NEW DERIVATIVES OF 1-ALKYLAMINE-(4(P-ALKYLOXY-BENZAMIDE)PHENOXY)-2-PROPANOL, HAVING BETA-SYMPATHOLYTIC ACTIVITY, THEIR SALTS, AND PRODUCTION PROCESSES THEREOF

Abstract: The invention comprises: - a derivative of 1-alkylamine-3-[4(p-alkyloxy-benz­ amide)phenoxy]-2-propanol of general formula I: where R₁ is a linear or branched alkyl chain with 1 to 8 carbon atoms included, an alkenyl chain with 2 to 8 carbon atoms included, or an arylalkyl chain with 7 to 10 carbon atoms included: R is a linear or branched alkyl group with 1 to 8 carbon atoms included or an aralkyl chain with 7-10 carbon atoms included. - a compound as above, in an optically active form; - pharmaceutically acceptable, non toxic salts of the above compounds; -synthesis processes for obtaining the above com­ pounds; and - a pharmaceutical composition based on a compound as defined above.

Description: SPECIFICATION The invention relates to new derivatives of 1alkylamine-3 [4(p-alkyloxybenzamide)phenoxy] 2-propanol, to pharmaceutical compositions containing said products, and to methods for producing and utilizing these 1 -alkylamine-3 24(p-alkyloxybenzamide)phenoxH 2-propanol derivatives. The main object of this patent is to provide a new group of compounds which present sympatholytic activity and can be used in the therapy of troubles induced by hyperactivity of the sympathetic nervous system. It is well known that many derivatives of 1-alkyl amine-3-phenoxy-2-propanol present beta-sympatholytic activity, but it is also known that these compounds are lacking in cardioselectivity while showing intensive liver metabolism and cardiac failure risk. Those products, as for example the 1-(p-acetamide-phenoxy)-3-isopropilamine- -2-propanol (A.F. Crowther, R. Howe, L.H. Smith J. Med. Chem. 14, 6, 511, 1971), which present ss1-cardioselectivity and poor liver metabolism, show, however, no chronotropic selectivity relative to the inotropism. On the contrary, compounds presenting chronotropic selectivity such as, for example, the 1-isopropil-amine-3- (2-methylindol-4- -yl)oxyg -2-propanol (Swiss 469.002), the (1-tert.butylamine -ethyl)-2,5-dimethoxybenzylalcohol (Levy, J. Pharmacol. Exp. Ther. 151, 413, 1966; Wilkenfels, Levy, Arch. Int. Pharmacodyn.Ther. 176, 218, 1968), have either no cardioselectivity or are more active on 2 receptors than on ss 1 receptors. The present invention relates to new compounds having an improved beta-sympatholytic activity, of general formula I: EMI2.1 where R1 is a linear or branched alkyl chain with 1 to 8 carbon atoms included, an alkenyl chain with 2 to 8 carbon atoms included, an arylalkyl chain with 7 to 10 carbon atoms included; R is a linear or branched alkyl group with 1 to 8 especially 1 - 6 carbon atoms included, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec. butyl, tert. butyl, pentyl, hexyl, heptyl or octyl; or R is an aralkyl chain with 7 - 10 carbon atoms included, such as benzyl, phenylethyl or phenylpropyl. It has been found that the new compounds of general formula I and the salts thereof are medicines which present improvedJ3-sympatholytic activity in that, besides having relevant ss 1-cardioselectivity, intrinsic sympathicomimetic activity and high biodisposability, they show also a high chronotropic selectivity. Non-limitative examples of compounds according, to the general formula I and included in the present invention are: 1) 1-isopropylamine-3- [4(p-methoxybenzamide)phenoxy] - 2-propanol (Form.I R=CH(CH3)2 R1=40OCH3) m.p. 174-176 C (Hydrochloride m.p. 208-210 C) I.R. (nujol) V (cm : 1640 (CO) H-NMR(DMSO) # (p.p.m.):1.15(d,2xCH3), 2.7-3.0(m,CH2+CH), 3,8-4.1(m,CH2+CH), 6.9-8.3 (m, 2xC6H4) 2) 1-t-butylamine-3- [4(p-methoxybenzamide)phenoxy - 2-propanol hydrochloride (Form.I R=C(CH3)3.HCl $R1=4OCH3) m.p. 