CA2109224A1 - Using the immunoactivating activity of 3-naphthyloxy-2-hydroxy-propylamines, in particular for providing cell immunity, e.g. against viral infections - Google Patents
Using the immunoactivating activity of 3-naphthyloxy-2-hydroxy-propylamines, in particular for providing cell immunity, e.g. against viral infectionsInfo
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- CA2109224A1 CA2109224A1 CA 2109224 CA2109224A CA2109224A1 CA 2109224 A1 CA2109224 A1 CA 2109224A1 CA 2109224 CA2109224 CA 2109224 CA 2109224 A CA2109224 A CA 2109224A CA 2109224 A1 CA2109224 A1 CA 2109224A1
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- radical
- naphthoxy
- radicals
- propanol
- carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Summary:
The present invention concerns the use of homocyclic compounds and more particularly of naphthalene derivatives as medicament with immunoactivating effect in man and in animals with neuroimmmune regulation analogous to the one in man, which is interesting especially for therapies where the function of the immune system has to be enhanced, for example for the treatment or the prophylaxis of viral infections and certain immunodeficient diseases, as well as for antitumoral therapy. Immunoactivation is defined as facilitated activation of the immune system in presence of foreign antigen. This immunoactivating effect is produced by .beta.-blockade of the CNS (nucleus paraventricularis) and of the immune system, which facilitates the activa-tion of functional biochemical pathways, imitating thus the regulation of the immune system by the nervous system and more specially the inverse regulation of the activity of the immune sys-tem by the level of sympathicotonus of the sympathetic nervous system.
The present invention concerns the immunoactivating effect of naphthalene derivatives of the formula:
The present invention concerns the use of homocyclic compounds and more particularly of naphthalene derivatives as medicament with immunoactivating effect in man and in animals with neuroimmmune regulation analogous to the one in man, which is interesting especially for therapies where the function of the immune system has to be enhanced, for example for the treatment or the prophylaxis of viral infections and certain immunodeficient diseases, as well as for antitumoral therapy. Immunoactivation is defined as facilitated activation of the immune system in presence of foreign antigen. This immunoactivating effect is produced by .beta.-blockade of the CNS (nucleus paraventricularis) and of the immune system, which facilitates the activa-tion of functional biochemical pathways, imitating thus the regulation of the immune system by the nervous system and more specially the inverse regulation of the activity of the immune sys-tem by the level of sympathicotonus of the sympathetic nervous system.
The present invention concerns the immunoactivating effect of naphthalene derivatives of the formula:
Description
~10922~
AMINES. ESPECIALLY INTERESTING IN CELL-MEDIATED ~MUNITY. FOR EXAM-PLE AGAINST VIRAL INFECTIONS
The present invention concerns the ~herapeutic use in man (and in animals with neuroimmune regulation analogous to that in man) of homocyclic compounds and more exactly of naphtha-lene derivatives as medicament with immunoactivating activity, which are especially interesting for cellular immunity, for example for the treatment or prophylaxis of viral infections, certain immunodeficient diseases and for antitumoral therapy. Immunoactivation ist defined as facili-tated activation of the immune system in presence of foreign antigen. Animals with neuroim-mune regulation analogous to that in man are those with inhibitory control of the immune sys-tem by hypothalamic centres of the CNS (nucleus paraventricularis) via ~e hypothalamo-adre-nocortical axis and the autonomic nervous system, especially the sympathetic nervous system.
This immunoactivating activity is generated by blockade of B-2 receptors in the central nervous system (CNS) and of cells of the immune system, which facilitates activation of biochemical functional pathways in the cell via blockade of the cAMP-PKA-pathway, which is the only physiological inhibitory pathway in leukocytes, thus imitating the functional regulation of the immune system by the nervous system and the inhibitory inverse regulation of immune activity by the permanent tonus of the sympathetic nervous system. Consequently, the function of the immune system is enhanced, because pathways activating the specific functions of leukocytes are not blocked any more. For example, immune response to a recall antigen of persons infec-ted by HIV was enhanced by 3 to 10 times when the cAMP-PKA-pathway was blocked phar-macologically. Only B-2 blocking drugs with minimal ISA activity and excellent penetration into the CNS are capable of producing sufficient immunoactivating activity.
The advantages of the claimed use of these compounds are that they normally are very well to-lerated in contrast to other immunopotentiating agents (e.g. BCG or levamisol), that they easi-ly penetrate the CNS, where they develop equally their immunoactivating activity in the im-mune cells of the CNS, for example microglia and astroglia. Consequently the possibility to use their immunoactivating activity is a very surprising result of recent scientific research and is an exceptional progress for the therapy for example of immunodeficient diseases or in any the-rapy where the function of the immune system has to be enhanced (e.g. immunodeficient &sea-ses, viral infections and tumours), because until now there has been no such therapy, espe-cially not one active in the CNS.
Accor&ng to the invention we provide the immunoactivating effect of naphthalene derivatives of the formula:
~o.CR3R4.CHoH.CHR5 NRlR2 -- ~10~224 wherein Rl stands for hydrogen or an alkyl, cycloalkyl alkenyl, aralkyl or alkanoyl radical, any of which may optionally be substituted. R2 stands for hydrogen or an alkyl, cycloalkyl, alke-nyl, alkynyl or aralkyl radical, any of which may optionally be substituted, or Rl and R2 are joined together with the adjacent nitrogen atom to form a heterocyclic radical optionally substi-tuted, wherein R3, R4 and Rs, which may be the same or different, stand for hydrogen or alkyl radicals, and wherein the naphthalene nucleus may optionally bear one or more additional sub-stituents P and Q, and the esters thereof, and the salts thereof, but excluding l-amino-, l-n-propylamino-, l-n-butylamino-, l-di-ethylamino-, l-di-n-propylamino-, l-di-isopropylamino-, l-di-n-butylamino-, l-morpholino- and l-piperidino-3-(2-naphthoxy)-2-propanol, and 1-(1-chloro-2-naphthoxy)-3-piperidino-2-propanol, and the esters thereof, and the salts thereof.
A preferred group of compounds comprises those of the said naphthalene derivatives wherein Rl, R3, R4 and Rs stand for hydrogen, R2 has the meaning stated above, and wherein the naphthalene nucleus may optionally bear one or more additional substituents, and the esters thereof, and the salts thereof, but excluding l-amino-, l-n-propylamino-and l-n-butylamino-3-(2-naphthoxy)-2-propanol, and the esters thereof, and the salts thereof.
As a suitable value for R 1 there may be mentioned, for example, an alkyl or hydroxyal-kyl radical of not more than S carbon atoms, for example the methyl ethyl, s-butyl or 2-hydro-xyethyl radical, or an ara1kyl radical of not more than 10 carbon atoms, for example the acetyl radical.
As a suitable value for R2 there may be mentioned, for example, a branched chain allyl radical of not more than 20 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, l-methyloctyl or l-methylhexadecyl radical, or an alkyl radi-cal of not more than 10 carbon atoms bearing one or more hydroxy radicals i.e. hydroxy-branched-chain-alkyl, or substituted amino radicals, for example alkylamino, di-alkylamino or heterocyclic radicals, for example alkylamino or dialkylamino radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 ring atoms, for example the dimethylamino or morpholino radical, or alkoxy radicals, for example alkoxy radicals of not more than S carbon atoms, for example the meth-oxy or n-propoxy radical, or alkoxyalkoxy radica1s, for example alkoxyalkoxy radicals of not more than 10 carbon atoms, for example the 2-n-butoxy-ethoxy radical, or aryloxy radicals, optiona11y substituted, for example aryloxy radicals of not more than 10 carbon atoms, optio-nally substituted, for example the 4-chlorophenoxy or 2,4-&chlorophenoxy ra&cal. Alterna-tively, R2 may stand for an aralkyl radical of not more than 15 atoms, optiona11y substituted with, for example, one or more alkoxy radicals, for example alkoxy ra&cals of not more than S
carbon atoms, for example the methoxy radical. Thus specific values for R2 when it stands for a substituted alkyl ra&cal or a substituted or unsubstituted aralkyl radical are, for example, the 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 3 ~109224 2-hydroxy- 1, I -dimethylethyl, 2-n-propoxyethyl, 3-methoxypropyl, 2-(2-n-butoxyethoxy)-ethyl, 3-morpholinopropyl, 3 -dimethylaminopropyl, 2-(4-chlorophenoxy)-ethyl, 2-(2,4-dichlorophenoxy) -ethyl, benzyl, l-methyl-2-phenylethyl, 1 -methyl-3-phenylpropyl, 1, 1-dimethyl-3-phenylpropyl, 4-methoxybenzyl, 3-(4-methoxyphenyl)-1-methylpropyl or 2-(3,4-dimethoxyphenyl)-ethyl radical.
Alternatively, R2 may stand for a cycloalkyl, alkenyl or alkynyl radical of not more than 10 carbon atoms, for example the cyclopentyl, allyl or l-methyl-2-propynyl radical.As a suitab1e value for the group -NRIR2 when it stands for a heterocyclic radical there may be mentioned, for example, a 5- or 6-membered nitrogen-containing heterocyclic radical, optionally substituted, for example a pyrrolidino-piperidino or morpholino radical, any of which may optionally be substituted by one or more alkyl radicals of not more than 5 carbon atoms, for example the methyl radical.
As a suitable value for R3, R4, or Rs when it stands for an aL~yl radical there may be mentioned, for example, an alkyl radical of not more than 5 carbon atoms, for example the me-thyl radical.
As suitable optional additional substituents P and Q in the naphthalene nucleus there may be mentioned, for example, halogen atoms, for example chlorine or bromine atoms, or al-kyl or hydroxyalkyl radicals of not more than 5 carbon atoms, for example the methyl or 1-hydroxyethyl radical, or acyl radicals, for example alkanoyl radicals of not more than 6 carbon atoms, for example the acetyl radical, or sulphamoyl radicals, optionally substituted, for example dialkylsulphamoyl radicals of not more than 10 carbon atoms, for example the dime-thylsulphymoyl radical.
Particularly valuable naphthalene derivatives of the present invention are, for example, l-isopropylamino-3-(1-naphthoxy)-2-propanol, l-t-butylamino-3-(1-naphthoxy)-2-propanol, 1-(2-hydroxy-1,1-dimethylethylamino)-3-(1-naphthoxy)-2-prapanol.
l-(l-methyl-3-phenylpropylamino)-3-(1-naphthoxy)-2-propanol, l-s-butylamino-3-(1-naphthoxy)-2-propanol, 1-( 1-methyloctylamino)-3-( 1-naphthoxy)-2-propanol, 4 ~092~
1-(1,1 -dimethyl-3-phenylpropylamino) -3-(1 -naphthoxy)-2-propanol, 1 -allylamino-3-( 1-naphthoxy)-2-propanol, I ~yclopentylamino-3-( 1 -naphthoxy)-2-propanol l-isopropylamino-3-(4-methyl-1-naphthoxy)-2-propanol and 1-(3-(4-methoxyphenyl)- 1-methylpropylamino)-3-(-naphthoxy)-2-propanol, and the esters thereof, and the salts thereof.
As suitable esters of the said naphthalene derivatives there may be mentioned, for ex-ample, O-es~ers derived from acids of the formula R6.COOH wherein R6 stands for an alkyl, alkenyl or aryl Mdical, optionally substituted, for example an alkyl or alkenyl radical of not more than 10 carbon atoms or an aryl radical of not more than 10 carbon atoms, for example the methyl, pentadecyl, heptadecyl, heptadeca-8-enyl or phenyl radical.
As suitable salts of the said naphthalene derivatives there may be mentioned acid-addi-tion salts, for exarnple salts derived from inorganic acids, for example hydrochlorides, hydro-bromides, phosphates, or sulphates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naphthoates, o-acetoxybenzoates, adipates, maleates or 1 ,1-methylene-bis-2-hydroxy-3-naphthoates or salts with acidic synthetic resins, for example sulphonated polystyrene resins, for example "Zeo-Karb" 225 ("Zeo Karb"
is a trademark). Relatively insoluble salts, for example the 1,1'-methylene-bis-2-hydroxy-3-naphthoates are useful in that they afford prolonged blood levels of the medicarnent.
A process for the manufacture of the naphthalene derivatives comprises the interaction of a halogeno compound of the formula:
~o.CR3R4.CHoH.CHRs.X
wherein X stands for a halogen atom, R3, R4 and Rs have the meanings stated above, and the naphthalene nucleus may optionally bear one or more additional substituents, with an amine of the formula NHRlR2, wherein Rl and R2 have the meanings stated above.
As a suitable value for X there may be mentioned, for example, a chlorine or bromine atom. The said interaction may be conveniently accelerated or completed by the application of heat.
Another process for the manufacture of the naphthalene derivatives comprises the inter-action of an epoxide of the fo~nula:
--` 2~22~
~o.CR3R4. CH--CHRs wherein R3, R4 and Rs have the meanings stated above and the naphthalene nucleus may optio-nally bear one or more additional substituents, with an amine of the formula NHR IR2, wherein Rl and R2 have the meanings stated above.
This process may be carried out in a diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.
Another process for the manufacture of ~e naphthalene derivatives com~ises the inter-action of a naphthol derivative of the formula:
~OH
wherein the naphthalene nucleus may optionally bear one or more additional substituents, with a compound of the formula:
X.CR3R4.CHoH.CHRs.NRlR2 or R3R4C--CH.CHRs.NRlR2 wherein Rl, R2, R3, R4, Rs and X have the meanings stated above.
