WO1993013049A1

WO1993013049A1 - Using the immunoactivating activity of 3-naphthyloxy-2-hydroxy-propylamines, in particular for providing cell immunity, e.g. against viral infections

Info

Publication number: WO1993013049A1
Application number: PCT/CH1992/000242
Authority: WO
Inventors: Karin Elisabeth Peuschel
Original assignee: Karin Elisabeth Peuschel
Priority date: 1991-12-20
Filing date: 1992-12-14
Publication date: 1993-07-08
Also published as: CA2109224A1; FI935056A0; AU3079692A; EP0587823A1

Abstract

Homocyclic compounds, and naphthalene derivatives in particular, having immunoactivating activity and being of particular interest in providing cell immunity, e.g. for treating or preventing viral infections and certain immunodeficiency diseases, are used as a drug having immunoactivating activity in humans (and animals with neuroimmune regulation equivalent to that of humans). Immunoactivation is by definition the enhanced activation of the immune system in the presence of a foreign antigen. This immunoactivating activity is achieved by blocking the beta receptors on immune system cells, whereby the activation of the functional biochemical processes of the cell is enhanced in a way that mimics immune system function regulation by the nervous system, and reverse immune activity regulation by the sympathetic nervous system tonus in particular. The immunoactivating activity of naphthalene derivatives having formula (I) is described.

Description

USE OF THE IMMUNOACTIVATING EFFECT OF 3-NAPHTHYLOXY-2-HYDROXY-PRO-PYLAMINES, ESPECIALLY INTERESTED IN CELLULAR IMMUNITY, FOR EXAMPLE AGAINST VIRAL INFECTIONS.

The present invention relates to the use as a medicament with immunoactivating effect in humans (and animals with neuroimmune regulation similar to that in humans) of homocyclic compounds and more particularly of naphthalene derivatives which have an immunoactivating effect and which are of particular interest for cellular immunity, for example for the treatment or prophylaxis of viral infections and certain immunodeficient diseases. This immunoactivating effect occurs by blockade of receptors on cells of the immune system, which facilitates the activation of the functional biochemical processes of the cell, thus imitating the regulation of the function of the immune system by the nervous system and more specifically the reverse regulation of immune activity by the tone of the sympathetic nervous system. Immunoactivation is by definition facilitated activation of the immune system in the presence of a foreign antigen. Animals with neuroimmune regulation analogous to that in humans are those with control of the immune system by hypothalamic nerve centers through on the one hand the hypothalamic-adrenocortical axis and on the other hand through the vegetative nervous system, especially the sympathetic nervous system.

The present invention relates to the immunoactivating effect in humans and animals with neuroimmune regulation analogous to that in humans of naphthalene derivatives of formula:

where R ¹ represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, R ² represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl or aralkyl radical, or alternatively R ¹ and R ² form with the neighboring nitrogen atom a heterocyclic radical, optionally substituted, R ³ , R ⁴ and R ⁵ , which may be identical or different, represent hydrogen atoms or alkyl radicals, and the naphthalenic nucleus carries optionally one or more additional substituents, as well as their esters and their salts, but excluding the 1-amino-, 1-n-propylamino-, 1-n-butylamino-, 1-diethylamino-, 1-di-n -propylamino, 1-di-isopropyl-amino-, 1-di-n-butylamino-, 1-morpholino- and l-piperidino-3- (l-naphthoxy) -2-propanol, 1- ethylamino-, 1- dimemylamino-, 1-diethylamino-, 1-morpholino- and l-piperidino-3- (2-naphth-oxy) -2-propanols, l- (l-chloro-2-naphthoxy) - 3-piperidino-2-propanol,. Of their esters, and their salts.

REPLACEMENT SHEET A preferred class of compounds includes those of naphthalene derivatives where R ¹ , R ³ , R ⁴ and R ⁵ represent hydrogen atoms and R ² has the meaning given to it above, and the naphthalenic ring optionally carries one or several additional substituents, as well as their esters and their salts, but excluding the 1-amino-, 1-n- propylaπ-ino- and ln-butyl-amino-3- (1-naphthoxy) -2-propanols, 1-ethylamino-3- (2-naphthoxy) -2-propanol, their esters and their salts.

R ¹ may represent, for example, an alkyl or hydroxyalkyl radical of 5 carbon atoms maximum, for example the methyl ^' , ethyl, s-butyl or 2-hydroxyethyl radical, or an aralkyl radical of 10 carbon atoms maximum, for example the acetyl radical.

R ² can represent, for example, an alkyl radical of 20 carbon atoms at most, for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, l-methyloctyl or radical 1-methylhexadecyl, or an alkyl radical of 10 carbon atoms maximum carrying one or more hydroxy radicals or substituted ino radicals, for example alkylamino, di-a-kylamino or heterocyclic radicals, such as alkylamino or dial_yla__ino radicals of 6 atoms of carbon at most or heterocyclic radicals of 6 atoms in the cycle at most, such as the dimethylamino or morpholino radicals, or alkoxy radicals, for example the alkoxy radicals of S carbon atoms at most, such as the methoxy radicals or n-propoxy, or alkoxyalkoxy radicals, for example alkoxyalkoxy radicals of 10 carbon atoms at most, such as the 2- n-butoxy-ethoxy radical, or optionally substituted aryloxy radicals, for example aryloxy radicals of 10 carbon atoms at most, optionally substituted, such as the 4-chlorophenoxy or 2,4-dichlorophenoxy radicals. As a variant, R ² may represent an aralkyl radical of 15 carbon atoms at most, optionally substituted, for example, by one or more alkoxy radicals, such as alkoxy radicals of 5 carbon atoms at most, such as the methoxy radical.

Thus, particular meanings of R ² for a substituted alkyl radical or substituted or unsubstituted aralkyl are the radicals:

2-hydroxyethyl,

2-hydroxy-1-methylethyl,

2-hydroxy-1,1-dimethylethyl,

2-n-propoxyethyl,

3-methoxypropyl,

2- (2-n-butoxyethoxy) -ethyl,

3-morpholinopτopyle,

3-dimethylaιmnopropyIe,

2- (4-chlorophenoxy) -ethyl _J

2- (2,4-dichlorophenoxy) -ethyl, benzyl,

REPLACEMENT SHEET l-methyl-2-phenylethyl,

1-methyl-3-phenylpropyl,

1,1-dimethyl-3-pheήylpropyl,

4-methoxybenzyle,

3- (4-methoxyphenyl) -1-methylpropyl or

2- (3,4-dimethoxyphenyl) - thyle.

