US3420822A - Quaternary salts of basic esters of beta-(1-naphthyl)-acrylic acid - Google Patents

Quaternary salts of basic esters of beta-(1-naphthyl)-acrylic acid Download PDF

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US3420822A
US3420822A US499014A US3420822DA US3420822A US 3420822 A US3420822 A US 3420822A US 499014 A US499014 A US 499014A US 3420822D A US3420822D A US 3420822DA US 3420822 A US3420822 A US 3420822A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/12—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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

Definitions

  • This invention relates to quaternary salts of basic esters of fl-(l-naphthyD-acrylic acid having valuable antibacterial and antifungal activities.
  • the quaternary salts of the invention possess the general formula wherein R is hydrogen or phenyl, R and R individually represent methyl or ethyl or when taken collectively with the nitrogen atom to which they are attached represent morpholino, piperidino or pyrrolidino; R represents methyl, ethyl, butyl, isoamyl, octyl, decyl, dodecyl, hexadecyl, octadecyl, bromohexyl, benzyl or an acetyl and X represents a bromide, chloride or iodide ion or a methyl sulfate ion.
  • the compounds according to the invention have valuable antibacterial and antifungal activities 3,420,822 Patented Jan. 7, 1969 ICC and are particularly intended for the topical treatment of bacterial and fungal infections.
  • R represents an aryl group
  • it preferably represents a phenyl group.
  • R and R represent alkyl groups, they advantageously represent alkyl groups containing from 1 to 6 carbon atoms; where R and R together with the adjacent nitrogen atom represent a heterocyclic group, this is advantageously a 5- or 6-membered saturated heterocyclic group such as for example a pyrrolidino, piperidino or morpholino group.
  • R preferably represents an alkyl group containing from 1 to 20 carbon atoms (e.g.
  • X preferably represents a chlorine, bromine or iodine atom, or a methyl sulphate group.
  • Particularly preferred compounds according to the invention by virtue of their especially valuable antibacterial and antifungal activities are compounds of the Formula I in which R represents an alkyl group containing from 8 to 12 carbon atoms such as, for example, the following:
  • compound (b) is particularly preferred for use in medicinal preparations.
  • the antibacterial activity of compounds according to the invention may be demonstrated by in vitro tests utilising the dilution technique (1:2 in tryptose phosphate broth [Difco]) against the following microorganisms: Bacillus subtilis ATCC 6633, Micrococcus pyogencs, var. aureus ATCC 6538P, Streptococcus haemolyticus C203 America, Escherichia coli McLeod ATCC 10536, Proteus vulgaris ATCC 7829 and Pscudomonas aeruginosa ATCC 10145.
  • the antifungal activity of compounds according to the invention has been demonstrated by in vitro tests utilising the dilution technique (1:2 in Sabourauds medium) against the following microorganisms: Candida albicans ATCC 10231. T ricophyton mentagrophytes ATCC 8757 and Saccharomyces cerevisiae ATCC 9763. With Candida albicans and Saccharomyces cerevisiae incubation was offected, after innoculation of the compounds to be tested, for a period of 24 hours prior to estimation of the minimum inhibitory concentration; with Tricophyton mentagrophytes, the incubation period was five days.
  • the quaternising agent will in general be a compound of the formula R X', where X is a halide or alkyl sulphate ion. Where it is desired that the final compound have an anion other than halide or alkyl sulphate this may be achieved by conventional ion-exchange techniques.
  • the reaction is conveniently carried out in the presence of an organic solvent such as, for example, benzene, toluene, acetone or acetonitrile, advantageously at a temperature between and 50 C.
  • the reaction time will generally vary between 2 and 60 days according to the nature of the reactants used.
  • the quaternary salts of Formula I are in general relatively insoluble in the organic solvent medium and slowly precipitate in crystalline form; in some cases, however, it is desirable to remove the solvent in order to isolate the product.
  • the compounds of Formula I obtained may be purified in any convenient way, for example by washing with ether.
  • the compounds of Formula II used as starting materials in the above-described process according to the invention may be prepared in any convenient manner, e.g. by one of the following methods:
  • R2 HOCH-CHr-N 1 1 ⁇ R3 (IV) (wherein R R and R are as hereinbefore defined).
  • the reaction is preferably carried out in the presence of an organic solvent such as for example ether, benzene or dioxan under substantially anhydrous conditions and in the presence of an acid-binding agent such as, for example, an excess of the aminoalcoholof Formula IV.
  • the reaction mixture is advantageously refluxed for 24 hours to effect the reaction.
  • vent such as for example ethanol or propanol, refluxing the reaction mixture for l5-24 hours.
  • the compounds of Formula II may be viscous liquids of pale yellow colour or white crystalline solids, insoluble in Water but soluble in the common organic solvents and in aqueous acid solutions.
  • Several of the compounds of Formula II useful as starting materials are now compounds.
  • the compounds of Formula I according to the inven tion are in general colourless crystalline solids having varying solubilities in water.
  • the quaternary salts formed with benzyl chloride, methyl chloride, butyl bromide and isoamyl bromide are for example soluble in Water whilst the salts formed with longer chain alkyl halides are either insoluble or only sparingly soluble in water.
  • compositions which comprise at least one compound of the Formula I in association with a pharmaceutical carrier or excipient.
  • the compositions according to the invention may for example be suitable for application to the skin, or alternatively may be adapted for use in the nose, ear or mouth.
  • the compositions may for example be in the form of ointments, creams, mouth washes, nasal and otological drop solutions, alcoholic tinctures, powders for topical use, vaginal tablets and suppositories, spray solutions and the like.
  • Preferred compositions according to the invention contain from 0.02 to 1.5% by weight of the compound or compounds of Formula I.
