NZ198748A - Piperidine derivatives and pharmaceutical compositions - Google Patents
Piperidine derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ198748A NZ198748A NZ198748A NZ19874881A NZ198748A NZ 198748 A NZ198748 A NZ 198748A NZ 198748 A NZ198748 A NZ 198748A NZ 19874881 A NZ19874881 A NZ 19874881A NZ 198748 A NZ198748 A NZ 198748A
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- Prior art keywords
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- general formula
- piperidine
- alkyl
- acid addition
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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
-
- 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
-
- 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, cocaine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number 1 98748
198:
Priority Dotsfs):
Complete Specification Fil&d: r1'
Cass:
PufoHcatiora Date: .. 7.7.
P.O. Journal, T^o: .. X^c\
y- £» «
LiftS
NEW ZEALAND
<^/344eT-
THE PATENTS ACT 1953
PATENTS FORM NO. 5
COMPLETE SPECIFICATION
"PIPERIDINE DERIVATIVES/ THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
WE, SYNTHELABO, a French Body Corporate of 58 Rue de la Glaciere, 75013 Paris, France,
hereby declare the invention for which we pray that a Patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by page 1
198748
DESCRIPTION
"PIPERIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
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-
The piperidine derivatives of the present invention are those compounds of the general formula:
y y- CH2 - O-^ - R (I)
wherein R represents a hydrogen atom, or a alkyl,
hydroxy(C^_4) alkyl, or (C1_4)alkoxycarbonyl radical,
or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^_^)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and x represents a hydrogen atom or one or more halogen atcms or
(C-^ ) alkyl, aikoxy, trifluororoethy1 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 not the hydrogen atom, and pharmaceutically acceptable acid
1 98748
addition salts thereof.
The piperidine derivatives of general formula (I)
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 methoxy radicals.
Of that class, those piperidine derivatives wherein R represents a hydrogen atom are particularly preferred.
the piperidine derivatives of general formula (I) 15 are prepared by the process which comprises the reaction of a compound of the general formula:
of symbol R, or a nitrogen-protecting radical such as 20 an optionally substituted benzoyl radical/ e.g.
4-nitrobenzoyl/ or an optionally substituted benzyl or alkyl radical) with a compound of the general formula:
According to a feature of the present invention/
(II)
(wherein R^ represents a radical within the definition
1 9874
3 -
^>-CH2-Y (III)
X
(wherein Y represents a reactive radical such as a chlorine or bromine atom/ and X is as hereinbefore defined) and/ when R"^" in the product obtained of the general formula:
// ^)-CH2-O-^ NST-R1 (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 10 atom, or reducing by methods known per se an optionally substituted benzoyl radical R"'" in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R.
According to a further feature of the invention, 15 a piperidine derivative of the general formula:
// V CH_-0-< ^ N-H (V)
X'
2 W
1 98748
(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 formula:
> Z-R2 (VI)
wherein Z represents a reactive atom or group, e.g. a
2
halogen atom, and R represents a (C^_4)alkyl, hydroxy-(C^_4)alkyl or (C^_^)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected 10 from halogen atoms and (C1_4)alkoxy radicals, or the phenethyl 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, 15 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 20 in this specification is meant methods heretofore used or described in the literature.
t.
1 98748
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 5 IR and NMR spectra confirm the structure of the compounds.
EXAMPLE 1
4-(4-Fluorobenzyloxy)-piperidine and its mandelate
1(1) 1-(4-Nitrobenzoyl)-4-(4-fluorobenzyloxy)-piperidine.
A mixture of 1.6 g of a 50% aqueous sodium hydroxide solution, 10 ml of methylene chloride, 2 g
(0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine,
2.3 2 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g — 4
(4 x 10 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50°C. 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 (MgS0„) and
H:
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, 1-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)-
198748
— 6 -
piperidine/ m.p. 120°Ci 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 5 48 ml of 10M aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50°C. The alcohol is driven off in vacuo and the residue is taken up in 200 ml of water/ 72 g 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 (MgSO^) and evaporated in vacuo.
This yields an oil which is converted to the d/1-mandelate by dissolving it in 100 ml of diethyl ether 15 and adding 4.57 g (0.03 mol) of d/l-mandelic acid.
The salt obtained is filtered off and recrystallised from isopropanol. Its melting point is 146°C.
EXAMPLE 2
4-(3/4/5-Trimethoxybenzyloxy)-piperidine and 20 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 98748
-4
and 0.08 g (2 x 10 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50°C. 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 (MgSO^) and evaporated in 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. 124°C/ 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 10M aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50°C. 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 (MgSO^) and evaporated in vacuo. This yields a pasty solid which is converted to the d/1-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 98748
8
been stirred overnight at ambient temperature. The precipitate obtained is recrystallised from methanol. The product crystallises with half a molecule of water. Its melting point is 114°C.
