Substituted 2-(Arylmethoxy) Phenol Compounds for the Treatment of Inflammation

Various nonsteroidal compositions, such as aspirin, phenylbutazone, indomethacin and other nonsteroidal compounds, as well as steroid compounds, such as adrenocorticosteroids, have been suggested and used as antiinflammatory agents. In addition, aminoethylphenols containing halogen and alkyl substituents have been suggested for use as antiinflammatory agents (see U.S. Pat. No. 3,928,624).

It is desirable to provide new and useful antiinflammatory agents and prostaglandins-synthetase inhibitors which are nonsteroid in nature and which avoid the disadvantages of the prior-art nonsteroid and steroid compositions.

My invention relates to the treatment of inflammation by the use of substituted 2-(arylmethoxy)phenol compounds and to novel antiinflammatory compositions containing, as active ingredients, certain substituted 2-(arylmethoxy)phenol compounds.

It has been discovered that the substituted 2-(arylmethoxy)phenol compounds of this invention act as medicinal agents which inhibit the synthesis of prostaglandins, inhibit platelet aggregation and are useful as topical and systemic antiinflammatory agents. Certain of my antiinflammatory compounds are novel, while others, while not novel, have not been used or suggested for use as medicinal agents.

My invention is directed to the use of known and novel 2-(arylmethoxy)phenols and 2-(hereroarylmethoxy)phenols as antiinflammatory agents. The compounds of my invention can be represented generally by the structural formula: ##STR2## where X is a naphthyl, pyridyl, quinolyl, 2-benzimidazolyl, or substituted phenyl having the formula: ##STR3## where R, R' and R" represent hydrogen or halogen, such as chloro, fluoro, bromo or iodo radicals, lower alkyl radicals, such as C.sub.1 -C.sub.6 alkyl radicals, such as methyl, ethyl, propyl and butyl, lower haloalkyl radicals, such as trifluoro, trichloro or tribromo methyl radicals, and lower alkoxy radicals, such as C.sub.1 -C.sub.6 radicals, such as methoxy, ethoxy and propoxy radicals or combinations thereof and the salts thereof.

In particular, my invention concerns those preferred compounds where there are one or two substituted groups where X is a substituted phenyl radical and, more particularly, where the substituted phenyl radical contains dihalides, such as the 2,3 and 2,6 dihalo compounds. Representative compounds where X is a substituted phenyl radical include, but are not limited to: 2,3 dimethyl; 2 methyl 3 chloro; 2 methyl 3 trichloromethyl; 2,6 dichloro; 2,5 dimethyl; 2,6 dichloro 5 methyl; 2,3 methoxy; and other compounds and the nontoxic salts thereof.

Those compounds where X represents the substituted phenyl radicals and wherein the substituent is hydrogen, parachloro, paramethoxy and 2,4 dichloro have been described in the literature for uses other than as antiinflammatory agents. For example, 2-(phenylmethoxy)phenol has been described in the literature as a bactericial compound (Klarmann, E., L. W. Gates and V. A. Shternov, J. Chem. Soc. 54: 1204-1211 (1932)). 2-(4-chlorophenylmethoxy)phenyl and 2-(2,4-dichlorophenylmethoxy)phenol are described in the literature as of potential use in the synthesis of sequential polypeptides (Cowell, R. D. and J. H. Jones, J. Chem. Soc. (6): 1082-1130 (1971)). Aminomethylphenols containing halogen and alkyl substituents have been described as antiinflammatory compounds in U.S. Pat. No. 3,928,624, issued Dec. 23, 1975.

My compounds may be employed alone or preferably in pharmaceutical nontoxic carrier materials in either liquid or solid form, such as in oil, alcohols; that is, as a solution, dispersion, suspension, emulsion or lotion, glycols, glycerine, starch, talc, sucrose and the like. My compounds may be employed as active antiinflammatory agents alone or in combination or with other agents, as well as in combination with those additive and supplemental materials typically employed and used in pharmaceutical compositions. My compounds may, for example, be used in those pharmaceutical compositions in the manner set forth in U.S. Pat. No. 3,928,624.

My compounds are used in the treatment of conditions in mammals (human and animal) exhibiting pain, fever and inflammation. The compounds may be administered in a variety of ways, but typically are employed in the area of pain or inflammation by topical application in a lotion, powder, solution or other form. A therapeutic amount of the 2-(arylmethoxy)phenol compound should be employed to reduce inflammation, which may range, for example, from a single to multiple treatments, such as 0.1 mg to 100 mg per kg of body weight per day; for example, 1 mg to 25 mg/kg/day. The topical composition may include from 0.001 to 5% by weight; for example, 0.01 to 1%, of the active compound.

My compounds may be incorporated in place of the aminomethylphenol compounds in the pharmaceutical compositions of U.S. Pat. No. 3,928,624.

Various standard in vitro tests have been carried out to demonstrate the effective antiinflammatory nature of my compounds, which tests can be correlated with tests in animals and humans.

The following examples are presented as illustrative of the compounds and use of such compounds in my invention.

For the synthesis of I, 10.0 g of a-bromo-o-xylene were added to 5.95 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.3 g dissolved in 50 ml of ethanol, was added dropwise over 30 min with stirring. The solution was then refluxed under nitrogen for 2 hours. The solution was filtered to remove KBr. The solution was cooled over night and filtered to remove di-substituted product. Ethanol was removed by rotary evaporation, and the oil was dissolved in 50 ml of chloroform. The pH was adjusted to neutrality with HCl and extracted three times with equal volumes of water, to remove unreacted catechol and salts. Chloroform was removed by rotary evaporation and the oil was vacuum-distilled at 8 mm Hg. Approximately 4 g of compound I were collected in the distillate that came over at 180.degree. C. The structure was confirmed by NMR and mass spectrum data.