  • compositions according to the invention may also contain :further therapeutic compounds in addition to compounds of the Formula I, for example anti-inflammatory steroids (e.g. prednisolone, triamcinolone, betamethazone or dexamethasone), antibiotics especially suitable for topical administration (e.g. neomycin) and local anaesthetics (e.g. xylocaine).
  • anti-inflammatory steroids e.g. prednisolone, triamcinolone, betamethazone or dexamethasone
  • antibiotics especially suitable for topical administration e.g. neomycin
  • local anaesthetics e.g. xylocaine
  • EXAMPLE 1 19.8 g. of B-(l-naphthyD-acrylic acid and 50 ml. of thionyl chloride are refluxed for 1 hour. The excess of thionyl chloride is distilled off at reduced pressure and the oily residue is redissolved in 20 ml. of anhydrous benzene. 14.5 g. of 2-(N-piperidino)-ethanol in 20 ml. of anhydrous benzene are then slowly added to the benzene solution which is externally cooled during the addition in order not to allow the temperature to rise above 20 C. A further 20 ml. of anhydrous benzene are then added and the reaction mixture is refluxed for 3 hours.
  • the free base obtained by treatment of an aqueous solution of the hydrochloride with alkali, is a viscous liquid of pale yellow colour boiling at 189l91 C./ 0.1 mm. Hg.
  • EXAMPLE 2 A suspension of 50 g. of sodium fi-(l-naphthyD-acrylate and 33.9 g. of 2-(N-morpholino)-1-chloroethane in 400 ml. of isopropanol is refluxed for 20 hours. The sodium chloride, formed during the reaction, is then filtered off in the warm. The crude 2-(N-morpholino)-ethyl fl- (1-naphthyl)-acrylate crystallizes upon cooling and, after recrystallisation from isopropanol, melts at 80-82 C.
  • EXAMPLE 3 11 ml. of a 18% solution of methyl bromide in benzene are added to 4.1 g. of 2-dimethylaminoethyl fl-(l-naphthyl)-acrylate in ml. of anhydrous benzene and the mixture is maintained at room temperature for 2 days. The precipitate thus formed is separated by filtration, Washed with benzene and then With ether. Z-dimethylaminoethyl fl-(l-naphthyD-acrylate methyl bromide is thus obtained as a white crystalline solid melting at 174 C.
  • EXAMPLE 4 3.62 g. of hexadecyl bromide are added, at 50 C., to 2.9 g. of Z-dimethylaminoethyl -(1-naphthyl)-acrylate dissolved in a mixture of ml. of anhydrous acetonitrile and 10 ml. of anhydrous benzene and the solution thus obtained is maintained at 50 C. for 20 days.
  • the solid thus formed is separated by filtration and then Washed first with benzene and then with ether.
  • the 2- dirnethylaminoethyl ,8(1-naphthyl)-acrylate hexadecyl bromide is thus obtained as a White crystalline solid melting at 157-160 C.
  • EXAMPLE 128 g. of benzyl chloride are added to a solution of 2.87 g. of 2-dimethylaminoethyl fi-(l-naphthyD-acrylate in 5 ml. of anhydrous acetone and the solution maintained at room temperature for 2 days. The solid which thus separates is separated by filtration and Washed with ether.
  • EXAMPLE 6 n-decyl bromide g 0.5 5 70% alcohol, q.s. to ml 100
  • EXAMPLE 7.-AQUEOUS SOLUTIONS (a) For pro-operative skin disinfectant:
  • R is selected from the group consisting of a hydrogen atom and a phenyl group; R and R taken individually represent a group selected from the group consisting of methyl and ethyl, or when taken collectively with the nitrogen atom to which they are attached represent a heterocycle selected from the group consisting of piperidino, morpholino and pyrrolidino; R is selected References Cited UNITED STATES PATENTS 2,415,079 2/1947 Magnoliae 260-469 3,077,470 2/1963 Burckhalter 260239 FOREIGN PATENTS 581,532 8/1959 Canada.

Description

United States Patent 3,420,822 QUATERNARY SALTS 0F BASIC ESTERS 0F fi-(l-NAPHTHYD-ACRYLIC ACID Silvano Casadio, Milan, Italy, assignor to Istituto de Angeli S.p.A., Milan, Italy, an Italian body corporate No Drawing. Filed Oct. 20, 1965, Ser. No. 499,014 Claims priority, application Italy, Nov. 2, 1964, 44,572 US. Cl. 260240 Claims Int. Cl. C091) 23/00; C09b 55/00; C07c 69/76 ABSTRACT OF THE DISCLOSURE This invention relates to quaternary salts of basic esters of fl-(l-naphthyD-acrylic acid having valuable antibacterial and antifungal activities. The quaternary salts of the invention possess the general formula wherein R is hydrogen or phenyl, R and R individually represent methyl or ethyl or when taken collectively with the nitrogen atom to which they are attached represent morpholino, piperidino or pyrrolidino; R represents methyl, ethyl, butyl, isoamyl, octyl, decyl, dodecyl, hexadecyl, octadecyl, bromohexyl, benzyl or an acetyl and X represents a bromide, chloride or iodide ion or a methyl sulfate ion.
