NO150881B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3,5-BIS (T-BUTYL) -4-HYDROXY-BENZOYL-SUBSTITUTED THIOPHENES - Google Patents

Description

The present invention relates to the production of hitherto unknown 3,5-bis(t-butyl)-4-hydroxybenzoyl-substituted thiophenes which can be used as anti-inflammatory agents.

Thiophene compounds substituted with bis(t-butyl)phenol groups have not previously been known. As far as the applicant knows, thiophenes substituted with mono-t-butylphenol groups are also not known - Compounds such as 4-(2*-thienyl)-phenyl, 4-(3'-thienyl)phenol, 3'(2'-thienyl)phenol, On the other hand, 3-(3'thienyl)phenol and 2-(2*-thienoyl)phenol are known.

The invention relates in particular to an analogue method for the preparation of therapeutically active compounds of formula I

in which R

denotes hydrogen, methyl or halogen,

Besides being useful as anti-inflammatory agents

are the compounds relatively active as stabilizers to avoid oxidation. Certain compounds are also analgesic, some are anti-pyretic, and some have mild immunosuppressive effects.

For investigation of the pharmacological activity, animal experiments are used using different methods which are well known to the person skilled in the field. The anti-inflammatory effect of the compounds can conveniently be demonstrated using a test designed to test the ability of these compounds to antagonize the local edema that is characteristic of an inflammatory response (rat foot edema test). The compounds of formula I have also been shown to inhibit the enzyme prostaglandin synthetase. The prostaglandin synthetase inhibition test is a rough assay for determining 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 in question are very active when administered dermally. Such topical activity has been measured using the guinea pig erythema test and a contact sensitivity test. Anti-inflammatory activity has also been demonstrated in other trials

are known in the art, such as the cotton pellet granuloma test and the aid arthritis test. Analgesic activity has been observed by standard test methods such as the phenylquinone twist (mouse) and Randall-Selitto (rat) tests.

Regarding edema in the rat's foot, refer to:

(1) Adamkiewicz et al, Canad, J. Biochem. Physio. 33:332, 1955,

(2) Selye, Brit. With. J. 2:1129, 1949, and

(3) Winter, Proe. Exper. Biol. With. 111:544, 1962.

The compound 2,6-bis(t-butyl)-4-(2<1->thenoyl)phenol has been compared with a number of known inflammatory active compounds, including indomethacin, naproxen and hydrocortisone.

The compound produced according to the invention exhibits a therapeutic index of 29.5, while the other known compounds have indices varying from 4.0 to 8.1, with the exception of hydrocortisone which has an index of 40.0, but which is known to have a completely different structure and which exhibit significant side effects.

The compounds are preferably administered orally as anti-inflammatory agents, but other known methods of administration can also be used, e.g. dermatocustally (e.g. dermally, rectally and the like) and parenterally, e.g. by subcutaneous injection, intramuscular injection, intra-articular injection, intra-venous injection and the like. Ocular administration is also included. The usual doses fall within the range from approx. 1 to approx. 500 mg/kg body weight for the mammal being treated, although oral doses usually do not exceed 100 mg/kg.

Currently, the following of the subject compounds are preferred in terms of their anti-inflammatory activity: 2,6-bis(t-butyl)-4-(2'-thenoyl)phenol,

2,6-bis(t-butyl)-4-(3'-thenoyl)phenol and 2,6-bis(t-butyl)-

4-(5<*->chloro-2'-thenoyl)phenol. At present the following of the new compounds are preferred as far as dermal activity is concerned: 2,6-bis-(t-butyl)'-4-(2'-thenoyl)-phenol and 2,6-bis(t-butyl)- 4-(5 1 -chloro-2'-thenoyl)phenol.

The analog method according to the invention is characterized by the fact that a compound of formula II

is reacted with a compound -of formula TII

in which formulas X and Y are different, and each represents hydrogen or the group -C0-C1, in the presence of a Friedel-Craft catalyst.

