NO852616L - PHENYLAMINOPROPIOPHENONE DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF. - Google Patents

Abstract

1. Phenylethylaminopropiophenone derivatives of the general formula (I) see diagramm : EP0167945,P10,F4 in which R**1 represents hydrogen, lower alkyl which is optionally substituted by fluorine, or halogen, R**2 denotes hydrogen or lower alkyl and R**3 denotes hydrogen, alkoxy or halogen, and their physiologically acceptable salts with inorganic or organic acids.

Description

The present invention relates to new phenylethyl-arainopropionphenone derivatives and salts thereof with physiologically measurable acids, a method for their preparation, as well as use in combating diseases, in particular use in the treatment of diseases in the central nervous system.

The invention relates to phenylethylaminopropiophenone derivatives of general formula (I):

where

R 1 stands for hydrogen, lower alkyl, as appropriate

may be substituted with fluorine, or halogen,

R 2 stands for hydrogen or lower alkyl, and

R 3 stands for hydrogen, alkoxy or halogen, as well as physiologically tolerable salts with inorganic or organic acids.

It is known that for molecules with one center of asymmetry there are two enantiomers and for molecules with two centers of asymmetry two diastereomers and thus two pairs of enantiomers.

The phenylethylaminopropiophenone derivatives of general formula (I) according to the present invention have two centers of asymmetry, respectively one center of asymmetry, consequently all optical isomers and diastereoisomers shall fall within the scope of the present invention.

The new compounds according to the invention of general formula (I) show a pronounced effect on the central nervous system.

The substituted phenylethylaminopropiophenones according to the invention are generally defined by formula (I). Preferred are the compounds of formula (I), where

R.J stands for hydrogen, lower alkyl with 1 to 2 carbon atoms, optionally substituted with fluorine, or halogen, preferably fluorine or chlorine,

R2 stands for hydrogen, or lower alkyl with 1 to 2

carbon atoms, and

R3 stands for hydrogen, alkoxy with 1 to 2 carbon atoms or halogen, preferably chlorine or fluorine.

The present invention further relates to a method for producing compounds of general formula (I), characterized by reacting halogen ketones of general formula (II),

where

R 1 has the above meaning, and X means halogen, preferably bromine,

with amines of general formula (III)

where

2 3

R and R have the meaning given above,

in the presence of inert solvents at temperatures between 0°C and 150°C, optionally in the presence of a proton acceptor, and the thus produced compounds of formula (I) are optionally then transferred in a known manner to acid addition salts.

The active substances according to the invention are new

and shows in animal experiments a distinct effect on the central nervous system. They are effective in experimental devices whereby anxiolytic, nootropic, but especially antidepressant effects are found. Consequently, they are particularly suitable for the treatment of depressive conditions and constitute an important addition to the stock of drugs in

The new active substances also have analgesic and antifog effects, such as e.g. can be detected in carrageenan paw edema in rats.

Preferred compounds of formula I, wherein

R 1 stands for hydrogen, halogen, particularly preferred fluorine or chlorine, or trifluoromethyl,

R 2 stands for hydrogen or methyl, and

R o stands for hydrogen, methoxy or halogen,

especially preferred for chlorine.

The preparation of the compound of general formula (I) can be described by the following reaction scheme:

The alkylation reaction takes place in solvents

which are inert towards the reaction participants.

These preferably include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; hydrocarbons, such as ligroin, hexane, cyclohexane, benzene, toluene, xylol, tetralin; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene; ketones, such as acetone, methyl ethyl ketone, diethyl ketone, methyl butyl ketone; nitrile, such as acetonitrile, propionitrile; carboxylic acid amides, such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide; further commercial technical mixtures of these solvents, particularly preferred is diethyl ketone.

The turnover can take place in a surplus of those used

the compounds of general formulas (II) and/or

(III) and optionally in the presence of an acid binder

agent, e.g. an alcoholate, such as potassium tert.-

butylate or sodium methylate, an alkali hydroxide,

such as sodium or potassium hydroxide, an alkaline earth hydroxide, such as calcium or barium hydroxide, an alkali or alkaline earth carbonate, such as sodium carbonate, potassium carbonate, calcium carbonate, sodium or potassium hydrogen carbonate or tertiary organic bases, such as triethylamine, ethyldiisopropylamine, N,N-dimethyl- aniline, pyridine, quinoline or isoquinoline, suitably at temperatures between 0°C and 150°,

preferably at temperatures between 20° and 120°C,

e.g. at the boiling temperature of the solvent used. However, the reaction can also be carried out without a solvent. However, it is particularly advantageous to carry out the turnover in diethyl-

ketone in the presence of potassium carbonate.

The turnover is normally carried out at atmospheric pressure.

