IE43375B1 - Substituted benzamides, their preparation, and compositions containing them - Google Patents

Substituted benzamides, their preparation, and compositions containing them

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IE43375B1
IE43375B1 IE1166/76A IE116676A IE43375B1 IE 43375 B1 IE43375 B1 IE 43375B1 IE 1166/76 A IE1166/76 A IE 1166/76A IE 116676 A IE116676 A IE 116676A IE 43375 B1 IE43375 B1 IE 43375B1
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hydroxyethyl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Other In-Based Heterocyclic Compounds (AREA)
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Abstract

1500105 Benzamides SOC D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-FRANCE 8 June 1976 [10 June 1975] 23695/76 Heading C2C Novel compounds (I) (including salts and oxides thereof) in which A is a hydrogen atom or a C 1-5 alkyl or 6 2-5 alkenyl group; X is a hydrogen atom or a C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyloxy or C 2-5 alkenyl group; Y is a hydrogen or halogen atom or a nitro, C 1-5 alkyl, C 1-5 alkoxy, amino or substituted amino group; Z is a hydrogen or halogen atom, a C 1-5 alkoxy or C 1-5 alkylsulphonyl group or a group of formula SO 2 NR 1 R 2 in which each of R 1 and R 2 , which may be the same or different, is a hydrogen atom or a C 1-5 alkyl group, or -NR 1 R 2 is a heterocyclic ring optionally containing another hetero atom; W is a C 1-4 straight or branched-chain alkylene group; B is a group of formula NR 3 R 4 in which R 3 is a C 1-5 alkyl group and R 4 is a C 1-5 hydroxyalkyl group; or B is a nitrogen-attached heterocyclic ring optionally containing a second nitrogen and optionally having a substituent; or B is a racemic, dextrorotary or laevorotary heterocyclic radical of Formula (IV) in which R is a C 1-5 alkyl group containing a reactive function and m is 1, 2 or 3, including the dextrorotatory and laevorotatory forms of the compounds, are made by interacting H 2 N-W-B and appropriate benzoic acids or derivatives thereof. Pharmaceutical preparations having antiemetic action contain (I) as active ingredient. Administration is parenterally.

Description

The present invention provides substituted benzamides of general formula: in which A is a hydrogen atom of a Cy_g alkyl or ^2-5 alkenyl group; X is a hydrogen atom or a Cy_g alkoxy, alkyl, C2_2 alkenyloxy or C2_g alkenyl group; Y is a hydrogen or a halogen atom or a nitro, c^_5 alkyl, Cy_galkoxy, amino or substituted amino group, examples of the latter being alkylamino, acylamino, benzylamino and alkoxycarbonylamino; Z is a hydrogen or a halogen atom, a Cy_5 alkoxy or alkylsulphonyl group, or a group of formula SO2NRyR2 in which each of Ry and R2, which may be the same or different, is a hydrogen atom of a Cy_5 alkyl group, or -NR.^ is a heterocyclic ring optionally containing another hetero atom; W is a straight or branched-chain alkylene group; B is a group of formula NR^R^, in which R^ is a Cy_galkyl group and R^ is a Cl-5 kydroxyalkyl group or B is a nitrogen-attached heterocyclic ring containing a second nitrogen atom substituted with a Cl-5 hydroxYalkyl group; or B is a racemic, dextrorotatory or laevorotatoty heterocyclic radical of formula (IV) ; (IV) R in which R is a C 5 alkyl group containing a reactive function, herein defined as hydroxy, mercapto, oxo, thioxo, oxa or thia and m is 1, 2 or 3.
The invention also provides quaternary ammonium salts, oxides and addition salts with pharmacologically acceptable acids of such compounds including not only the racemate but also the dextrorotatory and laevorotatory isomers.
The invention also provides medicaments containing as active ingredient a benzamide of Formula I, together with an acceptable pharmaceutical carrier.
The benzamides of the invention may be prepared by reacting a compound of formula: in which A, X. Y and Z are as defined above or a reactive derivative thereof with an amine of general formula (III): H2N-W-B (III) in which W and B are as defined above, or a reactive derivative thereof.
