FR2507602A1 - N-4,5-di:hydro-2-thiazolyl 4-hydroxy 3-quinoline-carboxamide derivs. - anxiolytics having strong affinity for benzodiazepine receptors, opt. used in association with neuroleptics or antidepressants - Google Patents

N-4,5-di:hydro-2-thiazolyl 4-hydroxy 3-quinoline-carboxamide derivs. - anxiolytics having strong affinity for benzodiazepine receptors, opt. used in association with neuroleptics or antidepressants Download PDF

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FR2507602A1
FR2507602A1 FR8111607A FR8111607A FR2507602A1 FR 2507602 A1 FR2507602 A1 FR 2507602A1 FR 8111607 A FR8111607 A FR 8111607A FR 8111607 A FR8111607 A FR 8111607A FR 2507602 A1 FR2507602 A1 FR 2507602A1
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thiazolyl
hydroxy
dihydro
quinoline
addition salts
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FR2507602B1 (en
Inventor
Francois Clemence
Peter Francis Hunt
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Sanofi Aventis France
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Roussel Uclaf SA
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Priority to FR8111607A priority Critical patent/FR2507602A1/en
Priority to HU821657A priority patent/HU190796B/en
Priority to MA19695A priority patent/MA19488A1/en
Priority to IL65943A priority patent/IL65943A/en
Priority to ES512852A priority patent/ES512852A0/en
Priority to ZA823982A priority patent/ZA823982B/en
Priority to PT75023A priority patent/PT75023B/en
Priority to EG32982A priority patent/EG15915A/en
Priority to US06/386,597 priority patent/US4450166A/en
Priority to FI822067A priority patent/FI78087C/en
Priority to JP57098602A priority patent/JPS57212181A/en
Priority to MX794482A priority patent/MX155120A/en
Priority to GR68384A priority patent/GR77201B/el
Priority to DE8282401062T priority patent/DE3262536D1/en
Priority to IE1394/82A priority patent/IE53520B1/en
Priority to AU84827/82A priority patent/AU552029B2/en
Priority to AT82401062T priority patent/ATE12111T1/en
Priority to NZ200931A priority patent/NZ200931A/en
Priority to CA000405006A priority patent/CA1216795A/en
Priority to DK262782A priority patent/DK150070C/en
Priority to KR8202613A priority patent/KR880000808B1/en
Priority to EP82401062A priority patent/EP0067772B1/en
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    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

N-(4,5-Dihydro-2-thiazolyl)- 6- or 7-R1-2-R-4-hydroxy -3-quinoline- carboxamide derivs. of formula (I) and their acid addition salts are new. (Where R is H or 1-4C alkyl; R1 is in position 6 or 7 and is H, halo, 1-4C linear alkyl, 3-5C branched alkyl, 1-4C alkoxy, trifluoromethylthio, methylthio, trifluoromethoxy or trifluoromethyl). Cpds. (I) are anxiolytics used to treat anxiety, such as chronic anxiety associated with insomnia, behaviour problems, distress etc. or used in association with neuroleptics or antidepressants to treat psychotic or depressive states. (I) have a strong affinity for the benzodiazepine receptors and may be administered orally or parenterally. Activity and toxicity tests are described. (I) where (a) R is H or methyl and R1 is H and (b) R is H and R1 is 6-ethyl or 6-chloro including their acid addn. salts are specifically claimed.

Description

La présente invention concerne un nouveau dérivé dihydrothiazolé de la quinoléine, à savoir le N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide ainsi que ses sels, le procédé de préparation, l'application à titre de médicaments de ces nouveaux dérivés et les compositions les renfermant. The present invention relates to a new dihydrothiazole derivative of quinoline, namely N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide and its salts, the preparation process, the application as drugs of these new derivatives and the compositions containing them.

