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

Abstract: 2-(4-Isobutylphenyl)propionate of 2-methyl-5-(1-hy­ droxy-1-methyl-ethyl)-cyclohexen-2-yl, having formula is endowed with marked antiinflammatory, analgesic, muc­ oregulating and anti-cough activities accompanied by a very low gastrolesivity.

Description: New compound having antiinflammatory, analgesic and mucoregulating activity, process for its production and relative pharmaceutical compositions It is an object of the present invention 2-(4isobutyl-phenyl)propionate 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-hydro xy-1methyl-ethyl)-2-cyclohexen-1-ol, or sobrerol (II) EMI1.2 are known since many ears. It has been used for the treatment of respiratory diseases (V. Dalla Valle -Boll. Chim. Farm., 109, (1970)), and more exactly as fluidifying agent brochosecrertago due and macouecretolytie activity in crues of neu te and chronic bronchitis with hypersecretive and obstructive component of the respiratory routes (R. Scuri et awl., I1 Farmaco ed. Pr. i 1, (1980)). On the other side, the antiinflammatory properties of 2-(4-isobutylphenyl)-propionic acid (Ibuprofen, see e.g. Adams et al., Pharmacodyn. Ther. 178, 115 (1969)) are also known. It has now unexpectedly found that the ester of the acid 2-(4-isobutylphenyl)propionic with sobrerol, that is compound I, exhibits a broncho secretogogtie activity markedly higher than that of sobrerol, and it is besides characterized by antiinflammatory and analgesic properties, comparable and partially higher than that of Ibuprofen, showing contemporaneously a gastrolesivity clearly lower than that of the latter drug. Finally, compound (I) is also endowed with an appreciable anti-cough effect. 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-(4-isobutylphenyl)pro pionate of 2-methyl-S- (1 -hydroxy-1 -methyl-ethyl) - cyclohexen-2-yl,characterized by reacting the chloride of 2-(4-isobutylphenyl)-propionic acid (III) with sobrerol, 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 from 0 and 800C, preferably from about 25 and 500C. The following example further illustrates, with out limiting it, the process according to the invention. EXAMPLE To 55 g of chloride of 2-(4-isobutylphenyl)propio nic acid and 20 ml of anhydrous pyridine 41.6 g of sobrerol (dl-transform) dissolved in 400 ml of anhydrous tetrahydrofuran are added. Immediately, precipitation of pyridine hydrochloride occurs. The reaction mixture is heated to 450C and then, always under magnetic stirring, is left at room temperature for 45 minutes. At the end the solvent is evaporated under redu red pressure, the crude residue is washed with 1 litre of water and extracted three times with dimethyl ether. After having dried the organic phase on anhydrous sodium sulphate and evaporated the solvent by means of the rotatory evapora tor, 70 g of crude product are obtained, which is purified by Florisil chromatography (100-200 Mesh) eluting with petroleum ether, then with petroleum ether-diethyl ether 10:1. 49 Grams of a dense, yellowish oil are obtained, perfectly pure in thin layer chromatography, sub stantially insoluble in water, easily soluble in the common organic solvents. Its structure is confirmed by analytical and spectroscopical data. Elemental analysis: for C 23H3403 (M.w. = 358.49) calcd. % C = 77.05; H = 9.56 found % C = 76.88; H = 9.60. I.R. Spectrum (liquid film; absorption band va lues are expressed in cm 1): stretch 0 - H 3400-3250 stretch C = 0 1735 stretch C - 0 1205 H1 NMR Spectrum (recorded in CDCl3, internal re ference TMS; values of the che mical shifts are expressed in ): 0.65-1.2 (m, 12H, -CH(CH3)2, C(CH3)2); 1.3-2 (m, 12H, CH2-OH-CH2, CH2-CH, CH3-CH, OH mo bile); 2.3 (d, 3H, =C-CH3); 3.5 (q, 1H, CH3-CH-CO); 4.7-5 (m, 1H, -CH-O-CO); 5.3-5.6 (m, 1H, =CH-CH2); 6.6-7 (m, 4H, aromatics). The bio-pharmaceutical characteristics of compound (I) which will be hereinafter defined, for the sake of brevity, with the abbreviation AFP 695,have been determined as follows. 