The interaction involving a naphthol derivative and a halogeno derivative may be conv~
niently carried out in the presence of an acid-binding agent; alt~natively, an aL1~ali metal deriva-tive of the naphthol derivative, for example the sodium or potassium derivative, may be used as starting material.
The process for the manufacture of those of the naphthalene derivatives wherein Rl stands for hydrogen and R2 stands for a radical of the formula -CHR7R8, wherein R7 stands for hydrogen or an alkyl, cycloalkyl, aLI~enyl, alkynyl, aryl ~r arallyl radical, optionally substi-tuted, and R8 stands for an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optional-ly substituted, or wherein R7 and R8 are joined togeterh with the adjacent car'oon atom to form a cycloalkyl radical, optionally substituted, which comprises the in~action of an amino deriva-tive of the formula:
r~ :
6 2~09224 :~:
~} o.CR3R4.CHoH.CHRs.NH2 wherein R3, R4 and R5 have the meanings stated above and the naphthalene nucleus may optionally bear one or more additional substituents, with a carbonyl compound of the fo~rnula R7.CO.R8, wherein R7 and R8 have the meanings stated above, under reducing conditions.
Suitable reducing conditions are those provided by the presence of hydrogen and a hy-drogenation catalyst, for example platinum, in an inert diluent or solvent, for example ethanol, and/or, in the case where, in the said carbonyl compound used as starting material, R7 stands ~or an alkyl, cycloalkyl, alkenyl, aLkynyl, aryl or aralkyl radical, optionally substituted, in an excess of the carbonyl compound used as starting material; or by the presence of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example aqueous methanol, and /or, in the case where, in the said carbonyl compound used as starting material, R7 stands for an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optionally substituted, in an excess of the carbonyl compound used as starting material; or by the presence of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example aqueous methanol, and/or in an excess of the carbonyl compound used as starting material. It is to be understood that, in the case where R7 or R8 or both stands or stand for an alkenyl or alkynyl radical, optionally substituted, if it is desired that this radical is not reduced to the corresponding alkyl radical or substitued alkyl radical during this process, suitable reducing conditions, for example those provided by the use of sodium borohydride, must be used. It is to be further understood that the amino derivatives used as starting materials may be generated in situ, for example by reduction of the corresponding alpha-diazoketone, alpha-azidoketone and -alcohol, cyanhydrin or acyl cyanide.
A process for the manufacture of those of the naphthalene derivatives wherein stands fw hydrogen comp~ises the hydrogenolysis of a compound of the formula:
~O.CR3R4.CHOH.CHR5.NR2R9 wherein R2, R3~ R4 and Rs have the meanings st~ted above, Rg stands for a hydrogenolysable radical, and the naphthalene nucleus may oq~tionally bear one or more additional substituents.
As a suitable value for R9 there may be mentioned an alpha-aralikyl radical of not more tha 10 carbon atoms, for example the benzyl radica]i. The said hy~ogenolysis may be effected ~,~" ~ t ' ~
~` ?;' 210922~
by catalytic hydrogenation, for example hydrogenation in the presence of a platinum or palla-dium-on-carbon catalyst, conveniently in an inert diluent or solvent, for example ethanol.
Another process comprises the manufacture of those of the naphthalene derivatives wherein the naphthalene nucleus bears as substituent a hydroxyalkyl radical, which comprises the reduction of the corresponding compound wherein the naphthalene nucleus bears as substi-tuent the corresponding oxoalkyl radical. As a suitable oxoalkyl radical there may be men-tioned, for example, an oxoalkyl radical of not more than 20 carbon atoms, for example an al-kanoyl radical of not more than 20 carbon atoms, for example the acetyl radical. As a suitable reducing agent there may be mentioned, for example, sodium borohydride.
The process for the manufacture of the esters of 3-naphthyloxy-2-hydroxy-propyl-amines comprises the acylation of the corresponding naphthalene derivative. As suitable acyla-ting agents there may be mentioned, for example, acyl halides or acid anhydrides, for example acetic anhydride or benzoyl chloride. The acylation may be carried out in a diluent or solvent, which, in the case where an acid anhydride is used, may conveniently be the acid from which the anhydride is derived.
The process for the manufacture of those naphthalene derivatives wherein R I stands for an alkanoyl radical comprises the isomerisation of an ester of the formula:
~.CR3R4.CH(o.CoRI0) .CHRs.NHR2 wherein R2, R3, R4 and Rs have the meanings stated above and Rl stands for an alkyl radical, for example an alkyl radical of not more than 5 carbon atoms, and wherein the naphthalene nucleus may optionally bear one or more additonal substituents.
The isomerisation may be effected by the interaction of the ester with a strong base, fo~
example an alkali metal hydroxide, for example sodium hydroxide, conveniently in a diluent or solvent, for example, methanol.
The parts by weight of the following examples (but not limited to these) are:
A mixture of 4,4 parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 16 parts of iso~ropylamine is heated in a sealed vessel at 70-80 C. for 10 hours. The vessel is cooled and to the contents there are added S0 parts of ether. The aqueous phase is decolourised with carbon, and then ad-ded to 50 parts of 1 N-sodium hydroxide solution at 0 C. The mixture is filtered. The solid re-sidue is washed with water, dried, and crystallised from cyclohexane. There is thus obtained 1-isopropylamino-3-(1-naphthoxy)-2-propanol, M.P. 96 C.
~` 210922~
The above procedure is repeated using the appropriate chloruhydrins and amines as starting materials except that a reaction temperature of 90-100 C. is use~ In a similar manner there are obtained the compounds listed in the following table. The hydrochlorides and oxalates listed are obtained by dissolving the base in ether, adding an ethereal solution of hydrogen chloride or oxalic acid, filtering the mixture, washing the sohd residue with ether, and drying.
The picrates listed are obtained by dissolving the base in ethanol, adding an ethanolic solution of picric acid, filtering the mixture, washing the solid residue with ethanol, and drying.
O.CH2.CHOH.CH2.NRlR2 [~
Rl R2 Additional Base or salt M.P.(C) Solvent(s) for recri-substituents stallisation on the naphtha- .
Iene nucleus H t-butyl - oxalic acid 230 ethanol (aque.) H 2-tydroxy-1,1- - base 148 ethanol dimethyl-ethyl H isobutyl - chlorhydrate 166-168 water H ethyl 4-chloro oxnlic acid 186-188 ethanol 9 ~10~22~
Rl R2 Additional Base or salt M.P.(C) Solvent(s~ for recri-substituents stallisation on the naphtha-lene nucleus __ _ _ __ H ethyl - base 109-110 cyclohe~ane H s-butyl - base 60,5-61 he~ane methyl methyl - base 82-83 petrol-ether 60 C/
methyl isopropyl - picrate 120-122 ethanol H 2-hydro~y- - base 84 he~ane ethyl ethyl 2-hydro~y- - picrate 157-158 ethanol cthyl 2-hydroxy- 2-hydroxy- - picrate 161-163 ethanol ethyl ethyl H 3-morpholino- - base 89-91 cyclohexane propyl H 2-(3,4-dimeth- - oxalic acid 309 water/propanol o~yphenyl)ethyl H isopropyl 4-methyl base 90-91 cyclohe~ane H isopropyl 5-dimethyl- chlorhydrate 190-193 butano1 sulfamoyl H isopropyl 5,8-dichloro base 115 cyclohe~ane s-butyl s-butyl - o~alic acid 160-161 ethanol H 2-propo~cy- - chlorhydrate 105-107 ethyl-acetate ethyl H benzyl - chlorhydrate 169 ethyl-acetate/etha- nol :~
H allyl - chlorhydrate 148 ethyl-acetate/etha- nol : ~`
By the use of l-chloro-3-(2-naphthoxy)-2-propanol in place of the 1-chloro-3-( l-naph-thoxy)-2-propanol used in example 1 there is obtained similarly 1-isoprowl-amino-3-(2-naphtoxy)-2-propanol, M.P. 138-140 C. (crystallised from ethanol). .
By the use of t-butylamine in place of the isopropylamine used in example 2 there is obtained similarly l-t-bulylamino-3-(2-naphthoxy)2-propanol, M.P. 120 C. (from cyclohe-xane).
21~922~
A mixture of 2,3 parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 2,6 parts of 1-methyl-3-phenylpropylamine is heated at 90-100 C. for 10 hours. The mixture is then cooled, diluted with S0 parts of water, acidified with 2 N-hydrochloric acid and filtered. The solid resi-due is shaken with 50 parts of ether. The mixture is separated, and the ethereal phase is dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is dissolved in S0 parts of ethyl acetate, and a solution of hydrogen chloride in ether is added. The mixture is fil-tered, and the solid residue is washed with ethyl acetate, dried, and crystallised from a mixture of methanol and ethyl acetate. There is thus obtained l-(methyl-3-phenylpropylamino)-3-(1-naphthoxy)2-propanol hydrochloride, M.P. 162-164 C.
A mixture of 1.84 parts of 1,2-epoxy-3-naphthoxy-propane and 1,7 parts of isopropyl-amine is heated under reflux for 16 hours. The mixture is acidified with 25 parts of 2 N-hydro-chloric acid and washed with 50 parts of ether. The aqueous solution is then added to 50 parts of 2 N-sodium hydroxide solution at 0 C., and the resulting mixture is filtered. The solid resi-due is washed with water, and dried, and then crystallised from cyclohexane. There is thus ob-tained l-isopropylamino-3-(1-naphthoxy)-2-propanol, M.P. 96 C.
The base may be converted into the hydrochloride as follows:
4,65 parts of the base are dissolved in 30 parts of warm acetone. To the warrn solution there are added 2 parts of 10 N-hydrochloric acid. The mixture is allowed to cool, and is then fil-tered. The solid residue is washed with acetone and then dried. The solid is crystaJlised from propanol, and there is thus obtaines l-isopropylamino-3-(1-naphthoxy)-2-propanol hydro-chloride, M.P. 163 C.
The above procedure is repeated using the appropriate epoxy-naphthoxypropanes and amines as starting materials, except that various reaction temperatures and times are used in a similar manner there are obtained the compounds listed in the following table. The hydrochlo-rides, oxalates and picrates are obtained by the general procedures described in example 1.
~.CH2.CHOH.CH2.NRIR2 i . -.. - ., , ... . ., ,.. ,. . . . .. . : . .... ..
tl 21~922~
Rl R2 Position of Addhional sub- React.- Duration Base or M.P. Sol~ent(s) for substituent stituents on the temp. of react. salt (C) recristallisation naphthalene nuc- (C) (hours leus __ _ _ ethyl butyl I - 100 1 o:calic 100 ethyl-ethanol/acetate acid H 2-hydro` 1 - 100 1 base 115 benzene xy-1-me-thylethyl H 3-meth- 1 - 100 1 oxalic 148- propanol oxypropyl acid 149 H 2-(2-but- 1 100 1 oxalic 138 water o~yetho~y)- acid ethyl H 2-(2,~di- 1 - 100 1 base 115 petrol-ether chloro-phen- 100 C/120 C
o~y)-ethyl H 2-(2,4-di- 1 - 100 1 base 115 petrol-ether 100 C/
chloro-phen- 120 C
o~cy)-ethyl ethyl 2-(4-chloro- 1 - 100 1 o~alic 149- water pheno~y)- acid 150 ethyl H 3-dimethyl- 1 - 20 72 dichlor- 234- methanol amino-pro- hydrate 235 H 1,1-dimethyl- 1 - 100 1 oxalate 210- 2-etho~y-ethanol 3-phenyl-pro-pyl benzyl 1-methyl-2- 1 - 100 1 picrate 166- propanol 2-propynyl 1 68 H isopropyl 1 2-chloro 20 16 chlor- 160- ethyl-ethanol/acetate hydrate 161 H isopropyl 1 4-acetyl 20 16 base 95 petrol-ether H isopropyl 1 2,4-dichloro 30 3 chlor- 194- ethyl-propsnoUacetate hydrate 195 H 2-hydro~:y- 2 - 100 1 base 80-81 petrol-ether l,1-dimethyl- 100 C/120 C
ethyl H allyl 2 - 83 1 chlor- 182 ethyl-ethanol/acetate hydrate '~ 2las22~
2,5 parts of 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride is added to a mixture of 100 parts of 2 N-sodium hydroxide solution and 200 parts of ethyl-acetate. The mixture is shaken and separated. The ethyl acetate layer is dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is dissolved in 80 parts of acetone, and 0,5 part of plati-num oxide is added. The mixture is shaken at ambient temperature and 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 ethereal hydrochloric acid is added until no more solid is precipitated. The mixture is filtered. The solid residue is washed with ethyl acetate, and then dried. The solid is crystallised from n-propanol and there is thus obtained l-isopropyl-amino-3-(1-naphthoxy)-2-propanol hydrochloride. M.P. 163-164 C.
By using a mixture of 2,8 parts of heptyl methyl ketone and 40 parts of ethanol in place of the 80 parts of acetone there is obtained similarly 1-(1-methyl-octyl-amino)-3-(1-naphth-oxy)-2-propanol hydrochloride, M.P. 116-118 C. (crystallised from ethyl acetate).
A mixture of 2,5 parts of 2-bromo-4-(naphthoxy)-3-butanol and 10 parts of isopropyl-amine is heated in a pressure vessel at 100 C. for 10 hours. The mixture is then evaporated under reduced pressure and the residue is acidified with 25 parts of 2 N-hydrochloric acid.
Carbon is added, and the mixture is stirred and then filtered. The filtrate is added to S0 parts of 2 N-sodium hydroxide solution, and the resulting mixture is then extracted with S0 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate, and then filtered and the filtrate is acidified with ethereal hydrochloric acid. The resulting mixture is filtered, and the solid residue is crystallised from a rnixture of ethyl acetate and ethanol. There is thus obtained l-isopropy1amino-4-(1-napht~xy)-3-butanol hydrochloride, M.P. 210-212 C.
