THIOPHENE DERIVATIVE HAVING A MUCOREGULATING AND ANTICOUGH ACTIVITY, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT

Abstract: Thiophen-2-carboxylate of 2-methyl-5-(1-hydroxy-1-­ methyl-ethyl)-cyclohexen-2-yl, having formula (I) is endowed with marked bronchosecretogogue, mucosecre­ tolytic and anti-cough characteristics.

Description: New compound having mucoregulating and anticough activity, process for its production and relative pharmaceutical compositions It is an object of the present invention the thiophen-2-carboxylate 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- hydroxy-1-methyl-ethyl)-2-cyclohexen-1-ol, or sobrerol (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 bronchosecretagogue and mucosecretolytic activi ty in cases of acute and chronic bronchitis with hypersecretive and obstructive component of the respiratory routes (R. Scuri et al., 11 Farmaco ed. Pr. , 1 (1980)). It has now unextectedly found that the ester of thiophen-2-carboxylic acid with sobrerol, that is compound I, possesses a bronchosecretogogue, mucosecretolytic and fluidifying activity higher than that of sobrerol and is moreover characterized by marked anti-cough properties, comparable to that of codeine. Thus, another object of the invention is provided by pharmacological compositions endowed with mucoregulating and anti-cough activities, containing as active principle compound (I). Finally, the invention relates to a process for the preparation of the thiophen-2-carboxylate of 2-methyl-5-( 1 -hydroxy-1 -methyl-ethyl) -cycloilexen- 2-yl, characterized by reacting thiophen-2-carbo xylic acid chloride (III) with sobrerol (II), according to the following scheme: EMI2.1 The reaction is suitably carried out in aprotic solvents, for example in ethers such as dimethyl ether, tetrahydrofuran, dioxane, and in presence of acidity acceptors. As such, tertiary bases are preferably used, such as pyridine or trie thylamine. One can operate at temperatures ranging from 0 and 400C, preferably at room tempera ture, The following example further illustrates without limiting it,the process according to the in invention. EXAMPLE 60 Grams of thiophen-2-carboxylic acid chloride are dissolved in 500 ml of anhydrous tetrahydrofuran; to this solution 30 ml of anhydrous pyridine and 60 g of sobrerol (in its dl-trans form), diluted in 500 ml of anhydrous tetrahydrofuran, are added. The mixture is allowed to react for two hours at room temperature. At the end, the solvent is evaporated under reduce pressure; the residue is diluted by ethylether and the organic phase is washed first with water, then with a saturated bicarbonate solution. The organic phase is dried over anhydrous sodium sulphate, fil tered and the solvent is evaporated under reduced pressure. The crude product so obtained is purified on a silica gel chromatographic co lumn, elating first with petroleum ether and the with a mixture of petroleum eter/ethyl e ther 1:1. 73 Grams of an oil impossible to crystallize, but perfectly pure in TIiC, are obtained. The compound so obtained, of a yellowish colour, is almost insoluble in water, and soluble in the common organic solvents. Elemental analysis: for C15H2003S (M.W. = 280.374) calcd.