CA1078408A - 3-phenyl-sec-butylamine derivatives - Google Patents
3-phenyl-sec-butylamine derivativesInfo
- Publication number
- CA1078408A CA1078408A CA245,616A CA245616A CA1078408A CA 1078408 A CA1078408 A CA 1078408A CA 245616 A CA245616 A CA 245616A CA 1078408 A CA1078408 A CA 1078408A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- lower alkyl
- compound
- alkyl group
- pharmaceutically acceptable
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds, and processes to make them, of the formula:
Compounds, and processes to make them, of the formula:
Description
PRIOR ART
Depressive disorders have with more or less success been treated with various compounds. Many types of chemical substances have been used, - among these amphetamine with the structure fH2-CH-NH2 ' ~ However, the euphoretic effect and the risk for dependence have to a great ~ extent restricted the use of amphetamine in the therapy.
The medical use of amphetamine is nowadays mainly restricted to the treatment of narcolepsy and asthenic states in aged people.
, 10 OUTLINE OF INVENTION
a) General outline We have found that by a proper modification of the amphetamine molecule the euphoric or central stimulant effect of the substance can be diminished or completely abolished. The pharmacological profile of the com-pounds of the invention suggests a potential value of the compounds as anti-depressants and also as a new type of anxiolytics.
The compounds of the invention are characterized by the general formula Rl~CH2- H-NH2 ~ N
R3 \ R4 20 or a pharmaceutically acceptable salt thereof, in which formula Rl and R2 arethe same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom, R3 represents a lower alkyl group or a benzyl grou~
represents a hydrogen atom, a lower alkyl group ~ abenzyl group, provided that Rl and/or R2 represents a lower alkyl group or a halogen atom when R3 1~7840~3 and R4 represents a methyl group.
Rl and R2 may be situated at any free position on the phenyl nucleus.
Illustrative examples of radicals included in the above definitions are lower alkyl group: methyl, ethyl, n-propyl and isopropyl halogen atom:
chlorine, bromine, iodine and fluorine.
By the expression "lower alkyl group" in this application is to be understood alkyl groups with 1 to 5 carbon atoms, inclusive.
The new compounds of this invention may be used therapeutically ~ ~
; 10 as the racemic mixtures of ~)- and ~-)-forms, which are obtained by synthesis. ~ -They may also be resolved into the corresponding optically active modifications which, likewise, may be used in therapy. The compounds of this invention may be administered in the form of free bases or their salts with non-toxic acids.
Some typical examples of these salts are the hydrobromide~ hydrochloride, phosphate, sulphate, citrate, tartrate.
b) Pharmaceutical preparations In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.
the hydrochloride, hydrobromide, lactate, acetate, sulphate, sulphamate and the like in association with a pharmaceutically acceptable carrier. According-ly, terms relating to the novel compounds of this invention whether generical-ly or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent or capsule.
These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and 99%
by weight of the preparation, more specifically between 0.5 and 20% by weight for preparation intencled for injection and between 2 and 50% by weight for preparations suitable for oral administration.
. . ~ - - . . . . ~ , . ~
78~0~3 .
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium di-oxide, and the like. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents.
Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combina-tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potatoe starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions for example, solutions containing from about 0.2% to 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Op-tionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared - 3 _ 78~08 in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10o by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosages unit ampoules.
Suitable peroral doses of the compounds of the invention are 2-20 mg, preferably 5-15 mg given 1 to 3 times a day~ preferably 2 times a day.
c) Preferred embodiment The preferred compound of the invention has the formula I
CH2-CH2-CH-NH2 .
Cl ~
N
CH3 \CH3 Preferably these compounds will be prepared and used in the form of their dihydrochloride salt.
d) Methods of preparation .
A. Reduction of a compound of the formula Rl A-C=N-OH
~ ~,."."''.
R2 ~ II
R3 ~ \R4 wherein Rl, R2, R3 and R4 are as previously described, and A is -CH2CH2- or -CH=CH- to the format:ion of a compound of the formula I.
The reduction can be effected by catalytic hydrogenation, using a metal catalyst such as Raney nickel or palladium on charcoal. The reaction is conducted in a suitable solvent e.g. methanol or acetic acid preferably in the presence of a mineral acid. If the reaction mixture becomes sluggish, . - . . .. : .. , - : : , ::
~7~34(~3 additional catalyst may be introduced thereinto. l~hen no more hydrogen is absorbed the catalyst is removed by filtration, and the filtrate is concen-trated. The residue is recrystallized from a suitable solvent.
B. Heating a ketone of the ~ormula fH3 R ~ ~
R3 / \ 4 Nherein Rl, R , R3 and R4 are as previously described, with Eormamide, ammonium formate or formamide and formic acid according to the Leuckart reac-tion to the formation of a compound of the formula I. In case the product obtained is a N-formyl derivative of the amine, hydrolysis will yield the compound of the formula I.
- C. Reductive amination of a ketone of the formula Rl -CH2-C=
R2~
R3 / \ R4 wherein Rl, R2, R3 and R4 are as previously described, with ammonia in the presence of a catalyst ~e.g. a metal catalyst) to the formation of a compound of the formula I.
D. Direc~ halogenation of a compound of the formula R \ CH2CH2CH-NH2 R2 _~
~ N
~$78408 wherein R3 and R4 are as previously described and either Rl or R2 or both are ` hydrogen, to the formation of a compound of the formula I wherein Rl or R2 or both are a halogen atom.
e) Intermediates For the preparation of the compounds of the formula I it has been found that a compound of the formula Rl~=N-OH 11 R3~ \ R4 in which formula A is -CH2CH2- or -CH=CH-, Rl and R2 are the same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom, R3 represents aloweralkyl group or a benzyl group, R4 represents a hydrogen atom, a lower alkyl group or a benzyl group, provided that Rl and/or R2 represents a lower alkyl group or a halogen atom when R3 and R4 represents a methyl group, is a valuable starting material.
