THIOPHENE RING-SUBSTITUTED ALPHA-(ALKYLAMINOPROPIONYL)-THIOPHENE DERIVATIVES, A PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The invention relates to thiophene ring-substituted α-(al­ kylaminopropionyl)-thiophene derivatives having the general formula (I); wherein X is methyl or chlorine, R is alkyl, linear or branched, having 3 to 4 carbon atoms, and the nontoxic addition salts thereof, as well as to a process for preparing these com­ pounds and to pharmaceutical compositions containing these compounds. These compounds are useful for treating depressions.

Description: The present invention relates to thiophene ring-substituted d-(alkylaminopropionyl )-thiophene derivatives of the general formula (I): EMI1.1 wherein X is a group different from hydrogen selected between methyl or chlorine and R is a linear or branched chain-alkyl group having 3 to 4 carbon atoms, and the ncntoxic addition salts thereof, as well as to a process ror preparing these compounds and to pharmaceutical compositions containing these compounds. The prererred addition salts are the hydrochlorides. The compounds of the present invention may be prepared according to the following scheme: EMI1.2 Bromine displacamant 'n the compunds Gt formula II, where in X is as defined above for (I), by-the a;ninas ot formula(III), wherein R is as defined above for (I), occurs in an inert medium,preferably acetonitrile, and at a maximal temperature of 50 C, followed by vacuum evaporation of solvent, removal and evaporation to dryness or extracts. From the residue thus obtained, corresponding to the compounds of formula (I), it is possible to form their pharmaceutically acceptable salts, preferably hydrochlorides, by treating the respective acids in an inert solvent; aliphatic-chlorinated hydrocarbons especially methylene chloride, or ethers, especially diethyl etheriare preferreds Then the formed precipitate is separated by filtration. Neutralization of respective salts allows to obtain the compounds of this invention as free bases. &alpha;-(Bromopropionyl)-thiophene precursors of general formula (II) are obtained by conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydrocarbon, for example, methylene chloride, chloroform or carbon tetrachloride, are preferred. In turn, propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives or respective thiophenes with propionitrile. When X is chlorine, starting compounds such as commercially-available chlorothiophenes or dichlorothiophenes are, if possible, used, and the substituent X= C1 may be introduced into the synthesis sequence on intermediate steps depending on the desired position. Sulphuryl chloride is preferred as a chlorinating agent. When X is methyl, respective methylthiophenes are, if possible, also used. The preparation of o(-(bromo propionyl)-thiophene precursors pt formula (II) is hereiratter illustrated. EMI2.1 (II, X=4-Cl; chain position= 2) EMI3.1 (II', X'=2-CH3, chain position=4) The compounds or the present invention have an errective antidepressant activity as evidenced by R.D. Porsolt (Immobility behavioural despair test in mice: Arch.Int.Pharmacodyn., 229, 327-336, 1977) which differ from the thiophene ring non-substituted O(-(alkylaminopropionyl)-thiophenes, as disclosed in French Patent No. 3414M and British Patent No. 1313450, because these known compounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing ana analgesic action respectively. Consequently, the presence or an X group difrerent from hydrogen, selected between methyl or chlorine, in the compounds of formula (r) leads to compounds having a very effective antidepressant action. Thus, the compounds of this invention are useful as a medicament for treating depressions. The compounds or the present invention mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syrups, solutions, etc., by injectable route and by rectal route at dialy doses