CA1173039A - 4-benzyloxypiperidine compounds - Google Patents
4-benzyloxypiperidine compoundsInfo
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- CA1173039A CA1173039A CA000388595A CA388595A CA1173039A CA 1173039 A CA1173039 A CA 1173039A CA 000388595 A CA000388595 A CA 000388595A CA 388595 A CA388595 A CA 388595A CA 1173039 A CA1173039 A CA 1173039A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A B S T R A C T
Piperidine derivatives of the general formula:
Piperidine derivatives of the general formula:
Description
~ I 73039 -- 1 ~
DESCRIPTION
" P IPER ID INE DER IVAT IVE S, THE IR PREPARAT ION
AND PH~RM~CEUTICAL COMPOSITIONS CONTAINING T~EM"
The present invention relates to new therapeutically useful piperidine derivatives, to a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
5The piperidine derivatives of the present invention are those compounds of the general formula: -X CH2 - { ~N -- R ( I ) wherein R represents a hydrogen atom, or a (Cl 4)alkyl, hydroxy(Cl 4)alkyl, or (Cl 4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (Cl 4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (Cl 4)alkyl, (Cl 4)alkoxy, trifluoromethyl or methylene-dioxy radicals, or alternatively X forms with the phenylnucleus a naphthyl radical. with the proviso that when R
represents a hydrogen atom X is other than a hydrogen atom, and pharmaceutically acceptable acid ~ 173039 addition salts thereof.
The piperidine derivatives of general formula (I) are therapeutically useful in that they possess antidepressive activity.
Preferred compounds of the invention are those of general formula (I) wherein X represents one or more chlorine atoms. or forms with the phenyl nucleus a naphthyl radical, or represents three metho~y radicals.
Of that class, those piperidine derivatives wherein R represents a hydrogen atom are particularly preferred.
According to a feature of the present invention, the piperidine derivatives of general formula (I) are prepared by the process which comprises the reaction of a compound of the general formula:
r~ 1 HO ~ N-R (II) (wherein Rl represents a radical within the definition of symbol R, or a nitrogen-protecting radical such as an optionally substituted benzoyl radical, e.g.
4-nitrobenzoyl, or an optionally substituted benzyl or alkyl radical) with a compound of the general formula:
! 1 73 0 3 9 ~ CH2-Y (III) (wherein Y represents a .reactive radical such as a chlorine or bromine atom, and X is as hereinbefore defined) and, when Rl in the product obtained of the general formula:
X ~ CH2 ~ N-Rl (IV) is other than a radical R as hereinbefore defined, removing the nitrogen-protecting radical to yield a compound of general formula (I) wherein R represents a hydrogen atom, or reducing by methods known E~ se an optionally substituted benzoyl radical Rl in the compound of general formula (IV) to a corresponding benzyl radical, as is within ~he definition of symbol R.
According to a further feature of the invention, a piperidine derivative of the general formula:
~ CH2-0-~ ~ N-H (V) X
~ 173039 (wherein X is as hereinbefore defined) so obtained by the aforedescribed process is converted to another compound of general formula (I) by reaction with a compound of the general ~ormula:
Z-R (VI) wherein Z represents a reactive atom or group, e.g. a halogen atom, and R represents a (Cl 4)alkyl, hydroxy-(Cl 4)alkyl or (Cl 4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C1 4)alkoxy radicals, or the phene-thyl radical or the 3-phenylpropyl radical.
Pharmaceutically acceptable acid addition salts of the piperidine derivatives of general formula (I), e.g. mandelates. fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the piperidine base with the appropriate acid in a solvent medium. e.g. an ether or an alkanol.
By the term 'methods known per se' as used in this specification is meant methods heretofore used or described in the literature.
! 1 7 3 0 3 9 The following Examples illustrate the preparation of piperidine derivatives of the present invention and acid addition salts thereof by the hereinbefore described process. The analyses and the IR and NMR spectra confirm the structure of the compounds.
4-(4-Fluorobenzyloxy)-piperidine and its mandelate 1(1) 1-(4-Nitrobenzoyl)-4 (0-r~lo~b_r~loxY)-Piperidine A mixture of 1.6 g of a 50% aqueous sodium hydroxide solution, 10 ml of methylene chloride, 2 y (0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine,
DESCRIPTION
" P IPER ID INE DER IVAT IVE S, THE IR PREPARAT ION
AND PH~RM~CEUTICAL COMPOSITIONS CONTAINING T~EM"
The present invention relates to new therapeutically useful piperidine derivatives, to a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
5The piperidine derivatives of the present invention are those compounds of the general formula: -X CH2 - { ~N -- R ( I ) wherein R represents a hydrogen atom, or a (Cl 4)alkyl, hydroxy(Cl 4)alkyl, or (Cl 4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (Cl 4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (Cl 4)alkyl, (Cl 4)alkoxy, trifluoromethyl or methylene-dioxy radicals, or alternatively X forms with the phenylnucleus a naphthyl radical. with the proviso that when R
represents a hydrogen atom X is other than a hydrogen atom, and pharmaceutically acceptable acid ~ 173039 addition salts thereof.