When carrying out the method according to the invention, 1 mol of the compound of formula (II) and at least 1 mol of the amine of formula (III) are used

and at least 1 mol of said acid binding agent. Preferably, 1 mol of the compound is used

of formula (II) 2 to 3 moles of the amine of the formula

(III).

It is also appropriate to carry out the turnover under inert gas, such as e.g. nitrogen or argon.

The processing takes place appropriately by in-

evaporation of the reaction solution, absorption of the concentrate in a suitable solvent, such as diethyl ether or methylene chloride, and purification, possibly by means of chromatography on silica gel, respectively aluminum oxide or other suitable absorbents.

The halogen ketones used as starting product

of general formula (II) are known and can be prepared according to known methods.

The following bromoketones of general formula (III)

was used:

α-bromopropiophenone (P.S. Bailey et al., J. Amer.

Chem. Soc. 71_, 2886 (1949));

3-Chloro-ct-bromopropiophenone (L. Szotyory et al.,

J. Magnificence. Chem. 23, 202

(1963); ABOUT. 60, 4045 (1064));

3-fluoro-α-bromopropio-

phenone (US Patent No. 3,885,046):

3-trifluoromethyl-α-bromo-

propiophenone (I.J. Borowitz et al., J.

Amer. Chem. Soc. 94, 6817

(1972)):

The amines of general formula (III), which are used

as starting product, are known and partly commercially available. Preparation of these compounds is described in numerous literature examples (see e.g.

W.H. Hartung et al., J. Amer. Chem. Soc. 53_, 1875

(1931); GB Bachman et al., J. Amer. Chem. Soc.

76, 3972 (1954); US Patent Nos. 2,408,345 and 2,590,079).

Of particular importance are connections of

general formula (I), where

R 1 stands for hydrogen, trifluoromethyl, fly or

chlorine,

R 2 stands for methyl, and

R 3 stands for hydrogen, methoxy or chlorine.

The following single compounds are to be mentioned as new active substances according to the invention: 1 -(3-chlorophenyl).2.(1-methyl-2-phenylethylamino)propan-1-one hydrochloride; 1-phenyl-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride; 1-(3-trifluoromethylphenyl)-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride; 1-(3-fluorophenyl)-2-(1,1-dimethyl-2-phenyl-ethylamino)-propan-1-one hydrochloride; 1-(3-chlorophenyl)-2-(1,1-dimethyl-2-phenylethylamino)-propan-1-one hydrochloride;

1-(3-chlorophenyl)-2-(1,1-dimethyl-2-(4-methoxyphenyl)-ethylamino)-propan-1-one hydrochloride;

1-(3-Chlorophenyl)-2-(1,1-dimethyl-2-(4-methoxyphenyl)-ethylamino)propan-1-one hydrochloride.

The compounds were investigated for anxiolytic, nootropic and antidepressant properties. As a test for the anxiolytic effect, the antagonism of shock-induced aggressiveness served, according to Tedeschi 1; for the anti-depressive effect antitetrabenazine<2> and the amphetamine potentiation test 2. For example, the following values were found for the antidepressant effect of the compound according to the invention:

1) T etrabenazine antagonism

Antidepressant active substance antagonizes

that of tetrabenazine-induced ptosis in mice. The DE,-Q value indicates the dose that reduces

that of 20 mg/kg i.p. tetrabenazine induced ptosis by 50%. The following examples -can be given:

1

Tedeschi et al., J. Pharmacol. Exp. Ther. 129, 28.34, 1959.

J. L. Howard et al., in:

Antidepressants: Neurochemical, Behavioral and Clinical Perspectives, edited by S.J. Enna et al., Raven Press N.Y., pp. 107-120. 1981.

2) Amphetamine potencies ing

Antidepressant active. substance potentiates the amphetamine-induced sterotype behavior in rats.

The specified DE^. The Q-value is the dose at which the amphetamine-induced behavior is enhanced by 50% by administration of 2 mg/kg DL-amphetamine sulphate, i.v.

The following examples can be mentioned:

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert, pharmaceutically suitable carrier substances, contain one or more of the compounds according to the invention, or salts thereof, or which consist of one or more of the compounds according to the invention or salts thereof, as well as methods for the production of these preparations. The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are available in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, whose content of active substance corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. contain 1, 2, 3 or 4 single doses, or 1/2, 1/3 or 1/4 - dose. A single dose preferably contains the amount of active substance that is administered during use, and which usually corresponds to 1/2 or 1/3 or 1/4 of the daily dose.

By non-toxic, inert, pharmaceutical suitable carriers are meant solid, semi-solid or liquid diluents, fillers and composition aids of each type.