The preparation of the oxime II is effected by treating a ketone of the formula A-C = 0 Rl ~ 3 R2 ~ III
3~ \ 4 wherein A, Rl, R2, R3 and R4 are the same as above, with a hydroxylamine salt according to known procedures. The reaction is performed at elevated tempera-tures in a suitable solvent, e.g. ethanol or acetic acid and preferably in the presence of sodium acetate.
The ketones of the formula III are prepared as outlined below:
: ' - , . ... ~ . . . .
1C~784~8 l CHO
R2 ~ ~ R ~ CH3COCH3 ' 3 ~ \ 4 R3~ \R4
Depressive disorders have with more or less success been treated with various compounds. Many types of chemical substances have been used, - among these amphetamine with the structure fH2-CH-NH2 ' ~ However, the euphoretic effect and the risk for dependence have to a great ~ extent restricted the use of amphetamine in the therapy.
The medical use of amphetamine is nowadays mainly restricted to the treatment of narcolepsy and asthenic states in aged people.
, 10 OUTLINE OF INVENTION
a) General outline We have found that by a proper modification of the amphetamine molecule the euphoric or central stimulant effect of the substance can be diminished or completely abolished. The pharmacological profile of the com-pounds of the invention suggests a potential value of the compounds as anti-depressants and also as a new type of anxiolytics.
The compounds of the invention are characterized by the general formula Rl~CH2- H-NH2 ~ N
R3 \ R4 20 or a pharmaceutically acceptable salt thereof, in which formula Rl and R2 arethe same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom, R3 represents a lower alkyl group or a benzyl grou~
represents a hydrogen atom, a lower alkyl group ~ abenzyl group, provided that Rl and/or R2 represents a lower alkyl group or a halogen atom when R3 1~7840~3 and R4 represents a methyl group.
Rl and R2 may be situated at any free position on the phenyl nucleus.
Illustrative examples of radicals included in the above definitions are lower alkyl group: methyl, ethyl, n-propyl and isopropyl halogen atom:
chlorine, bromine, iodine and fluorine.
By the expression "lower alkyl group" in this application is to be understood alkyl groups with 1 to 5 carbon atoms, inclusive.
The new compounds of this invention may be used therapeutically ~ ~
; 10 as the racemic mixtures of ~)- and ~-)-forms, which are obtained by synthesis. ~ -They may also be resolved into the corresponding optically active modifications which, likewise, may be used in therapy. The compounds of this invention may be administered in the form of free bases or their salts with non-toxic acids.
Some typical examples of these salts are the hydrobromide~ hydrochloride, phosphate, sulphate, citrate, tartrate.
b) Pharmaceutical preparations In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.
the hydrochloride, hydrobromide, lactate, acetate, sulphate, sulphamate and the like in association with a pharmaceutically acceptable carrier. According-ly, terms relating to the novel compounds of this invention whether generical-ly or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent or capsule.
These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and 99%
by weight of the preparation, more specifically between 0.5 and 20% by weight for preparation intencled for injection and between 2 and 50% by weight for preparations suitable for oral administration.
. . ~ - - . . . . ~ , . ~
78~0~3 .
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium di-oxide, and the like. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents.
Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combina-tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potatoe starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions for example, solutions containing from about 0.2% to 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Op-tionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared - 3 _ 78~08 in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10o by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosages unit ampoules.
Suitable peroral doses of the compounds of the invention are 2-20 mg, preferably 5-15 mg given 1 to 3 times a day~ preferably 2 times a day.
c) Preferred embodiment The preferred compound of the invention has the formula I
CH2-CH2-CH-NH2 .
Cl ~
N
CH3 \CH3 Preferably these compounds will be prepared and used in the form of their dihydrochloride salt.
d) Methods of preparation .
A. Reduction of a compound of the formula Rl A-C=N-OH
~ ~,."."''.
R2 ~ II
R3 ~ \R4 wherein Rl, R2, R3 and R4 are as previously described, and A is -CH2CH2- or -CH=CH- to the format:ion of a compound of the formula I.
The reduction can be effected by catalytic hydrogenation, using a metal catalyst such as Raney nickel or palladium on charcoal. The reaction is conducted in a suitable solvent e.g. methanol or acetic acid preferably in the presence of a mineral acid. If the reaction mixture becomes sluggish, . - . . .. : .. , - : : , ::
~7~34(~3 additional catalyst may be introduced thereinto. l~hen no more hydrogen is absorbed the catalyst is removed by filtration, and the filtrate is concen-trated. The residue is recrystallized from a suitable solvent.
B. Heating a ketone of the ~ormula fH3 R ~ ~
R3 / \ 4 Nherein Rl, R , R3 and R4 are as previously described, with Eormamide, ammonium formate or formamide and formic acid according to the Leuckart reac-tion to the formation of a compound of the formula I. In case the product obtained is a N-formyl derivative of the amine, hydrolysis will yield the compound of the formula I.
- C. Reductive amination of a ketone of the formula Rl -CH2-C=
R2~
R3 / \ R4 wherein Rl, R2, R3 and R4 are as previously described, with ammonia in the presence of a catalyst ~e.g. a metal catalyst) to the formation of a compound of the formula I.
D. Direc~ halogenation of a compound of the formula R \ CH2CH2CH-NH2 R2 _~
~ N
~$78408 wherein R3 and R4 are as previously described and either Rl or R2 or both are ` hydrogen, to the formation of a compound of the formula I wherein Rl or R2 or both are a halogen atom.
e) Intermediates For the preparation of the compounds of the formula I it has been found that a compound of the formula Rl~=N-OH 11 R3~ \ R4 in which formula A is -CH2CH2- or -CH=CH-, Rl and R2 are the same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom, R3 represents aloweralkyl group or a benzyl group, R4 represents a hydrogen atom, a lower alkyl group or a benzyl group, provided that Rl and/or R2 represents a lower alkyl group or a halogen atom when R3 and R4 represents a methyl group, is a valuable starting material.
