NEW COMPOUND HAVING ANALGESIC, ANTIINFLAMMATORY AND MUCOREGULATING ACTIVITIES, PROCESS FOR ITS PRODUCTION AND RELATIVE PHARMACEUTICAL COMPOSITIONS

Abstract: 2-Acetoxybenzoate of 2-methyl-5-(1-hydroxy-1-methyl­ ethyl)-cyclohexan-2-yl, having formula (I) is endowed with marked analgesic, antiinflammatory, mu­ coregulating activities.

Description: New compound having analgesic, antiinflammatory and mucoregulating activities, process for its production and relative pharmaceutical compositions It is an object of the present invention 2-acetoxybenzoate of 2-methyl-5-( 1 -hydroxy-1 -methyl- ethyl)-cyclohexen-2-yl, having formula (I) EMI1.1 The therapeutic properties of 2-methyl-5-(1-hy- droxy-1-methyl-ethyl)2-cyclohexen-1-ol, or sobre brerol (II) EMI1.2 are known since many years. It has been used for the treatment of respiratory diseases (V. Dalla Valle - Boll. Chim. Farm., 109, (1970)), and more exactly as fluidifying agent with bronchosecretago gue and mucosecretolytic activity i.z cares of ncu te and chronic bronchitis with hypersecretive and obstructive component of the respiratory routes (R. Scuri et al.,Il Farmaco ed Per. , 1 (1980)). On the other side, the pharmacological and therapeutic properties of 2-acetoxy-benzoic, or acetylsalicylic acid (ASA), are known to such an extent that is needless to dwell upon any longer. It has now unexpectedly found that the ester of acetylsalicylic acid with sobrerol, that is compound (I), while exhibiting a bronchosecre togogue activity higher than that of sobrerol and a imicosecretolytic and fluidifying activi ty comparable to that sobrerol itself, is moreover characterized by analgesic and antiinflammatory properties, comparable to that of ASA, in comparison with which it has however the advantage of a definitely lower gastrole sivity. Thus, another object of the invention is provided by pharmaceutical compositions endowed with antiinflammatory, analgesic and mucoregolating and anticough activities, containing as active principle compound (I). Finally, the invention relates to a process for the preparation of 2-acetoxybenzoate of 2-methyl-5-( 1 -hydroxy-1 -methyl-ethyl) cyclohexen-2-yl,characterized-by reacting 2-ace toxybenzoic acid chloride (III) with sobrerol (II) according to the following scheme: EMI3.1 The reaction is suitably carried out in aprotic solvents, for example in ethers such as diethyle ther, tetrahydrofuran, dioxane, and in presence of acidity acceptors. As such, tertiary bases are preferably used, such as pyridine or triethylamine. One can operate at temperatures ranging from10 and t0 C, preferably from about 20 and 800C. The following example further illustrates, with out limiting it, the process according to the invention. EXAMPLE To 90 g of ASA in 500 ml of benzene, 120 g of thionyl chloride are added. The mixture is reflu xed for three hours. At the end, the benzene is evaporated under reduced pressure to dryness. The acetylsalicylic acid chloride so obtained is dissolved in 500 ml of anhydrous tetrahydrofuran and added with 80 g of pyridine; to this solution 85 g of sobrerol (dl-trans form) are added. The reac tion is completed after two hours refluxing. At the end the solvent is evaporated under reduced pressure, the residue is washed with water and extracted with ethyl ether. The organic phase is washed with 0,5 N HCl and thereafter with water, then it is dried on anhydrous sodium sulphate and freed from solvent under reduced pressure. The crude product (130 g) is purified by chromatography on Florisil (100-200 mesh) eluting with petroleum ether and then with petroleum ether/ethyl ether 2:1. 