According to the present invention, there are provided compounds of the general formula:
in which:
As stated above, the compounds according to the invention have valuable antibacterial and antifungal activities 3,420,822 Patented Jan. 7, 1969 ICC and are particularly intended for the topical treatment of bacterial and fungal infections. In compounds of the Formula I in which R represents an aryl group, it preferably represents a phenyl group. When R and R represent alkyl groups, they advantageously represent alkyl groups containing from 1 to 6 carbon atoms; where R and R together with the adjacent nitrogen atom represent a heterocyclic group, this is advantageously a 5- or 6-membered saturated heterocyclic group such as for example a pyrrolidino, piperidino or morpholino group. R preferably represents an alkyl group containing from 1 to 20 carbon atoms (e.g. a methyl, ethyl, butyl, isoamyl, octyl, decyl, dodecyl, hexadecyl or octadecyl group), a bromoalkyl group such as for example a 6-bromo-hexyl group; a benzyl group; or an acetyl group. X preferably represents a chlorine, bromine or iodine atom, or a methyl sulphate group.
Particularly preferred compounds according to the invention by virtue of their especially valuable antibacterial and antifungal activities are compounds of the Formula I in which R represents an alkyl group containing from 8 to 12 carbon atoms such as, for example, the following:
(a) 2- dimethylamino ethyl [3- l-naphthyl) -acrylate dodecyl bromide,
(b 2- (N-pyrrolidino) ethyl )3- l-naphthyl) -acrylate decyl bromide,
(c) 2- (N-morpholino) ethyl p-( 1-naphthyl)-acrylate decyl bromide, and
(d) 1-phenyl-2 (N-piperidino) ethyl fil-naphthyl) acrylate decyl bromide.
Of these compounds, compound (b) is particularly preferred for use in medicinal preparations.
The antibacterial activity of compounds according to the invention may be demonstrated by in vitro tests utilising the dilution technique (1:2 in tryptose phosphate broth [Difco]) against the following microorganisms: Bacillus subtilis ATCC 6633, Micrococcus pyogencs, var. aureus ATCC 6538P, Streptococcus haemolyticus C203 America, Escherichia coli McLeod ATCC 10536, Proteus vulgaris ATCC 7829 and Pscudomonas aeruginosa ATCC 10145. 18-24 hours old cultures of the microorganisms, suitably diluted, were inoculated with the compounds to be tested and, after incubation for 24 hours at 37 C., the minimum concentration of compound which effected in hibition of the growth of the microorganisms was estimated.
The antifungal activity of compounds according to the invention has been demonstrated by in vitro tests utilising the dilution technique (1:2 in Sabourauds medium) against the following microorganisms: Candida albicans ATCC 10231. T ricophyton mentagrophytes ATCC 8757 and Saccharomyces cerevisiae ATCC 9763. With Candida albicans and Saccharomyces cerevisiae incubation was offected, after innoculation of the compounds to be tested, for a period of 24 hours prior to estimation of the minimum inhibitory concentration; with Tricophyton mentagrophytes, the incubation period was five days.
In the following table, the results of tests carried out on the compounds (a), (b), (c) and (d) according to the invention are summarised. These tests were carried out by means of the suspension technique according to the method of Said and coll. described in Annales pharmv franc. 21, 187, 1963, and the results demonstrate the bactericidal and fungicidal activities of the four compounds even at very low concentrations.
(wherein R R and R are as hereinbefore defined). The reaction is advantageously carried out in an organic sol- Compounds according to the invention have also been tested on rabbits eyes and by subcutaneous injection into the abdomen of mice in order to ascertain the suitability of the compounds for topical application. These tests demonstrated that the compounds according to the invention have good skin compatibility.
Further according to the invention, there is provided a process for the preparation of compounds of the Formula I which comprises reacting an amine of the general formula with a quaternising agent to introduce the substituent R and the anion X.
The quaternising agent will in general be a compound of the formula R X', where X is a halide or alkyl sulphate ion. Where it is desired that the final compound have an anion other than halide or alkyl sulphate this may be achieved by conventional ion-exchange techniques.
The reaction is conveniently carried out in the presence of an organic solvent such as, for example, benzene, toluene, acetone or acetonitrile, advantageously at a temperature between and 50 C. The reaction time will generally vary between 2 and 60 days according to the nature of the reactants used. The quaternary salts of Formula I are in general relatively insoluble in the organic solvent medium and slowly precipitate in crystalline form; in some cases, however, it is desirable to remove the solvent in order to isolate the product. The compounds of Formula I obtained may be purified in any convenient way, for example by washing with ether.
The compounds of Formula II used as starting materials in the above-described process according to the invention may be prepared in any convenient manner, e.g. by one of the following methods:
(1) Reaction of the corresponding B-(l-naphthyD- acrylic chloride with an aminoalcohol of formula:
R2 HOCH-CHr-N 1 1 \R3 (IV) (wherein R R and R are as hereinbefore defined). The reaction is preferably carried out in the presence of an organic solvent such as for example ether, benzene or dioxan under substantially anhydrous conditions and in the presence of an acid-binding agent such as, for example, an excess of the aminoalcoholof Formula IV. The reaction mixture is advantageously refluxed for 24 hours to effect the reaction.
(2) Reaction of the sodium B-(I-naphthyD-acrylate with a chloroamine of formula:
vent such as for example ethanol or propanol, refluxing the reaction mixture for l5-24 hours.
The compounds of Formula II may be viscous liquids of pale yellow colour or white crystalline solids, insoluble in Water but soluble in the common organic solvents and in aqueous acid solutions. Several of the compounds of Formula II useful as starting materials are now compounds.
The compounds of Formula I according to the inven tion are in general colourless crystalline solids having varying solubilities in water. The quaternary salts formed with benzyl chloride, methyl chloride, butyl bromide and isoamyl bromide are for example soluble in Water whilst the salts formed with longer chain alkyl halides are either insoluble or only sparingly soluble in water.