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 ssJ. 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 695 is endowed with a very low acute toxicity. TABLE I - Acute toxicity of AFP 695 EMI5.1 <tb> Species <SEP> Administration <SEP> route <SEP> LD50 <SEP> - <SEP> (mg/kg) <tb> <SEP> mouse <SEP> os <SEP> 1800 <tb> <SEP> rat <SEP> os <SEP> 2200 <tb> Bronchosecretogogue activity The bronchosecretogogue activity has been determined in male We star rat by per OB administration accor ding to the method of Mawatari # Mawatari H., Kagoshima Daigaku Igaku-Zasshi, 27, 561 (1976)/, comparing AFP-695 with carboxymethylcysteine and sobrerol at the doses hereinafter stated. The results are reported in the enclosed Table 2. TABLE 2 - Bronchos ecret ogogue activity (Mawatari technique) EMI6.1 <tb> Compound <SEP> Administered <SEP> N of <SEP> %Ingrease <SEP> of <tb> <SEP> Dose <SEP> animals <SEP> FINa(*) <SEP> in <SEP> com <tb> <SEP> mg/kg/os <SEP> parisen <SEP> with <tb> <SEP> controls <tb> APM-695 <SEP> 500 <SEP> 10 <SEP> 51.6 <tb> Carboxy- <SEP> <tb> methylcy <tb> steine <SEP> 500 <SEP> 10 <SEP> 39.7 <tb> Sobrerol <SEP> 500 <SEP> 10 <SEP> 33.4 <tb> (*) FiNa = Sodium fluoresceine. From the resulting values a more marked activity of AFP-695 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-Paris 1978), by administration by the oral route, comparing AFP-695 with carboxymethylcysteine and sobrerol at the dose hereinafter stated. The results are reported in the Table 3. TABLE 3 - Mucosecretolytic activity (tecnique of Giraldez etKal.) EMI7.1 <tb> Compound <SEP> Dose <SEP> N <SEP> ani <SEP> %Increase <SEP> of <SEP> se <tb> <SEP> mg/kg/os <SEP> mals <SEP> cretion <SEP> in <SEP> compa <tb> <SEP> rasion <SEP> with <SEP> con <tb> <SEP> trols <tb> <SEP> AFP-695 <SEP> 500 <SEP> 10 <SEP> 35.7 <tb> <SEP> 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 AFP-695 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, ibu profen, 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 cesse 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-695 treated rats, it turns out the very good antiinflammatory activity of the latter, comparable to that of ibuprofen, 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> AT <SEP> DIFFERENT <SEP> HOURS <SEP> AFTER <SEP> AREA <tb> <SEP> mg/kg <SEP> TREATMENT <SEP> Absolute <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> Ibuprofen <SEP> 100 <SEP> 22.5 <SEP> 26.7 <SEP> 28.9 <SEP> 29.8 <SEP> 32.4 <SEP> 35.5 <SEP> 152.4 <SEP> 44.2 <tb> AFP-695 <SEP> 150 <SEP> 22.8 <SEP> 27.2 <SEP> 29.2 <SEP> 29.6 <SEP> 31.4 <SEP> 32.6 <SEP> 34.9 <SEP> 159.2 <SEP> 42.8 <tb> b) Pleuritis by carrageenin It has been used the method described by Vinegar and Co-workers (Vinegar R., Irvaux J.F., Selph J.I. Proc. Soc. Exp. Biol. Med. 143, 3 (1973). Sprague-Dawley rats of both sexes, weighing 150-200 g, have been used, The animals have been divided in groups "at random" and left fasting since the preceding day, with water "ad libitum". The compounds under exam have been administered by the oral route, 30 minutes before of the intrapleural injection, at the doses hereinafter stated. The results are described in the enclo Bed Table 5, Table 5-Pleuritis by carrageenin EMI11.1 Treatment <SEP> Doses <SEP> N <SEP> ani <SEP> Hours <SEP> Volume <SEP> %Inhibition <SEP> %Leuco- <SEP> %Inhi <tb> <SEP> mg/kg <SEP> mals <SEP> in <SEP> comparison <SEP> cytes <SEP> bition <tb> <SEP> os <SEP> with <SEP> controls <SEP> x <SEP> 1000 <SEP> in <SEP> com <tb> <SEP> parison <tb> <SEP> with <SEP> con <tb> <SEP> trols <tb> Controls <SEP> 10 <SEP> 5 <SEP> 0.98 <SEP> - <SEP> 17.120 <SEP> <SEP> 24 <SEP> 0.90 <SEP> - <SEP> 18.460 <SEP> AFP-695 <SEP> 100 <SEP> 10 <SEP> 5 <SEP> 0.57 <SEP> 41.84 <SEP> 4.970 <SEP> 70.91 <tb> <SEP> 24 <SEP> 0.48 <SEP> 51.02 <SEP> 7.220 <SEP> 60.89 <tb> Ibuprofen <SEP> 100 <SEP> 10 <SEP> 5 <SEP> 0.54 <SEP> 44.90 <SEP> 4.420 <SEP> 74.18 <tb> <SEP> 24 <SEP> 0.79 <SEP> 19.39 <SEP> 17.430 <SEP> 5.58 <tb> From the comparison of the results it turns out that AFP-695 causes a 41.84g decrease of the exudate (provoked by pleuritis by carragee nin) at the fifth hour after animals"treatment, and a 70.91% decrease of the number of leucocz tes present at the same hour (decreases of the same order of magnitude than those provoked by the reference drug, used at equiponderant doses). At the 24 hours AFP-695 exerts a protective action by far higher than that of ibuprofen: in fact AFP-695 yet exerts &alpha;51.02% decrease of the exudate volume, in comparison with control, and a 60,89% decrease of leucocytes number, whilst the reference drug decreases the exudate volume only of 19.39% and leucocytes number of 5.58%. Such an experiment, considering that the two drugs have been used at equiponderant doses and not equimolar, and taking into account, besides to the volume of pleuric exudate, also the count of leucocytes present, shows an antiinflam matory activity higher in absolute way and of longer duration of AFP-695 in comparison with the reference drug. Such an higher pharmacological activity is probably due to BP-695 pulmona ty tropism shown by the pharmacokinetics study (see following pages). Gastrolesive action Rats fasting since 18 hours have been treated by oral route with AFP-695 and, for comparison, with Ibuprofen, at the doses hereinafter stated. 5 Hours and 30 minutes after treatments, the animals have been sacrificed and the stomach has been withdrawn for gastric mucosa examination. As it is possible to evidence from the results obtained, reported in the Table 6, the gastrolesivity of AFP-695, in the used experimental conditions, is by far lower than that of the reference drugs. TABLE 6 - Gastrolesive action EMI13.1 <tb> Treatment <SEP> Dose <SEP> Mean <SEP> ulcers <SEP> size <SEP> (mm) <tb> <SEP> mg/kg/os <SEP> <tb> Controls <SEP> - <SEP> <SEP> O <SEP> <tb> Ibuprofen <SEP> 100 <SEP> 9.6 <SEP> # <SEP> <SEP> 1.8 <tb> AFP-695 <SEP> 150 <SEP> 0.9 <SEP> # <SEP> <SEP> 0.3 <tb> Analgesic activity The test of writhings by phenylquinone in the mouse has been used. AFP-695 has been administered by oral route at the dose of 100 mg/kg in comparison with ibuprofen at the same doses. The two drugs have been administered per os 30 minutes after intraperitoneal injection of phe nylquinone The very good analgesic activity of AFP-695, sli ghtly lower than that of ibuprofen administered at equiponderant doses, is shown from the results obtained and reported in the Table 7. TABLE 7 - Analgesic activity - Writhing by phenyl quinone in the mouse EMI14.1 <tb> <SEP> Trest <SEP> Dose <SEP> Mean <SEP> N <SEP> %Inhibi <SEP> N <SEP> animals <tb> ment <SEP> mg/mg <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> Controls <SEP> 012.8 <SEP> + <SEP> 2. <SEP> 1 <SEP> 10/10 <SEP> <tb> <SEP> Ibuprofen <SEP> 100 <SEP> 1.3 <SEP> # <SEP> <SEP> 0.5 <SEP> 89.84 <SEP> 1/10 <tb> <SEP> AFP-695 <SEP> 100 <SEP> 3.7 <SEP> # <SEP> <SEP> 1.2 <SEP> 71.09 <SEP> 3/10 <tb> Anti-cough activity The anti-cough activity of AFP-695 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 colt. - Prog. Brit. Pharmac. Soc. Apr. 1970). As reference standard a group of codeine treated animals at the dose of 12.5 mg/kg has been used. TABLE 6 - Anti-cough activity EMI15.1 <tb> Terat- <SEP> Dose <SEP> N <SEP> ani <SEP> %Inhi <SEP> Statistical <SEP> ai <tb> ment <SEP> mg/mg <SEP> mals <SEP> bition <SEP> ghificance <SEP> (ba <tb> <SEP> in <SEP> com <SEP> sal <SEP> minus <SEP> final <tb> <SEP> parison <SEP> values) <tb> <SEP> with <tb> <SEP> controls <tb> Controls <SEP> - <SEP> 12 <SEP> 26.7 <SEP> <tb> Codeine <SEP> 12.5 <SEP> 12 <SEP> 76.7 <SEP> p <SEP> < 0.05 <tb> AFP-695 <SEP> 150 <SEP> 12 <SEP> 78.1 <SEP> p <SEP> < <SEP> 0.05 <tb> From the above stated results it becomes evident the very good anti-cough activity of AFP-695 in comparison with traditional standard of proved activity, in the used experimental conditions. Pharmagokinetios Two groups of rats have been treated per os, by gastric tube, with AFP-695 at the dose of 100 mg/kg; as a referance standard ibuprofen at the dose of 58 mg/kg g has been used. 