75 Grams of a dense, yellowish oil are obtained, slightly so luble in water and easily soluble in organic solvents, pure in TIC. Its structure is confir med by analytical and spectroscopical data: Elemental analysis: for C19H24O5 (M.W. = 332.39) calcd. ffi C = 68.66; H = 7.28 found % C = 68.79; H = 7.33. I.R, Spectrum (liquid film; values of absorp- tion bands are expressed in cm-1 ) stretch 0 - H 3550-3400 broad bands stretch C - H aromatics 3080-2910 alifatics stretch C = 0 alifat. ester 1780 stretch C = 0 aroma. ester 1730 stretch C = C 1615 stretch C(=O) - 0 acetate 1145 stretch C(=O) - 0 arilyc 1255 HÚ NMR Spectrum (recorded in CDCl3, internal reference TMS; values of chemi cal shifts are expressed in 1.2 (d, 6H, 2(CH3)); 1.8 (s, 3H, =C-aH ); 3 1.4-2.2 (m, 6H, CH2-CH-CH2, OH mobile); 2.3 (s, 3H, aO-CH3); 5.3 (m, 1H, CH-O-CO); 5.8 (m, 1H, CH=C-CH3); 7-7.7 (m, 3H aromatics); 8 (double d, 1H aromatic). The bio-pharmaceutical characteristics of compound (I) which will be hereinafter defined, for the sake of brevity, with the abbreviation AFP 696 have been determined as hereinafter described. Toxicity The acute toxicity has been determined in Swiss mou se and in Wistar rat for different administration routes, according to the method of-Litchfield J.T. and Wilcoxon [J. Pharm. Exp. Therap. 96, 99-113, (1949)7. The results obtained are reported in the following Table I; from the same it can be pointed out how AFP 696 is endowed with a very low acute toxicity, TABLE I - Acute toxicity of AFP 696 EMI6.1 <tb> Species <SEP> Administration <SEP> route <SEP> LD50 <SEP> - <SEP> (mg/kg) <tb> <SEP> mouse <SEP> os <SEP> 3500 <tb> <SEP> i.p. <SEP> 1600 <tb> <SEP> rat <SEP> os <SEP> > 4000 <tb> <SEP> i.p. <SEP> 1950 <tb> Bronchosecretogogue activity The bronchosecretogogue activity has been determined in male Wistar rat by per os administration accor ding to the method of Mawatari [ Mawatari H., Kagoshima Daigaku Igaku-Zasshi, 27, 561 (1976)], comparing AFP-696 with carboxymethylcysteine and sobrerol at the doses hereinafter stated, The results are reported in the enclosed Table 2. TABLE 2 - Bronchosecretogogue activity (Mawatari technique) EMI6.2 <tb> impound <SEP> Administered <SEP> N <SEP> of <SEP> ffi <SEP> Increase <SEP> of <tb> <SEP> Dose <SEP> animals <SEP> FlNa(*) <SEP> in <SEP> com <tb> <SEP> mg/kg/os <SEP> parison <SEP> with <tb> <SEP> controls <tb> APP-696 <SEP> 500 <SEP> 10 <SEP> 63.6 <tb> Carboxy <tb> methylcy <tb> <SEP> steine <SEP> 500 <SEP> 10 <SEP> 39.7 <tb> <SEP> Sobrerol <SEP> 500 <SEP> 10 <SEP> 33.4 <SEP> <tb> (*) FlNa = Sodium fluoresceine. From the resulting values a more marked activity of AFP-696 in the test under exam clearly turns out in comparison with reference drugs used at equiponderant doses. Mucosecretolytic activity The mucosecretolytic activity has been studied in the male rabbit according to the technique of Giraldez, Grass and Bruseghini (Abstr. Comp. Int. Pharm N. 1086-Palis 1978), by administration by the oral route, comparing AFP-696 with carboxymethylcysteine and sobrerol at the dose hereinafter stated. The results are reported in the Table 3. TABLE 3 - Mucosecretolytic activity (tecnique of Giraldez et al.) EMI7.1 <tb> Compound <SEP> Dose <SEP> NO <SEP> ani <SEP> % <SEP> <SEP> Increase <SEP> of <SEP> se <tb> <SEP> mg/kg/os <SEP> mals <SEP> cretion <SEP> in <SEP> compa <tb> <SEP> rison <SEP> with <SEP> con <tb> <SEP> trols <tb> AFP-696 <SEP> 500 <SEP> 10 <SEP> 39.5 <tb> Carboxy <tb> <SEP> methyl <tb> <SEP> cysteine <SEP> 500 <SEP> 10 <SEP> 40.2 <tb> <SEP> Sobrerol <SEP> 500 <SEP> 10 <SEP> 36.8 <tb> From the comparison of the results obtained by the test under exam the mucosecretolytic activity of AIP-696 results comparable to that of carboxymethylcysteine and sobrerol used at equi ponderant doses. Antiinflammatory activity a) Carrageenin edema Tests have been performed on the rat, employing the test of the subplantar edema induced by carrageenin. AFP-695 and, for comparison, ASA, have been administered by oral route 30 minutes before carrageenin, at the doses herein after stated. After edema induction, the animals of each group have been controlled, every 60 mi nutes for 5 consecutive hours, in order to point out the evolution of the inflammatory pro cress The results obtained, expressed as volume of edematous limbs, are reported in the Table 4. From the comparison between the values of control rats and those of AFP-696 treated rats, it turns out the very good antiinflammatory activity