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WO1993016056A1 - 3-(piperazin-1-yl)-propane-1,2-diol n-oxydes and n,n'-dioxides - Google Patents

3-(piperazin-1-yl)-propane-1,2-diol n-oxydes and n,n'-dioxides Download PDF

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Publication number
WO1993016056A1
WO1993016056A1 PCT/EP1993/000307 EP9300307W WO9316056A1 WO 1993016056 A1 WO1993016056 A1 WO 1993016056A1 EP 9300307 W EP9300307 W EP 9300307W WO 9316056 A1 WO9316056 A1 WO 9316056A1
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Prior art keywords
phenyl
piperazin
diol
propane
oxide
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PCT/EP1993/000307
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French (fr)
Inventor
Roberto Giani
Carmelo A. Gandolfi
Massimiliano Riscazzi
Marco Mantovanini
Claudio Omini
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Dompé Farmaceutici S.P.A.
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Publication of WO1993016056A1 publication Critical patent/WO1993016056A1/en

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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
    • C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to 3-(4-aryl-piperazin-1-yl)-propane-1,2-diol N-oxides, a process for the preparation thereof and pharmaceutical and veterinary compositions containing them.
  • - Ar is a substituent selected from phenyl; ⁇ - o ßnaphthyl; 3,4,5-trimethoxyphenyl; 2,3,4-trimethoxyphenyl; 3,5-dimethoxy-4-hydroxyphenyl; phenyl o-, m-, p-mono or disubstituted with C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy, fluorine, chlorine, bromine, nitro, amino, C 1 -C 4 acylamino, carboxy, C 1 -C 4 alkoxycarb ⁇ nyl, C 1 -C 4 alkoxycarbonylamino, aminocarbonylamino, diphenylmethyl, 4-chloro-diphenylmethyl;
  • R 1 and R 2 are hydrogen or the -OR 1 and OR 2 groups, taken together with the carbon atoms they are linked to, form a 1,3-dioxolane ring of formula:
  • Ra and Rb which are the same or different, hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl;
  • (I) can exist as the cis- or trans- isomers of N,N'-dioxides, both separated and in a mixture thereof, but the trans isomers, that are preferably obtained, are the preferred compounds.
  • the present invention also comprises the salts of compounds of formula (I) with acceptable acids for the pharmaceutical and veterinary uses.
  • pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, alkyl and aryl sulfates, phosphates and the like.
  • the salts of the invention have sometimes particular advantages, such as an increased solubility in aqueous carriers, an increased or reduced stability, possibility of crystallization, absence of taste and/or after-taste and the like, but all of these aspects are secondary to the pharmacological action which does not depend on the used acid.
  • Preferred compounds of the invention are those in which:
  • C 1 -C 3 alkyl is methyl
  • C 1 -C 3 alkoxy is methoxy
  • C 1 -C 4 acylamino is acetyla-mino or tert-butoxycarbony- 1amino
  • C 1 -C 4 alkoxycarbonyl is methoxycarbonyl or tert-butoxycarbonyl
  • C 1 -C 4 alkoxycarbonylamino is tert-butoxycarbonylamino.
  • Particularly preferred compounds of the invention are those in which n is zero and Ar is a phenyl which can be unsubstituted or o- , m-, p- monosubstituted with chlorine, fluorine, methoxy.
  • the compounds of the present invention are prepared by a process comprising the reaction of a compound of formula (II):
  • suitable oxidizing agents comprise hydrogen peroxide, an organic or inorganic peracid, both in form of the free acid and as a salt thereof.
  • compounds (I) can then be converted into the salts thereof, or into other compounds of formula (I), by means of an acetalization reaction with a compound of formula (III):
  • Ra-CO-Rb (III) in which Ra and Rb are as defined above; if desired, the resulting acetals can be converted into the corresponding diols by hydrolytic deacetalization. Any possible geometric or optical isomers can be separated using conventional methods.
  • n is the integer 1 are preferably obtained using a large molar excess of an oxidizing agent.