EXAMPLE 3
added dropwise to a stirred mixture of 6.83 g 10 (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0.056 mol) of dry I^CO^, 26 ml of water and 26 ml of chloroform. After stirring for 1 hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed 3 times with 20 ml of water 15 and dried (MgSO^). Evaporation of the solvent in vacuo gives a liquid, which is distilled in vacuo.
l-Ethoxycarbonyl-4-benzyloxypiperidine
3,4 g (0.033 mol) of ethyl chloroformate are
Boiling point (0.4 mm Hg): 149-151°C;
n^ = 1.5178.
EXAMPLE 4
l-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 9874
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 (0.12 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 HC1 (1-2 N). The aqueous phase is then rendered alkaline wi'th NaOH. It is extracted with diethyl ether and the ether extract is then washed 4 times with water. It is dried over magnesium sulphate, filtered and concentrated. The oil obtained is distilled twice and the fraction passing over at 94-98°C/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.
1 98748
EXAMPLE 5
l-Benzyl-4-(3/4,5-trimethoxybenzyloxy)-piperidine and its fumarate
In a 250 ml three-necked round-bottomed 5 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 10 ended/ the mixture is stirred for 1 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 15 to stand overnight. The reaction medium is poured into iced water and then extracted with diethyl ether. The product is then extracted with dilute HC1. The aqueous phase "is rendered alkaline with NaOH and then extracted with diethyl ether/ and the ether extract 20 is washed with water/ dried over MgSO^, 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
98748
formed is filtered off and dried. Its melting point is 160-161°C.
EXAMPLE 6
1-(4-Chlorobenzyl)-4-(3 ,415-trimethoxybenzyloxy)-5 piperidine and its fumarate
6(1) 1-(4-Chlorobenzoyl)-4-hydroxypiperidine
g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHCl^i 57.3 g (0.414 mol) of K^CO^ and 260 ml of water are placed in a one litre Erlenmeyer flask. 51.8 g 10 (0.296 mol) of ]D-chlorobenzoyl chloride, dissolved in 50 ml of CHCl^i 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 CHCl^ and 15 the CHCl^ 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-trimethoxybenzyloxy)-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 l-(4-chloro-benzoyl)-4-hydroxypiperidine obtained as described in 25 6(1), dissolved in 50 ml of DMF, are then added. After the addition has ended, the mixture is stirred for 1
l98748
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 MgSO^, 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: CHCl^). 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 AlLiH^ 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
I 987 4
is then rendered alkaline with NH^OH and extracted i
with diethyl ether. The ether extract is washed with water, dried over MgSO^, filtered and concentrated. This yields an oil, which is dissolved 5 in 30 ml of ethanol 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 10 dried. Its melting point is 178-180°C. ;. The compounds of the invention prepared by procedures described in the foregoing Examples are shown in the following Table. ;>mp ;1 ;2 ;3 ;4 ;5 ;6 ;7 ;8 ;9 ;10 ;TABLE ;N-R ;(I) ;X ;Salt ;Melting point (°C) of salt ;4-F 3,4-(<f ) ;x0- ;3/4,5-(OMe) ;2-Me 4-Me ;3-CF3 ;2-OMe ;3-OMe ;4-OMe 2-OEt ;H H H H H H H H H H ;d,1-mandelate d/1-mandelate d,1-mandelate d,1-mandelate d/1-mandelate d,1-mandelate hydrochloride d/1-mandelate d,1-mandelate d,1-mandelate ;146 137 114 112 119 126 170 117 129 135 ;H ;TABLE (continued) ;Compound ;X ;R ;Salt ;Melting point (°C) of salt ;11 ;3 , 4- (OMe ) 2 ;H ;d,1-mandelate ;108 ;12 ;H ;Me d,1-mandelate ;118 ;13 ;H ;C02Et oil boiling point ;(0.4 mm Hg) ;= 149-151 ;14 ;3"CF3 ;CH2CH2OH ;hydr och10 r i de ;102 ;15 ;3,4,5-(OMe) 3 ;CH(Me)2 ;citrate ;94-5 ;16 ;3 , 4,5-(OMe)3 ;C02Et base ;64 ;17 ;3-CF3 ;CH(Me)2 ;fumarate ;117 ;18 ;3-Me ;C02Et oil ;19 ;3-CF3 ;C02Et oil ;20 ;3,4,5-(OMe)3 ;Me citrate ;I ;H ;Ui I ;sO ;09 ;4* 00
• #
TABLE (continued)
Compound
X
R
Salt
Melting point (°C) of salt
21
4-Cl
Me hydrochloride
149-151
22
3-CF3
Me hydrochloride
111-2
23
3 , 4, 5- (OMe ) 3
CH2"0
fumarate
160-1
24
4-Cl
H
hydrochloride
157-9
3,4-Cl2
H
hydrochloride
142.5-144
26
3,4-Cl2
CH2^Q
hydrochloride
184-6
27
3,4-Cl2
Me hydrochloride
119-120
28
4-Cl
C02Et oil
29
4-Cl
Ch2^3
hydrochloride
171.5-173
3,4-Cl2
CH2CH2OH
hydrochloride
115.5-117