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 30 minutes, and in some instance also at t hour, unchanged AFP-695 has been found in pla sma showing that this product is at least partially absorbed as such. The plasma levels of Ibuprofen proved to be higher after administration of AFP-695 in comparison with the administration of Ibuprofen at equimolar doses. The difference (about 15%) was more marked in the first two hours and it is relative to a better bioavailability for Ibuprofen. Also pulmonary levels of Ibuprofen turned out higher after administration of AFP-695. The concentrations ratios between lung and plasma in case of Ibuprofen were 0.6 for Ibuprofen administration and 0.8 for AFP-695 administration. Compound (I) is therefore fit as an elective drug with antiinflammatory, analgesic, mucoregulating and anti-cough activities, in the therapy of acute and chronic tracheo-bronchopulmonary diseases on inflammatory basis asso ciated with catarrh, cough and algic synthoma thology. The present invention refers also to all the industrially applicable aspects connected with the use of AFP-695 as antiinflammatory, analge sic, mucoregulating and anti-cough agent. An essential aspect of the invention is therefore provided by pharmaceutical compositions containing predetermined amounts of AFP-695. Such a compound can be administered, particularly, by the oral route, as capsules, extemporary su spension, monodose sachets (in a granular sta te); or by aerosol, or as suppositories; or, finally, by parenteral route (vials for injec tion). Of course, the single pharmaceutical forms will contain the active principle together with vei chles, excipients, flavouring agents etc. of conventional use in pharmaceutical technique.

Claims: Claims: 1. As a novel compound, 2-(4-isobutylphenyl) propionate of 2-methyl-5-( 1 -hydroxy-1 -methyl- ethyl)-cyclohexen-2-yl, having formula I EMI18.1 2. Pharmaceutical compositions endowed with antiinflammatory, bronchosecretogogue, analge sic, mucoregulating and anti-cough activity, characterized by containing as active principle the compound of claim 1. 3. Process for the preparation of 2-(4-iso butylphenyl )-propionate of 2-methyl-5-( 1 -hy- droxy-1-methyl-ethyl)-cyclohexen-2-yl, having formula I, characterized by reacting the chlo ride of 2-(4-isobutylphenyl)propionic acid (III) with sobrerol (II), according to the following scheme: EMI19.1 4. Process according to claim 3, characterized by operating in inert solvents, such as diethyle then, tetrahydrofuran or dioxan. 5. Process according to claims 3-4,characterized by operating in the presence of acidity acceptors, such as triethylamine or pyridine. 6. Process according to claims 3-5, characteri zed by operating at temperatures ranging from about 0 to 800C, preferably from 25 to 50to. Claims: 1. Process for the preparation of 2-(4-isobutylphenyl)-propionate of 2-methyl-5-( 1-hy- droxy-1 -methyl-ethyl)-cyclohexen-2-yl, having formula (i) EMI20.1 characterized by reacting the chloride of 2 (4-isobutylphenyl)propionic acid (III) with sobrerol (II), according to the following sche me: EMI20.2 2. Process according to claim 1, characteri zed by operating in inert solvents, such as diethylether, tetrahydrofuran or dioxan. 3. Process according to claims 1-2, characterized by operating in -the presence of acidi ty acceptors, such as triethylamine or pyridine. 4. Process according to claims 1-3, characte rized by operating at temperatures ranging from about 0 to 800C, preferably from 25 to 5O0C.

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