  • peracids and salts thereof are persulfuric acid, potassium persulfate, m-chloroperbenzoic acid, monoperphthalic acid and the salts thereof (magnesium and the like), performi ⁇ acid and peracetic acid.
  • Preferred solvents are water; alcohols, such as methanol, ethanol, tert-butanol, glycol, propylene glycol, glycerin; halogenated hydrocarbons, such as dichloromethane, chloroform; ethers, such as dioxane or tetrahydrofuran; esters, such as ethyl formate, ethyl acetate or methyl acetate, and mixtures thereof, in the presence or in the absence of diluted solutions of ammonium or tetraaIkylammonium hydroxides or salts thereof.
  • n is zero are preferably prepared by reaction with hydrogen peroxide in an aqueous solution, at a reaction temperature from room temperature to 45-50°C, more preferably at room temperature. Under these conditions, the reaction time varies from a few minutes to some hours, but generally the reaction is complete after a short heating at 30-40°C.
  • the compounds in which n is 1 are preferably prepared using a hydrogen peroxide excess in an aqueous solution, at a temperature from room temperature to 80°C, for reaction times ranging from some hours to some days; generally the reaction is complete after 12- 15 hours, at a temperature above 50°C.
  • the compounds of the invention When the compounds of the invention are administered orally, intraperitoneally and intravenously to rats and mice, they show a lower toxicity than that of levodropropizin and a LD 50 higher than 0.6 g/kg/os.
  • the compounds of the invention show a potent antitussive activity, that is more long-lasting than that of the parent drugs.
  • the compounds of the invention better that their parent drugs, do not show any remarkable CNS side effect.
  • the compounds of the invention can be administered by the oral route, by infusion, aerosol, parenterally, for example by intramuscular or intravenous injections.
  • the compounds can be administered to the patient in pure form and/or as a pharmaceutical composition.
  • compositions can be prepared according to known techniques, for example those described in "Remington's Pharmaceutical Sciences Handbook", Mack Publishing Co, U.S.A.
  • the dose to be administered as an antitussive agent will vary according to the nature and intensity of the tussive stimulus, the administration route, the age, weight and conditions of the patient.
  • the amount of the active ingredient to be administered by the oral route can range from 0.01 mg/kg/die to 100 mg/kg/die, preferably from 0.5 mg/kg/die to 10 mg/kg/die, in one or more administrations.
  • a dose for the oral administration can contain, for example, from 0.1 to 1000 mg of the active ingredient.
  • Suitable oral forms comprise solid or liquid compositions, such as capsules, tablets, lozenges, suspensions, emulsions, syrups, drops, granulates, sachets.
  • the solid dose unit can be a hard or soft gelatin capsule containing lubricants and inert excipients such as lactose, saccharose, fructose, sweetening agents, flavours, starch.
  • suitable formulations can be prepared by dissolution of the compounds in physiologically acceptable diluents, such as water, mineral salt aqueous solutions, dextrose or sugars aqueous solutions, ethanol, glycols (propylene and polyethylene glycols).
  • physiologically acceptable diluents such as water, mineral salt aqueous solutions, dextrose or sugars aqueous solutions, ethanol, glycols (propylene and polyethylene glycols).
  • the doses can be the same as the ones for the oral route or lower than these.
  • the compounds can also be administered as suppositories, consisting of conventional carriers such as cocoa butter, waxes, polyvinylpyrrolidone and/or polyethylene glycols or derivatives thereof.
  • a suspension of 1.2 g of potassium carbonate in dichloromethane (25 ml) is added with 2 g of 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol and then with a solution of 2.35 g of m-chloroperbenzoic acid (81%) in dichloromethane (25 ml) that is added in small portions.
  • the mixture is filtered and the crystalline precipitate is dissolved in water.
  • the solution is acidified with aqueous 1N H 2 O 2 and filtered from the m-chlorobenzoic acid which separates.
  • the filtrate is alkalinized to pH 8-9 and reextracted with dichloromethane to remove traces of unreacted reagent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

3-(4-Aryl-piperazin-1-yl)-propane-1,2-diol N-oxides having pharmaceutical interest, particularly as antitussive agents.