Dans son brevet français nO 2 340 735 et son premier certificat dtaddition nO 2 377 400, la demanderesse a décrit des dérivés de 1 acide 3-quinoléine carboxylique doués de propriétés analgésiques, et dont la formule générale englobe le produit précité. Par contre, ce produit ntest pas spécifiquement décrit. In its French patent No. 2,340,735 and its first certificate of addition No. 2,377,400, the Applicant has described derivatives of 1 3-quinoline carboxylic acid endowed with analgesic properties, the general formula of which includes the aforementioned product. However, this product is not specifically described.

Or, il vient titre découvert, de manière surprenante, que le N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide et ses sels étaient doués de remarquables propriétés snxi olytiques.  However, it has just surprisingly found that N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide and its salts were endowed with remarkable snxi olytic properties.

Ctest ainsi que la présente invention a pour objet le N (4, 5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide, ainsi que ses sels draddition avec les acides minéraux ou or paniques
Les sels addition avec les acides minéraux ou organiques peuvent & e J par exemple, les sels formés avec les acides chlorhydrique, bromhydrique, nitrique, sulfurique, phosphorique, acétique, formique, priopionique, benzoSque, maléique, fumarique, succinique, tartrique, citrique, oxalique, glyoxylique, aspartique, alcane sulfoniques tels que les acides méthane ou éthane sulfoniques, arylsulfoniquesÇ tels que les acides benzène ou paratoluène sulfoniques et arylcarboxyliques.It is thus that the present invention relates to N (4, 5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide, as well as its addition salts with mineral acids or panic or
The addition salts with mineral or organic acids can for example be the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, priopionic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. oxalic, glyoxylic, aspartic, alkane sulfonic such as methane or ethane sulfonic, arylsulfonic Ç such as benzene or paratoluene sulfonic and arylcarboxylic acids.

Parmi les produits objet de ltinvention, on peut citer notamment les sels d'addition avec les acides minéraux et plus particulièrement le chlorhydrate. Among the products which are the subject of the invention, there may be mentioned in particular the addition salts with mineral acids and more particularly the hydrochloride.

L'invention a également pour objet un procédé de préparation du dérivé, tel que défini ci-dessus, ainsi que de ses sels, caractérisé en ce que lton fait réagir un produit de formule (II)

Figure img00010001

dans laquelle R représente un atome de chlore ou de brome, un radical hydroxy ou un radical alcoxy renfermant de 1 à 5 atomes de carbone, avec la 2-aminothiazoline, pour obtenir le produit attendu, que lton isole et, si désiré, salifie.The subject of the invention is also a process for the preparation of the derivative, as defined above, as well as of its salts, characterized in that it reacts a product of formula (II)
Figure img00010001

in which R represents a chlorine or bromine atom, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms, with 2-aminothiazoline, in order to obtain the expected product, which is isolated and, if desired, salified.

La réaction d'un halogénure d'acyle de formule (II) avec la 2-aminothiazoline peut s'effectuer dans des solvants ou milieux de suspension inertes tels que les cétones aliphatiques inférieures, le dioxane, le diméthylformamide, le benzène ou le toluène. On peut opérer avantageusement en présence d'un agent fixateur d'hydracides, tels que les hydroxydes alcalins comme la potasse, les carbonates alcalins comme le carbonate de potassium, les bicarbonates alcalins comme ceux de sodium ou de potassium, les alcoolates alcalins, comme l'éthylate de sodium, ou de préférence les amines tertiaires telles que des trialcqylamines ou la pyridine. The reaction of an acyl halide of formula (II) with 2-aminothiazoline can be carried out in inert solvents or suspension media such as lower aliphatic ketones, dioxane, dimethylformamide, benzene or toluene. One can advantageously operate in the presence of a hydracid fixing agent, such as alkali hydroxides such as potassium hydroxide, alkaline carbonates such as potassium carbonate, alkaline bicarbonates such as those of sodium or potassium, alkaline alcoholates, such as sodium ethoxide, or preferably tertiary amines such as trialkylamines or pyridine.

