CA1252794A - Benzamide derivatives - Google Patents
Benzamide derivativesInfo
- Publication number
- CA1252794A CA1252794A CA000445296A CA445296A CA1252794A CA 1252794 A CA1252794 A CA 1252794A CA 000445296 A CA000445296 A CA 000445296A CA 445296 A CA445296 A CA 445296A CA 1252794 A CA1252794 A CA 1252794A
- Authority
- CA
- Canada
- Prior art keywords
- signifies
- aminoethyl
- compound
- acid addition
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
Abstract It has surprisingly been found that benzamides of the formula I
wherein R1 and R2 each independently sig-nify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R1 and R2 on adjacent carbon atoms together signify a methylene-dioxy group, with the proviso that R2 is different from hydrogen when R1 signifies bromine in the 3-position, and their pharmaceutically usable acid addition salts have interesting monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treat-ment of depressive states and Parkinsonism. Those compounds of formula I in which R1 signifies halogen, cyano or tri-fluoromethyl in the para-position and R2 signifies hydrogen or R1 and R2 together signify 2,4-dichloro, 3,4-dichloro or 3,4-methylenedioxy are novel; these novel compounds can be manufactured according to methods known per se.
wherein R1 and R2 each independently sig-nify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R1 and R2 on adjacent carbon atoms together signify a methylene-dioxy group, with the proviso that R2 is different from hydrogen when R1 signifies bromine in the 3-position, and their pharmaceutically usable acid addition salts have interesting monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treat-ment of depressive states and Parkinsonism. Those compounds of formula I in which R1 signifies halogen, cyano or tri-fluoromethyl in the para-position and R2 signifies hydrogen or R1 and R2 together signify 2,4-dichloro, 3,4-dichloro or 3,4-methylenedioxy are novel; these novel compounds can be manufactured according to methods known per se.
Description
7~L
The present invention is concerned with benzamide derivatives. In par~icular, it is concerned wi~h N-amino-ethyl-su~stitu~ed benzamides of the general formula C
l ~ \ /C\N / \ /~;2 ~1 ~ 2 wherein Rl and R2 each independently ignify hydrogen, haLogen, lower alkyl, lower alkoxy, cyano, trifluoxomethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R and R on adjacent carbon atoms togeth~r signify a methylenedioxy group, with the proviso that R2 is different from hydrogen when Rl signifles bromine in the 3-positlon, and pharmaceutlcally usable acid addition salts thereof.
Some of these compounds are known from, ~or 30 example, German Ofenlegungsschrift 2.458.908, hut it has surprisingly been found that they exhibit interesting and therapeutically u~able pharmacodynamic properties with low toxicity. Thus, in animal experiments it has been found that the compounds of foxmula I above and their pharmaceutica'ly usable acid addition ~aLts ha~e monoamine oxidase (MAO) inhibiting properties.
Objects of the present invention are compounds o~
general formula r and their pharmaceutically usable acid Kbr/27.12.83 : ~ : ,........ .
The present invention is concerned with benzamide derivatives. In par~icular, it is concerned wi~h N-amino-ethyl-su~stitu~ed benzamides of the general formula C
l ~ \ /C\N / \ /~;2 ~1 ~ 2 wherein Rl and R2 each independently ignify hydrogen, haLogen, lower alkyl, lower alkoxy, cyano, trifluoxomethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R and R on adjacent carbon atoms togeth~r signify a methylenedioxy group, with the proviso that R2 is different from hydrogen when Rl signifles bromine in the 3-positlon, and pharmaceutlcally usable acid addition salts thereof.
Some of these compounds are known from, ~or 30 example, German Ofenlegungsschrift 2.458.908, hut it has surprisingly been found that they exhibit interesting and therapeutically u~able pharmacodynamic properties with low toxicity. Thus, in animal experiments it has been found that the compounds of foxmula I above and their pharmaceutica'ly usable acid addition ~aLts ha~e monoamine oxidase (MAO) inhibiting properties.
Objects of the present invention are compounds o~
general formula r and their pharmaceutically usable acid Kbr/27.12.83 : ~ : ,........ .
- 2 -addition salts as pharmaceutically active substances, medi-caments containing a compound of general formula I or a pharmaceutically usable acid addition salt thereof, the manufacture of such medicamen~s and the use of compounds of general formula I and their pharmaceutically usable acid addition salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of depressive sta~es and Parkinsonism.
0 Of the compounds embraced by formula I above the benzamides of the general formula ~. /C\ / \ / 2 Ia ! i! H
11/ ~. ~ 21 ~0 wherein Rll signifies halogen, cyano or trirluoromethyl and R21 signi~ies hydrogen or Rll and R21 each signify chlorine or Rll and R21 on adjacent carbon atoms together signify a methy-lenedioxy group, and their acid addition salts are novel and as such are likewise an object of the present invention.
A final object of the present lnv ntion is a process for the manufacture of the compounds of formula Ia above and their pharmaceutically usable acid addition salts.
The term "lower alkyl" used in this description refers to straight-chain and branched-chain hydrocarbon groups containing 1 ~, preferably 1 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl and the like. The term "lower alkoxy" refers to lower alkyl ether groups in which the term "lower alkyl"
~ ~5 ~ ~f~
has the above ~ignificance. The texm "halogen" embraces the four halogens fluorine, chlorine, bromine and iodine.
The term "leaving group" signifies in ~he scope o the present invention known groups such as halogen, preferably chlorine or bromine, arylsulphonyloxy such as, for example, tosyloxy, alkylsulphonyloxy such as, for example, mesyloxy, and the like.
The term "pharmaceutically usable acid addition salts" e~braces salts with inorganic and or~anic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sul-phuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartarlc acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
Such salts can be manufactuxed readily by any person skilled in the art having regard to the state of the art and bear-ing in mind the nature of the compound to be converted into a salt. 0 Preferred compounds of formula I are those in which Rl and R2 each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl.
Especially pr~ferred co~.pounds o~ formula I are those in which Rl and R2 each independently signify hydrogen~
halogen or lower alkyl.
If the compounds of formula I axe disubstituted, then the substituents are preferably situated in the 2,3-, 2,4-, 2,5 , 3,4- or 3,6-position, especially in the 2,4- or
11/ ~. ~ 21 ~0 wherein Rll signifies halogen, cyano or trirluoromethyl and R21 signi~ies hydrogen or Rll and R21 each signify chlorine or Rll and R21 on adjacent carbon atoms together signify a methy-lenedioxy group, and their acid addition salts are novel and as such are likewise an object of the present invention.
A final object of the present lnv ntion is a process for the manufacture of the compounds of formula Ia above and their pharmaceutically usable acid addition salts.
The term "lower alkyl" used in this description refers to straight-chain and branched-chain hydrocarbon groups containing 1 ~, preferably 1 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl and the like. The term "lower alkoxy" refers to lower alkyl ether groups in which the term "lower alkyl"
~ ~5 ~ ~f~
has the above ~ignificance. The texm "halogen" embraces the four halogens fluorine, chlorine, bromine and iodine.
The term "leaving group" signifies in ~he scope o the present invention known groups such as halogen, preferably chlorine or bromine, arylsulphonyloxy such as, for example, tosyloxy, alkylsulphonyloxy such as, for example, mesyloxy, and the like.
The term "pharmaceutically usable acid addition salts" e~braces salts with inorganic and or~anic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sul-phuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartarlc acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
Such salts can be manufactuxed readily by any person skilled in the art having regard to the state of the art and bear-ing in mind the nature of the compound to be converted into a salt. 0 Preferred compounds of formula I are those in which Rl and R2 each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl.
Especially pr~ferred co~.pounds o~ formula I are those in which Rl and R2 each independently signify hydrogen~
halogen or lower alkyl.
If the compounds of formula I axe disubstituted, then the substituents are preferably situated in the 2,3-, 2,4-, 2,5 , 3,4- or 3,6-position, especially in the 2,4- or
3,4-position.
Particularly preferred compounds of ormula I are: 5 N-(2 Aminoethyl)-p-chlorobenzamide, N-~2-aminoethyl)-p fluorobenzamide, N-(2-aminoethyl)-p-bromobenzamide, N-(2-aminoethyl)-3,4-dichlorobenzamide, ~2~;~7~
N-(2-aminoethyl)-2,4~dichlorobenzamide and N-(2-aminoe~hyl)benzamide, The compounds of formula Ia and their pharma-ceutically usable acid addition salts can be manufactured in accordance with the invantion by a) reacting a compound of the general formula '10 O
Il ~-\ /C OH
11/ ~. ~ 21 II
wherein Rll and R21 have tha above significance, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or ~) reacting a compound of the general formula .\ /C\ /~\ III
3 i 4 wherein Rll and R21 have the above significance, R3 sisnifies hydrogen and R signifies a leaving group or R3 and R4 together signify an additional bond, with ammonia, or c) converting the group RS in a compound of the general formula 1l R5 ~ N / \./ IV
wherein Rll and R21 have the above significance and R5 signifies a group convertible into the amino group, into the amino group, and, if desired, converting a compound obtained into a pharmaceutically usable acid addition salt~
As reactlve functional derivatives of the acids of formula II there come into consideratio~, for example, halides (e.g. chlorides), symmetric or mixed anhydrides, este~s (e.g methyl esters, p-nitrophenyl esters or N-hydroxysuccinimide esters), a2ides and amides (eOg.
imidazolides or succinimides~.
