FR2721513A1 - Use of 1,2,5,6-tetrahydropyridine derivatives for the manufacture of sedative drugs. - Google Patents
Use of 1,2,5,6-tetrahydropyridine derivatives for the manufacture of sedative drugs. Download PDFInfo
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- FR2721513A1 FR2721513A1 FR9407736A FR9407736A FR2721513A1 FR 2721513 A1 FR2721513 A1 FR 2721513A1 FR 9407736 A FR9407736 A FR 9407736A FR 9407736 A FR9407736 A FR 9407736A FR 2721513 A1 FR2721513 A1 FR 2721513A1
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- 230000001624 sedative effect Effects 0.000 title claims abstract description 6
- 239000003814 drug Substances 0.000 title claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical class C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 title description 2
- 239000000932 sedative agent Substances 0.000 title description 2
- 229940079593 drug Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000037870 generalized anxiety Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention concerne l'utilisation de dérivés de 1,2,5,6-tétrahydropyridine en thérapeutique, notamment comme sédatifs. The present invention relates to the use of 1,2,5,6-tetrahydropyridine derivatives in therapy, especially as sedatives.
La présente invention concerne plus spécifiquement l'utilisation en thérapeutique des composés de formule
Certains de ces composés ont déjà été décrits comme produits produits intermédiaires dans EP-A- 156 433 et FR-A-2 518 093. Le composé où R = 3-CF3 a été décrit
DANS DE-A-2 904 826 comme utile dans le traitement de l'obésité et d'états dépressifs et le composé où R = 3-OH a été décrit dans DE-A-3 149 703 comme utile dans le traitement de syndromes d'origine extrapyramidale.Some of these compounds have already been described as intermediate products in EP-A-156 433 and FR-A-2 518 093. The compound where R = 3-CF3 has been described
DE-A-2 904 826 as useful in the treatment of obesity and depressive states and the compound where R = 3-OH has been described in DE-A-3 149 703 as useful in the treatment of diabetic syndromes. extrapyramidal origin.
La présente invention a donc pour objet l'utilisation de composés de formule
dans laquelle R est choisi parmi les groupes 3-fluoro, 4-chloro, 3-méthyle, 3-trifluorométhyle, 3-méthoxy et 3hydroxy, et de leurs sels d'addition avec des acides pharmaceutiquement acceptables, pour la fabrication d'un médicament ayant un effet sédatif. The subject of the present invention is therefore the use of compounds of formula
wherein R is selected from 3-fluoro, 4-chloro, 3-methyl, 3-trifluoromethyl, 3-methoxy and 3-hydroxy, and their addition salts with pharmaceutically acceptable acids, for the manufacture of a medicament having a sedative effect.
La présente invention a également pour objet une composition thérapeutique contenant, à titre de principe actif, un composé de formule
dans laquelle R est choisi parmi les groupes 3-fluoro, 4-chloro, 3-méthyle et 3-méthoxy, ou un de ses sels d'addition avec un acide pharmaceutiquement acceptable.The present invention also relates to a therapeutic composition containing, as active principle, a compound of formula
wherein R is selected from 3-fluoro, 4-chloro, 3-methyl and 3-methoxy, or an addition salt thereof with a pharmaceutically acceptable acid.
Les "sels d'addition avec des acides pharmaceutiquement acceptables" désignent les sels qui donnent les propriétés biologiques des bases libres, sans avoir d'effet indésirable. Ces sels peuvent être notamment ceux formés avec des acides minéraux, tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique; des sels métalliques acides, tels que l'orthophosphate disodique et le sulfate monopotassique, et des acides organiques tels que l'acide formique, l'acide acétique, l'acide propionique, l'acide glycolique, l'acide oxalique, l'acide fumarique, l'acide maléique, l'acide citrique, l'acide malonique, l'acide méthane sulfonique, l'acide lactique, l'acide succinique, l'acide tartrique. "Pharmaceutically acceptable acid addition salts" means those salts which give the biological properties of the free bases without undesirable effects. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, acid fumaric, maleic acid, citric acid, malonic acid, methanesulfonic acid, lactic acid, succinic acid, tartaric acid.