La réaction d'un acide de formule (II) avec la 2-aminothiazoline est avantageusement effectuée en présence de dicyclohexylcarbodiimide, au sein du diméthylformamide.  The reaction of an acid of formula (II) with 2-aminothiazoline is advantageously carried out in the presence of dicyclohexylcarbodiimide, within dimethylformamide.

On opère avantageusement à partir d'un ester d'alcoyle de formule (Il).'On opère alors au reflux d'un solvant à point d'ébullition élevé de 500C à i500C par exemple ; le reflux est maintenu assez lontemps, par exemple de 12 à 48 heures. The operation is advantageously carried out from an alkyl ester of formula (II). The operation is then carried out under reflux of a solvent with a high boiling point of 500C to 1500C for example; reflux is maintained fairly long, for example from 12 to 48 hours.

La réaction est effectuée de préférence en présence d'un agent de condensation tel qu'un dérivé alcoylé de l'aluminium, par exemple, le triméthylaluminium et notamment le triisobutylaluminium. The reaction is preferably carried out in the presence of a condensing agent such as an alkylated derivative of aluminum, for example, trimethylaluminium and in particular triisobutylaluminium.

On peut également operer avantageusement en présence de traces d'un hydrure alcalin tel que celui de sodium. It is also possible to operate advantageously in the presence of traces of an alkaline hydride such as that of sodium.

Les produits de formule (II) sont connus, ou peuvent entre préparés comme indiqué dans le brevet français 2 340 735. The products of formula (II) are known, or can, inter alia, be prepared as indicated in French patent 2,340,735.

Le N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide présente un caractère basique. On peut avantageusement préparer ses sels d'addition, en faisant réagir, en proportions sensiblement stoechiométriques, un acide minéral ou organique avec ledit dérivé. Les sels peuvent être préparés sans isoler les bases correspondantes.  N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide has a basic character. Advantageously, its addition salts can be prepared by reacting, in substantially stoichiometric proportions, a mineral or organic acid with said derivative. The salts can be prepared without isolating the corresponding bases.

Les dérivés objet de la présente invention possèdent de très intéressantes propriétés pharmacologiques ; ils sont doués notamment de remarquables propriétés anxiolytiques. The derivatives which are the subject of the present invention have very advantageous pharmacological properties; they are endowed in particular with remarkable anxiolytic properties.

Ces propriétés sont illustrées plus loin dans la partie expérimentale. ~
Ces propriétés justifient l'utilisation du N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide, ainsi de ses sels, à titre de médicaments.These properties are illustrated later in the experimental part. ~
These properties justify the use of N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide, as well as its salts, as medicaments.

La présente demande a ainsi également pour objet l'application, à titre de médicaments du N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide, ainsi que de ses sels d'addition avec les acides pharmaceutiquement acceptables. The present application thus also relates to the application, as medicaments of N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide, as well as its addition salts with pharmaceutically acceptable acids .

Parmi les médicaments, objet de I'invention, on retient de préférence, les médicaments caractérisés en ce qu'ils sont
constitués par les sels d'addition avec les acides pharmaceutiquement acceptables du N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide.Among the drugs which are the subject of the invention, it is preferable to retain the drugs characterized in that they are
consisting of the addition salts with pharmaceutically acceptable acids of N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide.

Parmi ceux-ci, on retient notamment le chlorhydrate du N- (4, 5-dihydro 2-thiazolyl)-4-hydroxy 3-quinoléine carboxamide. Among these, there is in particular the hydrochloride of N- (4, 5-dihydro 2-thiazolyl) -4-hydroxy 3-quinoline carboxamide.