The piperidine derivatives of general formula (I) are therapeutically useful in that they possess antidepressive activity.
Preferred compounds of the invention are those of general formula (I) wherein X represents one or more chlorine atoms. or forms with the phenyl nucleus a naphthyl radical, or represents three metho~y radicals.
Of that class, those piperidine derivatives wherein R represents a hydrogen atom are particularly preferred.
According to a feature of the present invention, the piperidine derivatives of general formula (I) are prepared by the process which comprises the reaction of a compound of the general formula:
r~ 1 HO ~ N-R (II) (wherein Rl represents a radical within the definition of symbol R, or a nitrogen-protecting radical such as an optionally substituted benzoyl radical, e.g.
4-nitrobenzoyl, or an optionally substituted benzyl or alkyl radical) with a compound of the general formula:
! 1 73 0 3 9 ~ CH2-Y (III) (wherein Y represents a .reactive radical such as a chlorine or bromine atom, and X is as hereinbefore defined) and, when Rl in the product obtained of the general formula:
X ~ CH2 ~ N-Rl (IV) is other than a radical R as hereinbefore defined, removing the nitrogen-protecting radical to yield a compound of general formula (I) wherein R represents a hydrogen atom, or reducing by methods known E~ se an optionally substituted benzoyl radical Rl in the compound of general formula (IV) to a corresponding benzyl radical, as is within ~he definition of symbol R.
According to a further feature of the invention, a piperidine derivative of the general formula:
~ CH2-0-~ ~ N-H (V) X
~ 173039 (wherein X is as hereinbefore defined) so obtained by the aforedescribed process is converted to another compound of general formula (I) by reaction with a compound of the general ~ormula:
Z-R (VI) wherein Z represents a reactive atom or group, e.g. a halogen atom, and R represents a (Cl 4)alkyl, hydroxy-(Cl 4)alkyl or (Cl 4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C1 4)alkoxy radicals, or the phene-thyl radical or the 3-phenylpropyl radical.
Pharmaceutically acceptable acid addition salts of the piperidine derivatives of general formula (I), e.g. mandelates. fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the piperidine base with the appropriate acid in a solvent medium. e.g. an ether or an alkanol.
By the term 'methods known per se' as used in this specification is meant methods heretofore used or described in the literature.
! 1 7 3 0 3 9 The following Examples illustrate the preparation of piperidine derivatives of the present invention and acid addition salts thereof by the hereinbefore described process. The analyses and the IR and NMR spectra confirm the structure of the compounds.
4-(4-Fluorobenzyloxy)-piperidine and its mandelate 1(1) 1-(4-Nitrobenzoyl)-4 (0-r~lo~b_r~loxY)-Piperidine A mixture of 1.6 g of a 50% aqueous sodium hydroxide solution, 10 ml of methylene chloride, 2 y (0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine,
2.32 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g (4 x 10 4 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50C. After dilution of the reaction medium with 20 ml of water and 30 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral. dried (MgSO4) and evaporated in vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 2.23 g of a product which is purified by dissolving it in 11 ml of dimethylformamide (DMF) and reprecipitating it by the dropwise addition of 11 ml of water, whilst stirring. After washing with water and drying in vacuo, l-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)-! 1 730 39-- 6 piperidine, m.p. 120C. is obtained.
1(2) 4-(4-Fluorobenzyloxy)-piperidine (mandelate) A mixture of 11.48 g (0.032 mol) of the product obtained under 1(1), 192 ml of 96 ethanol and 48 ml of lOM aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is taken up in 200 ml of water, 72 ~ of sodium chloride and 200 ml of diethyl ether. After filtration. the 10 aqueous phase is extracted twice with 200 ml of diethyl ether and the total organic phase is dried (MgS04) and evaporated in vacuo.
This yields an oil which is converted to the d,l-mandelate by dissolving it in 100 ml o-f diethyl ether 15 and adding 4.57 g (0.03 mol) of d,1-mandelic acid.
The salt obtained is filtered off and recrystallised from isopropanol. Its melting point is 146C.
4-(3,4,5-Trimethoxybenzyloxy)-piperidine and its mandelate 2(1) 1-(4-Nitrobenzoyl)-4-(3,4,5-trimethoxybenzYloxy)-piperidine A mixture of 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of methylene chloride, 1 g 25 (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 1.30 g (0.006 mol) of 3,4,5-trimethoxybenzyl chloride ! 1 7 30 39 and 0.08 g (2 x 10 4 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50C. After dilution with 10 ml of water and 15 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgS04) and evaporated ln vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 1.36 g (79%) of a product which is purified by dissolving it in 7 ml of DMF and slowly reprecipitating it with 7 ml of water.
After washing with water and drying in vacuo, 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine, m.p. 124C, is obtained.