Description

3-(PIPERAZIN-1-YL)-PROPANE-1,2-DIOL N-OXIDES AND N,N'- DIOXIDES
The present invention relates to 3-(4-aryl-piperazin-1-yl)-propane-1,2-diol N-oxides, a process for the preparation thereof and pharmaceutical and veterinary compositions containing them.
More particularly, the invention relates to compounds of formula (I):
Figure imgf000003_0002
in which:
- Ar is a substituent selected from phenyl; α- o ßnaphthyl; 3,4,5-trimethoxyphenyl; 2,3,4-trimethoxyphenyl; 3,5-dimethoxy-4-hydroxyphenyl; phenyl o-, m-, p-mono or disubstituted with C1-C3 alkyl, C1-C3 alkoxy, hydroxy, fluorine, chlorine, bromine, nitro, amino, C1-C4 acylamino, carboxy, C1-C4 alkoxycarbσnyl, C1-C4 alkoxycarbonylamino, aminocarbonylamino, diphenylmethyl, 4-chloro-diphenylmethyl;
- R1 and R2 are hydrogen or the -OR1 and OR2 groups, taken together with the carbon atoms they are linked to, form a 1,3-dioxolane ring of formula:
Figure imgf000003_0001
in which Ra and Rb, which are the same or different, hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl;
- n is zero or the integer 1. When n is the integer 1, the compounds of formula
(I) can exist as the cis- or trans- isomers of N,N'-dioxides, both separated and in a mixture thereof, but the trans isomers, that are preferably obtained, are the preferred compounds.
Compounds of formula (I), moreover, contain an asymmetric carbon atom, therefore the present invention also relates to the single optical antipodes, the mixtures thereof and the racemic mixtures.
The present invention also comprises the salts of compounds of formula (I) with acceptable acids for the pharmaceutical and veterinary uses. Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, alkyl and aryl sulfates, phosphates and the like. The salts of the invention have sometimes particular advantages, such as an increased solubility in aqueous carriers, an increased or reduced stability, possibility of crystallization, absence of taste and/or after-taste and the like, but all of these aspects are secondary to the pharmacological action which does not depend on the used acid.
Preferred compounds of the invention are those in which:
C1-C3 alkyl is methyl;
C1-C3 alkoxy is methoxy;
C1-C4 acylamino is acetyla-mino or tert-butoxycarbony- 1amino;
C1-C4 alkoxycarbonyl is methoxycarbonyl or tert-butoxycarbonyl;
C1-C4 alkoxycarbonylamino is tert-butoxycarbonylamino.
Particularly preferred compounds of the invention are those in which n is zero and Ar is a phenyl which can be unsubstituted or o- , m-, p- monosubstituted with chlorine, fluorine, methoxy.
Specific examples of preferred compounds of the invention are:
(2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide
(2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide
(2S,R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide
(2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol- N1,N4-dioxide
(2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide
(2S,R)-3-(4-ρhenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide.
The compounds of the present invention are prepared by a process comprising the reaction of a compound of formula (II):
Ar-N-(CH2-CH2)2-N-CH2-CHOR1-CH2OR2 ( II ) in which Ar, R1 and R2 are as defined above, with at least one or more molar equivalents of a suitable oxidizing agent. Examples of suitable oxidizing agents comprise hydrogen peroxide, an organic or inorganic peracid, both in form of the free acid and as a salt thereof. If desired, compounds (I) can then be converted into the salts thereof, or into other compounds of formula (I), by means of an acetalization reaction with a compound of formula (III):
Ra-CO-Rb (III) in which Ra and Rb are as defined above; if desired, the resulting acetals can be converted into the corresponding diols by hydrolytic deacetalization. Any possible geometric or optical isomers can be separated using conventional methods.
Compounds of formula (I) in which n is zero, are obtained preferably by reacting a compound of formula (II) with at least one equivalent or a slight molar excess of one of the above described oxidizing agents. Compounds of formula (I) in which n is zero are selectively formed also in the presence of hydrogen peroxide molar excesses, as long as the temperature of the reaction mixture is kept below 45°C.
