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GB1560019A - 2-methoxy-benzamides - Google Patents

2-methoxy-benzamides Download PDF

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Publication number
GB1560019A
GB1560019A GB48451/77A GB4845177A GB1560019A GB 1560019 A GB1560019 A GB 1560019A GB 48451/77 A GB48451/77 A GB 48451/77A GB 4845177 A GB4845177 A GB 4845177A GB 1560019 A GB1560019 A GB 1560019A
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Prior art keywords
methoxy
pyrrolidinylmethyl
compound
racemate
optical isomer
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Synthelabo SA
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Synthelabo SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

(54) 2-METHOXYBENZAMIDES (71) We, SYNTHELABO, a French Body Corporate of 1, Avenue de Villars 75341 Paris Cedex 07, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to 2-methoxybenzamides, their addition salts with pharmaceutically acceptable acids, their preparation and medicaments which contain these compounds.
The main Patent, to which this a Patent of Addition, describes 2methoxybenzamides which correspond to the following formula:
in which: n is I or 2; R, represents either a (cycloalkyl)alkyl radical of formula
or a phenylalkyl radical of formula
in which m is an integer from 2 to 5 inclusive, A is a linear or branched alkylene chain containing 1 to 4 carbon atoms and R4 represents a hydrogen atom or a halogen atom, in particular fluorine or chlorine, a trifluoromethyl radical, or an alkyl or alkoxy radical containing I to 3 carbon atoms; R2 represents a chlorine atom, or an SO2R5 group, R5 being an alkyl radical containing I to 4 carbon atoms, or an SO2SH6R, group, R6 and R7, which are identical or different, representing, independently of each other, a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms; and R3 represents either a hydrogen atom or an alkyl radical containing I to 4 carbon atoms.
The present invention relates to further specific 2-methoxybenzamides within that formula, including their. racemates and optically active isomers the compounds being useful as medicaments in human and veterinary medicine acting on the central nervous system.
The compounds (I) of this invention may be prepared by reaction of a halide or an alkyl ester of 2-methoxybenzoic acid (II) with a pyrrolidine (III)
X being a halogen, R'1 being the aforesaid (cycloalkyl)alkyl radical, and R2 and R3 being as defined above.
The pyrrolidines (III) are obtained in the manner indicated in the main Patent.
The reaction with the halide is carried out preferably at a low temperature (-5" to +30 ) in a non-polar solvent, such as a ketone, and in the presence of an alkali metal carbonate. The condensation reaction with the ester is carried out either dry, at a temperature of 50 to 1200 C, under nitrogen, or in water, at a temperature of 50 to 100"C, under nitrogen. The optically active isomers are obtained either by resolution or by stereospecific synthesis.
The stereospecific synthesis consists of 1) preparing the optically active pyrrolidine (III) starting from an amino-acid, that is to say glutamic acid or (R)- or (S)-proline, or from a compound derived from these amino-acids (for example pyroglutamic acid or prolinol), via pyrrolidine intermediates containing an asymmetric carbon atom in the a-position to an amino group, by a series of condensations, esterifications, saponifications, cyclisations and reductions, and 2) reacting the optically active pyrrolidine (III) with the compound (II).
The following reaction scheme illustrates the stereospecific synthesis of the pyrrolidines (III).
Reaction scheme 1 " H SOC12 /C2H50H l X H COOH first stage ~K cooc21lS L-proline (S) Nri 2nd stage -3 tcXcH A- cOcl r (CICH-A'-COCI t k CONY2 3rd stage A ' CH 2 ) (S) (S) reduction 4th- stage A \CH2NH2)m (S) In the scheme, A' represents a bond or an alkylene radical of 1 to 3 carbon atoms. The reduction is preferably carried out by means of lithium aluminium hydride. The (R)-pyrrolidine may be obtained in the same manner bv starting from the (R)-proline.
Example of the preparation of a pyrrolidine (III).