Further according to the invention there are provided pharmaceutical compositions (and especially compositions adapted for topical use) which comprise at least one compound of the Formula I in association with a pharmaceutical carrier or excipient. The compositions according to the invention may for example be suitable for application to the skin, or alternatively may be adapted for use in the nose, ear or mouth. The compositions may for example be in the form of ointments, creams, mouth washes, nasal and otological drop solutions, alcoholic tinctures, powders for topical use, vaginal tablets and suppositories, spray solutions and the like. Preferred compositions according to the invention contain from 0.02 to 1.5% by weight of the compound or compounds of Formula I. If desired, the compositions according to the invention may also contain :further therapeutic compounds in addition to compounds of the Formula I, for example anti-inflammatory steroids (e.g. prednisolone, triamcinolone, betamethazone or dexamethasone), antibiotics especially suitable for topical administration (e.g. neomycin) and local anaesthetics (e.g. xylocaine).
In order that the invention may be well understood, the following examples are given by way of illustration only:
EXAMPLE 1 19.8 g. of B-(l-naphthyD-acrylic acid and 50 ml. of thionyl chloride are refluxed for 1 hour. The excess of thionyl chloride is distilled off at reduced pressure and the oily residue is redissolved in 20 ml. of anhydrous benzene. 14.5 g. of 2-(N-piperidino)-ethanol in 20 ml. of anhydrous benzene are then slowly added to the benzene solution which is externally cooled during the addition in order not to allow the temperature to rise above 20 C. A further 20 ml. of anhydrous benzene are then added and the reaction mixture is refluxed for 3 hours. After cooling, the suspended solid is filtered, washed with benzene and crystallised from absolute ethanol. The 2- (N-piperidino)-ethyl fi-(l-naphthyD-acrylate hydrochloride is thus obtained (M. Pt. 197 C.).
The free base, obtained by treatment of an aqueous solution of the hydrochloride with alkali, is a viscous liquid of pale yellow colour boiling at 189l91 C./ 0.1 mm. Hg.
Analysis for C H O N (percent). Calc.: C, 77.64; H 7.49; N, 4.53. Found: C, 77.95; H, 7.53; N, 4.49.
The following compounds are prepared in an analogous manner:
Z-dimethylaminoethyl ;3-( l-naphthyl) -acrylate B.P. 170-175 C./0.2 mm. Hg.
Analysis for C1'1H1902N (percent). Calc.: C, 75.81; H, 7.11; N, 5.20. Found: C, 76.3; H, 7.10; N, 5.39. Hydrochloride: M. Pt. 153 C.
2- (N-pyrrolidino -ethyl fl-( 1-naphthyl)-acrylate B.P. 197-199 C./mm. Hg.
Analysis for C H O N (percent). Calc.: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.50; H, 7.18; N, 4.88. Hydrochloride: M.P. 151 C.
1-phenyl-2-dimethylaminoethyl /8-( 1-naphthy1)-acrylate M.P. 82-83 C. (crystallized from isopropanol. Analysis for C H O N (percent). Calc.: C, 79.97; H, 6.71; N, 4.06. Found: C, 79.83; H, 6.82; N, 4.00. Hydrochloride: M.P.181-183 C.
l-phenyl-Z- (N-morpholino) -ethyl [3-( 1-naphthyl)- acrylate M.P. 117 C. (crystallized from 95% ethanol). Analysis for C H O N (percent). Calc.: C, 77.49; H, 6.50; N, 3.62. Found: C, 78.00; H, 6.59; N, 3.61. Hydrochloride: M.P. ZOO-204 C.
1-phenyl-2- (N-piperidino) -ethy1 fi- 1-naphthyl)- acrylate M.P. 78-79 C. (crystallized from 95% ethanol). Analysis for CzeHzqOzN (percent). Calc.: C, 81.01; H, 7.06; N, 3.63. Found: C, 81.46; H, 7.11; N, 3.67. Hydrochloride: M.P. 191192 C.
EXAMPLE 2 A suspension of 50 g. of sodium fi-(l-naphthyD-acrylate and 33.9 g. of 2-(N-morpholino)-1-chloroethane in 400 ml. of isopropanol is refluxed for 20 hours. The sodium chloride, formed during the reaction, is then filtered off in the warm. The crude 2-(N-morpholino)-ethyl fl- (1-naphthyl)-acrylate crystallizes upon cooling and, after recrystallisation from isopropanol, melts at 80-82 C.
Analysis for C H O N (percent). Calc.: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.01; H, 6.81; N, 4.60. Hydrochloride: M.P. 213 C.
EXAMPLE 3 11 ml. of a 18% solution of methyl bromide in benzene are added to 4.1 g. of 2-dimethylaminoethyl fl-(l-naphthyl)-acrylate in ml. of anhydrous benzene and the mixture is maintained at room temperature for 2 days. The precipitate thus formed is separated by filtration, Washed with benzene and then With ether. Z-dimethylaminoethyl fl-(l-naphthyD-acrylate methyl bromide is thus obtained as a white crystalline solid melting at 174 C.
Analysis for C H O NBr (percent). Calc.: C, 59.35; H, 6.08; N, 3.84; Br, 21.94. Found: C, 60.12; H, 6.10; N, 3.91; Br, 22.05.
The following quaternary salts are prepared in an analogous manner:
2-dimethylaminoethyl B-( 1-naphthyl)-acry1ate n.butyl bromide Reaction time: 4 days, M.P. 186188 C. Analysis for C H O NBr (percent). Calc.: C, 62.06; H, 6.94; N, 3.45; Br, 19.66. Found: C, 62.36; H, 7.01; N, 3.39; Br, 1915.