The compounds of the invention of formula (I) in which n is the integer 1 are preferably obtained using a large molar excess of an oxidizing agent.
Examples of peracids and salts thereof are persulfuric acid, potassium persulfate, m-chloroperbenzoic acid, monoperphthalic acid and the salts thereof (magnesium and the like), performiσ acid and peracetic acid.
Preferred solvents are water; alcohols, such as methanol, ethanol, tert-butanol, glycol, propylene glycol, glycerin; halogenated hydrocarbons, such as dichloromethane, chloroform; ethers, such as dioxane or tetrahydrofuran; esters, such as ethyl formate, ethyl acetate or methyl acetate, and mixtures thereof, in the presence or in the absence of diluted solutions of ammonium or tetraaIkylammonium hydroxides or salts thereof.
Compounds of formula (I) in which n is zero are preferably prepared by reaction with hydrogen peroxide in an aqueous solution, at a reaction temperature from room temperature to 45-50°C, more preferably at room temperature. Under these conditions, the reaction time varies from a few minutes to some hours, but generally the reaction is complete after a short heating at 30-40°C.
The compounds in which n is 1 are preferably prepared using a hydrogen peroxide excess in an aqueous solution, at a temperature from room temperature to 80°C, for reaction times ranging from some hours to some days; generally the reaction is complete after 12- 15 hours, at a temperature above 50°C.
Compounds of formula (II) are known, see for exampie US 3163649 and anyhow they can easily be prepared in the optically active or racemic forms, using well known methods, for example the reaction of a piperazine of formula (IV):
Ar-N (CH2-CH2)2 NH (IV) with glycidol, with an alkyl or aryl sulfonate (R. Giani et al., Arzneimittel Forschung Drug Res. 98, 1139, 1988; EP 147847; EP 409044).
When the compounds of the invention are administered orally, intraperitoneally and intravenously to rats and mice, they show a lower toxicity than that of levodropropizin and a LD50 higher than 0.6 g/kg/os.
The compounds of the invention show a potent antitussive activity, that is more long-lasting than that of the parent drugs. In addition, at comparative antitussive efficacy, the compounds of the invention, better that their parent drugs, do not show any remarkable CNS side effect.
To attain the desired pharmacological effects in man and in veterinary therapy, the compounds of the invention can be administered by the oral route, by infusion, aerosol, parenterally, for example by intramuscular or intravenous injections. The compounds can be administered to the patient in pure form and/or as a pharmaceutical composition.
The most suitable pharmaceutical compositions can be prepared according to known techniques, for example those described in "Remington's Pharmaceutical Sciences Handbook", Mack Publishing Co, U.S.A.
The dose to be administered as an antitussive agent will vary according to the nature and intensity of the tussive stimulus, the administration route, the age, weight and conditions of the patient.
The amount of the active ingredient to be administered by the oral route can range from 0.01 mg/kg/die to 100 mg/kg/die, preferably from 0.5 mg/kg/die to 10 mg/kg/die, in one or more administrations. A dose for the oral administration can contain, for example, from 0.1 to 1000 mg of the active ingredient.
Suitable oral forms comprise solid or liquid compositions, such as capsules, tablets, lozenges, suspensions, emulsions, syrups, drops, granulates, sachets. The solid dose unit can be a hard or soft gelatin capsule containing lubricants and inert excipients such as lactose, saccharose, fructose, sweetening agents, flavours, starch.
For the parenteral and aerosol administrations, suitable formulations can be prepared by dissolution of the compounds in physiologically acceptable diluents, such as water, mineral salt aqueous solutions, dextrose or sugars aqueous solutions, ethanol, glycols (propylene and polyethylene glycols). The doses can be the same as the ones for the oral route or lower than these.
The compounds can also be administered as suppositories, consisting of conventional carriers such as cocoa butter, waxes, polyvinylpyrrolidone and/or polyethylene glycols or derivatives thereof.
The invention is further illustrated in the following examples.