As a variant, R ² represents a cycloalkyl, alkenyl or alkynyl radical of 10 carbon atoms maximum, for example the cyclopentyl, allyl or 1-methyl-2-propynyl radical.

The group -NR ^J R ² representing a heterocyclic radical can be, for example, a heterocyclic nitrogen radical of S or 6 atoms optionally substituted, for example the pyrrolidino, piperidino or morpholino radical optionally substituted by one or more alkyl radicals of S atoms of carbon at most, like the methyl radical.

R ³ , R ⁴ and R ⁵ representing alkyl radicals can be, for example, alkyl radicals of 5 carbon atoms at most, such as the methyl radical.

Additional suitable substituents of the naphthalenic nucleus are, for example, halogen atoms, for example chlorine or bromine atoms, or alkyl or hydroxyalkyl radicals of 5 carbon atoms at most, for example the methyl radical or 1-hydroxyethyl, or acyl radicals, for example alkanoyl radicals of up to 6 carbon atoms, for example the acetyl radical, or sulfamoyl radicals, optionally substituted, for example dialkylsulfamoyl radicals of up to 10 carbon atoms, such as the dimethylsulfamoyl radical.

Naphthalenic derivatives of particular interest are, for example, l-isopr_pylan_Λθ-3- (l-naphthoxy) -2-propanol, le-1 -t-butylamino-3- (l-naphthoxy) -2-propanol, l- (2-hydroxy-1,1-dimethylet ylamino) -3- (l-naphthoxy) -2-propanol, l- (l-memyl-3-phenylpropylamino) -3- (l-naphthoxy) -2- propanol, 1 -s-butylamino-3- (l-naphthoxy) -2-propanol, l- (l-memyloctylajnino) -3- (l-naphthoxy) -2-propanol, l- (l, l- dimeώyl-3-phenylpropylarnino) -3- (l-naphthoxy) -2-propanol, l-allylaιnino-3- (l-naphthoxy) -2-propanol, 1 -cyclopentylamino-3- (l-naphthoxy) -2 -propanol, l-isopropylamino-3- (4-methyl-l-naphthoxy) -2-propanol and l- [3- (4-methoxyphenyl) -l-meΛylpr_pylamino] -3- (l-naphthoxy) -2 -propanol, as well as their esters and their salts.

Suitable esters of these naphthalene derivatives are, for example, the Q-esters of acids of formula R ⁶ .COOH where R ⁶ represents an optionally substituted alkyl, alkenyl or aryl radical, for example an alkyl or alkenyl radical of 20 carbon atoms at most, or an aryl radical of 10 carbon atoms at most, for example the radical

REPLACEMENT SHEET methyl, peπtadecyl, heptadecyl, heptadeca-8-enyl or phenyl.

Suitable salts of these naphthalenic derivatives are the acid addition salts, for example derived from inorganic acids, such as hydrochlorides, hydrobromides, phosphates or sulfates, or organic acids such as oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naphthoates, o-acetoxybenzoates, adipates, maleates or 1,1-methylene-bis-2-hydroxy-3-naphthoates or also of sulfonated polystyrene resins such as "Zeo- Karb "225. Relatively insoluble salts, for example l, 1'-methylène-bis-2-hydroxy-3-naphthoates, are interesting because they ensure a high concentration of the drug in the blood for a long time.

A process for the preparation of naphthalene derivatives comprises the reaction of a halogenated compound of formula:

where X represents a halogen atom, R ³ , R ⁴ and R ⁵ have the meanings which have been given to them above, and the naphthalenic nucleus optionally carries one or more additional substituents, with an ine, of formula NH ^ ² , where R ¹ and R ² have the meanings given to them above.

X can represent, for example, a chlorine or bromine atom. The reaction can advantageously be accelerated or completed by heating.

In another process for the preparation of naphthalene derivatives, an epoxide of the formula is reacted:

where R ³ , R ⁴ and R ⁵ have the meanings given to them above and the naphthalene nucleus optionally carries one or more additional substituents with an amine of formula NEER ⁱ R ² , where R ¹ and R ² have the meanings given to them above.

This process can be carried out in a diluent or a solvent such as ethanol and can be accelerated or completed by heating.

REPLACEMENT SHEET Another process for the preparation of naphthalene derivatives comprises the reaction of a naphthol of formula:

where the naphthalenic nucleus can carry one or more additional substituents, with a compound of formula:

O X.CR ³ R ⁴ .CHOH.CHR ⁵ .NR ¹ R ² or R ³ R ⁴ C— ^ CH.CHR ^ NR ^

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X have the meanings given to them above.

The reaction of a naphthol and a halogen derivative can advantageously be carried out in the presence of an acid acceptor, but as a variant, an alkali metal derivative of naphthol, for example the sodium or potassium derivative , may be the starting compound

Another process for the preparation of those of naphthalene derivatives where R ¹ represents a hydrogen atom and R ² a radical of formula -CHR ⁷ R ⁸ , where R ⁷ represents a hydrogen atom or an alkyl or cycloalkyl radical, alkenyl, alkynyl, aryl or aralkyl optionally substituted, and R ⁸ represents an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical optionally substituted, or else R ⁷ and R ⁸ form with the neighboring carbon atom an optionally substituted cycloalkyl radical , according to which an amino derivative of formula is reacted under reduction conditions:

where R ³ , R ⁴ and R ⁵ have the meanings which have been given to them above and the naphthalene ring optionally carries one or more additional substituents, with a carbonyl compound of formula R ⁷ .CO.R ⁸ , where R ⁷ and R ⁸ have the meanings given to them above.

Appropriate reduction conditions result from the presence of hydrogen and a hydrogenation catalyst, for example, platinum, in an inert diluent or solvent,

= as ethanol and / or, when in the starting carbonyl compound R ⁷ represents an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optionally substituted, in an excess of this starting carbonyl compound, or else the presence of an alkaline borohydride, for example sodium borohydride in an inert diluent or solvent such as aqueous methanol and or in an excess of the starting carbonyl compound When R ⁷ and or R ⁸ represent an optionally substituted alkenyl or alkynyl radical and qu we do not wish to reduce a corresponding optionally substituted alkyl radical by this process, it is necessary to have recourse, as may be noted, to suitable reduction conditions, for example adhesives created by the presence of sodium borohydride, π should be noted, in addition, that the starting amino derivatives can be formed in situ, for example by reduction of alpha-diazo-ketones, alpha-azidoketones and alpha -azidoalcohols, alpha-hydroxyaminoketones, alpha-nitro-ketones, alpha-nitro-alcohols, cyanohydrins and acyl cyanides corresponding.