Z-dimethylaminoethyl fi- 1-naphthyl)-acrylate isomayl bromide Reaction time: 5 days, M.P. 182186 C. Analysis for C H O NB1" (percent). Calc.: C, 62.87; H, 7.19; N, 3.33; Br, 19.01. Found: c, 62.01; H, 7.00; N, 3.31; Br, 19.11.
6 Z-dimethylaminoethyl ,B-( 1-naphthy1)-acrylate 6-bromohexyl bromide Reaction time: 7 days, M.P. 189190 C. Analysis for C H O NBr (percent) Calc.: C, 53.8; H, 6.09; N, 2.73; Br, 31.14. Found: C, 53.91; H, 6.11; N, 2.69; Br, 31.01.
2-dimethylaminoethyl fil-naphthyl) -acrylate n-octyl bromide Reaction time: 7 days, M.P. 157158 C. Analysis for C H O NBr (percent). Calc. C, 64.93; H, 7.85; N, 3.03; Br, 17.28. Found: C, 64.95; H, 7.77; N, 3.03; Br, 17.41.
Z-dimethylaminoethyl ,B-( 1-naphthyl-) acrylate n-decyl bromide Reaction time: 12 days, M.P. -168 C. Analysis for C H O NBr (percent). Calc.: C, 66.10; H, 8.22; N, 2.86; Br, 16.29; Found: C, 66.01; H, 8.19; N, 2.89; Br, 16.33.
Z-dimethylaminoethyl fl- 1-naphthyl)-acrylate n-dodecyl bromide Reaction time: 12 days, M.P. 156-15 8 C. Analysis for C H O NBr (percent). Calc.: C, 67.20; H, 8.55; N, 2.70; Br, 15.41. Found: C, 67.41; H, 8.56; N, 2.69; Br, 15.45.
2- (N-morpholino -ethyl ,3-( l-naphthyl) -acrylate methyl bromide Reaction time: 3 days, M.P. -177 C. Analysis for C H O NBr (percent). Calc. C, 59.12; H, 5.95; N, 3.45; Br, 19.67. Found: C, 59.91; H, 5.88; N, 3.43; Br, 19.66.
2-(N-piperidino)-ethyl fi- 1-naphthyl)-acrylate methyl bromide Reaction time: 2 days, M.P. 175 C. Analysis for C H O NBr (percent). Calc.: C, 62.38; H, 6.48; N, 3.46; Br, 19.77. Found: C, 62.43; H, 6.43; N, 3.51; Br, 19.60.
2-(N-pyrrolidino)-ethyl fi-( 1-naphthyl)-acrylate methyl bromide Reaction time: 2 days, M.P. 178 C. Analysis for C H O NBr (percent). Calc.: C, 61.54; H, 6.20; N, 3.59; Br, 20.47. Found: C, 61.10; H, 6.18; N, 3.51; Br, 20.39.
2- N-pyrrolidino -ethyl B- l-naphthyl) -acrylate n-butyl bromide Reaction time: 6 days, M.P. 214220 C. Analysis for C H O NBr (percent). Calc.: C, 63.90; H, 6.99; N, 3.24; Br, 18.48. Found: C, 63.10; H, 6.88; N, 3.21; Br, 18.53.
2- (N-pyrrolidino -ethyl fl-( l-naphthyl) -acrylate isoamyl bromide Reaction time: 6 days, M.P. 2132l8 C. Analysis for C H O NBr (percent). Calc.: C, 64.56; H, 7.23; N, 3.14; Br, 17.90. Found: C, 64.59; H, 7.21; N, 3.11; Br, 17.50.
2- N-pyrrolidino) ethyl ,8-( 1-naphthyl)-acrylate 6-bromohexyl bromide Reaction time: 7 days, M.P. 80100 C. Analysis for C H O NBr (percent). Calc.: C, 55.60; H, 6.16; N, 2.59; Br, 29.63. Found: C, 55.99; H, 6.11; N, 2.58; Br, 29.50.
2- (N-pyrrolidino -ethyl ,8-( l-naphthyl -acrylate n.0cty1 bromide Reaction time: 8 days, M.P. 132133 C. Analysis for C27H33O2NBr (percent). Calc.: C, 66.38; H, 7.84; N, 2.87; Br, 16.36. Found: C, 66.55; H, 7.81; N, 2.90; Br, 16.41.
1-penyl-2-dimethylaminoethyl fi-( 1-naphthyl)- acrylate methyl bromide Reaction time: 2 days, M.P. 218 C. Analysis for C H O NB1' (percent) Calc.: C, 65.48; H, 5.95 N, 3.18; Br, 18.15. Found: C, 65.91; H, 5.88; N, 3.18; Br, 18.67.
7 1-pheny1-2-dimethylaminoethyl ,B-( 1-naphthyl)- acrylate dimethylsulphate Reaction time: 14 days, M.P. 168-172 C. Analysis for C H O NS (percent). Calc.: C, 63.68; H, 6.20; N, 2.97. Found: C, 62.9; H, 6.21; N, 2.84.
1-phenyl-2-dimethylarninoethyl /3-( 1 -naphthyl acrylate methyl iodide Reaction time: 2 days, M.P. 173-176 C. Analysis for C H O NI (percent). Calc.: C, 59.12; H, 5.38; N, 2.87; I, 26.06. Found: C, 59.90; H, 5.29; N, 2.89; I, 26.19.
1-phenyl-2-dimethylaminoethyl ,B-(I-naphthyD- acrylate n-butyl bromide Reaction time: 20 days, M.P. 160-165 C. Analysis for CzqHgzOgNBI' (percent). Calc.: C, 67.20; H, 6.69; N, 2.91; Br, 16.57. Found: C, 67.44; H, 6.55; N, 3.01; Br, 16.66.