2(2) 4-(3,4,5-Trimethoxybenzyloxy)-piperidine (mandelate) A mixture of 12 g (0.028 mol) of the product obtained under 2(1), 168 ml of 96 ethanol and 48 ml of lOM aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is taken up in 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous phase is extracted twice with 70 ml of chloroform and the total organic phase is dried (MgS04) and evaporated in vacuo. This yields a pasty solid which is converted to the dll-mandelate by dissolving it in 120 ml of methanol, adding 4.26 g (0.028 mol) of d,l-mandelic acid and filtering the medium after it has ~ 1 73039 been stirred overnight at ambient temperature. The precipitate obtained is recr~stallised from methanol.
The product crystallises with half a molecule o-E
water. Its melting point is 114C.
l-Ethoxycarbonyl-4-benzyloxypiperidine CH2 0~ - COOC2H5
1(2) 4-(4-Fluorobenzyloxy)-piperidine (mandelate) A mixture of 11.48 g (0.032 mol) of the product obtained under 1(1), 192 ml of 96 ethanol and 48 ml of lOM aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is taken up in 200 ml of water, 72 ~ of sodium chloride and 200 ml of diethyl ether. After filtration. the 10 aqueous phase is extracted twice with 200 ml of diethyl ether and the total organic phase is dried (MgS04) and evaporated in vacuo.
This yields an oil which is converted to the d,l-mandelate by dissolving it in 100 ml o-f diethyl ether 15 and adding 4.57 g (0.03 mol) of d,1-mandelic acid.
The salt obtained is filtered off and recrystallised from isopropanol. Its melting point is 146C.
4-(3,4,5-Trimethoxybenzyloxy)-piperidine and its mandelate 2(1) 1-(4-Nitrobenzoyl)-4-(3,4,5-trimethoxybenzYloxy)-piperidine A mixture of 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of methylene chloride, 1 g 25 (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 1.30 g (0.006 mol) of 3,4,5-trimethoxybenzyl chloride ! 1 7 30 39 and 0.08 g (2 x 10 4 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50C. After dilution with 10 ml of water and 15 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgS04) and evaporated ln vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 1.36 g (79%) of a product which is purified by dissolving it in 7 ml of DMF and slowly reprecipitating it with 7 ml of water.
After washing with water and drying in vacuo, 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine, m.p. 124C, is obtained.
2(2) 4-(3,4,5-Trimethoxybenzyloxy)-piperidine (mandelate) A mixture of 12 g (0.028 mol) of the product obtained under 2(1), 168 ml of 96 ethanol and 48 ml of lOM aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is taken up in 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous phase is extracted twice with 70 ml of chloroform and the total organic phase is dried (MgS04) and evaporated in vacuo. This yields a pasty solid which is converted to the dll-mandelate by dissolving it in 120 ml of methanol, adding 4.26 g (0.028 mol) of d,l-mandelic acid and filtering the medium after it has ~ 1 73039 been stirred overnight at ambient temperature. The precipitate obtained is recr~stallised from methanol.
The product crystallises with half a molecule o-E
water. Its melting point is 114C.
l-Ethoxycarbonyl-4-benzyloxypiperidine CH2 0~ - COOC2H5
3,4 g (0.033 mol) of ethyl chloroformate are added dropwise to a stirred mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0-056 mol) of dry K2C03, 26 ml of water and 26 ml of chloroform. After stirring for 1 hourl the organic phase is decanted after dilution with 54 ml of chloroform, and wash~d 3 times with 20 ml of water and dried (MgS04). Evaporation of the solvent in vacuo gives a liquid. which is distilled ln vacuo.
Boiling point (0.4 mm Hg): 149-151C;
n21 - 1.5178.
1-Methyl-4-(4-chlorobenzyloxy)-piperidine and its hydrochloride In a 500 ml three-necked round-bottomed flask placed under an argon atmosphere, 4.4 g (0.1 mol) of a ! 1 7 3 0 3 9 _ g _ 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 10.1 g (0.1 mol) of l-methyl-4-hydroxypiperidine, dissolved in 100 ml of DMF, are then added. The mixture is stirred for 1 hour at ambient temperature and then cooled with a bath of iced water, and 19.3 g (0.~2 mol) of ~-chlorobenzyl chloride. dissolved in 50 ml of DMF, are added. Once the introduction has ended, the mixture is stirred for 4 hours at ambient temperature and left to stand overnight. The reaction medium is poured into iced water and extracted 3 times with diethyl ether. The organic phase is washed once with water and then extracted with dilute HCl (1-2 N).
The aqueous phase is then rendered alkaline with NaOH.
It is extracted with diethyl ether and the ether extract is then washed 4 times with water. It is dried over magnesium sulphate, riltered and concentrated.
The oil obtained is distilled twice and the fraction passing over at 94-98C/0.04 mm Hg is collected.
This yields an oil. which is taken up in diethyl ether, and the hydrochloride is precipitated by adding hydrogen chloride. The hydrochloride is filtered off and rinsed with diethyl ether. It is taken up in the minimum amount of hot isopropanol. 5 times the volume of ethyl acetate is then added and the compound is left to recrystallise. The hydrochloride melts at 149-151~C.