The reaction o an acid of formula II or a re-active ~unctional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out according to ccnventional methods. Thus, for example, a free acid o formula II can be reacted with ethylenediamine in the presence of a condensation agent in an inert solvent. If a carbodiimide such as dlcyclohexyl-car~odiimide is used as the condensation agent, then the reaction is conveniently carried out in an alkanecarboxylic acid ester such as ethyl acetate, an ether such as tetra-hydrofuran or dioxan, a chlorinated hydrocarbon such asmethylene chloride or chlorororm, an aromatic hydrocarbon such as ben2ene, toluene or xylene, acetonitrile Or di-methylformamide at a temperature between about -20C and room temperature, preferably at about 0C. I~ phosphorus 52~g~
trichloride is used as the condensation agent, then the reaction is conveniently carried out in a solvent such as pyridine at a temperature between about 0C and the reflux temperature of the reaction mixture, preferably at about 90C. In another embodiment of variant a), ethylenediamine is reacted with one of the aforementioned reactive functional derivatives of an acid of formula II. Thus, for exampie, a halide (e.gO ~he chloride) of an acid of formula II ca~ be reacted at about 0C with ethylene-diamine in the presence of a solvent such as diethyl ether.
The compounds of formula III in which R3 signifies hydrogen and R signiies a leaving group are, for example, N-(2-haloethyl)benzamldes such as ~-(2-chloroethyl)benza-mide, N~(2-me~hylsulphonylethyl)benzamide or N-[2-(p-toluenesulphonyl)ethyl]benzamide and the like. The com-pounds of formula III in which R3 and ~4 toge~her signify an additional bond are benzoylaziridines such as, for example, p-chlorobenzoylaziridine and the like.
In accordance with variant b) of the above process, a compound of formula III can be reacted with ammonia in a manner known per se at a temperature between about -40C
and 50C, if desired in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulphoxide and the like. The reaction is conveniently caxried out in the presence of a solvent at about room temperature.
When a benzoylaziridine of ormula III is used, the reaction is preferably carried out in the presence of a~ inert solvent such as dimethylformamide, toluene or benzene.
The conversion of the group R5 into the amino group in accordance with variant c) of the above process is liXe-wise carried out in a manner known per se depending on thenature of the group R5. If R5 signifies an amide group, then the conversion is conveniently carried out by acidic or basic hydrolysis. The acidic hydrolysis is advantage-ously carried out using a solution of a mineral acid such f~52 as hydrochlQric acid, aqueous hydrogen bromide, sulphuric acid, phosphoric acid and the like in an inert solvent such as an alcohol (e.g. methanol or ethanol) or an ether (e.g. tetrahydrofuran or dioxan). The basic hydrolysis can be carxied out using aqueous solutions of alkali metal hydroxides such as potassium hydroxide or sodium hydroxide, Inert organic solvents such as those mentioned above in connec~ion with the acidic hydrolysis can be added as solubilizers. The acidic and basic hydrolysis can be carried out in a temperature range of about room temperature to the re~lux temperature cf the mixtur~, with the boiling point o the mixture or a temperature slightly thereunder being preferred. If RS sisnifies the phthali-mido group, then this can be converted int~ the amino groupnot only by acidic and basic hydrolysis, but also by aminolysis with an aqueous solution of a lower alkylamine such as methylamine or ethylamineO ~s the organic solvent there can be used a lowex alkanol such as ethanol.
This reaction is preferably carried out at roo~ temperature.
A third method ~or the conversion of the phthalimido group into the amino group comprises reacting compounds o ormula IV in which R5 signifies the phthalimido group with hydra2ine in an inert solvent such as ethanol, a mixture of ethanol and chlorofor~, tetrahydrofuran or aqueous ethanol.
The reaction temperature can be varied in a range of about room temperature to about 100C, wi~h the boiling point of the chosen solvent being preerred. The resulting product can be extracted with dilute mineral acids and can sub-sequently be obtained from the acidic solution by basifi~cation. The t-butoxycarbonylamino group is conveniently converted into the amino group using trifluoroacetic acid or ormic acid in the presence or absence oi an inert solvent at about room temperature, while the conversion of the trichloroethoxycarbonylamino group into the amino group ls carried out using zinc or cadmium under acidic con-ditions. The acidic conditions are conveni~ntly achievçd by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent such as an ~ 7 ~
alcohol (e.g. methanol). The benzyloxycar~onylamino group c~n be converted into the amlno group in a known m~nner by acidic hydrolysis as descrlbed above or hydrogenolytically.
The a2ido group can be reduced to the amino group accord-ing to methods known per se; for example, using elemental hydrogen in the presence of a catalyst such as palLadium/
carbon, Raney-nickel~ platinum oxide and the like. A
he~amethylenetetraammonium group can also be converted into the amino group by acidic hydrolysis according to known methodsO
The compounds of formula II and their reactive functional derivatives used as starting materials in variant a) of the above process are known or can be prepa_ed in analogy to the preparation of the known com-pounds .
The compounds of formula III used as starting materials in variant b) of the above process are likewiseknown or are analogues o~ known compounds and can be pre-pared in a manner known per se. Thus, for example, the compounds o~ ~ormula III in which R3 signifies hydrogen and R4 signifies a leaving group can be prepared by reacting a compound of formula II or a reactive functional derivative thereof with ethanolamine under the reaction conditions described above in connection with variant a) and converting the resulting N-(2~hydroxyethyl)benzamide into the desired compound of formula III in a manner known per se; for example~ by reaction with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and the like, an arylsulphonyl halide such as tosyl chloride or an alkylsulphonyl halide such as mesyl chloride. A compound o formula III in which R3 and R4 together signify an additional bond can be prepared, for ~xample, by reacting a reactive functional derivati~e of a compound of ~ormula II ~ith ethyleneimine. The reaction can be carried out under the reaction conditions described above in connection wi~h variant a).
The compounds of foxmula IV used as starting ~aterials in variant c) o~ the above process are likewise known or are analogues of known compounds and can be prepared in a manner known per se. Thus, for example, a co~pound of ormula II or a reactive functional derivative thereof can be reacted under ~he conditions described above in connection with variant a) with a compound of the general formula H2N CH2 C~2 R V
wherein R5 has the above significance.
The compounds of formula V are known or can be prepa~ed in analogy to the preparation o the known compounds.
In accordance with an alternative process~ the compounds af fo~mula IV in which R5 signifies phthalimido, azido or hexamethyltetraammonium can be prepared by reacting a compound of formula III with potassium phthal-imide, an alkall metal azide or hexamethylenetetramine.
The reaction is carried out in a mannex known per se under the reaction conditions described above in connection with variant b).
As mentioned above, the compounds of ~or~ula I and their pharmaceutically usable acid addition salts have mono-amine oxidase (MAO) lnhibiting activity. On the basis o~this activity the compounds of formula I and their pharma ceutically usab~e acid addition salts can be used for the treatment of depressive states and Parkinsonism.
The MAO inhibiting activity of the compounds in accordance with ~he invention can be determined using standard methods. Thus, the substances to ~e tested were administered p.o. to rats. Two hours thereafter the I
animal~ were killed and the ~A0 inhibiting act~vity T~as mPasured in homogenates of the brain and the liver accord-ing to the method described in Biochem. Pharmacol. 12 5 (1963) 1439-1441, bu~ usiny phenethylamine (2-10 5 mol-1 1~ in place of tvramine as the substrate. The thus-determined activity o representative compounds in accordance with the invention as well as their toxicity are evident ~rom the following ED50 values (~mol/kg, p.o. in 1~ rats) and LD50 values (mg/kg, p.o. in mice), respectively:
, _~ .. , . -Compound ED50 LD50 . . . . __ N-(2-Aminoethyl)-p-chlorobenzamide 5.5 1000-2000 N-(2-Aminoethyl)-p-fluorobenzamide 4 >5000 N-(~-Aminoethyl)-p-bro~obenzamide 4 500-1000 N-(2 Aminoethyl)-3,4-dichloro-ben2amide 10.3 1000-2000 N-(2-.~mlnoethyl)-2,4-dichloro ~0 benzamide 1.5 625-1250 ~-(2~ 20 >5000 The compounds of formula I and their pharmaceuti-cally usable acid addition salts can be used as medicaments, or e~ample in the form of pharmaceutical preparations.
The pharmaceutical preparations can be administered orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions). The administration can, however also be carried out rectally (e.g. in the form of suppositories) or parenterally (e.g. in the form of injection solutions).
For the manufacture of tablets, coated tablets t dragées and hard gelatine capsules, the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients. Examples of such excipients which can ~25;~ 3~
be ~sed for tablets, dragéPs and hard gelatine capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts etc.
Suitable excipients for soft gelatine capsules are, for example, vegetabIe oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and s~rups are, for example, water, polyols, saccharose, invert sugar, glucose etcO
Suitable excipients for injection solutions are, or Pxample, water, alcohols, polyols, glycerine, vegetable oils etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or li~uid polyols etc.
The pharmaceutical pxeparations can also containpreserving agents, solubili2ing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agants, flavouring agents, salts for varying the osmotic pressure, buffers r coating agents or antioxidants. They can also contain still other thera-peutically valuable sub~tances.
In accordance wi~h the invention the compounds o~
general formula I and their pharmaceutically usable acid addition salts can be used in ~he control or prevention of depressive staces and Parkinsonism. The dosage can vary within wide limits and is, of course, fitted to the indi-vidual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to lOO mg of a compound of general formula I should be appropriate, although the upper limit given above can be exceeded should this be found to be indica~ed.