For the synthesis of II, 10.15 g of a,m-dichlorotoluene were added to 6.94 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.45 g dissolved in 50 ml of ethanol, was added dropwise over 30 minutes with stirring. The solution was then refluxed under nitrogen for 2 hours. The solution was filtered to remove KCl. The solution was cooled over night and filtered to remove di-substituted product. Ethanol was removed by rotary evaporation, and the oil was dissolved in 50 ml of chloroform. The pH was adjusted to neutrality with HCl and extracted three times with equal volumes of water to remove unreacted catechol and salts. Chloroform was removed by rotary evaporation, and the oil was vacuum-distilled at 8 mm Hg. Approximately 4 g of compound II were collected in the distillate that came over at 190.degree. C. The structure was confirmed by NMR and mass spectrum data.

For the synthesis of III, 15.000 g of a'-chloro-aaa-trifluoro-m-xylene are added to 7.83 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.99 g dissolved in 50 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml extracted five times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing III is collected.

For the synthesis of IV, 20 g of p-methoxybenzyl bromide are added to 10.95 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 5.58 g dissolved in 50 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KBr. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted three times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing IV is collected.

For the synthesis of V, 15.00 g of 2,5-dimethylbenzyl chloride are added to 10.68 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 5.44 g dissolved in 50 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted three times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing V is collected.

For the synthesis of VI, 15.00 g of 2-(bromomethyl)naphthalene were added to 6.94 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.80 g dissolved in 50 ml of ethanol, was added dropwise over 30 minutes with stirring. The solution was then refluxed under nitrogen for 2 hours. The solution was filtered to remove KBr. The solution was cooled over night and filtered to remove di-substituted product. Ethanol was removed by rotary evaporation, and the oil was dissolved in 50 ml of chloroform. The pH was adjusted to neutrality with HCl and extracted three times with equal volumes of water to remove unreacted catechol and salts. Chloroform was removed by rotary evaporation. The oil was vacuum-distilled at 1 mm Hg and 8 g of VI were collected in the distillate that came over at 135.degree. C.

For the synthesis of VII, 15.00 g of 2-picolyl chloride HCl is added to 10.07 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 10.26 g dissolved in 100 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted five times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing VII is collected.

For the synthesis of VIII, 15.00 g of 2-chloromethylbenzimidazole is added to 9.91 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 5.05 g dissolved in 50 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted five times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing VIII is collected.

For the synthesis of IX, 15.00 g of 2-(chloromethyl)quinoline HCl are added to 7.71 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 7.86 g dissolved in 51 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted five times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing IX is collected.

The compounds of Examples 1-9 are prostaglandin synthesis inhibitors and are antiinflammatory agents.

Inhibition of prostaglandin synthesis has been shown to be the major mode of action of nonsteroidal antiinflammatory drugs (Ferrira, S. H. and Vane, J. R., Ann. Rev. Pharmacol., 14: 57-73 (1974)). A commonly used model system for examination of prostaglandin synthetase inhibition is the sheep vesicular gland microsomal preparation (Wallach, D. P. and Daniels, E. G., Biochim. Biophys. Acta., 231: 445-457 (1971)). Prostaglandin synthetase activity was determined by following oxygen tension in a closed reaction chamber using a Clark-type oxygen electrode. For each assay, 2.9 ml of 0.1M tris HCl buffer, pH 8.0, 10 ul of 0.2M phenol, and 50 ul of enzyme suspension (2.5 mg microsomal preparation) were added to the reaction chamber. 10 ul of inhibitor in ethanol were added 1 minute prior to initiation of the reaction. The reaction was initiated by addition of 10 ul of 3.7 mM arachidonate solution. The concentration of an inhibitor that reduced prostaglandin synthesis by 50% ([I].sub.50) was determined from plots of activity v. log concentration of inhibitor. The results for three 2-(arylmethoxy)phenols are given in the following Table I.

The antiinflammatory activity of these compounds served in various standard pharmacological tests, such as, for example, carrageenan induced foot-pad edema in rats (Winter, C. A., Risley, E. A. and Nuss, G. W., J. Pharmacol. Exp. Ther., 141: 369-376 (1963)), or the reverse passive arthus reaction in rabbits (Goldlust, M. R. and Schreiber, W. F., Agents and Actions, 5: 39-47 (1975)).

Inhibition of platelet aggregation by prostaglandin synthetase inhibitors is of potential value in treating thromboembolic disorders. Aggregation experiments were performed in a single-channel Chrono-log Platelet Aggregometer at 37.degree. C. To 500 ul of platelet-rich plasm were added 2 ul of inhibitor solution and 50 ul of 10 mM arachidonate. The [I].sub.50 value was defined as the concentration of inhibitor which prevented irreversible aggregation 50% of the time. The [I].sub.50 of 2-(phenylmethoxy)phenol was 0.57 uM.

My antiinflammatory compounds may be employed in typical antiflammatory compositions, to replace hexylresorcinol in troches and lozenges and other medicinal materials, as the active or supplemental ingredients in the treatment of acne, in antibacterial, antifungal and antiitching preparations, as a nonnarcotic analgesic and for aid in the treatment of thromboembolic disorders.