As preferred pharmaceutical preparations can be mentioned

tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions. Tablets, dragees, capsules, pills and granules may contain the active substance(s) in addition to the usual carrier substances, such as (a) fillers and thickeners, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binder, e.g. carboxymethyl cellulose, alginate, gelatin, poly-. vinylpyrrolidone, (c) humectants, e.g. glycerin, (d) explosives, e.g. agar-agar, calcium carbonate and sodium dicarbonate, (e) dissolution retarders, e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerin minostearate, (h) adsorbent, e.g. kaolin and bentonite and (1) lubricant, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be equipped with the usual, possibly opalescent-containing overprints or covers, and be composed in such a way that they release the active substance(s) exclusively, or preferentially, in a specific part of the intestinal tract, possibly with delayed release, whereby it can be used as embedding compounds, e.g. polymeric compounds and waxes.

The active substance(s) may optionally be present with one or more of the carrier substances indicated above, also in microencapsulated form.

The suppository can contain the usual water-soluble and water-insoluble carrier substances, e.g. polyethylene glycols, fatty substances, e.g. cocoa fat, and higher esters (e.g. C^-alcohol with Cj g-f acetic acids)

or mixtures of these substances.

Solutions and emulsions can next to it or

the active substances contain common carrier substances such as solvents, solubilizers and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,

propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oils, cornseed oils, olive oil, castor oil and sesame oil, glycerin, glycerine informal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan,

or mixtures of these substances.

For parenteral use, the solutions and emulsions can also be present on sterile and blood iso-

tonic form.

In addition to the active substance(s), suspensions may contain the usual carrier substances, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonide, agar-agar and tragacanth or mixtures of these substances.

The aforementioned formulation forms may also contain colourants, preservatives, as well as odor

and flavor-enhancing additive, e.g. peppermint

oil and eucalyptus oil and sweetener, e.g. saccharin.

The therapeutically active compounds should preferably be present in the pharmaceutical preparations listed above in a concentration of approx. 0.1 to 99.5, preferably approx. 0.5 to 95% by weight of the total mixture.

The above-mentioned pharmaceutical preparations can

in addition to compounds of formula (I), and/or salts thereof, also contain other pharmaceuticals

active substances.

The preparation of the above pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance(s) with the carrier substances.

The present invention also includes the use of the compounds of formula (I), and/or salts thereof,

as well as pharmaceutical preparations containing one or more compounds of the formula (I), and/or salts thereof, in the field of human medicine for the prevention, improvement and/or cure of the above-mentioned diseases.

The active substances or the pharmaceutical preparations can preferably be used orally, parenterally and/or rectally, preferably orally and parenterally, especially orally and intravenously.

In general, it has proven advantageous to administer the active substance(s) by parenteral (i.v. or i.m.) application in amounts of approx. 0.01 to approx. 10, preferably 0.1 to 1 mg/kg body weight,

per day, and when used orally in amounts of approx.

0.05 to approx. 100, preferably 0.1 to 10 mg/kg body weight per day, possibly in the form of several single doses to achieve the desired results. A single dosage contains the active substance(s), preferably in amounts of approx. 0.01 to approx. 30,

especially 0.03 to 3 mg/kg body weight.

It may still be necessary to deviate from it

mentioned the dosage depending on the type and body weight for

the object to be treated, the type and extent of the disease, the type of preparation and use of the medicine, as well as the time or interval in which the administration takes place. In some cases, it may be sufficient to use less than the amount of active substance indicated above, while in other cases one must exceed the amounts of active substance indicated above. The determination of the optimal dosage required in each case and the type of application for the active substance can be easily determined by the person skilled in the art.

The present invention shall be described in more detail

using the following examples.

Example 1

Preparation of 1-(3-chlorophenyl)-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride

0.05 mol of 3-chloro-cx-bromopropiophenone is heated together with 0.15 mol of 1-phenyl-2-methyl-2-aminopropane in 100 ml of diethyl ketone under a 2-atmosphere for 5 hours at 100°C. Then the solvent is evaporated, the residue is taken

into 2N HC1 and decanted with diethyl ether.

The aqueous hydrochloric acid phase is mixed with solid NaHCO^ after which the base that is separated is taken up in diethyl ether and obtained as hydrochloride with the addition of a diethyl ether-HCl solution.

Dividend:

83% of theoretical value; freezing point 193°C (hydrochloride).

Example 5

Preparation of 1-(3-chlorophenyl)-2-(1,1-dimethyl-2-(4-methoxyphenyl)ethylamino)propan-1-one hydrochloride

To a solution of 0.02 mol of 3-chloro-α-bromopropiophenone and 0.02 mol of 1-(4-methoxyphenyl)-2-methyl-2-aminopropane in 30 ml of diethyl ketone, 0.02 mol of I^CO-j is added and it is boiled for 4 hours under reflux. The solvent is then evaporated, the residue is taken up in methylene chloride and washed with water. The base formed in the methylene chloride phase is purified by column chromatography on "silica gel 60".