EXAMPLE 1
30% w/v H2O2 in water (42 ml) is added to a solution of (2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol (30 g) in water (0.9 1). The mixture is kept for 2 hours at room temperature, then it is heated for 1 hour at 40°C. After cooling, the H2O2 excess is destroyed by careful addition of 0.2 g of 5% Pd/C; the mixture is concentrated to small volume under vacuum (150 ml). Upon cooling, a crystalline product separates which is filtered, dried under vacuum, to obtain 15 g of (2S)-3- (4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1- oxide.H2O, m.p. 194-196°C, [α]D = -16.7 (EtOH, c = 1%). By further concentration of the mother liquors, 5.83 g more of the product are obtained, m.p. 195-197°C.
EXAMPLE 2
30% w/v H2O2 in water (50 ml) is added to 50 ml of a (2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol (30 g) aqueous solution. The mixture is heated to 80°C overnight, then 5 more ml of 30% H2O2 are added and he ating is continued for 2 more hours at 80°C. After cooling to room temperature, the H2O2 excess is destroyed by addition of 0.1 g of 5% Pd/C. The catalyst is filtered off, the mixture is concentrated to small volume to obtain, after crystallization and filtration, 20.69 g of (2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide.
The subsequent crystallization from 98:2 ethanol/water yields an analytically pure sample, m.p. 228-231°C, [α]D = -21.4 (EtOH, c = 1%).
EXAMPLE 3
A solution of racemic 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol (50 g) in EtOH (400 ml) is added with 65 ml of 35% H2O2 and it is kept under slight stirring overnight at 35-38°C. The reagent excess is destroyed by addition of 5% Pd/C (0,2 g), the mixture is filtered and concentrated to 1/3 of the volume. Upon cooling at 4ºC, 45.6 g of rac. 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide separate; m.p. 178-180°C (dec).
Following the procedure described above, the following compounds are obtained:
rac. 3-(4-(2-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3-(4-(4-fluoro-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3- (4-(4-chloro-diphenylmethyl)-piperazin-1-yl)- propane-1,2-diol-N..-oxide;
rac. 3-(4-(2-carboxy-4-nitro-phenyl)-piperazin-1-yl)- propane-1,2-diol-N1-oxide;
(2S) 3-(4-(2-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide; (2S) 3-(4-(4-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide, m.p. 193-195°C, [α]D = -11.5 (EtOH, c = 1%);
2(2R) 3-(4-(4-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide, m.p. 192-194°C, [α]D = +12.3;
(2S) 3-(4-(4-chlorophenyl)-piperazin-1-yl)-propane-1,2-diol-N1-oxide;
(2S) 3-(4-(3-chloro-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3-(4-(2-chloro-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3-(4-(4-chloro-phenyl)-piperazin-1-yl)-propane- 1,2-diσl-N1-oxide;
rac. 3-(4-(4-fluoro-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1-oxide, m.p. 171-174°C;
rac. 3-(4-(3-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3-(4-(4-hydroxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide; (S-oxide, m.p. 205-207°C, monohydrate m.p. 210-213°C) [α]D= -16 (methanol, c=1%) rac. 3-(4-(3-hydroxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 3-(4-(2-hydroxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1-oxide;
rac. 2,2-dimethy1-4-((4-phenyl-piperazin-1-yl)methyl)- 1,3-dioxolane-N1-oxide (S-oxide, m.p. 154-156°C, [α]D= -26.7 (MeOH, c=2%).
EXAMPLE 4
A solution of 3-(4-phenyl-piperazin-1-yl)-propane- 1,2-diol (2 g) in dichloromethane (25 ml) is added at room temperature and under slight stirring to a solu tion of m-chloroperbenzoic acid (3.78 g, 81%) in dichloromethane (35 ml), at a rate of 0.5 ml/min. After about 2 hours, the peracid excess is destroyed with 0.1 g of Pd/C and the mixture is exhaustively extracted with water. After concentration of the aqueous extracts, 1.45 g of 3-(4-phenyl-piperazin-1-yl)-ρropane-1,2-diol-N1,N4-dioxide separate.
