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

Abstract: 5-[(2-methoxy-phenoxy)carbonyloxy]-α,α,4-trimethyl-3-­ cyclohexen-1-methanol, having formula (I) is endowed with marked mucoregulating and fluidifying characteristics.

Description: New compound having mucoregulating and fluidifying activity, process for its production and relative pharmaceutical compositions The present invention relates to 5-[(2-metho xy-phenoxy)carbonyloxy]-&alpha;,&alpha;,4-trimethyl-3 cyclohexen-i-methanol, having formula (I) EMI1.1 The therapeutic properties of 2-methyl-5-(1-hydro xy-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 bronchosecretago gue and mucosecretolytic activity in cases of acu te and chronic bronchitis with hypersecretive and obstructive component of the respiratory routes (R. Scuri et al., 11 Farmaco ed. Pr. 36, 1 (1980)). On the other side, the expectorant properties of 2-methoxyphenol, or guaiacol, are well known. It has now unexpectedly found that the mixed carbonate of guaiacole and sobrerole, that is compound having formula (I), exhibits bronchosecretogogue and fluidifying properties markedly higher than that both of guaiacol and of sobrerol, with a mucosecretolytic activity comparable to that of the two compounds herewith referred to. Thus, another object of the invention is provided by pharmaceutical compositions endowed with mucoregulating and fluidifying activities, containing as active principle compound (I). Finally, the invention relates to a process for the preparation of 5-/(2-methoxy-phenoxy)carbo- nyloxy]-&alpha;,&alpha;,4-trimethyl-3-cyclohexen-1-metha- nol, characterized by reacting guaiacol chlorocarbonate(III)with sobrerol (II), according to the following scheme: EMI3.1 The reaction is carried out in aprotic solvents, for example in ether such as diethylether, te trshydrofuran, 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 5 to 100 C, preferably from 20 and 8000. The following example further illustrates, without limiting it, the process according to the invention. EXAMPLE a) 124 Grams of guaiacol are dissolved in 500 ml of a 20% phosgene solution in toluene, keeping the temperature within 5 C; 130 g of N,N-dimethylaniline, diluted in 300 ml of benzene, are added, keeping the temperature below 1500. When the addition is over the solution is kept under stirring at room temperature for 30 minutes. The reaction mixture is then washed with water and then with diluted H2S04. The separated organic phase is dried on anhydrous sodium sulphate, filtered and concentrated under reduced pressure to dryness. The crude guaiacol chlorocarbonate is distilled at the mechanical pump; 150 g of pure product are then collected at the temperature of 5000/0.15 mm Hg. b) To a stirred solution of 70 g of sobrerol (dl-trans form) in 500 ml of tetrahydrofuran, 80 g of guaiacol chlorocarbonate dissolved in 200 ml of tetrahydrofuran are first added and then, in portions, 40 g of pyridine. The tempe rature raises to about 60 C, while a precipita te is formed. Stirring is continued for about two hours, the solvent is then evaporated under reduced pressure, the residue is treated with 500 g of water and ice, the oil is extracted with ether. The ether phase is washed with 2% acqueous HOl, then with water, thereafter with saturated soluzione of NaHCO3. By solvent's evaporation to dryness a semi solid product is obtained which is re-crystallized from diisopropylether (the solution is cooled to 0 C). In such a way 94.4 g of compound (I) are obtai ned, m.p. 62 C, almost insoluble in water, so luble in alcohols, acetone,diethylether,chloro form. The structure of compound (I) is confirmed by analytical and spectroscopical data. Elemental analysis: for C18H2405 (M.W.= 320.38) calcd. % C = 67.48; H = 7.55 found ffi C = 67.62; H = 7.59. I.R, Spectrum (nujol mull; absorption bands va -1 lues are expressed in cm 1) stretch 0 - H 3550-3450 stretch C - H aromatics 3080 stretch C - H alifatics 2980-2840 stretch C n O carbonate 1770 stretch C = C 1620 HÚ NMR Spectrum (record in CDCl3, internal reference TMS ; values of che mical shifts are expressed in: 1.2 (d, 6H, 2(CH)); 1.8 (d, 3H, =C-CH3); 1.4-2.3 (m, 6H, CH2-CH-C , OH mobile); 3.8 (s, 3H, OCH3); 5.3 (m, 1H, CH-O-CO); 5.8 (m, 1H, =CH-CH2); 6.8-7.3 (m, 4H aromaties). The bio-pharmacological characteristics of compound (I) - which will be hereinafter defined, for the sake of brevity, with the abbreviation AFP 736 - have been determined as hereinunder described. Toxicity The acute toxicity has been determined in Swiss mouse and in Wistar rat for different administra tion routes, according to the method of Litchfield J.T. and Wilcoxon ZJ. Pharm. Exp. Therap. 96, 99-113 (1949)]. The results obtained are reported in the following Table I; from the same it cah be pointed out how AFP 736 is endowed with a very low acute toxicity. TABLE I - Acute toxicity of AFP 736 EMI6.1 Species <SEP> Administration <SEP> LD50 <SEP> - <SEP> (mg/kg) <tb> <SEP> route <tb> <SEP> mouse <SEP> os <SEP> 3100 <tb> <SEP> i.p. <SEP> 1750 <tb> <SEP> rat <SEP> os <SEP> > 4000 <tb> <SEP> i.p. <SEP> 2340 <tb> Bronchsecrstogegus activity The bronchosecretogogue activity has beed deter mined in male Wistar rat by per os administration according to the method of Mawatari [Mawatari H., Kagoshima Daigaku, Igaku-Zasshi, 27, 561 (197627, comparing AFP 736 with carboxymethylcysteine, sobrerol and guaiphenesin at the doses hereinafter stated. The results are repor ted in the enclosed Table 2. TABLE 2 - Bronchosecretogogue activity (Mawatari EMI6.2 <tb> compound <SEP> # <SEP> <SEP> Administred <SEP> # <SEP> <SEP> N <SEP> of <SEP> # <SEP> <SEP> % <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> AFP <SEP> 736 <SEP> 500 <SEP> 10 <SEP> 79.3 <tb> Carboxy <tb> methylcy <tb> steine <SEP> 500 <SEP> 10 <SEP> 39.7 <tb> Sobrerol <SEP> 500 <SEP> 10 <SEP> 33.4 <tb> Gusiphe- <SEP> 500 <SEP> 10 <SEP> 12.6 <tb> nesine <tb> (*) FlNa = Sodium fluoresceine. From the resulting values a more marked activity of AFP 736 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 736 with carboxymethylcysteine and sobrerol at the doses 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> /'o <SEP> <SEP> Increase <SEP> of <SEP> se <tb> <SEP> mg/kg/os <SEP> mals <SEP> cretion <SEP> in <SEP> compz <SEP> <tb> <SEP> rison <SEP> with <SEP> con <tb> <SEP> trols <tb> <SEP> AFP <SEP> 736 <SEP> 500 <SEP> 10 <SEP> 45.5 <tb> Carboxy <tb> 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 736 results comparable to that of carboxymethylcysteine used at equiponderant doses and remarkably higher than that of sobrerol, always at equiponderant doses, Fluidifying activity "in vivo" The fluidifying effect has been determined with the microviscosimeter on the tracheo-bronchial mucus from rabbit after administration by oral route, comparing AFP 736 with sobrerol and guaiacol, at the doses hereinafter stated. The results are reported in the enclosed Table 4. TABLE 4 - Fluidifying activity "in vivo" in the rabbit EMI8.1 <tb> <SEP> Compound <SEP> Dose <SEP> NO <SEP> ani <SEP> % <SEP> Reduction <SEP> of <tb> <SEP> m <SEP> vk <SEP> vos <SEP> mals <SEP> mucus <SEP> viscosi <tb> <SEP> ty <tb> APP <SEP> 736 <SEP> 500 <SEP> 5 <SEP> 32.2 <tb> <SEP> Sobrerol <SEP> 500 <SEP> 5 <SEP> 15.6 <tb> <SEP> Guaiacol <SEP> 500 <SEP> 5 <SEP> 4.1 <tb> As it turns out from the values obtained the fluidifying activity of AFP 736 proves to be remarkably enhanced in comparison with referen ce drugs employed at equiponderant doses. Compound (I) is therefore fit as an elective drug with mucoregulating and fluidifying activity, in the therapy of acute and chronic disea ses of the respiratory apparatus, particularly of bronchitis, laryngo tracheitis, cough accom panied by catarrh. The present invention refers also to all the industrially applicable aspects connected with the use of AFP 736 as mucoregula ting and fluidifying agent. An essential aspect of the invention is therefore provided by phar maceutical compositions containing predetermi ned amounts of AFP 736. Such a compound can be administered, particularly, by the oral route, as capsules, extemporary suspension, monodose sachets (in a granular state); or by aerosol; or as suppositories; or, finally, by parenteral route (vials for injection). Of course, the single pharmaceutical forms will contain the active principle together with veichles, excipients, flavouring agents etc. of conventional use in pharmaceutical technique.