~ 173039 l-senzyl-4-(3~4~5-trimethox~benzyloxy) piperidine and its Eumarate In a 250 ml three-necked round-bottomed flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol) of a 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 9.6 g (0.05 mol) of l-benzyl-4-hydroxypiperidine, dissolved in 30 ml of DMF, are then introduced. Once the addition has ended, the mixture is stirred for l hour at ambient temperature. 13 g (0.06 mol) of 3,4,5-trimethoxy-benzyl chloride in 30 ml of DMF are then added, whilst cooling with a bath of iced water. The mixture is stirred for 5 hours at ambient temperature and then left to stand overnight. The reaction medium is poured into iced water and then extracted with diethyl ether.
The product is then extracted with dilute HCl. The aqueous phase is rendered alkaline with NaOH and then extracted with diethyl ether, and the ether extract is washed with water, dried over MgS04, filtered and concentrated. The oil obtained is taken up in hot pentane. The product crystallises. It is filtered off and recrystallised from isopropanol. This yields the base. which is dissolved in 70 ml of ethanol, and a 25 filtered solution of 2.9 g (0.025 mol) of fumaric acid in 140 ml of ethanol is added. The fumarate salt ! 1 7303 9 formed is filtered off and dried. Its melting point is 160-161C.
1-(4-ChlorobenzYl)-4-~3,4.5-trimethoxybenzYloxv)-piperidine and its fumarate 6(1) 1-(4-ChlorobenzoYl)-4-hydroxypiperidine 30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHC13, 57.3 g (0.414 mol) of K2C03 and 260 ml of water are placed in a one litre Erlenmeyer flask. 51.8 g (0.2g6 mol) of ~-chlorobenzoyl chloride, dissolved in 50 ml of CHC13, are added in the course of 15 minutes.
whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with CHC13 and the CHC13 extract is washed with water until the pH is 6-7. It is dried over MgS04, filtered and concentrated.
The product is recrystallised from ethyl acetate.
6(2) 1-(4-ChlorobenzoYl)-4-(3,4.5-trimethox~benzyloxy)-piperidine In a three-necked round-bottomed flask under a nitrogen atmosphere, 0.96 g (0.022 mol) of a 55%
suspension of sodium hydride in oil is washed 3 times with petroleum ether. 4.8 g (0.02 mol) of 1-(4-chloro-benzoyl)-4-hydroxypiperidine obtained as described in 6(1), dissolved in 50 ml of DMF, are then added. After the addition has ended, the mixture is stirred for 1 ~ 1 73039 - ~2 -hour at ambient temperature. It is -then cooled with a bath of iced water, and 5.4 g (0.025 mol) of 3,4,5-trimethoxybenzyl chloride, dissolved in 10 ml of DMF, are added. The mixture is stirred for 3 hours at ambient temperature and then left to stand overnight. It is poured into iced water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over MgS04, filtered and concentrated. The oil obtained is taken up in diethyl ether and the solution is then filtered. The filtrate is concentrated and passed through an alumina column (eluant: CHC13). The product does not crystallise and is used as such in the following step.
6(3) 1-(4-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine and its fumarate In a round-bottomed flask under a nitrogen atmosphere, 7 g (0.0167 mol) of the product obtained under 6(2), dissolved in 70 ml of dry diethyl ether, are added at ambient temperature to a suspension of 0.38 g (0.01 mol) of AlLiH4 in 30 ml of dry diethyl ether. The mixture is heated for 3 hours at the reflux temperature. It is hydrolysed with 2.6 ml of isopropanol and 3.3 ml of a saturated aqueous solution of NaCl.
The mixture is filtered and the material on the filter is rinsed with diethyl ether. The product is extracted into dilute hydrochloric acid and the reaction mixture ~ 173039 is then rendered alkaline with N~I~OH and extracted with diethyl ether. The ether extract is washed with water, dried over MgSO4, filtered and concentrated. This yields an oil, which is dissolved in 30 ml of e-thanol and the solution is added to a filtered solution of 1.2 g (0.0105 mol) of fumaric acid in 60 ml of ethanol. The fumarate precipitates gradually. It is filtered off, rinsed with a small amount of ethanol and then with diethyl ether, and dried. Its melting point is 178-180C.
~ he compounds of the invention prepared by procedures described in the foregoing Exarnples are shown in the following Table.
' 173039 ~ D O ~ ~ ~
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o ~ 173039 The piperidine derivatives of general formula (I) of the present invention were subjected to pharmacological experiments which demonstrated their antidepressive activity.
The toxicity of the compounds was determined on mice by intraperitoneal administration. The LD50 varies from 30 to 1000 mg/kg animal body weight.
The antidepressive activity was determined by the test for the antagonism towards the ptosis caused by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).
Mice (male, CDl Charles River, France, 18-22 g) simultaneously receive the products to be studied or the solvent (administered intraperitoneally) and reserpine (4 mg/kg animal body weight, administered subcutaneously).
Sixty minutes later. the degree of palpebral ptosis is estimated by means of a rating scale (0 to 4) for each mouse.
