NO163770B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE OMEGA AMINO ACID AMIDES. - Google Patents

Description

The present invention relates to the purification of w-amino acid amides as well as their pharmaceutically acceptable salts, with the general formula (I)

in which

R is an unbranched or branched alkyl residue with 2-12 carbon atoms or an unbranched or branched alkyl residue with 2-4 carbon atoms substituted with a phenyl or phenoxy residue which may optionally be substituted with a methyl residue, with one or two methoxy acid residues or with a chlorine atom,

R;L is hydrogen, an unbranched or branched alkanoyl residue with 2-11 carbon atoms or an unbranched or branched alkanoyl residue with 2-4 carbon atoms substituted with a phenyl residue which is optionally substituted with a methyl residue, a methoxy acid residue or with a chlorine or bromine atom, and n is 3, 4 or 5,

as well as their racemic or non-racemic mixtures of their optically pure isomers and their salts formed with pharmaceutically usable acids.

Examples of manufactured compounds are:

4-n-pentylaminobutanamide,

5-n-pentylaminopentanamide,

6-n-pentylamiohexanamide,

6-n-decylaminohexanamide,

6-[(2-p-Chlorophenoxyethylamino]hexanamide.

If u; -amino acid amides of formula I exist in the form of acid addition salts, it is possible to transfer them in the usual way to free bases or acid addition salts with other acids.

The salts most used are addition salts of non-toxic, pharmaceutically acceptable acids, formed with suitable inorganic acids, e.g. hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araphatic or heterocyclic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydrobenzoic acid. salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, Å-hydroxybutyric acid, oxalic acid, malonic acid, galactaric acid and galacuronic acid.

The prepared compounds of formula I may contain one or more asymmetric carbon atoms and may therefore exist in the form of optical or racemic isomers or diastereomers.

The compounds produced can thus be used either in the form of mixtures containing several diastereomers with arbitrary mutual proportions of these, or in the form of pairs of enantiomers in equal proportions (racemic mixtures) or not, or also in the form of optically pure compounds.

The prepared compounds can be used in the treatment of neurological, psychological or cardiovascular diseases, such as epilepsy, depression, dyskinesias, such as Parkinson's disease, muscle spasms of nervous origin, hypertension, hypotension, sleep problems, memory difficulties and an anti-intestinal worm as well as an analgesic.

Such pharmaceutical preparations contain as active ingredient at least one W-amino acid amide of the general formula (I) or one of its salts with an additive and/or carrier used in galenic pharmacy.

These preparations are prepared in such a way that they can be administered orally, rectally or parenterally. They can be solids, liquids or gels and can be presented, depending on the mode of administration, in the form of powders, tablets, pastilles, coated tablets, capsules, granules, viscous liquids, suspensions, emulsions, solutions, suspositories or gels. These preparations may also contain another therapeutic agent if it is usual for the intended use.

The compounds are produced according to procedures known per se.

According to the first method, one starts from a compound with the general formula

in which R, Ri and n have the above meanings, and Z stands for a nitrile group, and this compound is transferred in a corresponding uj-amino acid amide.

The transfer of the product (II) to the product (I) and thus the conversion of the group Z or -CH2-Z to the group -CONH2 can take place by classical reactions. Thus, the nitrile can either be hydrogenated in an acidic or basic environment. If the hydrolysis takes place in an acidic environment, concentrated sulfuric acid, concentrated aqueous hydrochloric acid, aqueous hydrobromic acid, nitric acid, formic acid without solvent or acetic acid in the presence of boron trifluoride can be used. Another way to convert a nitrile into an amide in an acidic environment consists in treating the nitrile in question with hydrochloric acid in an alcohol such as ethanol. Thereby, an imino ether is formed as an intermediate product, which is thermally converted into an amide. If the hydrolysis takes place in a basic environment, one can e.g. adding potassium hydroxide to t-butanol or an aqueous solution of an alkali or alkaline earth metal hydroxide. The presence of hydrogen superoxide favors the hydrolysis. The type of group formed (mid- or carboxyl group) depends to a significant extent on the reaction conditions used.