210-212 C I.R. (nujol) V (cm-1) : 1650 (CO) H-NMR(D2O) # (p.p.m.):1.30(s, 3xCH3) 2.8-3.2(m, CH2+CH) 3.5(s, CH3) 3.7-4.4(m,CH2+CH) 6.5-7.6(m, 2xC6H4) 3) 1 [4(p-ethoxybenzamide)phenoxy]-3-isopropylamine-2 -proanol hydrochloride (Form.I R=CH(CH3)2XHCl R1=4-OC H ) m.p. 215-2170C I.R. (nujol) # (cm-1) : 1640 (CO) H-NMR(DMSO) # (p.p.m.) : 1.15(d, 2xCH3) 1.25(t,CH3) 2.8-3.6(m,CH2+CH) 3.8-4.3 (m, 2xCH2+CH) 6.8-8.0(m,2xC6H4)10.0(s,NH) 4) 1[4(p-allyloxybenzamide)phenoxy]-3-isopropylamine -2-propanol hydrochloride (Form.I R=CH(CH3)2.HCl R1=4-OCH2CH=CH2) m.p. 200-202 C I.R. (nujol) V (cm-1) : 1635 (CO) 5) 1-isopropylamine-3- [4-(p-propyloxy-benzamide)phenoxy] -2-propanol hydrochloride (Form.I R=CH(CH3)2.HCl R1=4-OC3H7) m.p. 224-225 C I.R. (nujol) V (cm-1) : 1635 (CC) H-NMR(DMSO) # (p.p.m.) : 0.95(t,CH3) 1.25(d,2xCH3) 1.75(s,CH2)2.8-3.4(m,CH2+CH) 3.7-4.4(m,CH2+CH) 4(t,CH2) 6.8-8.1(m,2xC6H4) 10.1(s,NH) 6) 1-isopropylamin3-30 [4(p-isopropyloxybenzamide)phenoxy] -2-propanol hydrochloride (Form.I R=CH(CH3)2 R1=40CH(CH3)2) m.p. 218-219 C I.R. (nujol) V (cm-1) : 1635 (CO) H-NMR(DMSO) # (p.p.m.) : 1.20(d,4xCH3)6.8-8.0(m,2xC6H4) 10.0(s,NH) 7) 1[4(p-butyloxybenzamide)phenoxy]-3-isopropylamine -2-propanol (Form.I R=CH(CH3)2 R1=4-OC4H9) m.p. 152-154 C I.R. (nujol) V (cm-1) : 1635 (CO) H-NMR(DMSO) # (p.p.m.) : 1.05(t, CH3)1.10(d,2xCH3) 1.3-2.0(m,2xCH2)2.7-3.1 (m,CH2+CH) 3.6-4.2 m, CH2+CH)6.8-8.1 (m,2xC6H4) 10.0(s,NH) 8) 1-isopropylamine-3-[4-(p-pentyloxybenzamide)phenoxy] - 2-propanol (Form.I R=CH(CH3) 2 R1=4-OC5H11) m.p. 157-159 C I.R. (nujol) \) (cm : 1635 (CO) H-NMR(DMSO # (p.p.m.): 0.95(t, CH3)1.0(d,2xCH3) 1.2-2.0(m,3xCH2)2.6-3.0 (m,CH2+CH) 3.8-4.3(m,CH2+CH)6.9-8.05 (m,2xC6H4)10.0(s,NH) 9) 1 r4(phexyloxybenzamide):phenoxy7 -3-isopropylamine- -2-propanol hydrochloride (Form.I R=CH(CH3)2HCl R1=4-OC6H13) m.p. 199-201 C I.R. (nujol) \) (cm : 1635 (C0) H-NMR(DMSO) # (p.p.m.) : 0.8(t,CH3)1.10(d,2xCH3) 1.3-1.9(m,4xCH2)2.9-3.6 (m,CH2+CH) 3.6-4.5(m,CH2+CH) 6.8-8.2 (m,2xC6H4)10.1(s,NH) 10) 10-isopropylamine-3-[4(p-octyloxybenzamide)phenoxy] -2-propanol (Form.I R=CH(CH3)2 R1=4-OC8H17) m.p. 116-118 C I.R. (nujol) # (cm-1) : 1645 (CO) 11) 1[4(p-benzyloxybenzamide)phenoxy]-3-isopropylamine -2-propanol hydrochloride (Form.I R=CH(CH3)2HCl R1=40CH2-C6H5) m.p. 217-220 C I.R. (nujol) V (cm-1) : 1645 (CO) H-NMR(DMSO) # (p.p.m.) : 1.3(d,2xCH3)2.8-3.2 (m,CH2+CH) 3.8-4.4(m,CH2+CH)5.2(s,CH2) 6.85-7.10(m,2xC6H4+C6H5) 12) 1-methylamino-3-[4-(p-methoxybenzamido)-phenoxy]-2-pro panol hydrochlorid. (Form.I R=CH3 R1 = 40CH3) m.p. 247-49'C I.R. (nujul) V (cm-1): 1645(CO) H-NMR (DMSO) # (p.p.m.): 2,6 (s,CH3), 2,9-3,5 (m, CH2+CH), 2,85 (S,CH3), 6,8-8,1 (m,2xC6H4) 13) 1-Benzylamino-3-[4-(p-methoxybenzamido)-phenoxy]2-propa nol hydrochlorid (Form.I R=CH2-C6H5 R1=4-OCH3) m.p. 263-5'C I.R. (nujol) V (cm-1) : 1640(CO) H-NMR(DMSO) # (p.p.m.): 3,05(m,CH2), 3,8 (s,CH3), 4,15(s,CH2), 6,8-8,05(m,2xC6H4) Non-limitative examples of pharmaceutically acceptable non-toxic salts of the compounds above mentioned are: chloride, bromide, iodide, phosphate, sulfate, tartrate, citrate, as well as methyliodide, methylbromide,ethylbromide, ethyl iodide. The optical isomers of the compounds of general formula I are also included in the present invention. Another object of the present invention is to provide the compounds having general formula II to be used as intermediate compounds for preparing the derivatives of general formula I: EMI8.1 R1 CONH m.p. (OC) position 4-CH3 4 236-8 4-C2H5 4 235-7 4-C3H7 4 223-5 4-isoC3H7 4 213-5 4-C4H9 4 217-20 4-C5H11 4 216-17 4-C6H13 4 205-7 4-C6H5CH2 4 242-44 It is a further object of this patent to provide processes for preparing the products of general formulae I and II. The compounds of general formula I can be prepared by starting from a compound of formula: EMI8.2 where R1 has the same meaning as in formula I, and M is a hydrogen atom or an alkali metal and reacting it with a compound of formula: EMI9.1 where R has the same meaning as in formula I, R2 is a group EMI9.2 or a group EMI9.3 where Al is a halogen atom. The reaction is preferably carried out in a solvent such as alcohol, dioxane, dimethylformamide, water. The compounds of general formula II can be obtained, for example, by starting from the chloride of the appropriate benzoic acid and aminophenol. The compounds of formula III can be prepared for example by starting from a 1,3-dihalogen-2-propanol or from epihalogenidrin with an amine having formula RNH2 where R has the same meaning as in formula I. The compounds of general formula I can also be prepared by reacting a compound of formula EMI10.1 where R1 has the same meaning as in formula I and R3 is a group EMI10.2 where Al is a halogen atom, with an amine having formula: NH 2R where R is defined as in formula I. In this reaction the solvent to be used is either an amine excess or a preferably polar solvent, as for example ethanol. The halogenidrin of formula IV can be obtained by reacting a compound of formula II with epihalogenidrin as for example epichloridrin. The epoxide of formula IV can be obtained through conventional methods, for example, by the already cited halogenidrin with sodium hydrate. The compounds of formula I can also be obtained through the reduction of a compound having formula EMI10.3 where R and R1 are defined as in formula I. The reduction of the compound V is preferably carried out with hydride, as for example sodium boron hydride. The compounds of formula V can be obtained by start ing from compounds of formula II with 1,3 3 dihalogen- acetone, as for example 1J 3-dichloroacetone, through the corresponding compound EMI11.1 and subsequent treatment with amine RNH2 where R is defined as in formula I. The present invention has the further object to provide a process for preparing optical isomers, according to the classical techniques used to separate said isomers from the racemic forms. For example, the compound in racemic form can be reacted with an optically active acid, followed by fractionated crystallization of the diastereoisomers mixture obtained with a suitable solvent, such as for example ethanol, and then the optically active derivative is freed from the salt by treatment with a base. The present invention has also the object to provide a process for preparing the esters derived by starting from compounds of formula I and following the classical methods of treating, for example, with anhydride or acid chloride. The derivatives of general formula I, as well as the corresponding esters, can be transformed into addition salts of acids or of alkylhalides through the conventional methods. The invention has also the object to provide pharmaceutical compositions including, as active ingredient, one or more derivatives according to the general formula I (or esters, or addition salts) in association with a pharmaceutically acceptable diluent or carrier. As appropriate compositions, there may be mentioned for instance, tablets, capsules, acqueous or oily solutions or suspensions, emulsions, or dispersing powders, pulverizing or aerosol compositions. The invention is illustrated but not limitated by the following examples: Example 1: 1-isopropylamine-3 [4(p-methoxybenzamide) phenoxy-2-propanol 0.02 mol of 4(p-methoxybenzamide)phenol are put into 120 ml of a 0.02 N potassium hydrate acqueous solution, then 0.045 mol of epichlorohydrin are added in 10 ml methanol and the mixture is kept stirring at room temperature for two days. The reaction product is filtered out, washed twice with water (50 ml), then the resulting crude epoxide is suspended