ranging from z.5 to 250 mg/kg. By way of a non-limitative illustration within the essence of the invention, some examples are described hereinbelow referring to the possible way to obtain (I) by following the steps of the disclosed pro LesS. EXAMPLE 1: 2-Propionylthiophene 400 g of thiophene and 437.33 9 or propionyl chloride in 2850 ml of anhydrous benzene are introduced into a 6-liter flask fitted up with a mechanical stirrer, Then the fixture is cooled at 0-5 C in ice-salt both and by keeping this temperature, 1343.7 g of tin tetrachloride in 570 ml or anhydrous benzene ar added (approximate addition time: 2 hours). Cooling bath i8 removed and the mixture is stirred for 20 hours at room temperature, then it is poured onto 3.8 kg of ice and 1 liter of water and vigorously stirred for 1 hour. The aqueous phase is decanted and extracted with 1.5 liters of ethyl ether; the organic extracts are washed with water to neutralization and filtered off. After evaporation of solvent and vaccum distillation of the residue, 560 g (yield: 85) ofa colourless liquid are obtained. Boiling point: 77-79 /0.7-0.8 tors, nD20=1.5530, GLC: 100% and analysis correct. IR Spectrum (film), cm-1, 3090, 3000-2880, 1660, 1410, 1220, 1050, 900, 845, 715. 1H-NMR (Cl4C), ppm: 1.16 (t, 3H, J= 7Hz; CH3-), 2.83 (g, 2H,3=7Hz; -CH2-), 7.03(dd,1H,J3.4=3.75Hz,J4.5=4.75Hz; HTiophene), 7.50(dd,1H,J4.5=4.75Hz,J3.5=1Hz; HThiophene) and 7.59(dd,1H,J3.4=3.75Hz,J3.5=1Hz; HThiophene). EXAMPLE 2: 4-Chloro-2-propionylthiophene To a suspension of 400.02 9 of aluminium chloride in 200 ml of dry chloroform under cooling at 10-20 C, 280.4 g of 2-propionyl thiophene are added under vigorous stirring. The mixture is then brought to 25-30gC and 350.92 g of newly distilled sulfuryl chloride are slowly added (3.5 hours), then heated in water bath at 40-42QC for 1 hour and left to stand overnight at room temperature. Thereafter, it is slowly poured onto 2.8 kg of ice under stirring, the aqueous phase is extracted with 7.2 and C.5 liters of methylene chloride and the organic extracts are jointly washed with water (three times), sodium ticarbonate saturated solution, and water again to neutralization. After evaporation of solvent, the residue (370.5 g) under rectifying column (LD= 19 cm; with Raschig rings gives 216.6 g and re crystallizes from hexane (350 ml) to yield 157,4 9 (45%) of a white solid with m.p. 58-60 C, GLC: 98%. IR Spectrum (KBr), cm-1, 3080, 3000-2880, 1665, 1400, 1220, 1190, 910. 1H-NMR Spectrum (C14C), ppm: 1.16 (t, 3H, 3= 7Hz; CH3-), 2.81 (a, 2H, J= 7Hz; -CH2-) 7.2Y (d, 1H, J= 1.4Hz; HThiophene) and 7,43 (d,1H,3=1.4Hz; HThiophene). EXAMPLE 3: &alpha;-Bromo-4-chloro-2-propionylthiophene To a solution of 60 g of 4-chloro-2-propionylthiophene in 280 ml of dry methylene chloride under stirring and cooled at 0-5 C, the equimolecular anount or bromo (54.9 g) dissolved in 135 ml of dry methylene chloride is slowly added; as the reaction starts, decolorization of bromo occurs immediately while adding the reaction mixture. After completing the addition, the bath is removed, stirring for further 30 minutes is performed, the methylene chloride is evaporated under vaccum and the liquid residue is used without further purification. IR Spectrum (film), cm 1 3100, 1665, 1400, 1230, 1155, 980, 910, 84C. 1H-NMR Spectrum (Ci3C), ppm: 1.84 (d, 3H, 3= 6.6Hz; CH3-), 4.93 (a, 1H, J= 6.6Hz; -CHC), 7.36 (d, 1H, 3= 1.25Hz; HThiophene) and 7.59 (d, 1H, 3= 1.25Hz; HThiophene). EXAMPLE 4: 2-[&alpha;-(tert-butylaminopropionyl)]-4-chlorothiophene hydrochloride To 87.69 g of -&alpha;bromo-4-chloro-2-propionylthiophene in 100 ml of acetonitrile, 60.7 g of tert-butylamine in 100 ml of acetonitrile are slowly added without exceeding 32 C (water bath regulation). As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. ThE solvent is evaporated at vaccum (below 35 C), taken in methylene chloride (300 ml) and water (300 ml); the aqueous phase is removed with methylene chloride, the organic extracts are washed four times with 200 ml of water, dried and evaporated to dryness. The residue (80.7 g) is dissolved in 600 ml of dry methylene chloride, cooled with ice-salt bath at OUC and a dry HCl (9) stream is lowly spread. The precipitated hydrochloride is filtered off, washed twice with dry methylene chloride and dried at vaccum to give 52.7 9 of white solid (m.p. 245-250 C) which, after recrystalizing from ethanol, yields 28 9 (30%) of the hydrochloride (m.p. 250-255QC)g anal ysis correct. IR Spectrum (KDr), cm-1: 3420, 3100-2400, 1675, 1545, 400, 1240, 1205, 1125, 895, 795. 1H-NMR Spectrum (CD3OD), ppm: '1.39 (s, 9H; -C(CH3)3, 1.67 (d, 3H, 3= 7Hz; CH3-), 5.14 (q, 1H, J= 7Hz; -CH#), 7.97 (d, 1H, J=1,75Hz; HThiophene). Neutralization of the hydrochloride allows to isolate respective base, m.p. 79-81 C (hexane) and analysis correct. EXAMPLE 5: 5-Chloro-2-propionylthiophene To a solution of 77.44 g of 2-chlorothiophene and 60.42 g of propionyl chloride in 390 ml of anhydrous benzene under cooling at 0-5 C (ice-salt bath), 184.56 g of tin tetrachloride in 78 ml of anhydrous benzene are dropwise added for about 0 hour and at the above temperature while separating a redish solid. Then it is stirred for 20 hours at room temperature, poured onto 520 g of ice and 130 g of water under stirring and 15 minutes later the phases are decanted: the aqueous phase is extracted with 250 ml of ethyl ether and the organic extracts are washed (3 times) with sodium chloride saturated solution. The crude product (105.3 g) is rectified by Vigreaux Column (LD= 11 cm) thus obtaining 75.80 g (yield: 65%) of a white solid, m.p. 47-49uC, LGC: 100 and analysis correct. IR Spectrum (K8r), cm 1 3080, 3000-2860, 1650, 1410, 1210, 1010, 880, 780. 1H-NMR Spectrum (Cl4C), ppm: 1.14 (t, 3H, 3= 7.6Hz; CH3-), 2.75 (q, 2H, 0= 7.6Hz; -CH2-), 6.85 (d, 1H, J= 4Hz; HThiophene) and 7.37 (d, 1H, 3= 4Hz; HThiophene) EXAMPLE 6: &alpha;-Bromo-5-chloro-2-propionylthiophene To a solution of 112.37 9 of 5-chloro-2-propionylthio phene in 500 ml of dry methylene chloride under stirring and cooling at 0-5 C, 102.83 9 or bromine in 250 ml of methylene chloride are added. Processing as described in Ex. 3, 167.8 g of a liquid residue corresponding to the ci-bromo derivative are obtained which is pure enough to be used in the following synthesis step. IR Spectrum (film), cm 1. 3100, 3010-2880, 1660, 1420, 1240, 1010, 890, 800, 740. 1H-NMR (Cl4C) Spectrum, ppm: 1.81 (d, 3H, J= 6.6Hz; CH3-), 4.90 (q, 1H, 3= 6.6Hz; -CH(), 6.91 (d, 1H, 3= 4Hz; HThiophene) and 7.55 (d, 1H, 3= 4Hz; HThiophene) EXAMPLE 7: 2- [&alpha;-(tert-butylaminopropionyl)]-5-chlorothio- phene hydrochloride To 81.50 g of &alpha;-bromo-5-chloro-2-propionylthiophene in 100 lil or acetonitrile, 56.76 g of tert-butylamine in 100 ml of acetonitrile are slowly added without exceeding 32 C. As the exothermic diminishes, the mixture is left under stirring for 20 hours at room temperature. Processing as described in Ex. 4, 75.7 g of a crude product are isolated and respective hydrochloride in dry methylene chloride (700 ml) with HCl (g) is formed. The insolubilized hydrochloride (65.4 g, m.p. 246248 C) is recrystallized from ethanol thus obtaining 44.4 g (yield: 49%) of a white solid, m.p. 255-257 C and analysis correct. IR Spectrum KBr), cm 1 3440, 3110-2500, 1660, 1550, 1410, 1245, 1010, 880. ÚH-NMR Spectrum (CD30D), ppm: 1.37 (s, 9H; -C(CH3)3), 1.66 (d, 3H, 3= 7Hz; -CH3), 5.14 (q, 1H, 3= 7Hz; -CHC), 7.24 (d, 1H, J=4.25Hz; HThiophene) and 8.l9 (d, 1H, J= 4.25Hz; HThiophene) Thiophene Neutralization of the hydrochloride allows to isolate respective base, m.p. 72-75 C (hexane) and analysis correct. EXAMPLE 8: 2,5-Dichloro-3-propionylthiophene To a solution ot 65,1 9 of 2,5-dichlorothiophene and 77.79 9 of propionyl chloride in 325 ml of nitrosthane, 63.5 