Reaction between 3,5-bis(t-butyl)-4-hydroxybenzoyl chloride and optionally substituted thiophenes in the presence of Friedel-Craft catalysts is useful for the preparation of compounds in which the carbonyl group is attached to the 2-position of the thiophene, and R is in 3- or 5-position. Friedel-Craft catalysts which are useful include aluminum chloride, titanium tetrachloride, zinc chloride and the like. The reactions are usually carried out by dissolving the benzoyl chloride in an inert solvent such as carbon disulfide, dichloroethane or dichloromethane and the like, optionally under an inert gas atmosphere such as an atmosphere of nitrogen, with the addition of Friedel-Crafts catalysts at room temperature, and then adding of the thiophene component dropwise and by allowing the reaction to proceed to completion (as shown by complete hydrogen chloride evolution). Heating can sometimes be useful to promote the reaction.

Alternatively, 2,6-bis(t-butyl)phenol can be reacted by the Friedel-Craft reaction with a suitable thiophene carbonyl chloride. The procedure is essentially the same as above using the usual Friedel-Craft technique. A weaker catalyst such as titanium tetrachloride would be preferable if the reaction rate is too fast with aluminum chloride.

Using the methods described above, the preparation of the new compounds is demonstrated by means of the following examples.

Example 1

To a solution of 26.9 g (0.10 mol) of 3,5-bis(t-butyl)-4-hydroxybenzoyl chloride in 300 ml of carbon disulphide, 13.5 g of aluminum chloride is added. After 15 minutes of stirring and slight heating, 17 g (0.104 mol) of 2-bromothiophene are added. The reaction mixture gradually changes color from green to reddish brown. It is then poured into 10% hydrochloric acid and extracted with dichloromethane. The extracts are dried, after which the solvent is evaporated to form an oil which easily crystallizes. Recrystallization from hexane by treatment with decolorizing activated carbon gives 2,6-bis(t-butyl)-4-(5'-bromo-2'-thenoyl)phenol, m.p. 126 - 127.5°C.

Analysis: Calculated for C19H23Br02S: %C 57.7 %H 5.9

Found: 57.6 5.9.

Using a method analogous to that described in Example 1 and replacing the thiophene starting material with a suitable starting material, the following compounds are obtained:

Example 8

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

A solution of 14.66 g (0.10 mol) of thiophen-3-carbonyl chloride in 100 mg of dichloroethane is added to 20.87 g (0.1 mol) of titanium tetrachloride. To this solution is added 0.10 mol of 2,6-bis(t-butyl)phenol in a minimal amount of dichloroethane. The mixture is stirred for approx. 16 hours, after which it is poured into 500 ml of 10 Vs hydrochloric acid. The organic layer is separated, washed with water and dried. The solvent is evaporated to form an oil which is mixed with hexane and cooled. The product is separated and recrystallized from hexane to form 2,6-bis(t-butyl)-4-(3*-thenoyl)phenol, m.p. 101 - 102°C, then 127 - 128°C after an apparent change of crystal structure.

Example 9

Using the method in example 8, 5-chlorothiophene-3-carbonyl chloride is reacted with 2,6-bis(t-butyl)phenol to form 2,6-bis(t-butyl)-4-(5<1->chloro -3'-thenoyl)phenol.

Example 10

Using the method in example 8, 5-fluorothiophene-3-carbonyl chloride is reacted with 2,6-bis(t-butyl)phenol to form 2,6-bis(t-butyl)-4-(5<1->fluoro -3'-thenoyl)phenol•

Example H

To one solution of 0.2 mol of 3,5-bis(t-butyl)-4-hydroxy-benzoyl chloride in dichloroethane is added 42 g (0.20 mol) of 2-iodothiophene.

This solution is added dropwise to 37.9 g (0.20 mol) of titanium tetrachloride in 200 ml of dichloroethane at approx. 5°C during approx. 30 minutes. The solution is allowed to be heated to 20°C and stirred for 48 hours. It is then poured into 10% hydrochloric acid, and the organic layer is separated, washed with water, dried and evaporated to dryness. The residue obtained is washed with hexane and recrystallised. Li is then separated from methanol. The product is extracted again and washed with a hot mixture (90/10) of hexane/toluene. The pale yellow solid is recrystallized from methanol to give 2,6-bis(t-butyl)-4-(51-iodo-21-thenoyl)-phenol, m.p. 145/5 - 147°C.

Example 12

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

Claims (1)

Analogy method for the preparation of therapeutic active compounds of formula I in which R denotes hydrogen, methyl or halogen, characterized in that a compound of formula II is reacted with a compound of formula III in which formulas X and Y are different and each represents hydrogen or the group -CO-Cl, in the presence of a Friedel-Craft catalyst.