For each dose, the average rating and the percentage variation, compared with the control batch, are calculated.
For each product, the AD 50, or the dose which reduces the average ptosis score, compared with the controls. by 50%, is determined graphically.
The AD 50 varies from 4 to lO mg~kg animal body weight, administered lntraperitoneally.
The antidepressive activity was also determined by the test for potentiation of the head twitches caused by L-5-hydroxytryptophan tH. Van Riezen (1972) Arch.
Int. Pharmacology. 198, 256-269).
The procedure is as follows:
24 hours before the experiment, the animals are placed in the laboratory in which the operation is to be carried out. On the day of the experiment, the mice are weighed and put to sleep.
The products to be tested are then injected intraperitoneally before L5-HTP is injected subcutaneously in an amount of 125 mg/kg animal body weight as a suspension in Tween. 30 minutes after the injection of L5-HTP, the number of head twitches is counted for 60 seconds.
For each dose, the average number of head twitches and the percentage variation, relative to the control animals, are calculated. The 50% active dose is established from a curve.
The AD 50 varies from 0.1 to 5 mg~kg animal body weight, administered intraperitoneally.
The pharmacological results show that the piperidine derivatives of the present invention can be useful for the treatment of depression.
t 1 73039 The compounds of the invention can be presented in any form suitable for oral or parenteral administration. for example in the form of tablets, coated tablets, capsules, solutions to be -taken orally or injected, and the like, in association with any suitable excipient.
The daily posology can range from 5 to 200 mg.
Boiling point (0.4 mm Hg): 149-151C;
n21 - 1.5178.
1-Methyl-4-(4-chlorobenzyloxy)-piperidine and its hydrochloride In a 500 ml three-necked round-bottomed flask placed under an argon atmosphere, 4.4 g (0.1 mol) of a ! 1 7 3 0 3 9 _ g _ 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 10.1 g (0.1 mol) of l-methyl-4-hydroxypiperidine, dissolved in 100 ml of DMF, are then added. The mixture is stirred for 1 hour at ambient temperature and then cooled with a bath of iced water, and 19.3 g (0.~2 mol) of ~-chlorobenzyl chloride. dissolved in 50 ml of DMF, are added. Once the introduction has ended, the mixture is stirred for 4 hours at ambient temperature and left to stand overnight. The reaction medium is poured into iced water and extracted 3 times with diethyl ether. The organic phase is washed once with water and then extracted with dilute HCl (1-2 N).
The aqueous phase is then rendered alkaline with NaOH.
It is extracted with diethyl ether and the ether extract is then washed 4 times with water. It is dried over magnesium sulphate, riltered and concentrated.
The oil obtained is distilled twice and the fraction passing over at 94-98C/0.04 mm Hg is collected.
This yields an oil. which is taken up in diethyl ether, and the hydrochloride is precipitated by adding hydrogen chloride. The hydrochloride is filtered off and rinsed with diethyl ether. It is taken up in the minimum amount of hot isopropanol. 5 times the volume of ethyl acetate is then added and the compound is left to recrystallise. The hydrochloride melts at 149-151~C.
~ 173039 l-senzyl-4-(3~4~5-trimethox~benzyloxy) piperidine and its Eumarate In a 250 ml three-necked round-bottomed flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol) of a 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 9.6 g (0.05 mol) of l-benzyl-4-hydroxypiperidine, dissolved in 30 ml of DMF, are then introduced. Once the addition has ended, the mixture is stirred for l hour at ambient temperature. 13 g (0.06 mol) of 3,4,5-trimethoxy-benzyl chloride in 30 ml of DMF are then added, whilst cooling with a bath of iced water. The mixture is stirred for 5 hours at ambient temperature and then left to stand overnight. The reaction medium is poured into iced water and then extracted with diethyl ether.
The product is then extracted with dilute HCl. The aqueous phase is rendered alkaline with NaOH and then extracted with diethyl ether, and the ether extract is washed with water, dried over MgS04, filtered and concentrated. The oil obtained is taken up in hot pentane. The product crystallises. It is filtered off and recrystallised from isopropanol. This yields the base. which is dissolved in 70 ml of ethanol, and a 25 filtered solution of 2.9 g (0.025 mol) of fumaric acid in 140 ml of ethanol is added. The fumarate salt ! 1 7303 9 formed is filtered off and dried. Its melting point is 160-161C.
1-(4-ChlorobenzYl)-4-~3,4.5-trimethoxybenzYloxv)-piperidine and its fumarate 6(1) 1-(4-ChlorobenzoYl)-4-hydroxypiperidine 30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHC13, 57.3 g (0.414 mol) of K2C03 and 260 ml of water are placed in a one litre Erlenmeyer flask. 51.8 g (0.2g6 mol) of ~-chlorobenzoyl chloride, dissolved in 50 ml of CHC13, are added in the course of 15 minutes.
whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with CHC13 and the CHC13 extract is washed with water until the pH is 6-7. It is dried over MgS04, filtered and concentrated.
The product is recrystallised from ethyl acetate.