9 of aluminium chloride are slowly added in nitrogen atmosphere for about 20 minutes, thus causing the temperature of the mixture rise up to 37uC. Then, the mixture is stirred for 4 hrs, poured on to 500 g or ice and removed twice with 250 ml of ethyl ether. The brganic extracts are consecutively washed with 3N hydrochloric acid (150 ml), water (2x100 ml), 3N sodium hydroxide (3x600 ml) and saturated sodium chloride solution till neutralization. After drying and evaporating the solvent, the solid residue (68.9 g) is distilled and 58.00 g (yield: 65%) of a white solid are obtained; b.p. 96-105QC/1.2 tors, m.p. 63-66wC and analysis correct. IR Spectrum (K8r), cm 1 3120, 3080, 3000-2860, 1680, 1660, 1430, 1370, 1190, 1175, 1015, 800. 1H-NMR Spectrum (Cl4C), ppm: 1.12 (t, 3H, 3= 7Hz; CH3-), 2.83 (g, 2H, J=7Hz; -CH2-) and 7.15 (s, 1H; HThiophene). EXAMPLE 9: 2-Chloro-4-propionylthiophene To a suspension of 53.28 g of 2,5-dichloro-4-propionylthiophene in 57 ml of glacial acetic acid and 181 ml of water, 33.31 g of zinc dust (2 equivalents) are added in the course of 5 minutes and thus the temperature rapidly rises up to 72 C; then it is cooled in water bath till reaching 55 C within 10 minutes. 250 ml of ethyl ether are added, the insoluble solid is filtered off and the aqueous phase is removed with ether again; the extracts are washed with water, saturated ClN4 solution and dried with potassium carbonate. The residue (43.48 g), which is obtained after evaporating the solvent, recrystallizes from n-pentane to yield 28.9 g (65%) of a white solid, m.p. 50-53 C, LGC: 100% and analysis correct. IR Spectrum (KBr), cm : 3100, 3000-2800, 1665, 1435, 1180, 1000, 780. ÚH-NMR Spectrum (Cl4C), ppm: 1.13 (t, 3H, 3= 7Hz; CH3-), 2.75 (S, 2H, J= 7Hz; -CH2-), 7.28 (d, H, 3= 1.5Hz; HThiophene and 7.68 (d, 1H, 3= 1.5Hz; HThiophene) EXAMPLE 10: &alpha;-Bromo-2-chloro-4-propionylthiophene To a solution or 30.92 g of 2-chloro-4-propionylthiophene in 140 ml of dry methylene chloride under stirring and heating at 0-5 C, 28.29 g of bromine in 70 ml or methylene chloride are added. Processing as described in Ex. 3, 44.9 g of a coloured liquid are obtained with analysis correct. IR Spectrum (film), cm-1; 3100, 3000-2900, 1680, 1425, 1210, 1150, 1005, 845. 1H-NMR Spectrum (Cl4C), ppm: 1.80 (t, 3H, J= 7.0Hz; CH3-), 4.85 (o, 1H, 3= 7.0Hz; ,CH-) 7.35 (d, 1H, 3= 1.5Hz; HThiophene) and 7.87 (d, 1H, 3= 1.5Hz; HThiophene) EXAMPLE 11: 4-[&alpha;-(tert-butylaminopropionyl)]-2-chlorothiophene To 44,50 g of &alpha;-bromo-2-chloro-4-propionylthiophene in 55 ml of acetonitrile, 31 g of tert-butylamine in 55 ml of acetonitrile are slowly added without exceeding 32 C. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. Processing as described in Ex. 4, 42.4 g of a dark liquid are isolated and respective hydrochloride in methylene chloride (400 ml) at OUC with HCl (g) is formed. The insolubilized product (37.10 g) is recrystallized from ethanol to yield 38.5 g (40%) of a white solid, m.p. 257-259 C (d) and analysis correct. IR Spectrum (KBr), cm 1 3450, 3100-2400, 1675, 1545, 1230, 1200, 1175, 1000, 830. 1H-NMR Spectrum (CD30D), ppm: 1.40 (s, 9H, -C(CH3)3), 1.62 (d, 3H, 3= 7.QHz; CH3-), 5.10 (q, 1H, J= 7Hz; #CH-), 7.52 (d, 1H, J= 1.5Hz; HThiophene) and 8.72 (d, iH, 3= 1.5Hz; HThiophene EXAMPLE 12: 2-Propionyl-5-methylthiophene To a solution of 53.50 g of 2-methylthiophene and 50.45 g of propionyl chloride in 500 ml of anhydrous benzene under cooling at 0-5 C in an ice-salt bath, 141.97 g of tin tetrachloride in 60 ml or anhydrous benzene are dropwise added for about 7 hour at the above temperature. Then it is stirred for 22 hours at room temperature to give a dark red mixture which is poured onto 400 g of ice and 100 g of water under vigorous stirring; after 1 hour, the aqueous phase is removed with zO0 ml of ethyl ether and the organic extracts are washed three times with sodium chloride saturated solution. The crude product (76 g), which solidifies by standing, is distilled at vacuum and 68.z4 g (81%) are obtained, b.p. 85-95 C/0.5-0.6 tors and m.p. 52-34 C. IR Spectrum (KBr), cm-1; 3-00-2880, 1660, 1455, 1230, 1050, 890, 790. 