A process for the preparation of those of naphthalenic derivatives where R ¹ represents a hydrogen atom, comprises the hydrogenolysis of a compound of formula:

where R ² , R ³ , R ⁴ and R ⁵ have the meanings given to them above, R ⁹ represents a hydrogenolysable radical, and the naphthalenic ring optionally carries one or more additional substituents.

R ⁹ may represent an alpha-arylalkyl radical of 10 carbon atoms at most, for example the benzyl radical.

This hydrogenolysis can be carried out by catalytic hydrogenation, for example in the presence of a platinum or palladium on carbon catalyst optionally in a diluent or an inert solvent such as ethanol.

In a process for the preparation of those of naphthalene derivatives where the naphthalenic nucleus carries as a substituent a hydroxyalkyl radical, the corresponding compound is reduced where the naphthalenic nucleus carries as a substitute the corresponding oxoalkyl radical An appropriate oxoalkyl radical is, for example an oxoalkyl radical of 20 carbon atoms maximum, for example an alkanoyl radical of 20 carbon atoms maximum, such as the acetyl radical. A suitable reducing agent is, for example, sodium borohydride.

In another ester preparation product, the corresponding naphthalenic derivative is acylated. Suitable acylating agents are, for example, acyl halides and acid anhydrides, such as acetic anhydride and benzoyl chloride. Acylation can be carried out in a diluent or a solvent which, when an acid anhydride is used, is advantageously the acid from which the anhydride is derived.

A process for the preparation of those of the naphthalene derivatives where R ¹ represents an alkanoyl radical comprises the isomerization of an ester of formula:

O ^Û - ° .CR ³ R .CH (O.COR ¹⁰ ) .CHR ⁵ .NHR ²

where R ² , R ³ , R ⁴ and R ⁵ have the meanings given to them above and R ¹⁰ represents an alkyl radical, for example an alkyl radical of 5 carbon atoms at most, and the naphthalenic ring optionally carries one or more additional substituents.

The isomerization can be carried out by reacting the ester with a strong base, such as an alkali metal hydroxide, for example sodium hydroxide, advantageously in a diluent or a solvent such as methanol.

REPLACEMENT SHEET The parts by weight of the following illustrative examples, without being limited to them, are:

EXAMPLE 1

A mixture of 4.4 parts of 1-chloro-3- (1-naphthoxy) -2-propanol and 16 parts of isopropylamine is heated at 70-80 ° C for 10 hours in a sealed container. The container is cooled and its content is added with 50 parts of water. The mixture is acidified using 2N hydrochloric acid, then washed with 50 parts of ether. The aqueous phase is discolored using charcoal, then poured into 50 parts of 2N sodium hydroxide solution at 0 ° C. The mixture is filtered. The solid residue is washed with water, dried and recrystallized from cyclohexane. This gives l-isopropylamino-3- (l-naphthoxy) -2-propanol, melting point 96 ° C.

The above process is repeated using suitable hydrochlorins and starting amines, friends at a reaction temperature of 90 to 100 ° C. The compounds indicated in the following table are likewise obtained The hydrochlorides and oxalates mentioned are obtained by dissolving the base in ether, adding an ethereal solution of hydrochloric or oxalic acid, filtering the mixture, washing the solid residue with ether and drying it The picrates are obtained by dissolving the base in ethanol, adding an ethanolic solution of picric acid, filtering the mixture, removing the solid residue with ethanol and drying it

CHOH.CH, .NR ¹ 1R _D 2

REPLACEMENT SHEET

EXAMPLE 2

Using l-chloro-3- (2-naphthoxy) -2-propanol instead of the l-chloro-3- (l-naphthoxy) -2-propanol of Example 1, the analogy is obtained. l-isopropyl-amino-3- (2-naphthoxy) -2-propanol, melting point 138-140 ° C (after recrystallization from ethanol).

By replacing the isopropylamine used in Example 2 with t-butylamine, the same is obtained lt-butylan ___ o-3- (2-naphthoxy) -2-prσpanol, melting point 120 ° C (after recris¬ tallization in the cyclohexane).

REPLACEMENT SHEET EXAMPLE 3

A mixture of 2.3 parts of l-chloro-3- (l-naphthoxy) -2-propanol and 2.6 parts of l-methyl-3-phenylpropyl_jn_ne is heated at 90-100 ° C for 10 hours. The mixture is then cooled, diluted with 50 parts of 2N sodium hydroxide and 50 parts of ether. The mixture is separated and the ethereal phase is dried over anhydrous magnesium sulfate, then filtered and evaporated. The residue is dissolved in 50 parts of ethyl acetate and added with a solution of hydrochloric acid in ether. The mixture is filtered and the solid residue is washed with ethyl acetate, dried and recrystallized from a mixture of methanol and ethyl acetate. This gives 1- (methyl-3-phenylproylamino) -3- (l-naphthoxy) 2-propanoL hydrochloride, melting point 162-164 ° C.

EXAMPLE 4

A mixture of 1.84 parts of 1,2-epoxy-3-naphthoxy-propane and 1.7 parts of isopropylamine is heated at reflux for 16 hours. The mixture is acidified with 25 parts of 2N hydrochloric acid and washed with 50 parts of ether. The aqueous solution is then poured into 50 parts of a 2N sodium hydroxide solution at 0 ° C and the mixture obtained is filtered. The solid residue is washed with water and dried, then recrystallized from cyclohexane. This gives l-_soprOpyla_nino-3- (l-n_phthoxy) -2-propanol, melting point 96 ° C.

The base can be converted into the hydrochloride as follows: 4.65 parts of the base are dissolved in 30 parts of hot acetone. 2 parts of ION hydrochloric acid are then added to the hot solution. The mixture is cooled and then filtered. The solid residue is washed with acetone and dried. The solid is recrystallized from propanol to give l-iscφropylarnino-3- (l-naphthoxy) -2-propanol hydrochloride, melting point 163 ° C.

The above process is repeated starting from the appropriate epoxynaphthoxy-propanes and amines, but with other temperatures and reaction times, to give in an analogous manner the compounds indicated in the following table The hydrochlorides, oxalates and picrates are obtained from generally described in Example 1.