The preparation of the oxime II is effected by treating a ketone of the formula A-C = 0 Rl ~ 3 R2 ~ III
3~ \ 4 wherein A, Rl, R2, R3 and R4 are the same as above, with a hydroxylamine salt according to known procedures. The reaction is performed at elevated tempera-tures in a suitable solvent, e.g. ethanol or acetic acid and preferably in the presence of sodium acetate.
The ketones of the formula III are prepared as outlined below:
: ' - , . ... ~ . . . .
1C~784~8 l CHO
R2 ~ ~ R ~ CH3COCH3 ' 3 ~ \ 4 R3~ \R4
2 ~ 2 ,~
`3 ~ \ 4 ~N
R R
The formylation of the substituted aniline according to the Vilsmeyer-Haack reaction gives in a first step the corresponding aldehyde.
The formylation is effected by using a mixture of dimethylformamide and phos-phorus oxychloride. Alternatively the preparation is achieved by using a mixture of phosphorus tribromide and dimethylformamide (Acta Pharm3 Suecica 7 87, 1970).
The procedure involving the condensation of the aldehyde with ace-tone in a second step gives the intermediate benzylideneacetone. The condensa-tion is performed in a suitable solvent or with excess of acetone, in the presence of a base e.g. sodium hydroxide.
- In a third step the benzylideneacetone is subjected to catalytic hydrogenation to yield a 4-phenyl-2-butanone. The catalytic hydrogenation is performed using a metal catalyst such as platinum. The reaction is conducted in a suitable solvent e.g. ethyl acetate and ethanol.
~Ci78408 f) ~orking examples Preparation of starting materials ___ ________________________~____ ~
Example 1. 4-Dimethylamino-2-chlorobenzalacetone oxime ____ __________________________________________________ (a) 4-Dimethylamino-2-chlorobenzylide-n-acetone To a solution of 50 g of 2-chloro-4-dimethylaminobenzaldehyde in 200 ml of acetone was added dropwise 75 ml of 10% NaOH solution. The mix-ture was stirred over night at room temperature and then poured on 1.5 1 of ice water. The obtained precipitate was collected by suction filtration and air-dried.
Yield 62.5 g. M.p. 70-75C. Recrystallization from dimethylformamide-water yields 39.5 g ~65%). M.p. 80-81C.
Analysis. Calculated for C12H14ClN0: C 64.43, H 6.31, Cl 15.85, N 6.25, 0 7.15.
; Found: C 64.3, H 6.20, Cl 16.1, N 6.07, 0 7.26.
~) 4-Dimethylamino-2-chlorobenzylideneacetone oxime A mixture of 22.4 g ~0.1 mole) of 4-dimethylamino-2-chlorobenzal-acetone, 18 g of CH3COONa . 3H20 and 7.2 g hydroxylamine hydrochloride in 250 ml of abs. ethanol was refluxed for 4 hours. The mixture was then poured in 1 litre of ice water. The obtained precipitate was collected by suction filtration and washed with water. M.p. 160-166C. Yield 26.5 g. After recrystallization from ethanol the product melted at 170-171.5C. Yield 17.5 g ~73%). Calculated equivalent weight 238.73. Found equivalent weight 239.
Analysis. Calculated for C12H15N20Cl: C 60.37, H 6.33, N 11.73, 0 6.70, Cl 14.85. Found: C 60.3, H 6.37, N 11.5, 0 6.98, Cl 15.1.
Example 2. 4-Dimethylamino-2-methylbenzylideneacetone oxime ____________________________________________________________ (a) 4-Dimethylamino-2-methylbenzylideneacetone To a solution of 32.7 g of 4-dimethylamino-2-methylbenzaldehyde in 135 ml of acetone was added dropwise while stirring 49 ml of 10% NaOH solu-tion. The mixture was stirred overnight at room temperature and then poured into 1.5 1 of ice water. The obtained precipitate was collected by filtration, . ' ~ .
, . . . .
~07~408 .
washed ~ith ice water and air-dried.
Yield: 38.6 g ~95%). M.p. 65-75C.
Recrystallization from ligroin-ethanol yielded 22.4 g of the product ~55%).
hl p. 77-79C.
Analysis. Calculated for C13H17N0: C 76.81, H 8.43, N 6.89, 0 7.87.
Found: C 76.6, H 8.37, N 6.76, 0 8.020 (b) 4-Dimethylamino-2-methylbenzylideneacetone oxime A mixture of 4.1 g of 4-dimethylamino-2-methylbenzylideneacetone, 1.44 g of hydroxylamine hydrochloride and 3.72 g of sodium acetate trihydrate in 50 ml of ethanol was refluxed for 7 h. The mixture was then poured into ;~ 1 litre of ice water. The obtained precipitate was filtered off and dried.
Yield: 2.8 g ~64%). M. p. 155-157C.
After recrystallization from aqueous ethanol the product melted at 155-156.5C. Yield: 2.6 g ~60%).
Analysis. Calculated for C13H18N20: C 71.58, H 8.31, N 12.84, 0 7.33.
Found: C 71.20, H 8.25, N 12.6, 0 7.7.
Example ~ 4-(4-Dimethylamino-o-tolyl)-2-butanone A solution of 10.15 g of 4-dimethylamino-2-methylbenzylidene-acetone in 250 ml of ethyl acetate was hydrogenated in presence of 0.42 g of platinum dioxide at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporated. The residual oil was distilled at 114-123/0.3 mm, yielding 7.1 g (69%) of the compound.
Neut. equiv. (determined by potentiometric titration with perchloric acid in acetic acid). Calc. for C13H19N0: 205.30. Found 205.
Example 4. 4-~Dimethylamino-o-tolyl)-2-butanone oxime ______________________________________________________ A mixture of 8.24 g of 4-(dimethylamino-o-tolyl)-2-butanone, 2.88 g of hydroxylami-ne hydrochloride and 7.44 g of sodium acetate trihydrate in 100 ml of ethanol was refluxed for 5 h. The mixture was then poured into 1 litre of ice water and left overnight at 0C. The obtained precipitate was filtered off and dried.
_ g _ .
784~3 . .