1H-NMR (Cl3CD), ppm: 1.18 (t, 3H, J=8Hz; CH3-), z.50 (d, 3h, 3=1Hz; CH3-thiophene), 2.83 (o,2H,J=8Hz;-CH2-), 6.75 (dd, 1H, J=sHz and J'=ss.75Hz; H-thiophene) and 7.50 (d, -H, J=3.75Hz; H-thiophene). EXAMPLE 13; &alpha;-Bromo-2-propionyl-5-methylthiophene To a solution ot 34.12 g of 2-propionyl-5-methylthiophene in 180 ml of dry methylene chloride under stirring and cooling at 0-5 C, 35.35 g of bromine in 90 ml of methylene chloride are gently added. After completing the addition, the bath is removed, stirred for further 50 minutes, the methylene chloride is evaporated at vacuum and the residue (53.27 g, i00) is used for the following operation without further puritriostation. IR Spectrum (film), cm-1; 3100-2900, 1665, 1450, 245, 885. H-NMR (Cl4C), ppm: .81 (d, 3H, 3=7Hz; CH3-), z.52 (s, 3H; CH3-thiophene), 4.95 (o,1H,J=7Hgz;-CH#), 6.75 (dd,1H, J=1Hz,J'=3.75Hz;H-thiophene) and 7.55 (d,1H,J=3.75Hz; H-thiophene). EXAMPLE 14: 2-[&alpha;-(tert-butylamimopropionyl)]-5-methylthiophene hydrochloride To 44.5 g of &alpha;-bromo-2-propionyl-5-methylthiophene in 60 ml or acetonitrile, 36.57 g of tert-butylamine are gently added without exceeding 50 C), (water bath adjustment). The solvent is evaporated at vacuum (below 35 C), taken in 100 ml of methylene chloride and 100 ml of water, and the aqueous phase is removed again with 75 ml ot the solvent; the organic extracts are washed with water, dried and evaporated. The crude material (42.0 g) is dissolved in 400 ml of dry ethyl ether, and by cooling in water-ice bath a dry HCl (g) stream is spread; the precipitated hydrochloride is filtered off, washed with ether and dried at vacuum to give 35 g of a whitish solid which, after recrystallizing from ethanol, yields i9.7 g (40%) or a white solid corresponding to the hydrochloride (m.p. 262-263 C). In Spectrum (KBr), cm-1; 3100-2400, 1655, 1550, 1445, 1250, 1205, 1055, 880, 825. H-NMR (d6-DMSO), ppm: 1.35 (s, 9H; -C(CH3)3), l.64 (d, 3H,J=7Hz; CH3-), 2.58 (s,3H;CH3-thiophene), 5.13 (g,1H, J=7Hz;-CH#), 7.05 (d,1H,J=4Hz;H-thiophene) and 8.28 (d,1H, 3=4Hz; H-thiophene). EXAMPLE 15: 2-[&alpha;-(iso-propylamimopropionyl)]-5-methylthiophene hydrochloride From 53.27 g of o(-bromo-z-propionyl-5-methyl-thiophene in 65 ml of acetonitrile and 4.0 g of isopropylamine, and processing as described in Ex.14, 41.3 of crude material are isolated and respective hydrochloride (11.2 g) is recrystallized from ethanol to give 6.5 g (15%) of a white solid, m.p. 230-233 C and elemental analysis correct. IR Spectrum (KBr), cm-1; 3400-2400, 1645, 1550, 1445, i250, 1065, 860, 830. ÚH-NMR (d6=DMSO), ppm: 1.30 (d,6H,J=7Hz;CH(CH3)2), 1.54 (d,3H,J=7Hz;CH3-), 2.55 (s,3H,CH3-thiophene), 3.25 (m,1H,J=7Hz;CH(CH3)2), 5.05 (g,1H,J=7Hz;CO-CH-), 7.05 (d, 1H, J=4Hz; H-thiophene) and 8.20 (d, IH, J=4Hz; H-thiophene). EXAMPLE 16: 2-[&alpha;-(sec-butylamimopropionyl)]-5-methylthiophene hydrochloride From 24.16 g of &alpha;-bromo-2-propionyl-5-methylthiophene in )0 ml of acetonitrile and 20 g of sec-butylamine, and processing as described in Ex.14, 36 9 of crude material are isolated, and respective hydrochloride in ethyl ether (26.3 9) is recrystallized from acetonitrile to give e.35 g (35) of a white solid, m.p. 191-194 C and elemental analysis correct. IR Spectrum (KBr), cm-1; 3400-2400, 1650, 1550, 1440, 1240, 1060, 825, ÚH-NMR (D2O), ppm: 0.98 (t,3H,J=7Hz;CH-), 1.32 (d, 3H,J=6.5Hz;CH3-CH-NH), 1.67 (d+wide band,5H,J=7Hz;CH3and -CH2-), 2.59 (s,3H,CH3-thiophene), 3.22 (m,1H,#CH-NH), 5.06 (m,1H,#CH-CH3), 7.06 (d,1H,J=4Hz;H-thiophene) and 7.96 (d, ,'iH, J=4Hz; H-thiophene). EXAMPLE 17: z-Propionyl-4-methylthiophene To a solution of 44.9L g of S-methylthiophene