The 2-bromo-4-(naphthoxy)-3-butanol used as starting material may be obtained as fol-lows:
To a stirred solution of 3 parts of 2-bromo-4-(1-naphthoxy)-3-butanone in 20 parts of methanol at -5 C. there is added 0,S part of sodium borohydride. The mixture is stirred for 2 hours at 0 C., and is then poured into 100 parts of ice. There are then added 50 parts of ether, and the resulting mixture is separated. The ethereal phase is dried over anhydrous magnesium sulphate and then evaporated. The residue consists of 2-bromo-4-(1-naphthoxy)-3-butanol. 2-bromo-4-(1-naphthoxy)-3-butanone itself may be obtained as follows:
To a stirred solution of i3 parts of diazoethane in 300 parts of ether at -10 C. there is added a solution of 10 parts of l-naphthoxyacetyl chloride in 150 parts of ether. The mixture is stirred at 0 C. for 3 hours, and then at ambient temperature for 18 hours. The mixture is then stirred and cooled to -5 C., and 10 parts of 40% hydrobromic acid ~re added. The mixture is stirred at -5 C. foq 30 minutes. The mixture is separated, and the etheral phase is dried over anhydrous magnesium sulphate. The mixture is filtered and the filtrate is evapo~ated under re--~` 210~22~
duced pressure. The residue is extracted with 20 parts of cyclohexane, and the extract is fil-tered. The filtrate is evapoMted under reduced pressure; the residue consists of 2-bromo-4-(1-naphthoxy) -3 -butanone.
A solution of 0,46 part of sodium in 20 parts of ethanol is added to 2,42 parts of 1-chloro-3-(N-benzyl-N-isopropylamino)-2-propanol, and to this mixture 1,44 parts of l-naph-thol are added. The mixture is heated under pressure in a sealed tube at 100 C. during 10 hours, and then evaporated to dryness under reduced pressure. The residue is stirred together with 50 parts of 2 N-hydrochloric acid and 50 parts of ether. The mixture is separated and the aqueous layer is basified by the addition of 2-N-sodium hydroxide solution. The aL'Yaline solu-tion is extracted three times with 100 parts of ether. The combined ethereal extracts are washed twice with 50 parts of water, dried over anhydrous magnesium sulphate, and the ether is then removed by distillation. There is thus obtained l-N-benzyl-N-isopropylamino)-3-( l-naphth-oxy)-2-propanol, which, by means of the procedure described in example 1, may be converted into a picrate, M.P. 157-8 C., containing one molecule of water of crystallisation (crystallised from aqueous dimethylformamide). The fr~e base may be regenerated from the purified picrate as follows:
24 parts of the picrate are suspended in 100 parts of ethyl acetate, and this suspension is stirred together with 100 parts of 50% ammonia solution, until the extracts are practically colourless. The ethyl acetate solution is then washed twice with 50 parts of wate~, dried over anhydrous magnesium sulphate, and the ethyl acetate is then removed by distillation. There is thus obtained 1 -(N-benzyl-N-isopr~pylamino)-3-( 1 -naphthoxy)-2-propanol.
1 part of 1-(N-benzyl-N-isopropylamino)-3-(1-naphthoxy~-2-propanol is dissolved in 35 parts of ethanol. To the solution are added 2 parts of a saturated ethereal hydrogen chloride solution and 0,4 part of a 20% palladium on carbon cataly$. The mixture is shaken at ambient temperature and atmospheric pressure in an atmosphere of hydrogen until sufficient hydrogen has been absorbed to account for the hydrogenolysis of the benzyl group, and no further uptake of hydrogen is occurring. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from n-propanoI, and there is thus ob-tained l-iso propylamino-3-(1-naphthoxy)-2-propanol hydrochloride, M.P. 163-164 C.
A mixture of 1,25 parts of 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride, 1,34 parts of benzyl methyl ketone, 40 parts of ethanol and 0,1 part of platinum oxide is shaken in an atmosphere of hydrogen at ambient tempe~ature and atmospheric pressure until hydrogen ~ ~922~
absorption ceases. The mixture is filtered and the filtrate is evaporated to dryness under redu-ced pressure. 25 parts of acetone are added to the residue, and the resulting mixture is filtered.
The solid residue is washed with acetone, dried and crystallised from a mixture of ethanol and ethyl acetate. There is thus obtained l-(l-methyl-2-phenylethylamino)-3-(1-naphthoxy)-2-pro-panol hydrochloride, M.P. 186 C.
By using 1,25 parts of 2-(4-methoxyphenyl)-ethyl-methyl ketone in place of the 1.34 parts of benzyl methyl ketone there is similarly obtained 1-[3-(4-methoxy phenyl)-l-methyl-propylamino]-3-(naphthoxy)-2-propanol hydrochloride, M.P. 176-178 C. (crystallised from ethanol).
By using 0,84 part of cyclopentanone in place of the 1,34 parts of benzyl methyl ketone there is similarly obtained l-cyclopentylarnino-3-(1 -naphtoxy)-2-propanol hydrochloride, M.P.
808-809 C. (crystallised from ethanol).
By using 2,5 parts of 2-heptadecanone in place of the 1,34 parts of benzyl methyl ke-tone there is similarly obtained l-(l-methylhexadecylamino)-3-(1-naphthoxy)-2-propanol hy-drochloride, M.P. 105-106 C. (crystallised from ethyl acetate).
By using 1,36 parts of anisaldehyde in place of the 1,34 parts of benzyl methyl ketone there is similarly obtained 1-(4-methoxybenzylamino)-3-(1-naphthoxy)-2-propanol hydrochlo-ride, M.P. 190-192 C. with decomposition (~ystallised from ethanol).
A mixture of 2 parts of 1,2-epoxy-3-(2-naphthoxy)-propane and 5 parts of 1-methyl-3-phenylpropylamine is heated at 100 C. for 1 hour. The mixture is then cooled and stirred to-gether with 25 parts of 2 N-hydrochloric acid and 50 parts of ether. The ethereal and aqueous phases are decanted, and the residue is crystallised from a mixture of ethanol and ethyl acetate.
There is thus obtained l-(l-methyl-3-phenylpropylamino)-1-(2-naphthoxy)-2-propanol hydro-chloride, M.P. 174-176 C.
6,6 parts of 1-chloro-2-naphthol, 20 parts of epichlorohydrin and 0,1 part of piperidine are refluxed together for 6 hours. The mixture is then evaporated to remove unreacted epichlo-rohydrin. To the residue there are added 8 parts of iso-propylamine, and the mixture is heated under reflux for 10 hours. The mixture is then evaporated and the residue is heated together with 80 parts of petroleum ether (B.P. 80-100 C.). The solution thus obtained is cooled and filtered. The solid residue is washed with petroleum ether (B.P. 80~100 C.) and dried, and is then crystallised from petroleum ether (B.P. 8~100 C.). There is thus obtained l-(l-chloro~2-naphthoxy)-3-isopropylamino-2-propanol, M.P. 104 C.
By the use of S parts of l-methyl-2-naphthol in place of the 6,6 parts of 1-chloro-2-naphthol there may be obtained in a similar manner l-isopropylamino-3-(1-methyl-2-naphth-oxy)-2-propanol, M.P. 122 C. Lcrystallised from petroleum ether (B.P. 8~tO0 C.)].
-` 210g22~
A mixture of 0,3 part of 3-bromo-1-(1-naphthoxy)-2-propanol and 5 parts of isopro-pylamine is heated in a sealed vessel at 100 C. for 10 hours. The vessel is cooled, and to the contents there are added 10 parts of 2-N-hydrochloric acid. The mixture is filtered and the filtrate is basified with 2 N-sodium hydroxide solution and shaken together with 25 parts of ether. The mixture is separated and the ethereal phase is dried over anhydrous magnesiums sulphate and then filtered. The filtrate is evaporated to dryness. The residue consists of 1-isopropylamino-3-(1-naphth-oxy)-2-propanol, M.P. 96 C.
The 3-brom~l-(naphthoxy)-2-propanol used as starting material may be obtained asfollows: -A solution of 0,28 part of 3-bromo-1-(l -naphthoxy)-acetone and 5 parts of methanol is stirred and cooled to 0 C. whilst 0,25 part of sodium borohydride is added.
The mixture is tben stirred for a further 30 minutes at 0 C. The mixture is then poured onto ice, acidified with 2-N-hydrochloric acid and extracted with 20 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate and filtered, and the filtrate is evaporated to dryness. The residue consists of 3-bromo-1-(1-naphthoxy)-2-propanol. It possesses a cha-racteristic absorption band in the infrared at 3450 cm-l.
3-bromo-1-(1-naphthoxy) acetone itself may be obtained as follows:
A solution of 10 parts of l-naphthoxyacetyl chloride in 150 parts of ether is stirred and cooled to -5 to -10 C. whilst there is added during 30 minutes a solution of 11 parts of diawmethane in 300 parts of ether. The solution is stirred for 2 hours at -5 C. and then for 18 hours at ambient temperature. The solution is then stirred and cooled to -10 C. whilst there are added 10 parts of 11 N-hydrobromic acid. The mixture is then stirred for 30 minutes. The mixture is separated and the ethereal phase is dried over anhydrous magnesium sulphate and filtered. The filtrate is evaporated to dryness, and the residue is crystallised from cyclohexane. There is thus obtained 3-bromo-1-(1-naphthoxy) acetone, M.P. 92-94 C.
EXAMPLEi 13 A mixture of 8 parts of 1-chloro-3-methyl-3-(1-naphthoxy)-2-butanol and 40 parts of isopropylamine is heated in a sealed vessel at 100 C. for 10 hours. The excess of isopropyl-amine is evaporated and the residue is dissolved in 100 parts of N-hydrochloric acid. The solution is washed with ether, and 10 parts of 8 N-sodium hydroxide solution are then added to the aqueous acid solution. The mixture is extracted with 100 parts of ether and the ethereal extract is washed with water and then dried with anhydrous magnesium sulphate. ~e ethereal solution is evaporated to dryness. The residual gum is dissolved in 30 parts of ether, and ethe-real hydrogen chloride is added until the precipitation of solid is substantially complete. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ethyl acetate. There is thus obtained l-isopropylamino-3-methyl-3-(1-naphthoxy)-2-butanol hydr~
chloride, M.P. 138-139 C.
.~' ' 21~ 2~
IThe l-chloro-3-methyl-3-(naphthoxy)-2-butanol used as starting material may be pre-pared as follows.
A solution of 68 parts of alpha-(l-naphthoxy)-isobutyric acid in 450 parts of chloro-form and 53 of thionyl chloride is heated under reflux for 3 hours, and then the chloroform and the excess of thionyl chloride are evaporated. The residual gum is heated under reflux together with 600 parts of petroleum ether (B.P. 60-80 C.) and 50 parts of active carbon for 15 mi-nutes. The mixture is cooled to ambient temperature and then filtered. The filtrate is evapoqated to dryness, and there is thus obtained alpha-(l-naphthoxy)-isobutyrylchloride as an oil.
A solution of 70 parts of alpha-(l-naphthoxy)-isobutyrylchloride in 200 parts of ether is treated with an excess of diazomethane in ether at 0 C. for 24 hours, and then the ether and the excess of diazomethane are evaporated. The residual gum is dissolved in 250 parts of ether, and hydrogen chloride gas is passed into the solution at 0 C. until the solution is saturated.
The solution is stirred and 300 parts of ice are added gradually. The mixture is se~arated and the ethereal solution is washed successively three times with 100 parts of water each time, three times with 150 parts of 10% sodium carbonate solution each time and finally three times with 100 parts of water each time. The ethereal solution is dried with anhydrous magnesium sul-phate and then evaporated.10 parts of the residue are dissolved in 80 parts of methanol, the s~
lution is stirred, and S parts of sodium borohydride are added during 45 minutes at 0 C. After 12 hours the methanol is evaporated and the residue is shaken together with 30 parts of ether and 20 parts of water. The mixture is separated, the ethereal solution is dried with anhydrous magnesium sul-phate and then evaporated to dryness. There is thus obtained l-chloro-3-me-thyl-3-(1-naphthoxy)-2-butanol as an oil.
The process of exarnple 13 is repeated using 40 parts of t-butylarnine in place of 40 parts of isopropylamine. There is thus obtained l-t-butylamino-3-methyl-3-(1-naphthoxy)-2-butanol hydrochloride, M.P. 219-220 C.
The procedure of example 13 is repeated using 8 parts of 1-chloro-3-(1-naphthoxy)-1-butanol in place of 8 parts of 1-chloro-3-methyl-3-(1-naphthoxy)-2-butanol. There is thus obtained t-isopropylamino-3-(1-naphthoxy)-2-butanol hydrochloride, M.P. 158-159C.
The l-chloro-3-(1-naphthoxy)-2-butanol used as starting material may be obtained as follows:
A solution of 20 parts of alpha-(l-naphthoxy)-propionic acid in 300 parts of chloro-form and 16,5 parts of thionyl chloride is heated under reflux for 3 hours, and then the chloro-form and the excess of thionyl chloride are evaporated. The residual oil 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, and then the ether and the excess ~ 2~0922~
of diazomethane are evaporated. The residual gum is dissolved in 150 parts of ether, and then hydrogen chloride gas is passed into the solution at 0 C. until the solution is saturated. The solution is stirred and 100 parts of ice are added gradually. The mixture is separated and the ethereal solution is washed successively three times with 50 parts of water each time, three times with 50 parts of 10% sodium carbonate solution each time, and finally three times with 50 parts of water each time. The ethereal solution is dried with anhydrous magnesium sulphate and then evapoMted to give chloromethyl l-(l-naphthoxy)ethyl ketone, M.P. 70-71 C. rcrys-tallised from petroleum ether (B.P. 60-80 C.)].