Another possibility consists in converting a nitrile into an ester. For this conversion, the nitrile is reacted with an alcohol in an acidic environment. Alcohol or any inert solvent can be used as solvent. In this way, an imino ether is formed as an intermediate product, which is hydrolysed to an ester. The aminolysis of the ester takes place in the classic way either in water or in an inert organic solvent, reacting the ester with ammonia.

A second method consists in reacting an amide with the general formula RNH-(CH2)n-<C>ONH2 or R^NH-(CH2)n-CONH2 with a compound of the general formula

or an amine of the general formula is condensed with a compound of the general formula Cl(C<H>2)n-C0NH2 or OHC-(CH2)n_1-CCNH2, and optionally with subsequent reduction of the intermediate imine obtained, where R , R^ and n in these formulas have the meaning mentioned above, and the group obtained after condensation with any subsequent reduction

where R 9 and R 10 have meanings corresponding to R and R-^

A third method consists in opening a lactam (XVIII) under the influence of a base or an acid. This lactam (XVIII) is obtained in a known manner from the lactone (XVII) according to the scheme below:

in which R and n have the above meaning and M means hydrogen or a metal such as lithium, sodium, potassium or magnesium.

The conversion of the lactone to the lactam takes place in an inert organic solvent, preferably at the reflux temperature of the reaction medium. The opening of the lactam can take place under the influence of ammonia or an alkaline earth thalamide. It takes place in water or in an inert organic solvent such as ester, alcohol or an aliphatic, aromatic or chlorinated hydrocarbon.

The following examples illustrate the preparation of some compounds prepared according to the invention.

Example 1 Preparation of 4-n-pentylaminobutanamide

5 g (0.041 mol) of 4-chlorobutanamide was dissolved in 19 ml (0.165 mol) of pentanamine and stirred for 48 hours at ambient temperature. By adding 400 ml of ether, a precipitate was formed which was filtered off and recrystallized twice in isopropanol. M.p.: 187°C.

Example 2

Preparation of 5-n-pentylaminopentanamide

a) A mixture of 4.5 g (0.040 mol) 5-chloropentanenitrile, 3.8 g (0.044 mol) pentanamine and 3.7 g sodium bicarbonate in 60 ml

absolute ethanol was boiled with reflux for 48 hours. The sodium chloride formed was filtered off, and the filtrate was evaporated to dryness under vacuum to remove excess pentanamine. The remaining oil was dissolved in ether, and ether/HCl was added. A white precipitate formed which was filtered off (5-n-pentylaminopentanenitrile hydrochloride). in

M.p.: 207-209°C.

b) 2.78 g (0.013 mol) of 5-n-pentylaminopentanenitrile hydrochloride was suspended in 3.4 ml of concentrated HCl and stirred at 5°C for 6

days. The clear solution obtained was poured into 20 ml of isopropanol, and the solid that crystallized was filtered off and washed with isopropanol.

M.p.: 216-217°C.

Example 3

Preparation of 6-decylaminohexanamide

4.5 g (0.030 mol) of 6-chlorohexanamide was refluxed in 100 ml of ethanol containing 5.2 g (0.033 mol) of decaneamine and 2.52 g (0.033 mol) of NaHCO 3 . After 2 days and 2 nights stayed

the solution cooled, filtered and evaporated. A solid was recrystallized twice from ethyl acetate. The solid obtained was dissolved in ethanol and ether/HCl was added. The solid substance thus obtained was recrystallized twice in isopropanol.

M.p.: 206°C.

Example 4

Preparation of 6-[3-(3,4-dimethoxyphenyl)propanoylamino]hexanamide

4.6 g (0.02 mol) of 3-(3,4-dimethoxyphenyl)propaioyl chloride

and 2.4 g of NaOH in 20 ml of water were simultaneously added to a solution of 2.6 g (0.020 mol) of 6-aminohexanamide and 0.8 g of NaOH in 15 ml of water, cooled to 0°C. The suspension was stirred for 2 hours at room temperature. The solid was then filtered off and recrystallized in isopropanol.

M.p.: 137°C.

Example 5

Preparation of 6-n-pentylaminohexanamide

■A mixture of 5 g (0.033 mol) of 6-chlorohexanamide, 4.25 ml (0.037 mol) of pentanamine and 2.8 g (0.034 mol) of sodium bicarbonate in 100 ml of ethanol was refluxed for 4 days. Then, after cooling the solution, salts were filtered off,

and the solvents evaporated completely. The solid was crystallized twice in ethyl acetate, dissolved in as little methanol as possible, and ether/HCl was added. The solid that formed was filtered off and dried.