Of the substituted amino groups represented by Y, examples of alkylamino are C2_g monoalkylamino and di(C2_galkyl) amino, and examples of acylamino are acetamido, formamido, propionamido, butyramido, benzamido and phthalimido groups.
Among the reactive acid derivatives of the acid used as starting material are C1-5 alkyl esters such as methyl, ethyl, propyl, butyl, isobutyi, pentyl and isopentyl esters; reactive acid esters such as cyanomethyl or methoxymethyl esters; carbamates, which are formed by treatment with Nhydroxyimides; optionally substituted aromatic esters; acid amides; acid halides; acid hydrazides; acid azides; symmetrical anhydrides; mixed anhydrides, for example formed with carbonic acid esters or haloformic esters; azolides, such as triazolides tetrazolides or imidazolideg; aqid isothiocyanates; substituted ω-trihaloacetophenones; and α-oxobenzeneacetonitriles.
The invention is however not limited to the aforementioned derivatives.
According to the process of the invention, the amine may take part in the reaction in the form of one of its reactive derivatives, which may optionally be isolated. As examples there may be mentioned the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl or orthophenylene chlorophosphites, alkyl or aryl dichlorophosphites, the amine isothiocyanate, the symmetrical or non-symmetrical sulphamide of the amine, the corresponding symmetrical urea , and the corresponding enamines. The aforementioned reactive derivatives may react with the acid in situ or after preliminary isolation.
It is also possible to carry out the reaction between the free acid and free amine in the presence of a condensation agent, such as for example silicon tetrachloride, phosphoric anhydride, a carbodiimide such as dicyclohexyl carbodiimide, or alkoxyacetylenes such as methoxyacetylene or ethoxyacetylene.
The amidation reaction of the invention may be carried out in the presence or absence of a solvent. The systems used as solvent, which are inert with respect to the amidation reaction, are for example alcohols, polyols, benzene, toluene, dioxane, chloroform, or diethyleneglycol dimethyl ether. It is also possible to use as solvent an excess of the amine used as starting material. It may be preferable to heat the reaction mixture during the amidation, for example to the boiling point of the aforementioned solvents.
The compound obtained according to the invention may be reacted if necessary with a pharmaceutically acceptable mineral or organic acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methanesulphonic acid, to give an acid-addition salt.
It may also be reacted, if necessary, with an alkyl halide or sulphate to give a quaternary ammonium salt.
The following Examples are provided to illustrate the technical characteristics of the present invention.
EXAMPLE 1.
N-(1-(2hydroxyethyl)-2-pyrrolidlnylmethyl)-2-methoxy5-sulphamoylbenzamide g of ethyl 2-methoxy-5-sulphamoylbenzoate, 17 g of water and 32 g of 1-(2-hydroxyethyl)-2-aminomethylpyrrolidine were placed in a 250-ml flask. The mixture was heated on a water bath until a test sample was found to be completely soluble in dilute acetic acid. The solution was cooled and then diluted with 300 ml of water. The crystals formed were suction filtered, washed with water and dried at 40°C.
The benzamide obtained was purified by conversion into the acetate followed by liberation of the base. - 5 4 3 3 7 5 g of N-{1-(21-hydroxyethyl)-2-pyrrolidinylmethyl)2-methoxy-5-sulphamoylbenzamide was obtained. (Yield 59%; melting point 135-136°C).
EXAMPLE 2.
N— (1—(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy5-ethylsulphonylbenzamide hydrochloride 38.8 g of 2-methoxy~5-ethylsulphonylbenzoic acid methyl ester, 13.5 ml of water and 28.4 g of l-(3-hycirQxypropyl)-2-aminomethylpyrrolidine were placed in a 250-ml flask. The mixture was heated for 10 hours at 85-9O°C. After evaporation, the residue was dissolved in 200 ml of ethanol and the solution was acidified to a pH of 1 with alcoholic hydrochloric aoid. Tetrahydrofuran was added and the crystals formed were filtered, washed and dried in an oven at 50°c. g of N-(1-(3’-hydroxypropyl)-2-pyrrolidinylmethyl)-2methoxy-5-ethylsulphonylbenzamide hydrochloride was obtained by recrystallization from alcohol (Yield = 55.5%; m.p. 184186°C).