Yield: 4.9 g ~56%). M.p. 83-90C.
After recrystallization from aqueous ethanol the product melted at 87-89C.
Yield: 3.6 g.
Analysis. Calculated for C13H20N20: C 70.87, H 9.15, N 12.72, 0 7.26.
Found: C 70.87, H 9.3, N 12.4, 0 7.0 Preparation of end compounds Example 5. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline dihydrochloride. Method A.
_ _ _ _ _ _ _ . .
A solution of 4.8 g (0.02 mole) of 4-dimethylamino-2-chloro-benzal-acetone oxime in 150 ml of acetic acid and 4 ml of concentrated HCl was hydrogenated with H2/Pd-C 5% at room temperature and normal pressure. The consumption of H2 stopped at 900 ml (2.5 hours). The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from ethanol-ether. M.p. 200-202C (decomposition). Yield 1.2 g (20~). The pro-duct was recrystallized from ethanol-isopropylether. M.p. 204-205C
~decomposition). Yield 0.8 g. A further recrystallization yielded 0.5 g of the product. M.p. 206-207C (decomposition~.
Analysis. Calculated for C12HlgClN2 . 2HCl: C 48.09, H 7.06, Cl 23.66, ; , ` Cl+Cl 35.49, N 9.35.
Found: C 48.2, H 7.77, Cl 23.4, Cl+Cl 34.9, N 9.14.
Example 6. 4-(3-Aminobutyl~-N,N-dimethyl-m-toluidine dihydro-chloride. Method A.
____________________________________________.________________ A solution of 10.92 g of 4-dimethylamino-2-methylbenzylidene-acetone oxime in 200 ml of acetic acid and 8 ml of concentrated hydrochloric acid was hydrogenated in presence of 2 g Pd-C 10% at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporat-ed. The residue was dissolved in 200 ml of water and the solution was ex-tracted with ether and evaporated. The residue was recrystallized from aqueous ethanol-isopropylether.
Yield: 6.7 g ~48%). M.p. 220.5-222.5C. A further recrystallization yielded _ 10 -1C! 78~618 ; 3.6 g of the product melting at 227-228C.
Analysis. Calculated for C13H22N2 . 211Cl: C 55.91, H 8.66, N 10.03, Cl 25.39. Found: C 55.6, H 8.6, N 9.8, Cl 25Ø
Example 7. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine dihydro-chloride. Method B
--_ _____ ____________________________ A solution of 8.21 g of 4-~4-dimethylamino-o-tolyl)-2-butanone in 15.2 g of formamide was heated at 200C for 20 h. After the addition of 25 ml of 30% NaOH solution the mixture was refluxed for 12 h. An equal volume of water was added and the solution was extracted with ether. The ether layer was separated and extracted with 2 N hydrochloric acid. The extracts were alkalized with sodium hydroxide solution and extracted with ether. The ether layer was separated, dried with sodium sulphate and evaporated. The residue was distilled at about 150/0.6 mm yielding 2.05 g o~ the crude base. The product was treated with anhydrous hydrogen chloride in ether and the obtained crude, semicrystalline hydrochloride salt was recrystallized twice from aqueous ethanol-isopropylether.
Yield: 1.5 g ci3%). ~I.p. 219.5-223C.
g) Pharmacological tests It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible antidepressive effect of new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indic.ation of the potential anti-depressive effects of the test substances, is described in Europ. J. Pharmacol.
_, 107, 1972. This method involves the measurement of the potentiation of the syndromes produced by 5-hydroxytryptophan ~5-llTP) in a laboratory animal.
The lack of euphoric effects, that is lack of central stimulatory activity, is tested by measuring the motor activity in mice after administra-tion of the test substance.
Potential anxiolytic activity is tested by measuring the anti-aggressivity in isolated mice after administration of the test substance. In , 7~4~8 ' thi5 test not amphetamine but Valiu ~ - a well-known anYiolytic substance -is used as a reference.
5-HTP response potentiation test Inhibition of the uptake of 5-HI` potentiates the effects of administered 4-hydroxytryptophan (S-HTP) probably by increasing the amount of 5-HT at the receptor. Three mice are given the test drugs one hour ~or 4, 24 hours) before dl-5-HTP~ 90 mg/kg i.v. 5-HTP alone gives only a weak behavioural syndrome but in pretreated mice there is seen a characteristic behavioural syndrome, which comes within five minutes: tremor, lordosis, abduction of the hindlegs, head-twitches.
The absence or presence of respective syndrome is scored in groups of ten mice. The compound was administered in at least five doses and the quantal responses were analysed by probit analysis and ED50 determined accor-ding to the method of Litchfield and Wilcoxon.
~lotor activity in mice ______________________ The exploratory activity of mice was recorded in a locomotion cage in which the movements were counted each time the animals cross-circuits an electrical current in the bottom plate. The activity was recorded for ten minutes one hour after the administration of the drug. The animals were test-ed individually. Groups of six mice were used and the mice were only used once. The activity was expressed in per cent of the activity of control groups ran simultaneously. The compounds were administered in at least four doses. The increase C+) or decrease ~-) of the activity compared to control groups was determined from log dose response curves.
Aggressive behaviour in mice _ _ _ _ _ _ Male mice kept isolated for 3 weeks or longer develop an aggres-sive behaviour when caged together. The method used follows that o Valzelli et al. ~Europ. J. Pharmacol. 2, 144, 1967);
- lla -~;~ .. .
, '.
.. . .
- ~78408 with the exception that 2 mice were tested on each other. The aggressive-ness was scored during a 5 minute test according to the following schedule:
O the animals show no interest in each other except occasional nosing frequent vigorous nosing and tail rattling, the animals assume a fighting position and occasionally attack each other - no more than 3-4 times in the 5 minute period tail rattling, powerful attacks - no more than 10 times in the test period the animals follow their partners, attacking and biting for most of the time lO0 attacks over the entire period.
Controls administered with the solvent were tested, the repeated testing did not influence on the aggressiveness. The animals were used for several experiments but with intervals of at least one week. Groups of 10 mice were used.