M.p.: 190.5°C.

Example 6

Preparation of 4-n-hexylaminobutanamide

a) A mixture of 18.5 ml (0.2 mol) 4-chlorobutanenitrile, 29.1 ml (0.22 mol) hexaneamine and 18.5 g (0.22 mol) sodium bicarbonate in 500 ml ethanol was refluxed for 2 days. The suspension was then cooled, salts filtered off and the filtrate evaporated. The residue was partitioned between water and dichloromethane. The dichloromethane phase was washed with water, dried over I 2 CO 2 and evaporated at room temperature. The excess hexaneamine was evaporated under high vacuum and the remaining oil was dissolved in anhydrous ether and ether/HCl was added. The solid that was formed

was filtered, washed in as little methanol as possible, and anhydrous ether was added. The product thus obtained was used as such in the subsequent step.

b) 4.2 g (0.02 mol) of 4-hexylaminobutanenitrile was stirred for four days at 5°C in 5 ml of concentrated HCl. Then this was

solution completely in 50 ml of cooled acetone. The white solid that formed was recrystallized from isopropanol.

M.p.: 194°C.

Example 7

Preparation of 4-|(N-n-hexyl-N-4-chlorophenylacetyl)amino]butane-amide

650 mg (0.003 mol) of 4-hexylaminobutanamide hydrochloride was dissolved in 9.4 ml of 1 N KOH at 10°C. For this solution, drop-

show added 0.65 ml of 4-chlorophenylacetic acid chloride. An oil immediately formed which solidified. After two hours of reaction, the oil was extracted with ether, the ether phase was washed with water and 1 N hydrochloric acid, dried over ^CO^ and evaporated. The remaining solid was recrystallized from ethyl acetate.

M.p.: 105-106°C.

Example 8

Preparation of 5-n-dodecylaminopentanamide

a) 7.4 g (0.04 mol) dodecanamine, 4.23 g (0.036 mol) of 5-chloropentanenitrile and 3.4 g (0.04 mol) sodium bicarbonate in 100

ml of ethanol was boiled with reflux for two days. The cooled solution was then filtered and the filtrate evaporated. The remaining oil was distilled below 0.25 mm Hg. The fraction that distilled at 170°C was collected. It was dissolved in ethanol and ether/HCl was added. The solid that precipitated was filtered and used without further purification in the subsequent step.

b) 2 g (0.007 mol) of 5-dodecylaminopentanenitrile hydrochloride was dissolved in 50 ml of acetic acid. This solution was saturated with dry

HC1 and stirred at room temperature for two days. The acetic acid was then evaporated, and the solid, which was taken up in ether, was filtered and recrystallized twice in isopropanol.

M.p.: 212°C.

Example 9

Preparation of 4-n-pentylaminobutanamide

a) A mixture of 18.5 ml (0.2 mol) 4-chlorobutanenitrile, 19.1 g

(0.22 mol) of pentanamine cg 18.5 g (0.22 mol) of sodium bicarbonate in 500 ml of ethanol was refluxed for two days. The suspension was then cooled, the salts were filtered off, and the filtrate was evaporated. The residue was partitioned between water and dichloromethane. The dichloromethane phase was washed with water, dried over ^CO^ and evaporated at room temperature. The excess pentanamine was evaporated under high vacuum and the remaining oil was dissolved in anhydrous ether and ether/HCl was added. The solid that formed was filtered, dissolved in as little methanol as possible, and anhydrous ether was added until a large precipitate had formed which was filtered off and used as such in the subsequent step, b) 3.1 g (0.02 mol) of 4-pentylaminobutanenitrile was dissolved in 30 ml of glacial acetic acid and saturated with HCl at room temperature. •After stirring for 24 hours, the acetic acid was evaporated, and the remaining solid was recrystallized in isopropanol. M.p.: 187.5°C.