The following Examples illustrate the prese~t inven-tion, but are not intended to limit its extent. All temp-eratures are given in degxees Celsius.
s Example 1 18~5 g of ethyl 4~chlorobenzoate and 24 g of ethyl-enediamine are stirred at 130 for 17 hours. The mixture is cooled to room temperature, evaporated, and the residue is txeated with 200 ml of ethyl acetate. The insoluble N,N'-ethyle~ebis(4-chlorobenzamide) (2.3 g), m.p. 266-268, is iltered of under suction, and the filtrate is washed three times with 50 ml of water each ~ime and evaporated. The residue is treated with 100 ml of lN hydrochloric acid, the insoluble N,N'-ethylenebis(4-chlorobenzamide) (1.0 g) is ~iltered off under suction, and the fil~rate is evaporated to dryness. The residue is then evaporated twice with 100 ml of ethanol/benzene each time and recrystallized from ethanol/e~her. There are obtained 13.7 g of N-(2-amino-ethyl)-4-chlorobenzamide hydrochloride, m.p. 216-217.
9.25 g of ethyl 4-chlorobenzoate and lÇ.0 g of N
~t-butoxycarbonyl)ethylenediamine are stirred at 130 for 15 hours. The mixture is cooled to room temp~rature, taken up in 100 ml o~ water and axtracted three times with 50 ml of e~hyl acetate each time. The ethyl acetate extract is washed twice with S0 ml of water each time, dried over s~d-ium sulphate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered off under suction. There are obtained 3.9 g of t-butyl ~2-(4-chlorobenzamido)ethyl]carbamate, m.p. 141-143.
A solution o~ 2.8 g o t-butyl [2-(4-chlorobenz-amido)ethyl]carbamate in 50 ml of formic acid is left to stand at room temperature fox 1.5 hours. The mi~ture is then concentrated to dr~ness, and the residue is dissolved in 50 ml of hydrochloric acid (1:1; VfV). Tha solution is concentrated, the residue is evaporated twice with ethanol/
benzene and ~hen rec~ystallized from ethanolO There are obtained 2.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product obtained in Example l.
Example 3 23 ml (0.17 mol) of triethylamine are added drop-wise at 0 to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloro-formate in 200 ml of chloroform. Af~er completion of the addi~ion (0.5 hour), the solution obtained is added drop-wise at 0 to a solution of 50 ml (0.75 mol) of etb~lene-diamine in lO0 ml of chloroform. After completion of the reaction, llS mL of concentrated hydrochloric acid are added dropwise at 0. The acidic mixture ls filtered and the neutral constituents remaining are removed by extract ion with chloroform. The aqueous phase is then made alka-li~a with sodium hydroxide solution and extracted several times with chloroformO The ehloroform extracts are dried and concentrated. The residue is converted into the hydrochloride which ls rec~ystallized from ethanol/etherO
There are obtained 15.1 g of N-(2-aminoethyl)-4 chloro~
benzamlde hydrochloride, m.p. 212-214. The free base melts at 43-45.
19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine.
10 ml (0.1 mol) of athyl chloroformate are then added drop-wise at 0. After completion of the addition (0.5 hour), the mixture is poured on to ice/water. The methylene chlori~e phase is separated, dried over magnesium sulphate - ]4 -and concen~rated to about 30 mlO This solution is added dropwise at 0 to a solution of 20 ml (0.3 mol) of ethylene-diamine in 100 ml of tetrahydrofuran~ After completion of the addition (0.5 hour), the mixture is filtered, the filtra~e is acidified with dilu~e hydrochloric acid and -the neutral constituents are removed by extraction with ethyl acet~te. The aqueous phase is made alkaline with sodium hydxoxide solution and extracted s~vexal times with chloro~
orm. After drying and concentrating the chlorofoxm phases, ~he residue is converted into the hydrochloride~ After recrystallization rom ethanol/ether, ~here are obtained 7.1 g of N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride, m.p. 179-182.
Example 5 22.1 ml (0016 mol) of triethylamine are added drop-wise at 10 to a suspension of 23.5 g (0.15 mol) of 2-chloro-benzoic acid in 200 ml o~ c~loroform. 14q8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temparature. After completion of the addition (l houx), the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulphate and gently concentrated to about 60 ml. The thus~obtained solution is added dropwise at 10 to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After completion of the addition, the difficultly soluble neutral consti-tuents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydro-chloride which is purified by recrystallization from ethanol/
ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschxift 2.362.568), m.p. 155-158. ~n analy-tically pure sample melts at 159-161.
In an analogous manner, from 23.5 g (0015 mol) of 3-chlorobenzoic acid there were obtained 13.5 g of N-(2-aminoethyl)-3-chlorobenzamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p. 201-203~
The free base melts at 69-71~ (from ethyl acetate/n-hexane)O
-Example 6 24.4 g (0.2 mol) of benzoic acid are reacted with triethylamine and e~hyl chloroformate in a manner analogous to that descri~ed in Example 5 and added dropwise at 10 to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform. After removing ~he difficul~ly soluble neutral constituents ~y filtrati~n, the chloroorm solution is concentrated and excess ethylenediamine is removed in a high vacuum. The oily residue (36.3 g) is taken up in 200 ml of 2N sodium hydroxide solution, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate ex-tracts are dried over magnesium sulphate and concentrated. The crude product is converted into the hydrochloride which is puri~ied by recrystallization rom ethanol, there being obtained 5.2 g o N-(2-aminoethyl)benzamide hydrochloride ~J~ Amer. Chem.
Soc. 61, 822 (1939)~, m.p. 163-165.
~5 Exam~e 7 To a suspension o 6.4 g (0.04 mol) of 4-methoxy~
benzoic acid in 60 ml of chloro~orm are added dropwise at 10 5.5 ml (0.04 mol) of triethylamine and then 3.8 ml (0.04 mol) of ethyl chloroformate. The solution obtained is then added dropwise at 5 to a solution OI lQ . 7 ml (0.16 mol) o ethylenediamine in 100 ml of chloroform. A~ter stirring at room temperature for 2 hours, the mixture is filtered. The iltrate is concentrated under reduced pressure and then excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydro-chloric acid and extracted several times with ethyl acetate.
The aqueous phase is made alkaline with 28% sodium hydrox~
ide solution and extracted three times with chloroform.
~ ~2~
After drying and concentrating the chloroform extracts, the residue is converted into the hydrochlo~ide. By re-crystallization from ethanol/ether there are obtained 3.4 g of N-(2 aminoethyl)-4-anisamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p.
186-189. The fxee base melts at 37-38.
In a manner analogous to that described above, 1~
- from 20.4 g ~0.15 mol) of 4-methylbenzoic acid there were obtained 8.7 g of N-(2-aminoe~hyl)-4~
toluamide hydrochloride (see Example 7 of German Ofenlegungschrift 2.616.486), m.p. 164-166i 1~
- from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid there were obtained 9.1 g of N-(2-aminoethyl)-3,4-dichlorobenzamide hydrochloride, m.p. 183-185;
the free base melts at 98-100;
- from 12.2 g (0.08 mol~2 methoxybenzoic acid ~here were obtained 9.3 g of N-(2-aminoethyl)-2 anisamide hydrochloride (see Example 6 of German Offenlegu~gs-schrift 2.362~568), m.p. 109-111;
~5 - from 12.2 g (0.08 mol) of 3-methoxybenzoic acid there were obtained 6.2 g of N-(2-aminoethyl)-3-anisamlde hydrochloride, m.p. 96-98;
- from 3.9 g ~0.015 mol) of S-(dimethylsulphamoyl)-2-methoxybenzoic acid there were obtained lc4 g of N-(2-aminoethyl)-5-(dimethylsulphamoyl~ 2-anisamide hydrochlorida~ m.p. 193-195 (decomposition). The free base melts at 118-123.
In a manner analogous to that described in Example 7, 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted with 2~
triethylamine and ethyl chloroormate and worked-up and then added dropwise to a solution of 21.4 ml of ethvlene-diamine in 350 ml O~r chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60 for 1 hour. After iltration, the filtrat~ i5 con-centrated, and the residue is treated in the same manner as described in Example 7. There are obtained 3.5 g of N-~2-aminoethyl)-4-cyanobenzamide hydrochloride, m.p. 212-215 (decomposition). The free base melts at 124-126.
In an analgous manner, from 405 g (0.023 mol) o~
Particularly preferred compounds of ormula I are: 5 N-(2 Aminoethyl)-p-chlorobenzamide, N-~2-aminoethyl)-p fluorobenzamide, N-(2-aminoethyl)-p-bromobenzamide, N-(2-aminoethyl)-3,4-dichlorobenzamide, ~2~;~7~
N-(2-aminoethyl)-2,4~dichlorobenzamide and N-(2-aminoe~hyl)benzamide, The compounds of formula Ia and their pharma-ceutically usable acid addition salts can be manufactured in accordance with the invantion by a) reacting a compound of the general formula '10 O
Il ~-\ /C OH
11/ ~. ~ 21 II
wherein Rll and R21 have tha above significance, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or ~) reacting a compound of the general formula .\ /C\ /~\ III
3 i 4 wherein Rll and R21 have the above significance, R3 sisnifies hydrogen and R signifies a leaving group or R3 and R4 together signify an additional bond, with ammonia, or c) converting the group RS in a compound of the general formula 1l R5 ~ N / \./ IV
wherein Rll and R21 have the above significance and R5 signifies a group convertible into the amino group, into the amino group, and, if desired, converting a compound obtained into a pharmaceutically usable acid addition salt~
As reactlve functional derivatives of the acids of formula II there come into consideratio~, for example, halides (e.g. chlorides), symmetric or mixed anhydrides, este~s (e.g methyl esters, p-nitrophenyl esters or N-hydroxysuccinimide esters), a2ides and amides (eOg.
imidazolides or succinimides~.