1-phenyl-2-dirnethylaminoethyl ,8-( 1-n aphthyl acrylate isoamyl bromide Reaction time: 20 days at 50 C. The product was isolated by removal of the solvent. M.P. 84-88 C. Analysis for C H O NBr (percent). Calc.: C, 67.73; H, 6.90; N, 2.82; Br, 16.10. Found: C, 67.91; H, 6.83; N, 2.86; Br, 16.44.
1pheny1-2-dimethylaminoethyl B- 1-naphthyl)-acrylate 6-bromohexyl bromide Reaction time: 7 days, M.P. 70-75 C. Analysis for C H O NBr (percent). Calc.: C, 59.12; H, 5.99; N, 2.38; Br, 27.11. Found: C, 59.01; H, 6.03; N, 2.18; Br, 27.03.
1-phenyl-2-dimethylaminoethyl fl-( 1-naphthyl)-acrylate n-octyl bromide Reaction time: 8 days, M.P. 82 C. Analysis for C H O NB1 (percent). Calc.: C, 69.13; H, 7.49; N, 2.60; Br, 14.84. Found: C, 69.51; H, 7.57; N, 2.59; Br, 14.99.
1-pheny1-2-dimethylaminoethyl fi-( 1-naphthyl)-acrylate n-decyl bromide Reaction time: 20 days, M.P. 74-78 C. Analysis for C H O NBr (percent). Calc.: C, 70.00; H, 7.82; N, 2.47; Br, 14.10. Found: C, 70.61; H, 7.94; N, 2.47; Br, 14.14.
1-phenyl-2-dimethylaminoethyl B-( 1-naphthyl)-acrylate n-dodecyl bromide Reaction time: 25 days, M.P. 98-102 C. Analysis for C H O NB1" (percent). Calc.: C, 70.7; H, 8.14; N, 2.36; Br, 13.44. Found. C, 70.8; H, 8.11; N, 2.40; Br, 13.39.
1-phenyl-2 N-morpholino -ethyl ,8-(1-naphthyl)- acrylate methyl bromide I-phenyl-Z-(N-piperidino)-ethyl ,8-( 1-naphthyl)- acrylate methyl bromide Reaction time: 8 days, M.P. 212 C. Analysis for C27H3 O NBr (percent). Calc.: C, 67.50; H, 6.29; N, 2.91; Br, 16.63. Found: C, 67.39; H, 6.27; N, 2.70; Br, 16.91.
l-phenyl-Z-(N-piperidino)-ethyl B-(l-naphthyD-acrylate acetyl chloride Reaction time: 2 days, M.P. 193-194" C. Analysis for C H O NCI (percent). Calc.: C, 72.50; H, 6.52; N, 3.02; Cl, 7.64. Found: C, 72.81; H, 6.39; N, 3.18; Cl, 7.80.
EXAMPLE 4 3.62 g. of hexadecyl bromide are added, at 50 C., to 2.9 g. of Z-dimethylaminoethyl -(1-naphthyl)-acrylate dissolved in a mixture of ml. of anhydrous acetonitrile and 10 ml. of anhydrous benzene and the solution thus obtained is maintained at 50 C. for 20 days. The solid thus formed is separated by filtration and then Washed first with benzene and then with ether. The 2- dirnethylaminoethyl ,8(1-naphthyl)-acrylate hexadecyl bromide is thus obtained as a White crystalline solid melting at 157-160 C.
Analysis for C H O NBr (percent). Calc.: C, 69.00; H, 9.12; N, 2.44; Br, 13.91. Found: C, 69.21; H, 9.10; N, 2.39; Br. 14.06.
The following quaternary ammonium salts are obtained in an analogous manner:
2-(N-morpholino)-ethyl B-(l-naphthyD-acrylate n-butyl bromide Reaction time: 5 days. The compound was isolated by removal of the solvent. M.P. 177-187 C. Analysis for C H O NBr (percent). Calc.: C, 61.6; H, 6.74; N, 8.12; Br, 17.82. Found: C, 62.0; H, 6.77; N, 3.21; Br, 17.91.
2-(N-morpholino)-ethyl B-(l-naphthyD-acrylate n-octyl bromide Reaction time: 20 days, M.P. 86-88" C. Analysis for C27H3303NBr (percent). Calc.: C, 64.28; H, 7.59; N, 2.78; Br, 15.84. Found: C, 65.00; H, 7.61; N, 2.70; Br. 15.89.
2- Nmorpholino) ethyl fi-( 1-naphthyl)-acrylate n-decyl bromide Reaction time: 60 days. The product was isolated by removal of the solvent. M.P. 88-92 C. Analysis for C H O NBr (percent). Calc.: C, 65.40; H, 7.95; N, 2.63; Br, 15.01. Found: C, 65.10; H, 7.88; N, 2.67; Br, 15.15.
Z-(N-morpholino -et-hyl fl-( 1-naphthyl)-acrylate n-dodecyl bromide Reaction time: 60 days. The product was isolated by removal of the solvent. M.P. 7680 C. Analysis for C H O NBr (percent). Calc.: C, 66.40; H, 8.27; N, 2.50; Br, 14.26. Found: C, 66.93; H, 8.31; N, 2.50; Br, 14.38.
2- N-piperidino -ethyl [i-(1-naphthy1)-acrylate n-octyl bromide Reaction time: 8 days, M.P. -157 C. Analysis for C H O NB1 (percent). Calc.: C, 66.92; H, 8.02; N, 2.79; Br, 15.90. Found: C, 66.18; H, 8.01; N, 2.81; Br, 15.66.