of the latter, comparable to that of ASA, in the used experimental conditions and at the used doses. TABLE 4 -Antiinflammatory activity - subplantar edema by carrageenin in the rat. EMI9.1 Treatment <SEP> Dose <SEP> MEAN <SEP> LIMB <SEP> VOLUME <SEP> AT <SEP> DIFFERENT <SEP> HOURS <SEP> AFTER <SEP> AREA <tb> <SEP> mg/kg <SEP> TREATMENT <SEP> Absolute <SEP> % <SEP> Inhibi <tb> <SEP> os <SEP> value <SEP> tion <SEP> in <tb> <SEP> compari <SEP> 0 <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> son <SEP> with <tb> <SEP> controls <tb> Controls <SEP> - <SEP> 23.8 <SEP> 30.7 <SEP> 35.1 <SEP> 40.2 <SEP> 43.7 <SEP> 44.8 <SEP> 273.1 <SEP> Acetyl- <SEP> 250 <SEP> 24.3 <SEP> 27.4 <SEP> 32.2 <SEP> 37.8 <SEP> 38.6 <SEP> 38.6 <SEP> 181.28 <SEP> 33.6 <tb> salicylic <tb> acid <tb> AFP-696 <SEP> 500 <SEP> 24.1 <SEP> 28.1 <SEP> 31.4 <SEP> 37.4 <SEP> 38.1 <SEP> 38.1 <SEP> 183.0 <SEP> 33.0 <tb> Gastrolesive action Rats fasting since 18 hours have been treated by oral route with AFP-696 and, for comparison, with acetylsalicylic acid, at the doses hereinafter stated. 5 Hours and 30 minutes after treat ments, the animals have been sacrificed and the stomach has been withdrawn for gastric mucose examination. As it is possible to evidence from the results obtained, reported in the Table 5, the gastrolesivity of AFP-696, in the used experimental conditions, is by far lower than that of the reference drugs, TABLE 5 - Gastrolesive action EMI10.1 <tb> Treatment <SEP> Dose <SEP> Mean <SEP> ulcers'size <SEP> (mm) <tb> <SEP> mg/kg/os <tb> Controls <SEP> - <SEP> <SEP> O <SEP> <tb> Acetylsali <tb> cylic <SEP> <SEP> - <SEP> 100 <SEP> 3.9 <SEP> + <SEP> 1.2 <SEP> <tb> acid <tb> AFP-696 <SEP> 150 <SEP> 0.7 <SEP> + <SEP> 0.4 <tb> Analgesic activity The test of writhings by phenylquinone in the mouse has been used. AFP-696 has been administered by oral route at the dose of 500 mg/kg in comparison with acetylsalicylic acid at the dose of 250 mg. The two drugs have been administered per os 30 minutes after intraperitoneal injection of phe nil quinone. The very good analgesic activity of AFP-696, slightly lower than that of acetylsalicylic acid administered at equimolar doses, is shown from the results obtained and reported in the Table 6. TABLE 6 - Analgesic activity EMI11.1 <tb> Treat <SEP> Dose <SEP> Mean <SEP> N <SEP> % <SEP> Inhibi <SEP> N <SEP> animals <tb> ment <SEP> mg/kg <SEP> of <SEP> wri- <SEP> tion <SEP> in <SEP> with <SEP> wri <tb> <SEP> os <SEP> things <SEP> compari- <SEP> things <tb> <SEP> son <SEP> with <tb> <SEP> controls <tb> <SEP> Controls <SEP> = <SEP> 12.8 <SEP> 2.6 <SEP> # <SEP> 10/10 <SEP> <tb> Acetylsa- <SEP> 250 <SEP> 0.6+ <SEP> 0.5 <SEP> 95.3 <SEP> 1/10 <tb> <SEP> AFP-696 <SEP> 500 <SEP> 1.3+ <SEP> 0.9 <SEP> 89.8 <SEP> 3/10 <tb> Anti-cough activity The anti-cough activity of AFP-696 has been asses sed after administration by endoperitoneal route (30% in tween) on rabbits of both sexes, weighing 200-350 g, according to the method of the cough induced by citric acid aerosol administration, and evaluating the mean number of cough strokes in comparison with the same basal values (Boura and coll. - Prog. Brit Pharmac. Soc. Apr. 1970). As reference standard a group of codeine treated animals at the dose of 12.5 mrl/ktt has been used. TABLE 7 - Anti-cough activity EMI12.1 <SEP> Treat- <SEP> Dose <SEP> N <SEP> ani <SEP> % <SEP> Inhi <SEP> Statistical <SEP> si <tb> <SEP> ment <SEP> mg/kg <SEP> mals <SEP> bition <SEP> gnificance <SEP> (ba <tb> <SEP> in <SEP> com <SEP> sal <SEP> minus <SEP> final <tb> <SEP> parison <SEP> values) <tb> <SEP> controls <tb> <SEP> Controls <SEP> - <SEP> 12 <SEP> 26.7 <SEP> <tb> <SEP> Codeine <SEP> 12,5 <SEP> 12 <SEP> 76.7 <SEP> p <SEP> < <SEP> 0.05 <tb> <SEP> AFP-696 <SEP> 150 <SEP> 12 <SEP> 82.4 <SEP> p <SEP> < <SEP> 0.05 <tb> From the above stated results it becomes evident the very good anti-cough activity of AFP-696 in comparison with traditional standard of proved activity, in the used experimental conditions. Pharmacokinetics Two groups of rats have been treated per