REPLACEMENT SHEET RI R2 Position of Substitutes Temp. of Base Duration or PF Solvent (s) of recris¬ substituent supplementai¬ reaction reaction salt (° C) tallization res on the nucleus ( ^β C) (hours) naphthalenic

none 100 oxalate 100 ethanol / ethyl acid acetate none 100 base 115 benzene

none 100 oxalate 148- acid propanol 149 none 100 oxalate 138 acid water

none 100 base 115 petroleum ether 100 ^e C / 120 ° C

none 100 base 115 petroleum ether 100 ^e Cl 120 ^e C

none 100 oxalate 149- acid water 150

none 20 72 dichlor- 234- methanol hydrate 235

none 100 1 oxalate 210- 2-ethoxy-ethanol

none 100 picrate 166- propanol 168

2-chloro 20 16 chlor- 160- ethanol / ethyl acetate hydrate 161

H isopropyl 4-acetyl 20 16 base 95 petroleum ether 100 ^e C / 120 ^e C

H isopropyl 2,4-dichloro 30 chlor-194-propanol / ethyl acetate hydrate 195

H 2-hydroxy- 2 none 100 base 80-81. petroleum ether

1,1-dimethyl- 100 ° C / 120 ° C ethyl

H allyl 2 none 83 chlor- 182 ethanol / ethyl acetate hydrate EXAMPLE 5

2.5 parts of 1-amino-3- (1-naphthoxy) -2-propanol hydrochloride are added to a mixture of 100 parts of 2N sodium hydroxide solution and 200 parts of ethyl acetate. The mixture is stirred and separated. The ethyl acetate layer is dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is dissolved in 80 parts of acetone and added with 0.5 part of platinum oxide. The mixture is stirred at room temperature and under atmospheric pressure for 12 hours. The mixture is then filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and added with a solution of hydrochloric acid in ether until the solid has finished precipitation. The mixture is filtered. The solid residue is washed with ethyl acetate and dried. The solid is recrystallized from n-propanol to give l-isopropylamino-3- (l-naphthoxy) -2-propanol hydrochloride, melting point 163-164 ° C.

By using a mixture of 2.8 parts of heptylmethylketone and 40 parts of ethanol instead of the 80 parts of acetone, the same is obtained of l- (l-methyloctyl- armno) -3- (l-naphthoxy hydrochloride ) -2-propanol, melting point 116-118 ° C (after recrystallization from ethyl acetate).

EXAMPLE 6

A mixture of 2.5 parts of 2-bromo-4- (naphthoxy) -3-butanol and 10 parts of isopropylamine is heated at 100 ° C for 10 hours in an autoclave. The mixture is then evaporated under reduced pressure and the residue is acidified using 25 parts of 2N hydrochloric acid. Charcoal is added and the mixture is stirred and then filtered. The filtrate is poured into 50 parts of 2N sodium hydroxide solution and the mixture obtained is extracted using 50 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate then filtered and the filtrate is acidified using a solution of hydrochloric acid in ether. The mixture obtained is filtered and the solid residue is recrystallized from a mixture of ethyl acetate and ethanol. This gives l-isopropylamino-4- (l-naphthoxy) -3-butanol hydrochloride hydrochloride, melting point 2L0 ° -212 ° C

The starting 2-bromo-4- (naphthoxy) -3-butanol can be obtained in the following way: A stirred solution of 3 parts of 2-bromo-4- (1-naphthoxy) -3-butanone in 20 parts of methanol at -5 ° C. 0.5 part of sodium borohydride is added. The mixture is stirred for 2 hours at 0 ° C. and then poured onto 100 parts of ice. 50 parts of ether are then added and the mixture obtained is separated. The ethereal phase is dried over anhydrous magnesium sulfate and then evaporated. The residue consists of 2-bromo-4- (1-naphthoxy) -3-butanol. 2- bromo-4- (l-naphthoxy) -3-butanone can be obtained as follows

To a stirred solution of 13 parts of diazoethane in 300 parts of ether at -10 ° C, we

REPLACEMENT SHEET add a solution of 10 parts of 1-naphthoxyacetyl chloride in 150 parts of ether. The mixture is stirred at 0 ° C for 3 hours, then at room temperature for 18 hours. The mixture is then stirred and cooled to -5 ° C and added with 20 parts of 40% hydrobromic acid. The mixture is stirred at -5 ° C for 30 minutes. The mixture is separated and the ethereal phase is dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is extracted using 20 parts of cyclohexane and the extract is filtered. The filtrate is evaporated under reduced pressure and its residue consists of 2-bromo-4- (1-naphthoxy) -3-butanone.

EXAMPLE 7

A solution of 0.46 part of sodium in 20 parts of ethanol is added to 2.42 parts of l-chloiO-3- (N-ben_yl-N-isoprt) pyl_-nino) -2-propanol, then the mixture is added with 1.44 parts of 1-naphthol. The mixture is heated under pressure at 100 ° C for 10 minutes in a sealed tube, then evaporated to dryness under reduced pressure. The residue is stirred with 50 parts of 2N hydrochloric acid and 50 parts of ether. The mixture is separated and the aqueous layer is made alkaline by the addition of a 2N sodium hydroxide solution. The alkaline solution is extracted three times with 100 parts of ether. The combined ether extracts are washed twice with 50 parts of water, dried over anhydrous magnesium sulfate and the ether is distilled off. This gives l- (N-ben_yl-N-isopropy__mino) -3- (l-naphthoxy) -2- propanol which, by the process of Example 1, can give a picrate melting at 157-8 ° C, and containing 1 molecule of water of crystallization (after recrystallization from aqueous dimethylformamide). The free base can be regenerated as follows from the purified picrate.

2 parts of the picrate are suspended in 100 parts of ethyl acetate and the suspension is stirred with 100 parts of a 50% ammonia solution. When all the picrate is dissolved, the mixture is separated. The organic layer is then extracted several times with 50 parts of 50% ammonia solution until the extracts are practically colorless. The ethyl acetate solution is then washed twice with 50 parts of water and dried over anhydrous magnesium sulfate, then the ethyl acetate is distilled off. This gives 1- (N-benzyl-N-isopropylamino) -3- (1-naphthoxy) -2-propanol.

EXAMPLE 8

1 part of 1- (N-benzyl-N-isopropylamino) -3- (1-naphthoxy) -2-prop_nol is dissolved in 35 parts of ethanol. To the solution is added 2 parts of a saturated solution of hydrochloric acid in ether and 0.4 part of a 20% palladium on carbon catalyst. The mixture is stirred at room temperature and under atmospheric pressure in a hydrogen atmosphere until sufficient hydrogen is absorbed for the hy-

REPLACEMENT FEUSLLE drolysis of the benzyl group, the absorption of hydrogen then ceasing. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from n-propanol to give l-iso-propylamino-3- (l-naphthoxy) -2-propanol hydrochloride, melting point 163-164 ° C.

