PHARMACEUTICAL COMPOUNDS AND PROCESS FOR THE MANUFACTURE OF SAME

Abstract: An analgesic and anti-inflammatory product comprising an acetyl salicylic derivative composition having the for­ mula: wherein both R and R¹ are hydrocarbon radicals and process for the manufacture thereof.

Description: BACKGROUND OF THE INN'MENTION - FIELD OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART The present invention relates to new pharmaceutical compounds and to a process for the preparation thereof. In particular, the present invention relates to analgesic and anti-inflammatory compounds. Acetyl salicylic acid, or aspirin as it is more commonly knwn, is amongst the most widely used of proprietary medicines. Aspirin can be used in the treatment of numerous ailments and is indicated to have analgesic, antiinflammatory, antipyretic and antirheumatic activity. However, side effects of the drug may limit its application. For example, acetyl salicylic acid may cause gastric irritation and is contra-indicated where such irritation must necessarily be avoided. SUMMARY OF THE INVENTION The object of the present invention is to provide pharmaceutical substances and compositions which exhibit some or all of the advantageous properties of aspirin but in which the contra-indications are minimized. According to the present invention it has been discovered that certain ester derivatives of acetyl salicylic acid provide useful pharmaceutical activity with minimal contra-indications. The invention provides a pharmaceutical composition containing a glycol ester of acetyl salicylic acid or derivatives thereof. Monoglycol esters have been found suitable. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The invention also provides an acetyl salicylic derivative of the formula I: EMI3.1 wherein R and R1 which may be the same or different represent any suitable radical such as a hydrocarbon group. The present invention further provides pharmaceutically acceptable derivatives thereof and bioprecursors therefor. Pharmaceutically acceptable derivatives thereof may include acid addition salts. In E preferred form R may represent an alkyl group. The alkyl group may include for example from 1 to 15 carbon atoms. The alkyl group may be a straight chain alkyl group. In E preferred form R represents E straight chained alkyl group of from 7 to Il carbon atoms. In a preferred form of the invention R1 represents a lower alkyl group, for example, a methyl, ethyl or propyl group. A methyl group has been found most satisfactory. Thus by way of example the compounds of the present invention may be of the formula II: EMI3.2 where R is a straight chain alkyl radical having from 1 to 15 carbon atoms and preferably from 7 toll carbon atoms. The compounds of the present invention have analgesic and anti-inflammatory activity similar to thcse of acetyl salicylic acid. It has been found that the following tests provided a valuable guide to the activity of the compounds of the present invention. These tests are the animal model experiments described by L.B. Witkin et al., J. Pharmacol. E?tl. Therap., i33, 400 (1961) and C.A. Winter et al., Proc Soc, Exp. Biol. Med., 111, 544 (1962). The use of compounds of the formula I is particularly advantageous since gastric irritation associated with acetyl salicylic acid therapy is avoided or at least minimized. The salicylic derivatives of the present invention may be manufactured by any chemical process known to be useful for the manufacture of chemically analagous compounds. A preferred process for the manufacture of a salicylate derivative of the present invention comprises the reaction of en acetyl salicylic acid derivative with a monoglycol ester of the general formula III: EMI4.1 wherein R and R1 have the meanings given above. An acid halide derivative of acetyl salicylic acid, that is an, O-acetyl salicyloyl halide such as Cacetyl salicyloyl chloride may be used. The reaction may be undertaken in an inert organic solvent, for example, carbon