15 parts of chloromethyl l(l-naphthoxy)-ethyl ketone are dissolved in 200 parts of methanol, the solution is stirred at 0 C., and 7,5 parts of sodium borohydride are added during 45 minutes. After 12 hours the methanol is evapoMted and the residue is shaken together with 50 parts of ether and 30 parts of water. The mixture is separated, and the ethereal solution is dried with anhydrous magnesium sulphate and then evapoMted to dryness. There is thus ob-tained l-chloro-3-(1-naphthoxy)-2-butanol as an oil.
A solution of 1,25 parts of l-isopropylamino 3-(1-naphthoxy)2-propanol and 1 part of acetic anhydride in 10 parts of acetic acid is kept at ambient temperature for 18 hours, and is then added to a mixture of 50 parts of ice and 10 parts of 11 N-ammonium hydroxide solution.
The aqueous phase is decanted, and as much as possible of the residue is dissolved in 2 N-hydrochloric acid at 0 C. The solution is basified with 2 N-sodium hydroxide solution and then extracted with 50 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate, and filtered. To t}!e filtrate there is added a saturated solution of oxalic acid in ether unti1 precipitation is substantia11y complete. The mixture is filtered an the solid residue is crys-tallised from ethanol. There is thus obtained l-isopropylaminomethy1-2-(1-naphthoxyethyl acetate as its hydrogen oxalate, M.P. 202-204 C. In place of the oxalic acid there may be used hydrogen chloride and in a similar manner there is obtained l-iso-propylaminomethyl-2-(1-naphthoxy)-ethyl acetate as its hydrochloride, M.P. 17~171 C. (c~ysta11ised from a mixklre of ethanol and ethyl acetate).
A mixture of 2,95 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochlo-ride and 6 parts of benzoyl chloride are heated at 100 C. for 6 hours. The mixture is cooled, and there are then added 50 parts of ether. The mixture is kept at ambient temperature for 3 days and is then filtered. The solid residue is washed with ether, and crystallized from 25 parts of benzene. There is thus obtained l-isopropylaminomethyl-2-(1-naphthoxy)ethyl benzoate as its hydrochloride, M.P. 13~132 C.
. . , ,~. - .. . . . ., ., .. : : , . : : .. : . .... . :
2 parts of sodium borohydride are added during 10 minutes to a stirred solution of 2 parts of 1-(4-acetyl-1-naphthoxy)-3-isopropylamino-2-propanol in 80 parts of methanol at 0 C. for 1 hour and then poured onto 100 parts of ice, acidified with 2 N-hydrochloric acid, and filtered. The filtrate is basified with 2 N-sodium hydroxide solution and extracted with 500 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate and then fil-tered. To the filtrate there is added a saturated solution of oxalic acid in ether until precipitation is substantially complete. The mixture is filtered, and the solid residue is crystallised from a mixture of ethanol and ether. There is thus obtained 1-(4-alpha-hydroxy-ethyl-1-naphtoxy)-3-isopropylamino-2-propanol hydrogen oxalate, M.P. 146-147 C. with decomposition.
A solution of 0,77 part of 1-isopropylaminomethyl-2-(1-naphthoxy)-ethyl acetate hy-drochloride in 16 parts of methanol is treated with 3,5 parts of N-sodium hydroxide at ambient temperature, and after 1 hour the methanol is evaporated under reduced pressure. The residue is shaken together with 20 parts of ether and 10 parts of N-hydrochloric acid. The mixture is separated and the ethereal solution is washed with water, dried over anhydrous magnesium sulphate and then evaporated to dryness. The residue is crystallised from a mixture of acetate and light-petro1eum (B.P. 40-60 C.), and there is thus obtained N-acetyl-l-isopropylamino-3-(l-naphthoxy)-2-propanol, M.P .91 C.
A solution of 29,5 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochlo-ride in 300 parts of water is added to a solution of 43,2 parts of disodium l,l'-methylene-bis-(2-hydroxy-3-naphthoate) in 4000 parts of water. The mixture is filtered and the solid residue is washed with water and dried. The solid is crystal-lised from ethanol, and there is thus ob-tained di-[l-isopropylamino-3-~1-naphthoxy)-2-propanol] 1,1'-methylene-bis-(2-hydroxy-3-naphthoate), M.P. 212 C.
A solution of 1,3 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol in 25 parts of ethyl acetate is added to a solution of 0,7 part of benzoic acid in 5 parts of ether. The mixture is filtered and the solid residue is washed with ether and dried. There is thus obtained l-isopro-pylamino-3-(1-naphthoxy)-2-propanol benzoate, M.P.143-144 C. (crystallised from wate~).
By substituting 0,96 part of beta-naphthoic acid foq the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol beta-naphthoate, M.P 132 C. (crystallised from a mixture of cyclohexane and ethanol).
, .. .. ., .. .. . ..... ~ . . . . . . . . .. . . . ~
--" 2109224 ,9 By substituting 0,98 part of 0-acetoxybenzoic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol 0-acetoxyben-zoate, M.P. 122-124 C. (crystallised from ethyl acetate).
By substituting 0,7 part of adipic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-iso-propylamino-3-(1-naphthoxy)-2-propanol adipate, M.P. 145-147 C.
(crystallised from a mixture of ethyl acetate and ethanol).
By substituting 0,6 part of maleic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol maleate, M.P. 145-146 C.
(crystallised from a mixture of ethyl acetate and ethanol).
By substituting 0,62 part of oxalic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol oxalate, M.P. 180-182 C.
(crystallised from a mixture of methanol and ethyl acetate).
EXA~IPLE22 To a stirred solution of 10 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hy-drochloride in 100 parts of water there is added a suspension of 100 parts of a sulphonated polystyrene resin ["Zeo Karb" 225 (SCR) 3 UZeo Karb" is a trademark] in the sodium forrn in 400 parts of water. The mixture is stirred for 60 minutes at ambient temperature and is then fil-tered. The solid residue is washed with water and dried at ambient temperature. There is thus obtained a complex salt of l-iso-propylamino-3-(1-naphthoxy)-2-propanol with the sulpho-nated polystyrene resin which has a base content of 9% .
AMINES. ESPECIALLY INTERESTING IN CELL-MEDIATED ~MUNITY. FOR EXAM-PLE AGAINST VIRAL INFECTIONS
The present invention concerns the ~herapeutic use in man (and in animals with neuroimmune regulation analogous to that in man) of homocyclic compounds and more exactly of naphtha-lene derivatives as medicament with immunoactivating activity, which are especially interesting for cellular immunity, for example for the treatment or prophylaxis of viral infections, certain immunodeficient diseases and for antitumoral therapy. Immunoactivation ist defined as facili-tated activation of the immune system in presence of foreign antigen. Animals with neuroim-mune regulation analogous to that in man are those with inhibitory control of the immune sys-tem by hypothalamic centres of the CNS (nucleus paraventricularis) via ~e hypothalamo-adre-nocortical axis and the autonomic nervous system, especially the sympathetic nervous system.
This immunoactivating activity is generated by blockade of B-2 receptors in the central nervous system (CNS) and of cells of the immune system, which facilitates activation of biochemical functional pathways in the cell via blockade of the cAMP-PKA-pathway, which is the only physiological inhibitory pathway in leukocytes, thus imitating the functional regulation of the immune system by the nervous system and the inhibitory inverse regulation of immune activity by the permanent tonus of the sympathetic nervous system. Consequently, the function of the immune system is enhanced, because pathways activating the specific functions of leukocytes are not blocked any more. For example, immune response to a recall antigen of persons infec-ted by HIV was enhanced by 3 to 10 times when the cAMP-PKA-pathway was blocked phar-macologically. Only B-2 blocking drugs with minimal ISA activity and excellent penetration into the CNS are capable of producing sufficient immunoactivating activity.
The advantages of the claimed use of these compounds are that they normally are very well to-lerated in contrast to other immunopotentiating agents (e.g. BCG or levamisol), that they easi-ly penetrate the CNS, where they develop equally their immunoactivating activity in the im-mune cells of the CNS, for example microglia and astroglia. Consequently the possibility to use their immunoactivating activity is a very surprising result of recent scientific research and is an exceptional progress for the therapy for example of immunodeficient diseases or in any the-rapy where the function of the immune system has to be enhanced (e.g. immunodeficient &sea-ses, viral infections and tumours), because until now there has been no such therapy, espe-cially not one active in the CNS.
Accor&ng to the invention we provide the immunoactivating effect of naphthalene derivatives of the formula:
~o.CR3R4.CHoH.CHR5 NRlR2 -- ~10~224 wherein Rl stands for hydrogen or an alkyl, cycloalkyl alkenyl, aralkyl or alkanoyl radical, any of which may optionally be substituted. R2 stands for hydrogen or an alkyl, cycloalkyl, alke-nyl, alkynyl or aralkyl radical, any of which may optionally be substituted, or Rl and R2 are joined together with the adjacent nitrogen atom to form a heterocyclic radical optionally substi-tuted, wherein R3, R4 and Rs, which may be the same or different, stand for hydrogen or alkyl radicals, and wherein the naphthalene nucleus may optionally bear one or more additional sub-stituents P and Q, and the esters thereof, and the salts thereof, but excluding l-amino-, l-n-propylamino-, l-n-butylamino-, l-di-ethylamino-, l-di-n-propylamino-, l-di-isopropylamino-, l-di-n-butylamino-, l-morpholino- and l-piperidino-3-(2-naphthoxy)-2-propanol, and 1-(1-chloro-2-naphthoxy)-3-piperidino-2-propanol, and the esters thereof, and the salts thereof.
A preferred group of compounds comprises those of the said naphthalene derivatives wherein Rl, R3, R4 and Rs stand for hydrogen, R2 has the meaning stated above, and wherein the naphthalene nucleus may optionally bear one or more additional substituents, and the esters thereof, and the salts thereof, but excluding l-amino-, l-n-propylamino-and l-n-butylamino-3-(2-naphthoxy)-2-propanol, and the esters thereof, and the salts thereof.
As a suitable value for R 1 there may be mentioned, for example, an alkyl or hydroxyal-kyl radical of not more than S carbon atoms, for example the methyl ethyl, s-butyl or 2-hydro-xyethyl radical, or an ara1kyl radical of not more than 10 carbon atoms, for example the acetyl radical.
As a suitable value for R2 there may be mentioned, for example, a branched chain allyl radical of not more than 20 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, l-methyloctyl or l-methylhexadecyl radical, or an alkyl radi-cal of not more than 10 carbon atoms bearing one or more hydroxy radicals i.e. hydroxy-branched-chain-alkyl, or substituted amino radicals, for example alkylamino, di-alkylamino or heterocyclic radicals, for example alkylamino or dialkylamino radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 ring atoms, for example the dimethylamino or morpholino radical, or alkoxy radicals, for example alkoxy radicals of not more than S carbon atoms, for example the meth-oxy or n-propoxy radical, or alkoxyalkoxy radica1s, for example alkoxyalkoxy radicals of not more than 10 carbon atoms, for example the 2-n-butoxy-ethoxy radical, or aryloxy radicals, optiona11y substituted, for example aryloxy radicals of not more than 10 carbon atoms, optio-nally substituted, for example the 4-chlorophenoxy or 2,4-&chlorophenoxy ra&cal. Alterna-tively, R2 may stand for an aralkyl radical of not more than 15 atoms, optiona11y substituted with, for example, one or more alkoxy radicals, for example alkoxy ra&cals of not more than S
carbon atoms, for example the methoxy radical. Thus specific values for R2 when it stands for a substituted alkyl ra&cal or a substituted or unsubstituted aralkyl radical are, for example, the 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 3 ~109224 2-hydroxy- 1, I -dimethylethyl, 2-n-propoxyethyl, 3-methoxypropyl, 2-(2-n-butoxyethoxy)-ethyl, 3-morpholinopropyl, 3 -dimethylaminopropyl, 2-(4-chlorophenoxy)-ethyl, 2-(2,4-dichlorophenoxy) -ethyl, benzyl, l-methyl-2-phenylethyl, 1 -methyl-3-phenylpropyl, 1, 1-dimethyl-3-phenylpropyl, 4-methoxybenzyl, 3-(4-methoxyphenyl)-1-methylpropyl or 2-(3,4-dimethoxyphenyl)-ethyl radical.
Alternatively, R2 may stand for a cycloalkyl, alkenyl or alkynyl radical of not more than 10 carbon atoms, for example the cyclopentyl, allyl or l-methyl-2-propynyl radical.As a suitab1e value for the group -NRIR2 when it stands for a heterocyclic radical there may be mentioned, for example, a 5- or 6-membered nitrogen-containing heterocyclic radical, optionally substituted, for example a pyrrolidino-piperidino or morpholino radical, any of which may optionally be substituted by one or more alkyl radicals of not more than 5 carbon atoms, for example the methyl radical.
As a suitable value for R3, R4, or Rs when it stands for an aL~yl radical there may be mentioned, for example, an alkyl radical of not more than 5 carbon atoms, for example the me-thyl radical.
