another alternative is direct introduction of one or two tertiary butyl groups into the 4'-thienylphenylphenol or 4'-thenoylphenol nucleus by a Friedel-Crafts reaction.

Using the methods described hereinabove the preparation of compounds of the invention is illustrated using the following examples.

Example 1 To a solution of 26.9 g. (0.10 mole) of 3,5 - bis(t - butyl) - 4 - hydroxybenzoyl chloride in 300 ml. of carbon disulfide is added 13.5 g. of aluminum chloride. After stirring 15 minutes and warming slightly 17 g. (0.104 mole) of 2-bromothiophene is added. The reaction mixture gradually turns from a green color to a maroon color.

It is then poured into 10% hydrochloric acid, and extracted with dichloromethane.

The extracts are dried, then the solvent is evaporated to provide an oil which readily crystallizes. Recrystallization from hexane with treatment with decolorizing charcoal provides 2,6 - bis(t - butyl) - 4 - (5' - bromo - 2' - thenoyl)phenol, m.p.

126-127.5 C.

Analysis: %C %H Calculated for C19H23BrO2S: 57.7; 5.9 Found: 57.6; 5.9.

Utilizing substantially the method of Example 1 (and making suitable substitutions for the thiophene starting material) the following are obtained: Melting Point Ex. No. Compound "C.

2 2,6-bis(t-b utyl)4-(5'-methyl 2'-thenoyl)phenol 126-127.5 3 2,6-bis(t-butyl)-4-(5'-chloro 2'-thenoyl)phenol 114.5-115.5 4 2,6-bis(t-butyl)-4-(2'-thenoyl) phenol 5 2,6-bis(t-butyl)-4-(5'-fluoro 2'-thenoyl)phenol 6 2,6-bis(t-butyl)-4-(3'-methyl- 105.5-107.5 2'-thenoyl)phenol 7 2,6-bis(t-butyl)-4-(3'-bromo 2'-thenoyl)phenol 116-118 Example 8 A Grignard reagent of 0.0181 mole of 2-bromothiophene is prepared by reaction with 0.45 g. of magnesium in diethyl ether. This reagent is added to a solution of 4.0 g. (0.018 mole) of 2,6-bis(t-butyl)benzoquinone in 75 ml. of diethyl ether. The mixture is heated to its reflux temperature and maintained at reflux for about 5 hours. The product obtained is 2,6 - bis(t - butyl) - 4 - hydroxy - 4 - (2' thienyl) - 2,5 - cyclohexadien - 1 - one. It is used in the next step as the mixture obtained. To this mixture is added cautiously a slight excess of lithium aluminum hydride. After stirring for about 16 hours at room temperature water is cautiously added, then 10 percent hydrochloric acid, The mixture is extracted with dichloromethane, the extracts are dried, then evaporated to provide an oil. The oil is extracted with petroleum ether, then the extracts are cooled at 20a for about 16 hours. The product is separated by filtration, then sublimed at 80--820C/0.1 mm.

Hg. Recrystallization from hexane provides 2,6 - bis(t - butyl) - 4 - (2' thienyl)phenol, m.p. 9394 C.

Analysis: %C sH Calculated for C,8H24OS: 74.9; 8.4 Found: 75.2; 8.6.

Example 9 Using the method of Example 8, the Grignard reagent of 4 - bromo - 2 fluorothiophene is reacted with 2,6 - bis(t - butyl)benzoquinone to provide 2,6 bis(t - butyl) - 4 - (5' - fluoro - 3' - thienyl)phenol.

Example 10 Thiophene-3-carboxylic acid is converted to the acid chloride by reaction with thionyl chloride. Thiophene-3-carbonyl chloride is isolated by distillation at 80- 85"C/0.25 mm.