tetrachloride, chloroform, dichloromethane, acetonitrile, ether, tetrahydrofuran or dioxane or the like. Compounds of the formula m may be prepared via en acylation reaction of a hydroxyketone of the formula 70 EMI5.1 wherein R1 has the meaning given above; with a carboxylic acid of the formule V: EMI5.2 wherein R has the meaning given above; to yield compounds of the formula VI: EMI5.3 A particularly preferred hydroxyketone is the monohydroxy acetone. This yields a monoglycol ester of the formula VII: EMI5.4 This subsequently provides a salicylic acid derivative of the formula n: EMI6.1 These reactions may be achieved by standard procedures. For example, the acid V may be ectivated by conversion to an acid halide e.g. the acid chloride prior to coupling with the hydroxyketone. Alternatively the hydroxyketone may be reacted directly with the acid V in the presence of a condensing agent. The condensing agent may be a carbodiimide such as NN-dicyclo- hexylcarbodiimide. For a review of these methods reference may be made to J. March, "Advanced Organic Chemist Reactions, Mechanisms and Structure", McGraw-Hill, New York, 1968, p. 319324. The process is completed by reduction of the intermediates of the formula VI to compounds of formula m. The reduction may be achieved by use of a reducing agent. The reducing agent may be sodium borohydride for example. Particularly preferred compounds of the present invention exhibiting analgesic and anti-inflammatory activity but with reduced gastric irritation include 2-(Decanoyloxypropyl) O Acetylsalicylate and 2-(1-Dodecanoyloxypropyl) O-Acetylsalicylate. A suitable aciaddition salt of a salicylate derivative of the invention is, for example, e salt derived from an organic ecid, for example, E hydrochloride, hydrobromide, phosphate or sulphate, or a salt derived frorr. an organic acid, for example an oxalate, lactate, succinate, tartrate, acetate, salicylate, citrate, benzoate, Bnaphthoate, or adipate. The salicylate derivatives of the present invention may be administered to animals including man, in the form of a pharmaceutical composition comprising as active ingredient at least one salicylate derivative of the present invention, or an acidaddition salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor. The composition may further comprise a physiologically acceptable excipient, binder, preservative, stabilizer, flavoring or other compounding ingredient. The composition may be prepared in a conventional unit dosage form as called for by accepted pharmaceutical practice. The composition may be included in soft gelatin capsules, two piece hard gelatin shell capsules, tablets, elixirs, suspensions, emulsions or in injectible solutions or suspensions or oily solutions or suspensions. The amount of active substances included is selected so as to provide an individual unit dosage, preferably from about 30 milligrams to 1500 milligrams of the active ingredient. Other therapeutically valuable substances may also be included. Caffeine, phenacetin, paracetamol may be used in addition to the active i1redient of the present invention. The following examples are illustrative of the invention, or of intermediates which may lead to the invention, and represent preferred embodiments but are not to be construed as being limitations thereon. All temperatures are in degrees Celsius. EXAMPLE 1: l-Decanoyloxypropan-2-one Monohvdroxyacetone was distilled prior to use. Chloroform was distilled from phosphorous pentoxide prior to use. Decanoyl 3 chloride (fi5 cm , 0.3146 mole) was added dropwise to stirred 3 solution of monohydroxyacetone (21.8 cm@, 0.3146 mole) and anhydrous pyridine (25.4 cm3, 0.3146 mole) in anhydrous chloroform (500 cm3). During the addition the solution was maintained in an ice bath. The mixture was then stirred at room temperature overnight. The solution was washed with water (4 x 200 cm3) and saturated sodium chloride solution (200 em3). The organic phase was dried over sodium sulphate and