BENZOFURANCARBOXAMIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM

Abstract: Benzofurancarboxamides represented by the formula (I): wherein Z represents the atoms necessary to complete a benzo[b]furan or a dihydrobenzo[b]furan ring; R¹, R² and R³ may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an amino group, an alkylamino group, a nitro group, an acylamido group having 1 to 6 carbon atoms, and a sulfonamido group having up to 6 carbon atoms; and A represents a tertiary aminoalkyl group containing the atomic sequence and pharmaceutical preparations containing the same.

Description: OFURANCARBOXAMIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PEPARAT) ONS CO]TA) NJ NG THEM The present invention relates to a novel group of benzamides which are useful as antiemtic and/or antipsychotic agents. More particularly, it relates to a novel group of benzofuran-7-carboxamides. There has been little treatment in the literature of the relationship between structure and activity of antiemetic and antipsychotic agents. A large number of chemically quite diverse compounds have been used particularly as antiemetic agents. This is due to the fact that there is more than one physiological cause for these disorders. U.S. Patent No. 3,342,826 discloses a number of benzamide derivatives which are useful antipsychotic and antiemetic agents. Among the compounds disclosed in the patent is sulpiride, 2-methoxy-N-(l-ethyl-2pyrrolidinylmethyl)-5-sulfamoyl benzamide. U.S. Patent 3,177,252 to Thominet discloses metoclopramide, 4-amino-5chloro-N-{(2-diethylamino)ethyl]-2-methoxybenzamide, which has been used clinincally to prevent emesis. Benzamide derivatives function as antiemetic and antipsychotic agents by blocking dopamine receptors in the brain. The administration of sulpiride, metoclopramide, and other prior benzamide derivatives is accompanied by several undesirable side effects including an increase in the release of prolactin and extrapyramidal side effects. It is believed that in blocking certain dopamine receptors benzamide derivatives prevent the secretion of prolactin inhibiting factor or PIF, which regulates the release of prolactin. As a result, there is an elevation in prolactin levels and mammary hypertrophy in the form of breast engorgement, galactorrhea, and amenorrhea results. Thus, there is a need for effective antiemetic and antipsychotic agents and, particularly, for antiemetic and antipsychotic agents which are free from the aforementioned side effects. The principal object of the present invention is to provide benzofurancarboxamides which are useful as antiemetic and, or antipsychotic agents and pharmaceutical preparations containing the same. In the case of benzamide derivatives, it appears that the 2-methoxy group located adjacent to the carboxamide linkage in both sulpiride and metoclopramide plays an important role in providing good antipsychotic and antiemetic activity. The compounds of the present invention are characterized in that the oxygen atom in the benzofuran ring is adjacent thse carboxamide linkage. The compounds of the present invention are represented by the general formula (I): EMI2.1 wherein Z represents the atoms necessary to complete a benzotb)furan or a dihydrobenzo[b]furan ring; R1, R2 and R3 may be the same or different and represent a member selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an amino group, an alkyl substituted amino group, an acylamido group having 1 to 6 carbon atoms, a sulfonamido group having up to 6 carbon atoms, a halogen atom, and a nitro group; A represents a tertiary aminoalkyl group containing the atomic sequence: EMI3.1 Typical examples of the tertiary alkylamino groups represented by A in formula (I) are: EMI3.2 wherein R6, R7 and R8 are selected from the group consisting of a hydrogen atom and a lower alkyl group containing 1 to 6 carbon atoms. The present invention is more specifically directed to benzolb]furan and dihydrobenzoib]furan- carboxamides represented by the formula II and III wherein R1, R2 and R3 are defined as above and R9 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and to pharmaceutical preparations containing the same. EMI4.1 The present invention is still more specifically directed to compounds of the formula I, II or III wherein R2 is a lower alkyl group and to pharmaceutical compositions containing the same. With reference to formulae I, II, and III above, in more detail Z represents the atoms necessary to complete a benzolb]furan or a dihydrobenzo[b]furan ring which may be substituted in the 2- or 3-position by a lower alkyl group such as a methyl group or an ethyl group or may be unsubstituted. Thus, where Z represents the atoms necessary to form a dihydrobenzolb]furan ring, Z may be a CnH2n group where n is 2 to 4 such as -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH(Ch3)CH2-, CH2CH(C2Hs)- etc. Where Z represents the atoms necessary to form a benzofuran ring, Z may represent -CH=CH-, -CH=CCH3, or -CH3C=CH-. Representative examples of the alkyl group represented by R1, R2 or R3 include lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, and t-butyl groups. Representative examples of the halogen atoms represented by R1 R2 and R3 include fluorine, chlorine, bromine and iodine atoms. The amino group represented by R1, R2 or R3 may be an unsubstituted amino group or a substituted amino group of-the formula -NR4R5 wherein R4 and R5 may be the same or different and selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, etc. Otherwise, the amino group can be a substituted amino group such as an acylamido or a sulfonamido group of the formula -NHCOR4 and NHSO2R4 wherein R4 is defined as above. Representative examples of the alkoxy groups for R1, R2 and R3 include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, and propoxy. Of the compounds represented by the formula I, II and III, those which appear to be particularly preferred are compounds in which R2 is an alkyl group and A is a 2-(N-ethyl)pyrrolidinylmethyl group. The compounds of the present invention exhibit antipsychotic and antiemetic activitiy in in vivo screening tests as shown below. The compounds can be compounded with a suitable pharmaceutical carrier for parenteral or oral administration. In most cases the compounds are useful in the form of the acid addition salt, e.g., the hydrochloride, phosphate, fumarate, citrate, tartarate. Therapeutically