6-Phenyl-2,3-Bis-(4-Methoxyphenyl)-Pyridine Derivatives Having Anti-Inflammatory Activity

It is an object of this invention to provide novel 6-phenyl-2,3-bis(4-methoxyphenyl)pyridine derivatives. These compounds are active as prostaglandin synthetase inhibitors, analgesic agents, anti-inflammatory agents, anti-arthritic agents, antipyretic agents, and antithrombotic agents.

This invention provides for compounds of the Formula I ##STR1## and pharmaceutically acceptable salts thereof, wherein R is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo.

Further provided by this invention are pharmaceutical formulations for these compounds and a method for treating pain, fever, thrombosis, inflammation, and arthritis in mammals using compounds of Formula I or their pharmaceutical formulations.

The present invention relates to new organic compounds that are useful in the treatment of pain, fever, thrombosis, inflammation, and arthritis in mammals. The compounds of Formula I are chemically known as 6-phenyl-2,3-bis(4-methoxyphenyl)pyridines. A preferred group of compounds are the compounds of Formula I wherein R is bromo, chloro, or fluoro. Especially preferred compounds are those wherein the halo substituents are substituted at the 4-position of the phenyl ring.

The compounds of this invention can be prepared by the following reaction scheme: ##STR2## wherein Q is 4-methoxyphenyl and X is chloro, bromo, or iodo.

According to Scheme I, desoxyanisoin (II) is treated with dimethylamine or any other suitable secondary amine to provide the corresponding enamine III. The transformation to the enamine is preferably carried out in a non-reactive solvent, such as diethyl ether or toluene, in the presence of a Lewis Acid such as titanium tetrachloride, at temperatures from about -20.degree. C. to about 30.degree. C. The enamine is then reacted with a .beta.-halopropiophenone to provide the corresponding diketone IV. This reaction is best accomplished simply by heating the two compounds in a non-reactive solvent, such as acetonitrile, preferably at the reflux temperature of the solution. The diketone IV can then be cyclized to the desired product I by heating with hydroxylamine (or its salt) in a non-reactive solvent such as an alcohol for 6-24 hours. The preferred conditions employ heating the reaction mixture in methanol at the reflux temperature of the mixture for 15-20 hours.

The trifluoromethyl derivatives of this invention may also be prepared by heating the corresponding aryl iodide with bis(trifluoromethyl)mercury, copper, and N-methyl-2-pyrrolidinone.

The starting materials and reagents required for the preparation of the compounds of Formula I are either commercially available, are known in the art, or can be prepared by methods known in the art.

The pharmaceutically acceptable acid addition salts of this invention include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, and the like, as well as salts derived from nontoxic strong organic acids such as aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts thus include sulfate, nitrate, chloride, bromide, iodide, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and the like salts.

The compounds of this invention may be administered by various routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, being usually employed in the form of a pharmaceutical composition, although it is a special feature of these compounds that they are effective following oral administration. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the invention includes a pharmaceutical composition comprising as active ingredient a compound of Formula I associated with a pharmaceutically acceptable carrier.

In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, exlixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate or mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

The oral absorption of the novel compounds of this invention in mammals is greatly enhanced by administering the compounds of Formula I in a lipid-containing vehicle. Lipid vehicles include oils, oil emulsions, sterol esters, waxes, vitamin A esters, vegetable oils such as corn oil, coconut oil, and safflower oil, animal fats such as lard and spermaceti, phospholipids, and synthetic triglycerides such as Medium Chain Triglycerides (MCT-C.sub.8 -C.sub.10 chain) and Long Chain Triglycerides (LCT-C.sub.16 -C.sub.18 chain).

Excipients can also be added and include glycols, such as polyethylene glycol and polypropylene glycol, cellulose, starch, and the like.

Although oil alone can be used to administer the compound, if the mammal receiving the compound-oil mixture can rapidly digest and absorb the oil, an oil emulsion is the preferred method of administration. The preferred oil emulsion is a corn oil-acacia emulsion, formed by dissolving the compound in corn oil and then emulsifying the mixture with a ten percent acacia solution.

