Antiinflammatory 4,5-Diaryl-2-Arylthioimidazoles

This invention relates to antiinflammatory substituted diaryl arylthioimidazoles.

U.S. Pat. No. 4,190,666 discloses antiinflammatory 4,5-diaryl-2-(substituted-thio)imidazoles and their corresponding sulfoxides and sulfones of the formula ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 represent various defined substituents.

Bhatt et al., Current Sci., 17, pages 184 and 185 (1948) discloses 4,5-diphenyl-1H-imidazole-2-thiol derivatives including 4,5-diphenylimidazoles with 4-nitrophenylthio or 2,4,6-trinitrophenylthio substituents in the 2-position of the imidazole. Utility for the compounds is not disclosed.

There is a continuing need for safe and effective antiinflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling and pain. Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment. The usefulness of most commercial antiinflammatories is limited because of toxicity and adverse sideeffects. Many produce gastric irritation and other effects, such as change in blood cells and central nervous system. Adrenocortical steroids produce gastric irritation and suppression of normal adrenal function.

The present invention results from efforts to develop new antiarthritic compounds with good antiinflammatory activity and minimal side effects that could be more effective in treating arthritis than presently available drugs.

This invention relates to novel antiinflammatory compounds of formula I, pharmaceutical compositions containing them, and methods of using them to treat arthritis in mammals. ##STR2## where X=H, F, Cl or OCH.sub.3 ; and

n=0, 1 or 2.

Preferred compounds for utility considerations and/or ease of synthesis are where X=Cl or OCH.sub.3 ; or n=0.

More preferred are the combination of X and n of the preferred constituents.

Compounds I (n=0) of the subject invention are prepared by reaction of an S-arylisothiourea with .alpha.-bromodesoxyanisoin. The .alpha.-bromodesoxyanisoin can be prepared according to the general teachings of U.S. Pat. No. 3,901,908. Optional oxidation of the products I (n=0) with a suitable oxidizing agent such as m-chloroperbenzoic acid affords compounds where n=1 or 2.

The desired S-arylisothioureas can be prepared by reaction of the appropriately substituted thiophenol with cyanamide according to procedures described in F. Arndt, Ann., 396, 7 (1913). ##STR3##

To a mixture of 58.0 g of 4-chlorothiophenol and 37.5 g of cyanamide in 400 ml of ether was added a catalytic amount of triethylamine. An exothermic reaction began and the ether was allowed to reflux spontaneously. After cooling to room temperature, the reaction mixture was poured onto a cold mixture of 150 ml of acetic acid and 500 ml of water. The ether layer was separated and the aqueous layer was washed several times with ether. The aqueous layer was made basic with solid potassium carbonate and a precipitate was collected by filtration. The solid was dissolved in a mixture of 500 ml of water and 25 ml of concentrated sulfuric acid. A small amount of insolubles were removed by filtration. Then 30 ml of 70% nitric acid were added and 41.7 g of the nitrate-sulfate salt of S-(4-chlorophenylthio)-isothiourea was collected by filtration, m.p. 228.degree. C.

Anal. Calcd. for (C.sub.7 H.sub.7 ClN.sub.2 S).sub.3 H.sub.2 SO.sub.4.HNO.sub.3 : C, 34.98: H, 3.33; N, 13.60. Found: C, 35.1; H, 3.61; N, 13.6.

Other S-arylisothioureas have been prepared similarly.

A mixture of 12.0 g of .alpha.-bromodesoxyanisoin, 8.6 g of S-(4-chlorophenyl)isothiourea nitrate-sulfate salt and 14.9 g of pulverized anhydrous potassium carbonate in 100 ml of dimethylformamide was stirred and heated at 100.degree. C. for 4 hours. The reaction mixture was allowed to cool to room temperature and then poured onto water. The product was extracted into ether, which, after washing with water, was evaporated to give 15.0 of an amber oil. Chromatography on silica gel eluting with chloroform followed by recrystallization from 1-chlorobutane gave 3.0 g of 4,5-bis-(4-methoxyphenyl)-2-(4-chlorophenylthio)-1H-imidazole as colorless crystals, m.p. 121.degree.-122.degree. C. The NMR and infrared spectra were consistent with this structure.