As suitable optional additional substituents P and Q in the naphthalene nucleus there may be mentioned, for example, halogen atoms, for example chlorine or bromine atoms, or al-kyl or hydroxyalkyl radicals of not more than 5 carbon atoms, for example the methyl or 1-hydroxyethyl radical, or acyl radicals, for example alkanoyl radicals of not more than 6 carbon atoms, for example the acetyl radical, or sulphamoyl radicals, optionally substituted, for example dialkylsulphamoyl radicals of not more than 10 carbon atoms, for example the dime-thylsulphymoyl radical.
Particularly valuable naphthalene derivatives of the present invention are, for example, l-isopropylamino-3-(1-naphthoxy)-2-propanol, l-t-butylamino-3-(1-naphthoxy)-2-propanol, 1-(2-hydroxy-1,1-dimethylethylamino)-3-(1-naphthoxy)-2-prapanol.
l-(l-methyl-3-phenylpropylamino)-3-(1-naphthoxy)-2-propanol, l-s-butylamino-3-(1-naphthoxy)-2-propanol, 1-( 1-methyloctylamino)-3-( 1-naphthoxy)-2-propanol, 4 ~092~
1-(1,1 -dimethyl-3-phenylpropylamino) -3-(1 -naphthoxy)-2-propanol, 1 -allylamino-3-( 1-naphthoxy)-2-propanol, I ~yclopentylamino-3-( 1 -naphthoxy)-2-propanol l-isopropylamino-3-(4-methyl-1-naphthoxy)-2-propanol and 1-(3-(4-methoxyphenyl)- 1-methylpropylamino)-3-(-naphthoxy)-2-propanol, and the esters thereof, and the salts thereof.
As suitable esters of the said naphthalene derivatives there may be mentioned, for ex-ample, O-es~ers derived from acids of the formula R6.COOH wherein R6 stands for an alkyl, alkenyl or aryl Mdical, optionally substituted, for example an alkyl or alkenyl radical of not more than 10 carbon atoms or an aryl radical of not more than 10 carbon atoms, for example the methyl, pentadecyl, heptadecyl, heptadeca-8-enyl or phenyl radical.
As suitable salts of the said naphthalene derivatives there may be mentioned acid-addi-tion salts, for exarnple salts derived from inorganic acids, for example hydrochlorides, hydro-bromides, phosphates, or sulphates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naphthoates, o-acetoxybenzoates, adipates, maleates or 1 ,1-methylene-bis-2-hydroxy-3-naphthoates or salts with acidic synthetic resins, for example sulphonated polystyrene resins, for example "Zeo-Karb" 225 ("Zeo Karb"
is a trademark). Relatively insoluble salts, for example the 1,1'-methylene-bis-2-hydroxy-3-naphthoates are useful in that they afford prolonged blood levels of the medicarnent.
A process for the manufacture of the naphthalene derivatives comprises the interaction of a halogeno compound of the formula:
~o.CR3R4.CHoH.CHRs.X
wherein X stands for a halogen atom, R3, R4 and Rs have the meanings stated above, and the naphthalene nucleus may optionally bear one or more additional substituents, with an amine of the formula NHRlR2, wherein Rl and R2 have the meanings stated above.
As a suitable value for X there may be mentioned, for example, a chlorine or bromine atom. The said interaction may be conveniently accelerated or completed by the application of heat.
Another process for the manufacture of the naphthalene derivatives comprises the inter-action of an epoxide of the fo~nula:
--` 2~22~
~o.CR3R4. CH--CHRs wherein R3, R4 and Rs have the meanings stated above and the naphthalene nucleus may optio-nally bear one or more additional substituents, with an amine of the formula NHR IR2, wherein Rl and R2 have the meanings stated above.
This process may be carried out in a diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.
Another process for the manufacture of ~e naphthalene derivatives com~ises the inter-action of a naphthol derivative of the formula:
~OH
wherein the naphthalene nucleus may optionally bear one or more additional substituents, with a compound of the formula:
X.CR3R4.CHoH.CHRs.NRlR2 or R3R4C--CH.CHRs.NRlR2 wherein Rl, R2, R3, R4, Rs and X have the meanings stated above.
The interaction involving a naphthol derivative and a halogeno derivative may be conv~
niently carried out in the presence of an acid-binding agent; alt~natively, an aL1~ali metal deriva-tive of the naphthol derivative, for example the sodium or potassium derivative, may be used as starting material.
The process for the manufacture of those of the naphthalene derivatives wherein Rl stands for hydrogen and R2 stands for a radical of the formula -CHR7R8, wherein R7 stands for hydrogen or an alkyl, cycloalkyl, aLI~enyl, alkynyl, aryl ~r arallyl radical, optionally substi-tuted, and R8 stands for an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optional-ly substituted, or wherein R7 and R8 are joined togeterh with the adjacent car'oon atom to form a cycloalkyl radical, optionally substituted, which comprises the in~action of an amino deriva-tive of the formula:
r~ :
6 2~09224 :~:
~} o.CR3R4.CHoH.CHRs.NH2 wherein R3, R4 and R5 have the meanings stated above and the naphthalene nucleus may optionally bear one or more additional substituents, with a carbonyl compound of the fo~rnula R7.CO.R8, wherein R7 and R8 have the meanings stated above, under reducing conditions.
Suitable reducing conditions are those provided by the presence of hydrogen and a hy-drogenation catalyst, for example platinum, in an inert diluent or solvent, for example ethanol, and/or, in the case where, in the said carbonyl compound used as starting material, R7 stands ~or an alkyl, cycloalkyl, alkenyl, aLkynyl, aryl or aralkyl radical, optionally substituted, in an excess of the carbonyl compound used as starting material; or by the presence of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example aqueous methanol, and /or, in the case where, in the said carbonyl compound used as starting material, R7 stands for an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optionally substituted, in an excess of the carbonyl compound used as starting material; or by the presence of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example aqueous methanol, and/or in an excess of the carbonyl compound used as starting material. It is to be understood that, in the case where R7 or R8 or both stands or stand for an alkenyl or alkynyl radical, optionally substituted, if it is desired that this radical is not reduced to the corresponding alkyl radical or substitued alkyl radical during this process, suitable reducing conditions, for example those provided by the use of sodium borohydride, must be used. It is to be further understood that the amino derivatives used as starting materials may be generated in situ, for example by reduction of the corresponding alpha-diazoketone, alpha-azidoketone and -alcohol, cyanhydrin or acyl cyanide.
A process for the manufacture of those of the naphthalene derivatives wherein stands fw hydrogen comp~ises the hydrogenolysis of a compound of the formula:
~O.CR3R4.CHOH.CHR5.NR2R9 wherein R2, R3~ R4 and Rs have the meanings st~ted above, Rg stands for a hydrogenolysable radical, and the naphthalene nucleus may oq~tionally bear one or more additional substituents.
As a suitable value for R9 there may be mentioned an alpha-aralikyl radical of not more tha 10 carbon atoms, for example the benzyl radica]i. The said hy~ogenolysis may be effected ~,~" ~ t ' ~
~` ?;' 210922~
by catalytic hydrogenation, for example hydrogenation in the presence of a platinum or palla-dium-on-carbon catalyst, conveniently in an inert diluent or solvent, for example ethanol.
Another process comprises the manufacture of those of the naphthalene derivatives wherein the naphthalene nucleus bears as substituent a hydroxyalkyl radical, which comprises the reduction of the corresponding compound wherein the naphthalene nucleus bears as substi-tuent the corresponding oxoalkyl radical. As a suitable oxoalkyl radical there may be men-tioned, for example, an oxoalkyl radical of not more than 20 carbon atoms, for example an al-kanoyl radical of not more than 20 carbon atoms, for example the acetyl radical. As a suitable reducing agent there may be mentioned, for example, sodium borohydride.
The process for the manufacture of the esters of 3-naphthyloxy-2-hydroxy-propyl-amines comprises the acylation of the corresponding naphthalene derivative. As suitable acyla-ting agents there may be mentioned, for example, acyl halides or acid anhydrides, for example acetic anhydride or benzoyl chloride. The acylation may be carried out in a diluent or solvent, which, in the case where an acid anhydride is used, may conveniently be the acid from which the anhydride is derived.
The process for the manufacture of those naphthalene derivatives wherein R I stands for an alkanoyl radical comprises the isomerisation of an ester of the formula:
~.CR3R4.CH(o.CoRI0) .CHRs.NHR2 wherein R2, R3, R4 and Rs have the meanings stated above and Rl stands for an alkyl radical, for example an alkyl radical of not more than 5 carbon atoms, and wherein the naphthalene nucleus may optionally bear one or more additonal substituents.
The isomerisation may be effected by the interaction of the ester with a strong base, fo~
example an alkali metal hydroxide, for example sodium hydroxide, conveniently in a diluent or solvent, for example, methanol.
The parts by weight of the following examples (but not limited to these) are:
A mixture of 4,4 parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 16 parts of iso~ropylamine is heated in a sealed vessel at 70-80 C. for 10 hours. The vessel is cooled and to the contents there are added S0 parts of ether. The aqueous phase is decolourised with carbon, and then ad-ded to 50 parts of 1 N-sodium hydroxide solution at 0 C. The mixture is filtered. The solid re-sidue is washed with water, dried, and crystallised from cyclohexane. There is thus obtained 1-isopropylamino-3-(1-naphthoxy)-2-propanol, M.P. 96 C.
~` 210922~
The above procedure is repeated using the appropriate chloruhydrins and amines as starting materials except that a reaction temperature of 90-100 C. is use~ In a similar manner there are obtained the compounds listed in the following table. The hydrochlorides and oxalates listed are obtained by dissolving the base in ether, adding an ethereal solution of hydrogen chloride or oxalic acid, filtering the mixture, washing the sohd residue with ether, and drying.
The picrates listed are obtained by dissolving the base in ethanol, adding an ethanolic solution of picric acid, filtering the mixture, washing the solid residue with ethanol, and drying.
O.CH2.CHOH.CH2.NRlR2 [~
Rl R2 Additional Base or salt M.P.(C) Solvent(s) for recri-substituents stallisation on the naphtha- .
Iene nucleus H t-butyl - oxalic acid 230 ethanol (aque.) H 2-tydroxy-1,1- - base 148 ethanol dimethyl-ethyl H isobutyl - chlorhydrate 166-168 water H ethyl 4-chloro oxnlic acid 186-188 ethanol 9 ~10~22~
Rl R2 Additional Base or salt M.P.(C) Solvent(s~ for recri-substituents stallisation on the naphtha-lene nucleus __ _ _ __ H ethyl - base 109-110 cyclohe~ane H s-butyl - base 60,5-61 he~ane methyl methyl - base 82-83 petrol-ether 60 C/
methyl isopropyl - picrate 120-122 ethanol H 2-hydro~y- - base 84 he~ane ethyl ethyl 2-hydro~y- - picrate 157-158 ethanol cthyl 2-hydroxy- 2-hydroxy- - picrate 161-163 ethanol ethyl ethyl H 3-morpholino- - base 89-91 cyclohexane propyl H 2-(3,4-dimeth- - oxalic acid 309 water/propanol o~yphenyl)ethyl H isopropyl 4-methyl base 90-91 cyclohe~ane H isopropyl 5-dimethyl- chlorhydrate 190-193 butano1 sulfamoyl H isopropyl 5,8-dichloro base 115 cyclohe~ane s-butyl s-butyl - o~alic acid 160-161 ethanol H 2-propo~cy- - chlorhydrate 105-107 ethyl-acetate ethyl H benzyl - chlorhydrate 169 ethyl-acetate/etha- nol :~
H allyl - chlorhydrate 148 ethyl-acetate/etha- nol : ~`
By the use of l-chloro-3-(2-naphthoxy)-2-propanol in place of the 1-chloro-3-( l-naph-thoxy)-2-propanol used in example 1 there is obtained similarly 1-isoprowl-amino-3-(2-naphtoxy)-2-propanol, M.P. 138-140 C. (crystallised from ethanol). .
By the use of t-butylamine in place of the isopropylamine used in example 2 there is obtained similarly l-t-bulylamino-3-(2-naphthoxy)2-propanol, M.P. 120 C. (from cyclohe-xane).
21~922~
A mixture of 2,3 parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 2,6 parts of 1-methyl-3-phenylpropylamine is heated at 90-100 C. for 10 hours. The mixture is then cooled, diluted with S0 parts of water, acidified with 2 N-hydrochloric acid and filtered. The solid resi-due is shaken with 50 parts of ether. The mixture is separated, and the ethereal phase is dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is dissolved in S0 parts of ethyl acetate, and a solution of hydrogen chloride in ether is added. The mixture is fil-tered, and the solid residue is washed with ethyl acetate, dried, and crystallised from a mixture of methanol and ethyl acetate. There is thus obtained l-(methyl-3-phenylpropylamino)-3-(1-naphthoxy)2-propanol hydrochloride, M.P. 162-164 C.
A mixture of 1.84 parts of 1,2-epoxy-3-naphthoxy-propane and 1,7 parts of isopropyl-amine is heated under reflux for 16 hours. The mixture is acidified with 25 parts of 2 N-hydro-chloric acid and washed with 50 parts of ether. The aqueous solution is then added to 50 parts of 2 N-sodium hydroxide solution at 0 C., and the resulting mixture is filtered. The solid resi-due is washed with water, and dried, and then crystallised from cyclohexane. There is thus ob-tained l-isopropylamino-3-(1-naphthoxy)-2-propanol, M.P. 96 C.
The base may be converted into the hydrochloride as follows:
4,65 parts of the base are dissolved in 30 parts of warm acetone. To the warrn solution there are added 2 parts of 10 N-hydrochloric acid. The mixture is allowed to cool, and is then fil-tered. The solid residue is washed with acetone and then dried. The solid is crystaJlised from propanol, and there is thus obtaines l-isopropylamino-3-(1-naphthoxy)-2-propanol hydro-chloride, M.P. 163 C.