31
4-0-isoPr
H
fumarate
140-141.5
32
3 / 4, 5- (OMe ) 3
CH2"0"C1
fumarate
178-180
•
•
TABLE
•
(continued)
•
Compound
X
R
Salt
Melting point (°C) of salt
33
34
4-OMe 4-isoPr
CH2CH2-0
H
hydrochloride fumarate
165-7 145-6
-c>
H
fumarate
170-171.5
36
4-OMe
CH2-(^~VoMe fumarate
138-9
37
3,4,5- (OMe ) 3
CH2^P>
fumarate
167.5-168.5
38
4-OMe
/
CI
ch2^3-ci fumarate
167-8
39
4-OMe
CH2^V3
fumarate
152-3
. 40
4-OMe
MC1
CH2"0
CI
fumarate
137-8
41
2,4-Cl2
CH2CH2OH
fumarate
106-7
TABLE (continued)
Compound
X
R
Salt
Melting point (°C) of salt
42
3,4,5-(OMe) 3
CH2CH2^3>
fumarate
147-8
43
44 ■
4-Cl 3 , 4,5-(OMe)3
CH2CH2CH2"0
fumarate fumarate
148-9 180-181.5
45
4-OMe
CH2CH2CH2^0>
fumarate
125.5-127
46
3,4-Cl2
C02Me oil
47
2,4-Cl2
C02Et oil boiling point =164-8°C/
0.001 mm
48
C02Et oil boiling point
= 183-5°C/ 0.003 mm
49
4-Br
H
hydrochloride
205-7
198748
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 10 by reserpine (C. Gouret et a_l. , 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 15 (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 25 controls, by 50%, is determined graphically.
198748
The AD 50 varies from 4 to 10 mg/kg animal body weight, administered intraperitoneally.
The antidepressive activity was also determined by the test for potentiation of the head twitches caused 5 by L-5-hydroxytryptophan (H. Van Riezen (197 2) 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 10 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 15 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 20 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 25 piperidine derivatives of the present invention can be useful for the treatment of depression.
1 9874
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.
i 98748
22
Claims (9)
1- Piperidine derivatives of the general formula: X !H2-'0 < \ / N - R (I) wherein R represents a hydrogen atom, or a (C^_^)alkyl, hydroxy(C^_^)alkyl, or (C^_4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C-^_^)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents a hydrogen atom or one or more halogen atoms or (C1-4)alkyl, (C^_4)alkoxy, trifluoraiethyl or roethylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atcm then X is not the hydrogen atcm, and pharmaoeutically acceptable acid addition salts thereof.
2. Piperidine derivatives according to claim 1 wherein X represents one or more chlorine atoms, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals, and pharmaceutically acceptable acid addition salts thereof. 198 - 23 -
3. Piperidine derivatives according to claim 1 or 2 wherein R in the general formula depicted in claim 1 represents a hydrogen atom, or a alkoxycarbonyl radical and pharmaceutical^ acceptable acid addition salts thereof.
4. A piperidine derivative and salts thereof < according to claim 1 as indicated in compounds 1 to 49 in the Table herein.
5- A process for the preparation of a piperidine. derivative as claimed in claim 1 which comprises the reaction of a compound of the general formula: (wherein R1 represents a radical within symbol R as defined in claim 1, or a nitrogen-protecting radical') with a compound of the general formula: 1 O 0 A Q I ; o / -i- o - 24 - // V CH2-Y (III) (wherein Y represents a reactive radical and X is as defined in claim 1) and, when in the product obtained of the general formula: ■ CH2-0—/N-R1 (IV) is other than a radical R as defined in claim li removing the nitrogen-protecting radical to yield a piperidine derivative of general formula (I) depicted in claim 1 wherein R represents a hydrogen atom, or reducing by methods known per se an optionally substituted benzoyl radical' R"*" in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R.;6. A process for the preparation of a piperidine derivative as claimed in claim 1 wherein R represents a (C^_4)alkyl, hydroxy(C^_4)alkyl or (C-^_4)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^_^)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl r<V o* rr i [ £-8 MAY 1984^ V%. jf j i 98748 - 25 - radical/ and X is as defined in claim 1, which comprises the reaction of a piperidine derivative of the general formula: (V) (wherein X is as defined in claim 1) with a compound of the general formula: Z-R2 (VI) wherein Z represents a reactive atom or group
A 2 , ■ and R represents a (C-^^Jalkyl, hydroxy- (C-^_^)alkyl or (C^ ^)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^_^)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl radical.