Other emulsifiers or emulsifying agents can include natural emulsifiers, such as acacia, phospholipids such as lecithin, gelatin, and cholesterol, and synthetic emulsifiers such as glyceryl esters, like glyceryl monostearate, sorbitan fatty acid esters, like sorbitan monopalmitate (Span 40), polyoxyethylene sorbitan fatty acid esters, like polyoxyethylene sorbitan monopalmitate (Tween 40) and polyoxyethylene sorbitan monooleate (Tween 80), and polyoxyethylene glycol esters, like polyoxyethylene glycol monostearate.

Other methods of administration include fluid or solid unit dosage forms, such as capsules, slurries, suspensions, and the like. For example, one form is a hard gelatin capsule containing the compound dissolved in fat. First, the compound is dissolved in the fat, while the fat is in a liquid state, and the mixture is then solidified, resulting in a homogenous amorphous solution. The mixture is then pulverized and placed in a hard gelatin capsule. An emulsifier can also be added to the mixture, if desired.

Alternatively, fluid unit dosage forms, such as soft gelatin capsules, can be used to administer the compounds. These capsules are prepared by machine encapsulation of a slurry of the compound and an acceptable lipid vehicle. A slurry alone without encapsulation can also be administered.

Still another fluid unit dosage form is a suspension, which is prepared with a syrup vehicle aided by a suspending agent, such as acacia, tragacanth, methylcellulose, and the like.

A further method of administration is to orally administer the compound to a mammal previously fed a fatty meal, thereby using the fats consumed in the meal as the lipid-containing vehicles. Before the compound is administered to the mammal, the compound is micronized and coated with a surfactant, such as acacia.

Therefore, one preferred aspect of this invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable lipid-containing vehicle. A surfactant or emulsifier can also be added to the formulation.

Another preferred aspect of the invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable surfactant-containing vehicle. This formulation is administered with or after the mammal has a fatty meal.

Preferably the compositions are formulated in a unit dosage form, each dosage containing from about 5 to 500 mg., more usually about 25 to 300 mg., of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for mammals, including human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.5 to 300 mg./kg. In the treatment of adult humans, the range of about 1 to 50 mg./kg., in single or divided doses, is preferred. However it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

The following preparations and examples further illustrate the preparation of the starting materials, intermediates, and compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

A solution of 307.56 g. of desoxyanisoin in three liters of diethyl ether was cooled to about 0.degree. C. by means of an external ice/alcohol bath. Under a nitrogen atmosphere, 441 ml. of dimethylamine were added to the solution with stirring. A solution of 79 ml. of titanium tetrachloride in 500 ml. of toluene was then added to the reaction mixture over a 90 minute period at such a rate to keep the temperature below 5.degree. C. The reaction was then allowed to stir overnight at room temperature. The reaction was filtered and the precipitate was washed with two liters of diethyl ether. The ether filtrate and wash were combined and evaporated in vacuo. The residue was crystallized from ether/Skelly B to provide 272.2 g. of the desired title intermediate, m.p. about 67.degree.-69.degree. C.

A solution of 34.0 g. of 4-methoxy-.alpha.-[(4-methoxphenyl)methylene]-N,N-dimethylbenzenemethanami ne and 25.0 g. of .beta.-chloro-4-fluoropropiophenone in 350 ml. of acetonitrile was heated at reflux overnight. The solution was evaporated in vacuo and then stirred with 350 ml. of 4N hydrochloric acid for two hours. The aqueous layer was extracted four times with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo. Upon the addition of 250 ml. of diethyl ether, yellow crystals immediately formed which were recovered by filtration affording 38.6 g. of the desired dione intermediate, m.p. about 71.degree.-74.degree. C.