EXAMPLE 5
A suspension of 1.2 g of potassium carbonate in dichloromethane (25 ml) is added with 2 g of 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol and then with a solution of 2.35 g of m-chloroperbenzoic acid (81%) in dichloromethane (25 ml) that is added in small portions. The mixture is filtered and the crystalline precipitate is dissolved in water. The solution is acidified with aqueous 1N H2O2 and filtered from the m-chlorobenzoic acid which separates. The filtrate is alkalinized to pH 8-9 and reextracted with dichloromethane to remove traces of unreacted reagent. The peracid excess is destroyed, as usual, by addition of 0.3 g of 5% Pd/C. After filtration, the aqueous solution is concentrated to small volume to give 1.82 g of 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide; (S)-monooxide, m.p. 196-199ºC; [α]D = -17.0.
EXAMPLE 6
A solution of 2.7 g of magnesium mono-perphthalate in aqueous methanol (8:2, 6 ml) is added to a solution of 3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol (2 g) in 10 ml of aqueous methanol, in the presence of a NaHCO, excess (0.9 g). After some hours at room temperature, the solids which separate are filtered off; the solution is treated with 0.3 g of 5% Pd/C, filtered again and then it is evaporated to dryness. The residue is dissolved in some warm water and it is left to crystallize. Upon cooling to 8-10ºC, 0.68 g of 3-(4-phenyl-piperazin-1-yl)-proρane-1,2-diol-N1-oxide separate; (S-oxide; m.p. 197-200°C).
EXAMPLE 7
Following the procedure of example 2 and of example 4, the following N1,N4-dioxides are obtained:
rac. 3-(4-(2-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1,N4-dioxide;
rac. 3-(4-(4-fluoro-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1-oxide;
rac. 3-(4-(4-chloro-diphenylmethy1)-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide;
(2S) 3-(4-(2-methoxy-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1,N.-dioxide;
(2S) 3-(4-(4-chloro-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide;
(2S) 3-(4-(3-chloro-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide;
rac. 3-(4-(2-chloro-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide;
rac. 3-(4-(4-chloro-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1,N4-dioxide;
rac. 3-(4-(4-fluoro-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1,N4-dioxide;
rac. 3-(4-(3-methoxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1,N4-dioxide;
rac. 3-(4-(4-hydroxy-phenyl)-piperazin-1-yl)-propane- 1,2-diol-N1,N4-dioxide; rac. 2,2-dimethyl-4-((4-phenyl-piperazin-l-yl)-methyl)-1,3-dioxolane-N1,N4-dioxide.
rac. 3-(4-(3-hydroxy-phenyl)-piperazin-1-yl)-propane-1,2-diol-N1,N4-dioxide.
rac. 3-(4-(2-hydroxy-phenyl)-piperazin-l-yl)-propane-1,2-diol-N1,N4-dioxide.
EXAMPLE 8
By replacing (2S)-3-(4-phenyl-piperazin-l-yl)-propane-1,2-diol with the enantiomer (2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol in the processes of the examples 1 and 2 , the following compounds are obtained: (2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-1-N-oxide; m.p. 198-200°C; [α]D = +17.4 (MeOH, c = 3%); (2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-1,4-N,N'-dioxide; m.p. 203-5°C [α]D = +23.5 (MeOH, c = 3%).
EXAMPLE 9
A solution of racemic 3-(4-phenyl-piperazin-1-yl)- propane-1,2-diol-N1-oxide in absolute ethanol (50 ml) is salified by treatment at 30ºC with a solution of R(-) campho-10-sulfonic acid (17.2 g) in ethanol. After a night at 4ºC, the precipitated crystalline material is filtered to give a R(-) campho-10-sulfonate salt [11.2 g, m.p. 132-135ºC, [α]D=-24.6 (MeOH, c=1%)]. After two consecutive crystallization of this material from ethanol, enantiomeric pure (2S)-3-(4-phenyl-piperazin-1-yl)-ρropane-1,2-diol-N1-oxide R(-)-campho-10- sulfonate salt [6.1 g, m.p. 142-143°C, [α]D =-32.4, (MeOH c=1%)] is obtained.