The reaction o an acid of formula II or a re-active ~unctional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out according to ccnventional methods. Thus, for example, a free acid o formula II can be reacted with ethylenediamine in the presence of a condensation agent in an inert solvent. If a carbodiimide such as dlcyclohexyl-car~odiimide is used as the condensation agent, then the reaction is conveniently carried out in an alkanecarboxylic acid ester such as ethyl acetate, an ether such as tetra-hydrofuran or dioxan, a chlorinated hydrocarbon such asmethylene chloride or chlorororm, an aromatic hydrocarbon such as ben2ene, toluene or xylene, acetonitrile Or di-methylformamide at a temperature between about -20C and room temperature, preferably at about 0C. I~ phosphorus 52~g~
trichloride is used as the condensation agent, then the reaction is conveniently carried out in a solvent such as pyridine at a temperature between about 0C and the reflux temperature of the reaction mixture, preferably at about 90C. In another embodiment of variant a), ethylenediamine is reacted with one of the aforementioned reactive functional derivatives of an acid of formula II. Thus, for exampie, a halide (e.gO ~he chloride) of an acid of formula II ca~ be reacted at about 0C with ethylene-diamine in the presence of a solvent such as diethyl ether.
The compounds of formula III in which R3 signifies hydrogen and R signiies a leaving group are, for example, N-(2-haloethyl)benzamldes such as ~-(2-chloroethyl)benza-mide, N~(2-me~hylsulphonylethyl)benzamide or N-[2-(p-toluenesulphonyl)ethyl]benzamide and the like. The com-pounds of formula III in which R3 and ~4 toge~her signify an additional bond are benzoylaziridines such as, for example, p-chlorobenzoylaziridine and the like.
In accordance with variant b) of the above process, a compound of formula III can be reacted with ammonia in a manner known per se at a temperature between about -40C
and 50C, if desired in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulphoxide and the like. The reaction is conveniently caxried out in the presence of a solvent at about room temperature.
When a benzoylaziridine of ormula III is used, the reaction is preferably carried out in the presence of a~ inert solvent such as dimethylformamide, toluene or benzene.
The conversion of the group R5 into the amino group in accordance with variant c) of the above process is liXe-wise carried out in a manner known per se depending on thenature of the group R5. If R5 signifies an amide group, then the conversion is conveniently carried out by acidic or basic hydrolysis. The acidic hydrolysis is advantage-ously carried out using a solution of a mineral acid such f~52 as hydrochlQric acid, aqueous hydrogen bromide, sulphuric acid, phosphoric acid and the like in an inert solvent such as an alcohol (e.g. methanol or ethanol) or an ether (e.g. tetrahydrofuran or dioxan). The basic hydrolysis can be carxied out using aqueous solutions of alkali metal hydroxides such as potassium hydroxide or sodium hydroxide, Inert organic solvents such as those mentioned above in connec~ion with the acidic hydrolysis can be added as solubilizers. The acidic and basic hydrolysis can be carried out in a temperature range of about room temperature to the re~lux temperature cf the mixtur~, with the boiling point o the mixture or a temperature slightly thereunder being preferred. If RS sisnifies the phthali-mido group, then this can be converted int~ the amino groupnot only by acidic and basic hydrolysis, but also by aminolysis with an aqueous solution of a lower alkylamine such as methylamine or ethylamineO ~s the organic solvent there can be used a lowex alkanol such as ethanol.
This reaction is preferably carried out at roo~ temperature.
A third method ~or the conversion of the phthalimido group into the amino group comprises reacting compounds o ormula IV in which R5 signifies the phthalimido group with hydra2ine in an inert solvent such as ethanol, a mixture of ethanol and chlorofor~, tetrahydrofuran or aqueous ethanol.
The reaction temperature can be varied in a range of about room temperature to about 100C, wi~h the boiling point of the chosen solvent being preerred. The resulting product can be extracted with dilute mineral acids and can sub-sequently be obtained from the acidic solution by basifi~cation. The t-butoxycarbonylamino group is conveniently converted into the amino group using trifluoroacetic acid or ormic acid in the presence or absence oi an inert solvent at about room temperature, while the conversion of the trichloroethoxycarbonylamino group into the amino group ls carried out using zinc or cadmium under acidic con-ditions. The acidic conditions are conveni~ntly achievçd by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent such as an ~ 7 ~
alcohol (e.g. methanol). The benzyloxycar~onylamino group c~n be converted into the amlno group in a known m~nner by acidic hydrolysis as descrlbed above or hydrogenolytically.
The a2ido group can be reduced to the amino group accord-ing to methods known per se; for example, using elemental hydrogen in the presence of a catalyst such as palLadium/
carbon, Raney-nickel~ platinum oxide and the like. A
he~amethylenetetraammonium group can also be converted into the amino group by acidic hydrolysis according to known methodsO
The compounds of formula II and their reactive functional derivatives used as starting materials in variant a) of the above process are known or can be prepa_ed in analogy to the preparation of the known com-pounds .
The compounds of formula III used as starting materials in variant b) of the above process are likewiseknown or are analogues o~ known compounds and can be pre-pared in a manner known per se. Thus, for example, the compounds o~ ~ormula III in which R3 signifies hydrogen and R4 signifies a leaving group can be prepared by reacting a compound of formula II or a reactive functional derivative thereof with ethanolamine under the reaction conditions described above in connection with variant a) and converting the resulting N-(2~hydroxyethyl)benzamide into the desired compound of formula III in a manner known per se; for example~ by reaction with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and the like, an arylsulphonyl halide such as tosyl chloride or an alkylsulphonyl halide such as mesyl chloride. A compound o formula III in which R3 and R4 together signify an additional bond can be prepared, for ~xample, by reacting a reactive functional derivati~e of a compound of ~ormula II ~ith ethyleneimine. The reaction can be carried out under the reaction conditions described above in connection wi~h variant a).
The compounds of foxmula IV used as starting ~aterials in variant c) o~ the above process are likewise known or are analogues of known compounds and can be prepared in a manner known per se. Thus, for example, a co~pound of ormula II or a reactive functional derivative thereof can be reacted under ~he conditions described above in connection with variant a) with a compound of the general formula H2N CH2 C~2 R V
wherein R5 has the above significance.
The compounds of formula V are known or can be prepa~ed in analogy to the preparation o the known compounds.
In accordance with an alternative process~ the compounds af fo~mula IV in which R5 signifies phthalimido, azido or hexamethyltetraammonium can be prepared by reacting a compound of formula III with potassium phthal-imide, an alkall metal azide or hexamethylenetetramine.
The reaction is carried out in a mannex known per se under the reaction conditions described above in connection with variant b).
As mentioned above, the compounds of ~or~ula I and their pharmaceutically usable acid addition salts have mono-amine oxidase (MAO) lnhibiting activity. On the basis o~this activity the compounds of formula I and their pharma ceutically usab~e acid addition salts can be used for the treatment of depressive states and Parkinsonism.
The MAO inhibiting activity of the compounds in accordance with ~he invention can be determined using standard methods. Thus, the substances to ~e tested were administered p.o. to rats. Two hours thereafter the I
animal~ were killed and the ~A0 inhibiting act~vity T~as mPasured in homogenates of the brain and the liver accord-ing to the method described in Biochem. Pharmacol. 12 5 (1963) 1439-1441, bu~ usiny phenethylamine (2-10 5 mol-1 1~ in place of tvramine as the substrate. The thus-determined activity o representative compounds in accordance with the invention as well as their toxicity are evident ~rom the following ED50 values (~mol/kg, p.o. in 1~ rats) and LD50 values (mg/kg, p.o. in mice), respectively:
, _~ .. , . -Compound ED50 LD50 . . . . __ N-(2-Aminoethyl)-p-chlorobenzamide 5.5 1000-2000 N-(2-Aminoethyl)-p-fluorobenzamide 4 >5000 N-(~-Aminoethyl)-p-bro~obenzamide 4 500-1000 N-(2 Aminoethyl)-3,4-dichloro-ben2amide 10.3 1000-2000 N-(2-.~mlnoethyl)-2,4-dichloro ~0 benzamide 1.5 625-1250 ~-(2~ 20 >5000 The compounds of formula I and their pharmaceuti-cally usable acid addition salts can be used as medicaments, or e~ample in the form of pharmaceutical preparations.
The pharmaceutical preparations can be administered orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions). The administration can, however also be carried out rectally (e.g. in the form of suppositories) or parenterally (e.g. in the form of injection solutions).
For the manufacture of tablets, coated tablets t dragées and hard gelatine capsules, the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients. Examples of such excipients which can ~25;~ 3~
be ~sed for tablets, dragéPs and hard gelatine capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts etc.
Suitable excipients for soft gelatine capsules are, for example, vegetabIe oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and s~rups are, for example, water, polyols, saccharose, invert sugar, glucose etcO
Suitable excipients for injection solutions are, or Pxample, water, alcohols, polyols, glycerine, vegetable oils etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or li~uid polyols etc.
The pharmaceutical pxeparations can also containpreserving agents, solubili2ing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agants, flavouring agents, salts for varying the osmotic pressure, buffers r coating agents or antioxidants. They can also contain still other thera-peutically valuable sub~tances.
In accordance wi~h the invention the compounds o~
general formula I and their pharmaceutically usable acid addition salts can be used in ~he control or prevention of depressive staces and Parkinsonism. The dosage can vary within wide limits and is, of course, fitted to the indi-vidual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to lOO mg of a compound of general formula I should be appropriate, although the upper limit given above can be exceeded should this be found to be indica~ed.