A solution of 14.66 g (0.10 mole) of thiophene-3-carbonyl chloride in 100 mg.

of dichloroethane is added to 20.87 g. (0.1 mole) of titanium tetrachloride. To this solution is added 0.10 mole of 2,6 - bis(t - butyl)phenol in a minimum amount of dichloroethane. The mixture is stirred for about 16 hours, then poured into 500 ml.

of 10% hydrochloric acid. The organic layer is separated, washed with water and dried. The solvent is evaporated to provide an oil which is mixed with hexane and cooled. The product is separated and recrystallized from hexane to provide 2,6 bis(t - butyl) -4 - (3' - thenoyl)phenol, m.p. 101102 C., then 127218 C. in an apparent change of crystal structure.

Analysis: %C H Calculated for C19H24O2S: 72.1; 7.7 Found: 72.0: 7.8.

Example 11 Using the method of Example 10, 5 - chlorothiophene - 3 - carbonyl chloride is reacted with 2,6 - bis(t - butyl) - phenol to provide 2,6 - bis(t - butyl) - 4 - (5' chloro - 3' - thenoyl) - phenol.

Example 12 Using the method of Example 10, 5 - fluorothiophene - 3 - carbonyl chloride is reacted with 2,6 - bis(t - butyl) - phenol to provide 2,6 - bis(t - butyl) - 4 - (5' fluoro - 3' - thenoyl) - phenol.

Example 13 To a solution of 0.2 mole of 3,5 - bis(t - butyl) - 4 - hydroxybenzoyl chloride in dichloroethane is added 42 g. (0.20 mole) of 2-iodothiophene.

This solution is added dropwise to 37.9 g. (0.20 mole) of titanium tetrachloride in 20 ml. of dichloroethane at about 5 C. over about 30 minutes. The solution is allowed to warm to 200 C. and is stirred for 48 hours. It is then poured into ten percent hydrochloric acid and the organic layer is separated, washed with water.

dried and evaporated to dryness. The residue obtained is washed with hexane, then recrystallized from methanol. The product is again extracted and washed with a hot (90/10) hexane/toluene mixture. The pale yellow solid is again recrystallized from methanol to provide 2,6 - bis(t - butyl) - 4 - (5' - iodo - 2' - thenoyl)phenol, m.p.

l45.5l470 C.

Analysis: %C %H Calculated for C19H23IO2S: 51.8; 5.3 Found: 51.7; 5.4.

Example 14 To a solution of 3.8 g. (0.02 mole) of titanium tetrachloride in 50 ml. of dichloroethane under nitrogen is added a dichloroethane solution of 3.21 g. (0.02 mole) of 4 - methylthiophene - 2 - carbonyl chloride. The solution is then cooled with an ice bath, and 4.12 g. (0.02 mole) of 3,5 - di(t - butyl)phenol in dichloroethane is added dropwise over 30 minutes. The mixture is stirred for about 20 hours, then filtered through silica gel, eluting with a mixture of hexane/chloroform (20/80). Recrystallization from hexane provides white solid 2,6 - bis(t - butyl) - 4 - (4' - methyl - 2' - thenoyl) - phenol, m.p. 111.5--113" C.

Analysis: fOC %H Calculated for C20H26O2S: 72.7; 7.9 Found: 73.3; 7.9.