ED50 is the dose which reduces the aggressiveness score by 50%.
TABLE
Pharmacological effects CH2cH2-cH-NH2 R
R2~
R3~ \ R4 Compound Potentiation of Motor activity Antiaggressive Rl R2 R3 R4 5-HTP + = increase behaviour in mice ED50 mg/kg i.p. - - decrease ED50 mg/kg i.p.
Vali~n** 2.5 Amphetamine ~ 5 +-~+ x p-Aminoamphetamine 11.5 5-10 p-Chloroamphetamine 0.8 ++ 0.3 H 3-Cl CH3 CH3 1.6 o 3.4 H 3-CH3 CH3 CH3 2.0 x not tested, due to interference with motor activity **Trade Mark -~ ~., ., ;, 1C!7~3408 As can be seen from the test values of the Table the tested substance of the invention differs considerably in activity from amphet-amine both qualitatively and quantitatively. In contrast to amphetamine the tested compound of the invention strongly potentiates the 5-HTP
response. Furthermore the tested compound lacks the central stimulation which is pronounced after amphetamine ancl p-chloroamphetamine. Thus, the potential antidepressive activity as indicated by the potentiation of 5-HTP and the lack of central stimulatory activity may give the com-pounds of this invention value as potential antidepressive agents.
The tested compound antagonizes the aggressive behaviour of male mice which have been kept isolated for one month or more. The com-pound is almost as active as Valium* in this test which may indicate that the compound may have therapeutic value as an anxiolytic compound.
*Trade ~lark.
`3 ~ \ 4 ~N
R R
The formylation of the substituted aniline according to the Vilsmeyer-Haack reaction gives in a first step the corresponding aldehyde.
The formylation is effected by using a mixture of dimethylformamide and phos-phorus oxychloride. Alternatively the preparation is achieved by using a mixture of phosphorus tribromide and dimethylformamide (Acta Pharm3 Suecica 7 87, 1970).
The procedure involving the condensation of the aldehyde with ace-tone in a second step gives the intermediate benzylideneacetone. The condensa-tion is performed in a suitable solvent or with excess of acetone, in the presence of a base e.g. sodium hydroxide.
- In a third step the benzylideneacetone is subjected to catalytic hydrogenation to yield a 4-phenyl-2-butanone. The catalytic hydrogenation is performed using a metal catalyst such as platinum. The reaction is conducted in a suitable solvent e.g. ethyl acetate and ethanol.
~Ci78408 f) ~orking examples Preparation of starting materials ___ ________________________~____ ~
Example 1. 4-Dimethylamino-2-chlorobenzalacetone oxime ____ __________________________________________________ (a) 4-Dimethylamino-2-chlorobenzylide-n-acetone To a solution of 50 g of 2-chloro-4-dimethylaminobenzaldehyde in 200 ml of acetone was added dropwise 75 ml of 10% NaOH solution. The mix-ture was stirred over night at room temperature and then poured on 1.5 1 of ice water. The obtained precipitate was collected by suction filtration and air-dried.
Yield 62.5 g. M.p. 70-75C. Recrystallization from dimethylformamide-water yields 39.5 g ~65%). M.p. 80-81C.
Analysis. Calculated for C12H14ClN0: C 64.43, H 6.31, Cl 15.85, N 6.25, 0 7.15.
; Found: C 64.3, H 6.20, Cl 16.1, N 6.07, 0 7.26.
~) 4-Dimethylamino-2-chlorobenzylideneacetone oxime A mixture of 22.4 g ~0.1 mole) of 4-dimethylamino-2-chlorobenzal-acetone, 18 g of CH3COONa . 3H20 and 7.2 g hydroxylamine hydrochloride in 250 ml of abs. ethanol was refluxed for 4 hours. The mixture was then poured in 1 litre of ice water. The obtained precipitate was collected by suction filtration and washed with water. M.p. 160-166C. Yield 26.5 g. After recrystallization from ethanol the product melted at 170-171.5C. Yield 17.5 g ~73%). Calculated equivalent weight 238.73. Found equivalent weight 239.
Analysis. Calculated for C12H15N20Cl: C 60.37, H 6.33, N 11.73, 0 6.70, Cl 14.85. Found: C 60.3, H 6.37, N 11.5, 0 6.98, Cl 15.1.
Example 2. 4-Dimethylamino-2-methylbenzylideneacetone oxime ____________________________________________________________ (a) 4-Dimethylamino-2-methylbenzylideneacetone To a solution of 32.7 g of 4-dimethylamino-2-methylbenzaldehyde in 135 ml of acetone was added dropwise while stirring 49 ml of 10% NaOH solu-tion. The mixture was stirred overnight at room temperature and then poured into 1.5 1 of ice water. The obtained precipitate was collected by filtration, . ' ~ .
, . . . .
~07~408 .
washed ~ith ice water and air-dried.
Yield: 38.6 g ~95%). M.p. 65-75C.
Recrystallization from ligroin-ethanol yielded 22.4 g of the product ~55%).
hl p. 77-79C.
Analysis. Calculated for C13H17N0: C 76.81, H 8.43, N 6.89, 0 7.87.
Found: C 76.6, H 8.37, N 6.76, 0 8.020 (b) 4-Dimethylamino-2-methylbenzylideneacetone oxime A mixture of 4.1 g of 4-dimethylamino-2-methylbenzylideneacetone, 1.44 g of hydroxylamine hydrochloride and 3.72 g of sodium acetate trihydrate in 50 ml of ethanol was refluxed for 7 h. The mixture was then poured into ;~ 1 litre of ice water. The obtained precipitate was filtered off and dried.
Yield: 2.8 g ~64%). M. p. 155-157C.
After recrystallization from aqueous ethanol the product melted at 155-156.5C. Yield: 2.6 g ~60%).
Analysis. Calculated for C13H18N20: C 71.58, H 8.31, N 12.84, 0 7.33.
Found: C 71.20, H 8.25, N 12.6, 0 7.7.