% C = 64.26; H = 7.19; S = 11.43 found % C = 64.09; H = 7.24; s = 11.38. The structure of compound I is confirmed by spectroscopical data. IR Spectrum (liquid film; values of absorption -1 bands are expressed in cm stretch 0 - H broad band 3560-3300 stretch C = 0 1710 stretch C - 0 1050 H1 NMR Spectrum (recorded in CDCl3; internal reference TMS; values of che mical shifts are expressed in #): CH3 1.2 (d, 6H, -C-CH3 1.3-2.5 (m, 9H, =C-CH3, CH2-CH-CH2, OHmobile); 5.5 (m, 1H, CH-O-CO); 5.8 (m, 1H, C=CH-); 7.1 (double t, 1H in C4 of thiophen ring); 7.5 ( " d, " " C5 " " " ) 7.8 ( " d, " " C3 " " " ) The bio-pharmacological characteristics of com pound (I) which will be hereinafter defined, for the sale of brevity, with the abbreviation AFP 862 have been determined as hereinunder described, Toxicity The acute toxicity has beed determined in Swiss mouse and in Wistar rat for different administra tion 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 862 is endowed with a very low acute toxicity ty. TABLE I - Acute toxicity of AFP 862 EMI5.1 <tb> Species <SEP> Administration <SEP> LD50- <SEP> (mg/kg) <tb> <SEP> route <SEP> 50 <tb> mouse <SEP> # <SEP> <SEP> os <SEP> # <SEP> <SEP> > 4000 <tb> <SEP> i.p. <SEP> 2500 <SEP> <tb> <SEP> rat <SEP> os <SEP> > 4000 <SEP> <tb> <SEP> i.p. <SEP> 2650 <SEP> <tb> Broncosecretagogue activity The broncosecretagogue activity has been determined in male We star rat by per os administration according to the method of Mawatari [Mawatari H., KAgoshima Daigaku, Igaku-Zasshi, 27, 561 (1976)], comparing AFP 62 with carboxymethylcysteine, so brerol and guaiphenesin at the doses hereinafter stated. The results are reported in the enclosed Table 2. TABLE 2 - Bronchosecretagogue activity (Mawatari technique) EMI6.1 <tb> impound <SEP> Administered <SEP> N <SEP> of <SEP> % <SEP> Increase <SEP> of <tb> <SEP> Dose <SEP> animals <SEP> FlNa(X) <SEP> in <SEP> com <SEP> <tb> <SEP> mg/kg/os <SEP> parison <SEP> with <SEP> <tb> <SEP> controls <tb> APP <SEP> 862 <SEP> 500 <SEP> 10 <SEP> 76.4 <tb> Carboxy <tb> methylxy <tb> steine <SEP> 500 <SEP> 10 <SEP> 39.7 <tb> <SEP> Sobrerol <SEP> 500 <SEP> 10 <SEP> 33.4 <tb> (*) FlNa = Sodium fluoresceine. From the resulting values a more marked activity of M"P 862 in the test under exam clearly turns out in comparison with reference drugs used at equlponderant 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 862 with carboxymethylcysteine and sobrerol at the dose hereinafter stated. The results are reported in the Table 3. TABLE 3 - Mucosecretolytic activity (technique) ol Giraldez et al.) EMI7.1 <tb> Compound <SEP> Dose <SEP> N <SEP> ani <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> <SEP> AFP <SEP> 862 <SEP> 500 <SEP> 10 <SEP> 54.1 <tb> <SEP> Carboxy <tb> methyl <tb> <SEP> cysteine <SEP> 500 <SEP> 10 <SEP> 40.2 <tb> <SEP> Sobrerol <SEP> 500 <SEP> 10 <SEP> 36.8 <tb> Prom the comparison of the results obtained by the test under exam the mucosecretolytic acti vity of AFP 862 results comparable to that of carboxymethylcysteine and sobrerol used at equi ponderant doses. 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 witti the same basal values (Boura and coll. - Prog. Brit. Pharmyc. Soc. Apr. 1970). As reference standard a group of condeine treated unimals at the done of 12.5 mg/kg has boen used TABLE 4 - Anti-cough activity EMI8.1 <tb> Treat- <SEP> Dose <SEP> N <SEP> ani <SEP> %Inhi <SEP> Statistical <SEP> si <tb> 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> 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> < <SEP> 0.05 <tb> AFP <SEP> 862 <SEP> 250 <SEP> 12 <SEP> 78.6 <SEP> p <SEP> < <SEP> 0.05 <tb> From the above stated results it becomes evident the very good anti-cough activity of AFP 862 in comparison with traditional standard of proved activity, in the used experimental conditions. Fluidifying activity "in vivo" The fluidifying effect has beed determined with the microviscosimeter on the tracheo-bronchial mucus from rabbit after administration by