The following Examples illustrate the prese~t inven-tion, but are not intended to limit its extent. All temp-eratures are given in degxees Celsius.
s Example 1 18~5 g of ethyl 4~chlorobenzoate and 24 g of ethyl-enediamine are stirred at 130 for 17 hours. The mixture is cooled to room temperature, evaporated, and the residue is txeated with 200 ml of ethyl acetate. The insoluble N,N'-ethyle~ebis(4-chlorobenzamide) (2.3 g), m.p. 266-268, is iltered of under suction, and the filtrate is washed three times with 50 ml of water each ~ime and evaporated. The residue is treated with 100 ml of lN hydrochloric acid, the insoluble N,N'-ethylenebis(4-chlorobenzamide) (1.0 g) is ~iltered off under suction, and the fil~rate is evaporated to dryness. The residue is then evaporated twice with 100 ml of ethanol/benzene each time and recrystallized from ethanol/e~her. There are obtained 13.7 g of N-(2-amino-ethyl)-4-chlorobenzamide hydrochloride, m.p. 216-217.
9.25 g of ethyl 4-chlorobenzoate and lÇ.0 g of N
~t-butoxycarbonyl)ethylenediamine are stirred at 130 for 15 hours. The mixture is cooled to room temp~rature, taken up in 100 ml o~ water and axtracted three times with 50 ml of e~hyl acetate each time. The ethyl acetate extract is washed twice with S0 ml of water each time, dried over s~d-ium sulphate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered off under suction. There are obtained 3.9 g of t-butyl ~2-(4-chlorobenzamido)ethyl]carbamate, m.p. 141-143.
A solution o~ 2.8 g o t-butyl [2-(4-chlorobenz-amido)ethyl]carbamate in 50 ml of formic acid is left to stand at room temperature fox 1.5 hours. The mi~ture is then concentrated to dr~ness, and the residue is dissolved in 50 ml of hydrochloric acid (1:1; VfV). Tha solution is concentrated, the residue is evaporated twice with ethanol/
benzene and ~hen rec~ystallized from ethanolO There are obtained 2.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product obtained in Example l.
Example 3 23 ml (0.17 mol) of triethylamine are added drop-wise at 0 to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloro-formate in 200 ml of chloroform. Af~er completion of the addi~ion (0.5 hour), the solution obtained is added drop-wise at 0 to a solution of 50 ml (0.75 mol) of etb~lene-diamine in lO0 ml of chloroform. After completion of the reaction, llS mL of concentrated hydrochloric acid are added dropwise at 0. The acidic mixture ls filtered and the neutral constituents remaining are removed by extract ion with chloroform. The aqueous phase is then made alka-li~a with sodium hydroxide solution and extracted several times with chloroformO The ehloroform extracts are dried and concentrated. The residue is converted into the hydrochloride which ls rec~ystallized from ethanol/etherO
There are obtained 15.1 g of N-(2-aminoethyl)-4 chloro~
benzamlde hydrochloride, m.p. 212-214. The free base melts at 43-45.
19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine.
10 ml (0.1 mol) of athyl chloroformate are then added drop-wise at 0. After completion of the addition (0.5 hour), the mixture is poured on to ice/water. The methylene chlori~e phase is separated, dried over magnesium sulphate - ]4 -and concen~rated to about 30 mlO This solution is added dropwise at 0 to a solution of 20 ml (0.3 mol) of ethylene-diamine in 100 ml of tetrahydrofuran~ After completion of the addition (0.5 hour), the mixture is filtered, the filtra~e is acidified with dilu~e hydrochloric acid and -the neutral constituents are removed by extraction with ethyl acet~te. The aqueous phase is made alkaline with sodium hydxoxide solution and extracted s~vexal times with chloro~
orm. After drying and concentrating the chlorofoxm phases, ~he residue is converted into the hydrochloride~ After recrystallization rom ethanol/ether, ~here are obtained 7.1 g of N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride, m.p. 179-182.
Example 5 22.1 ml (0016 mol) of triethylamine are added drop-wise at 10 to a suspension of 23.5 g (0.15 mol) of 2-chloro-benzoic acid in 200 ml o~ c~loroform. 14q8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temparature. After completion of the addition (l houx), the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulphate and gently concentrated to about 60 ml. The thus~obtained solution is added dropwise at 10 to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After completion of the addition, the difficultly soluble neutral consti-tuents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydro-chloride which is purified by recrystallization from ethanol/
ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschxift 2.362.568), m.p. 155-158. ~n analy-tically pure sample melts at 159-161.
In an analogous manner, from 23.5 g (0015 mol) of 3-chlorobenzoic acid there were obtained 13.5 g of N-(2-aminoethyl)-3-chlorobenzamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p. 201-203~
The free base melts at 69-71~ (from ethyl acetate/n-hexane)O
-Example 6 24.4 g (0.2 mol) of benzoic acid are reacted with triethylamine and e~hyl chloroformate in a manner analogous to that descri~ed in Example 5 and added dropwise at 10 to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform. After removing ~he difficul~ly soluble neutral constituents ~y filtrati~n, the chloroorm solution is concentrated and excess ethylenediamine is removed in a high vacuum. The oily residue (36.3 g) is taken up in 200 ml of 2N sodium hydroxide solution, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate ex-tracts are dried over magnesium sulphate and concentrated. The crude product is converted into the hydrochloride which is puri~ied by recrystallization rom ethanol, there being obtained 5.2 g o N-(2-aminoethyl)benzamide hydrochloride ~J~ Amer. Chem.
Soc. 61, 822 (1939)~, m.p. 163-165.
~5 Exam~e 7 To a suspension o 6.4 g (0.04 mol) of 4-methoxy~
benzoic acid in 60 ml of chloro~orm are added dropwise at 10 5.5 ml (0.04 mol) of triethylamine and then 3.8 ml (0.04 mol) of ethyl chloroformate. The solution obtained is then added dropwise at 5 to a solution OI lQ . 7 ml (0.16 mol) o ethylenediamine in 100 ml of chloroform. A~ter stirring at room temperature for 2 hours, the mixture is filtered. The iltrate is concentrated under reduced pressure and then excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydro-chloric acid and extracted several times with ethyl acetate.
The aqueous phase is made alkaline with 28% sodium hydrox~
ide solution and extracted three times with chloroform.
~ ~2~
After drying and concentrating the chloroform extracts, the residue is converted into the hydrochlo~ide. By re-crystallization from ethanol/ether there are obtained 3.4 g of N-(2 aminoethyl)-4-anisamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p.
186-189. The fxee base melts at 37-38.
In a manner analogous to that described above, 1~
- from 20.4 g ~0.15 mol) of 4-methylbenzoic acid there were obtained 8.7 g of N-(2-aminoe~hyl)-4~
toluamide hydrochloride (see Example 7 of German Ofenlegungschrift 2.616.486), m.p. 164-166i 1~
- from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid there were obtained 9.1 g of N-(2-aminoethyl)-3,4-dichlorobenzamide hydrochloride, m.p. 183-185;
the free base melts at 98-100;
- from 12.2 g (0.08 mol~2 methoxybenzoic acid ~here were obtained 9.3 g of N-(2-aminoethyl)-2 anisamide hydrochloride (see Example 6 of German Offenlegu~gs-schrift 2.362~568), m.p. 109-111;
~5 - from 12.2 g (0.08 mol) of 3-methoxybenzoic acid there were obtained 6.2 g of N-(2-aminoethyl)-3-anisamlde hydrochloride, m.p. 96-98;
- from 3.9 g ~0.015 mol) of S-(dimethylsulphamoyl)-2-methoxybenzoic acid there were obtained lc4 g of N-(2-aminoethyl)-5-(dimethylsulphamoyl~ 2-anisamide hydrochlorida~ m.p. 193-195 (decomposition). The free base melts at 118-123.
In a manner analogous to that described in Example 7, 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted with 2~
triethylamine and ethyl chloroormate and worked-up and then added dropwise to a solution of 21.4 ml of ethvlene-diamine in 350 ml O~r chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60 for 1 hour. After iltration, the filtrat~ i5 con-centrated, and the residue is treated in the same manner as described in Example 7. There are obtained 3.5 g of N-~2-aminoethyl)-4-cyanobenzamide hydrochloride, m.p. 212-215 (decomposition). The free base melts at 124-126.
In an analgous manner, from 405 g (0.023 mol) o~
4-trifluoromethylbenzoic acid there were obtained 301 g of N-(2-aminoethyl)-a,,a-tri~luoro-4-toluamide hydrochloride, iS m.p. 196-199; the free base melts at 66-68.
Example 9 A solution o~ 6.2 ml (0.05 mol? of 4-chlorobenzoyl chlorida in 150 ml of ether is added dropwise at -10 over a period of 0.5 hour to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether. The mixtuxe is left to warm to room temperature, filtered and the white residue is rinsed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and ex-tracted several times with chloroform. A~ter e~aporating the chloroform, converting the residue into ~he hydro-chloride and recrystallization from ethanol/ether, there are obtained 1.8 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product ob tained in Example 1.
In an analogous manner, from 7 ml (0.05 mol) of 2~4-dichlorobenzoyl chloride there were obtained 1.7 g of N-(2-aminoethyl)-2,4~dichlorobenzamide hydrochloride of melting point 178 179 which is identicaL with the product ob-~ 2~i;2-- 1 8 tained in Example 4.
Exam~Le 10 7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0 126 mol) of e~hylenediamine are hsated to lCQ (ba~h temperature) for 205 hours. After cooling, the e~cess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and e~tracted with chloroform. The aqueous phase is made al-kali~e with sodium hydroxide solution and then extracted several times with chloroform. After evaporating the sol-vent and recrystallizing the residue from chloroform/
hexane, there are obta~ned 3.4 g of N-(2-aminoethyl~-1,3 benzdioxol-S-carboxamide, m.p. 120-123. The hydro-chloride melts at 210-213.