Les médicaments selon l'invention trouvent leur emploi, par exemple dans le traitement des états anxieux tels que l'anxiété chronique, associé ou non à de l'insomnie ou à des troubles du comportement, de l'angoisse chez l'adulte ou l'enfant, ou en complément lors des traitements par neuroleptiques ou antidépresseurs dans les états psychotiques ou dépressifs.
La dose usuelle, variable selon le dérivé utilisé,le sujet et l'affection en cause peut être,par exemple, de 1 mg à 100 mg par jour, par voie orale chez l'homme du dérivé de l'exemple 1 pour le traitement de l'anxiété chronique.The medicaments according to the invention find their use, for example in the treatment of anxiety states such as chronic anxiety, associated or not with insomnia or behavioral disorders, anxiety in adults or child, or in addition during treatments with neuroleptics or antidepressants in psychotic or depressive states.
The usual dose, which varies according to the derivative used, the subject and the condition in question, can be, for example, from 1 mg to 100 mg per day, orally in humans for the derivative of Example 1 for the treatment chronic anxiety.

L'invention a enfin pour objet les compositions pharmaceutiques qui renferment au moins le dérivé précité ou l'un de ses sels d'addition avec les acides pharmaceutiquement acceptables, à titre de principe actif.A subject of the invention is finally pharmaceutical compositions which contain at least the abovementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.

A titre de médicaments le N-(4,5-dihydro 2-thiazolyl) 4hydroxy 3-quinoléine carboxamide et ses sels d'addition avec les acides pharmaceutiquement acceptables peuvent être incorporés dans des compositions pharmaceutiques destinées à la voie digestive ou parentérale. As medicaments, N- (4,5-dihydro 2-thiazolyl) 4hydroxy 3-quinoline carboxamide and its addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

Ces compositions pharmaceutiques peuvent etrey par exemple, solides ou liquides et se présenter sous les formes pharmaceutiques couramment utilisées en médecine humaine, comme par exemple, les comprimés, simples ou dragéifiés, les gélules, les granulés, les suppositoires, les préparations injectables ; elles sont préparées selon les méthodes usuelles. Le ou les principes actifs peuvent y être incorporés à des excipients habituellement employés dans ces compositions pharmaceutiques, tels que le talc, la gomme arabique, le lactose, l'amidon, le stéarate de magnésium, le beurre de cacao, les véhicules aqueux ou non, les corps gras d'origine animale ou végétale, les dérivés paraffiniqles, les glycols, les divers agents mouillantsr dispersants ou émulsifiants, les conservateurs. These pharmaceutical compositions can, for example, be solid or liquid, and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, simple or coated, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

Les exemples qui suivent illustrent la présente inven- tion , sans toutefois la limiter. The following examples illustrate, but do not limit, the present invention.

Exemple 1 : le N-(4,5-dihvdro 2-thiazolvl) 4-hydroxy-3-cuino- léine carboxamide et son chlorhydrate.Example 1: N- (4,5-dihvdro 2-thiazolvl) 4-hydroxy-3-cuinoline carboxamide and its hydrochloride.

On agite 37,4 g de 2-aminothiazoline dans 800 cm3 de chlorure de méthylène, ajoute en 20 mn., à 80Ù-100C, 167 cm3 d'une solution toluènique de triisobutylaluminium à 25 %, agite encore 30 mn. à 80C, ajoute 15,89 g de 3-carbéthoxy 4hydroxy quinoléine,. agite 3Q mn., porte au reflux pendant 16 heures, évapore à sec sous pression réduite, reprend dans I litre d'une solution aqueuse normale d'acide chlorhydrique, filtre, glace pendant 16 heures, filtre le précipité, lave à l'eau, alcalinise les eaux mères à l'aide de carbonate de sodium, filtre,lave à l'eau, sèche le précipité et obtient 11, 7 g de la base attendue. 37.4 g of 2-aminothiazoline are stirred in 800 cm3 of methylene chloride, added in 20 min., At 80Ù-100C, 167 cm3 of a toluene solution of triisobutylaluminum 25%, stirred for another 30 min. at 80C, add 15.89 g of 3-carbethoxy 4hydroxy quinoline ,. stir 3Q min., reflux for 16 hours, evaporate to dryness under reduced pressure, take up in I liter of a normal aqueous solution of hydrochloric acid, filter, ice for 16 hours, filter the precipitate, wash with water , alkalinizes the mother liquors using sodium carbonate, filters, washes with water, dries the precipitate and obtains 11.7 g of the expected base.