Anal. Calcd. for C.sub.23 H.sub.19 ClN.sub.2 O.sub.2 S. C, 65.32; H, 4.50; N, 6.63. Found: C, 65.0, 65.2; H, 4.80, 4.87; N, 6.77, 6.67.

Other compounds of this invention where n=o have been prepared similarly.

A mixture of 2.5 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylthio)-1H-imidazole and 2.5 g of m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred overnight at room temperature. Excess oxidizing agent was destroyed with methyl sulfide, and the solvent, after drying, was removed under vacuum to give 3.66 g of a solid. Recrystallization from toluene gave 1.28 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylsulfonyl)-1H-imidazole as colorless crystals, m.p. 187.degree.-188.degree. C. The NMR spectrum was consistent with the assigned structure.

Anal. Calcd. for C.sub.23 H.sub.19 ClN.sub.2 O.sub.4 S. C, 60.72; H, 4.21; N, 6.16. Found: C, 60.8; H, 4.31; N, 6.09.

Other compounds of the invention where n=2 have been prepared similarly.

The antiarthritic agents of this invention can be administered to treat arthritis by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be about 0.01 to 100 milligrams per kilogram of body weight. Ordinarily 0.05 to 50, and preferably 0.1 to 20 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E. W. Martin, a standard reference text in this field.

Useful pharmaceutical dosage forms for administration of the compounds of this invention can be illustrated as follows:

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 75 milligrams of powdered active ingredient 150 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate.

A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 75 milligrams of the active ingredient. The capsules are washed in petroleum ether and dried.

A large number of tablets are prepared by conventional procedures so that the dosage unit is 75 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 260 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 88.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 25 milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.

A parenteral composition suitable for administration by injection is prepared by stirring 1% by weight of active ingredient in sodium chloride injection U.S.P. XV and sterilizing by commonly used techniques.

To detect and compare the anti-inflammatory activities of compounds in this series and standard drugs, a test was used based on a standard model of arthritis for which there is good correlation with human efficacy. The model is adjuvant-induced arthritis in rats. Federation Proceedings, Vol. 32, No. 2, 1973, "Models Used for the Study and Therapy of Rheumatoid Arthritis"--Symposium of the American Society for Pharmacology and Experimental Therapeutics--states "The rat polyarthritis produced by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) has been used extensively for the screening of drugs of potential use in rheumatoid arthritis."

Compounds of this invention have shown activity in adjuvant-induced arthritis in rats which is widely recognized as a good model of human rheumatoid arthritis.

Lewis (Wistar) male rats (Charles River Breeding Laboratories, Wilmington, Mass.) weighing 175-220 grams were injected subcutaneously with 0.1 ml of adjuvant in the plantar area of the right hind paw. The adjuvant was prepared by bead-milling, heat-killed, lyophilized Mycobacterium butyricum (Difco #0640) in light mineral oil (Fisher Scientific Co. #0-119 Paraffin Oil-Saybolt Viscosity 125/135) 5 mg/ml. Twenty non-arthritic control rats were injected with mineral oil. The animals received water and Wayne Lab-Blox ad libitum*.

The rats were held for 14 days to allow the development of polyarthritis. The volume of the uninjected, left-hind paw of each rat was measured by using a Ugo Basile Volume Differential Meter, Model 7101. Adjuvant injected rats showing no evidence of arthritis were discarded and the arthritic rats were distributed into groups of 10 having equal mean paw volumes with equal standard deviation. Non-arthritic (oil-injected) control rats were distributed to 2 groups of 10. Suspensions of test compounds were prepared for dosing by bead-milling (4 mm glass beads in rubber stoppered serum bottles) for 4-5 hours in aqueous 1% polyvinyl alcohol, 5% gum acacia and 0.5% methylparaben.

Test compounds were given orally by gavage once daily for 7 days (days 14-20). The 2 groups of oil injected, non-arthritic control rats and the 2 groups of arthritic control rats received vehicle only for 7 days. Paw volumes (uninjected left hind paw) were measured 20 hours after the last dose (on day 21).

Percent decrease from control mean paw volume was calculated with the following formula: ##EQU1##

Dose-response regression lines of the % decrease were plotted on semi-log paper and the ED.sub.50 % for decrease from control paw volume was estimated by inspection.