in methanol (300 ml), to which water (0.5 ml) and isopropylamine (0.6 mol) are added. After stirring for two days at room temperature, the reaction product is filtered out, vacuum dried, and added to some water again. The reaction product, once crystallized, yields n-propanol m.p. 174-1760C. This product, dissolved into ether over anhydrous gaseous hydrochloric acid yields the hydrochloride (ethyl alcohol) m.p. 208-210 C. Example 2: 1-terbutylamine-3 [4(p-methoxybenzamide)phenoxy] - 2-propanol To 0.028 mol of crude 1-[4(p-methoxybenzamide)phenoxy] -2,3-epoxypropane, obtained as in example 1, and suspended in methanol (300 ml), water (0.5 ml) and ter-butylamine (0.6 mol) are added. After stirring for 48h at room temperature, the reaction product is filtered out, vacuum dried, taken up with acetone (20 ml! and subjected to @aseous hydrochloric acid: the precipitate thus obtained is filtered out and dissolved in water, and through alkalinization there is obtained a precipitate which is filtered, washed and dried: the latter, once dissolved in acetone and subjected to gaseous HCl, yields a hydrochloride (dioxane/isopropanol) (m.p. 210-212 C). Example 3: 1 [4(p-butyloxybenzamide)phenoxy]-3-iso propylamine- 2-propanol 0.08 mol of 4(p-butyloxybenzamide)phenol are heated for 6 h over b.m. in epichlorohydrin (0.64 mol) and piperidine (0.1 ml). The epichlorohydrin excess is distilled, then the reside is taken up with ether and filtered to the pump. The crude product 1 [4(p-butyloxybenzamide)phenoxy]- -3-chlorine-2-propanol thus obtained is suspended in methanol 500 ml; after addition of isopropylamine (1.8 mol), the product is stirred at room temperature for 48 hours and then filtered out. The filtrate is dried, taken up with acetone [15 ml), filtered and crystallized from ethanol: m.p. 152-154 C. Example 4: 1[4(p-allyloxybenzamide)phenoxy]-3-iso -ropyl arnine-2-propanol Q.OR mcl of 4(p-allyloxybenzamide)phenol are heated for 6 @ over b.m. in epichlorohydrin (0.64 mol) and piperidine (0.1 ml). The epichlorohydrin excess is distilled, then the residue is taken up with ether and filtered o the pump. The crude product 1[4(p-allyloxybenzamide)phenoxy] -3-chlorine-2-propanol thus obtained is suspended in methanol (1 lt) to which isopropylamine (1.8 mol) is added. After stirring for 72 h at room temperature, the product is filtered, dried, washed with water, filtered and dried again, and then the product is taken up with acetone and subjected to anhydrous gaseous hydrochloric acid to obtain the hydrochloride crystallized from isopropanol (m.p. 200-202 C). example 5 1 [4(p-ethoxybenzamide)phenoxy] -3-isopro- pylamine-2-propanol 0.02 mol of 4(p-ethoxybenzamide)phenol are put into 120 ml of a potassium hydrate 0.02 N acqueous solution, afterwards epichlorohydrin (OÓ45 mol) in methanol (10 ml) is added, followed by stir at room temperature for 48 h. The product is filtered, washed twice with water (50 ml) and the crude 1 [4(p-ethoxybenzamide)phenoxy] -2,3-epoxypropane is suspended in methanol (200 ml), and water (0.2 ml) and isopropylamine (0.5 mol) are added. After having stirred for two days at room temperature, the product is filtered and driers. It is dissolved in acetone and treated with anhydrous gaseous hydrochloric acid: the hydrochloride crystallized from isopropanol has m.p. of 215-217 C. Biological activity The betasympatholytic activity of the compounds under examination has been tested in vivo as antagonist to the± chronotropic effects (cardiac frequency increase), ),± 1-inotropic effects (systolic ejection velocity increase), and ss 2 effects (diastolic pressure a lowering) of the isoprenaline upon the ar3çsthetized and reserpenized rat, after oral administration, and in vitro as antagonist to the ss 1 chronotropic effects (cavy right atrium), ss 1 inotropic effects (cavy ventricle) and 2 2 effects (cavy trachea) of the isoprenaline. Through the in vivo and in vitro results it is evident that the 1-alkylamine-3[4(p-alkyloxybenzamide)phenoxy] -2-propanol derivatives, which are the object of the present invention, show-blocking activity of a competitive type and, on the contrary of 5 -blocking constituents as propranolol, they show cardioselectivity and inherent sympathicomimetic activity, the latter being revealed by the relevant increase of the cardiac frequency in the reserpenized animal at rest. The beta-sympatholytic activity of the 1-alkylamine -3 L4(p-alkyloxybenzamide) phenoxy -2-propanol compounds is in yivo significantly greater than the compounds such as propranolol which, although more active in vitro, are subjected to a relevant decrease of the in vivo activity owing to an intense liver metabolism. All these favourable characteristics, that is, cardioselectivity, inherent sympathicomimetic activity and lack of a significant power gap between vivo and vitro are also present in the 4-benzamide (or acetamide)phenoxy-3-isopropylamine-2- -propanol derivatives, such as for example 1-(4-benzamide phenoxy)-3-isopropylamine-2-propanol (Ralph Howe, Leslie Harold Smith U.S. 3.408.387; A.F. Crowther, R. Howe, L.H. Smith, J. Med. Chem. 14 (6), 511, 1971), 1 -chlorobenzamide)pnenoxy -3-isopropylamine-2-propanol (A.F. Crowther, R. Howe, L.M. Smith, J. Med. Chem. 14, (6), 511, 1971), practolol (Howe, Smith, U.S. 3.408.387; Scales, Cosgrove, J. Pharmacol. Exp. Ther. 175, 338, 1970). On the other hand, compared to the latter compounds, the 1 [4(p-alkyloxybenzamide)phenoxy]-3-isopropylamine-2 -propanol derivatives present also a new pharmacological characteristic, namely a significantly greater power to block the ss 1 chronotropic effects with respect to the ss 1 inotropic effects of the isoprenaline. The in vivo tests have shown that at certain dosage levels the compounds of this invention determine a significant beta -sympatholytic effect on the cardiac frequency (chronotropism) without a concurrent reduction of the myocardium contractility (inotropism). Since the antianginal activity of the beta-sympatholytic agents is performed through the reduction of the cardiac frequency (Bardaux A. et Eur. J. Pharmacol. 39, 287, 1966; Gross .J. and Falter Dc. J. Pharm. Exp. Ther. 203, 544, 1977)7the 1 [4(p-alkyloxybenzamide)phenoxy] -3 -isopropylamine-2-propanol derivatives should carry out, as compared to the beta-blocking agents of current use in therapy, a significant anti-ischemic action with a very minor risk of determining a hypocinetic condition of the myocardium which, in turn, is considered a decisive element for the appearance of angor crysis (Kaverina N.V. and Chumburidze V.B. Pharmac. Ther. 4, 109, 1979). It is also interesting to note that the 1 [4(p- -alkyloxybenzamide .... or 1 [4(m-alkyloxybenzamide) phenoxy3 3-isopropylamine-2-propanol derivatives, as well as the 1 [2(p-alkyloxybenzamide .... or 1 alkyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol derivatives, although endowed with -sympatholytic activity of a competitive type, with cardioselectivity, and with inherent sympathicomimetic activity, present a minor activity as compared to the corresponding deriva tives of the present invention, and in some cases they are lacking in chronotropic activity. From these results it will be apparent the fundamental importance of the full replacemont of the phenoxy roup with a p-alkyloxybenzamide group. The replacement of an alkyloxy group with another group will determine either a distinct reduction of activity or a loss of selectivity: a reduction of activity or a loss of selectivity will occur also by introducing more alkoxyl groups.