evaporated in vacuo. The resulting oil was distilled to yield l-decanoyloxypropan-2-one as a mobile liquid, bp 154-60 (1 mm) (52.4 g, 0.230 mole, 73%), ir (neat) 2860, 1700, 1400, 1340, 1150, 1110 and 1050 cm-1; pmr (CDCI3) 4.6 (s, 2 H), 2.4 (t, 2 H), 2.1 (s, 3 H), 1.8-1.0 (bm, 14 H) and 0.9 (t, 3 H) ppm. EXAMPLE 2: l-Decanoyloxypropan-2one (44.3 g, 0.194 mole) was dissolved in a solution of tetrahydrofuran (1100 em3) and benzene (200 em3). After cooling to a , ice water (80 cm3) was added. Sodium borohydride (11 g, 0.291 mole) was added to the stir@ed solution in small proportions to maintain the temperature at 5 . After addition the reaction was stirred at 50 for 45 minutes and glacial acetic acid (14 cm3) was added dropwise. Stirring at 50 was continued for a further 30 minutes. Diethvl ether and chloroform (200 cm3 each) were added and the mixture washed with water (2 x 200 em3), a 1% sodium bicarbonate solution (200 cm3) and brine (200 em3). The organic phase was dried over sodium sulphate and evaporated to yield 1-decanoyloxypropan-2-ol as a colorless liquid (44.0 g, 0.191 mole, 98%), ir (neat) 3600-3100, 2920, 2860, 1730, 1460, 1375, 1240, 1175, 1110, 1055 cm-1; pmr (CDCI3) 4.0 (m, 2 H), 3.6 (m, 2 H), (D2) m, 1 H), 2.3 (t, 2 H), 2.0-1.0 (bm, 17 H) and 0.85 (t, 3 H) ppm. EXAMPLE 3: 2-(1-Decanoyloxypropyl) o-Zcetylsalicylate A solution of 0-acetylsalicyloyl chloride (12.5 g, 0.0629 mole) in dry earbontetrachloride (25 cm3) was added slowly to a stirred solution of 1-decanoyloxypropan-2-ol (4.85 g, 0.0211 mole) and dry pyridine (D.1 cm3, 0.0630 mole) in dry carbontetrachloride (150 cm3) at O The solution was then stirred at 250 for two hours and poured over ice (100 g). The mixture was stirred for two hours and the organic layer separated, washed with water, (2 x 150 cm3), 196 hydrochloric acid, water, 196 sodium bicarbonate, water and brine (2 x 100 cm 3 each), dried over sodium sulphate and evaporated in vacuo. The product was chromatographed on silica gel (500 g) in petroleum ether (40-60 ) : ether (80:20) and treated with charcoal in acetone to yield (2-(1-decanoyloxypropyl) 0-acetylsalicyate as a colorless liquid (3.4 g. 0.00866 mole, 41%); ir (neat) 2920, 2850, 1770,1725,1605, 1480, 1450, 1365, 1290, 1250, 1190, 1160, 1115,1075, and 915 cm4; pmr (CDCI3) 7.9 (dd, 1 H), 7.6-6.9 (m, 3 H), 5.3 (m, 1 H), 4.2 (m, 2 H), 2.3 (2, 3 H), 2.3 (m, 2 H), 1,9-1.0 (bm, 17 H) and 0.9 (t, 3 H) ppm. Anal. calcd, for C22H3206 : C, 67.32; H 8.22% Found: C, 6725; H, 8.07% EXAMPLE 4: l-Dodecanoyloxypropan-2o1 By replacing decanoyl chloride in Example 1 with dodecanoyl chloride, ldodecanoyloxypropan-2one and subsequently 1dodecanoyloxypropan-2-ol, as in Example 2, can be obtained. EXAMPLE 5: 2-(l-Dodecanoyloxypropyl) FAcetylsalicylate By replacing l-decanoyloxypropan-2-ol with l-dodecanoyloxypropan-2-ol in Example 3, 2-(1-dodecanoyloxypropyl) Oacetylsalicylate can be obtained. Finally, it is to be understood that various other modifications and/or alterations may be made without departing from the spirit of the present invention as outlined herein.

Claims: CLAIMS 1. An analgesic and anti-inflammatory compound having the formula: EMI10.1 wherein both R and R1 are hydrocarbon radicals. 2. The product of Claim 1 wherein R is an alkyl group having I to 15 carbon atoms. 3. The product of Claim 2 wherein said alkyl group is E straight chain alkyl group. 4. The product oi Claim 3 wherein said straight chain alkyl group has 7 to Il carbon Etoms. 5 The product of Claim 1 wherein R is a lower alkyl group. 6. The product of Claim 5 wherein R1 is 8 methyl, ethyl or propyl group. 7. A process for preparing an analgesic anti-inflammatory compound comprising the step of reacting an acetyl salicylic acid derivative with a monoglycol ester hEving the formula: EMI10.2 wherein R and R1 are hydrocarbon radicals.

Inventors: BATEMAN, NEIL E., WOODS, ROSS A.
Applicants: R.P. SCHERER CORPORATION
Application year: 1983
Main classification: C07C69
IPC codes: A61K31, C07C69, C07C67