Formation du chlorhydrate : On dissout le produit ci-dessus dans 600 cm3 d'éthanol, filtre, ajoute 8 cm3 d'une solution éthanolique d'acide chlorhydrique 5,3 N, glace, filtre, sèche récupère 8,5 g. P.F. : ~ 300 C.Formation of the hydrochloride: The above product is dissolved in 600 cm3 of ethanol, filter, added 8 cm3 of an ethanolic solution of 5.3N hydrochloric acid, ice, filter, dry recovers 8.5 g. P.F.: ~ 300 C.

Analyse : C13H11N302S, HCl = 309,78
Calculé : C 96 50,41 E % 3,g -N , 13,56 S 96 10,35 C1 % --11,44
Trouvé : 50,1- - 4,0 13,3 10,4 11,2
Exemple 2
On a préparé des comprimes répondant à la formule
- Chlorhydrate de N-(4,5-dibydro 2-thiazolyl)
4-bydi-oxy 3-quinoléine carboxamide ............... 5 mg
- Excipient q. s. pour un comprimé terminé à ..... 100 mg (Détail de l'excipient : .lactose, amidon, talc, stéarate de magnésium).Analysis: C13H11N302S, HCl = 309.78
Calculated: C 96 50.41 E% 3, g -N, 13.56 S 96 10.35 C1% --11.44
Found: 50.1- - 4.0 13.3 10.4 11.2
Example 2
We prepared tablets corresponding to the formula
- N- (4,5-dibydro 2-thiazolyl) hydrochloride
4-bydi-oxy 3-quinoline carboxamide ............... 5 mg
- Excipient qs for a tablet finished at ..... 100 mg (Details of the excipient: lactose, starch, talc, magnesium stearate).

Etude pharmacologique : 1) Affinité pour les récepteurs des benzodiazéoines
La technique est inspirée de celle de Moula et Okada
Science n 198 p. 849-851 (1977). Pharmacological study: 1) Affinity for benzodiazepine receptors
The technique is inspired by that of Moula and Okada
Science No. 198 p. 849-851 (1977).

On homogéinise au vingtième (poids/volume) dans le sucrose 0,32M, les cortex prélevés sur des cerveaux de rats males pesant 150 g en moyenne. Après centrifugation à 1000g du mélange homogéinisé pendant 10 minutes à OOC, le a=iageant est centrifugé à 30 000 g pendant 20 minutes à +40C. Le culot est mis en suspension dans 20 volumes de tampon Tris HCl 50 mM pH 7,4, et centrifugé à 30 000 g pendant 20 minutes à +4 C. Le nouveau culot obtenu est mis en suspension dans 50ml de tampon Krebs Tris HCl pH i,4.  One homogenizes to the twentieth (weight / volume) in 0.32M sucrose, the cortices taken from the brains of male rats weighing 150 g on average. After centrifugation at 1000 g of the homogenized mixture for 10 minutes at OOC, the a = iagant is centrifuged at 30,000 g for 20 minutes at + 40C. The pellet is suspended in 20 volumes of 50 mM Tris HCl buffer pH 7.4, and centrifuged at 30,000 g for 20 minutes at +4 C. The new pellet obtained is suspended in 50 ml of Krebs Tris HCl pH buffer i, 4.

On fait ensuite incuber pendant 30 minutes à OOC, 2 ml de suspension en présence de 3H Diazepam à la-concentration O-gM, seul, avec des concentrations croissantes du produit à tester, ou, pour déterminer la fixation non spécifique, avec du Diazepam non radioactif à la concentration 10-6M.  2 ml of suspension are then incubated at OOC for 30 minutes in the presence of 3H Diazepam at the concentration O-gM, alone, with increasing concentrations of the product to be tested, or, to determine the non-specific binding, with Diazepam non-radioactive at 10-6M concentration.