os, by gastric tube, with AFP-696 at the dose of 100 mg/kg and acetylsalicilyc acid at the dose of .54 mg/kg. At the moment of treatment rats were fasting since 18 hours. Rats have been then sacrificed in groups of 4 at different times: 30 min., 1 h, 2 h, 4 h, 6 h. The concentration both of unchanged products and of their metabolites have been measured by gaschromatography in plasma and in the lung. At 3(! minutes, and in some instance also at 1 hour, unchanged AFP-696 has been found in plasma showing that this product is at least par tially absorbed as such. The plasma levels of acetylsalicylic acid proved to be higher after administration of AFP-696 in comparison with the administration of acetylsalicylic acid at equimolar doses. The difference was more marked in the first two hours and it is relative to a better bioavailability for acetylsali cylic acid of about 200. Also pulmonary levels of salicylic acid proved to be higher after administration of AFP-696. Concentration ratios between lung and plasma in the case of salicylic acid were 0.8 for the admini stration of acetylsalicylic acid, and 1.1 for the administration of AFP-696. The experiment shows a particularly good oral bioavailability and a clear tropism for the lung. The compound (I) is therefore fit as an elective drug with analgesic, antiinflammatory, mucoregula ting and anti-cough, in the therapy of acute and chronic catarrhal diseases of respiratory apparatus, also ensuing from influenza and cold conditions. The present invention refers also to all the indu strially applicable aspects connected with the use of AFP-696 as analgesic, antiinflammatory, mucoregulating and anti-cough agent. An essential aspect of the invention is therefore provided b pharma ceutical compositions containing predetermined amounts of AFP-696. Such a compound can be admi nistered, particularly, by the oral route,as cae sules, extemporary suspension, monodose sachets (in a granular state); or by aerosol; or as suppositories; or, finally, by parenteral route (vials of injection). Of course, the single pharmaceutical forms will contain the active principle together with veichles, excipients, flavouring agents etc. of con ventional use in pharmaceutical technique.

Claims: Claims: 1. As a novel compound, 2-acetoxybenzoate of 2-methyl-5-(1-hydroxy-1-methyl-ethyl)-cyclohexen- 2-yl, having formula (I) EMI15.1 2. Pharmaceutical composition endowed with analgesic, antiinflammatory, mucoregulating and anti-cough activities, characterized by containing as active principle the compound of claim 1. 3. Process for the preparation of 2acetoxyben zoate of 2-methyl-5-(1-hydroxy-1-methyl-ethyl)-c;y clohexen-2-yl, having formula (I),characterized by reacting acetylsalicylic acid chloride (III) with sobrerol (II), according to the following scheme: EMI15.2 4. Process according to claim 3, characterized by operating in inert solvents, such as diethylether, tetrahydrofuran or dioxan. 5. Process according to claims 3-4, characterized by operating in the presence of acidity accede tors, such as triethylamine or pyridine. 6. Process according to claims 3-5, characterized by operating at temperatures ranging from about 10 to 1000C, preferably from 20 to 80 C. Claims EMI17.1 1. Process for the preparation of 2-acetoxybenzonate of 2-methyl-5-(1-hydroxy-1-methylethyl)-cyclohexen-2-yl, having formula (I) EMI17.2 characterized by reacting acetylsalicylic acid chloride (III) with sobrerol (II), according to the following scheme: EMI17.3 2. Process according to claim 1, characterized by operating in inert solvents, such as die thylether, tetrahydrofuran or dioxan. 3. Process according to claims 1-2, characte rized by operating in the presence of acidity acceptors, such as triethylamine or pyridine. 4. Process accordion to claims 1-3, characte rized by operating at temperatures ranging from about 10 to 1000C, preferably from 20 to 800C.

Inventors: DE VINCENTIIS, LEONARDO
Applicants: AUSONIA FARMACEUTICI S.R.L.
Application year: 1982
Main classification: C07C69
IPC codes: C07C69