Les compositions thérapeutiques contenant les composés de formule I peuvent être administrées chez l'homme ou aux animaux par voie orale ou parentérale. Therapeutic compositions containing the compounds of formula I can be administered in humans or animals orally or parenterally.
Elles peuvent être sous la forme de préparations solides, semi-solides ou liquides. Comme exemple, on peut citer les comprimés, les gélules, les suppositoires, les solutions ou suspensions injectables, ainsi que les formes-retard et les formes implantées à libéra tion lente. They can be in the form of solid, semi-solid or liquid preparations. Examples include tablets, capsules, suppositories, injectable solutions or suspensions, as well as delayed forms and slow-release implanted forms.
Dans ces compositions, le principe actif est généralement mélangé avec un ou plusieurs excipients pharmaceutiquement acceptables habituels bien connus de l'homme de l'art. In these compositions, the active ingredient is generally mixed with one or more conventional pharmaceutically acceptable excipients well known to those skilled in the art.
La quantité de principe actif administrée dépend évidemment du patient qui est traité, de la voie d'administration et de la sévérité de la maladie. The amount of active ingredient administered obviously depends on the patient being treated, the route of administration and the severity of the disease.
On donnera ci-après des résultats pharmacologiques et toxicologiques mettant en évidence les propriétés des composés de formule I. Pharmacological and toxicological results highlighting the properties of the compounds of formula I will be given hereinafter.
Les composés testés sont les suivants
<tb> Exemple <SEP> Code <SEP> R <SEP> Sel
<tb> <SEP> 1 <SEP> CRL <SEP> 41 <SEP> 919 <SEP> 3-F <SEP> HC1 <SEP>
<tb> <SEP> 2 <SEP> CRL <SEP> 41 <SEP> 997 <SEP> 4-C1 <SEP> HC1 <SEP>
<tb> <SEP> 3 <SEP> CRL <SEP> 41 <SEP> 998 <SEP> 3-CH3 <SEP> HC1 <SEP>
<tb> <SEP> 4 <SEP> CRL <SEP> 42 <SEP> 000 <SEP> 3-OCH3 <SEP> HC1 <SEP>
<tb> <SEP> 5 <SEP> I <SEP> CRL <SEP> 41 <SEP> 721 <SEP> 3-CF3 <SEP> HC1 <SEP>
<tb> <SEP> 6 <SEP> CRL <SEP> 42 <SEP> 024 <SEP> 3-OH <SEP> HC1 <SEP>
<tb>
I - Prétoxicité
Des études de prétoxicité ont été effectuées chez la souris NMRI (3 animaux par dose) avec des doses croissantes de 16, 32, 64, 128, 256 et 512 mg/kg, de produits administrés par voie intrapéritonéale. On donnera la dose provoquant la mort des trois animaux testés.<tb> Example <SEP> Code <SEP> R <SEP> Salt
<tb><SEP> 1 <SEP> CRL <SEP> 41 <SEP> 919 <SEP> 3-F <SEP> HC1 <SEP>
<tb><SEP> 2 <SEP> CRL <SEP> 41 <SEP> 997 <SEP> 4-C1 <SEP> HC1 <SEP>
<tb><SEP> 3 <SEP> CRL <SEP> 41 <SEP> 998 <SEP> 3-CH3 <SEP> HC1 <SEP>
<tb><SEP> 4 <SEP> CRL <SEP> 42 <SEP> 000 <SEP> 3-OCH3 <SEP> HC1 <SEP>
<tb><SEP> 5 <SEP> I <SEP> CRL <SEP> 41 <SEP> 721 <SEP> 3-CF3 <SEP> HC1 <SEP>
<tb><SEP> 6 <SEP> CRL <SEP> 42 <SEP> 024 <SEP> 3-OH <SEP> HC1 <SEP>
<Tb>
I - Pretoxicity
Pre-toxicity studies were performed in the NMRI mouse (3 animals per dose) with increasing doses of 16, 32, 64, 128, 256 and 512 mg / kg of intraperitoneally administered products. Give the dose causing the death of the three animals tested.