Example 10

Preparation of 4-n-pentylaminobutanamide

2.76 g (0.02 mol) of 4-aminobutanamide hydrochloride, 1.9 g

(0.022 mol) pentanal, 100 mg of 10% Pd/C and 50 ml of ethanol were introduced into a Parr flask. This flask was shaken overnight under an atmosphere of hydrogen at ambient temperature. The catalyst was then filtered off, the solvent evaporated and the residue precipitated in ether. The solid obtained was recrystallized three times in isopropanol.

M.p.: 186.5°C.

Example li

Preparation of 4-n-pentylaminobutanamide

3.1 g (0.02 mol) of N-pentylpyrrolidone was introduced into a 200 ml flask containing 3.9 g (0.1 mol) of sodium amide suspended in 50 ml of toluene. The suspension was refluxed for 3 hours, after which 10 ml of H 2 O and sufficient 1 N hydrochloric acid were added to make the solution acidic, pH 2. The aqueous phase was decanted and lyophilized. The residue was extracted with boiling isopropanol, the solid that crystallized out was filtered off and recrystallized twice in isopropanol.

M.p.: 186°C.

The following table is a list of the UJ-amino acid amides prepared according to the preceding examples and further. All compounds listed in the table give a correct C.H.N. elemental analysis.

The products produced according to the present invention were used

in a series of pharmacological tests where the methodology is described below.

The LDj-g values were calculated according to the method of Lichtfield

and Wilcoxon (J. Pharmacol. Exp. Ther. Vol 96, 1949, p. 99) and is expressed in mg/kg. The products were administered orally to mice. In general, the products produced according to the invention proved to have low toxicity. The effect was studied using a method derived from the method of S. Irwin in Gordon Res.

Conf. on Medicinal Chem., Vol 133, 1959. The substances suspended in a mucilage of 1 per cent gum tragacanth were administered

orally into the stomach by means of a probe to groups of

five male mice that had fasted for 18 hours. The doses tested as a function of the observed activity ranged from 3,000 to 3 mg/kg.

The effect was studied 2, 4, 6 and 24 hours after treatment. The observation was extended if the symptoms persisted during this period. Mortality was recorded within 14 days of treatment. None of the tested products had caused any abnormal behavior in the animals.

In general, certain of the products produced according to the invention have an anticonvulsant effect. The anticonvulsant effect was investigated in pre-

hold to tonic convulsions caused by bicuculline. The compounds produced according to the invention were administered orally in a dose of 10 mg/kg to 20 mice three hours before intravenous injection of bicuculline in a dose of 0.7 mg/kg. The number of mice protected from tonic convulsion and death was noted. In this test, compounds no.

1, 5, 8, 10 and 13 were found to be particularly active and gave a protection percentage of 55% or more.

CP 2081 (compound no. li Table I) was subjected to a more thorough evaluation. In the test concerning inhibition of convulsions caused by bicuculline, ed,-q was 3 mg/kg. At a dose of 300 mg/kg, the percentage protection against convulsions caused by bicuculline was 75%.

CP 2081 likewise has an effect that counteracts convulsions caused by leptazole and by electric shocks.

Biochemical tests have shown that certain of the compounds prepared according to the invention have a GABA-mimetic effect. This effect was investigated in vitro using a method derived from the method of C. Braestrup and M. Nielsen (Brain Research Bulletin, Vol 5, suppl. 2, 1980, p. 681-684).

A paste of rat brain (without cerebellum), which had been washed to remove GABA (γ-aminobutyric acid), was used to measure receptor binding (binding) by ^H-flunitrazepam with and without increasing concentrations of the compounds to be tested or of a reference compound (in the present case GABA).

The non-specific (binding) was determined in the presence of "Diaze-pam".

Incubation lasted 60 minutes at 0°C for a paste diluted 200-fold. After incubation, the samples were filtered and washed over Whatman GFB filters. After drying the filter at 60°C for 20 minutes, residual radioactivity was measured using a liquid scintillation apparatus in a suitable medium.

Under these conditions, the compound CP 2818 (compound no. 16 in Table I) behaved GABA-mimetically, characterized by an EC^q ("Enhancement concentration 50%)" of 4.7 x 10 M compared to the ECj-q of 8.2 x 10 7 M for GABA and with the same efficiency as for GABA.

CP 2818 was also examined in vitro in this test for the behavior of ^H-muscimol towards rat brain synaptic membranes. This test is specific for GABA-ergic receptors and makes it possible to show an effect for or against the GABA receptors. These are directly connected to the benzodiazepine receptors.