6(2) 1-(4-ChlorobenzoYl)-4-(3,4.5-trimethox~benzyloxy)-piperidine In a three-necked round-bottomed flask under a nitrogen atmosphere, 0.96 g (0.022 mol) of a 55%
suspension of sodium hydride in oil is washed 3 times with petroleum ether. 4.8 g (0.02 mol) of 1-(4-chloro-benzoyl)-4-hydroxypiperidine obtained as described in 6(1), dissolved in 50 ml of DMF, are then added. After the addition has ended, the mixture is stirred for 1 ~ 1 73039 - ~2 -hour at ambient temperature. It is -then cooled with a bath of iced water, and 5.4 g (0.025 mol) of 3,4,5-trimethoxybenzyl chloride, dissolved in 10 ml of DMF, are added. The mixture is stirred for 3 hours at ambient temperature and then left to stand overnight. It is poured into iced water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over MgS04, filtered and concentrated. The oil obtained is taken up in diethyl ether and the solution is then filtered. The filtrate is concentrated and passed through an alumina column (eluant: CHC13). The product does not crystallise and is used as such in the following step.
6(3) 1-(4-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine and its fumarate In a round-bottomed flask under a nitrogen atmosphere, 7 g (0.0167 mol) of the product obtained under 6(2), dissolved in 70 ml of dry diethyl ether, are added at ambient temperature to a suspension of 0.38 g (0.01 mol) of AlLiH4 in 30 ml of dry diethyl ether. The mixture is heated for 3 hours at the reflux temperature. It is hydrolysed with 2.6 ml of isopropanol and 3.3 ml of a saturated aqueous solution of NaCl.
The mixture is filtered and the material on the filter is rinsed with diethyl ether. The product is extracted into dilute hydrochloric acid and the reaction mixture ~ 173039 is then rendered alkaline with N~I~OH and extracted with diethyl ether. The ether extract is washed with water, dried over MgSO4, filtered and concentrated. This yields an oil, which is dissolved in 30 ml of e-thanol and the solution is added to a filtered solution of 1.2 g (0.0105 mol) of fumaric acid in 60 ml of ethanol. The fumarate precipitates gradually. It is filtered off, rinsed with a small amount of ethanol and then with diethyl ether, and dried. Its melting point is 178-180C.
~ he compounds of the invention prepared by procedures described in the foregoing Exarnples are shown in the following Table.
' 173039 ~ D O ~ ~ ~
., ~ ,~ ~ ~ r-l ~ ~ ~ -1 ~1 ~ o~ o H
-a) ~ a) a) ~ a) a ~ a) ~ a) o a) a) a P
U~
, ~ 1~
X
~ -o o o ~
~ o~ ~
x - ~
~ ,~ O
u - l , ~
~ ~ CO C~
.,, ~ ~ o ,, .,, ~ o , ~ ,, ~ ~ ~o ~ o 11 $ $
a) o +~
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o ~ o o ~
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~ ~ u~ Ln~ ~ ~ ~n - ~
~1 ~ ~ ~ u~ ~1` CO ~ O
c~
' 173039 ~ ~ ~ I~
o ~ ~ o 1` ~ ~ o -- ~U~ ~ N r-l ' I ~1 CO
~1 ~ N ~1 ~ I ~0 r~
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ci~ ~1 0 1 ~1 r~ ~ ,~ ~ If) N ~ ~1 ~I L~O
O
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11 o ~ Q1l ,Q 11~
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O _ . __ ___ ~ X ~ ~ 0~ m ~ .
o o X I ~ ' o ~ m 0~ ~ d' d' ~'d' d, ~ a~
o ~ 173039 The piperidine derivatives of general formula (I) of the present invention were subjected to pharmacological experiments which demonstrated their antidepressive activity.
The toxicity of the compounds was determined on mice by intraperitoneal administration. The LD50 varies from 30 to 1000 mg/kg animal body weight.
The antidepressive activity was determined by the test for the antagonism towards the ptosis caused by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).
Mice (male, CDl Charles River, France, 18-22 g) simultaneously receive the products to be studied or the solvent (administered intraperitoneally) and reserpine (4 mg/kg animal body weight, administered subcutaneously).
Sixty minutes later. the degree of palpebral ptosis is estimated by means of a rating scale (0 to 4) for each mouse.
For each dose, the average rating and the percentage variation, compared with the control batch, are calculated.
For each product, the AD 50, or the dose which reduces the average ptosis score, compared with the controls. by 50%, is determined graphically.
The AD 50 varies from 4 to lO mg~kg animal body weight, administered lntraperitoneally.
The antidepressive activity was also determined by the test for potentiation of the head twitches caused by L-5-hydroxytryptophan tH. Van Riezen (1972) Arch.
Int. Pharmacology. 198, 256-269).
The procedure is as follows:
24 hours before the experiment, the animals are placed in the laboratory in which the operation is to be carried out. On the day of the experiment, the mice are weighed and put to sleep.