EXAMPLE 3.
N-(1'-acetyl-2’-pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide g of ethyl 2-methoxy-5-sulphamoylbenzoate was reacted with 31.5 g of N-acetyl-2-amino-methylpyrrolidine in a similar manner to that described above, and resulted in 34.5 g of N-(1'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5sulphamoylbenzamide (Yield = 52.5%; m.p. 2O4°C).
EXAMPLE 4.
N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy-4amino-5-chlorobenzamide 6.1 g of 2-methoxy-4-amino-5-chlorobenzoic acid and 8 g of N-ethyl-N-2-hydroxyethyl-ethylenediamine were placed - 6 in a 250-ml flask. The mixture was heated to 100°C and 6.5 g of phosphoric anhydride then added. The mixture was carefully heated to 110°C and the temperature was then rapidly raised to 15O-16O°C. This temperature was maintained for \ hour and then, after the mixture had cooled to 100°C, 100 ml of water was added. Caustic soda was added after the components had completely dissolved. The mixture was cooled and the resulting precipitate was filtered, washed with water and dried. 6.6 g of N-(Ν'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)2-methoxy-4-amino-5-chlorobenzamide was obtained (Yield= 69.8%; m.p. 111-112°C).
EXAMPLE 5.
N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2yg methoxy-5-sulphamoylbenzamide g of l-(2'-benzhydryloxyethyl)-2-aminomethylpyrrolidine and 500 ml of methyl ethyl ketone were placed in a 4-litre flask. The mixture was cooled to 15°C and a solution of 80 g of 2-methoxy-5-sulphamoylbenzoyl chloride in 1500 ml 2Q of methyl ethyl ketone was added. The mixture was stirred for 2 hours at ambient temperature. The precipitate formed was filtered, washed with a small amount of methyl ethyl ketone, and dried. The hydrochloride obtained was made alkaline while hot with ammonia, and the product was crystallised by cooling. The crystals were filtered, washed, and dried in an oven at 50°C. 88 g of N-(1-(21-benzhydryloxyethyl)-2pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide was obtained after recrystallization from ethanol, filtration through carbon black, and drying (Yield = 52.6%; m.p. 124°C).
EXAMPLE 6. 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-(2'-hydroxyethyl)piperazine - 7 4 3 3 7 5 g of 1-(2'-hydroxyethy1-4-(31-aminopropyl)piperazine and 180 ml of chloroform were placed in a 1-litre flask. A solution of 51 g of 2-methoxy-4-nitrobenzoyl chloride was poured into the mixture at a temperature of 5° to °C. At the end of the addition the mixture was brought to ambient temperature and then heated for 1 hour to 1 hour 15 minutes at 4O-45°C. Water was added and the chloroform was evaporated off. The solution obtained was filtered using carbon black and the benzamide base was precipitated by adding 50 g of potassium carbonate. After decanting, the product was dissolved in methyl chloride and the aqueous solution was extracted with methylene chloride.
The organic phase was dried with potassium carbonate, and the methylene chloride was then distilled in vacuo. The oily benzamide obtained was purified by forming the hydrochloride and treatment with ammonia. g of 1-(2'-methoxy-4,-nitroben2amidopropyl)-4-(2'hydroxyethyl)piperazine was obtained in the form of an oil (Yield = 67.2%). Purity by quantitative determination in a non-aqueous medium with perchloride acid : 97.8%.
EXAMPLE 7.
N-(1-(21-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5ethylsulphonyl benzamide hydrochloride g of 1-(2-hydroxyethyl)-2-aminomethylpyrrolidine, Zg 250 ml of methyl ethyl ketone, and, While maintaining the temperature between 5° and 10°C, 70 g of 2-methoxy-5-ethylsulphonylbenzoyl chloride were placed in a 500-ml flask. After stirring overnight, the crystallised product was suction filtered, washed with methyl ethyl ketone, and dried at 30 45°C. The crude product was recrystallised in 200 ml of alcohol at 95°c, 73 g of N-(l-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)2-methoxy-5-ethylsulphonylbenzamide hydrochloride was obtained (Yield 66.5%; m.p. 175-178°C). - 8 EXAMPLE 8.