Exam~le 11 10.7 g (0.05 mol) o~ methyl 4-bromobenzoate and 10.4 ml (O.lS mol) o~ ethylenediamine are heated ~o 130 (bath temperature) for 30 minutes. After working-up in a manner analogous to that described in Example 10 and recrystal-lization from methanol/ether, there are obtained 6.5 g ofN-(2-aminoethyl)-4-hromoben2amide hydrochlori de, m.p.
2~-23~.
~e~
3~
10.7 ml (0.16 mol) of ethylenediamine are added to 6.65 g (0.04 mol) of methyl 4-methoxy~enzoate. The solution is heated to 13G (bath temperature) for 2 hours and, after cooling, excess ethylenediamine is removed in a high vacuum.
The residue is acidified with dilute hydrochloric acid.
The di~fi~ultly soluble neutral constituents are removed by ~iltration and subsequent extraction with ethyl acPtate~
The aqueous phase is made alkaline with 28~ sodium hy-droxide solution, saturated with sodium chloride~ and ex-~252~
tracted three times with chloroform. The chloroformextracts are dried over magnesium sulpha~e and concentrated.
The residue is converted into the hydrochloride which is re crystallized from ethanol~ether. There are o~tained 3.8 g of N~(2-aminoethyl)~4-anisamide hydrochloride (see Example 7 of German Ofenlegungsschrift 2.616.486), m.p. 201-204.
In an analogous manner, from 20 g (o.l mol) of methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine there were obtained 8.9 g o N-(2-amino-ethyl)-4-chloro-2-anisamide hydrochloride, m~p. 132-135 (decomposition).
ExamPle 13 7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) o ethylene diamine are heated to 130 (bath temperature) for 2 hoursO The mixture ls poured on to ice/hydrochloric acid and extracted with ethyl acetate in order ~o remove the neutral constituents.
The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform.
Ater drying and concentratin~ ~he chloroform extracts, the residue (7.6 g) is recrystallized rom et~yl acetate/
hexa~e, thexe being o~tained N-(2-aminoethyl)-4-fluoro-benzamide, m.p. 57-60. The hydrochloride melts at 214-216.
Examl~le 14 A solution of 1.3 ml (0.01 mol) of 4-chloro-benzoyl chloride in 15 ml of chloroform is added drop~
wise at G to a solution of 1.02 g (0.01 mol) of acetyl-ethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939)~ and 1.4 ml (0.01 mol) of triethylamine in 25 ml o chloroform.
After 15 minutes, the resulting crystals are iltered off, washed with chloroform and dried. There are obtained 1.9 g of N-(2-acetylaminoethyl)-4-chlorobenzamide, m.p. 222-224.
~$~
In order to cleave the protecting group~ the N-(2-acetylaminoethyl)~4-chlorobenzamide obtained is heated t~
reflux for 22 hours in a mixture of 24 ml of 2N hydro-chloric acid and 15 ml of ethanoL After concentrating the solution, the crude product is recrystallized from ethanol/
ether. There are o~tained 1.2 g of N-(2 aminoethyl-4-chlorobenzamide hydrochloride, m.p. 211-213, which is identical with the product obtained in Example lo 2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at 0 to a solu~ion of 1.2 ml ~0.02 mol) of 1~ ethanolamine and 3 ml (about 0.02 mol) OL triethylamine in 30 ml of methylene chloxide. The mixture is then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulpha~e and concentratedO After 2~ puriication on silica gel usin~ chloroform and chloroform/
methanol (9~1) as the eluting agent, there are obtained 3.1 g of N-(2-hydroxyethyl)-4-chlorobenzamide.
A solution of 0.6 ml o methanesulphonyl chloride in 3 ml of methylene chloride is added dropwise at 0 to a solution of 1.5 g (0.0075 mol) of N-(2-hydroxyethyl)-4-chlorobenæamide and 1 ml of triethylamine in 15 ml of methylene chloride. A~ter 15 minutes, the mixture is poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.
The N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide obtained is dissolved in S ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia in dimethylformamide. After stirring for 2 hours, the mixture is worked~up and there is obtained N-(2-amino-ethyl)-4-chloxobenzamide which is identical with the pro-.
i2~
- 21 ;
duct obtained in Example l.
Example Interlocking gelatine capsules (5 m~3 In~redients 1. N~(2-Aminoethyl)-2,4-dichlorobenzoamide *) hydrochloride 5.7~ mg 2~ Lactose (powdered) 80.22 mg 3. ~aize starch 40.00 mg 4. Talc 3.60 mg 15 5, Magnesium stearate 0.40 mg 6. Lactose (crystalline) llO.00 mg Capsule fill weight 240.00 mg ) corresponding to 5 mg of base.
Procedùre:
.
1-5 are mixed and ~he mixture is sieved throuyh a sieve having a mesh size o 0.5 mm. 6 is then added and the resulting mixture is mixed. This finished mixture is illed into interlocking gelatine capsules of suitable size (e.g. No. 2) having an individual fill weight of 240 mg.
Tablets (5 m~
Ingredients:
1. N-(2-Aminoethyl)-2,4-dichlorobenzamide *
hydrochloride 5.78 mg 2. Lactose (powdered) 104.22 mg 3. Maize starch 45.00 mg 4. Polyvinylpyrrolidone I~ 3015.00 mg
Example 9 A solution o~ 6.2 ml (0.05 mol? of 4-chlorobenzoyl chlorida in 150 ml of ether is added dropwise at -10 over a period of 0.5 hour to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether. The mixtuxe is left to warm to room temperature, filtered and the white residue is rinsed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and ex-tracted several times with chloroform. A~ter e~aporating the chloroform, converting the residue into ~he hydro-chloride and recrystallization from ethanol/ether, there are obtained 1.8 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product ob tained in Example 1.
In an analogous manner, from 7 ml (0.05 mol) of 2~4-dichlorobenzoyl chloride there were obtained 1.7 g of N-(2-aminoethyl)-2,4~dichlorobenzamide hydrochloride of melting point 178 179 which is identicaL with the product ob-~ 2~i;2-- 1 8 tained in Example 4.
Exam~Le 10 7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0 126 mol) of e~hylenediamine are hsated to lCQ (ba~h temperature) for 205 hours. After cooling, the e~cess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and e~tracted with chloroform. The aqueous phase is made al-kali~e with sodium hydroxide solution and then extracted several times with chloroform. After evaporating the sol-vent and recrystallizing the residue from chloroform/
hexane, there are obta~ned 3.4 g of N-(2-aminoethyl~-1,3 benzdioxol-S-carboxamide, m.p. 120-123. The hydro-chloride melts at 210-213.
Exam~le 11 10.7 g (0.05 mol) o~ methyl 4-bromobenzoate and 10.4 ml (O.lS mol) o~ ethylenediamine are heated ~o 130 (bath temperature) for 30 minutes. After working-up in a manner analogous to that described in Example 10 and recrystal-lization from methanol/ether, there are obtained 6.5 g ofN-(2-aminoethyl)-4-hromoben2amide hydrochlori de, m.p.
2~-23~.
~e~
3~
10.7 ml (0.16 mol) of ethylenediamine are added to 6.65 g (0.04 mol) of methyl 4-methoxy~enzoate. The solution is heated to 13G (bath temperature) for 2 hours and, after cooling, excess ethylenediamine is removed in a high vacuum.
The residue is acidified with dilute hydrochloric acid.
The di~fi~ultly soluble neutral constituents are removed by ~iltration and subsequent extraction with ethyl acPtate~
The aqueous phase is made alkaline with 28~ sodium hy-droxide solution, saturated with sodium chloride~ and ex-~252~
tracted three times with chloroform. The chloroformextracts are dried over magnesium sulpha~e and concentrated.
The residue is converted into the hydrochloride which is re crystallized from ethanol~ether. There are o~tained 3.8 g of N~(2-aminoethyl)~4-anisamide hydrochloride (see Example 7 of German Ofenlegungsschrift 2.616.486), m.p. 201-204.
In an analogous manner, from 20 g (o.l mol) of methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine there were obtained 8.9 g o N-(2-amino-ethyl)-4-chloro-2-anisamide hydrochloride, m~p. 132-135 (decomposition).
ExamPle 13 7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) o ethylene diamine are heated to 130 (bath temperature) for 2 hoursO The mixture ls poured on to ice/hydrochloric acid and extracted with ethyl acetate in order ~o remove the neutral constituents.
The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform.
Ater drying and concentratin~ ~he chloroform extracts, the residue (7.6 g) is recrystallized rom et~yl acetate/
hexa~e, thexe being o~tained N-(2-aminoethyl)-4-fluoro-benzamide, m.p. 57-60. The hydrochloride melts at 214-216.
Examl~le 14 A solution of 1.3 ml (0.01 mol) of 4-chloro-benzoyl chloride in 15 ml of chloroform is added drop~
wise at G to a solution of 1.02 g (0.01 mol) of acetyl-ethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939)~ and 1.4 ml (0.01 mol) of triethylamine in 25 ml o chloroform.
After 15 minutes, the resulting crystals are iltered off, washed with chloroform and dried. There are obtained 1.9 g of N-(2-acetylaminoethyl)-4-chlorobenzamide, m.p. 222-224.