in 250 ml of dry ethyl ether under nitrogen atmosphere and cooled with water bath, 286 ml of n-butyllithium 1.6M solution in hexane are added for about 7 hour. Then, the mixture is refluxed for z hours and cooled, and in the course of 50 minutes at -60 C 25.2; g of propionitrile in 115 ml of ethyl ether are added under stirring for 4 hours, and allowed to stand overnight under cooling. Then, the imine is hydrolyzed by slow aadition of z 0 ml o zN hydrochloric acid and subsequent distillation of the ethyl ether by heating at 55C in oil bath. Dsitillation is stopped and the hydrochloric solution is refluxed for hour. Then, it is cooled, removed twice with 150 ml of ethyl ether and the extracts are washed with water and dried. After evaporation of solvent, the residue weighs 54 g and contains a mixture of ,4-isomer 75 and 2,3-isomer 25%. By distilla tion, an serly richer fraction in 2,3-isomer and 40.4 g are collected at 80-85 C/0.5-0.8 tors (yield: 57%) containing 81% of 2-propionyl-4-methylthiophene (LGC). IR Spectrum (film), cm-1; 3400-2800, 1660, 1420, 1230, 1205, 1150, 885, B60 800. ÚH-NMR (CDCl3), ppm: 1.20 (t,3H,J=7.25Hz;CH3-), 2.27 (s,3H,CH3-thiophene), 2.86 (g,2H,J=7.25Hz;CH2-), 7.20 (g, 1H; H-thiophene) and 7.48 (s, IH; H-thiophene). EXAMPLE 18: &alpha;-Bromo-2-propionyl-4-methylthiophene From 39.22 g of z-propionyl-4-methylthiophene (81%) in 200 ml of methylene chloride and 40.64 g of bromine in the same solvent, and processing as described in Ex. 13, 59.8 g(100%) or &alpha;-bromoderivative are obtained, which is used without further purification. IR Spectrum (film), cm-1; 3400-2900, 1665, 1420, 1240, 145, 1060, 980, 770. 1H-NMR (CDCl3), ppm: 1.87 (d, 3H, J=7Hz; CH3-), 2.30 (s,3H,CH3-thiophene), 5.10 (g,1H,J=7Hz;-CHBr-), 7.27 (s, 1H; H-thiophene) and 7.65 (s, iH; H-thiophene). EXAMPLE 19: 2-[-&alpha;-tert-butylaminopropionyl)]-4-methylthiophene hydrochloride From 59.6 g of &alpha;-bromo- < -propionyl-4-methylthiophene, as described in Ex. 14, in 75 ml of acetonitrile and 46.85 g of tert-butylamine, and processing as described in Ex. 3, 51.2 g of crude material are isolated, and respective hydrochloride In ethyl ether (43.2 g) is recrystallized in ethanol to give 17.8 g (30), m.p. 255-258 C (d) and elemental analysis correct. IR Spectrum (KBr), cml: 3400-2400, 1665, 1550, -1455, 4250, 1120, 870, 800. 1H-NMR (D2O), ppm: 1.37 (s, 9H; -C(CH3)3), l.68 (d, JH, J=7.0Hz;CH3-), 2.34 (s,3H,CH3-thiophene), 5.05 (o,1H, J=7.0Hz), 7.76 (s,1H,H-thiophene) and 8.04 (s,1H,H-thiophene). EXAMPLE 20: 2-[&alpha;-(iso-propylaminopropionyl)]-4-methylthiophene hydrochloride From 32.72 g or &alpha;-bromo-2-propionyl-4-methylthiophene in 40 ml of acetonitrile and Z0.7 9 of iso-propylamine, end processing as described in Ex.14, 26.93 g of crude material are isolated, end respective hydrochloride in ethyl ether (13.59) is recrystallized in ethanol to give 7.0 g (25%), m.p. 230 234±C (d),deprived from 2,3-isomer and elemental analysis correct. IR Spectrum (KBr), cm-1; 3100-200, 1675, 1445, 1420, 1320, 1230, 1150, 770. 1H-NMR (D20), ppm: l.39 (d, 6H, 3=6.5Hz; -CH(CH3)2), 1.70 (d, 3H, 3=7Hz; CH3-), 2.33 (s, 3H; CH3-thiophene), 3.50 (m, 1H, 3=6.5Hz; -CH(CH3)2), 5.08 (g, 1H, 3=7Hz; -CO-CH-), 7.71 (s, 1H; H-thiophene) and 7.98 (s, 1H; H-thiophene). EXAMPLE 21 4-Bromo-2-methylthiophene 100 g of 4-bromothiophene-2-aldehyde, 193 g of 100% hydrazine hydrate and 520 ml of ethylene glycol are introduced into a three-necked flask (1-liter capacity) fitted up with a mechanical stirrer and a distillation device. The mixture is heated at 160 C in oil bath which allows to distill the water and the excess of hydrazine; from the distillate the lower phase is separated and introduced intc the reactor again. After completing distillation (6 hcure apprciximately), the mixture is cooled, 117.5 g of potassium hydroxide (excthermic reaction) are added and then carefully treated