Composé mq/kq IP
Exemple 1 64
Exemple 2 128
Exemple 3 128
Exemple 4 128
Exemple 5 128
Exemple 6 128
II - Effet sédatif
a) Action sur la motilité spontanée chez la souris
Une demi-heure après avoir reçu le composé à tester par voie intrapéritonéale, les souris sont placées en actimètre où leur motilité est enregistrée pendant 30 minutes.Compound mq / kq IP
Example 1 64
Example 2 128
Example 3 128
Example 4 128
Example 5 128
Example 6 128
II - Sedative effect
a) Action on spontaneous motility in mice
Half an hour after receiving the test compound intraperitoneally, the mice are placed in an actimeter where their motility is recorded for 30 minutes.
On observe une diminution significative de la locomotion dès la dose de 0,125 mg/kg avec le composé de l'exemple 1 et dès la dose de 0,5 mg/kg avec les composés des exemples 2 et 3. A significant decrease in locomotion was observed at a dose of 0.125 mg / kg with the compound of Example 1 and at a dose of 0.5 mg / kg with the compounds of Examples 2 and 3.
b) Action sur l'agressivité intergroupes
Après avoir séjourné pendant 3 semaines dans chacune des moitiés d'une cage séparées par une cloison opaque, des groupes de 3 souris reçoivent le composé à tester. Une demi-heure plus tard, les deux groupes d'une même cage sont réunis par retrait de la cloison et on note le nombre de combats qui surviennent en 10 minutes.b) Action on intergroup aggression
After having stayed for 3 weeks in each of the halves of a cage separated by an opaque septum, groups of 3 mice receive the compound to be tested. Half an hour later, the two groups of the same cage are gathered by removing the partition and we note the number of fights that occur in 10 minutes.
On observe une diminution du nombre de combats dès la dose de 0,063 mg/kg avec le composé de l'exemple 1 et dès la dose de 0,125 mg/kg avec les composés des exemples 2 et 3. A reduction in the number of fights was observed at the dose of 0.063 mg / kg with the compound of Example 1 and at the dose of 0.125 mg / kg with the compounds of Examples 2 and 3.
c) Affinité pour les récepteurs a2 du cortex cérébral du rat
- Méthode
Les rats (mâles, CDl, Sprague Dawley, 200-250 g) sont sacrifiés par décapitation. Le cortex cérabral est immédiatement prélevé. Les cortex cérébraux de 4 rats sont homogénéisés dans 40 ml de tampon. Les homogénats sont centrifugés à 20.000 tours/minute pendant 15 minutes. Le culot remis en suspension dans 40 ml de tampon est soumis à une deuxième centrifugation (20.000 tours/minute pendant 15 minutes). Le culot ainsi obtenu est mis en suspension dans 8 ml de tampon, puis conservé à -80 C jusqu'à utilisation. Le jour de l'essai, une suspension membranaire est préparée à partir de la suspension congelée.Des aliquots de cette suspension membranaire sont mélangés aux ligands radioactifs (utilisés comme marqueur de chaque type de récepteur) et à des concentrations croissantes du composé à tester, puis mis à incuber (volume final : 1 ml). L'arrêt de la réaction se fait par filtration sur un système HARVESTER 48 trous (bande diltre GF/B WHATMAN). La bande filtre est ensuite lavée 3 fois par 5 Ml de tampon puis placée dans un système automatique (BRANDEL) de découpe. Les filtres coupés tombent dans des fioles de comptage de 4 ml de liquide scintillant (Aquasafe 300, ZINSSER) sont distribués automatiquement par le même système (BRANDEL).c) Affinity for the a2 receptors of the rat cerebral cortex
- Method
The rats (males, CD1, Sprague Dawley, 200-250 g) are sacrificed by decapitation. The cerebral cortex is immediately removed. The cerebral cortex of 4 rats are homogenized in 40 ml of buffer. The homogenates are centrifuged at 20,000 rpm for 15 minutes. The pellet resuspended in 40 ml of buffer is subjected to a second centrifugation (20,000 rpm for 15 minutes). The pellet thus obtained is suspended in 8 ml of buffer and then stored at -80 ° C. until use. On the day of the test, a membrane suspension is prepared from the frozen suspension. Aliquots of this membrane suspension are mixed with the radioactive ligands (used as a marker for each type of receptor) and at increasing concentrations of the test compound. then incubated (final volume: 1 ml). The reaction is stopped by filtration on a 48-hole HARVESTER system (GF / B WHATMAN dilator tape). The filter strip is then washed 3 times with 5 ml of buffer and then placed in an automatic cutting system (BRANDEL). The cut filters fall into counting vials of 4 ml of scintillating liquid (Aquasafe 300, ZINSSER) are automatically dispensed by the same system (BRANDEL).