effective dosages will lie in the range of about 0.01 to 10 mg/kg. The compounds of the present invention are conveniently prepared by condensing benzo[b]furan-7carboxylic or dihydrobenzo [b) furan-7-carboxylic acid chlorides or esters with appropriate amines and recovering the carboxamides as acid salts. Hereinbelow, four synthetic approaches to the carboxamides are described. The synthesis of the benzofuran-7-carboxylic acid esters, which are convertible to the acid chloride to produce benzofurancarboxamides in accordance with the present invention proceeds along Reaction Scheme I: REACTION SCHEME I EMI7.1 The compounds of the present invention can be prepared from commercially available substituted or unsubstituted salicylic acids. In accordance with Reaction Scheme I, 2-,3-,4-,5- or 6- substituted or unsubstituted benzofuran-7-carboxamides can be synthesized from salicylic acid (1) by treating the acid with methanol in the presence of sulfuric acid, as a catalyst, to produce the methyl ester (2). The ester (2) can be alkylated to give the intermediate (3) in over 90% yield by nucleophilic substitution of the phenoxide ion with an allyl halide in acetone containing potassium carbonate. The 2-unsubstituted derivatives are prepared by substitution with allyl bromide. The 2- or 3- alkyl substituted derivatives are prepared by reacting with 3-chloro-2-alkyl propene or 3-chloro-3-alkyl propene. The products are clean and can be used for subsequent reaction without purification. By heating the intermediate 3 at about 2000C under argon either without any solvent (Method A) or with N,N-dimethylaniline (Method B), a Claisen rearrangement takes place resulting in the compound 4. Table I below summarizes the Claisen rearrangement conditions for obtaining eight intermediates (Compounds 4a-4h) by this method and provides the relevant analytical data. Attempts to distill compounds 4f and 4g led to mixtures possibly due to production of para isomers by further rearrangement. Chromatography of the reaction mixture 49 gave the desired compound 4g along with the p-isomer in 3.7% yield. Column chromatography of compound 4f led to isolation of four products including compound 4f. EMI9.1 TABLE I Claisen Rearrangement Reaction Formula Compounds RÚ R2 X2 Method temp ( C) time (hr) Yield (%) bp(mm) (Calc'd) 4a H H H A 195-200 16 92.5 80-95(0.02) C11H12O3 4b H Br H A 190 20 89.4 110-126(0.25 0.5) C11H11BrO3 4c H Cl H A 200 20 88.5 130-136 (3.5) C11H11ClO3 4d H F H A 190-200 20 88.0 83.89 (1.0) C11H11FO3 4e H OCH3 H A 205 64 87.0 142-144 (3.0) C12H14O4 4f Cl H H A 200 38 32.9 117-121 C11H11ClO3 B 190-205 20 71.1 4g OCH3 H H B 190-205 18 59.5 55-58 (mp) C12H14O4 4h H H CH3 A 200 18 90.8 102-108 (3.0) C12H14O3 The intermediate 4 can be oxidized by reaction with OsO4/Na104 in ethyl ether and water at room temperature to produce the corresponding aldehydes or ketones (5) in very good yields. Due to the instability of the aldehydes and ketones (5), they are carried to the next step (acid-catalyzed -cyclization) without purification. Acid catalysts are employed for cyclization of the aldehydes or ketones to produce compound (6). The acid catalysts of choice are either Amberlyst-XN1010 and trifluoroacetic acid (TFA). TFA is more preferred because it requires a shorter reaction time and generates fewer by-products. Using either catalyst, the phenolic hydroxy group attacks the aldehyde to form a hemiacetal which loses water and results in the benzofuran ester (6). Table II below provides the analytical data for six benzofuran-7-carboxylic acid esters produced by Reaction Scheme I. EMI11.1 TABLE II Chromato Cyclization graphic Recryst. Analytical Compounds RÚ R2 X2 Catalysts solvent solvent Yield (%) mp( C) Analysis* 6a H H H Amberlyst Hexane ---- 50.7 liquid C10H8O3 XN1010 (100%) to EtOAc/ hexane(7.5/100) 6b H Br H " Hexane ---- 62.4 156-158 C10H7BrO3 CH2Cl2 1/1 to 1/3) 6c H Cl H " CH2Cl2 CH2Cl2/ 21.0 144-145 C10H7FO3 hexane TFA/ CH2Cl2 ---- 63.2 6d H F H TFA/rt CH2Cl2 EtO/ 57.8 100-102 C10H7FO3 hexane 6f Cl H H TFA/rt CH2Cl2 ---- 32.3 105-106 C10H7ClO3 6h H H CH3 Amberlyst Hexane ---- 54.0 liquid C11H10O3 XN1010 hexane(1/9) * Actual values dor elemental combustion analysis were within 0.4% of calculated values. Nitrogen containing compounds were analyzed for C, H, N; others for C, H only. The ester (6) can be easily converted to the acid (7) and from the acid (7) to the acid chloride (8). Reaction of acid chloride (8) with an amine such as 2-aminomethyl-1-ethylpyrrolidine as illustrated provides the 7-carboxamide (9) without difficulty. Table III below summarizes the analytical data for six benzojb)furan-7-carboxamides in accordance with the present invention produced by Reaction Scheme I. EMI13.1 TABLE III Recryst Analytical Compounds RÚ Rê Xê Salt Solvent Yield(%) mp( C) Analysis* 9a H H H 1.5C4H4O4** 2-butanone 38.9 131-132.5 C16H20N2O2 #1.5C4H4O4 9b H Br H ---- EtOAC/hexane 49.7 81-83 C16H19BrN2O2 9c H Cl H 0.5C4H4O4 2-butanone 44.3 158-159 C16H19ClN2O2 #0.5C4H4O4 C4H4O4 2-butanone 64.9 126.5- C16H19ClN2O2 128.5 C4H4O4 9d H F H C4H4O4 2-butanone 64.6 140-142 C16H19FN2O2 #C4H4O4 9f Cl H H 1.25C4H4O4 2-butanone 30.4 115-118 C16H19ClN2O2 1.25C4H4O4 9h H H CH3 ---- ---- 51.1 liquid C17H22N2O2 * Actual values for element combustion analysis were within 0.4% of calculated values. Nitrogen containing compounds were analyzed for C, H, N; others for C, H only. ** C4H4O4 = fumrate Reaction Scheme I above is illustrated in more detail in Synthesis Example 1 below by reference to the synthesis of 5-chloro-N- (l-ethyl-2-pyrrolidinylmethyl) benzolb]furan-7-carboxamide fumarate (Compound 9c). Reaction Schemes II-IV below are alternative syntheses for dihydrobenzoiblfuran-7-carboxamides. Reaction Scheme II which is particularly useful in synthesizing the 2-alkyl-2,3-dihydrobenzo[b]furan derivatives proceeds from the Claisen rearrangement product (4) of Reaction Scheme (I) as follows: REACTION SCHEME II EMI14.1 The intermediate (10) is obtained by reacting the product (4) with mercuric acetate in dry THF in the dark. Reduction of intermediate (10) with sodium borohydride in 3N NaOH gives, upon workup by column chromatography, the dihydrobenzotblfuran-7-carboxylic ester (11). The ester can be converted to the corresponding acid chloride and reacted with an appropriate amine to give dihydrobenzo[b]furans such as compound (13) as previously outlined. Table IV below provides the analytical data for dihydrobenzo[b]furan esters (11) obtained by Reaction Scheme II. EMI16.1 TABLE IV Chromato graphic Recryst. Analytical Compounds RÚ R2 X2 solvent solvent Yield (%) mp( C) Analysis* 11a H H H EtOAc/hexane ---- 54.0 oil C11H12O3 (0/100 to 20/100) 11b H Br H EtOAc/hexane Hexane 47.2 67-68 C11H11BrO3 (0/100 to 25/100) 11e H OCH3 H ---- Hexane 68.3 75-77 C12H14O4 11f Cl H H ---- Hexane 71.9 77-80 C11H11ClO3 11g OCH3 H H CH2Cl2 ---- 63.2 65.5-68.5 C12H14O3 11h H H CH3 EtOAc/hexane ---- 53.0 oil C12H14O3 (0/100 to 10/100) * Actual values dor elemental combustion analysis were within 0.4% of calculated values. Nitrogen containing compounds were analyzed for C, H, N; others for C, H only. Substituents can be introduced into the benzene ring by selecting the appropriate substituted salicyclic acid as a starting material or by reacting the benzofuran carboxylic acid with the appropriate electrophilic reagent. For example, chlorination of the 4-chloro derivative (12f) with sulfuryl chloride at room temperature furnishes the 4,5-dichloro derivative (12i) (Table V) in 54% yield. Nitration of compound (12f) in refluxing HN03/TFA gives the 4-chloro-5-nitro derivative (12j) in moderate yield. In general it is desired to perform the electrophilic substitutions before condensing the amine to avoid hydrolysis of the amine during the substitution. Other modifications can be performed after condensation and are discussed below. Table V below provides the reaction conditions for hydrolysis/substitution of the esters (11) with the yield and melting point for seven dihydrobenzofuran-7carboxylic acid derivatives produced by following Reaction Scheme II. The carboxamides (13) are prepared by reaction of the acid chlorides or the esters (11) by heating with the appropriate amine, which in the case of compound (13) is 2-aminomethyl-l-ethylpyrrolidine. In most cases, the carboxamides are most conveniently isolated as their fumarate salts. Reaction Scheme II is illustrated in more detail in Synthesis Example 2 for the synthesis of 4-chloro-N-(lethyl-2-pyrrolidinylmethyl)-2-methyl-2,3-dihydrobenzolblfuran-7-carboxamide fumarate (compound 13f). Table VI below summarizes the analytical data of several dihydrobenzofuran-7-carboxamides in accordance with the present invention. EMI18.1 TABLE V Reaction Recryst. Compounds RÚ Rê Xê Conditions Solvent Yield (%) mp ( C) 12a H H H 10% NaOH ---- 96.5 oil 12b H Br H KOH/CH3OH/H2O ---- 95.3 206-209 12e H OCH3 H " ---- 95.6 122-124 12f Cl H H " ---- 99.0 210-213 12g OCH3 H H " ---- 96.5 209-211 12i Cl Cl H SO2Cl2 EtOAc 54.3 204-207 12j Cl NO2 H HNO3/TFA EtOAc 34.8 193-197 EMI19.1 TABLE VI Recryst. Analytical Compounds RÚ Rê Xê Methods Salts Solvent Yield (%) mp ( C) Analysis* 13a H H H A ---- ---- 76.5 oil C17H24N2O2 13b H Br H B HCl CH2Cl2/ 53.2 160-170 C17H23BrN2O2#HCl 13e H OCH3 H B C4H4O4** ---- 62.8 143.5-145 C18H26N2O3#C4 H4O4 13f Cl H H A C4H4O4 2-butanone 45.2 163-164.5 C17H23ClN2O2#C 4H4O4 13g OCH3 H H A C4H4O4 2-butanone 33.3 144-147 C18H26N2O3#C4 H4O4 13h H H CH3 B C4H4O4 EtOH/ 42.3 158-160 C18H26N2O2#C4 acetone H4O4 13i Cl Cl H A C4H4O4 2-butanone 37.3 157-159 C17H22ClN2O2#C 4H4O4 13j Cl NO2 H A ---- ---- 87.9 solid C17H22ClN3O4 13k Cl NH2 H Pd/C C4H4O4 acetone 31.2 165-168 C17H24ClN3O2. C4H4O4 Actual values for elemental combustion analysis were within 0.40 of calculated value. Nitrogen containing compounds were analyzed for C, H, N; others for C, H only. * C4H4O4 = fumarate 2,3-Dihydrobenzo[b]furan-7-carboxylic acids (15) ean be prepared according to Reaction Scheme III by lithiation of 2,3-dihydrobenzo[b]furan (14) with n-butyl lithium in TMEDA/hexane at -room temperature, followed by quenching with dry ice and acidifying with concentrated HCl. REACTION SCHEME III EMI20.1 (15a) Rê=H (16a) Rê=H (15b) Rê=Br (16b) Rê=Br (15c) Rê=Cl (16c) Rê=Cl (15k) Rê=NO2 (16k) Rê=NO2 EMI20.2 The acid (15a) serves as a starting material for other 5-substituted derivatives. Bromination of 15a with bromine in acetic acid containing a trace amount of iron yields the 5-bromo derivative (15b). Chlorination of (15a) with sulfuryl chloride at room temperature affords the 5-chloro derivative (15c). Nitration of (15a) carried out in either HNO3/TFA at OOC to room temperature or HNO3 in acetic acid at 700C yields the 5-nitro derivative (15k). Other modifications can be performed after condensation with the amine. In particular, the 5-nitro derivative can be catalytically reduced'to produce the 5-amino derivative. Acetylation or sulfonylation of the 5-amino compound produces the corresponding acylamide and sulfonamide. These compounds together with their melting point and analytical data are shown in Table VII below. The reactions are illustrated in Synthesis Examples 5, 6 and 7 below. EMI22.1 TABLE VII Recryst. Analytical Compounds Rê Salts Solvent Yield (%) mp ( C) Analysis* 16a H 1.5C4H4O4** 2-butanone 49.7 151-152.5 C16H22N2O2#C4H4O4 16b Br C4H4O4 2-butanone 41.1 160-161.5 C16H21BrN2O2#C4H4O4 16c Cl 1.5C4H4O4 2-butanone 42.9 149-150 C16H21ClN2O2#1.5C4H4 O4 16k NO2 HCl 2-butanone 56.2 206.5-208.5 C16H21N3O4#HCl 16l NH2 C4H4O4#O#5H2O 2-butanone 41.4 98-101 C16H23N3O2#C4H4O4. 0.5H2O 16m NHCOCH3 C4H4O4 EtOh 69.4 179-181 C18H25N3O3#C4H4O4 16n NHSO2- ---- EtOH 74.6 180-182 C17H25N3O4S CH3 Actual values for elemental combustion analysis were within 0.40 of calculated value. Nitrogen containing compounds were analyzed for C, H, N; others for C, H only. * C4H4O4 = fumarate Reaction Scheme III is illustrated in more detail by reference to the synthesis of 2,3-dihydrobenzotb]furan -7-carboxylic acid (15a) and the 5-bromo and 5-nitro derivatives thereof in Synthesis Example 3 below. Dihydrobenzofuran-7-carboxamides can also be obtained through the following Reaction Scheme IV from 2, 6-dibromophenols. REACTION SCHEME IV EMI23.1 Reaction Scheme IV proceeds via alkylation of a 2,6-dibromophenol (18) by reaction with 1,2-dibromoethane to provide the phenyloxyethyl bromide (19). By lithiating the bromide (19) using n-butyl lithium, quenching in dry ice and acidifying 2,3-dihydrobenzo[b]furan-7-carboxylic acid (20) is obtained. This acid is then converted to the acid chloride and this is reacted with the appropriate amine to give the carboxamide; alternatively, the acid can be first converted to the ester. Reaction of this with the amie leads to the carboxamides Reaction Scheme IV is illustrated in more detail in Synthesis Example 4 below wherein 5-methyl-N-(1-ethyl-2- pyrrolidinylmethyl)-2,3-dihydrobenzo[b]furan-7 carboxamide hydrochloride (21) is prepared by this reaction route. Hereinbelow the foregoing syntheses are illustrated in more detail by the following non-limiting Synthesis Examples. SYNTHESIS EXAMPLE 1 a. Methyl 5-chloro-2-hydroxybenzoate (2c) A mixture of 5-chloro-2-hydroxybenzoic acid (lOOg, 0.57 mol), 20 ml of conc. H2SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2SO4 was then added and the solution heated for an additional 24 hours. -The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2C03 and then extracted with CH2C12 (2 x 400 ml). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44-460C. IR (nujol) 1680 (ester) cm 1. NMR (CDC13) S 10.60 (s, 1H, OH), 7.73 (d, 1H, HBC=3 Hz HC), 7.33(d of d, 1H, JAB=9 Hz, 1B), 6.87 (d, 1H, HY), and 3.92(s, 3H, CH3). b. Preparation of methyl 2-allyloxy-5-chlorobenzoate (3c) A mixture of methyl 5-chloro-2-hydroxybenzoate (2c) (45.0 g, 0.24 mol), allyl bromide (62.6 ml, 0.75 mol) and ground potassium carbonate (66.67 g, 0.48 mol) in 750 ml of dry acetone was heated under reflux for 2 1/2 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide in the filtrate was evaporated to dryness to yield compound 3c quantitatively as a white solid, mp 25-260C. IR (nujol) 1738 (ester) cm 1. NMR (CDCl3) # 7.63 (d, lH, JBC=3 Hz, HC), 7.27 (d of d, 1H, JAB=9 Hz, HB), 6,77 (d. 1H, HA), 6.30-6.47 (m, 3H, olefinic protons) and 3.87 (s, 3H, CH3). c. Preparation of methyl 5-chloro-2-hydroxy-3-(2-propenyl)- benzoate (4c) Methyl 2-allyloxy-5-chlorobenzoate (3c) (76.66 g, 0.34 mol) was heated at 200 C without solvent under argon for 20 hours. The dark brown liquid was distilled to give 67.9 g (88.5%) of product 4c as a clear liquid,b.p. 130-1360C (3.4 torr). IR (neat) 1675 (ester) cm-1. (CDCl3) 6 10.50 (s, 1H, OH), 7.20 (d, lH, J=3 Hz, aromatic proton), 7.13 (d, 1H, aromatic proton), 6.23-4.80 (m, 3H, olefinic protons), 3.90 (s, 3H, CH3), and 3.32 (d, 2H, J=6 Hz, CH2). d. Preparation of 3-carbomethoxy-5-chloro-2-hydroxy phenylacetaldehyde (5c) Osmium tetroxide (1.0 g, 3.9 mmol) was added to a mixture of methyl 5-chloro-2-hydroxy-3-(2-propenyl)benzoate (4c) (22.7 g, 0.1 mol), ether (400 ml), and water (400 ml). After stirring at room temperature for 5 minutes, sodium periodate (47.06 g, 0.22 mol) was added in portions. The mixture was stirred at room temperature for another 21 hours, and then poured into 800 ml of water. The layers were separated and the aqueous layer extracted with ethyl ether (2 x 400 ml). The organic layers were combined,-dried over anhydrous Na2S04 and then filtered through a column of Florisil (85 g) to remove inorganic impurity. Evaporation of the ether yielded Sc quantitatively as a brown solid, m.p. 49-590C, which appeared hygroscopic. The crude product was used for the next reaction without purification. NMR (CDC13) # 10.90 (s, lH, OH), 9.67 (t, lH, J=1.5 Hz, CHO), 7.70 (d, lH, J=3 Hz, aromatic proton), 7.23 (d, lH, aromatic proton), 3.97 (s, 3H, CH3) and 3.70(d, 2H, CH2). e. Preparation og 7-carbomethoxy-5-chlorobenzo[b]furan (6c) A trifluroracetic acid (25 ml) solution of 3-carbomethoxy-5-chloro-2-hyoroxyphenylacetaldehyde (5c) (5.20 g, 22.7 mmol) was refluxed for 2 hours under argon, and then poured into saturated Na2C03. The resulting precipitate was collected by filtration, and then purified by column chromatography (100% CH2C12) to give 6c as a cream colored solid (3.02 9, 63.2% yield). Analytical sample was prepared by recrystallization from ethyl ether, mp 144-145 C. IR (nujol) 1710 (ester) cm'l. NMR (CDC13) # 7.87-6.70 (m, 4H, aromatic protons) and 4.0 (s, 3H, CH3). Anal. Calcd for C10H7ClO3: C, 57.03; H, 3.35. Found: C, 57.03, H, 3.48. f. Preparation of 5-chlorobenzo[b]furan-7-carboxylic acid ,(7c) A solution of 7-carbomethoxy-5-chlorobenzo[b]furan (6c) (3.02 g, 14.3 mmol) containing potassium hydroxide (3.22 g) in 100 ml of aqueous methanol (CH3OH/H2O=3/2) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was acidified with conc. HC1 to pH of about 1, cooled in freezer for several hours and filtered to give 7c as an off-white solid (2.65 g, 94.3%), mp 212-2150C. NMR (DMSO-d6) i 8.0-6.87 (m, SB, aromatic protons and OH). g. Preparation of 5-chloro-N-(1-ethyl-2-pyrrolidinyl- methyl)benzo[b]furan-7-carboxamide fumarate (9c) A mixture of S-chlorobenzo[b)furan-7-carboxylic acid (7c) (4.41 g, 22.4 mmol) and thionyl chloride (6.5 ml, 89.1 mmol) in 90 ml of toluene was heated under reflux for 2 1/2 hours. The solvent and excess thionyl chloride were removed under reduced pressure to give the corresponding 7-carboxylic acid chloride (8c) as a yellow stolid. The acid chloride was then dissolved in 90 ml of methylene chloride and cooled to OOC with an ice bath. To this solution was added dropwise 2-aminomethyl-l ethylpyrrolidine (2.88 g, 22.4 mmol) in 20 ml of methylene chloride. The yellow solution was stirred at ambient temperature overnight, and then poured into 90 ml of 10% NaOB. The layers were separated, and the organic layer dried over anhydrous Na2SO4 and evaporated- to give the desired product 9c as its free base (6.46 g, 94.0% yield). The carboxamide is conveniently isolated as its fumarate by adding to the free base in 100 ml of absolute ethanol 1 equivalent of fumaric acid. After stirring at room temperature for 1 hour, the solution was reduced to a small volume, this was triturated with acetone, cooled in the freezer briefly, and the solid collected on a filter to give 9c as an off-white solid (7.64 g, 80.7%). The analytical sample was prepared by recrystallization from 2-butanoate, mp 126.5-128.5 C NMR (DMSO-d6) # 8.70 (br s, 1H, exchangeable with D20, NH), 8.0 (d, 1H, J=2 Hz, aromatic proton), 7.77 (d, 1H, aromatic proton), 7.57 (d, 1H, aromatic proton) 7.20 (br s, exchangeable with D20, 2 COOH), 6.93 (d, 1H, aromatic proton), 6.47 (2, 2H, 2CH), 3.70-1.60 (m, llH, 5CH2 and CHN), and 1.20 (t, 3H, J=7 Hz, CH3). Anal. Calcd for C16HlgClN202. C4H4O4: C, 56.81; H, 5.48; N, 6.62. Found: C, 57.11; H, 5.52; N, 6.52. SYNTHESIS EXAMPLE 2 a. Preparation of methyl 4-chloro-2-hydroxybenzoate (2f) A mixture of 4-chloro-2-hydroxybenzoic acid (200 g, 1.16 mol) and 40 ml conc. sulfuric acid in 400 ml of methanol was heated under reflux for 20 1/2 hours. The solvent was evaporated