7. A process according to claim 5 or 6 followed by the step of converting by methods known per se a piperidine derivative of the general formula depicted in claim 1 so obtained into an acid addition salt.
8 . Pharmaceutical compositions which comprise, as active ingredient, at least one piperidine derivative as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof/ in association with any suitable excipient. y ft it MAYt984r I 9874c - 26 -
9 . Piperidine derivatives of the general formula depicted in claim 1, wherein R and X are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof in a form suitable for use as a medicament. - Sy ?>Jtfiarise^ Agents.,
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA817373A ZA817373B (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 |
| 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. |
| ES506500A ES506500A0 (en) | 1981-10-23 | 1981-10-23 | PIPERIDINE DERIVATIVES PREPARATION PROCEDURE |
| PT73875A PT73875B (en) | 1981-10-23 | 1981-10-23 | PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES |
| JP56170536A JPS5872565A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
| CA000388595A CA1173039A (en) | 1981-10-23 | 1981-10-23 | 4-benzyloxypiperidine compounds |
| GR66337A GR75364B (en) | 1981-10-23 | 1981-10-23 | |
| DK469381A DK157853C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES |
| AU76769/81A AU545739B2 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives |
| IE2500/81A IE51707B1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
| NO813577A NO153890C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS. |
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA817373A ZA817373B (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 |
| 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. |
| ES506500A ES506500A0 (en) | 1981-10-23 | 1981-10-23 | PIPERIDINE DERIVATIVES PREPARATION PROCEDURE |
| PT73875A PT73875B (en) | 1981-10-23 | 1981-10-23 | PROCESS FOR THE PREPARATION OF THERAPEUTICALLY APPLICABLE PIPERIDINE DERIVATIVES |
| JP56170536A JPS5872565A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivative and application to medicine |
| CA000388595A CA1173039A (en) | 1981-10-23 | 1981-10-23 | 4-benzyloxypiperidine compounds |
| GR66337A GR75364B (en) | 1981-10-23 | 1981-10-23 | |
| DK469381A DK157853C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF 4-BENZYLOXYPIPERIDE INGREDIATES |
| AU76769/81A AU545739B2 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives |
| IE2500/81A IE51707B1 (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives,their preparation and pharmaceutical compositions containing them |
| NO813577A NO153890C (en) | 1981-10-23 | 1981-10-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERIDE INGREDIENTS. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ198748A true NZ198748A (en) | 1984-08-24 |
Family
ID=27582840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ198748A NZ198748A (en) | 1981-10-23 | 1981-10-23 | Piperidine derivatives and pharmaceutical compositions |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5872565A (en) |
| AU (1) | AU545739B2 (en) |
| CA (1) | CA1173039A (en) |
| DK (1) | DK157853C (en) |
| ES (1) | ES506500A0 (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 ES ES506500A patent/ES506500A0/en active Granted
- 1981-10-23 PT PT73875A patent/PT73875B/en unknown
- 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
- 1981-10-23 IE IE2500/81A patent/IE51707B1/en not_active IP Right Cessation
- 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 JP JP56170536A patent/JPS5872565A/en active Granted
- 1981-10-23 AU AU76769/81A patent/AU545739B2/en not_active Ceased
- 1981-10-23 CA CA000388595A patent/CA1173039A/en not_active Expired
- 1981-10-23 NZ NZ198748A patent/NZ198748A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI77850C (en) | 1989-05-10 |
| ES8206476A1 (en) | 1982-08-16 |
| ZA817373B (en) | 1983-03-30 |
| FI77850B (en) | 1989-01-31 |
| FI813330L (en) | 1983-04-24 |
| AU545739B2 (en) | 1985-08-01 |
| NO813577L (en) | 1983-04-25 |
| GR75364B (en) | 1984-07-13 |
| IE51707B1 (en) | 1987-02-18 |
| AU7676981A (en) | 1983-04-28 |
| JPS5872565A (en) | 1983-04-30 |
| NO153890B (en) | 1986-03-03 |
| CA1173039A (en) | 1984-08-21 |
| IE812500L (en) | 1983-04-21 |
| JPS6135177B2 (en) | 1986-08-12 |
| NO153890C (en) | 1986-06-11 |
| PT73875B (en) | 1983-01-25 |
| DK157853B (en) | 1990-02-26 |
| ES506500A0 (en) | 1982-08-16 |
| DK469381A (en) | 1983-04-24 |
| PT73875A (en) | 1981-11-01 |
| DK157853C (en) | 1990-08-06 |
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