Chaque échantillon est soumis au comptage de la radioactivité à l'aide d'un compteur à scintillation liquide (KONTRON). Trois séries d'essai sont réalisées avec le composé à tester, chaque essai étant réalisé en double.Each sample is counted for radioactivity using a liquid scintillation counter (KONTRON). Three test series are carried out with the test compound, each test being performed in duplicate.
La liaison spécifique est définie comme la différence entre la liaison totale et la liaison non spécifique (déplacée par un excès de ligand non radioactif). Les valeurs obtenues en coups par minute (c.p.m.) sont ensuite transformées en désintégrations par minute (d.p.m.) en fonction du rendement du compteur. Specific binding is defined as the difference between total binding and non-specific binding (displaced by excess non-radioactive ligand). The values obtained in counts per minute (c.p.m.) are then converted into disintegrations per minute (d.p.m.) as a function of the meter performance.
Le CI50 est défini comme la concentration de la substance étudiée, nécessaire pour déplacer 50 * du marqueur radioactif lié spécifiquement. IC50 is defined as the concentration of the test substance required to displace 50% of the specifically bound radioactive label.
Les données expérimentales sont analysées au moyen du logiciel LIGAND* qui calcule la concentration inhibitrice 50 % (CIw
On donnera ci-après les résultats obtenus en utilisant comme marqueur [H]clonidine.
The results obtained using the [H] clonidine marker will be given below.
<tb><Tb>
Composé <SEP> testé <SEP> CI50 <SEP> (mole/1) <SEP>
<tb> Composé <SEP> de <SEP> l'exemple <SEP> 1 <SEP> 1,6.10-7 <SEP>
<tb> <SEP> (CRL <SEP> 41 <SEP> 919)
<tb>
Les composés de formule I peuvent être utilisés pour le traitement de l'anxiété, en particulier des états d'anxiété généralisée et des troubles de panique (tels que définis dans DSM III-R) chez l'homme.Compound <SEP> tested <SEP> IC50 <SEP> (mole / 1) <SEP>
<tb> Compound <SEP> of <SEP> Example <SEP> 1 <SEP> 1.6.10-7 <SEP>
<tb><SEP> (CRL <SEP> 41 <SEP> 919)
<Tb>
The compounds of formula I can be used for the treatment of anxiety, particularly generalized anxiety states and panic disorders (as defined in DSM III-R) in humans.
Dans ces indications, ils peuvent être administrés à des doses journalières de 1 à 100 mg. In these indications, they may be administered at daily doses of 1 to 100 mg.