I Cyclopropylmethyl2aminomethyl-(S)(-)-pyrrolidine Stage 1.
2-Ethoxycarbonyl-(S)-pyrrolidine 34.8 g (0.3 mol) of L-proline (S) and 360 ml of ethanol are introduced into an Erlenmeyer flask. 54.8 g (0.46 mol) of thionyl chloride are added dropwise whilst cooling in an ice bath.
The mixture is stirred for one hour at ambient temperature and heated under reflux for three hours. The mixture is then evaporated to dryness, and the residual oil is dissolved in chloroform and saturated with ammonia. The ammonium chloride is filtered off and the organic phase is evaporated. An oil is recovered, which is distilled.
Boiling point (20 mm Hg)= 820 C.
Stage 2.
2-Carbamoyl-(S)(-)-pyrrolidine 200 ml of methanol are introduced into an Erlenmeyer flask and saturated with ammonia while cooling. 17.2 g (0.12 mol) of the ester obtained in Stage I are introduced into the methanol. The mixture is stirred for two hours and allowed to stand overnight.
The mixture is evaporated to dryness and a solid is recovered, which is recrystallised from benzene Melting point = l0l.50-l020C [ct]25 = -780 (c = 1, water) [a]3 N6 =258.5 (c = 1, water) Stage 3.
1 -Cyclopropylcarbonyl-2-carbamoyl-(S)-pyrrolidine 11.4 g (0.1 mol) of (5)-prolinamide, 13.8 g (0.1 mol) of potassium carbonate and some anhydrous acetone are introduced into an Erlenmeyer flask.
The mixture is cooled with an ice bath and 10.45 g (0.1 mol) of cyclopropanecarboxylic acid chloride in acetone are added dropwise.
The mixture is stirred for one hour at the same temperature and is allowed to stand overnight at ambient temperature. It is then evaporated to dryness (T < 30"C), and extracted with chloroform, and the extract is washed with the minimum amount of water. The organic phase is dried over magnesium sulphate and evaporated. A solid which melts at 1290--1300C is recovered.
Stage 4.
1 -Cyclopropylmethyl-2-aminoethyl-(S)(-)-pyrrolidine 13.3 g (0.35 mol) of lithium aluminium hydride and 200 ml of anhydrous ether are introduced into an Erlenmeyer flask. 16 g (0.088 mol) of the preceding diamide are added in small amounts and the mixture is heated under reflux for 16 hours. It is then hydrolysed with a 10 ó strength solution of sodium potassium tartrate and the solid is filtered off, and washed several times with ether. The ether phases are mixed and evaporated.
An oil is recovered, which is distilled.
Boiling point (20 mm Hg) = 88"C.
[ & 23O65 = 201.50 (C = 1, D.M.F.) [al020 = 68.50 (C = 1, D.M.F.) The other optically active pyrrolidines (III) are prepared in the same manner.
The following examples illustrate the invention.
The analyses, the IR spectra and the NMR spectra confirmed the structure of the compounds.
EXAMPLE 1.
Racemic N-( 1 -cyclopropylmethyl-2-pyrrolidinylmethyl)-2-methoxy-5- sulphamoylbenzamide, its (S)(-) optical isomer and its (S)(+)-methanesulphonate.
Racemic compound.
7.78 g (0.03 mol) of the ethyl ester of 2-methoxy-5-sulphamoylbenzoic acid, 4.86 g (0.0315 mol) of 2-aminomethyl-l-cyclopropylmethylpyrrolidine and 12 ml of water are placed in a 250 ml round-bottomed flask and the mixture is then heated at 100" for 9 hours. A solid appears during heating.
The mixture is allowed to cool and diluted with water; the suspension is stirred and filtered, and then the solid is washed with water and ether before being dried.
Weight = 7.62 g; Yield = 69.14%; Melting point = 159.50-160.50C.
(S)(-) isomer.
8.8 g (0.057 mol) of l-cyclopropylmethyl-2-aminomethyl-(S)(-)-pyrrolidine.