till reflux ty keeping for 15 minutes. Then, it is allowed to stand overnight and distributed with ethyl ether (250 ml) and water (250 ml); the aqueous phase is removed twice with ether and the organic extracts are washed with 6N hydrcchloric acid and water till neutralization. The crude material is distilled at vacuum and 66.1 g (71.5%), b.p. 66-73 C/12-5 tors are cbtained as colourless liquid. IR Spectrum (film), cam : 3120, 3000-2850, 1530, 330, 1190, 810, 720. ÚH-NMR (CDCl3), pmm: 2.44 (g,3H;CH3-), 6.66 (m,1H; H-thiophene) and 6.59 (d,1H,J=1.5Hz;H-thiophene). EXAMPLE 22: 2-Methyl-4-propionylthiophene In a three-necked flask (1-llter capacity) fitted up with a mechanical stirrer and nitrogen atmosphere, a solution of n-butyllithium is prepared by adding 57.45 g of 1-bromo- butane in 50 ml of dry ethyl ether to 4.90 g of lithium in 400 ml of ethyl ether. It is cooled at -70 C (ethanol/CO2 solid) and 38.04 g of 4-bromo-2-methylthiophene in 200 ml of ethyl ether arR added along 45 minutes; it is kept for 2 hours at -70uC in order to secure the fornation of the lithium salt. Then, et the same temperature, 11.82 9 cf propionitrile in 50ml of ethyl ether are added and allowed to stand under stirring for 4 hours and overnight at low temperature. At -15 C, 110 ml of 2N hydrochloric acid are added, the bath is withdrawn and the ether is distilled under pressure; when distillation temperature reaches 100 C, the mixture is refluxed for ' hour, cooled and the insolubilized oil is removed twice with 200 ml of ethyl ether, then washed with ester till neutralization and dried By distillation of the residue, 12.e g (40%) of a colourless liquid are obtained, b.p. 85-100uC/1.5 tors. IR Spectrum (film), cm : 3120, 3020-2880, 1680, 1466, 1210, 1145, 860. 1K-NMR (CDCl3), ppm: 1.17 (t, 3H, J=7Hz; CH3-), 2.46 (s, 3H; CH3-thiophene), 2.82 (q, 2H, 3=7Hz; -CH2-), 7.1E (m, 1H; K-thiophene) and 7.75 Cd, 1H, J=1.5Hz; H-thiophene. EXAMPLE 23: &alpha;-Bromo-2-methyl-4-propionylthiophene From 12.75 g of 2-methyl-4-propionylthiophene in 65 ml of methylene chloride and 13.22 g of bromine in 35 ml of the same solvent, as described in Ex.13, 19.4 g (100%) of &alpha;-bromo- derivative are obtained and subsequently used without further purification. IR Spectrum (film) cm 1 3110, 2980, 2930-2860, 670, 1440, 1220, 1130, 850. 1H-NMR (CDCl3), ppm: 1.81 Cd, 3H, 3=7Hz; CH3-), 2.45 (s,3H;CH3-thiophene), 5.03 (c,1H,J=7Hz;#CH-), 7.22 (d, 1H, J=1.5Hz; H-thiophene) and 7.92 (d, 1H, J=1.5hz; H-thiophene), EXAMPLE 24: 4-[&alpha;-(tert-butylaminopropionyl)]-2-methylthiophene - hydrochloride Frcim i9,3 g of the &alpha;-bromoderivative described in Ex. 23, in 25 ml or ecetonitrile and 15.4 9 of tert-butylamine, end processing as described in Ex.14, 13.2 g of crude material are isolated, and respective hydrnchloride in ethyl ether (8.0 g) is recrystallized in ethanol to give 4.1 g (22%), m.p. 241.8-242.4 C and elemental analysis correct. IR Spectrum (KBr), cm 1 3200-2400, 1670, 1550, 1450, 1230, 1200, 1120, 1C10, 840. 1H-NMR (d6-DMS0), ppm: 1.29 (s, 9H; -C(CH3)3), 1.58 (d, 3K, J=7Hz; CH3-), 2.48 (d, 3K, J=0.5Hz; CH3-thiophene), 5.10 (g,1h,J=7Hz;#CH-), 7.36 (m,1H;H-thiophene) and 8.8 (d, 1H, 3=1.5Hz; H-thiophene). EXAMPLE 25: 4-[&alpha;-(iso-propionylaminopropionyl)]-2-methylthiophene hydrochloride To 22.27 g of the &alpha;-bromoderivative described in Ex.23, in 30 ml of acetonitrile and 141.1 g of iso-butylamine, and processing as described in Ex.14, 16 g of crude material are isolated, and respective hydrochloride is ethyl ether (13 g) is recrystallized in ethanol to give 4.5 g (21%), in m.p. 231.5-233.5 C and elemental analysis correct. IR Spectrum (KLr), cm 1 3140-2400, 1665, 150C, 1460, 1210, 1100, 1010,.840, 745. 