Claims (4)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9407736A FR2721513B1 (en) | 1994-06-23 | 1994-06-23 | Use of 1,2,5,6-tetrahydropyridine derivatives for the manufacture of drugs with a sedative effect. |
| AU28902/95A AU2890295A (en) | 1994-06-23 | 1995-06-23 | Utilisation of derivatives of 1,2,5,6-tetrahydropyridine for the preparation of sedative medicaments |
| CA002193397A CA2193397A1 (en) | 1994-06-23 | 1995-06-23 | Utilisation of derivatives of 1,2,5,6-tetrahydropyridine for the preparation of sedative medicaments |
| EP95924363A EP0766561A1 (en) | 1994-06-23 | 1995-06-23 | Utilisation of derivatives of 1,2,5,6-tetrahydropyridine for the preparation of sedative medicaments |
| JP8502867A JPH10502069A (en) | 1994-06-23 | 1995-06-23 | Use of 1,2,5,6-tetrahydropyridine derivatives for the preparation of a medicament having a sedative effect |
| PCT/FR1995/000844 WO1996000063A1 (en) | 1994-06-23 | 1995-06-23 | Utilisation of derivatives of 1,2,5,6-tetrahydropyridine for the preparation of sedative medicaments |
| FI965186A FI965186A (en) | 1994-06-23 | 1996-12-20 | Use of 1,2,5,6-tetrahydropyridine derivatives for the preparation of sedative drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9407736A FR2721513B1 (en) | 1994-06-23 | 1994-06-23 | Use of 1,2,5,6-tetrahydropyridine derivatives for the manufacture of drugs with a sedative effect. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2721513A1 true FR2721513A1 (en) | 1995-12-29 |
| FR2721513B1 FR2721513B1 (en) | 1996-09-06 |
Family
ID=9464580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9407736A Expired - Fee Related FR2721513B1 (en) | 1994-06-23 | 1994-06-23 | Use of 1,2,5,6-tetrahydropyridine derivatives for the manufacture of drugs with a sedative effect. |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0766561A1 (en) |
| JP (1) | JPH10502069A (en) |
| AU (1) | AU2890295A (en) |
| CA (1) | CA2193397A1 (en) |
| FI (1) | FI965186A (en) |
| FR (1) | FR2721513B1 (en) |
| WO (1) | WO1996000063A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2783658B1 (en) | 1998-09-23 | 2000-10-13 | Thomson Multimedia Sa | PROTECTION AGAINST COPYING OF DIGITAL DATA STORED ON AN INFORMATION MEDIUM |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2904826A1 (en) * | 1978-02-08 | 1979-08-09 | Roussel Uclaf | NEW DERIVATIVES OF 3-PHENYLTETRAHYDROPYRIDINE AND THEIR SALT, PROCESS FOR THEIR PRODUCTION, THEIR USE AS A MEDICINAL PRODUCT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2496099A1 (en) * | 1980-12-15 | 1982-06-18 | Roussel Uclaf | NOVEL HYDROXYPHENYL TETRAHYDROPYRIDINE DERIVATIVES, THEIR SALTS, PROCESS AND PREPARATION INTERMEDIATES, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
| CA1133479A (en) * | 1977-09-13 | 1982-10-12 | Thomas H. Althuis | 3-(2-hydroxy-4-(substituted) phenyl) azacycloalkanes and derivatives thereof as analgesic agents and intermediates thereof |
| FR2518093A2 (en) * | 1980-12-15 | 1983-06-17 | Roussel Uclaf | 3-1,2,5,6-Tetra:hydro-1-substd.-3-pyridyl phenol derivs. - dopaminergic agonists and/or antagonists and antiemetics, used to treat Parkinson's disease, psychic disorders etc. |
| EP0156433A2 (en) * | 1984-03-26 | 1985-10-02 | Janssen Pharmaceutica N.V. | Anti-virally active pyridazinamines |
| EP0192521A1 (en) * | 1985-02-01 | 1986-08-27 | LABORATOIRE L. LAFON Société anonyme dite: | 3-Phenyl-tetrahydropyridine derivatives, process for their preparation and their therapeutical use |