N-(Niethyl-N1-(2'-hydroxyethyl)aminoethyl)-2-methoxy-5sulphamoylbenzamide g of ethyl 2-methoxy-5-sulphamoylbenzoate, 27 ml of water and 51 g of N-ethyl-N-hydroxyethyl ethylene diamine were placed in a 250-ml flask. The mixture was heated for 10 hours on a water bath. The solution was diluted, and the benzamide base then crystallised. It was purified hy forming the hydrochloride and reprecipitating the base with ammonia. The crystals obtained were suction filtered, washed with water until chloride ions had all been removed, and dried in an oven at 40°C. g of N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2methoxy-5-sulphamoylben2amide was obtained (Yield = 64%; m.p. 149-150°C).
EXAMPLE 9.
N-(1-(31-hydroxypropy1)-2-pyrrolidinylmethyl)-2-methoxy5-sulphamoylbenzamide hydrochloride 38.9 g of ethyl 2-methoxy-5-sulphamoylbenzoate, 13.5 ml of water and 28.4 g of N-l-(3'-hydroxypropyl)-2-aminomethylpyrrolidine were placed in a 250 ml flask. The mixture was heated for 10 hours at 80°C; after cooling, 100 ml of benzene was added and the solvents were distilled off. The mixture was cooled and 500 ml of water was then added. The crystals formed were filtered off, washed with water, and dried in an oven at 50°C. g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)2-methoxy-5-sulphamoylbenzamide was obtained (Yield = 72%).
The benzamide was converted into the hydrochloride hy dissolution in absolute alcohol and treatment with 50 ml of 25% concentration ethanolic hydrochloride acid. The solid - 9 43375 obtained was recrystallised from methyl alcohol. g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)2-methoxy-5-sulphamoylbenzamide hydrochloride was obtained (Yield 62.2%; m.p. 226-229°c).
EXAMPLE 10. 1- (2'-methoxy-41-aminobenzamidopropyl)-4-(2'-hydroxyethyl)piperazine diphosphate 2.8 g of 2-methoxy-4-aminobenzoic acid, 3.4 g of 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine and 60 ml of pyridine were placed in a 250 ml flask, and 2.3 g of silicon tetrachloride was added drop by drop. The mixture was heated for 3 hours at the reflux temperature. The pyridine Was distilled off in vacuo. 30 ml of water was added, followed by hydrochloric acid until the pH was 1. The mixture was heated to the boil and filtered after checking that the pH was still acid, and then ammonia was added while hot.
After cooling, the precipitated liquid was decanted. 3.9 g of 1-(2'-methoxy-41-aminobenzamidopropyl)-4-(2^ hydroxyethyl)piperazine were obtained (Yield 69.6%).
Purity by quantitative determination in a non-aqueous medium Was 97.5%.
The base obtained was dissolved in alcohol and then converted into its phosphate with phosphoric acid. The phosphate obtained was a double phosphate which crystallised with 3 moles of water. 3.2 g of 1-(2'-methoxy-4'-aminobenzamidopropyl) -4-(2'-hydroxyethyl)piperazine diphosphate was obtained (m.p, 114-145°C).
Benzamides of the invention have valuable therapeutic properties, particularly as antiemetics. Their low toxicity is compatible with use in human therapy without any risk of producing side effects. - 10 The acute toxicity of certain of the products of the invention was determined in mice by the parenteral route (endovenous or intraperitoneally). The LD5O values, calculated according to Behrens and Karber's method, are given in the following Table.
The antiemetic activity of the products of the invention to counteract apomorphine was studied in dogs according to Chen and Ensor's technique as developed by Ducrot and Decourt.