14.07 g (0.054 mol) of the ethyl ester of 2-methoxy-5-sulphamoylbenzoic acid and 18 ml of water are introduced into an Erlenmeyer flask.
The mixture is heated at 1000C for 10 hours. A solid appears on cooling. Ether and water are added and the mixture is stirred. The solid is filtered off and dissolved in chloroform and the solution is dried over magnesium sulphate, and then evaporated. A solid is recovered, which is recrystallised from ethyl acetate.
Melting point = 1340--134.50C [D2O - 770 (c = 1, D.M.F.) (S)(+)-Methanesulphonate.
The methanesulphonate is prepared by reaction of the benzamide with methanesulphonic acid in acetone.
Melting point = l20.50-l2l.50C.
[a]20 = +5.20 (c = 1, D.M.F.) EXAMPLE 2.
N - (1 - Cyclopentylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide, in the form of the (S)(-) optical isomer, and its (S)(+)methanesulphonate.
13.2 g (0.0724 mol) of 1-cyclopentylmethyl-2-aminomethyl-(S)(-)pyrrolidine, 10 g of potassium carbonate and some acetone are introduced into an Erlenmeyer flask. At a temperature of < 100 C, 18 g (0.0724 mol) of 2-methoxy-5sulphamoylbenzoic acid chloride are added dropwise. The mixture is stirred for two hours.
The mixture is evaporated to dryness and triturated with a mixture of water and ether. A solid is filtered off, and is dissolved in chloroform. The solution is dried over magnesium sulphate and evaporated.
A solid is recovered, which is recrystallised from ethyl acetate.
Melting point = 1230-l23.50C [D2O = -99.50 (e = 0.5, D.M.F.) The methanesulphonate of this benzamide is obtained by reaction of the benzamide with methanesulphonic acid in acetone. It is a white solid which is filtered off and recrystallised from isopropanol.
Melting point = 123"--124"C []DO = +2.5 (c = 1, D.M.F.) EXAMPLE 3.
Racemic N - (1 - cyclohexylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5- sulphamoylbenzamide and its methanesulphonate.
12 g (0.061 mol) of l-cyclohexylmethyl-2-aminomethylpyrrolidine, 8.44 g (0.061 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
At a temperature of < 100C and under a stream of nitrogen 15.2 g (0.061 mol) of 2-methoxy-5-sulphamoylbenzoic acid chloride in acetone are added dropwise.
The mixture is stirred for two hours.
The mixture is evaporated to dryness and the residue is triturated with a mixture of water and ether. The solid is filtered off and dissolved in chloroform; the solution is dried over magnesium sulphate and evaporated. A solid is recovered which is recrystallised from ethyl acetate.
Melting point = 155.50-l560C The methanesulphonate is obtained by reaction of the benzamide with methanesulphonic acid in methanol.
The solid is recrystallised from isopropanol.
Melting point = 162"--163"C.
EXAMPLE 4.
N-( l -Cyclobutylmethyl-2-pyrrolidinylmethyl) - 2 - methoxy-5-sulphamoylbenzamide in the form of the (S)(-) optical isomer and its (SX+)methanesulphonate and in the form of the racemate.
8.4 g (0.0499 mol) of l-cyclobutylmethyl-2-aminomethyl-(S)(-)-pyrrolidine, 6.9 g (0.0499 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. At a temperature of < 100C, 12.46 g (0.0499 mol) of 2-methoxy-5sulphamoylbenzoic acid chloride in acetone are added dropwise.
The mixture is stirred at the same temperature for two hours; it is then evaporated to dryness and the solid is taken up again in water and ether. The solid is filtered off and dissolved in chloroform; the organic phase is dried over magnesium sulphate and evaporated to dryness. The solid is recrystallised from a mixture of ether and ethyl acetate and insoluble material is filtered off from the hot solution.