The products to be tested are then injected intraperitoneally before L5-HTP is injected subcutaneously in an amount of 125 mg/kg animal body weight as a suspension in Tween. 30 minutes after the injection of L5-HTP, the number of head twitches is counted for 60 seconds.
For each dose, the average number of head twitches and the percentage variation, relative to the control animals, are calculated. The 50% active dose is established from a curve.
The AD 50 varies from 0.1 to 5 mg~kg animal body weight, administered intraperitoneally.
The pharmacological results show that the piperidine derivatives of the present invention can be useful for the treatment of depression.
t 1 73039 The compounds of the invention can be presented in any form suitable for oral or parenteral administration. for example in the form of tablets, coated tablets, capsules, solutions to be -taken orally or injected, and the like, in association with any suitable excipient.
The daily posology can range from 5 to 200 mg.
Claims (6)
1. A process for the preparation of a piperidine derivative of the general formula:
(I) wherein R represents a hydrogen atom, or a (C1-4)alkyl, hydroxy(C1-4)alkyl, or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl or methylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom X is other than a hydrogen atom, which comprises (A) the reaction of a compound of the general formula:
(II) (wherein R1 represents a radical within symbol R as hereinbefore defined, or a nitrogen-protecting radical selected from substituted and unsubstituted benzoyl, benzyl and alkyl radicals) with a compound of the general formula:
(III) (wherein Y represents a reactive radical selected from a chlorine or bromine atom, and X is as hereinbefore defined) and, when R1 in the product obtained of the general formula:
(IV) is other than a radical R as hereinbefore defined, removing the nitrogen-protecting radical to yield a piperidine derivative of general formula (I) wherein R
represents a hydrogen atom, or reducing a substituted or unsubstituted benzoyl radical R1 in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R, or (B) in the case of a compound of general formula (I) wherein R is other than a hydrogen atom, the reaction of a piperidine derivative of the general formula:
(V) (wherein X is as hereinbefore defined) with a compound of the general formula:
Z-R2 (VI) wherein Z represents a reactive atom or group such as a halogen atom, and R2 represents a (C1-4)alkyl.
hydroxy(C1-4)alkyl or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl radical, and when an acid addition salt is required, reacting the free base obtained with a corresponding acid.
(I) wherein R represents a hydrogen atom, or a (C1-4)alkyl, hydroxy(C1-4)alkyl, or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl or methylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom X is other than a hydrogen atom, which comprises (A) the reaction of a compound of the general formula:
(II) (wherein R1 represents a radical within symbol R as hereinbefore defined, or a nitrogen-protecting radical selected from substituted and unsubstituted benzoyl, benzyl and alkyl radicals) with a compound of the general formula:
(III) (wherein Y represents a reactive radical selected from a chlorine or bromine atom, and X is as hereinbefore defined) and, when R1 in the product obtained of the general formula:
(IV) is other than a radical R as hereinbefore defined, removing the nitrogen-protecting radical to yield a piperidine derivative of general formula (I) wherein R
represents a hydrogen atom, or reducing a substituted or unsubstituted benzoyl radical R1 in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R, or (B) in the case of a compound of general formula (I) wherein R is other than a hydrogen atom, the reaction of a piperidine derivative of the general formula:
(V) (wherein X is as hereinbefore defined) with a compound of the general formula:
Z-R2 (VI) wherein Z represents a reactive atom or group such as a halogen atom, and R2 represents a (C1-4)alkyl.
hydroxy(C1-4)alkyl or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl radical, and when an acid addition salt is required, reacting the free base obtained with a corresponding acid.
2. Piperidine derivatives of the general formula:
(I) wherein R represents a hydrogen atom, or a (C1-4)alkyl, hydroxy (C1-4)alkyl, or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl or methylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom X is other than a hydrogen atom, and acid addition salts thereof, when prepared by the process claimed in claim 1 or an obvious chemical equivalent.
(I) wherein R represents a hydrogen atom, or a (C1-4)alkyl, hydroxy (C1-4)alkyl, or (C1-4)alkoxycarbonyl radical, or a benzyl radical or such radical carrying a substituent selected from halogen atoms and (C1-4)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl or methylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom X is other than a hydrogen atom, and acid addition salts thereof, when prepared by the process claimed in claim 1 or an obvious chemical equivalent.
3. A process according to claim 1 wherein X
represents at least one chlorine atom, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals.
represents at least one chlorine atom, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals.
4. Piperidine derivatives as defined in formula (I) in claim 2 wherrein X represents one or more chlorine atoms, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals, and acid addition salts thereof, when prepared by the process claimed in claim 3 or an obvious chemical equivalent.
5. A process according to claim 1 wherein X
represents at least one chlorine atom, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals and R is a hydrogen atom or a (C1-4) alkoxycarbonyl radical.
represents at least one chlorine atom, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals and R is a hydrogen atom or a (C1-4) alkoxycarbonyl radical.