Example ~ 4-(4-Dimethylamino-o-tolyl)-2-butanone A solution of 10.15 g of 4-dimethylamino-2-methylbenzylidene-acetone in 250 ml of ethyl acetate was hydrogenated in presence of 0.42 g of platinum dioxide at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporated. The residual oil was distilled at 114-123/0.3 mm, yielding 7.1 g (69%) of the compound.
Neut. equiv. (determined by potentiometric titration with perchloric acid in acetic acid). Calc. for C13H19N0: 205.30. Found 205.
Example 4. 4-~Dimethylamino-o-tolyl)-2-butanone oxime ______________________________________________________ A mixture of 8.24 g of 4-(dimethylamino-o-tolyl)-2-butanone, 2.88 g of hydroxylami-ne hydrochloride and 7.44 g of sodium acetate trihydrate in 100 ml of ethanol was refluxed for 5 h. The mixture was then poured into 1 litre of ice water and left overnight at 0C. The obtained precipitate was filtered off and dried.
_ g _ .
784~3 . .
Yield: 4.9 g ~56%). M.p. 83-90C.
After recrystallization from aqueous ethanol the product melted at 87-89C.
Yield: 3.6 g.
Analysis. Calculated for C13H20N20: C 70.87, H 9.15, N 12.72, 0 7.26.
Found: C 70.87, H 9.3, N 12.4, 0 7.0 Preparation of end compounds Example 5. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline dihydrochloride. Method A.
_ _ _ _ _ _ _ . .
A solution of 4.8 g (0.02 mole) of 4-dimethylamino-2-chloro-benzal-acetone oxime in 150 ml of acetic acid and 4 ml of concentrated HCl was hydrogenated with H2/Pd-C 5% at room temperature and normal pressure. The consumption of H2 stopped at 900 ml (2.5 hours). The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from ethanol-ether. M.p. 200-202C (decomposition). Yield 1.2 g (20~). The pro-duct was recrystallized from ethanol-isopropylether. M.p. 204-205C
~decomposition). Yield 0.8 g. A further recrystallization yielded 0.5 g of the product. M.p. 206-207C (decomposition~.
Analysis. Calculated for C12HlgClN2 . 2HCl: C 48.09, H 7.06, Cl 23.66, ; , ` Cl+Cl 35.49, N 9.35.
Found: C 48.2, H 7.77, Cl 23.4, Cl+Cl 34.9, N 9.14.
Example 6. 4-(3-Aminobutyl~-N,N-dimethyl-m-toluidine dihydro-chloride. Method A.
____________________________________________.________________ A solution of 10.92 g of 4-dimethylamino-2-methylbenzylidene-acetone oxime in 200 ml of acetic acid and 8 ml of concentrated hydrochloric acid was hydrogenated in presence of 2 g Pd-C 10% at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporat-ed. The residue was dissolved in 200 ml of water and the solution was ex-tracted with ether and evaporated. The residue was recrystallized from aqueous ethanol-isopropylether.
Yield: 6.7 g ~48%). M.p. 220.5-222.5C. A further recrystallization yielded _ 10 -1C! 78~618 ; 3.6 g of the product melting at 227-228C.
Analysis. Calculated for C13H22N2 . 211Cl: C 55.91, H 8.66, N 10.03, Cl 25.39. Found: C 55.6, H 8.6, N 9.8, Cl 25Ø
Example 7. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine dihydro-chloride. Method B
--_ _____ ____________________________ A solution of 8.21 g of 4-~4-dimethylamino-o-tolyl)-2-butanone in 15.2 g of formamide was heated at 200C for 20 h. After the addition of 25 ml of 30% NaOH solution the mixture was refluxed for 12 h. An equal volume of water was added and the solution was extracted with ether. The ether layer was separated and extracted with 2 N hydrochloric acid. The extracts were alkalized with sodium hydroxide solution and extracted with ether. The ether layer was separated, dried with sodium sulphate and evaporated. The residue was distilled at about 150/0.6 mm yielding 2.05 g o~ the crude base. The product was treated with anhydrous hydrogen chloride in ether and the obtained crude, semicrystalline hydrochloride salt was recrystallized twice from aqueous ethanol-isopropylether.
Yield: 1.5 g ci3%). ~I.p. 219.5-223C.
g) Pharmacological tests It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible antidepressive effect of new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indic.ation of the potential anti-depressive effects of the test substances, is described in Europ. J. Pharmacol.
_, 107, 1972. This method involves the measurement of the potentiation of the syndromes produced by 5-hydroxytryptophan ~5-llTP) in a laboratory animal.
The lack of euphoric effects, that is lack of central stimulatory activity, is tested by measuring the motor activity in mice after administra-tion of the test substance.
Potential anxiolytic activity is tested by measuring the anti-aggressivity in isolated mice after administration of the test substance. In , 7~4~8 ' thi5 test not amphetamine but Valiu ~ - a well-known anYiolytic substance -is used as a reference.
5-HTP response potentiation test Inhibition of the uptake of 5-HI` potentiates the effects of administered 4-hydroxytryptophan (S-HTP) probably by increasing the amount of 5-HT at the receptor. Three mice are given the test drugs one hour ~or 4, 24 hours) before dl-5-HTP~ 90 mg/kg i.v. 5-HTP alone gives only a weak behavioural syndrome but in pretreated mice there is seen a characteristic behavioural syndrome, which comes within five minutes: tremor, lordosis, abduction of the hindlegs, head-twitches.
The absence or presence of respective syndrome is scored in groups of ten mice. The compound was administered in at least five doses and the quantal responses were analysed by probit analysis and ED50 determined accor-ding to the method of Litchfield and Wilcoxon.
~lotor activity in mice ______________________ The exploratory activity of mice was recorded in a locomotion cage in which the movements were counted each time the animals cross-circuits an electrical current in the bottom plate. The activity was recorded for ten minutes one hour after the administration of the drug. The animals were test-ed individually. Groups of six mice were used and the mice were only used once. The activity was expressed in per cent of the activity of control groups ran simultaneously. The compounds were administered in at least four doses. The increase C+) or decrease ~-) of the activity compared to control groups was determined from log dose response curves.