The above procedure is repeated using the appropriate epoxy-naphthoxypropanes and amines as starting materials, except that various reaction temperatures and times are used in a similar manner there are obtained the compounds listed in the following table. The hydrochlo-rides, oxalates and picrates are obtained by the general procedures described in example 1.
~.CH2.CHOH.CH2.NRIR2 i . -.. - ., , ... . ., ,.. ,. . . . .. . : . .... ..
tl 21~922~
Rl R2 Position of Addhional sub- React.- Duration Base or M.P. Sol~ent(s) for substituent stituents on the temp. of react. salt (C) recristallisation naphthalene nuc- (C) (hours leus __ _ _ ethyl butyl I - 100 1 o:calic 100 ethyl-ethanol/acetate acid H 2-hydro` 1 - 100 1 base 115 benzene xy-1-me-thylethyl H 3-meth- 1 - 100 1 oxalic 148- propanol oxypropyl acid 149 H 2-(2-but- 1 100 1 oxalic 138 water o~yetho~y)- acid ethyl H 2-(2,~di- 1 - 100 1 base 115 petrol-ether chloro-phen- 100 C/120 C
o~y)-ethyl H 2-(2,4-di- 1 - 100 1 base 115 petrol-ether 100 C/
chloro-phen- 120 C
o~cy)-ethyl ethyl 2-(4-chloro- 1 - 100 1 o~alic 149- water pheno~y)- acid 150 ethyl H 3-dimethyl- 1 - 20 72 dichlor- 234- methanol amino-pro- hydrate 235 H 1,1-dimethyl- 1 - 100 1 oxalate 210- 2-etho~y-ethanol 3-phenyl-pro-pyl benzyl 1-methyl-2- 1 - 100 1 picrate 166- propanol 2-propynyl 1 68 H isopropyl 1 2-chloro 20 16 chlor- 160- ethyl-ethanol/acetate hydrate 161 H isopropyl 1 4-acetyl 20 16 base 95 petrol-ether H isopropyl 1 2,4-dichloro 30 3 chlor- 194- ethyl-propsnoUacetate hydrate 195 H 2-hydro~:y- 2 - 100 1 base 80-81 petrol-ether l,1-dimethyl- 100 C/120 C
ethyl H allyl 2 - 83 1 chlor- 182 ethyl-ethanol/acetate hydrate '~ 2las22~
2,5 parts of 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride is added to a mixture of 100 parts of 2 N-sodium hydroxide solution and 200 parts of ethyl-acetate. The mixture is shaken and separated. The ethyl acetate layer is dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is dissolved in 80 parts of acetone, and 0,5 part of plati-num oxide is added. The mixture is shaken at ambient temperature and 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 ethereal hydrochloric acid is added until no more solid is precipitated. The mixture is filtered. The solid residue is washed with ethyl acetate, and then dried. The solid is crystallised from n-propanol and there is thus obtained l-isopropyl-amino-3-(1-naphthoxy)-2-propanol hydrochloride. M.P. 163-164 C.
By using a mixture of 2,8 parts of heptyl methyl ketone and 40 parts of ethanol in place of the 80 parts of acetone there is obtained similarly 1-(1-methyl-octyl-amino)-3-(1-naphth-oxy)-2-propanol hydrochloride, M.P. 116-118 C. (crystallised from ethyl acetate).
A mixture of 2,5 parts of 2-bromo-4-(naphthoxy)-3-butanol and 10 parts of isopropyl-amine is heated in a pressure vessel at 100 C. for 10 hours. The mixture is then evaporated under reduced pressure and the residue is acidified with 25 parts of 2 N-hydrochloric acid.
Carbon is added, and the mixture is stirred and then filtered. The filtrate is added to S0 parts of 2 N-sodium hydroxide solution, and the resulting mixture is then extracted with S0 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate, and then filtered and the filtrate is acidified with ethereal hydrochloric acid. The resulting mixture is filtered, and the solid residue is crystallised from a rnixture of ethyl acetate and ethanol. There is thus obtained l-isopropy1amino-4-(1-napht~xy)-3-butanol hydrochloride, M.P. 210-212 C.
The 2-bromo-4-(naphthoxy)-3-butanol used as starting material may be obtained as fol-lows:
To a stirred solution of 3 parts of 2-bromo-4-(1-naphthoxy)-3-butanone in 20 parts of methanol at -5 C. there is added 0,S part of sodium borohydride. The mixture is stirred for 2 hours at 0 C., and is then poured into 100 parts of ice. There are then added 50 parts of ether, and the resulting mixture is separated. The ethereal phase is dried over anhydrous magnesium sulphate and then evaporated. The residue consists of 2-bromo-4-(1-naphthoxy)-3-butanol. 2-bromo-4-(1-naphthoxy)-3-butanone itself may be obtained as follows:
To a stirred solution of i3 parts of diazoethane in 300 parts of ether at -10 C. there is added a solution of 10 parts of l-naphthoxyacetyl chloride in 150 parts of ether. The mixture is stirred at 0 C. for 3 hours, and then at ambient temperature for 18 hours. The mixture is then stirred and cooled to -5 C., and 10 parts of 40% hydrobromic acid ~re added. The mixture is stirred at -5 C. foq 30 minutes. The mixture is separated, and the etheral phase is dried over anhydrous magnesium sulphate. The mixture is filtered and the filtrate is evapo~ated under re--~` 210~22~
duced pressure. The residue is extracted with 20 parts of cyclohexane, and the extract is fil-tered. The filtrate is evapoMted under reduced pressure; the residue consists of 2-bromo-4-(1-naphthoxy) -3 -butanone.
A solution of 0,46 part of sodium in 20 parts of ethanol is added to 2,42 parts of 1-chloro-3-(N-benzyl-N-isopropylamino)-2-propanol, and to this mixture 1,44 parts of l-naph-thol are added. The mixture is heated under pressure in a sealed tube at 100 C. during 10 hours, and then evaporated to dryness under reduced pressure. The residue is stirred together with 50 parts of 2 N-hydrochloric acid and 50 parts of ether. The mixture is separated and the aqueous layer is basified by the addition of 2-N-sodium hydroxide solution. The aL'Yaline solu-tion is extracted three times with 100 parts of ether. The combined ethereal extracts are washed twice with 50 parts of water, dried over anhydrous magnesium sulphate, and the ether is then removed by distillation. There is thus obtained l-N-benzyl-N-isopropylamino)-3-( l-naphth-oxy)-2-propanol, which, by means of the procedure described in example 1, may be converted into a picrate, M.P. 157-8 C., containing one molecule of water of crystallisation (crystallised from aqueous dimethylformamide). The fr~e base may be regenerated from the purified picrate as follows:
24 parts of the picrate are suspended in 100 parts of ethyl acetate, and this suspension is stirred together with 100 parts of 50% ammonia solution, until the extracts are practically colourless. The ethyl acetate solution is then washed twice with 50 parts of wate~, dried over anhydrous magnesium sulphate, and the ethyl acetate is then removed by distillation. There is thus obtained 1 -(N-benzyl-N-isopr~pylamino)-3-( 1 -naphthoxy)-2-propanol.
1 part of 1-(N-benzyl-N-isopropylamino)-3-(1-naphthoxy~-2-propanol is dissolved in 35 parts of ethanol. To the solution are added 2 parts of a saturated ethereal hydrogen chloride solution and 0,4 part of a 20% palladium on carbon cataly$. The mixture is shaken at ambient temperature and atmospheric pressure in an atmosphere of hydrogen until sufficient hydrogen has been absorbed to account for the hydrogenolysis of the benzyl group, and no further uptake of hydrogen is occurring. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from n-propanoI, and there is thus ob-tained l-iso propylamino-3-(1-naphthoxy)-2-propanol hydrochloride, M.P. 163-164 C.
A mixture of 1,25 parts of 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride, 1,34 parts of benzyl methyl ketone, 40 parts of ethanol and 0,1 part of platinum oxide is shaken in an atmosphere of hydrogen at ambient tempe~ature and atmospheric pressure until hydrogen ~ ~922~
absorption ceases. The mixture is filtered and the filtrate is evaporated to dryness under redu-ced pressure. 25 parts of acetone are added to the residue, and the resulting mixture is filtered.
The solid residue is washed with acetone, dried and crystallised from a mixture of ethanol and ethyl acetate. There is thus obtained l-(l-methyl-2-phenylethylamino)-3-(1-naphthoxy)-2-pro-panol hydrochloride, M.P. 186 C.
By using 1,25 parts of 2-(4-methoxyphenyl)-ethyl-methyl ketone in place of the 1.34 parts of benzyl methyl ketone there is similarly obtained 1-[3-(4-methoxy phenyl)-l-methyl-propylamino]-3-(naphthoxy)-2-propanol hydrochloride, M.P. 176-178 C. (crystallised from ethanol).
By using 0,84 part of cyclopentanone in place of the 1,34 parts of benzyl methyl ketone there is similarly obtained l-cyclopentylarnino-3-(1 -naphtoxy)-2-propanol hydrochloride, M.P.
808-809 C. (crystallised from ethanol).
By using 2,5 parts of 2-heptadecanone in place of the 1,34 parts of benzyl methyl ke-tone there is similarly obtained l-(l-methylhexadecylamino)-3-(1-naphthoxy)-2-propanol hy-drochloride, M.P. 105-106 C. (crystallised from ethyl acetate).
By using 1,36 parts of anisaldehyde in place of the 1,34 parts of benzyl methyl ketone there is similarly obtained 1-(4-methoxybenzylamino)-3-(1-naphthoxy)-2-propanol hydrochlo-ride, M.P. 190-192 C. with decomposition (~ystallised from ethanol).
A mixture of 2 parts of 1,2-epoxy-3-(2-naphthoxy)-propane and 5 parts of 1-methyl-3-phenylpropylamine is heated at 100 C. for 1 hour. The mixture is then cooled and stirred to-gether with 25 parts of 2 N-hydrochloric acid and 50 parts of ether. The ethereal and aqueous phases are decanted, and the residue is crystallised from a mixture of ethanol and ethyl acetate.
There is thus obtained l-(l-methyl-3-phenylpropylamino)-1-(2-naphthoxy)-2-propanol hydro-chloride, M.P. 174-176 C.
6,6 parts of 1-chloro-2-naphthol, 20 parts of epichlorohydrin and 0,1 part of piperidine are refluxed together for 6 hours. The mixture is then evaporated to remove unreacted epichlo-rohydrin. To the residue there are added 8 parts of iso-propylamine, and the mixture is heated under reflux for 10 hours. The mixture is then evaporated and the residue is heated together with 80 parts of petroleum ether (B.P. 80-100 C.). The solution thus obtained is cooled and filtered. The solid residue is washed with petroleum ether (B.P. 80~100 C.) and dried, and is then crystallised from petroleum ether (B.P. 8~100 C.). There is thus obtained l-(l-chloro~2-naphthoxy)-3-isopropylamino-2-propanol, M.P. 104 C.
By the use of S parts of l-methyl-2-naphthol in place of the 6,6 parts of 1-chloro-2-naphthol there may be obtained in a similar manner l-isopropylamino-3-(1-methyl-2-naphth-oxy)-2-propanol, M.P. 122 C. Lcrystallised from petroleum ether (B.P. 8~tO0 C.)].
-` 210g22~
A mixture of 0,3 part of 3-bromo-1-(1-naphthoxy)-2-propanol and 5 parts of isopro-pylamine is heated in a sealed vessel at 100 C. for 10 hours. The vessel is cooled, and to the contents there are added 10 parts of 2-N-hydrochloric acid. The mixture is filtered and the filtrate is basified with 2 N-sodium hydroxide solution and shaken together with 25 parts of ether. The mixture is separated and the ethereal phase is dried over anhydrous magnesiums sulphate and then filtered. The filtrate is evaporated to dryness. The residue consists of 1-isopropylamino-3-(1-naphth-oxy)-2-propanol, M.P. 96 C.
The 3-brom~l-(naphthoxy)-2-propanol used as starting material may be obtained asfollows: -A solution of 0,28 part of 3-bromo-1-(l -naphthoxy)-acetone and 5 parts of methanol is stirred and cooled to 0 C. whilst 0,25 part of sodium borohydride is added.
The mixture is tben stirred for a further 30 minutes at 0 C. The mixture is then poured onto ice, acidified with 2-N-hydrochloric acid and extracted with 20 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate and filtered, and the filtrate is evaporated to dryness. The residue consists of 3-bromo-1-(1-naphthoxy)-2-propanol. It possesses a cha-racteristic absorption band in the infrared at 3450 cm-l.
3-bromo-1-(1-naphthoxy) acetone itself may be obtained as follows:
A solution of 10 parts of l-naphthoxyacetyl chloride in 150 parts of ether is stirred and cooled to -5 to -10 C. whilst there is added during 30 minutes a solution of 11 parts of diawmethane in 300 parts of ether. The solution is stirred for 2 hours at -5 C. and then for 18 hours at ambient temperature. The solution is then stirred and cooled to -10 C. whilst there are added 10 parts of 11 N-hydrobromic acid. The mixture is then stirred for 30 minutes. The mixture is separated and the ethereal phase is dried over anhydrous magnesium sulphate and filtered. The filtrate is evaporated to dryness, and the residue is crystallised from cyclohexane. There is thus obtained 3-bromo-1-(1-naphthoxy) acetone, M.P. 92-94 C.