2-(N-pyrro1idino)-ethyl /3-(1-naphthyl)-acrylate n-decyl bromide Reaction time: 20 days, M.P. 92.95 C. Analysis for C H O NBr (percent). Calc.: C, 67.45; H, 8.20; N, 2.71; Br, 15.47. Found: C, 67.91; H, 8.19; N, 2.83; Br, 15.41.
2- (N-pyrro1idino)-ethyl 3-(1-naphthyl)-acrylate n-dodecyl bromide Reaction time: 25 days, M.P. 90-95 C. Analysis for C H O NBr (percent). Calc.: C, 68.40; H, 8.52; N, 2.57; Br, 14.67. Found: C, 68.10; H, 8.55; N, 2.59; Br, 14.55.
2- N-pyrrolidino -ethyl 18- 1-naphthyl)-acrylate n-octadecyl bromide Reaction time: 25 days, M.P. 82-86 C. Analysis for C37H5302NBI' (percent). Calc.: C, 70.68; H, 9.30; N, 2.23; Br, 12.71. Found: C, 70.00; H, 9.19; N, 2.18; Br, 12.75.
1-phenyl-Z-dimethylaminoethyl ,8-(1-naphthyl)-acrylate n-octadecyl bromide Reaction time: 45 days. The compound was isolated by removal of the solvent. M.P. 8286 C. Analysis for 9 C H O NBr (percent). Calc.: C, 72.52; H, 8.92; N, 2.06; Br. 11.77. Found: C, 72.80; H, 8.99; N, 2.15; Br, 11.51.
1-phenyl-2- (N-piperidino) -ethy1 B-( l-naphthyl) -aorylate n-octyl iodide Reaction time: 20 days. The product was isolated by removal of the solvent. M.P. 158-163 C. Analysis for C H O NI (percent). Calc.: C, 65.28; H, 7.09; N, 2.24; I, 20.29. Found: C, 65.53; H, 7.12; N, 2.25; I, 20.23.
1-pheny1-2- (N-piperidino) -ethyl B-( 1-naphthy1)-acry1ate n-decyl bromide Reaction time: 20 days, M.P. 168-171 C. Analysis for C H O NBr (percent) Calc.: C, 71.30; H, 7.98; N, 2.31; Br, 13.17. Found: C, 71.48; H, 8.05; N, 2.47; Br, 13.21.
EXAMPLE 1.28 g. of benzyl chloride are added to a solution of 2.87 g. of 2-dimethylaminoethyl fi-(l-naphthyD-acrylate in 5 ml. of anhydrous acetone and the solution maintained at room temperature for 2 days. The solid which thus separates is separated by filtration and Washed with ether.
The Z-dimethylaminoethyl fi-(l-naphthyD-acrylate benzyl chloride is thus obtained as a white crystalline solid melting at 197198 C.
Analysis for C H O NCI (percent). Calc.: C, 72.80; H, 6.62; N, 3.55; Cl, 8.95. Found: C, 72.51; H, 6.60; N, 3.57; Cl, 9.01.
The following quaternary ammonium salts are obtained in an analogous manner:
2- (N-morpholino -ethyl ,8-( 1-naphthyl)-acrylate benzyl chloride Reaction time; reaction temperature: 5 days at 50 C. M.P. 166167 C. Analysis for C H O NCl (percent). Calc.: C, 71.30; H, 6.44; N, 3.20; Cl, 8.09. Found: C, 70.99; H, 6.43; N, 312; Cl, 8.13.
2-(N-piperidino)-ethyl /3-( l-naphthyl) -acrylate benzyl chloride Reaction time: 5 days, M.P. 189191 C. Analysis for C27H3002NC]. (percent). Calc.: C, 74.38; H, 6.94; N, 3.21; Cl, 8.13. Found: C, 74.42; H, 6.99; N, 3.19; Cl, 8.16.
2-(N-pyrrolidino)-ethyl fl-(l-naphthyD-acrylat benzyl chloride Reaction time: 5 days, M.P. 176 C. Analysis for C H O NCl (percent). Calc.: C, 74.01; H, 6.69; N, 3.32; CI, 8.40. Found: C, 74.62; H, 6.83; N, 3.31; Cl, 8.39.
1-phenyl-2-dimethylaminoethyl ;8-( 1-naphthy1)-acrylate benzyl bromide Reaction time: 15 days. Reaction temperature: 50 C. The compound was isolated by removal of the solvent. M.P. 60-65 C. Analysis for C H O NBr (percent). Calc.: C, 69.75; H, 5.85; N, 2.71; Br, 15.47. Found: C, 69.95, H, 5.72; N, 2.58; Br, 15.39.
1-phenyl-2-dimethylaminoethyl 18- 1-naphthy1)-acrylate benzyl chloride Reaction time: 20 days, M.P. 178181 C. Analysis for C H O NCl (percent). Calc.: C, 76.34; H, 6.41; N, 2.97; Cl, 7.51. Found: C, 76.34; H, 6.31; N, 2.79; Cl, 7.61.
1-phenyl-2- (N-piperidino -ethyl ;8-( 1-naphthyl)-acrylate benzyl chloride Reaction time: 20 days. Reaction temperature: 50 C., M.P. 1051 C. Analysis for C H O NCl (percent). Calc.: C, 77.40; H, 6.69; N, 2.73; Cl, 692. Found: C, 77.10; H, 6.80; N, 2.75; Cl, 6.84.