Les suspensions incubées sont filtrées sur Whatman GF/C et les filtres sont lavés par deux fois 5ml de tampon Krebs
Tris HCl pH 7,4 à 0 C. The incubated suspensions are filtered on Whatman GF / C and the filters are washed with twice 5 ml of Krebs buffer
Tris HCl pH 7.4 at 0 C.

La radioactivité des filtres est mesurée par scintillation liquide.The radioactivity of the filters is measured by liquid scintillation.

L'activité du produit est exprimée en C.I. 50 : concentration inhibant 50 de la liaison spécifique du 3H Diazepam déterminé graphiquement. The activity of the product is expressed in C.I. 50: concentration inhibiting 50 of the specific binding of 3H Diazepam determined graphically.

Résultat
Le produit de l'exemple a une C.I. 50 égale à 0,50 nM.Result
The product of the example has an IC 50 equal to 0.50 nM.

2) Test des 4 plaques Technique
L'appareil (Apelab) et le protocole utilisé ont été décrits par BOISSIER et COLL. (European J. Pharmacol. 1968, 4, 145). Les plaques sont reliées à un stimulateur (U. Sachs,
Roucaire) qui permet de délivrer des chocs électriques de 120 volts pendant 0,5 s. Les essais sont réalisés sur des lots de 10 souris 1/2 heure après administration per os du composé étudié. Chaque animal est déposé individuellement sur l'appareil. Après 15 secondes d'exploration libre, il est soumis à un choc éléctrique chaque fois qu'il passe d'une plaque à 1 autre, un minimum de 3 secondes étant observé entre deux chocs. Le nombre de chocs délivrés est compté pendant 1 minute.Les résultats obtenus sont comparés à ceux observés chez des animaux témoins par un test de Dunnett.2) Test of the 4 Technical plates
The device (Apelab) and the protocol used have been described by BOISSIER and COLL. (European J. Pharmacol. 1968, 4, 145). The plates are connected to a stimulator (U. Sachs,
Roucaire) which delivers 120 volts electric shocks for 0.5 s. The tests are carried out on batches of 10 mice 1/2 hour after oral administration of the compound studied. Each animal is placed individually on the device. After 15 seconds of free exploration, it is subjected to an electric shock each time it passes from one plate to another, a minimum of 3 seconds being observed between two shocks. The number of shocks delivered is counted for 1 minute. The results obtained are compared with those observed in control animals by a Dunnett test.

Lorsque le produit de l'exemple nO 1 est administré à la dose de 10 mg/Kg per os, le nombre de chocs délivrés est significativement augmenté. Ce produit présente donc une bonne activité anxiolytique. When the product of Example No. 1 is administered at a dose of 10 mg / kg per os, the number of shocks delivered is significantly increased. This product therefore has good anxiolytic activity.

3) Action sur le taux de corticostérone Te~cl-tque
Les essais sont effectués sur des lots de 5 rats. Le composé étudié est administré per os entre 8 et 9 heures du matin, les animaux étant groupés par 5 depuis 24 heures
Une heure après, le stress est appliqué ; il consiste à changer les animaux de cage, à les amener dans une pièce où un poste de radio fonctionne bruyamment puis, 1/2 heure plus tard, à leur faire une piqûre intrapéritonéale. Dix minutes après cellé-ci, les rats sont anesthésiés à l'halothane et environ 3 ml de sang sont prélevés après décapitation.3) Action on the level of corticosterone Te ~ cl-tque
The tests are carried out on batches of 5 rats. The studied compound is administered per os between 8 and 9 am, the animals being grouped by 5 for 24 hours
An hour later, stress is applied; it consists of changing the animals in the cage, bringing them to a room where a radio works noisily and then, 1/2 hour later, giving them an intraperitoneal bite. Ten minutes after celling, the rats are anesthetized with halothane and approximately 3 ml of blood are taken after decapitation.