~$~
In order to cleave the protecting group~ the N-(2-acetylaminoethyl)~4-chlorobenzamide obtained is heated t~
reflux for 22 hours in a mixture of 24 ml of 2N hydro-chloric acid and 15 ml of ethanoL After concentrating the solution, the crude product is recrystallized from ethanol/
ether. There are o~tained 1.2 g of N-(2 aminoethyl-4-chlorobenzamide hydrochloride, m.p. 211-213, which is identical with the product obtained in Example lo 2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at 0 to a solu~ion of 1.2 ml ~0.02 mol) of 1~ ethanolamine and 3 ml (about 0.02 mol) OL triethylamine in 30 ml of methylene chloxide. The mixture is then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulpha~e and concentratedO After 2~ puriication on silica gel usin~ chloroform and chloroform/
methanol (9~1) as the eluting agent, there are obtained 3.1 g of N-(2-hydroxyethyl)-4-chlorobenzamide.
A solution of 0.6 ml o methanesulphonyl chloride in 3 ml of methylene chloride is added dropwise at 0 to a solution of 1.5 g (0.0075 mol) of N-(2-hydroxyethyl)-4-chlorobenæamide and 1 ml of triethylamine in 15 ml of methylene chloride. A~ter 15 minutes, the mixture is poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.
The N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide obtained is dissolved in S ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia in dimethylformamide. After stirring for 2 hours, the mixture is worked~up and there is obtained N-(2-amino-ethyl)-4-chloxobenzamide which is identical with the pro-.
i2~
- 21 ;
duct obtained in Example l.
Example Interlocking gelatine capsules (5 m~3 In~redients 1. N~(2-Aminoethyl)-2,4-dichlorobenzoamide *) hydrochloride 5.7~ mg 2~ Lactose (powdered) 80.22 mg 3. ~aize starch 40.00 mg 4. Talc 3.60 mg 15 5, Magnesium stearate 0.40 mg 6. Lactose (crystalline) llO.00 mg Capsule fill weight 240.00 mg ) corresponding to 5 mg of base.
Procedùre:
.
1-5 are mixed and ~he mixture is sieved throuyh a sieve having a mesh size o 0.5 mm. 6 is then added and the resulting mixture is mixed. This finished mixture is illed into interlocking gelatine capsules of suitable size (e.g. No. 2) having an individual fill weight of 240 mg.
Tablets (5 m~
Ingredients:
1. N-(2-Aminoethyl)-2,4-dichlorobenzamide *
hydrochloride 5.78 mg 2. Lactose (powdered) 104.22 mg 3. Maize starch 45.00 mg 4. Polyvinylpyrrolidone I~ 3015.00 mg
5. ~aize starch 25.00 my
6. Talc 4.50 mg 5 7, Magnasium stearate 0.50 mg Tablet weight 200.00 mg ) corresponding to 5 mg of base.
Procedure:
1-3 are mixed and the mixture is sieved through a sieve having a mesh size o 0.5 mm~ This powder mixture is moistened with an alcoholic solution of 4 and kneaded.
The mcist mass is granulated, dried and converted into a suitable particle size. 5, 6 and 7 are added in succes-sion to ~he dried granulate and the resulting mixture is mixed. The finished mixture is pressed to tablets of suitable size having an i~dividual weight of 200 mg.
~_) Ingredlents:
1. N-(2-Aminoethyl)-p-chlorobenzamide *
hydrochloride 11.84 mg 2, Lactose (powdered) 74.16 mg 3. Maize starch 40.00 mg 4. Talc 3,60 mg 5, Magnesium s~earate o.40 mg 6. Lactose (crystalline) llO.00 mg Capsule fill weight 240.00 mg *) corresponding to 10 mg of base.
Procedure:
1~5 are mixed and the mixture is sieved through a sieve having a mesh size of 0.5 mm. 6 is then added and the resulting mixture is mixed. This finished mixture is filled into interlocking gelatine capsules of suitable size (e.g. ~o. 2) having an individual fill weight o~ 240 mg.
Exam~le D
In ~edients:
(2;Aminoethyl)-p-chlorobenzamide *
hydrochloride 11.84 mg 2. Lactose (powdered) 103.16 mg 3. Maize starch 40.00 mg 4. Polyvinylpyrrolidone K 30 15.00 mg S. Maize starch 25.00 mg 6. Talc 4~50 mg
Procedure:
1-3 are mixed and the mixture is sieved through a sieve having a mesh size o 0.5 mm~ This powder mixture is moistened with an alcoholic solution of 4 and kneaded.
The mcist mass is granulated, dried and converted into a suitable particle size. 5, 6 and 7 are added in succes-sion to ~he dried granulate and the resulting mixture is mixed. The finished mixture is pressed to tablets of suitable size having an i~dividual weight of 200 mg.
~_) Ingredlents:
1. N-(2-Aminoethyl)-p-chlorobenzamide *
hydrochloride 11.84 mg 2, Lactose (powdered) 74.16 mg 3. Maize starch 40.00 mg 4. Talc 3,60 mg 5, Magnesium s~earate o.40 mg 6. Lactose (crystalline) llO.00 mg Capsule fill weight 240.00 mg *) corresponding to 10 mg of base.
Procedure:
1~5 are mixed and the mixture is sieved through a sieve having a mesh size of 0.5 mm. 6 is then added and the resulting mixture is mixed. This finished mixture is filled into interlocking gelatine capsules of suitable size (e.g. ~o. 2) having an individual fill weight o~ 240 mg.
Exam~le D
In ~edients:
(2;Aminoethyl)-p-chlorobenzamide *
hydrochloride 11.84 mg 2. Lactose (powdered) 103.16 mg 3. Maize starch 40.00 mg 4. Polyvinylpyrrolidone K 30 15.00 mg S. Maize starch 25.00 mg 6. Talc 4~50 mg
7. Magnesium stearate 0.50 mg Tablet weight 200.00 mg ) cor_esponding to 10 mg of base.
Procedure:
:
1-3 are mixed and the mixture is sieved through a sieve having a mesh size o 0.5 mm. This powder mix~ure is moistened with an alcoholic solution of 4 and kneaded.
The moist mass is granulated, dxied and converted into a suitable particle size. 5, 6 and 7 are added in succession to the dried granulate and the resuLting mixture is mixed.
The finished mixture is pressed to tablets of suitable size having an individual weight of 200 mg.
Procedure:
:
1-3 are mixed and the mixture is sieved through a sieve having a mesh size o 0.5 mm. This powder mix~ure is moistened with an alcoholic solution of 4 and kneaded.
The moist mass is granulated, dxied and converted into a suitable particle size. 5, 6 and 7 are added in succession to the dried granulate and the resuLting mixture is mixed.
The finished mixture is pressed to tablets of suitable size having an individual weight of 200 mg.
Claims (26)
1. A process for the manufacture of benzamide deriva-tives of the general formula Ia wherein R11 signifies halogen, cyano or tri-fluoromethyl and R21 signifies hydrogen or R11 and R21 each signify chlorine or R11 and R21 on adjacent carbon atoms together sig-nify a methylenedioxy group, and of pharmaceutically usable acid addition salts thereof, which process comprises a) reacting a compound of the general formula II
wherein R11 and R21 have the above significance, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or b) reacting a compound of the general formula III
wherein R11 and R21 have the above significance, R3 signifies hydrogen and R4 signifies a leaving group or R3 and R4 together signify an additional bond, with ammonia, or c) converting the group R5 in a compound of the general formula IV
wherein R11 and R21 have the above significance and R5 signifies a group convertible into the amino group, into the amino group, and, if desired, converting a com-pound obtained into a pharmaceutically usable acid addit-ion salt.
wherein R11 and R21 have the above significance, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or b) reacting a compound of the general formula III
wherein R11 and R21 have the above significance, R3 signifies hydrogen and R4 signifies a leaving group or R3 and R4 together signify an additional bond, with ammonia, or c) converting the group R5 in a compound of the general formula IV
wherein R11 and R21 have the above significance and R5 signifies a group convertible into the amino group, into the amino group, and, if desired, converting a com-pound obtained into a pharmaceutically usable acid addit-ion salt.
2. A process according to claim 1, wherein a compound of formula II, III or IV is used as starting material wherein R11 signifies halogen, cyano or trifluoromethyl and R21 signifies hydrogen or R11 and R21 each signify chlorine.
3. A process according to claim 2, wherein a compound of formula II, III or IV is used as starting material wherein R11 signifies halogen and R21 signifies hydrogen or R11 and R21 each signify chlorine.
4. A process according to claim 3 wherein a compound of formula II, III or IV is used as starting material wherein R11 signifies chlorine and R21 signifies hydrogen.
5. A process according to claim 3 wherein a compound of formula II, III or IV is used as starting material wherein R11 signifies fluorine and R21 signifies hydrogen.
6. A process according to claim 3 wherein a compound of formula II, III or IV is used as starting material wherein R11 signifies bromine and R21 signifies hydrogen.
7. A process according to claim 3 wherein a compound of formula II, III or IV is used as starting material wherein R11 and R21 each signify chlorine and R21 is situated in the 3-position.
8. A process according to claim 3 wherein a compound of formula II, III or IV is used as starting material wherein R11 and R21 each signify chlorine and R21 is situated in the 2-position.
9. Benzamide derivatives of the general formula Ia wherein R11 signifies halogen, cyano or tri-fluoromethyl and R21 signifies hydrogen or R11 and R21 each signify chlorine or R11 and R21 on adjacent carbon atoms together sig-nify a methylenedioxy group, and pharmaceutically usable acid addition salts thereof whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.
10. Compounds according to claim 9, wherein R11 sig-nifies halogen, cyano or trifluoromethyl and R21 signifies hydrogen or R11 and R21 each signlfy chlorine, whenever prepared by the process claimed in claim 2 or by an obvious chemical equivalent thereof.
11. Compounds according to claim 10, wherein R11 sig-nifies halogen and R21 signifies hydrogen or R11 and R21 each signify chlorine, whenever prepared by the process claimed in claim 3 or by an obvious chemical equivalent thereof.