under reduced pressure, the residue poured into aqueous saturated Na2CO3, and then extracted with ethyl ether (3 x 500 ml). The combined organic layers were dried over anhydrous Na2S04, and evaporated to give 2f (191.6 g, 88.6% yield) as an oil. This was used for the next reaction without purification. IR (neat) 3150 (OH), 1728 (C=O), and 1678 (C=O) cm'l. NMR (CDCl3) d 10.27 (br S, 1H, OH), 7.47 (d, 1H, 3BC=8 Hz, Hc), 6.80 (d, 1H, JAB=2 Hz, HA), 6.63 (d of d, 1H, HB), and 3.85 (s, 3H, CH3). b. Preparation of methyl 2-allyloxy-4-chlorobenzoate (3f) A mixture of methyl 4-chloro-2-hydroxybenzoate (2f) (96.3 g, 0.52 mol), allyl bromide (134 ml, 1.55 mol) and ground potassium carbonate (107 g, 0.77 mol) in 1500 ml of dry acetone was heated under reflux for 20 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide evaporated to dryness to give 3f (117 g, 99.6% yield) as a yellow solid, mp 47-550C. NMR (CDC13) t 7.73 (d, 1H, J=8 Hz, aromatic proton meta to Cl), 6.97 (m. 2H, aromatic protons alpha to C1), 6.40-5.17 (m, 3H, olefinic protons), 4.57 (m, 2H, CH2) and 3.90 (s, 3H, CH3). c. Preparation of methyl 4-chloro-2-hydroxy-3-(2-propenyl benzoate (4f) A solution of methyl 2-allyloxy-4-chlorobenzoate (3f) (50.6 g, 0.22 mol) in 100 ml of N,N-dimethylaniline was heated under argon in an oil bath at 190-205 C for 20 hours. The solvent was removed by distillation and the residue purified by column chromatography (silica gel, CH2cl2thexane) to give 4f (36.0 g, 71.18 yield) as a very light oil. IR (nujol) 1665 (C=O) cm-1. NMR (CDC13) # 11.23 (s, 1H, OH), 7.47 (d, 1H, J=9 Hz, aromatic proton meta to C1), 6.77 (d, 1H, aromatic proton alpha to C1), 6.17-4.77 (m, 3H, olefinic protons), 3.87 (s, 3H, CH3) and 3.50 (m, 2H, CH2). d. Preparation of 7-carbomethoxy-4-chloro-2-methyl-2,3 dihydrobenzo[b]furan (11f) A solution of methyl 4-chloro-2-hydroxy-3 (2-propenyl)benzoate (4f) (4.17 g, 18.4 mmol) and mercuric acetate (5.86 g, 18.4 mmol) in 60 ml of THF was heated under reflux for 3 hours, and then cooled to room temperature. To this was added dropwise at 0 C a solution of 0.70 g (18.4 mmol) sodium borohydride in 4.2 ml of 3 N NaOH. When the addition was complete, the mixture was stirred at ambient temperature for an additional 2 hours. and then treated with S5 ml saturated Na2c03 The precipitated mercury was removed by filtration with the aid of Celite. The organic layer was separated, dried over anhydrous Na2so4 and evaporated to give a mixture of product lif and starting material (4f) (total 3.89 g). The product lif was isolated by recrystallization from hexane to afford 3.0 g (71.9% yield) of white solid, mp 77-80 C. IR (KBr) 1685 (C=O) cm 1. NMR (CDC13) d 7.50 (d, 1H, 5=8 Hz, aromatic proton meta to Cl), 6.67 (d, lH, aromatic proton alpha to Cl), 5.03 (m, 1H, CH), 3.83 (s, 3H, OCH3) 3.03 (m, 2H, CH2) and 1.52 (d, 3H, J=6 Hz, CH3). Anal. Calcd for 011H11C103: C, 58.29; H, 4.89. Found: C, 58.27; H, 4.99. e. Preparation of 4-chloro-2-methyl-2,3-dihydro benzo[b)furan-7-carboxylic acid (12f) To a solution of 7-carbomethoxy-4-chloro-2methyl-2,3-dihydrobenzo[b]furan (11f) (2.76 g, 12.2 mmol) in 48 ml of methanol there was added 3.0 g (53 mmole) of KOH in 32 ml of water. The solution was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was treated with 100 ml of water, and then acidified with conc. HC1 to pH of about 1. The resulting white solid 12f was collected on a filter to yield 2.88-g (g9.08) of acid, mp 210-213 C. IR (KBr) 1668 (C=O) cm-1. NMR (DMSO-d6) # 7.63 (d, 1H, J=9 Hz, aromatic proton meta to Cl), 6.93 (d, 1B, aromatic proton alp to Cl), 5.13 (m, 2H, OH, and CH), 3.63-2.60 (m, 2E, CE2) and 1.50 (d, 3B, J=6 Hz, CE3). Preparation of 4-chloro-N-(1-ethyl-2-pyrrolidinyl methyl)-2-methyl-2,3-dihydrobenzo[b]furan-7 carboxamide fumarate (13f) A mixture of 4-chloro-2-methyl-2,3-dihydrobenzo- [b]furan-7-carboxylic acid (12f) (2.42 9, 11.4 mmol) and thionyl chloride (4.2 rtl, 57.0 mmol) in 30 ml of toluene was heated under reflux for 3 hours. The solvent and excess thionyl chloride were removed under reduced pressure to give the corresponding 7-carboxylic acid chloride as a cream colored solid. The acid chloride was then dissolved in 30 ml of CH2Cl2 and cooled to 0 C in an ice bath. To this there was added dropwise 2-aminiomethyl-1-ethylpyrrolidine (1.46 g, 11.4 mmol) in 5 ml of methylene chloride. The solution was stirred at ambient temperature overnight, and then poured into saturated Na2C03. -The organic layer was separated, dried over anhydrous Na2SO4 and evaporated to give the desired product as a brown oil (2.77 9). To a solution of the free base in 50 ml of absolute ethanol was added 1.0 g (8.6 mmoi) of fumaric acid. The mixture was stirred at room temperature for 2 hours, ano cooled in the freezer for I hour. The resulting precipitate was collected on a filter and the solid purified by recrystallization from 2-butanone to give 13f (2.26 9, 45.2E yield) as white cystals, mp 163-164.5 C. IR (nujol) 3350 (MH), 1710 (CO2H), and 1660 (CONH) cm-1. NMR (DMSO-d6) # 8.20 (br s, 1H, NH), 7.63 (d, 1H, J=8 Hz, aromatic proton meta to Cl), 7.33 (br s, 2H, COOH), 6.97 (d, 1H, aromatic proton alpha to C1), 6.57 (S, 2H, 2CH=), 5.17 (m, 1H, CHO), 3.77-1.63 (in, 12H, 6CH2), 1.45 (d, 3H, J=6 Hz, CH3CHO), and 1.13 (t, 3H, 3=7 Hz, CH2CH3). Anal. Calcd for C17H23ClN2O2#C4H4O4: C, 57.47; H, 6.20; N, 6.38. Found: C, 57.62; H, 6.29; N, 6.22. SYNTHESIS EXAMPLE 3 a. Preaparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room -temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA),- followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for- 4 hours,-and then poured into dry ice (pre-washing witch anhydrous either). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The agueous layer was acidified with conc. HC1 to pH 1, cooled and the precipitate collected on-a filter. This was recrystallized from CH2C12 to give 15a (9.43 g, 54.7%) as a white solid, mp 167-169.5 C. b. Preparation of 5-bromo-2,3-dihydrobenzo[b]furan-7- carboxylic acid (15b) To an ice-cooled acetic acid solution (5 ml) of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 9, 2.0 mmol) there was added ifen (8 mg, 0.14 mmol) and bromine (0.32 g, 2.0 mmol) in 1 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). After cooling in the freezer for 1 1/2 hours the product was collected on a filter, and recrystalli;ed from ethyl acetate to give 0.24 g (50.3%) of 15b as a white crystalline solid, mp 228-229 0C. c. Preaparation of 5-nitro-2,3-dihydrobenzo[b]furan-7 carboxylic acid 815k) Method A To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) in 3 ml of TFA there was added dropwise 0.6 ml of HN03. At the end of 1 hour, the cooling bath was removed. After an additional 3 hours of stirring, the mixture was poured into ice-water. The precipitate was collected on a filter to give 0.22-g (52.6%) of crude 15k. This was recrystallized from ethyl acetate to provide 88 mg of acid 15k (21.4%), mp 249-251.5 C. Method B: To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 rmnol) in 3 ml of -acetic acid there was added dropwise 0.6 ml of HN03. The mixture was stirred in a warm oil bath (7000) for 24 hours, and then poured into water. After cooling, the product was collected on a filter to give 0.21 g of solid (50.2%). This was recystallized from ethyl acetate to afford 0.14 g (33.5%) of 15k, mp 249-251.5 C. d, Preparation of N-(1-ethyl-2-pyrrolidionylmethyl)-5- nitro-2,3-dihydrobenzo[b]furan-7-carboxamide(16k) A mixture of (15k) (3.0 tmnol) and thionyl chloride (12.3 mmol) in 15 ml of toluene was heated under reflux for 3 hours. The solvent and excess of thionyl chloride was removed under reduced pressure to give the corresponding 7-carboxylic acid chloride. This was then dissolved in 15 X methylene chloride and cooled to OOC in an ice bath. To this there was added dropwise 2-aminomethyl-1-ethylpyrrolidine (3.0 mnnol) in 5 ml of methylene chloride. The yellow solution was stirred at ambient temperature overnight, and then taken to dryness in vacuum. The residue was recrystallized from 2-butanone to give 16k as a solid. SYNTHESIS EXAMPlE 4 a. Preparation of 2-(2,6-dibromo-4-methylphenyloxy)ethyl bromide (19) A mixture of 2,6-dibromo-4-methylphenol (18) (26.59 g, o.l mol), 1,2-dibromoethane (11.2 ml, 0.13 mcl) and potassium hydroxide (8.42 g, 0.15 mol) in 200 ml of absolute ethanol was heated under reflux for 24 hours. The inorganic salt was collected on a filter and the filtrate taken to dryness. The resulting mixture was treated with ethyl ether, chilled, and the solid, which proved to be recovered phenol, collected on a filter. The filtrate was evaporated to afford the ether 19 (24.5 g, 65.7%) as a liquid. This was purified by distillation (0.5 torr, 120-124 C) to yield 19.79 g (53.0%) of product. NMR (0DC13) 6 7.25 (s, 2H, aromatic protons), 3.55 - 4.38 (m, 4H, 2CH2), and 2.27 (s, 3H, CH3) b. Preparation of 5-methyl-2,3-dihydrobenzo[b]furan-7- carboxylic acid (20) To a stirred solution of 2-(2,6-dibromo-4-methyl- phenyloxy)ethyl bromide (19) (5.82 g, 15.6 mmol) in dry THE (90 ml) and hexane (30 ml) under argon there was added 7.8 ml of n-BuLi (2.5 M in hexane) at 780C (dry ice/acetone bath). After 30 minutes at 78 C, an additional 7.8 ml of n-BuLI was added. After an additional 1 hour stirring, the light yellow reaction solution was poured into a slurry of dry ice (prewashed with dry ether). After the mixture had come to room temperature, the precipitated white solid was collected on a filter, treated with 1N HCl to adjust the pH of the supernatant liquid to 1. The mixture was cooled briefly in the freezer, and the solid collected on a filter to afford 2.52 g (90.7%) of acid 20. The crude product was recrystallized from CH3OH/H2O to yield 1.70 9 (61.2%) of 3 as a white solid, mp 177-179 C. IR(KBr) 3420 (OH) and 16S0(O=0) cm-1. NMR(CDC13) S 8.47 (br s, 1H, OH), 7.50 (s, 1H, aromatic proton), 7.15 (s, 1H, aromatic) proton), 4.70 (t, 2E, J=9 Hz, OC 2), 3.20 (t, 2B, OCH2CH2), and 2.32 (s, 3H, CH3). Anal. Calcd for c10H10O3: C, 67.41; H, 5.66. Found: C, 67.45; B, 5.78. c. Preparation of N-l-ethyl-2-pyrrolidinylQmethyl) -5-methyl-2,3-dihydrobenzo[b]furan-7-carboxamide hydrochloride (21) A mixture of 2-methyl-2,4-dihydrobenzo[b]furan-7- carboxylic acid (20) (3.43 g, 19.25 mmol) and thionyl chloride (7.0 ml, 96.2 mmol) in 40 ml of toluene was heated under reflux for 3 hours. The solvent and excess of thionyl chloride were removed under reduced pressure to give the corresponding 7-carboxylic acid chloride. This was then dissolved in 25 ml of CH2C12 and cooled at OOC with an ice bath. To this there was added dropwise 2-aminomethyl-1-ethylpyrrolidine (2.47 g, 19.25 mmol) in 10 ml of CH2C12. The solution was stirred overnight at room temperature and then evaporated to dryness to afford crude carboxamide (6.24 9, 100%). This was purified by recrystallization from acetone to give 5.29 g (84.68) as white crystals, mp 203.5-2050C. IR (nujol) 3340 (NH), and 1645 (C=O) cm 1. NMR (DMSO # 8.13 (br s, 1H, NH), 7.25 (s, 1H, aromatic proton), 7.10 (s, lH, aromatic proton), 4.58 (t, 2H, J=9 Hz, OCH2), 1.88 (s, 3H, CH3), and 1.25 (t, 3H, J=7 Hz, CH2CH3). Anal. Calcd for C17H24N202.ECl C, 62.85; H, 7.76; N, 8.62. Found: C, 62.99; H, 7.79; N, 8.56. SYNTHESIS EXAMPLE 5 a. Preparation of 5-amino-N-(1-ethyl-2-pyrrolidinyl methyl)-2,3-dihydrobenzo[b]furan-7-carboxyamide fumarate (161) A mixture of N- (l-ethyl-2-pyrrolidinylmethyl)-5 nitro-2,3-dihydrobenzo[b]furan-7-carboxamide (16k) (1.08 g, 3.4 mmol) and¯palladium dn carbon (5%) (0.10 g) in 25 ml of absolute ethanol was shaken under hydrogen for 18 hours. The catalyst was collected on a filter with the aid of Celite and the filtrate evaporated. The residue was purified by column chromatography (silica gel, NH4OH/CH3OH/CH2C12 = 0.1/1/100 to 0.1/6/100). The product was isolated as the fumarate and recrystallized from 2-butanone to afford 0.57 g (41.4%) of 161 as a yellow solid, mp 98-101 c. SYNTHESIS EXAMPLE 6 a. Preparation of 5-acetamido-N-(1-ethyl-2-pyrrolidinyl- methyl)-2,3-dihydrobenzo[b]furan-7-carboxamide fumarate (16m) A solution of 5-amino-N-(l-ethyl-2-pyrrolidinyl- inethyl)-2,3-dihydrobenzo[b)furan-7-carboxamide (161) (1.02 g, 3.5 mmol) in 10 ml of acetic anhydride was stirred at room temperature overnight. The mixture was added to 50 ml of ethyl ether, cooled and the precipitate collected on a filter. This solid was dissolved in 50 ml of CH2C12, and washed with saturated NaHCO3 (2 x 50 ml). The organic layer was dried over anhydrous Na2SO4,-and evaporated to give the free base (1.03 g, 88.8%). The product was characterized as its fumarate; there was obtained 1.26 g of the salt (80.3%), mp 179-181 C (EtOH). SNYNTHESIS EXAMPLE 7 a. Preparation of N-(1-ethyl-2-pyrrolidinylmethyl)-5- methanesulfonylamido-2,3-dihydrobenzo[b]furan-7- carboxamide (16n) A solution of 5-amino-N-(l-ethyl-2-pyrrolidinylmethyl)-2,3-dihydrobenzo[b]furan-7-carboxamide (161) (1.80 g. 6.2 mmol) and methanesulfonyl chloride (12.78 g. 0.11 mol) in 30 ml of methylene chloride was heated to reflux overnight. The solution was diluted with CH2C12 (30 ml), and then extracted with water (2 x 30 ml). The combined aqueous layers were made basic with NaHC03 powder, and extracted with CH2C12 (4 x 50 ml). The organic extracts were combined, dried over anhydrous Na2S04, and evaporated to give crude 16n (2.25 g, 98.8%). This was recrystallized from EtOH,charcoal to afford 1.70 g of amide as a white solid, mp 180-1820C. Hereinabove the invention has been described by reference to the synthesis of. pyrrolidinylmethyl derivatives by reacting benzo[b]furan-7-carboxylic or dihydrobenzob)furan-7-carboxylic acids or the corresponding esters or acid chlorides with 2-aminomethyl-1-ethylpyrroline. Other benzofuran carboxamides as defined in A in general formula I can be prepared in an analogous manner by reacting the aforementioned acids, esters or acid chlorides with other amines as shown in Synthesis Example 8 to 10 below. SYNTHESIS EXAMPLE 8 a. Preparation of 5-bromobenzo[b]furan-7-carboxylic acid chloride A mixture of 5-bromobenzo[bafuran-7-carboxylic acid (5.5 g, 22.8 mmol) and thionyl chloride (6.7 ml, 91.9 mmol) in 40 ml of toluene was heated under reflux for 3 hours. The solvent and excess thionyl chloride were then removed under reduced pressure to give 8b (5.04 9, 85.28) as a yellow solid. This was used for subsequent reactions with amines without purification. b. Preparation of 5-bromo-N-(2-diethylaminoethyl)benzo[b]- furan-7-carboxamide hydrochloride To an ice-cooled solution of 5-bromobenzo[b]furan- carboxylic acid chloride (1.5 g, 5.8 mmol) in 15 ml of CH2C12, there was added N,N-diethylethylenediamine (0.74 g, 6.4 mmol) in 10 ml of CH2Cl2. After stirring at ambient temperature overnight, the precipitate was collected on a filter to give the crude amide (1.14 g, 53.2%). This was recrystallized from ethanol (decolorization with charcoal) to give 0.54 g (24.8%) of the desired amide as a white solid, mp 202-203.5 C. IR (KBr) 1675 (C=O) cm Anal. Calcd for C15H19BrN2O2#HCl: C, 47.95; H, 5.37; N, 7.46. Found: C, 47.87; H. 5.48; N, 7.33. SYNTHESIS EXAMPLE 9 a. Preparation of lexo]-5-bromo-N-i8- (phenylmethyl) -8- azabicyclo[3,2,1]oct-3-yl]benzo[b]furan-7-carboxamide To an ice-cooled solution of 5-bromobenzo(b)furan- 7-carboxylic acid chloride prepared as in Synthesis Example 8 (1.5 g, 5.8 mmol) in 15 ml of CH2C12, there was added 8-benzyl-3 B -amino-l aH,5 &alpha;H-nortropane (1.25 g, 5.8 mmol) in 10 ml of CH2C12. The mixture was stirred at ambient temperature overnight and then poured into saturated aqueous NaHC03. The layers were separated, and the organic layer dried over anhydrous Na2SO4. Evaporation of solvent gave crude amide (2.28 g, 89.5%). The analytical samlple was obtained by two recrystallizations from ethanol to give a sample of the target amide pure (0.81 g, 31.8%) as a white crystalline solid, mp 161-163 C. IR (KBr) 1662 (C=O) cm 1. Anal. Calcd for C23H23BrN2O2: C. 62.88; H, 5.28; N, 6.38. Found: C, 62.99; H, 5.37; N, 6.27. SYNTHESIS EXAMPLE 10 1. Preparation of N-(1-benzyl-3-pyrrolidinyl)-5-bromo benzo[b]furan-7-carboxamide furamarate To an ice-cooled solution of 5-bromobenzo[b]furan7-carboxylic acid chloride prepared as in Synthesis Example 8 (1.82 g, 7.0 mmol) in 25 ml of OH2Cl2, there was added 3-amino-l-benzylpyrrolidine (1.24 g, 7.0 mmol) in 10 ml of CH2C12. The mixture was stirred at ambient temperature overnight, and then poured into saturated aqueous NaHOO3. The layers were separated, and the organic layer dried over anhydrous Na2S04. Evaporation of the solvent afforded the desired product as its free base (1.93 g, 68.9%). This was more conveniently isolated as its fumarate by adding to the free base in 15 ml of absolute ethanol 0.56 g of fumaric acid, and the mixture stirred at room temperature for 1 hour. The resulting precipitate was collected on a filter to give the salt (2.12 g, 58.6%'). This was recrystallized from ethanol to furnish an analytically pure sample of the desired amide (1.10 g, 30.5%) as a beige solid, mp 197-200tC. IR (KBr) 1710 (COOB), 1655 (CONH) cm Anal. Calcd for O20H19BrN202.C4H4O4: C, 55.93; H, 4.50; N, 5.44. Found: C, 56,44; H, 4.85; N, 5.81. IN VIVO SCREENING TESTS a. Antipsychotic Screen The effect of each of the benzofurancarboxamides shown in Table VIII below on apomorphine induced climbing behavior was tested under the conditions described by Costetin et al, "Rapid and Dissociated Changes in Sensitivities of Different Dopamine Receptors in Mouse Brain", Nature, 257, 405 (1975). Each mouse was administered from 0.1 to 50 mg/kg of test compound and antagonism was observed 20 minutes after injection of 1 mg,kg apomorphine induced climbing behavior. The ED 50 values are shown in Table VIII. b. Antiemetic Screen Each of the test compounds shown in Table VIII was administered subcutaneously to two beagle dogs at dosage levels of 0.05, 0.1, 1.0 and 10.0 mgtkg. One hour following administration of the test compound, each animal received 0.1 mgkg, sc, of apomorphine HC1. Apomorphine consistently evokes an immediate emetic response through direct dopaminergic interaction at the medullary chemoreceptor trigger zone (CTZ). Antiemetic compounds which act at the OTZ and, or the midbrain vomiting center will block this effect. If both animals receiving a particular treatment are protected, (i.e., no emetic response within one hour after apomorphine), the test compound is considered active. The dosage at which both animals were protected (100% effect) is shown in Table VIII. TABELE VIII Effects of Benzofuran/Dihydrobenzofuran Compounds In Vivo Screening Test EMI42.1 <SEP> Adomorphine <SEP> Emesis <SEP> (Dog) <tb> <SEP> 100% <SEP> Effect <SEP> Apomorphine <SEP> Climbing <SEP> (Mouse) <tb> Structure <SEP> Dosage <SEP> level <SEP> mg/kg, <SEP> s.c. <SEP> Approx. <SEP> 50% <SEP> ED <SEP> (mg/kg, <SEP> s.c.) <tb> # <tb> R=H <SEP> 10.0 <SEP> 12 <SEP> (i.p.) <tb> R=CH3 <SEP> 10.0 <SEP> 3 <SEP> (i.p.) <tb> # <tb> R=H <SEP> 1.0 <SEP> 20 <SEP> (i.p) <tb> R=Cl <SEP> 1.0 <SEP> 15 <SEP> (oral) <tb> <SEP> 5 <SEP> (i.p.) <tb> R=NO2 <SEP> 1.0 <SEP> 20 <SEP> (i.p.) <tb> <SEP> 15 <SEP> (oral) <tb> R=Br <SEP> 1.0 <SEP> 15 <SEP> (oral) <tb> R=NH2 <SEP> ---- <SEP> 