The amine obtained by elution with an acetic acid ethyl ester-methylene chloride mixture (2:8) is converted to hydrogen chloride from diethyl ether by introducing HCl gas.

Dividend:

50% of theoretical; freezing point 103°C (hydrogen chloride).

Example 6

Preparation of 1-(3-fluorophenyl)-2-(1,1-dimethyl-2-

(4-Methoxyphenyl)ethylamino)-propan-1-one hydrochloride

0.05 mol of 3-fluoro-α-bromopropiophenone and 0.15 mol of 1-phenyl-2-methyl-2-aminopropane are stirred into 100 ml of diethyl ketone in the presence of 0.1 mol of finely powdered I^CO^ for 24 hours at 20- 25°C.

Processing takes place as described in example 1.

Dividend:

61% of theoretical; freezing point 181°C (hydrogen chloride).

Example 7

Preparation of 1-(3-trifluoromethylphenyl)-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride

0.05 mol of 3-(trifluoromethylphenyl)-a-bromopropiophenone and 0.15 mol of 1-phenyl-2-methyl-2-aminopropane are stirred in 100 ml of diethyl ketone for 72 hours at 25°C. The solvent is then distilled off, the residue is taken up in methylene chloride, and purified by chromatography on

>"kieselgel 60", a methylene chloride-methanol mixture (98:2) is used as eluent.

The clean, oily base that results is mixed with a diethyl ether-HCl solution, evaporated in vacuo and the hydrogen chloride brought to crystallisation with the addition of a little diethyl ether.

Dividend:

37% of theoretical; freezing point 177°C (hydrogen chloride).

Claims (10)

1. Phenylethylaminopropiophenone derivatives of general formula (I) characterized by that R 1 stands for hydrogen, alkyl which is optionally substituted fluorine, or halogen, R 2 stands for hydrogen or lower alkyl and R 3 stands for hydrogen, alkoxy or halogen, as well as their physiologically tolerable salts with inorganic or organic acids. 2. Phenylethylaminopropiophenone derivatives according to claim 1, characterized in that R i stands for hydrogen, lower alkyl with 1 to 2 carbon atoms, optionally substituted with fluorine, or fluorine or chlorine, R 2 stands for hydrogen or lower alkyl with 1 to 2 carbon atoms, and R 3 stands for hydrogen, alkoxy with 1 to 4 carbon atoms or chlorine or fluorine. 3. Phenylethylaminopropiophenone derivatives according to claim 1, characterized in that R i stands for hydrogen, fluoride, chlorine or trifluoromethyl, R 2 stands for hydrogen, or methyl, and R 3 stands for hydrogen, methoxy or chlorine. 4. Phenylethylaminopropiophenone derivatives according to claim 1, characterized in that the derivatives from the group consisting of 1-(3-chlorophenyl)-2-(1-methyl-2-phenylethylamino)-propan-1-one hydrochloride; 1-phenyl-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride; 1-(3-trifluoromethylphenyl)-2-(1,1-dimethyl-2-phenylethylamino)propan-1-one hydrochloride; 1-(3-fluorophenyl)-2-(1,1-dimethyl-2-phenylethylamino)-propan-1-one hydrochloride; 1-(3-chlorophenyl)-2-(1,1-dimethyl-2-phenylethylamino)-propan-1-one hydrochloride; 1-(3-chlorophenyl)-2-(1,1-dimethyl-2-(4-chlorophenyl)-ethylamino)propan-1-one hydrochloride and 1-(3-Chlorophenyl)-2-(1,1-dimethyl-2-(4-methoxy-phenyl)-ethylamino)propan-1-one hydrochloride. 5. Process for the preparation of phenylatyl-aminopropiophenone derivatives of general formula (I) characterized by reacting halogen ketones of general formula (II) where R i has the meaning given above, and X stands for halogen, preferably bromine, with amines of general formula (III) where 2 3 R and R have the meaning given above, in the presence of inert solvents at temperatures between 0°C and 150°C, optionally in the presence of a proton acceptor, and the thus produced compounds of formula (I) are then optionally transferred in a known manner to the acid addition salts. 6. Method according to claim 5, characterized in that ether, hydrocarbons, halogenated hydrocarbons are used as inert solvents, ketones, nitriles, carbonamides or commercial technical mixtures of these solvents. 7. Process according to claim 5, characterized in that at least 1 mol of the amine of formula (III) and at least 1 mol of an acid binding agent are used for 1 mol of the compound (II). 8. Medicine, characterized in that it contains at least 1 phenylethylaminopropiophenone derivative of the formula (I) 9. Use of ,phenylethylaminopropiophenone derivatives of the formula (I) for the manufacture of pharmaceuticals. 10. Use of phenylethylaminopropiophenone derivatives of formula (I) when combating disease states and disturbances in the central nervous system.