EXAMPLE 9

A mixture of 1.25 parts of 1-amino-3- (1-naphthoxy) -2-propanol hydrochloride, 1.34 parts of benzylmethyl ketone, 40 parts of ethanol and 0.1 parts of platinum oxide is stirred in a hydrogen atmosphere at room temperature under atmospheric pressure until the end of absorption of hydrogen. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. 25 parts of acetone are added to the residue and the mixture obtained is filtered. The solid residue is washed with acetone, dried and recrystallized from a mixture of ethanol and ethyl acetate. This gives 1- (1-methyl-2-phenylethylamino-2- (1-naphthoxy) -2-propanol hydrochloride, melting point 186 ° C.

By using 1.25 part of 2- (4-methoxyphenyl) ethylmethyl ketone instead of 1.34 part of benzylmethylketone, the same is obtained from l- [3- (4-methoxyphenyl) - 1-methylpropylamino] hydrochloride - 3- (1-naphthoxy) -2-propanol, melting point 176-178 ° C (after recrystallization from ethanol).

By using 0.84 part of cyclopentanone instead of 1 part of benzylmethylketone, the same is obtained of l-cyclc entylamino-3- (l-naphthoxy) -2-propanol hydrochloride, melting point 208-209 ° C (after recrystallization from ethanol).

By using 2.5 parts of 2-heptadecanone instead of 1.34 part of benzylmethylcé¬ tone, the same is obtained from l- (l-memylhexadecylamino) -3- (l-naphthoxy) -2-propanol hydrochloride, period mp 105-106 ° C (after recrystallization from ethyl acetate.

By using 1 part of anisaldehyde instead of 1.34 part of benzylmethyl ketone, the same is obtained of 1- (4-methoxybenzyla_n__o) -3- (l-_aphthoxy) -2-propanol hydrochloride, melting point 190-192 ° C with decomposition (after recrystallization from ethanol).

EXAMPLE 10

A mixture of 2 parts of 1,2-epoxy-3- (2-naphthoxy) -prop_ne and 5 parts of 1-me I-3-phenylpropylamine is heated at 100 ° C for 1 hour. The mixture is then cooled and stirred with 25 parts of 2N hydrochloric acid and 50 parts of ether. The ethereal and aqueous phases are decanted and the residue is recrystallized from a mixture of ethanol and ethyl acetate. This gives l- (l-mé_ιyl-3-phenylpr_pylam_no) -l- (2-naphth-oxy) -2-propanol hydrochloride, melting point 174-176 ° C.

REPLACEMENT SHEET EXAMPLE 11

6.6 parts of 1-chloro-2-naphthol are heated at reflux for 6 hours with 20 parts of epichlorohydrin and 0.1 part of piperidine. The mixture is then evaporated to remove unchanged epichlorohydrin. 8 parts of isopropylamine are added to the residue and the mixture is heated under reflux for 10 hours. The mixture is evaporated and the residue is heated with 80 parts of petroleum ether (boiling range 80-100 ° C). The solution obtained is cooled and filtered. The solid residue is washed with petroleum ether (boiling range 80-100 ° and dried, then recrystallized from petroleum ether (boiling range 80-100 ° Q. The l- ( l-chloro-2-naphthoxy) -3-isopropylamino-2-propanol, melting point 104 ° C.

Using 5 parts of l-methyl-2-naphthol instead of 6.6 parts of l-chloro-2-naphthol, the same is obtained l-isopropylamino-3- (l-methyl-2-naphthoxy) -2 -propanol, melting point 122 ° C [after recrystallization from petroleum ether (boiling range 80-100 ° C)].

EXAMPLE 12

A mixture of 0.3 parts of 3-bromo-1- (l-naphthoxy) -2-propanol and 5 parts of isopropylamine is heated for 10 hours at 100 ° C in a sealed container. The container is cooled and 10 parts of 2N hydrochloric acid are added to its content. The mixture is filtered and the filtrate is basified with a 2N sodium hydroxide solution, then stirred with 25 parts of ether. The mixture is separated and the ethereal phase is dried over anhydrous magnesium sulfate, then filtered. The filtrate is evaporated to dryness. The residue consists of l-isoprσpylamino-3- (l-naphthoxy) -2-propanol, melting point 96 ° C.

The starting 3-bromo-l- (l-naphthoxy) -2-propanol can be obtained in the following way: A solution of 0.28 part of 3-bromo-l- (l-naphthoxy) -acetone in 5 parts of methanol is stirred and cooled to 0 ° C during the addition of 0.25 part of sodium borohydride. The mixture is then stirred for a further 30 minutes at 0 ° C. The mixture is poured onto ice, acidified with 2N hydrochloric acid and extracted with 20 parts of ether. The ethereal extract is dried over anhydrous magnesium sulfate and filtered, and the filtrate is evaporated to dryness. The residue consists of 3-bromo-1- (1-naphthoxy) -2-propanol. This compound has a characteristic absorption band in the infrared at 3450 cm ^{* 1} .

3-bromo-1- (1-naphthoxy) acetone can be obtained in the following way: A solution of 10 parts of 1-naphthoxyacetyl chloride in 150 parts of ether is stirred and cooled to between -5 and 10 ° C for the addition over 30 minutes of a solution of 11 parts of diazomethane in 300 parts of ether. The solution is stirred for 2 hours at -5 ° C, then for another 18 hours at room temperature. The solution is then stirred and cooled to -10 ° C during the addition of 20 parts of 1 IN hydrobromic acid. The mixture is stirred for 30 minutes. The mixture is separated and the ethereal phase is dried over sulphate of

REPLACEMENT SHEET anhydrous and filtered magnesium. The filtrate is evaporated to dryness and the residue is recrystallized from cyclohexane. 3-bromo-l- (l-naphthoxy) acetone is thus obtained, melting point 92-94 ° C.