The results obtained are compared with those obtained by Courvoisier for the phenothiazines, and with those of Schallek for trimethobenzamide, and are given in the following Table. The activity index by the subcutaneous route has been calculated taking chlorpromazine in as reference substance. rt ο •P co 0) P fi •H -P β £ fi •H M-i O CO fi fi o Ol e o □ 0) Φ fi XJ •P Φ Χί P +) nJ Xi P Φ > fi a CO -p rH fi CO 0) fi xi Eh I o xi +i I •rf fi •P 'fi § co Φ fi •rl N fi •rl Xi P O fi Φ Xi a 0) fi fi xi -P CO □ •rl -P Φ e P Φ > •rl -P ϋ fi Φ fi o ε □ •H -P O fi Φ fi fi Φ rt •H N β ffl Λ

Claims (30)

1. CLAIMS:1. A compound of the general formula: (I) in which A is a hydrogen atom or a or C 2~5 group; X is a hydrogen atom or a C^_j- alkoxy, c ^_g alkyl, C 2 _5 alkenyloxy or alkenyl group; Y is a hydrogen or halogen atom or a nitro, C-[_ 5 alkyl, alkoxy, amino or substituted amino group; Z is a hydrogen or halogen atom, a C 1 _ 5 alkoxy or 0 χ _ 5 alkylsulphonyl group or a group of formula SC^NRjRj in which each of and R which may be the same or different, is a hydrogen atom or a C 1-5 alkyl group, or -NR^R 2 is a heterocyclic ring optionally containing another hetero atom; W is a straight or branchedchain alkylene group; B is a group of formula NR^R^ in which R 3 is a C 3 _ 5 alkyl group and R^ is a C^_ 5 hydroxyalkyl group, or B is a nitrogen-attached heterocyclic ring containing a second nitrogen atom substituted with a hydroxyalkyl group? or B is a racemic, dextrorotatory or laevorotatory heterocyclic radical of formula (IV): Ν' ! R Wm (IV) in which R is a C alkyl group containing a reactive function as hereinbefore defined and m is 1, 2 or 3, including the dextrorotatory and laevorotatory forms of the compounds
2. An acid-addition salt of a compound as claimed in 5 claim 1 with a pharmacologically acceptable acid.
3. A quaternary ammonium salt of a compound as claimed in claim 1.
4. An oxide of a compound as claimed in claim I.
5. N-(1-(2 1 -hydroxyethyl)-2-pyrrolidinylmethyl)-210 rnethoxy-5-sulphamoylbenzamide.
6. N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2methoxy-5-ethylsulphonylbenzamide hydrochloride.
7. N- (1'-acetyl-2’-pyrrolidinylmethyl)-2-methoxy-5sulphamoylbenzamide. 15
8. N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy4- amino-5-chlorobenzamide.
9. N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2methoxy-5-sulphamoylbenzamide.
10. 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-(2'-hydroxy20 ethyl)-piperazine.
11. N-(1- (2 1 -hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy5- ethylsulphonylbenzamide hydrochloride.
12. Ν-(Ν 1 -ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2methoxy-5-sulphamoylbenzamide.
13. Ν-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2methoxy-5-sulphamoylbenzamide hydrochloride.
14. 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-^'-hydroxyethyl ) -piperazine.
15. 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-(2'-hydroxyethyl) -piperazine diphosphate.
16. A method of preparing a compound according to claim 1 that comprises reacting a compound of formula: in which A, X, Y and Z are as defined in claim 1, or a reactive derivative thereof, with an amine of the general formula f^N-W-B, in which W and B are as defined in claim 15 1, or a reactive derivative thereof.
17. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 5.
18. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 6.
19. 20 19. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 7. Λ 3 3 7 S 20. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 8.
20. 21. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 9. 5
21. 22. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 10.
22. 23. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 11.
23. 24. A method as claimed in claim 16, as applied to the 10 preparation of the compound claimed in claim 12.
24. 25. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 13.
25. 26. A method as claimed in claim 16, as applied to the preparation of the compound claimed in claim 15. 15
26. 27. A method as claimed in claim 16, substantially as hereinbefore described in any one of the Examples.
27. 28. A compound as claimed in claim 1, when prepared by a method as claimed in any one of claims 16-27.
28. 29. A method as claimed in any one of claims 16-27, 20 including the further step of converting the product to an acid-addition salt, quaternary ammonium salt or oxide.