| EP0369887A2 (en) * | 1988-11-18 | 1990-05-23 | Sanofi | Use of trifluoromethyl phenyl-tetrahydropyridines in the manufacture of a medicament for the treatment of anxio-depressive disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2703354B1 (en) * | 1993-03-31 | 1995-06-30 | Lafon Labor | DERIVATIVES OF 1, 2, 5, 6-TETRAHYDROPYRIDINE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS. |
-
1994
- 1994-06-23 FR FR9407736A patent/FR2721513B1/en not_active Expired - Fee Related
-
1995
- 1995-06-23 CA CA002193397A patent/CA2193397A1/en not_active Abandoned
- 1995-06-23 AU AU28902/95A patent/AU2890295A/en not_active Abandoned
- 1995-06-23 EP EP95924363A patent/EP0766561A1/en not_active Withdrawn
- 1995-06-23 WO PCT/FR1995/000844 patent/WO1996000063A1/en not_active Application Discontinuation
- 1995-06-23 JP JP8502867A patent/JPH10502069A/en active Pending
-
1996
- 1996-12-20 FI FI965186A patent/FI965186A/en unknown
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1133479A (en) * | 1977-09-13 | 1982-10-12 | Thomas H. Althuis | 3-(2-hydroxy-4-(substituted) phenyl) azacycloalkanes and derivatives thereof as analgesic agents and intermediates thereof |
| DE2904826A1 (en) * | 1978-02-08 | 1979-08-09 | Roussel Uclaf | NEW DERIVATIVES OF 3-PHENYLTETRAHYDROPYRIDINE AND THEIR SALT, PROCESS FOR THEIR PRODUCTION, THEIR USE AS A MEDICINAL PRODUCT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2416886A1 (en) * | 1978-02-08 | 1979-09-07 | Roussel Uclaf | NEW 3-PHENYL-TETRAHYDROPYRIDINE DERIVATIVES AND THEIR SALTS, METHODS OF PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS |
| FR2496099A1 (en) * | 1980-12-15 | 1982-06-18 | Roussel Uclaf | NOVEL HYDROXYPHENYL TETRAHYDROPYRIDINE DERIVATIVES, THEIR SALTS, PROCESS AND PREPARATION INTERMEDIATES, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
| DE3149703A1 (en) * | 1980-12-15 | 1982-06-24 | Roussel-Uclaf, 75007 Paris | "NEW HYDROXYPHENYL-TETRAHYDROPYRIDINE DERIVATIVES, THEIR SALTS, THEIR PRODUCTION PROCESS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION, THEIR USE AS A MEDICINAL PRODUCT AND THE COMPOSITIONS CONTAINING THE SAME" |
| FR2518093A2 (en) * | 1980-12-15 | 1983-06-17 | Roussel Uclaf | 3-1,2,5,6-Tetra:hydro-1-substd.-3-pyridyl phenol derivs. - dopaminergic agonists and/or antagonists and antiemetics, used to treat Parkinson's disease, psychic disorders etc. |
| EP0156433A2 (en) * | 1984-03-26 | 1985-10-02 | Janssen Pharmaceutica N.V. | Anti-virally active pyridazinamines |
| EP0192521A1 (en) * | 1985-02-01 | 1986-08-27 | LABORATOIRE L. LAFON Société anonyme dite: | 3-Phenyl-tetrahydropyridine derivatives, process for their preparation and their therapeutical use |
| EP0369887A2 (en) * | 1988-11-18 | 1990-05-23 | Sanofi | Use of trifluoromethyl phenyl-tetrahydropyridines in the manufacture of a medicament for the treatment of anxio-depressive disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2890295A (en) | 1996-01-19 |
| FR2721513B1 (en) | 1996-09-06 |
| FI965186A (en) | 1997-02-14 |
| JPH10502069A (en) | 1998-02-24 |
| EP0766561A1 (en) | 1997-04-09 |
| CA2193397A1 (en) | 1996-01-04 |
| WO1996000063A1 (en) | 1996-01-04 |
| FI965186A0 (en) | 1996-12-20 |
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| Date | Code | Title | Description |
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| ST | Notification of lapse |