EXAMPLE 13

A mixture of 8 parts of 1-chloro-3-methyl-3- (1-naphthoxy) -2-butanol and 40 parts of isopropylamine is heated at 100 ° C for 10 hours in a sealed container. The excess isopropylamine is evaporated and the residue is dissolved in 100 parts of IN hydrochloric acid. The solution is washed with ether and the acidic aqueous solution is added with 20 parts of 8N sodium hydroxide solution. The mixture is extracted using 100 parts of ether and the ethereal extract is washed with water, then dried over anhydrous magnesium sulfate. The ethereal solution is evaporated to dryness. The residual gum is dissolved in 30 parts of ether and added with a solution of hydrochloric acid in ether until the precipitation of the solid is substantially complete. The mixture is filtered and the solid residue is recrystallized from a mixture of methanol and ethyl acetate. 1-isopropyl-3-methyl-3- (1-naphthoxy) -2-butanol hydrochloride is thus obtained, melting point 133-139 ° C.

The starting l-chloro-3-methyl-3- (l-naphthoxy) -2-butanol can be obtained in the following way:

A solution of 68 parts of alpha- (1-naphthoxy) -isobutyric acid in 450 parts of chloroform and 53 parts of thionyl chloride is stirred at reflux for 3 hours, then the chloroform and the excess of thionyl chloride are evaporated . The residual gum is heated to reflux with 600 parts of petroleum ether (boiling range 60-80 ° C) and 5 parts of activated carbon for 15 minutes. The mixture is cooled to room temperature and then filtered. The filtrate is evaporated to dryness to give alpha- (1-naphthoxy) -isobutyryl chloride in the form of an oil.

A solution of 70 parts of alpha- (1-naphthoxy) -isobutyryl chloride in 200 parts of ether is treated with an excess of diazomethane in ether at 0 ° C for 24 hours, then the ether and the excess diazomethane is evaporated. The residual gum is dissolved in 250 parts of ether and gaseous hydrochloric acid is passed into the solution at 0 ° C until saturation. The solution is stirred and gradually added 300 parts of ice. The mixture is separated and the ethereal solution is washed successively three times with 100 parts of water, three times with 150 parts of a 10% sodium carbonate solution and finally three times with 100 parts of water. The ethereal solution is dried over anhydrous magnesium sulfate, then evaporated. 10 parts of the residue are dissolved in 80 parts of methanol, the solution is stirred and 5 parts of sodium borohydride are added thereto at 0 ° C over 45 minutes. After 12 hours, the methanol is evaporated and the residue is stirred with 30 parts of ether and 20 parts of water. The mixture is separated, the ethereal solution is dried over anhydrous magnesium sulphate, then evaporated to dryness. 1-chloro-3-methyl-3- (l-naphthoxy) -butanoL is thus obtained in the form of an oil.

REPLACEMENT SHEET EXAMPLE 14

The process of Example 13 is repeated using 40 parts of t-butylamine instead of 40 parts of isopropylamine. This gives l-t-butylamino-3-methyl-3- (l-naphthoxy) -2-butanol hydrochloride, melting point 219-220 ° C.

EXAMPLE 15

The process of Example 13 is repeated using 8 parts of l-chloro-3- (l-naphth-oxy) -2-butanol instead of 8 parts of l-chloro-3-methyl-3- (l- naphthoxy) -2-butanol. This gives l-isopropylamino-3- (l-naphthoxy) -2-butanol hydrochloride, melting point 158-159 ° C.

The starting l-chloro-3- (l-naphthoxy) -2-butanol can be obtained in the following way: A solution of 20 parts of alpha- (l-naphthoxy) propionic acid in 300 parts of chloroform and 16, 5 parts of thionyl chloride is heated at reflux for 3 hours, then the chloroform and the excess of thionyl chloride are evaporated. The oily residue consists of alpha- (l-naphthoxy) propionyl chloride. A solution of 20 parts of this oil in 100 parts of ether is treated with an excess of diazomethane in ether at 0 ° C for 16 hours then the ether and the excess diazomethane are evaporated. The residual gum is dissolved in 150 parts of ether and gaseous hydrochloric acid is passed into the solution at 0 ° C until saturation. The solution is stirred and gradually added with 200 parts of ice. The mixture is separated and the ethereal solution is washed successively three times with 50 parts of water, three times with 50 parts of a 10% solution of sodium carbonate and finally three times with 50 parts of water. The ethereal solution is dried over anhydrous magnesium sulfate, then evaporated to give chloromethyl-1- (l-naphthoxy) ethyl ketone, melting point 70-71 ° C [after recrystallization from petroleum ether (boiling range 60-80 ° C)].

15 parts of chloromethyl-1- (1-naphthoxy) ethyl ketone are dissolved in 200 parts of methanol, and the solution is stirred at 0 ° C with the addition of 7.5 parts of sodium borohydride over 45 minutes. After 12 hours, the methanol is evaporated and the residue is stirred with 50 parts of ether and 30 parts of water. The mixture is separated and the ethereal solution is dried over anhydrous magnesium sulphate, then evaporated to dryness. 1-chloro-3- (1-naphthoxy) -2-butanol is thus obtained in the form of an oil.

EXAMPLE 16

A solution of 1.25 parts of 1-propylamino-3- (1-naphthoxy) -2-propanol and 1 part of acetic anhydride in 10 parts of acetic acid is maintained at room temperature for 18 hours, then added a mixture of 50 parts of ice and 10

REPLACEMENT SHEET parts of a 1 IN ammonium hydroxide solution.

The aqueous phase is decanted and as much of the residue as possible is dissolved in 2N hydrochloric acid at 0 ° C. The solution is made alkaline with a 2N sodium hydroxide solution, then extracted with using 50 parts of ether. The ethereal extract is dried over anhydrous magnesium sul¬ fate, then filtered. To the filtrate is added a saturated solution of oxalic acid in ether until precipitation is substantially complete. The mixture is filtered and the solid residue is recrystallized from ethanol. 1-isopropyl-amino-methyl-2- (1-naphthoxy) ethyl acetate is thus obtained in the form of its acid oxalate, melting point 202-204 ° C. Instead of oxalic acid, it is possible to use hydrochloric acid and obtain analogously l-isopropylaminomethyl-2- (l-naphthoxy) ethyl acetate in the form of its hydrochloride, melting point 170-171 ° C (after recrystallization from a mixture of ethanol and ethyl acetate).

EXAMPLE 17

A mixture of 2.95 parts of 1-isopropylamino-3- (1-naphthoxy) -2-propanol hydrochloride and 6 parts of benzoyl chloride is heated at 100 ° C for 6 hours. The mixture is cooled and added with 50 parts of ether. The mixture is kept at room temperature for 3 days, then filtered. The solid residue is washed with ether and recrystallized from 25 parts of benzene. This gives l-isopropylaminomethyl-2- (l-naphthoxy) ethyl benzoate in the form of its hydrochloride, melting point 130-132 ° C.