The production of the synaptic membranes and the preparation

of the test concerning <3>H-muscimol's behavior towards synaptic membranes is as published by S.J. Enna and S.H. Snyder in Brain Research, Vol 100, 1978, pp. 81-97.

The value for the specific behavior of "^H-muscimol towards the membranes is produced by calculating the difference between the compound for "^H-muscimol alone and this compound in the presence of 10 µM

GABA.

Different concentrations of CP 2818 were used for

to determine the concentration of the compound required to inhibit 50% of "^H-muscimol's behavior towards the membranes (IC5Q). For CP 2818, an IC5Q of 2.5 x 10~<5> M was obtained. IC50 for GABA in this system was 2 x 10 M.

The effect that counteracts convulsions caused by bicuculline, leptazole and electric shock and the GABA-mimetic effect indicate that the compound produced according to the invention has pharmaceutical properties that make it particularly suitable for the treatment of various forms of epilepsy and dyskinesia, such as Parkinson's disease. Moreover, the activity of these compounds at the level of the central nervous system makes them potentially of interest in the treatment of certain cardiac problems, such as hyper- and hypotension,

for the treatment of mental disorders, such as depression, memory loss and sleep problems, and as analgesics.

Certain of the compounds produced according to the invention also have an anthelmintic effect. This effect is measured in rats infected with nippostrongylus brasiliensis (stage L3). The compound to be tested is administered by means of an oesophageal tube in the form of mucus, 8 days after the attack. The rats were slaughtered on the twelfth day, and the number of parasites in the intestine was determined.

The results obtained are expressed in percentage efficiency in relation to a control group.

In this test, the product had CP 2081 (compound no. 1

in Table I) an efficiency percentage of 91 with a dose of 50 mg/kg.

In humans, the compound prepared according to the invention will be administered orally in doses which may be from 50 mg to 4,000 mg. For intravenous administration, the doses will be from 5 mg to 1,000 mg.

Claims (6)

1. Analogy method in the production of therapeutic ak tive amino acid amides of the general formula I in which R is an unbranched or branched alkyl residue with 2-12 carbon atoms or an unbranched or branched alkyl radical with 2-4 carbon atoms substituted with a phenyl or phenoxy radical which may optionally be substituted with a methyl radical, with a or two methoxy acid residues or with a chlorine atom, R-L is hydrogen, an unbranched or branched alkanoyl residue of 2-11 carbon atoms or an unbranched or branched alkanoyl residue of 2-4 carbon atoms substituted by a phenyl residue which is optionally substituted with a methyl residue, a methoxy acid residue or with a chlorine or bromine atom, and n is 3,4 or 5, characterized by) a derivative with the general formula (II) wherein R, R^ and n have the above-mentioned meanings are transferred to a corresponding amino acid amide, or b) an amide of the general formula RNH-(CH2)n-CONH2 or R^NH-(CH2)n-CONH2, is reacted with a compound of the general formula or an amine of the general formula is condensed with a compound of the general formula Cl-(C<H>2)n-CONH2 or OHC-(CH2)n_1-CONH2, and optionally with subsequent reduction of the imine obtained as an intermediate product, where R, R^ and n in these formulas have the meaning mentioned above and the group obtained after condensation with any subsequent reduction where Rg and RlQ have meanings corresponding to R and B.-^ or c) a lactam of the general formula (XVIII) in which R and n have the meaning given above, is transferred to an -amino acid amide by reaction with ammonia or an alkaline earth metal. 2. Method according to claim 1 for the production of 4-n-pentylaminobutanamide, characterized in that one starts from correspondingly substituted starting compounds. 3. Process according to claim 1 for the production of 5-n-pentylaminopentanamide, characterized in that one starts from correspondingly substituted starting compounds. 4. Process according to claim 1 for the production of 6-n-pentylaminohexanamide, characterized in that one starts from correspondingly substituted starting compounds. 5. Process according to claim 1 for the production of 6-n-decylaminohexanamide, characterized in that one starts from correspondingly substituted starting compounds. 6. Process according to claim 1 for the production of 6-(2-p-chlorophenoxyethyl)aminohexanamide, characterized in that one starts from correspondingly substituted starting compounds.