WHAT WE CLAIM IS: 1. A compound of the formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Example 10 Thiophene-3-carboxylic acid is converted to the acid chloride by reaction with thionyl chloride. Thiophene-3-carbonyl chloride is isolated by distillation at 80- 85"C/0.25 mm. A solution of 14.66 g (0.10 mole) of thiophene-3-carbonyl chloride in 100 mg. of dichloroethane is added to 20.87 g. (0.1 mole) of titanium tetrachloride. To this solution is added 0.10 mole of 2,6 - bis(t - butyl)phenol in a minimum amount of dichloroethane. The mixture is stirred for about 16 hours, then poured into 500 ml. of 10% hydrochloric acid. The organic layer is separated, washed with water and dried. The solvent is evaporated to provide an oil which is mixed with hexane and cooled. The product is separated and recrystallized from hexane to provide 2,6 bis(t - butyl) -4 - (3' - thenoyl)phenol, m.p. 101102 C., then 127218 C. in an apparent change of crystal structure. Analysis: %C óH Calculated for C19H24O2S: 72.1; 7.7 Found: 72.0: 7.8. Example 11 Using the method of Example 10, 5 - chlorothiophene - 3 - carbonyl chloride is reacted with 2,6 - bis(t - butyl) - phenol to provide 2,6 - bis(t - butyl) - 4 - (5' chloro - 3' - thenoyl) - phenol. Example 12 Using the method of Example 10, 5 - fluorothiophene - 3 - carbonyl chloride is reacted with 2,6 - bis(t - butyl) - phenol to provide 2,6 - bis(t - butyl) - 4 - (5' fluoro - 3' - thenoyl) - phenol. Example 13 To a solution of 0.2 mole of 3,5 - bis(t - butyl) - 4 - hydroxybenzoyl chloride in dichloroethane is added 42 g. (0.20 mole) of 2-iodothiophene. This solution is added dropwise to 37.9 g. (0.20 mole) of titanium tetrachloride in 20 ml. of dichloroethane at about 5 C. over about 30 minutes. The solution is allowed to warm to 200 C. and is stirred for 48 hours. It is then poured into ten percent hydrochloric acid and the organic layer is separated, washed with water. dried and evaporated to dryness. The residue obtained is washed with hexane, then recrystallized from methanol. The product is again extracted and washed with a hot (90/10) hexane/toluene mixture. The pale yellow solid is again recrystallized from methanol to provide 2,6 - bis(t - butyl) - 4 - (5' - iodo - 2' - thenoyl)phenol, m.p. l45.5l470 C. Analysis: %C %H Calculated for C19H23IO2S: 51.8; 5.3 Found: 51.7; 5.4. Example 14 To a solution of 3.8 g. (0.02 mole) of titanium tetrachloride in 50 ml. of dichloroethane under nitrogen is added a dichloroethane solution of 3.21 g. (0.02 mole) of 4 - methylthiophene - 2 - carbonyl chloride. The solution is then cooled with an ice bath, and 4.12 g. (0.02 mole) of 3,5 - di(t - butyl)phenol in dichloroethane is added dropwise over 30 minutes. The mixture is stirred for about 20 hours, then filtered through silica gel, eluting with a mixture of hexane/chloroform (20/80). Recrystallization from hexane provides white solid 2,6 - bis(t - butyl) - 4 - (4' - methyl - 2' - thenoyl) - phenol, m.p. 111.5--113" C. Analysis: fOC %H Calculated for C20H26O2S: 72.7; 7.9 Found: 73.3; 7.9. WHAT WE CLAIM IS:

1. A compound of the formula

wherein L is carbonyl or a carbon-carbon bond and R is hydrogen, methyl or halogen.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according to claim 1 or 2 wherein L is carbonyl.

4. 2,6 - Di (t - butyl) - 4 - (2' - thenoyl)phenol.

5. 2,6 - Di - butyl) - 4 - (3' - thenoyl)phenol.

6. 4 - (5' - Chloro - 2' - thenoyl) - 2,6 - di(t - butyl) - phenol.

7. 2,6 - Di(t - butyl) - 4 - (2' - thienyl)phenol.

8. A method for combatting inflammatory processes in a non-human mammal which comprises administering an effective dose less than the toxic amount of a compound according to any preceding claim.

9. A substituted thiophene according to claim 1 and substantially as hereinbefore described in any one of Examples 1 to 5 and 8 to 12.

10. A substituted thiophene according to claim 1 and substantially as hereinbefore described in any one of Examples 6, 7, 13 and 14.

11. A method of preparing a compound of formula I herein substantially as hereinbefore described.

12. A composition comprising a compound according to any one of claims 1 to 7 and 9 in a pharmaceutically acceptable carrier.

13. A composition comprising a compound according to claim 10 in a pharmaceutically acceptable carrier.