Aggressive behaviour in mice _ _ _ _ _ _ Male mice kept isolated for 3 weeks or longer develop an aggres-sive behaviour when caged together. The method used follows that o Valzelli et al. ~Europ. J. Pharmacol. 2, 144, 1967);
- lla -~;~ .. .
, '.
.. . .
- ~78408 with the exception that 2 mice were tested on each other. The aggressive-ness was scored during a 5 minute test according to the following schedule:
O the animals show no interest in each other except occasional nosing frequent vigorous nosing and tail rattling, the animals assume a fighting position and occasionally attack each other - no more than 3-4 times in the 5 minute period tail rattling, powerful attacks - no more than 10 times in the test period the animals follow their partners, attacking and biting for most of the time lO0 attacks over the entire period.
Controls administered with the solvent were tested, the repeated testing did not influence on the aggressiveness. The animals were used for several experiments but with intervals of at least one week. Groups of 10 mice were used.
ED50 is the dose which reduces the aggressiveness score by 50%.
TABLE
Pharmacological effects CH2cH2-cH-NH2 R
R2~
R3~ \ R4 Compound Potentiation of Motor activity Antiaggressive Rl R2 R3 R4 5-HTP + = increase behaviour in mice ED50 mg/kg i.p. - - decrease ED50 mg/kg i.p.
Vali~n** 2.5 Amphetamine ~ 5 +-~+ x p-Aminoamphetamine 11.5 5-10 p-Chloroamphetamine 0.8 ++ 0.3 H 3-Cl CH3 CH3 1.6 o 3.4 H 3-CH3 CH3 CH3 2.0 x not tested, due to interference with motor activity **Trade Mark -~ ~., ., ;, 1C!7~3408 As can be seen from the test values of the Table the tested substance of the invention differs considerably in activity from amphet-amine both qualitatively and quantitatively. In contrast to amphetamine the tested compound of the invention strongly potentiates the 5-HTP
response. Furthermore the tested compound lacks the central stimulation which is pronounced after amphetamine ancl p-chloroamphetamine. Thus, the potential antidepressive activity as indicated by the potentiation of 5-HTP and the lack of central stimulatory activity may give the com-pounds of this invention value as potential antidepressive agents.
The tested compound antagonizes the aggressive behaviour of male mice which have been kept isolated for one month or more. The com-pound is almost as active as Valium* in this test which may indicate that the compound may have therapeutic value as an anxiolytic compound.
*Trade ~lark.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS
1. A process for the preparation of a compound of the formula I
or a pharmaceutically acceptable salt thereof, in which formula:
R1 and R2 may be the same or different and are each chosen from hydrogen, a lower alkyl group, or a halogen atom;
R3 represents a lower alkyl group or a benzyl group, and R4 represents a hydrogen atom> a lower alkyl group, or a benzyl group, provided that when R3 and R4 both represent methyl groups then R1 and/or R2 represent a lower alkyl group or a halogen atom, which process comprises:
(a) reducing a compound of the formula II
in which formula R1, R2, R3 and R4 are as defined above and A represents either -CH2-CH2- or -CH=CH-; or (b) heating a ketone of the formula III
III
wherein R1, R2, R3 and R4 are as defined above with a reagent chosen from formamide, ammonium formate or a mixture of formamide and formic acid, and, if necessary converting a thus produced N-formyl derivative to the free amine;
and (c) if desired separating a compound of formula I to provide a substantially pure stereoisomer thereof, and (d) if desired, converting a compound of formula I into a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof, in which formula:
R1 and R2 may be the same or different and are each chosen from hydrogen, a lower alkyl group, or a halogen atom;
R3 represents a lower alkyl group or a benzyl group, and R4 represents a hydrogen atom> a lower alkyl group, or a benzyl group, provided that when R3 and R4 both represent methyl groups then R1 and/or R2 represent a lower alkyl group or a halogen atom, which process comprises:
(a) reducing a compound of the formula II
in which formula R1, R2, R3 and R4 are as defined above and A represents either -CH2-CH2- or -CH=CH-; or (b) heating a ketone of the formula III
III
wherein R1, R2, R3 and R4 are as defined above with a reagent chosen from formamide, ammonium formate or a mixture of formamide and formic acid, and, if necessary converting a thus produced N-formyl derivative to the free amine;
and (c) if desired separating a compound of formula I to provide a substantially pure stereoisomer thereof, and (d) if desired, converting a compound of formula I into a pharmaceutically acceptable salt thereof.
2. A process for the preparation of a compound of the formula I
I
or a pharmaceutically acceptable salt thereof, in which formula:
R1 represents a hydrogen atom;
R2 represents a 3-halo or 3-lower alkyl group;
R3 and R4 each represent lower alkyl groups, which process comprises:
(a) reducing a compound of the formula II
II
in which formula R1, R2, R3 and R4 are as defined above and A represents either -CH2-CH2- or -CH=CH-; or (b) heating a ketone of the formula III
III
wherein R1, R2, R3 and R4 are as defined above with a reagent chosen from formamide, ammonium formate or a mixture of formamide and formic acid, and, if necessary converting a thus produced N-formyl derivative to the free amine;
and (c) if desired separating a compound of formula I to provide a substantially pure stereoisomer thereof, and (d) if desired, converting a compound of formula I into a pharmaceutically acceptable salt thereof.
I
or a pharmaceutically acceptable salt thereof, in which formula:
R1 represents a hydrogen atom;
R2 represents a 3-halo or 3-lower alkyl group;
R3 and R4 each represent lower alkyl groups, which process comprises:
(a) reducing a compound of the formula II
II
in which formula R1, R2, R3 and R4 are as defined above and A represents either -CH2-CH2- or -CH=CH-; or (b) heating a ketone of the formula III
III
wherein R1, R2, R3 and R4 are as defined above with a reagent chosen from formamide, ammonium formate or a mixture of formamide and formic acid, and, if necessary converting a thus produced N-formyl derivative to the free amine;
and (c) if desired separating a compound of formula I to provide a substantially pure stereoisomer thereof, and (d) if desired, converting a compound of formula I into a pharmaceutically acceptable salt thereof.