25 <SEP> (i.p.) <tb> <SEP> 20 <SEP> (oral) <tb> R=NHCOCH3 <SEP> ---- <SEP> 50 <SEP> (i.p.) <tb> R=NHSO2CH3 <SEP> 1.0 <SEP> 50 <SEP> (oral) <tb> R=CH3 <SEP> 0.1 <SEP> 3 <SEP> (i.p.) <tb> EMI43.1 <SEP> Adomorphine <SEP> Emesis <SEP> (Dog) <tb> <SEP> 100% <SEP> Effect <SEP> Apomorphine <SEP> Climbing <SEP> (Mouse) <tb> Structure <SEP> Dosage <SEP> level <SEP> mg/kg, <SEP> s.c. <SEP> Approx. <SEP> 50% <SEP> ED <SEP> (mg/kg, <SEP> s.c.) <tb> # <tb> R=H <SEP> R'=H <SEP> 0.05 <SEP> 20 <SEP> (i.p.) <tb> R=Br <SEP> R'=H <SEP> 0.005 <SEP> 2 <SEP> (i.p.) <tb> R=OCH3 <SEP> R'=H <SEP> 0.1 <SEP> 25 <SEP> (i.p.) <tb> <SEP> 1 <SEP> (oral) <tb> R=Cl <SEP> R'=Cl <SEP> ---- <SEP> 10 <SEP> (oral) <tb> R=H <SEP> R'=OCH3 <SEP> ---- <SEP> 25 <SEP> (oral) <tb> R=NH2 <SEP> R'=Cl <SEP> ---- <SEP> 25 <SEP> (i.p.) <tb> <SEP> 50 <SEP> (oral) <tb> R=H <SEP> R'=Cl <SEP> ---- <SEP> 25 <SEP> (i.p.) <tb> <SEP> 40 <SEP> (oral) <tb> EMI44.1 <SEP> Adomorphine <SEP> Emesis <SEP> (Dog) <tb> <SEP> 100% <SEP> Effect <SEP> Apomorphine <SEP> Climbing <SEP> (Mouse) <tb> Structure <SEP> Dosage <SEP> level <SEP> mg/kg, <SEP> s.c. <SEP> Approx. <SEP> 50% <SEP> ED <SEP> (mg/kg, <SEP> s.c.) <tb> # <tb> R= <SEP> 1.0 <SEP> 25 <SEP> (i.p.) <tb> <SEP> 5 <SEP> (oral) <tb> # <tb> R= <SEP> ---- <SEP> 10 <SEP> (i.p.) <tb> <SEP> 10 <SEP> (oral) <tb> # <tb> R= <SEP> 0.1 <SEP> 0.5 <SEP> (i.p.) <tb> # <tb> R= <SEP> ---- <SEP> 30 <SEP> (i.p.) <tb> # <tb> EMI45.1 <SEP> Adomorphine <SEP> Emesis <SEP> (Dog) <tb> <SEP> 100% <SEP> Effect <SEP> Apomorphine <SEP> Climbing <SEP> (Mouse) <tb> Structure <SEP> Dosage <SEP> level <SEP> mg/kg, <SEP> s.c. <SEP> Approx. <SEP> 50% <SEP> ED <SEP> (mg/kg, <SEP> s.c.) <tb> # <tb> R=H <SEP> R'=H <SEP> 10.0 <SEP> 12 <SEP> (i.p.) <tb> R=Cl <SEP> R'=H <SEP> 0.1 <SEP> 5 <SEP> (oral) <tb> R=Br <SEP> R'=H <SEP> 0.1 <SEP> --- R=F <SEP> R'=H <SEP> 1.0 <SEP> --- R=H <SEP> R'=Cl <SEP> ---- <SEP> --- EMI46.1 <SEP> Adomorphine <SEP> Emesis <SEP> (Dog) <tb> <SEP> 100% <SEP> Effect <SEP> Apomorphine <SEP> Climbing <SEP> (Mouse) <tb> Structure <SEP> Dosage <SEP> level <SEP> mg/kg, <SEP> s.c. <SEP> Approx. <SEP> 50% <SEP> ED <SEP> (mg/kg, <SEP> s.c.) <tb> # <tb> R= <SEP> 1.0 <SEP> 20 <SEP> (i.p.) <tb> # <tb> R= <SEP> 1.0 <SEP> 20 <SEP> (i.p.) <tb> <SEP> 15 <SEP> (oral) <tb> # <tb> # <tb> R1=R2=H <SEP> 1.0 <SEP> 20 <SEP> (i.p.) <tb> E1=H, <SEP> R2=CH3 <SEP> 0.85 <SEP> 20 <SEP> (i.p.) <tb> E1=R2=CH3 <SEP> 10.0 <SEP> 100 <SEP> (i.p.) <tb>

Claims: CLAIMS 1. A compound of the formula (I) EMI47.1 wherein Z represents the atoms necessary to complete a benzo[bJfuran ring or a dihydrobenzo[b)furan ring, either of which may be substituted, RÚ, Rê and R may be the same or different and each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an amino group, an alkylamino group in which the alkyl substituent(s) contain 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acylamido group having 1 to 6 carbon atoms, a sulfonamido group having up to 6 carbon atoms, or a nitro group; and A represents a tertiary amino alkyl group containing the atomic sequence EMI47.2 and acid addition salts thereof. 2. A compound of the formula II EMI47.3 wherein A, R1, R 2 and R3 are as defined in claim 1, and R9 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; and acid addition salts thereof. 3. A compound of the formula III EMI48.1 wherein A, R1, R2 and R3 are as defined in claim 1, and R9 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; and acid addition salts thereof. 4. A compound of the formula (IV): EMI48.2 wherein Z represents the atoms necessary to complete a benzo[b]furan ring or a dihydrobenzo[b]furan ring, and 1 R2 and R are as defined in claim 1, and R6 R2 R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and acid addition salts thereof. 5. A compound according to any one of claims 1 to 3, wheerein A represents a substituent selected from: EMI49.1 wherein R , R and R each represent a hydrogen atom and an alkyl group containing 1 to 6 carbon atoms. 6. A compound according to claim 5 wherein A represents a 2-pyrrolidinylmethyl group. 7. A compound according to claim 1 or claim 4 wherein Z represents the atoms necessary to complete a- - 2-methyl tr 3-methyl benzoEbjfuran ring. 8. A compound according to claim 1 or claim 4 wherein Z represents the atoms necessary to complete a 2-methyl or 3-methyl 2,3-dihydrobenzo[b]furan ring. 9. A compound according to any preceding claim wherein at least one of R1., R2 and R- is a halogen atom. 10. A compound according to any preceding claim 1 2 3 wherein at least one of R , R and R is a methoxy group. 11. A compound according to any preceding claim wherein at least one of RÚ, Rê and R is a acylamido group. 12. A compound according to any preceding claim wherein at least one of R1, R2 and R is a sulfonamido group. 13. A compound according to any preceding claim wherein at least one of R11 R 2 and R3 is an amino group or an alkylamino group. 14. A compound according to any preceding claim wherein at least one of RÚ, Rê and R is a nitro group. 15. A pharmaceutical preparation useful as an antipsychotic or antiemetic agent comprising a pharmaceutically acceptable carrier is combination with a therapeutically effective amount of a compound according to any preceding claim. 16. A compound according to any one of claims 1 to 14 for use as an antipsychotic or antiemetric agent. 17. A process for producing a benzofurancarboxamide having the general formula: EMI50.1 wherein Z represents the atoms necessary-to complete a benzo±b3furan ring or a dihydrobenzo[b]furan ring, einther of which may be substitutd, RÚ, R2 and R may be the same or different and each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an amino group, an alkylamino group in which the alkyl substituent(s) contain 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acylamido group having 1 to 6 carbon atoms, a sulfonamido group having up to 6 carbon atoms, or a nitro group; and A represents a tertiary aminoalkyl group containing the atomic sequence-C-C-Nsc, or or an acid addition salts thereof, which comprises condensing a benzo- or dihydrobenzo-[b]furan-7-carboxylic acid chloride or ester with an amine and recovering a carboxamide in the form-of its acid salt.

Inventors: LEDNICER, DANIEL, SUN, JUNG-HUI
Applicants: ADRIA LABORATORIES INC.
Application year: 1984
Main classification: C07D307
IPC codes: A61K31, A61P25, C07D451, C07D405, A61P1, C07D307, C07C43