29.
30. A pharmaceutical composition containing as active ingredient a compound as claimed in any one of claims 1-15 and 28, together with an acceptable pharmaceutical carrier.
IE1166/76A 1975-06-10 1976-06-01 Substituted benzamides, their preparation, and compositions containing them IE43375B1 (en)

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NZ186175A (en) * 1977-01-27 1980-03-05 Shionogi & Co Meta-sulphonamidobenzamide derivatives
FR2415099A1 (en) * 1978-01-20 1979-08-17 Ile De France NEW DERIVATIVES OF 4-AMINO-5-ALKYLSULFONYL ORTHO-ANISAMIDES, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS PSYCHOTROPES
FR2438650A1 (en) * 1978-10-11 1980-05-09 Ile De France N- (1-METHYL 2-PYRROLIDINYL METHYL) 2,3-DIMETHOXY 5-METHYLSULFAMOYL BENZAMIDE AND DERIVATIVES THEREOF, THEIR PREPARATION METHODS AND THEIR APPLICATION IN THE TREATMENT OF LOWER URINARY DISORDERS
JPS597160A (en) * 1982-06-28 1984-01-14 ラボラトリーオス・デラグランヘ・エセ・ア N-(1-propyl-2-pyrrolidinylmethyl)-2-methoxy-5- sulfamoylbenzamide, manufacture and antidepressive
US4820715A (en) * 1984-06-28 1989-04-11 Bristol-Myers Company Anti-emetic quinuclidinyl benzamides
US4808624A (en) * 1984-06-28 1989-02-28 Bristol-Myers Company Pharmacologically active substituted benzamides
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides
JP3026845B2 (en) * 1991-02-20 2000-03-27 日清製粉株式会社 Piperidine derivative
US9375486B2 (en) 2012-09-17 2016-06-28 Nektar Therapeutics Oligomer-containing benzamide-based compounds

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MX3580E (en) 1981-03-19
AU1436076A (en) 1977-12-01
NO761977L (en) 1976-12-13
NL186382C (en) 1990-11-16
DE2623075A1 (en) 1976-12-30
HK46979A (en) 1979-07-20
LU75104A1 (en) 1977-03-09
CH596175A5 (en) 1978-02-28
AR210888A1 (en) 1977-09-30
SE415971B (en) 1980-11-17
FI761669A (en) 1976-12-11
AU506001B2 (en) 1979-12-13
MW1676A1 (en) 1977-10-12
ES448643A1 (en) 1977-07-01
AT358571B (en) 1980-09-25
IE43375L (en) 1976-12-10
FR2313935A1 (en) 1977-01-07
SE7606424L (en) 1976-12-11
DD124380A5 (en) 1977-02-16
ZM6576A1 (en) 1977-06-21
PT65164B (en) 1977-11-17
PH13912A (en) 1980-11-04
SU607551A3 (en) 1978-05-15
NL7606284A (en) 1976-12-14
FR2313935B1 (en) 1979-04-27
NZ181072A (en) 1978-07-28
YU131876A (en) 1982-06-30
RO70265A (en) 1981-06-30
ZA763042B (en) 1977-04-27
NL186382B (en) 1990-06-18
PT65164A (en) 1976-07-01
GB1500105A (en) 1978-02-08
CA1064930A (en) 1979-10-23
YU39352B (en) 1984-10-31
SU645557A3 (en) 1979-01-30
HU172195B (en) 1978-06-28
PL103075B1 (en) 1979-05-31
DK255276A (en) 1976-12-11
NO146058B (en) 1982-04-13
NO146058C (en) 1982-07-28
ATA400176A (en) 1980-02-15
IN142899B (en) 1977-09-03
BG27360A3 (en) 1979-10-12
PL190247A1 (en) 1978-03-13
OA05350A (en) 1981-02-28
PL102929B1 (en) 1979-05-31
EG12285A (en) 1978-09-30
JPS5231041A (en) 1977-03-09
BE842059A (en) 1976-11-22
JPS6055503B2 (en) 1985-12-05
CS189007B2 (en) 1979-03-30

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