3. A compound of the formula I
I
or a pharmaceutically acceptable salt, or a substantially pure stereoisomer thereof, in which formula:
R1 and R2 may be the same or different and are each chosen from hydrogen, a lower alkyl group, or a halogen atom;
R3 represents a lower alkyl group or a benzyl group, and R4 represents a hydrogen atom, a lower alkyl group, or a benzyl group, provided that when R3 and R4 both represent methyl groups then R1 and/or R2 represent a lower alkyl group or a halogen atom, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
I
or a pharmaceutically acceptable salt, or a substantially pure stereoisomer thereof, in which formula:
R1 and R2 may be the same or different and are each chosen from hydrogen, a lower alkyl group, or a halogen atom;
R3 represents a lower alkyl group or a benzyl group, and R4 represents a hydrogen atom, a lower alkyl group, or a benzyl group, provided that when R3 and R4 both represent methyl groups then R1 and/or R2 represent a lower alkyl group or a halogen atom, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
4. A compound of the formula I
I
or a pharmaceutically acceptable salt or a substantially pure stereoisomer thereof, in which formula:
R1 represents a hydrogen atom;
R2 represents a 3-halo or 3-lower alkyl group;
R3 and R4 each represent lower alkyl groups, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
I
or a pharmaceutically acceptable salt or a substantially pure stereoisomer thereof, in which formula:
R1 represents a hydrogen atom;
R2 represents a 3-halo or 3-lower alkyl group;
R3 and R4 each represent lower alkyl groups, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
5. A process for the preparation of 4-(3-aminobutyl)-3-chloro-N,N-dimethylaniline, which comprises reducing 4-dimethylamino-2-chlorobenzal-acetone oxime by means of hydrogen and a palladium/carbon catalyst.
6. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of 4-(3-aminobutyl)-N,N-dimethyl-m-toluidine, or the hydrochloride thereof which comprises:
(a) reducing 4-dimethylamino-2-methylbenzylideneacetone oxime with hydrogen and a palladium/carbon catalyst, or (b) heating 4-(4-dimethylamino-o-tolyl)-2-butanone with formamide and hydrolysing the thus-obtained product with sodium hydroxide; and (c) if desired converting the free base into its hydrochloride salt by reaction with ethereal hydrogen chloride.
(a) reducing 4-dimethylamino-2-methylbenzylideneacetone oxime with hydrogen and a palladium/carbon catalyst, or (b) heating 4-(4-dimethylamino-o-tolyl)-2-butanone with formamide and hydrolysing the thus-obtained product with sodium hydroxide; and (c) if desired converting the free base into its hydrochloride salt by reaction with ethereal hydrogen chloride.
8. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7501956A SE396748B (en) | 1975-02-21 | 1975-02-21 | PROCEDURE FOR PREPARATION OF 3-PHENYL-SEC -BUTYLAMINE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078408A true CA1078408A (en) | 1980-05-27 |
Family
ID=20323758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA245,616A Expired CA1078408A (en) | 1975-02-21 | 1976-02-12 | 3-phenyl-sec-butylamine derivatives |
Country Status (12)
| Country | Link |
|---|---|
| AT (1) | AT340384B (en) |
| AU (1) | AU499650B2 (en) |
| BE (1) | BE838739A (en) |
| CA (1) | CA1078408A (en) |
| CH (1) | CH609673A5 (en) |
| DE (1) | DE2606393A1 (en) |
| FR (1) | FR2301236A2 (en) |
| GB (1) | GB1536195A (en) |
| IE (1) | IE43129B1 (en) |
| LU (1) | LU74386A1 (en) |
| NL (1) | NL7601605A (en) |
| SE (1) | SE396748B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0780381A1 (en) | 1995-12-21 | 1997-06-25 | Sumitomo Chemical Company Limited | Triazole derivatives and uses thereof |
-
1975
- 1975-02-21 SE SE7501956A patent/SE396748B/en unknown
-
1976
- 1976-02-06 AT AT82076A patent/AT340384B/en not_active IP Right Cessation
- 1976-02-12 CA CA245,616A patent/CA1078408A/en not_active Expired
- 1976-02-13 CH CH180076A patent/CH609673A5/en not_active IP Right Cessation
- 1976-02-17 NL NL7601605A patent/NL7601605A/en not_active Application Discontinuation
- 1976-02-18 DE DE19762606393 patent/DE2606393A1/en not_active Withdrawn
- 1976-02-19 AU AU11247/76A patent/AU499650B2/en not_active Expired
- 1976-02-20 FR FR7604707A patent/FR2301236A2/en active Granted
- 1976-02-20 BE BE164457A patent/BE838739A/en unknown
- 1976-02-20 GB GB6837/76A patent/GB1536195A/en not_active Expired
- 1976-02-20 IE IE341/76A patent/IE43129B1/en unknown
- 1976-02-20 LU LU74386A patent/LU74386A1/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE43129B1 (en) | 1980-12-31 |
| AT340384B (en) | 1977-12-12 |
| CH609673A5 (en) | 1979-03-15 |
| FR2301236B2 (en) | 1980-07-04 |
| GB1536195A (en) | 1978-12-20 |
| NL7601605A (en) | 1976-08-24 |
| DE2606393A1 (en) | 1976-09-09 |
| AU499650B2 (en) | 1979-04-26 |
| LU74386A1 (en) | 1977-01-06 |
| SE7501956L (en) | 1976-08-23 |
| ATA82076A (en) | 1977-04-15 |
| IE43129L (en) | 1976-08-21 |
| SE396748B (en) | 1977-10-03 |
| FR2301236A2 (en) | 1976-09-17 |
| BE838739A (en) | 1976-08-20 |
| AU1124776A (en) | 1977-08-25 |
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