Melting point = 153"--153.5"C [D2O = ~ -920 (c = 0.5, D.M.F.) The methanesulphonate is prepared by reaction of the benzamide with methanesulphonic acid.
Melting point = l200-12l0C [a]20 = +2.40 (c = 0.5, D.M.F.) The racemic compound is prepared by reaction of 2-methoxy-5sulphamoylbenzoic acid chloride with l-cyclobutylmethyl-2-aminomethylpyrrolidine.
Melting point = 197.50-l980C The methanesulphonate melts at 154.50--1550C.
EXAMPLE 5.
Racemic N-(l-cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5- methylsulphonylbenzamide and its methan esulphonate.
7.71 g (0.05 mol) of 2-aminomethyl-l-cyclopropylmethylpyrrolidine in 200 ml of acetone and 6.91 g (0.05 mol) of potassium carbonate are placed in a 500 ml Erlenmeyer flask and the mixture is cooled in ice.
Whilst stirring magnetically and maintaining the temperature below 10"C, a solution of 12.43 g (0.05 mol) of 2-methoxy-5-methylsulphonylbenzoic acid chloride in 220 ml of acetone is introduced dropwise into the mixture. The reactants are left in contact in the melting ice for 2 hours. When the reaction is completes the acetone is evaporated to dryness, the solid residue is taken up again between water and chloroform; the organic phase is decanted off, washed with water and dried over magnesium sulphate in the presence of charcoal. After filtration of the solid, the chloroform is driven off from the filtrate and a viscous yellow oil is obtained, which crystallises very rapidly when it is stirred in the presence of ether.
After purification, the solid is yellowish white.
The methanesulphonate melts at 124.50--1260C.
EXAMPLE 6.
Racemic N - (1 - cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5ethylsulphonylbenzamide and its hydrochloride.
The reaction is carried out as in Example 5, employing 2-methoxy-5-ethylsulphonylbenzoic acid chloride.
The hydrochloride is prepared by reaction of the oily base with a solution of hydrogen chloride in ether.
Melting point = l87'.50-188.50C EXAMPLE 7.
Racemic N - (I - cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5dimethylsulphamoylbenzamide and its hydrochloride.
The procedure followed is as in Example 5 using 2-methoxy-5-dimethylsulphamoylbenzoic acid chloride.
The hydrochloride is prepared from the base.
Melting point = 159.50-l60.50C EXAMPLE 8.
Racemic N - (I - cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5chlorobenzamide and its hydrochloride.
10.43 g (0.0676 mol) of 2-aminomethyl-l-cyclopropylmethylpyrrolidine, 13.04 g (0.065 mol) of methyl ester of 2-methoxy-5-chlorobenzoic acid and 20 ml of water are introduced into an Erlenmeyer flask under an atmosphere of nitrogen.
The mixture is heated at 1000C for 14 hours. The mixture is cooled and extracted with ether, and the organic phase is separated off, dried over magnesium sulphate and evaporated. An oil is recovered.
The hydrochloride is prepared in a mixture of ether and HCI. A white solid crystallises. This is filtered off and recrystallised from isopropyl alcohol.
Melting point = 1810-l820C The compounds of the invention are shown in Table I below. (R3 = H).
TABLE I
Compound Rj R2 | Characteristic molting points (0C) 1 | 231-232 (HC1) racemic > CH2 SO2NH2 ; 159.5-160 (base) 2 L L 1 SO2NH2 | 134-134.5 (base) (S)(-) (s)(+) cH2 CH i 120.5-121.5 (methane sulphonate) | (S) (+) 2 CH2 S02NH2 123-124 (methanesul (s)(+) < CH2 2 2 | phonate) 3 CSO,NH, 162-161 (nethanesulracemic 162-163 ri phonate) 4 SO,NH, 120-121 (methanesul (s)(+)H, Fhonate) 4 S0 NH 120-121 (methanesul (S)(+) ~H 2 2 phonate) racemic + < " 2 154.5-155 (methanesul phonate) 5 -CHI SO2CH3 1 60-64 (base) rac emic 1 124.5-126 (methanesul phonate) I racemic CH2 2 2 5 187.5-188.5 compositio)(HC1: 7 > H2 S02N(CH3)2 159.5-164.5 kHC1) racemic I 8 1\ C1 181-182 (HC1) racemic The compounds of the invention were subjected to pharmacological tests.