A solution of 79.16 g. of 1,2-bis(4-methoxyphenyl-5-(4-fluorophenyl)-1,5-pentanedione and 139 g. of hydroxylamine hydrochloride in two liters of methanol was heated at reflux overnight. The reaction solution was then cooled and evaporated in vacuo. The residue was partitioned between 500 ml. of ethyl acetate and 500 ml. of water. The layers were separated and the aqueous layer was extracted three times each with 350 ml. of ethyl acetate. The combined ethyl acetate layers were washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by high pressure liquid chromatography followed by crystallization from diethyl ether to afford 26.63 g. of the desired product, m.p. about 118.degree.-120.degree. C.

Analysis: C.sub.25 H.sub.20 FNO.sub.2 ; Calc.: C, 77.90; H, 5.23; N, 3.63; Found: C, 77.99; H, 5.47; N, 3.38.

Following the procedures of Examples 1B and 1C, the following compounds were prepared from the appropriate .beta.-chloropropiophenone derivative.

2. 6-Phenyl-2,3-bis(4-methoxyphenyl)pyridine, m.p. about 120.degree.-123.degree. C.

Analysis: C.sub.25 H.sub.21 NO.sub.2 ; Calc.: C, 81.72; H, 5.76; N, 3.81; Found: C, 81.61; H, 5.98; N, 3.89.

3. 6-(4-Chlorophenyl)-2,3-bis(4-methoxyphenyl)pyridine, m.p. about 138.degree.-140.degree. C.

Analysis: C.sub.25 H.sub.20 ClNO.sub.2 ; Calc.: C, 74.72; H, 5.02; N, 3.49; Found: C, 74.82; H, 5.23; N, 3.33.

4. 6-(4-Bromophenyl)-2,3-bis(4-methoxyphenyl)pyridine, m.p. about 140.degree.-142.degree. C.

Analysis: C.sub.25 H.sub.20 BrNO.sub.2 ; Calc.: C, 67.27; H, 4.52; N, 3.14; Found: C, 66.96; H, 4.47; N, 2.82.

5. 6-(4-Iodophenyl)-2,3-bis(4-methoxyphenyl)pyridine, m.p. about 138.degree.-140.degree. C.

Analysis: C.sub.25 H.sub.20 INO.sub.2 ; Calc.: C, 60.87; H, 4.09; N, 2.84; Found: C, 60.50; H, 3.95; N, 2.84.

A solution of 0.49 g. of p-toluenesulfonic acid in 50 ml. of diethyl ether was added to a solution of 1.00 g. of 6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)pyridine in 50 ml. of diethyl ether. The resulting light yellow precipitate was recovered by filtration affording 1.29 g. of the desired title product, m.p. about 166.degree.-167.degree. C.

Analysis: C.sub.32 H.sub.28 FNO.sub.5 S; Calc.: C, 68.92; H, 5.06; N, 2.51; S, 5.75; Found: C, 68.88; H, 4.94; N, 2.58; S, 5.79.

6-(4-Trifluoromethylphenyl)-2,3-bis(4-methoxyphenyl)pyridine

A mixture of 22.4 g. of bis(trifluoromethyl)mercury, 16.77 g. of copper powder and 284 ml. of N-methyl-2-pyrrolidinone was heated at 140.degree. C. for three hours. A solution of 10.88 g. of 6-(4-iodophenyl)-2,3-bis(4-methoxyphenyl)pyridine in 140 ml. of N-methyl-2-pyrrolidinone was added over a 30 minute period. The reaction was heated at 150.degree. C. for three hours and then allowed to stir overnight at room temperature. Two liters of diethyl ether were added and the mixture was filtered. To the filtrate were added 250 ml. of water and the layers were separated. The organic layer was washed four times with water, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was crystallized from diethyl ether affording 7.48 g. of the desired title product, m.p. about 144.degree.-147.degree. C.

Analysis: C.sub.26 H.sub.20 F.sub.3 NO.sub.2 ; Calc.: C, 71.72; H, 4.63; N, 3.22; F, 13.07; Found: C, 71.97; H, 4.49; N, 3.37; F, 12.93.