6. Piperidine derivatives as defined in formula (I) in claim 2 wherein X represents at least one chlorine atom, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals and R is a hydrogen atom or a (C1-4) alkoxycarbonyl radical, when prepared by the process claimed in claim 5 or an obvious chemical equivalent.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU76769/81A AU545739B2 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives |
FI813330A FI77850C (en) | 1981-10-23 | 1981-10-23 | Process for the preparation of 4-benzyloxy or 4-naphthylmethoxypipe ridin derivatives which have antidepressant effect. |
CA000388595A CA1173039A (en) | 1981-10-23 | 1981-10-23 | 4-benzyloxypiperidine compounds |
NO813577A NO153890C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS. |
ES506500A ES8206476A1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
DK469381A DK157853C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES |
ZA817373A ZA817373B (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
JP56170536A JPS5872565A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
PT73875A PT73875B (en) | 1981-10-23 | 1981-10-23 | PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES |
GR66337A GR75364B (en) | 1981-10-23 | 1981-10-23 | |
IE2500/81A IE51707B1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
NZ198748A NZ198748A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives and pharmaceutical compositions |
Applications Claiming Priority (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU76769/81A AU545739B2 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives |
FI813330A FI77850C (en) | 1981-10-23 | 1981-10-23 | Process for the preparation of 4-benzyloxy or 4-naphthylmethoxypipe ridin derivatives which have antidepressant effect. |
CA000388595A CA1173039A (en) | 1981-10-23 | 1981-10-23 | 4-benzyloxypiperidine compounds |
NO813577A NO153890C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS. |
ES506500A ES8206476A1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
DK469381A DK157853C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES |
ZA817373A ZA817373B (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
JP56170536A JPS5872565A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
PT73875A PT73875B (en) | 1981-10-23 | 1981-10-23 | PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES |
GR66337A GR75364B (en) | 1981-10-23 | 1981-10-23 | |
IE2500/81A IE51707B1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
NZ198748A NZ198748A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives and pharmaceutical compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1173039A true CA1173039A (en) | 1984-08-21 |
Family
ID=27582840
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000388595A Expired CA1173039A (en) | 1981-10-23 | 1981-10-23 | 4-benzyloxypiperidine compounds |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS5872565A (en) |
AU (1) | AU545739B2 (en) |
CA (1) | CA1173039A (en) |
DK (1) | DK157853C (en) |
ES (1) | ES8206476A1 (en) |
FI (1) | FI77850C (en) |
GR (1) | GR75364B (en) |
IE (1) | IE51707B1 (en) |
NO (1) | NO153890C (en) |
NZ (1) | NZ198748A (en) |
PT (1) | PT73875B (en) |
ZA (1) | ZA817373B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02148948U (en) * | 1989-05-17 | 1990-12-18 | ||
US5169855A (en) * | 1990-03-28 | 1992-12-08 | Du Pont Merck Pharmaceutical Company | Piperidine ether derivatives as psychotropic drugs or plant fungicides |
JPH0535676U (en) * | 1991-06-06 | 1993-05-14 | 株式会社カネマス | Pack for reconstitution of dried seaweed |
-
1981
- 1981-10-23 AU AU76769/81A patent/AU545739B2/en not_active Ceased
- 1981-10-23 DK DK469381A patent/DK157853C/en not_active IP Right Cessation
- 1981-10-23 ZA ZA817373A patent/ZA817373B/en unknown
- 1981-10-23 NZ NZ198748A patent/NZ198748A/en unknown
- 1981-10-23 ES ES506500A patent/ES8206476A1/en not_active Expired
- 1981-10-23 JP JP56170536A patent/JPS5872565A/en active Granted
- 1981-10-23 PT PT73875A patent/PT73875B/en unknown
- 1981-10-23 IE IE2500/81A patent/IE51707B1/en not_active IP Right Cessation
- 1981-10-23 CA CA000388595A patent/CA1173039A/en not_active Expired
- 1981-10-23 GR GR66337A patent/GR75364B/el unknown
- 1981-10-23 FI FI813330A patent/FI77850C/en not_active IP Right Cessation
- 1981-10-23 NO NO813577A patent/NO153890C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NZ198748A (en) | 1984-08-24 |
JPS5872565A (en) | 1983-04-30 |
FI77850B (en) | 1989-01-31 |
IE51707B1 (en) | 1987-02-18 |
AU545739B2 (en) | 1985-08-01 |
NO813577L (en) | 1983-04-25 |
DK157853B (en) | 1990-02-26 |
IE812500L (en) | 1983-04-21 |
FI813330L (en) | 1983-04-24 |
ES506500A0 (en) | 1982-08-16 |
GR75364B (en) | 1984-07-13 |
PT73875A (en) | 1981-11-01 |
JPS6135177B2 (en) | 1986-08-12 |
DK157853C (en) | 1990-08-06 |
FI77850C (en) | 1989-05-10 |
DK469381A (en) | 1983-04-24 |
NO153890C (en) | 1986-06-11 |
PT73875B (en) | 1983-01-25 |
ZA817373B (en) | 1983-03-30 |
NO153890B (en) | 1986-03-03 |
ES8206476A1 (en) | 1982-08-16 |
AU7676981A (en) | 1983-04-28 |
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