EXAMPLE 18

2 parts of sodium borohydride are added in 10 minutes to a stirred solution of 2 parts of 1- (4-acé ^ Il-naphthoxy) -3-isopropylam.ino-2-propanol in 80 parts of methanol at 0 ° C. The mixture is stirred at 0 ° C for 1 hour, then poured onto 100 parts of ice, acidified with 2N hydrochloric acid and filtered. The filtrate is made alkaline with a 2N sodium hydroxide solution and extracted with 500 parts of ether. The ethereal extract is dried over anhydrous magnesium sulfate, then filtered.

The filtrate is added with a saturated solution of oxalic acid in ether until the precipitation is substantially complete. The mixture is filtered and the solid residue is recrystallized from a mixture of ethanol and ether. There is thus obtained 1- (4-alpha-hydroxyethyl-1-naphthoxy) -3-isopropylamino-2-propanol acid oxalate, melting point 140-147 ° C with decomposition.

REPLACEMENT SHEET ^" EXAMPLE 19

A solution of 0.77 part of 1-isopropylaminomethyl-2- (l-naphthoxy) ethyl acetate hydrochloride in 16 parts of methanol is treated with 33 parts of IN sodium hydroxide at room temperature, and after 1 hour the methanol is evaporated under reduced pressure. The residue is stirred with 20 parts of ether and 10 parts of IN hydrochloric acid. The mixture is separated and the ethereal solution is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of ethyl acetate and petroleum ether (boiling range 40-60 ° C) to give N-acetyl-1-isopropylamino- 3 (1-naphthoxy) -2- propanol, melting point 91 ° C.

EXAMPLE 20

A solution of 293 parts of 1-isopropylamino-3- (1-naphthoxy) -2-propanol hydrochloride in 300 parts of water is added to a solution of 43.2 parts of 1,1 '-methylene-bis- ( 2-hydroxy-3-naphthoate) disodium in 4000 parts of water. The mixture is filtered and the probe residue is washed with water and dried. The solid is recrystallized from ethanol to give l, -methylene-bis (2-hydroxy-3-naphthoate) di-ll-isopropylamino-3- (l-naphthoxy) - 2-propanolic], melting point 212 ° vs.

EXAMPLE 21

A solution of 1.3 parts of l-isopropylamino-3- (1-naphthoxy) -2-propanol in 25 parts of ethyl acetate is added to a solution of 0.7 parts of benzoic acid in 5 parts of 'ether. The mixture is filtered and the solid residue is washed with ether and dried. This gives l-isopropylamino-3- (l-naphthoxy) -2-propanol benzoate, melting point 143-144 ° C (after recrystallization from water).

By replacing 0.7 part of benzoic acid with 0.96 part of β-naphthoic acid, the same is obtained of l-isopropylamino-3- (l-naphthoxy) -2-propanol β-naphthoate, melting point 132 ° C (after recrystallization from a mixture of cyclohexane and ethanol).

By replacing 0.7 part of benzoic acid with 0.98 part of Q-acetoxybenzoic acid, the same is obtained for l-isopropylamino-3- (l-naphthoxy) -2-propanol u-acetoxy-benzoate, melting point 122-124 ° C (after recrystallization from ethyl acetate).

By replacing 0.7 part of benzoic acid with 0.7 part of adipic acid, the same is obtained for l-isopropyl-aminp-3- (l-naphthoxy) -2-propanol adipate, melting point 145 - 147 ° C (after recrystallization from a mixture of ethyl acetate and ethanol).

By replacing 0.7 part of benzoic acid with 0.62 part of oxalic acid, the same is obtained l-i_opropylar ox o-3- (l-naphthoxy) -2-propanol poxalate, melting point 180-182 ° C (after recrystallization from a mixture of methanol and ethyl acetate).

REPLACEMENT SHEET EXAMPLE 22

To a stirred solution of 10 parts of 1-isopropylamino-3- (1-naphthoxy) -2-propanol hydrochloride in 100 parts of water, a suspension of 100 parts of a sulfonated polystyrene resin is added [ "Zeo-Karb" 225] (SCR 3) in sodium form in 400 parts of water. The mixture is stirred for 60 minutes at room temperature, then filtered. The solid residue is washed with water and dried at room temperature. A complex salt of l-isoprcφylamino-3- (l-naphthoxy) -2-ρropanol is thus obtained with the sulfonated polystyrene resin having a base content of 9%.

REPLACEMENT SHEET

Claims

CLAIMS:

1. Naphthalenic derivatives of formula:

where R ¹ represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, R ² represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl or aralkyl radical, or although R ¹ and R ² form with the neighboring nitrogen atom an optionally substituted heterocyclic radical, R ³ , R ⁴ and R ⁵ , which may be identical or different, represent hydrogen atoms or alkyl radicals, and the naphthalenic nucleus may carry one or more additional substituents, as well as their esters and their salts, but with the exclusion of 1-ammo-ln-propylamino-, 1- n-butylamino, 1-di-n-butylamino-, 1-morpholino- and l-piperidino-3- (l-naphthoxy) -2-propanols, 1-ethylamino-, 1-dimethylamino-, 1-diethylamino-, 1-morpholino- and l-pipέridino-3- (2-naphthoxy) -2-propanols and l- (l-chloro-2-naphthoxy) -3-piperidino-2-propanol, as well as-their esters and their salts, characterized by the use as a drug with immuno¬ activating effect (facilitated activation of the immune system in the presence of foreign antigen) in humans.

2. Compounds according to claim 1, in which R ¹ , R ³ , R ⁴ and R ⁵ represent hydrogen atoms and R ² has the meaning given to it in claim 1 and the naphthhaene lenium optionally carries one or more additional substituents, as well as their esters and their salts, but excluding the 1-amino-, 1-n-propylamino- and ln-butyl-amino-3- (l-naphthoxy) -2- propanols and l-ethylamino-3- (2-naphthoxy) -2-propanol, as well as their es¬ ters and their salts, characterized by the use as a drug with immunoactivating effect in humans.

3. Compounds according to claim 1, in which R ¹ represents an alkyl or hydroxyalkyl radical of 5 carbon atoms at most, for example the methyl, ethyl, s-butyl or 2-hydroxyethyl radical, or an aralkyl radical of 10 carbon atoms maximum, for example the benzyl radical, or an alkanoyl radical of 6 carbon atoms at most, for example-

REPLACEMENT SHEET pie acetyl radical, characterized by the use as a drug with immunoactivating effect in humans.