EXAMPLEi 13 A mixture of 8 parts of 1-chloro-3-methyl-3-(1-naphthoxy)-2-butanol and 40 parts of isopropylamine is heated in a sealed vessel at 100 C. for 10 hours. The excess of isopropyl-amine is evaporated and the residue is dissolved in 100 parts of N-hydrochloric acid. The solution is washed with ether, and 10 parts of 8 N-sodium hydroxide solution are then added to the aqueous acid solution. The mixture is extracted with 100 parts of ether and the ethereal extract is washed with water and then dried with anhydrous magnesium sulphate. ~e ethereal solution is evaporated to dryness. The residual gum is dissolved in 30 parts of ether, and ethe-real hydrogen chloride is added until the precipitation of solid is substantially complete. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ethyl acetate. There is thus obtained l-isopropylamino-3-methyl-3-(1-naphthoxy)-2-butanol hydr~
chloride, M.P. 138-139 C.
.~' ' 21~ 2~
IThe l-chloro-3-methyl-3-(naphthoxy)-2-butanol used as starting material may be pre-pared as follows.
A solution of 68 parts of alpha-(l-naphthoxy)-isobutyric acid in 450 parts of chloro-form and 53 of thionyl chloride is heated under reflux for 3 hours, and then the chloroform and the excess of thionyl chloride are evaporated. The residual gum is heated under reflux together with 600 parts of petroleum ether (B.P. 60-80 C.) and 50 parts of active carbon for 15 mi-nutes. The mixture is cooled to ambient temperature and then filtered. The filtrate is evapoqated to dryness, and there is thus obtained alpha-(l-naphthoxy)-isobutyrylchloride as an oil.
A solution of 70 parts of alpha-(l-naphthoxy)-isobutyrylchloride in 200 parts of ether is treated with an excess of diazomethane in ether at 0 C. for 24 hours, and then the ether and the excess of diazomethane are evaporated. The residual gum is dissolved in 250 parts of ether, and hydrogen chloride gas is passed into the solution at 0 C. until the solution is saturated.
The solution is stirred and 300 parts of ice are added gradually. The mixture is se~arated and the ethereal solution is washed successively three times with 100 parts of water each time, three times with 150 parts of 10% sodium carbonate solution each time and finally three times with 100 parts of water each time. The ethereal solution is dried with anhydrous magnesium sul-phate and then evaporated.10 parts of the residue are dissolved in 80 parts of methanol, the s~
lution is stirred, and S parts of sodium borohydride are added during 45 minutes at 0 C. After 12 hours the methanol is evaporated and the residue is shaken together with 30 parts of ether and 20 parts of water. The mixture is separated, the ethereal solution is dried with anhydrous magnesium sul-phate and then evaporated to dryness. There is thus obtained l-chloro-3-me-thyl-3-(1-naphthoxy)-2-butanol as an oil.
The process of exarnple 13 is repeated using 40 parts of t-butylarnine in place of 40 parts of isopropylamine. There is thus obtained l-t-butylamino-3-methyl-3-(1-naphthoxy)-2-butanol hydrochloride, M.P. 219-220 C.
The procedure of example 13 is repeated using 8 parts of 1-chloro-3-(1-naphthoxy)-1-butanol in place of 8 parts of 1-chloro-3-methyl-3-(1-naphthoxy)-2-butanol. There is thus obtained t-isopropylamino-3-(1-naphthoxy)-2-butanol hydrochloride, M.P. 158-159C.
The l-chloro-3-(1-naphthoxy)-2-butanol used as starting material may be obtained as follows:
A solution of 20 parts of alpha-(l-naphthoxy)-propionic acid in 300 parts of chloro-form and 16,5 parts of thionyl chloride is heated under reflux for 3 hours, and then the chloro-form and the excess of thionyl chloride are evaporated. The residual oil 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, and then the ether and the excess ~ 2~0922~
of diazomethane are evaporated. The residual gum is dissolved in 150 parts of ether, and then hydrogen chloride gas is passed into the solution at 0 C. until the solution is saturated. The solution is stirred and 100 parts of ice are added gradually. The mixture is separated and the ethereal solution is washed successively three times with 50 parts of water each time, three times with 50 parts of 10% sodium carbonate solution each time, and finally three times with 50 parts of water each time. The ethereal solution is dried with anhydrous magnesium sulphate and then evapoMted to give chloromethyl l-(l-naphthoxy)ethyl ketone, M.P. 70-71 C. rcrys-tallised from petroleum ether (B.P. 60-80 C.)].
15 parts of chloromethyl l(l-naphthoxy)-ethyl ketone are dissolved in 200 parts of methanol, the solution is stirred at 0 C., and 7,5 parts of sodium borohydride are added during 45 minutes. After 12 hours the methanol is evapoMted and the residue is shaken together with 50 parts of ether and 30 parts of water. The mixture is separated, and the ethereal solution is dried with anhydrous magnesium sulphate and then evapoMted to dryness. There is thus ob-tained l-chloro-3-(1-naphthoxy)-2-butanol as an oil.
A solution of 1,25 parts of l-isopropylamino 3-(1-naphthoxy)2-propanol and 1 part of acetic anhydride in 10 parts of acetic acid is kept at ambient temperature for 18 hours, and is then added to a mixture of 50 parts of ice and 10 parts of 11 N-ammonium hydroxide solution.
The aqueous phase is decanted, and as much as possible of the residue is dissolved in 2 N-hydrochloric acid at 0 C. The solution is basified with 2 N-sodium hydroxide solution and then extracted with 50 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate, and filtered. To t}!e filtrate there is added a saturated solution of oxalic acid in ether unti1 precipitation is substantia11y complete. The mixture is filtered an the solid residue is crys-tallised from ethanol. There is thus obtained l-isopropylaminomethy1-2-(1-naphthoxyethyl acetate as its hydrogen oxalate, M.P. 202-204 C. In place of the oxalic acid there may be used hydrogen chloride and in a similar manner there is obtained l-iso-propylaminomethyl-2-(1-naphthoxy)-ethyl acetate as its hydrochloride, M.P. 17~171 C. (c~ysta11ised from a mixklre of ethanol and ethyl acetate).
A mixture of 2,95 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochlo-ride and 6 parts of benzoyl chloride are heated at 100 C. for 6 hours. The mixture is cooled, and there are then added 50 parts of ether. The mixture is kept at ambient temperature for 3 days and is then filtered. The solid residue is washed with ether, and crystallized from 25 parts of benzene. There is thus obtained l-isopropylaminomethyl-2-(1-naphthoxy)ethyl benzoate as its hydrochloride, M.P. 13~132 C.
. . , ,~. - .. . . . ., ., .. : : , . : : .. : . .... . :
2 parts of sodium borohydride are added during 10 minutes to a stirred solution of 2 parts of 1-(4-acetyl-1-naphthoxy)-3-isopropylamino-2-propanol in 80 parts of methanol at 0 C. for 1 hour and then poured onto 100 parts of ice, acidified with 2 N-hydrochloric acid, and filtered. The filtrate is basified with 2 N-sodium hydroxide solution and extracted with 500 parts of ether. The ethereal extract is dried over anhydrous magnesium sulphate and then fil-tered. To the filtrate there is added a saturated solution of oxalic acid in ether until precipitation is substantially complete. The mixture is filtered, and the solid residue is crystallised from a mixture of ethanol and ether. There is thus obtained 1-(4-alpha-hydroxy-ethyl-1-naphtoxy)-3-isopropylamino-2-propanol hydrogen oxalate, M.P. 146-147 C. with decomposition.
A solution of 0,77 part of 1-isopropylaminomethyl-2-(1-naphthoxy)-ethyl acetate hy-drochloride in 16 parts of methanol is treated with 3,5 parts of N-sodium hydroxide at ambient temperature, and after 1 hour the methanol is evaporated under reduced pressure. The residue is shaken together with 20 parts of ether and 10 parts of N-hydrochloric acid. The mixture is separated and the ethereal solution is washed with water, dried over anhydrous magnesium sulphate and then evaporated to dryness. The residue is crystallised from a mixture of acetate and light-petro1eum (B.P. 40-60 C.), and there is thus obtained N-acetyl-l-isopropylamino-3-(l-naphthoxy)-2-propanol, M.P .91 C.
A solution of 29,5 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochlo-ride in 300 parts of water is added to a solution of 43,2 parts of disodium l,l'-methylene-bis-(2-hydroxy-3-naphthoate) in 4000 parts of water. The mixture is filtered and the solid residue is washed with water and dried. The solid is crystal-lised from ethanol, and there is thus ob-tained di-[l-isopropylamino-3-~1-naphthoxy)-2-propanol] 1,1'-methylene-bis-(2-hydroxy-3-naphthoate), M.P. 212 C.
A solution of 1,3 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol in 25 parts of ethyl acetate is added to a solution of 0,7 part of benzoic acid in 5 parts of ether. The mixture is filtered and the solid residue is washed with ether and dried. There is thus obtained l-isopro-pylamino-3-(1-naphthoxy)-2-propanol benzoate, M.P.143-144 C. (crystallised from wate~).
By substituting 0,96 part of beta-naphthoic acid foq the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol beta-naphthoate, M.P 132 C. (crystallised from a mixture of cyclohexane and ethanol).
, .. .. ., .. .. . ..... ~ . . . . . . . . .. . . . ~
--" 2109224 ,9 By substituting 0,98 part of 0-acetoxybenzoic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol 0-acetoxyben-zoate, M.P. 122-124 C. (crystallised from ethyl acetate).
By substituting 0,7 part of adipic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-iso-propylamino-3-(1-naphthoxy)-2-propanol adipate, M.P. 145-147 C.
(crystallised from a mixture of ethyl acetate and ethanol).
By substituting 0,6 part of maleic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol maleate, M.P. 145-146 C.
(crystallised from a mixture of ethyl acetate and ethanol).
By substituting 0,62 part of oxalic acid in place of the 0,7 part of benzoic acid there is similarly obtained l-isopropylamino-3-(1-naphthoxy)-2-propanol oxalate, M.P. 180-182 C.
(crystallised from a mixture of methanol and ethyl acetate).
EXA~IPLE22 To a stirred solution of 10 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hy-drochloride in 100 parts of water there is added a suspension of 100 parts of a sulphonated polystyrene resin ["Zeo Karb" 225 (SCR) 3 UZeo Karb" is a trademark] in the sodium forrn in 400 parts of water. The mixture is stirred for 60 minutes at ambient temperature and is then fil-tered. The solid residue is washed with water and dried at ambient temperature. There is thus obtained a complex salt of l-iso-propylamino-3-(1-naphthoxy)-2-propanol with the sulpho-nated polystyrene resin which has a base content of 9% .
Claims (15)
1. Use of naphthalene derivatives of the following formula for the production of a medicament for the therapeutic use of their immunoactivating effect (facilitated activation of the immune system in presence of foreign antigen) in man:
where R1 represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radi-cal optionally substituted, R2 represents an hydrogen atom or an alkyl, cycloalkyl, alkenyl, al-kynyl or aralkyl radical optionally substituted, or R1 et R2 form together with the neighbou-ring nitrogen atom a heterocyclic radical optionally substituted, R3, R4 et R5, which may be equal or different, represent hydrogen atoms or alkyl radicals, and the naphthalene nucleus may have one or more additional substituents, and their esters and their salts, but excluding 1-amino-1-n-propylamino-, 1-n-butylamino, 1-di-n-butylamino-, 1-morpholino-, 1-piperidino-3-(1-naphthoxy)-2-propanols, 1-?thylamino-, 1-dim?thylamino-, 1-di?thylamino-, 1-morpho-lino- and 1-pip?ridino-3-(2-naphthoxy)-2-propanols and 1-(1-chloro-2-naphthoxy)-3-pip?ridi-no-2-propanol, as well as their esters and their salts.
This immunoactivating activity is produced by .beta.-2 blockade of the CNS (nucleus paraventricu-laris and of the cAMP-PKA-pathway in cells of the immune system, which is the only physio-logical inhibitory pathway in leukocytes. Therefore the functional performance of the immune system is enhanced, because activating pathways in leukocytes are not inhibited any more.
The advantages of the claimed use of these compounds are that they normally are very well tolerated in contrast to other immunopotentiating agents (e.g. BCG or levamisol), that they easily penetrate the CNS where they equally develop their immunoactivating effect in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore the possi-bility to use their immunoactivating effect is the surprising result of lately done scientific re-search and is an exceptional progress for the therapy for exemple of immunodeficient diseases, because until today there is no such therapy, and especially not one effective in the CNS.
where R1 represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radi-cal optionally substituted, R2 represents an hydrogen atom or an alkyl, cycloalkyl, alkenyl, al-kynyl or aralkyl radical optionally substituted, or R1 et R2 form together with the neighbou-ring nitrogen atom a heterocyclic radical optionally substituted, R3, R4 et R5, which may be equal or different, represent hydrogen atoms or alkyl radicals, and the naphthalene nucleus may have one or more additional substituents, and their esters and their salts, but excluding 1-amino-1-n-propylamino-, 1-n-butylamino, 1-di-n-butylamino-, 1-morpholino-, 1-piperidino-3-(1-naphthoxy)-2-propanols, 1-?thylamino-, 1-dim?thylamino-, 1-di?thylamino-, 1-morpho-lino- and 1-pip?ridino-3-(2-naphthoxy)-2-propanols and 1-(1-chloro-2-naphthoxy)-3-pip?ridi-no-2-propanol, as well as their esters and their salts.
This immunoactivating activity is produced by .beta.-2 blockade of the CNS (nucleus paraventricu-laris and of the cAMP-PKA-pathway in cells of the immune system, which is the only physio-logical inhibitory pathway in leukocytes. Therefore the functional performance of the immune system is enhanced, because activating pathways in leukocytes are not inhibited any more.