10 EXAMPLE 6.--TINCTURES n-decyl bromide g 0.5 5 70% alcohol, q.s. to ml 100 (b) 2- (-N-pyrrolidino) -ethyl fl- 1-naphthyl)-acrylate n-decyl bromide 'g 1 Industrial methylated spirits ml 75 Distilled water, q.s. to ml 100 10 EXAMPLE 7.-AQUEOUS SOLUTIONS (a) For pro-operative skin disinfectant:
2- (-N-pyrrolidino -ethyl 3- l-naphthyl -acryla n-decyl bromide -g 1 Propylene glycol ml 5 Distilled water, q.s. to ml 100 (b) Disinfectant for the hands and arms of the surgeon before sungical procedures: A B 2- (N pyrrolidino) -ethyl ,8- 1-naphthyl acrylate n-decyl bromide g 0.5 0.1 Propylene glycol ml 5 5 'Distilled water, q.s. to ml 100 100 (c) Disinfectants for use in obstetrics and for burns and wounds:
2- (N pyrrolidino) -ethyl B- 1-naphthyl -acrylate n-decyl bromide g 0.05 Propropylene lglycol ml 5 Distilled water, q.s. to ml 100 EXAMPLE 8.-CREAMS Grams (a) 2-(N-pyrrolidino)-ethyl fl-(l-naphthyD- ecrylate n-decyl bromide 0. 5 0. 1 Cetostearyl alcohol. 10 10 Liquid parafiin 10 10 Distilled water, q.s. t 100 100 (b) 2-(N-pyrrolidino)-ethyl 40 acrylate n-decyl bromide 0. 5 0. 1 Polyethylene 1000 monocetyl ether. 2 2 Cetostearyl cohol 8 8 Cetyl alcohol 5 5 Yellow soft parafiin 10 10 Liquid paraflin 10 10 Glycerin 5 5 Distilled water, q.s. to 100 100 EXAMPLE 9.-LOTIONS Grams 2-(N-pyrrolidino) ethyl B-(l-naphthyD-acrylate n-decyl bromide 0. 5 0. 1 01 3 3 2 2 20 20 2 2 100 100 EXAMPLE 10.VAGINAL TABLETS Grams Each tablet contains:
2-(N-pyrrolidino)-ethyl fl-(l-naphthybacrylate n-decyl bromide 0. 005 0 0005 Polysorbate 80 0. 010 0 010 Lactose, q.s. to 2 EXAMPLE 11.-VAGI'NAL SUPPOSITOR-IES Grams Each suppository contains:
2-(N-pyrrolidino)-ethyl B-(l-naphthyD- acrylate n-decyl bromide 0. 005 0. 0005 Glycerinated gelatine, q.s. to 2 2 EXAMPLE 12.LOZENGES Grams Each lozenge contains:
acrylate n-decyl bromide. 0. 002 0. 0005 Mannitol 0. 200 0.200
Talc 0.020 0.020
Flavour, q.s
Sugar, q.s. to 1 1 EXAMPLE 13.EAR DROPS 2-(N-pyrrolidino)-ethyl fl-(l-naphthyl) -aeryla-te ndeeyl bromide, g 0. 0. 02
Propylene glycol (ml.), q.s. to 100 100 I claim:
1. A compound of the formula wherein R is selected from the group consisting of a hydrogen atom and a phenyl group; R and R taken individually represent a group selected from the group consisting of methyl and ethyl, or when taken collectively with the nitrogen atom to which they are attached represent a heterocycle selected from the group consisting of piperidino, morpholino and pyrrolidino; R is selected References Cited UNITED STATES PATENTS 2,415,079 2/1947 Blicke 260-469 3,077,470 2/1963 Burckhalter 260239 FOREIGN PATENTS 581,532 8/1959 Canada.
OTHER REFERENCES Chemical Abstracts, vol. 46, col. 11168 (1952) (abstract of Sergievskaya et a1.)
Chemical Abstracts, vol. 65, cols. 1752 to 1754 (1965) (abstract of Crescenzi et a1.)
Chemical Abstracts, vol. 65, col. 2135 (1965 (abstract of Coppi et 211.)
JOHN D. RANDOLPH, Primary Examiner.
US. Cl. X.R. 260469; 424308, 274, 267, 248
US499014A 1964-11-02 1965-10-20 Quaternary salts of basic esters of beta-(1-naphthyl)-acrylic acid Expired - Lifetime US3420822A (en)

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FR2676224A1 (en) * 1991-05-10 1992-11-13 Gastaud Jean Marie NOVEL QUATERNARY AMMONIUM SALTS, PROCESSES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME.

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Publication number Priority date Publication date Assignee Title
US2415079A (en) * 1944-02-26 1947-02-04 Regents Basic-alkyl esters and their salts
CA581532A (en) * 1959-08-18 Abbott Laboratories Method of preparing quaternary ammonium salts
US3077470A (en) * 1961-03-21 1963-02-12 Univ Kansas Res Foundation 3-[4-hydroxy-3-(aminomethyl)-phenyl]-4-(4-oxyphenyl)-alkanes and alkenes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA581532A (en) * 1959-08-18 Abbott Laboratories Method of preparing quaternary ammonium salts
US2415079A (en) * 1944-02-26 1947-02-04 Regents Basic-alkyl esters and their salts
US3077470A (en) * 1961-03-21 1963-02-12 Univ Kansas Res Foundation 3-[4-hydroxy-3-(aminomethyl)-phenyl]-4-(4-oxyphenyl)-alkanes and alkenes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2676224A1 (en) * 1991-05-10 1992-11-13 Gastaud Jean Marie NOVEL QUATERNARY AMMONIUM SALTS, PROCESSES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME.
WO1992020646A1 (en) * 1991-05-10 1992-11-26 Gastaud Jean Marie Novel quaternary ammonium salts, process for obtaining same and pharmaceutical compositions containing them
US5399590A (en) * 1991-05-10 1995-03-21 Gastaud; Jean M. Quaternary ammonium salts and pharmaceutical compositions containing them

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