4. Compounds according to any one of claims 1 to 3, in which R ² represents an alkyl radical of 20 carbon atoms at most, for example the methyl, ethyl, n-propyl, isopropyl, n- radical. butyl, isobutyl, s-butyl, t-butyl, 1-methyloctyl or 1-methylhexa-decyl, or an alkyl radical of 20 carbon atoms maximum carrying one or more hydroxy or substituted amino radicals, for example alkylamino, dialkylamino or heterocyclic radicals, such as alkylamino or dialkylamino radicals of up to 6 carbon atoms or heterocyclic radicals of up to 6 carbon atoms or heterocyclic radicals of up to 6 atoms , such as the dimethylamino or morpholino radicals, or alkoxy radicals, for example alkoxy radicals of 5 carbon atoms at most, such as methoxy or n-propoxy radicals, or alkoxyalkoxy radicals, for example alkoxyalkoxy radicals of 10 atoms maximum carbon mum, such as the 2-n-butoxethoxy radical, or optionally substituted aryloxy radicals, such as the 4-chlorophenoxy or 2,4-chlorophenoxy radicals, characterized by the use as a medicament with immunoactivating effect in humans.

5. Compounds according to either of claims 1 to 3, in which R ² represents an aralkyl radical of 15 carbon atoms at most optionally substituted, for example by one or more alkoxy radicals such as alkoxy radicals of 5 atoms carbon as much as the methoxy radical, characterized by the use as a drug with an immunoactivating effect in humans.

6. Compounds according to Claims 4 or 5, in which R ² represents the radical 2-hydroxyé_ιyle, 2-hydroxy-l-methylethyl, 2-hydroxy-l, l-dimethylethyl, 2-n-propoxyethyl, 3-methoxypropyl, 2- (2-n-butoxyethoxy) ethyl, 3-morpholino-propyl, 2-dimethyl-aminopropyl, 2- (4-chlorophenoxy) ethyl, 2- (2,4-dichlorophenoxy) ethyl, benzyl, 1-methyl-2 -phenylethyl, 1- methyl-3-phenylpropyl, 1,1-dimethyl-3-phenylpropyl, 4-methoxybenzyl, 3- (4-methoxy-phenyl) -1-methylpopopyl or 2- (3,4-dimethoxyphenyl) ethyl, characterized by the use as a drug with immunoactivating effect in humans

7. Compounds according to either of claims 1 to 3, in which R ² represents a cyalkyl, alkenyl or alkynyl radical of 10 carbon atoms at most, for example the cyclopentyl, allyl or l-methyl- radical. 2-propynyl, characterized by the use as a drug with immunoactivating effect in humans

8. Compounds according to claim 1, wherein the group -NR ^! R ² represents a nitrogen heterocyc¬ radical of 5 or 6 atoms optionally substituted, for example, the pyrrolidino, piperidino or morpholino radical optionally substituted by one or more alkyl radicals of 5

SUBSTITUTE SHEET carbon atoms at most, such as the methyl radical, characterized by the use as a drug with immunoactivating effect in humans.

9. Compounds according to either of Claims 1 and 3 to 8, in which R ³ , R ⁴ or R ⁵ represents an alkyl radical of 5 carbon atoms at most, for example the methyl radical, characterized by use as a drug with immunoactivating effect in humans.

10. Compounds according to either of claims 1 to 9, in which the optional substituents of the naphthalenic nucleus are chosen from the class formed by halogen atoms, for example chlorine or bromine atoms, by the alkyl or hydroxyalkyl radicals of 5 carbon atoms at most, for example the methyl or 1-hydroxyethyl radical, by the acyl radicals for example the alkanoyl radicals of 6 carbon atoms at most, such as the acetyl radical and by optionally substituted sulfamoyl radicals, for example dialkylsulfamoyl radicals of 10 carbon atoms maximum, such as the dimethylsulfamoyl radical, characterized by the use as a medicament with immunoactivating effect in humans.

11. The following chemical compounds, characterized by the use as a drug with immunoactivating effect in humans:

L-isopropyl_rnino-3- (l-naphthoxy) -2-propanol, lt-butylamino-3- (l-naphthoxy) -2-propanol, l- (2-hydroxy-l, l-dimemylethylamino) -3- (l-naphthoxy) -2-prop_nol, l- (2-methyl- 3-phenylpropylamino) -3- (l-naphthoxy) -2-propanol, ls-butylamino-3- (l-naphthoxy) -2-propanol, l- (l-methyloctylamino) -3- (l-naphthoxy) -2-propanol, l- (1,1-dimethyl-3-phenylpropylamino) -3- (1-naphthoxy) -2-propanol, 1 -allylamino-3- (1 -naphthoxy) -2-propanol, l-cyclopentylamino-3- (l-naphthoxy) -2-propanol, l-isopro-pylamino-3- ( 4-methyl-1-naphthoxy) -2-propanol and l- [3 ((4-methoxyphenyl) -l-memylpr_-pylariîino] -3- (l-naphu.oxy) - 2-propanol, their esters and their salts.

12. Esters according to any one of claims 1 to 11, which are Q-esters of acids of formula R ⁶ .COOH where R ⁶ represents an optionally substituted alkyl, alkenyl or aryl radical, for example a an alkyl or alkenyl radical of 20 carbon atoms maximum, or an aryl radical of 10 carbon atoms maximum, for example the methyl, pentadecyl, heptadecyl, heptadeca-8-enyl or phenyl radical, as well as their salts, characterized by use as a drug with immunoactivating effect in humans

13. Salts according to any one of claims 1 to 12, which are acid addition salts, for example derived from inorganic acids, such as hydrochlorides, hydrobromides, phosphates or sulfates, or d organic acids such as oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naphthoates, s-acetoxy-benzoates, adipates, maleates or 1,1'-methylene-bis-2-hydroxy-3-naphthoates or still acidic synthetic resins such as sulfonated polystyrene resins, characterized by the use as a drug with immu- noactivating in humans

14. Compounds according to claims 1 to 13, characterized by their use for the production of a medicament for the therapeutic use of their antiviral effect in humans.

15. Compounds according to claims 1 to 14, characterized by their use in animals with neuroimmune regulation similar to that in humans, that is to say with control of the immune system by hypothalamic nerve centers through d on the one hand the hypothalamic-adrenocortical axis and on the other hand through the vegetative nervous system, especially the sympathetic nervous system.

REPLACEMENT SHEET