Claims: C L A I N S 1) A derivative of 1-alkylamine-3-[4(p-alkyloxybenzamide) phenoxy]-2-propanol of general formula I: EMI20.1 ere R1 is a linear or branched alkyl chain wit 1 *0 carbon atoms included, an alkenyl chain with 2 to 8 carbon atoms included, or an arylalkyl chain with 7 to 10 carbon atoms included: R is a linear or branched alkyl group with 1 to 8 carbon atoms included or an aralkyl chain with 7 - 10 carbon atoms included. 2) A compound as claimed in claim 1, in optically active form. 3) Pharmaceutically acceptable, non toxic salts of compounds according to claim 1. 4) Pharmaceutically acceptable, non toxic salts of compounds according to claim 2. ) A compound according to claim 1, selected from the group consisting of 1-isopropylamine 3 [4(p-metoxybenzamide) prenoxy]-2-propanol and a pharmaceutically acceptable salt thereof, 1-t-butylamine-3 [4(p-methoxybenzamide)phenoxy] -2-propanol and a pharmaceutically acceptable salt thereof, 1[4(p-ethoxybenzamide)phenoxy]-3-isopropylamine-2 -propanol and a pharmaceutically acceptable salt thereof, 1 p- allyloxybenzamide )phenoxy -3-isopropylamine-2propanol and a pharmaceutically acceptable salt thereof, 1-isopropylamine-3[4(p-propyloxybenzamide)phenoxy]-2 -propanol and a pharmaceutically acceptable salt thereof, 1-isopropylamine-3[4(p-isopropyloxybenzamide)phenoxy]-2 -propanol and a pharmaceutically acceptable salt thereof, 1 C4(p-butyloxybenzamide)pheno -3-isopropylamine-2 -propanol and a pharmaceutically acceptable salt thereof, 1-isopropylamine-3[4-(p-pentyloxybenzamide)phenoxy]-2 -propanol and a pharmaceutically acceptable salt thereof, 1[4(p-exyloxybenzamide)phenoxy]-3-isopropylamine-2 -propanol and a pharmaceutically acceptable salt thereof, 1-isopropylamine-3[4(p-octyloxybenzamide)phenoxy]-2 -propanol and a pharmaceutically acceptable salt thereof, 1[4(p-benzyloxybenzamide)phenoxy]-3-isopropilamine-2 -propanol and a pharmaceutically acceptable salt thereof 1-methylamino-3-[4-(p-methoxybenzamido)-phenoxy]-2propanol and a pharmaceutically acceptable salt thereof and 1-benzylamino-3-[4(p-methoxybenzamido)-phenoxy]-2 propanol and a pharmaceutically acceptable salt thereof. 5) Process of synthesis for obtaining the compounds according to claim 1, including the reaction between the suitable benzamidephenol, in alkaline ambient, and the appropriate 3-amino- 2-idroxy-l-halogen propane or the appropriate 3-amino- 1,2- epoxypropane. 7) Process of synthesis for obtaining the compounds according to claim 1, including the reaction of the suitable benzamidephenoxy epihalogenidrin (or epoxide) with the appropriate amine. 8) Process of synthesis for obtaining the compounds according to claim 1, including the reaction starting from the suitable benzamidephenol with a dihalogen acetone, subsequent treatment with the appropriate amine and then reduction into the corresponding alcohol. 9) A pharmaceutical composition comprising at least a compound according to claim 1, as active principle in association with a carrier. 10) A composition according to claim 9, in a suitable form for oral, parenteral or rectal administration.

Inventors: GHELARDONI, MARIO, GIANNOTTI, DANILO, GIOLITTI, ALESSANDRO, GRIMALDI, GUGLIELMO, MAGGI, CARLO ALBERTO, MANZINI, STEFANO, MELI, ALBERTO, PESTELLINI, VITTORIO
Applicants: A. MENARINI S.A.S.
Application year: 1983
Main classification: C07C103
IPC codes: C07C233