The following formulation examples may employ as active compounds any of the pharmaceutical compounds of this invention.

Hard gelatin capsules are prepared using the following ingredients:

The above ingredients are mixed and filled into hard gelatin capsules in 460 mg. quantities.

A tablet formula is prepared using the ingredients below:

The components are blended and compressed to form tablets each weighing 665 mg.

An aerosol solution is prepared containing the following components:

The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30.degree. C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted further with the remainder of the propellant. The valve units are then fitted to the container.

Tablets each containing 60 mg. of active ingredient are made up as follows:

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50.degree.-60.degree. C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Capsules each containing 80 mg. of medicament are made as follows:

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg. quantities.

Suppositories each containing 225 mg. of active ingredient are made as follows:

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g. capacity and allowed to cool.

Suspensions each containing 50 mg. of medicament per 5 ml. dose are made as follows:

The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

The compounds of this invention are useful as prostaglandin synthetase inhibitors, analgesic agents, anti-inflammatory agents, anti-arthritic agents, antipyretic agents, and antithrombotic agents. The compounds are especially useful as analgesic and anti-inflammatory agents. In addition, the compounds have been demonstrated to have a low potential for phototoxic side effects.

The analgesic activity of a number of compounds provided by this invention has been determined in the standard mouse writhing assay. Writhing, which is characterized by contraction of the abdominal musculature, extension of the hindlegs, and rotation of the trunk, was induced in Cox standard strain albino male mice. The mice, weighing 18-24 grams, were fasted overnight and given the test compound by gavage in a corn oil-acacia emulsion (5%) three hours before writhing was induced by the intraperitoneal administration of acetic acid (0.60 percent). Each treatment group consisted of five mice. The total number of writhes for the treatment group was determined during a 10-minute observation starting five minutes after acetic acid administration. Control groups had a total of 40-60 writhes per observation period. Table I which follows presents typical test results obtained with certain of the compounds of this invention. The results in the mouse writhing assay are presented as the effective oral (p.o.) dose in mg./kg. of the tested compound required to inhibit induced writhing in the test animals by fifty percent (ED.sub.50).

Certain compounds of this invention were tested for their ability to alter hind paw swelling and bone damage resulting from adjuvant-induced edema in rats. In order to quantitate the inhibition of hind paw swelling resulting from adjuvant-induced arthritis, two phases of inflammation have been defined: (1) the primary and secondary injected hind paw, and (2) the secondary uninjected hind paw, which generally begins developing about eleven days from the induction of inflammation in the injected paw.

One group of five rats received no treatment (normal control). Adjuvant arthritis was induced in male Lewis-Wistar rats (200-210 grams) on test day one by a single subplantar injection into the right hind paw of 0.1 ml. of a 0.5% suspension of heat-killed, lyophilized Mycobacterium tuberculosis (Calbiochem-Perrigen-C) in mineral oil (a modification of a method reported by Winter et al., Arth. Rheum., 9, 394-397 (1966)). Only animals in which the non-injected paw measured at least a volume of 0.5 ml. greater than normal control animals on day 14 were selected for the rest of the experiment. One group of ten rats ("TB control") received no further treatment. Each compound to be tested was administered as a corn oil-acacia emulsion by gavage to rats (groups of five each) in daily oral doses, beginning on day 15 and continuing through the 29th day after the adjuvant injection (15 doses). Paw volumes were measured by mercury displacement using a Statham pressure transducer and digital voltmeter. Volumes of both the injected and the uninjected hind paws were measured on days 14, 16, 18, 21, 23, 25, 28, and 30. The paw volume measurements of the uninjected paw beginning with day 14 through day 30 were computer plotted for the TB controls, the normal controls, and the drug-treated animals, and the areas under the curves [(TB controls minus normal controls) and (drug-treated animals minus normal controls)] were determined. The results are summarized in Table II.