The toxicity was evaluated intraperitoneally on male, Swiss CD I mice, of a mean weight of 20 g.
The neuroleptic activity was determined by the antagonism towards the "climbing" induced in the mice by apomorphine (C. Gouret, J. Pharmacol. (Paris), (1973), 4, 341).
The results of these tests are indicated in Table II below.
TABLE II
LD 50 Antiapomorphine activity administered intra- in mice AD 50 peritoneally to mice (mg/kg) administered COMPOUND (mg/8kg) intraperitoneally racemic hydrochloride 1 400 15 1 (S) (+)-methane- 350 4 sulphonate 3 I 360 8 5 235 1.5 7 240 1 3 8 135 0.1 6 310 3 Furthermore, certain compounds possess an antiemetic activity. This was determined by the antagonism towards the emetic effect induced in dogs by apomorphine (Shallek et al, Arch. Int. Pharmacodyn., (1968), 174, No. 2, 350-372; Boissier et al, Med. Exp., (1962), 6, 320-326).
The results are given below.
Antiemetic activity in dogs AD 50 llg/kg COMPOUND administered orally Racemic hydrochloride 37 (S) (+)-Methanesulphonate 14 of (S) (-) isomer 7 Racemic hydrochloride 40
An examination of the various results shows that the compounds of the invention are applicable in the treatment of various psychosomatic complaints, such as gastro-duodenal ulcers, migraine, dizziness, depressive and psychic disturbances, in particular senescence and, in stronger doses, in psychoses, by virtue of their neuroleptic properties.
Furthermore, certain compounds may be used in the treatment as well as in the prevention of vomiting and nausea of all origins.
The invention includes all pharmaceutical compositions containing the compounds (I) and their salts as active principles, in association with all excipients which are appropriate to their oral, endorectal or parenteral administration.
All the pharmaceutical forms which are appropriate to the oral, endorectal or parenteral methods are suitable, the usual daily dosage ranging from 5 to 300 mg.
WHAT WE CLAIM IS: 1. The (S)(-) isomer of N-(l-cyclopropylmethyl-2-pyrrolidinylmethyl)-2methoxy-5-sulphamoylbenzamide.
2. N - (1 - Cyclopentylmethyl- 2 - pyrrolidinylmethyl) - 2 - methoxy-5sulphamoylbenzamide in the form of the racemate or an optical isomer.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (14)

**WARNING** start of CLMS field may overlap end of DESC **. TABLE II LD 50 Antiapomorphine activity administered intra- in mice AD 50 peritoneally to mice (mg/kg) administered COMPOUND (mg/8kg) intraperitoneally racemic hydrochloride 1 400 15 1 (S) (+)-methane- 350 4 sulphonate 3 I 360 8 5 235 1.5 7 240 1 3 8 135 0.1 6 310 3 Furthermore, certain compounds possess an antiemetic activity. This was determined by the antagonism towards the emetic effect induced in dogs by apomorphine (Shallek et al, Arch. Int. Pharmacodyn., (1968), 174, No. 2, 350-372; Boissier et al, Med. Exp., (1962), 6, 320-326). The results are given below. Antiemetic activity in dogs AD 50 llg/kg COMPOUND administered orally Racemic hydrochloride 37 (S) (+)-Methanesulphonate 14 of (S) (-) isomer 7 Racemic hydrochloride 40 An examination of the various results shows that the compounds of the invention are applicable in the treatment of various psychosomatic complaints, such as gastro-duodenal ulcers, migraine, dizziness, depressive and psychic disturbances, in particular senescence and, in stronger doses, in psychoses, by virtue of their neuroleptic properties. Furthermore, certain compounds may be used in the treatment as well as in the prevention of vomiting and nausea of all origins. The invention includes all pharmaceutical compositions containing the compounds (I) and their salts as active principles, in association with all excipients which are appropriate to their oral, endorectal or parenteral administration. All the pharmaceutical forms which are appropriate to the oral, endorectal or parenteral methods are suitable, the usual daily dosage ranging from 5 to 300 mg. WHAT WE CLAIM IS:
1. The (S)(-) isomer of N-(l-cyclopropylmethyl-2-pyrrolidinylmethyl)-2methoxy-5-sulphamoylbenzamide.
2. N - (1 - Cyclopentylmethyl- 2 - pyrrolidinylmethyl) - 2 - methoxy-5sulphamoylbenzamide in the form of the racemate or an optical isomer.
3. N - (1 - Cyclohexylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl
benzamide in the form of the racemate or of an optical isomer.
4. N - (1 - Cyclobutylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide in the form of the racemate or of an optical isomer.
5. N - (1 - Cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5-methylsulphonylbenzamide in the form of the racemate or of an optical isomer.
6. N - (1 - Cyclopropylmethyl - 2- pyrrolidinylmethyl)-2-methoxy-5-ethylsulphonylbenzamide in the form of the racemate or of an optical isomer.
7. N - (I - Cyclopropylmethyl - 2 - pyrrolidinylmethyl)-2-methoxy-5-dimethylsulphamoylbenzamide in the form of the racemate or of an optical isomer.
8. N - (1 - Cyclopropylmethyl - 2 - pyrrolidinylmethyl) - 2 - methoxy-5chlorobenzamide in the form of the racemate or of an optical isomer.
9. A pharmaceutically acceptable acid addition salt of a compound according to any one of the preceding claims.
10. A process for the preparation of a compound (I) according to any one of claims 1 to 8, wherein a halide or an alkyl ester of 2-methoxybenzoic acid (II) is caused to react with a racemic or optically active 2-aminomethylpyrrolidine (III) according to the following formula:
the radicals R'1, R2 and R3 being chosen appropriately for the compound I to be produced and X being halogen.
11. A process according to claim 10, substantially as described in any one of the foregoing Examples 1 to 8.
12. A compound (I) produced by a process according to claim 10 or 11.
13. A medicament containing as the active principle a compound claimed in any one of claims 1 to 8 and 12, or its pharmaceutically acceptable acid addition salt.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and 12, or its pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable carrier or diluent therefor.
GB48451/77A 1977-06-13 1977-11-21 2-methoxy-benzamides Expired GB1560019A (en)

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IE (1) IE45999B1 (en)
IT (1) IT1206606B (en)
LU (1) LU78681A1 (en)
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ZA (1) ZA776950B (en)

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IT1095415B (en) * 1978-02-16 1985-08-10 Ravizza Spa PROCESS FOR THE PRODUCTION OF AN OPTICALLY ACTIVE BENZAMIDE, OPTICALLY ACTIVE BENZAMIDE SO OBTAINED AND COMPOSITIONS
AU542211B2 (en) * 1980-03-07 1985-02-14 Gruppo Lepetit S.P.A. Mercaptocycloalkyl carbonyl prolines

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LU78681A1 (en) 1978-07-11
IT7823749A0 (en) 1978-05-24
AU3151477A (en) 1979-06-21
FR2394529A2 (en) 1979-01-12
JPS545969A (en) 1979-01-17
ZA776950B (en) 1978-09-27
FR2394529B2 (en) 1980-01-18
AU509543B2 (en) 1980-05-15
IT1206606B (en) 1989-04-27
BE861866R (en) 1978-06-14
NL7713631A (en) 1978-12-15
IE45999B1 (en) 1983-01-26

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PS Patent sealed [section 19, patents act 1949]