1H-NMR (D2O), ppm: l.37 (d, 6H, 3=6.5Hz; -CK(CH3)2), 1.64 (d, 3H, 3=7Hz; CH3), 2.50 (s, 3H; CH3-thiophene), 3.48 (m, 1H, J=6.5Hz; -CH(CH3)2), 5.02 (g, 1H, 3=7Hz; -C0-CHC), 7.31 (d, 1H, 3=1.5Hz; H-thiophene) and 8.37 Cd, 1H, 3=1.5Hz; H-thiophene). EXAMPLE 26: 2-[&alpha;-(iso-propionylaminopropionyl)]-4-chlorothiophene hydrochloride To 63.8 g of &alpha;-bromo-4-chloro-2-propionylthiophene obtained according to Example 3 in 70 ml of acetonitrile, 37.2 g of iso-propylamine are gently added without exceeding 32 C. When the exothermia stops, the mixture is left under stirring for 20 hours at room temperature. The solvent is evaporated at vacuum (below 35 C), token in methylene chloride (150 ml) and water (150 ml); the aqueous phaee is removed with methylene chloride, and the organic extracts are washed with water, dried and evaporated to dryness. The crude material (51 g) is dissolved in 400 mlof dry ethyl ether, and by cooling in a water-ice bath a HCl (g) stream is spread; the insolubilized hydrochloride is filtered ofr, washed with ether and dried at vacuum to give 17.04 g of a white-yellowish solid whose recrystallization in ethanol yields 10.1 g (16%) of a white solid, m.p. 225-230 C (d), corresponding to the hydrochloride. IR Spectrum (KBr), cm-1, 3140-2400, 1675, 1555, 140C, 1235, 860. ÚH-NMR (d6-DMSO), ppm: 1.33 (d,6H;J=7Hz;CH(CH3)2), 1.58 (d,3H;J=7Hz;CH3-), 3.38 (m,1H;CH(CH3)2), 5.20 (g,1H, 3=7Hz; CO-CH-), 8.25 (d, 1H, J=1.5Hz; H-thiophene) and 8.54 (d, 1H, J=1.5Hz; H-thiophene). EXAMPLE 27: 2-[&alpha;-(n-propylaminopropionyl)]-4-chlorothiophene hydrochloride Frcm 36.3 g of &alpha;-bromo-4-chloro-2-propionylthiophene in 45 ml of acetonitrile and 20.42 g of n- propylamine, and processing as described in the above examples, Jz.05 g of crude material are isolated, and respective hydrochloride (31.5 g) in ethyl ether is recrystallized in ethyl acetate/acetcnitrile to give a2.7 g (33%) of a white solid, m.p. 192.5-193.5 C and elemental analysis correct. IR Spectrum (KBr), cm-1; 3100-2400, 1680, 1440, 1405, 1230, 1190, 1110, 940, 770. ÚH-NMR (CD3OD), ppm: 0.99 (t,3H;J=7Hz;CH3-), 1.62 (d,3H;J=7Hz;CH3-), 1.76 (m,2H;J=7Hz;CH2-CH3), 3.0 (m, 2H;CH2-NH), 5.00 (g,1H,J=7Hz;CH-CO), 7.90 (d,1H,J=1.5Hz; H-tiophene) and 8.05 (, 1H, J=1.5Hz; H-thiophene).

Claims: CLAIMS: 1. Thiophene ring-substituted oL-(alkylaminopropionyl)- thiophene derivatives having the general formula (I): EMI19.1 wherein X is methyl or chlorine, R is alkyl, linear or branched, having 3 to 4 carbon atoms, and the nontoxic addition salts thereof. 2. A process for preparing the compounds according to Claim l, characterized in that an o(-(alkylaminopropionyl)- thiophene of the general formula (II): EMI19.2 wherein X has the same meaning as defined in claim 1, is reacted with an amine of the general formula (III): H2N-R (III) wherein R has the same meaning as defined in claim 1, in an inert medium, and at a maximal temperature of 50 C, and,if desired, the free base is treated with an acid to obtain a non-toxic addition salt, or a salt of a compound of the general formula I is neutralised to obtain the free base. 3. The process of Claim 2, characterized in that acetonitrile is used as inert medium in the reaction between (II) and (III). 4. The prccess of Claim 2, characterized in that a chlorinated hydrocarbon or an ether is--used as inert medium in the formation of the nontoxic addition salts. 5. The process of Claim 2 according to Claim 4, wherein the chlorinated hydrocarbon is methylene chloride and the ether is diethyl ether. 6. Pharmaceutical composition comprising at least one of the compounds of Claim 1, optionally together with pharmaceutical carriers and/or adjuvants. 7. The use of the compounds according to claim 1 for the preparation of pharmaceutical compositions for treating depressions.

Inventors: FOGUET, RAFAEL, FORNE, ERNESTO, DR., ORTIZ, JOSE A., DR., SACRISTAN, AURELIO, Forné, Ernesto, Dr., Ortiz, José A., Dr., Sacristán, Aurelio
Applicants: FERRER INTERNACIONAL, S.A.
Application year: 1986
Main classification: C07D333
IPC codes: C07D333