12. N-(2-Aminoethyl)-p-chlorobenzamide or a pharma-ceutically usable acid addition salt thereof, whenever pre-pared by the process claimed in claim 4 or by an obvious chemical equivalent thereof.
13. N-(2-Aminoethyl)-p-fluorobenzamide or a pharma-ceutically usable acid addition salt thereof, whenever pre-pared by the process claimed in claim 5 or by an obvious chemical equivalent thereof.
14. N-(2-Aminoethyl)-p-bromobenzamide or a pharma-ceutically usable acid addition salt thereof, whenever pre-pared by the process claimed in claim 6 or by an obvious chemical equivalent thereof.
15. N-(2-Aminoethyl)-3,4-dichlorobenzamide or a pharma-ceutically usable acid addition salt thereof, whenever pre-pared by the process claimed in claim 7 or by an obvious chemical equivalent thereof.
16. N-(2-Aminoethyl)-2,4-dichlorobenzamide or a pharma-ceutically usable acid addition salt thereof, whenever pre-pared by the process claimed in claim 8 or by an obvious chemical equivalent thereof.
17. Benzamide derivatives of the general formula Ia wherein R11 signifies halogen, cyano or tri-fluoromethyl and R21 signifies hydrogen or R11 and R21 each signify chlorine or R11 and R21 on adjacent carbon atoms together sig-nify a methylenedioxy group, and pharmaceutically ucable acid additlon salts thereof.
18. Compounds according to claim 17, wherein R11 sig-nifies halogen, cyano or trifluoromethyl and R21 signifies hydrogen or R11 and R21 each signify chlorine.
19. Compounds according to claim 18, wherein R11 sig-nifies halogen and R21 signifies hydrogen or R11 and each signify chlorine.
20. N-(2-Aminoethyl)-p-chlorobenzamide or a pharma-ceutically usable acid addition salt thereof.
21. N-(2-Aminoethyl)-p-fluorobenzamide or a pharma-ceutically usable acid addition salt thereof.
22. N-(2-Aminoethyl)-p-bromobenzamide or a pharma-ceutically usable acid addition salt thereof.
23. N-(2-Aminoethyl)-3,4-dichlorobenzamide or a pharma-ceutically usable acid addition salt thereof.
24. N-(2-Aminoethyl)-2,4-dichlorobenzamide or a pharma-ceutically usable acid addition salt thereof.
25. A pharmaceutical composition comprising a compound according to claim 17, 18 or 19, together with a pharmaceu-tically acceptable carrier.
26. A pharmaceutical composition having monoamine oxidase inhibiting properties with low toxicity, useful for the treatment of depressive states and Parkinsonism, com-prising an effective amount of a compound according to claim 17, 18 or 19, together with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1150/83A CH653670A5 (en) | 1983-03-03 | 1983-03-03 | BENZAMIDE DERIVATIVES. |
| CH1150/83 | 1983-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1252794A true CA1252794A (en) | 1989-04-18 |
Family
ID=4203649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445296A Expired CA1252794A (en) | 1983-03-03 | 1984-01-13 | Benzamide derivatives |
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| JP (1) | JPS59167552A (en) |
| KR (1) | KR910008202B1 (en) |
| AR (1) | AR243155A1 (en) |
| AT (1) | AT390948B (en) |
| AU (2) | AU570431B2 (en) |
| BE (1) | BE899059A (en) |
| CA (1) | CA1252794A (en) |
| CH (1) | CH653670A5 (en) |
| DE (1) | DE3407654C2 (en) |
| DK (1) | DK166382C (en) |
| ES (3) | ES8504680A1 (en) |
| FI (1) | FI79297C (en) |
| FR (1) | FR2541996B1 (en) |
| GB (1) | GB2135998B (en) |
| GR (1) | GR81866B (en) |
| HU (1) | HU193556B (en) |
| IE (1) | IE57004B1 (en) |
| IL (1) | IL71078A (en) |
| IT (1) | IT1173365B (en) |
| LU (1) | LU85231A1 (en) |
| MC (1) | MC1568A1 (en) |
| NL (1) | NL8400459A (en) |
| NO (1) | NO165999C (en) |
| NZ (1) | NZ207272A (en) |
| PH (1) | PH19623A (en) |
| PT (1) | PT78187B (en) |
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|---|---|---|---|---|
| CA1261335A (en) * | 1984-08-29 | 1989-09-26 | Hoffmann-La Roche Limited/Hoffmann-La Roche Limitee | Ethylenediamine monoamide derivatives |
| US4772630A (en) * | 1984-11-23 | 1988-09-20 | Ciba-Geigy Corp. | Benzamides and their salts |
| NZ219974A (en) * | 1986-04-22 | 1989-08-29 | Goedecke Ag | N-(2'-aminophenyl)-benzamide derivatives, process for their preparation and their use in the control of neoplastic diseases |
| FR2642972B1 (en) * | 1989-02-14 | 1994-08-05 | Inst Nat Sante Rech Med | AGENTS FOR THE DIAGNOSIS AND TREATMENT OF MELANOMAS, HALOGENATED AROMATIC DERIVATIVES SUITABLE FOR USE AS SUCH AGENTS AND THEIR PREPARATION |
| WO2014155184A1 (en) * | 2013-03-28 | 2014-10-02 | Rhenovia Pharma | Treatment for parkinson's disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3342679A (en) * | 1967-09-19 | Parts by weight of acid chloride to react with parts of amine in | ||
| FR6557M (en) * | 1967-06-20 | 1968-12-23 | Ile De France | |
| GB1455116A (en) * | 1972-12-15 | 1976-11-10 | Ici Ltd | Pharmaceutical compositions |
| GB1520584A (en) * | 1975-04-02 | 1978-08-09 | Yamanouchi Pharma Co Ltd | 2 - alkoxy - 5 substituted benzamide derivatives and their use in pharmaceutical compositions |
| DE2616486A1 (en) * | 1976-04-14 | 1977-11-03 | Basf Ag | Perylene tetracarboxylic acid diimide pigments - for use in paints, thermoplastics, etc. and as vat dyes |
| CA1206964A (en) * | 1980-11-12 | 1986-07-02 | Nobuo Shinma | Tetra-substituted benzene derivatives |
| DE3200258A1 (en) * | 1982-01-07 | 1983-07-21 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | SUBSTITUTED 1-BENZOYL-2-PHENYLIMINO IMIDAZOLIDINE, THE ACID ADDITION SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THE SAME |
| IL69997A0 (en) * | 1983-01-03 | 1984-01-31 | Miles Lab | Procainamide and n-acetylprocainamide immunogens,antibodies prepared therefrom,labeled conjugates,and the use of such antibodies and labeled conjugates in immunoassays |
| US4808624A (en) * | 1984-06-28 | 1989-02-28 | Bristol-Myers Company | Pharmacologically active substituted benzamides |
-
1983
- 1983-03-03 CH CH1150/83A patent/CH653670A5/en not_active IP Right Cessation
-
1984
- 1984-01-13 CA CA000445296A patent/CA1252794A/en not_active Expired
- 1984-02-13 NL NL8400459A patent/NL8400459A/en not_active Application Discontinuation
- 1984-02-22 FI FI840734A patent/FI79297C/en not_active IP Right Cessation
- 1984-02-23 IT IT19778/84A patent/IT1173365B/en active
- 1984-02-24 NZ NZ207272A patent/NZ207272A/en unknown
- 1984-02-24 ZA ZA841394A patent/ZA841394B/en unknown
- 1984-02-27 HU HU84767A patent/HU193556B/en not_active IP Right Cessation
- 1984-02-27 AU AU25066/84A patent/AU570431B2/en not_active Ceased
- 1984-02-27 IL IL71078A patent/IL71078A/en not_active IP Right Cessation
- 1984-02-29 PH PH30315A patent/PH19623A/en unknown
- 1984-02-29 LU LU85231A patent/LU85231A1/en unknown
- 1984-02-29 DK DK147584A patent/DK166382C/en not_active IP Right Cessation
- 1984-03-01 FR FR8403219A patent/FR2541996B1/en not_active Expired
- 1984-03-01 JP JP59037410A patent/JPS59167552A/en active Granted
- 1984-03-01 MC MC841696A patent/MC1568A1/en unknown
- 1984-03-01 GR GR73975A patent/GR81866B/el unknown
- 1984-03-01 DE DE3407654A patent/DE3407654C2/en not_active Expired - Fee Related
- 1984-03-02 AT AT0072484A patent/AT390948B/en not_active IP Right Cessation
- 1984-03-02 IE IE512/84A patent/IE57004B1/en not_active IP Right Cessation
- 1984-03-02 BE BE0/212488A patent/BE899059A/en not_active IP Right Cessation
- 1984-03-02 GB GB08405486A patent/GB2135998B/en not_active Expired
- 1984-03-02 PT PT78187A patent/PT78187B/en not_active IP Right Cessation
- 1984-03-02 AR AR84295901A patent/AR243155A1/en active
- 1984-03-02 ES ES530230A patent/ES8504680A1/en not_active Expired
- 1984-03-02 SE SE8401190A patent/SE466447B/en not_active IP Right Cessation
- 1984-03-02 NO NO840797A patent/NO165999C/en unknown
- 1984-03-03 KR KR1019840001083A patent/KR910008202B1/en not_active IP Right Cessation
- 1984-10-25 ES ES537046A patent/ES8506601A1/en not_active Expired
- 1984-10-25 ES ES537045A patent/ES537045A0/en active Granted
-
1987
- 1987-12-24 AU AU83079/87A patent/AU609758B2/en not_active Ceased
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