EXAMPLE 10
R(-) campho-10-sulfonic acid (9.25 g) is added to a suspension of racemic 3-(4-phenyl-piperazin-1- yl)propane-1,2-diol-N1-oxide in acetone, and the mixture is warmed at 40-50°C to reach complete reagent solution. After cooling at room temperature, 9.05 g of: (2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide R(-) campho-10-sulfonate salt [m.p. 140-143°C, [α]D =-30.8, (MeOH c=2%)] are filtered. Following crystallization from acetone-ethanol 98:2 produces the enantiomeric pure salt.
EXAMPLE 11
(2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol- N1-oxide S(+)-campho-10-sulfonate salt [m.p. 142-145°C, [α]D =+33.4, (MeOH c=2%)] is obtained using S(+) campho-10 sulfonic acid in the procedure of the example 9.

Claims

1. Compounds of formula (I)
Figure imgf000016_0002
in which:
- Ar is a substituent selected from phenyl; α- o ß- naphthyl; 3,4,5-trimethoxyphenyl; 2,3,4-trimethoxyphenyl; 3,5-dimethoxy-4-hydroxyphenyl; phenyl o-, m-, p-mono or disubstituted with C1-C3 alkyl, C1-C3 alkoxy, hydroxy, fluorine, chlorine, bromine, nitro, amino, C1- C4 acylamino, carboxy, C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonylamino, aminocarbonylamino, diphenylmethyl, 4-chloro-diphenylmethyl;
- R1 and R2 are hydrogen or the -OR, and OR2 groups, taken together with the carbon atoms they are linked to, form a 1,3-dioxolane ring of formula:
Figure imgf000016_0001
in which Ra and Rb, which are the same or different, are hydrogen, C1-C3 alkyl, phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimetho-xyphenyl, 3,5-dimethoxy-4-hydroxyphenyl;
- n is zero or the integer 1;
the pharmaceutically acceptable salts, optical or geometric isomers and mixtures thereof.
2. Compounds according to claim 1 in which n is zero.
3. Compounds according to claim 1 in which n is the integer 1.
4. Compounds according to claims 1-3 in which Ar is phenyl.
5. Compounds according to any on of the above claims, in which R1 and R2 are hydrogen.
6. Compounds according to any one of the above claims, selected from:
(2S)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide
(2R)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol-N1-oxide
( 2S ,R) -3-( 4-phenyl-piperazin-l-yl ) -propane-1 , 2-diol-N1 ,N4-dioxide
( 2S) -3- (4-phenyl-piperazin-l-yl ) -propane-l , 2-diol-N1 ,N4-dioxide
(2R)-3-(4-phenyl-piperazin-l-yl)-propane-1,2-diol-N,,N4-dioxide
(2S,R)-3-(4-phenyl-piperazin-l-yl)-propane-1,2-diol-N1-oxide.
7. A process for the preparation of the compounds of claims 1-6, which comprises the reaction of a compound of formula (II):
Ar-N-(CH2-CH2)2-N-CH2-CHOR1-CH2OR2 ( II ) in which Ar, R1 and R2 are as defined above, with at least one or more molar equivalents of a suitable oxidizing agent.
8. Pharmaceutical compositions containing as the active ingredient a compound of claims 1-6.
9. The use of a compound according to claims 1-6 for the preparation of a medicament having antitussive activity.
PCT/EP1993/000307 1992-02-14 1993-02-09 3-(piperazin-1-yl)-propane-1,2-diol n-oxydes and n,n'-dioxides WO1993016056A1 (en)

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WO2002010149A1 (en) * 2000-07-28 2002-02-07 Dompe' S.P.A. 1,3-dioxolanes with antitussive activity
WO2002010150A1 (en) * 2000-07-28 2002-02-07 Dompe' S.P.A. 2,2-disubstituted 1,3-dioxolanes as antitussive agents

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WO2002010150A1 (en) * 2000-07-28 2002-02-07 Dompe' S.P.A. 2,2-disubstituted 1,3-dioxolanes as antitussive agents
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KR100788532B1 (en) * 2000-07-28 2007-12-24 돔페 파르마 에스.피.에이. Nautical aqueous 2,2-disubstituted 1,3-dioxolane

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