Claims: Claims: 1. As a novel compound, 5-Z(2-methoxy-pheno xy)carbonyloxy]-&alpha;,&alpha;,4-trimethyl-3-cyclohexan- 1-methanol, having formula (I) EMI10.1 2. Pharmaceutical compositions endowed with bronchosecretogogue, mucosecretolytic and anticough activity, characterized by containing as active principle the compound of claim 1. 3. Process for the preparation of 5-T2-metho xy-phenoxy)carbonyloxy]-&alpha;,&alpha;,4-trimethyl-3-cy- clohexen-1-methanol, having formula (I), charac terized by reacting guaiacole chlorocarbonate (III) with sobrerol (II), according to the following scheme: EMI10.2 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 5 to1000C, preferably from 20 to 800C. Claims: 1. Process for the preparation of 5-[(2-metho xy-phenoxy) carbonylox27- Ok, ck , 4-trimethyl-3-cy- clohexen-1-methanol, having formula (I) EMI12.1 characterized by reacting guaiacole chlorocarbo nate (III) with sobrerol (II), according to the following scheme: EMI12.2 2. Process according to claim 1, characterized by operating in inert solvents, such as diethylether, tetrahydrofuran or dioxan. 3. Process according to claim 1-2, characterized by operatin 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 5 to 100 C, preferably from 20 to 80 C.

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