oral route, comparing AFP 862 with sobrerol, at the doses hereinafter stated. The results are reported in the enclosed Table 5. TABLE 5 - Fluidifying activity "in vivo" in the rabbit EMI8.2 <tb> Compound <SEP> # <SEP> <SEP> Dose <SEP> N <SEP> of <SEP> # <SEP> % <SEP> Reduction <SEP> of <SEP> the <tb> <SEP> mg/kg/os <SEP> animals <SEP> mucus <SEP> viscosity <tb> APP <SEP> 862 <SEP> 500 <SEP> 5 <SEP> <SEP> i9 <SEP> i <SEP> <tb> Sobrerol <SEP> 500 <SEP> 5 <SEP> <SEP> 15.t <SEP> <tb> As it turns out from the values obtained, the fluidifying activity of AFP 862 proves to be remarkably enhanced in comparison with the reference drug employed at equiponderant dose. Pharmac okinet i c s From the pharmacokinetics tests performed in the animal after oral administration of AFP 862 and sobrerol in equimolar doses, higher sobrerol concentrations at pulmonary level have been surprisingly noticed, as a demonstration of an higher pulmonary tropism for APP 862. Compound (I) is therefore fit as an elective drug with mucoregulating, mucolytic and anti-cough activities, in the therapy of acute and chronic diseases of the respiratory apparatus, particularly of acute and chronic bronchitis and of cough of any nature. The present invention refers also to all the industrially applicable aspects connected with the use of AFP 862 as mucoregulating and anti-cough agent. An essential aspect of the invention is therefore provided by pharmaceutical compositions containing predetermined amounts of AFP 862. Such a compound can be administered, particularly, by the oral route, as capsules, extemporary susnension, monodose sachets (in a granular state), or by aerosol; or as suppositories; or, finally, );; parenteral route (vials for innection). Of course, the sinFrle pharmaceutical forms will co;ltain trew active principle together with veihcles, excipients, flavouring agents etc. of conventional use in pharmaceutical technique.

Claims: Claims: 1. As a novel compound, the thiophen-2-carboxylate of 2-methyl-5-( 1 -hydroxy-1 -methyl-ethyl)- cyclohexen-2-yl, having formula (I) EMI11.1 2. Pharmaceutical composition endowed with bronchosecretogogue, mucosecretolytic and anticough activities, characterized by containing as active principle the compound of claim 1. 3. Process for the preparation of the thio phen-2-carboxylate of 2-methyl-5-( 1 -hydroxy-1 - methyl-ethyl)-cyclohexen-2-yl, having formula I, characterized by reacting thiophen-2-carbo xylic acid chloride (III) with sobrerol (II), according to the following scheme: EMI11.2 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 acceptors, such as triethylamine or pyridine. 6. Process according to claims 3-5, characteri zed by operating at temperatures ranging from about 0 to 400C, preferably at room temperature. Claims: 1. Process for the preparation of the thiophen2-carboxylate of 2-methyl-5-(1-hydroxy-1-methylethyl)-cyclohexen-2-yl, having formula (I) EMI13.1 characterized by reacting thiophen-2-carboxylic acid chloride (III) with sobrerol (II), according to the following scheme: EMI13.2 2. Process according to claim 1, characterized by operating in inert solvents, such as diethylether, tetrahydrofuran or dioxan. 3. Process according to claims 1-2, characteri zed by operating in the presence of acidity acceptors, such as triethylamine or pyridine. 4. Process according to claims 1-3, characte rized by operating at temperatures ranging from about 0 to 400C, preferably at room temperature.

Inventors: DE VINCENTIIS, LEONARDO
Applicants: AUSONIA FARMACEUTICI S.R.L.
Application year: 1982
Main classification: C07D333
IPC codes: C07D333