The advantages of the claimed use of these compounds are that they normally are very well tolerated in contrast to other immunopotentiating agents (e.g. BCG or levamisol), that they easily penetrate the CNS where they equally develop their immunoactivating effect in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore the possi-bility to use their immunoactivating effect is the surprising result of lately done scientific re-search and is an exceptional progress for the therapy for exemple of immunodeficient diseases, because until today there is no such therapy, and especially not one effective in the CNS.
2. Use of compounds according to claim 1 for the production of a medicament for the thera-peutic use of their immunoactivating effect in man, where R1, R3, R4 and R5 represent hydro-gen atoms and R2 has the meaning given in claim 1 and the naphthalene nucleus may have one or more additional substituents, as well as their esters and their salts, but excluding 1-amino-, 1-n-propyl-amino- and 1-n-butyl-amino-3-(1-naphthoxy)-2-propanols and 1-ethylamino-3-(2-naphthoxy)-2-propanol, as well as their esters and their salts.
3. Use of compounds according to claim 1 for the production of a medicament for the therapeu-tic use of their immunoactivating effect in man, where R1 represents an alkyl or hydroxyalkyl radical of not more than 5 carbon atoms for example the methyl, ethyl, s-butyl or 2-hydroxy-ethyl radical, or an aralkyl radical with not more than 10 carbon atoms, for example the benzyl radical, or an alkanoyl radical of not more than 6 carbon atoms for example the acetyl radical.
4. Use of compounds according to claims 1 to 3 for the production of a medicament for the the-rapeutic use of their immunoactivating effect in man, where R2 represents an alkyl radical of not more than 20 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, 1-m?thyloctyl or 1-methylhexadecyl radical, or an alkyl radical of not more than 20 carbon atoms with one or more substituted hydroxy or amino radicals, for exam-ple alkylamino, dialkylamino or heterocyclic radicals, like alkylamino or dialkylamino radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 carbon atoms or heterocyclic radicals of not more than 6 atoms in the cycle, as dimethylamino or morpholino radicals, or alkoxy radicals, for example alkoxy radicals of not more than 5 carbon atoms, as methoxy or n-propoxy radicals, or alkoxyalkoxy radicals, for example alkoxyalkoxy radicals of not more than 10 carbon atoms, like the 2-n-butoxethoxy radical, or aryloxy radicals optionally substituted, as 4-chlorophenoxy ou 2,4-chlorophenoxy radicals.
5. Use of compounds according to claims 1 to 3 for the production of a medicament for the the-rapeutic use of their immunoactivating effect in man, where R2 represents an aralkyl radical of not more than 15 carbon atoms optionally substituted, for example by one or more alkoxy radicals with not more than 5 carbon atoms like the methoxy radical.
6. Use of compounds according to claims 4 or 5 for the production of a medicament for the therapeutic use of their immunoactivating effect in man, where R2 represents the radical 2-hyd-roxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 2-n-propoxyethyl, 3-meth-oxypropyl, 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-phe-nyl)-1-methylpropyl or 2-(3,4-dimethoxyphenyl)ethyl.
7. Use of compounds according to claims 1 to 3 for the production of a medicament for the the-rapeutic use of their immunoactivating effect in man, where R2 represents an cycloalkyl, alke-nyl or alkynyl radical of not more than de 10 carbon atoms, for example the cyclopentyl, allyl or 1-methyl-2-propynyl radical.
8. Use of compounds according to claim 1 for the production of a medicament for the therapeu-tic use of their immunoactivating effect in man, where the group -NR1R2 represents an hetero-cyclic nitrogen containing radical of 5 or 6 atoms optionally substituted, for example, the pyr-rolidino, piperidino or morpholino radical possibly substituted by one or more alkyl radicals of not more than 5 carbon atoms, like for example the methyl radical.
9. Use of compound according to claims 1 and 3 to 8 for the production of a medicament for the therapeutic use of their immunoactivating effect in man, where R3, R4 or R5 represent an alkyl radical of not more than 5 carbon atoms, for example the methyl radical.
10. Use of compounds according to claims 1 to 9 for the production of a medicament for the therapeutic use of their immunoactivating effect in man, where the additional possible substi-tuents of the naphthalene nucleus are chosen among halogen atoms, for example chlorine or bromine atoms, among alkyl radicals or hydroxyalkyl radicals of not more than 5 carbon atoms, for example the methyl or 1-hydroxyethyl radical, among the acyl radicals for example the alkanoyl radicals of not more than 6 carbon atoms, as the acetyl radical and among the sulfamoyl radicals optionally substituted, for example the dialkylsulfamoyl radicals of not more than 10 carbon atoms, as the dimethylsulfamoyl radical.
11. Use of the following compounds for the production of a medicament for the therapeutic use of their immunoactivating effect in man:
1-isopropylamino-3-(1-naphthoxy)-2-propanol, 1-t-butylamino-3-(1-naphthoxy)-2-propanol, 1-(2-hydroxy-1,1-dimethylethylamino3-3-(1-naphthoxy)-2-propanol, 1-(2-methyl-3-phenyl-propylamino)-3-(1-naphthoxy)-2-propanol, 1-s-butylamino-3-(1-naphthoxy)-2-propanol, 1-(1-methyloctylamino)-3-(1-naphthoxy)-2-propanol, 1-(1,1 -dimethyl-3-phenylpropylamino)-3-( 1-naphthoxy)-2-propanol, 1-allylamino-3-(1-naphthoxy)-2-propanol, 1-cyclopentylamino-3-(1-naphthoxy)-2-propanol, le 1-isopropylamino-3-(4-methyl-1-naphthoxy)-2-propanol and 1-[3((4-methoxyphenyl)-1-methylpropylamino]-3-(1-naphthoxy)-2-propanol, their esters and their salts.
The advantages of the claimed use of these compounds are that they are very well tolerated in contrast to other immunopotentiating drugs, that they easily penetrate the CNS where they equally develop their immunoactivating activity in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore, the possibility to use their immunoactivating effect is a surprise and an exceptional progress for therapy of for example immunodeficient diseases, because until now there was no such therapy, especially not one effective in the CNS.
1-isopropylamino-3-(1-naphthoxy)-2-propanol, 1-t-butylamino-3-(1-naphthoxy)-2-propanol, 1-(2-hydroxy-1,1-dimethylethylamino3-3-(1-naphthoxy)-2-propanol, 1-(2-methyl-3-phenyl-propylamino)-3-(1-naphthoxy)-2-propanol, 1-s-butylamino-3-(1-naphthoxy)-2-propanol, 1-(1-methyloctylamino)-3-(1-naphthoxy)-2-propanol, 1-(1,1 -dimethyl-3-phenylpropylamino)-3-( 1-naphthoxy)-2-propanol, 1-allylamino-3-(1-naphthoxy)-2-propanol, 1-cyclopentylamino-3-(1-naphthoxy)-2-propanol, le 1-isopropylamino-3-(4-methyl-1-naphthoxy)-2-propanol and 1-[3((4-methoxyphenyl)-1-methylpropylamino]-3-(1-naphthoxy)-2-propanol, their esters and their salts.
The advantages of the claimed use of these compounds are that they are very well tolerated in contrast to other immunopotentiating drugs, that they easily penetrate the CNS where they equally develop their immunoactivating activity in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore, the possibility to use their immunoactivating effect is a surprise and an exceptional progress for therapy of for example immunodeficient diseases, because until now there was no such therapy, especially not one effective in the CNS.
12. Use of the esters according to claims 1 to 11 for the production of a medicament for the therapeutic use of their immunoactivating effect in man, which are 0-esters of acids of the formula R6.COOH where R6 represents an alkyl, alkenyl or aryl radical optionally substituted, for example, an alkyl or alkenyl radical of not more than 20 carbon atoms, or an aryl radical of not more than 10 carbon atoms, for example the methyl, pentadecyl, heptadecyl, heptadeca-8-enyl or phenyl radical, as well as their salts.
13. Use of the salts according to claims 1 to 12 for the production of a medicament for the the-rapeutic us of their immunoactivating effect in man, which are acid-addition salts, for example deriving from inorganic acids, like chlorhydrates, bromhydrates, phosphates or sulfates, or organic salts like oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naph-thoates, o-acetoxy-benzoates, adipates, maleates or 1,1'-methylene-bis-2-hydroxy-3-naph-thoates or synthetic acidic resins like sulfonated polystyrene resins.
14. Use of compounds according to claims 1 to 13 for the production of a medicament for the therapeutic use of their indirect antiviral effect in man.This indirect antiviral effect is produced via blockade of .beta.-receptors of the CNS (nucleus paraventricularis) and of the cAMP-PKA-pathway in th cells of the immune system, which is the only physiologicyl inhibitory pathway in leukocytes. Therefore, the functional performance of the immune system is enhanced, because biochemical pathways activating the specific function of leukocytes are not inhibitied any more. The enhanced function of the immune system is associated with an enhanced antiviral activity. For example, the immune response to a recall antigen of persons infected by HIV was ameliorated 3 to 10 times under pharmacological blockade of the cAMP-PKA-pathway. The advantages of the claimed use of these compounds are that they are very well tolerated in contrast to other immunopotentiating agents, that they easily penetrate the CNS
where they equally develop their immunoactivating activity in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore, the use of their indirect antiviral activity is the surprising result of recent scientific research and an exceptional progress for the therapy of viral infections, because until now no tolerable antiviral therapy exists, especially not one effective in the CNS.
where they equally develop their immunoactivating activity in the cells of the immune system of the CNS, for example in microglia and astroglia. Therefore, the use of their indirect antiviral activity is the surprising result of recent scientific research and an exceptional progress for the therapy of viral infections, because until now no tolerable antiviral therapy exists, especially not one effective in the CNS.
15. Use of compounds according to claims 1 to 13 for the production of a medicament for the therapeutic use of their immunoactivating effect in animals with neuroimmune regulation analogous to that in man, that is with inhibitory control of the immune system by hypothalamic nervous centres via the hypothalamo-adrenocortical axis and the autonomic nervous system, expecially the sympathetic nervous system.
For veterinary therapy, this is also a big and surprising progress to have a possibility to en-hance the function of the immune system and therefore to have a possibility to enhance the function of the immune system and to have a possibility for antiviral therapy, because this was not possible before.
For veterinary therapy, this is also a big and surprising progress to have a possibility to en-hance the function of the immune system and therefore to have a possibility to enhance the function of the immune system and to have a possibility for antiviral therapy, because this was not possible before.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH379591 | 1991-12-20 | ||
| CH03795/91-6 | 1991-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2109224A1 true CA2109224A1 (en) | 1993-06-21 |
Family
ID=4263624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2109224 Abandoned CA2109224A1 (en) | 1991-12-20 | 1992-12-14 | Using the immunoactivating activity of 3-naphthyloxy-2-hydroxy-propylamines, in particular for providing cell immunity, e.g. against viral infections |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0587823A1 (en) |
| AU (1) | AU3079692A (en) |
| CA (1) | CA2109224A1 (en) |
| FI (1) | FI935056A0 (en) |
| WO (1) | WO1993013049A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5013761A (en) * | 1988-06-03 | 1991-05-07 | Eli Lilly And Company | Serotonin antagonists |
| GB0023467D0 (en) * | 2000-09-25 | 2000-11-08 | Btg Int Ltd | Amine compounds |
| CN107556203B (en) * | 2016-06-30 | 2022-05-03 | 康普药业股份有限公司 | Preparation method of propranolol |
| CN113336656B (en) * | 2021-05-28 | 2022-03-01 | 常州康普药业有限公司 | Method for synthesizing propranolol hydrochloride |
| US11998013B1 (en) | 2023-09-01 | 2024-06-04 | King Faisal University | 1-(morpholin-4-yl)-3-(naphthalen-2-yloxy)propan-2-ol as an eco-friendly insecticidal agent against spodoptera littoralis (boisd.) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4022776A (en) * | 1974-01-31 | 1977-05-10 | Otsuka Pharmaceutical Company Limited | 5-[1-Hydroxy-2-(substituted-amino)]ethyl-8-hydroxycarbostyril derivatives |
| US4329502A (en) * | 1978-08-28 | 1982-05-11 | Syva Company | Propranolol antigen conjugates and antibodies |
| DE3066975D1 (en) * | 1980-08-04 | 1984-04-19 | Syva Co | Propranolol antigen conjugates and antibodies and method of using them |
| US4652681A (en) * | 1982-04-15 | 1987-03-24 | Drug Science Foundation | Aminoalkoxy derivatives of propranolol for immunoassay applications |
| US4472301A (en) * | 1982-05-27 | 1984-09-18 | Miles Laboratories, Inc. | Propranolol immunogen and antibodies |
| CA1329937C (en) * | 1987-04-09 | 1994-05-31 | Dennis Charles Thompson | 1-phenyl-3-naphthalenyloxypropanamines |
-
1992
- 1992-12-14 CA CA 2109224 patent/CA2109224A1/en not_active Abandoned
- 1992-12-14 EP EP19920924530 patent/EP0587823A1/en not_active Withdrawn
- 1992-12-14 WO PCT/CH1992/000242 patent/WO1993013049A1/en not_active Application Discontinuation
- 1992-12-14 AU AU30796/92A patent/AU3079692A/en not_active Abandoned
-
1993
- 1993-11-15 FI FI935056A patent/FI935056A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0587823A1 (en) | 1994-03-23 |
| WO1993013049A1 (en) | 1993-07-08 |
| AU3079692A (en) | 1993-07-28 |
| FI935056A0 (en) | 1993-11-15 |
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