Les taux sériques de oorticostérone sont déterminés par une méthode radio-immunologique. Compte tenu de ltimpor- tance, chez le rat mâle, des concentrations sériques de corticostérone, le dosage est réalisé directement, sans extraction -pr4alablee l'hormone, sur 0,1 ml de lséchantillon dilué au 1/100.A la prise dressai sont ajoutés dans des tubes à hémolyse (12x65mm) 0,1 ml d'une solution aqueuse de 3H-corticostérone (5000 cpm) et 0,5ml de tampon phosphate (0,02M ; pH 6,9) additionné de 0,02% de gélatine et 0,02% d'azoture de sodium, renfermant en suspension l'antisérum anticorticostérone (dilution 1/300000), l'antisérum de mouton anti- globuline de lapin (dilution 1/50) et du sérum normal de lapin traité au charbonDextran (dilution 1/500). Serum oorticosterone levels are determined by a radioimmunological method. Taking into account the importance, in the male rat, of the serum corticosterone concentrations, the assay is carried out directly, without extraction -pr4alablee the hormone, on 0.1 ml of the sample diluted to 1/100. added to hemolysis tubes (12x65mm) 0.1 ml of an aqueous solution of 3H-corticosterone (5000 cpm) and 0.5 ml of phosphate buffer (0.02M; pH 6.9) supplemented with 0.02% of gelatin and 0.02% sodium azide, containing in suspension the anticorticosterone antiserum (dilution 1/300000), the sheep antiserum rabbit globulin (dilution 1/50) and normal rabbit serum treated with coal Dextran (dilution 1/500).

Le volume est ajusté à 1 ml et l'incubation réalisée en une nuit à 40C. Après centrifugation (3000t/mn) pendant 20mn, le surnageant est éliminé et la radioactivité contenue dans le précipité est mesurée dans un compteur, après addition de 2 ml de liquide de scintillation renfermant 5% de Soluène 350.The volume is adjusted to 1 ml and the incubation carried out overnight at 40C. After centrifugation (3000 rpm) for 20 min, the supernatant is removed and the radioactivity contained in the precipitate is measured in a counter, after addition of 2 ml of scintillation liquid containing 5% of Soluene 350.

Les concentrations de corticostérone sont déterminées au moyen d'une courbe d'étalonnage (0-4000pg) établie dans les conditions du traitement des échantillons.Corticosterone concentrations are determined using a standard curve (0-4000pg) established under the conditions of sample processing.

Le taux sérique individuel de corticostérone, exprimé en g/100 ml, est la moyenne de trois déterminations. Les résultats sont ensuite comparés par le test de Student à ceux obtenus chez les aminaux témoins ayant subi le même stress. The individual serum corticosterone level, expressed in g / 100 ml, is the average of three determinations. The results are then compared by the Student test with those obtained in the control amino acids having undergone the same stress.

Le produit de l'exemple n 1, administré à la dose de 10 mg/Kg per os diminue de 50 % le taux de corticostérone des animaux traités. The product of Example No. 1, administered at a dose of 10 mg / kg per os, decreases the corticosterone level of the animals treated by 50%.

Le produit de l'exemple n 1 présente donc une bonne activité anxiolytique. The product of Example No. 1 therefore exhibits good anxiolytic activity.

4) Etude de la toxicité aiguë. 4) Study of acute toxicity.

On a évalué la dose létale Duo du produit de l'exemple 1 après administration par les voies intrapéritonéale et orale chez la souris. The lethal Duo dose of the product of Example 1 was evaluated after administration by the intraperitoneal and oral routes in mice.

On appelle Duo la dose maximale ne provoquant aucune mortalité en 8 jours. Duo is called the maximum dose causing no mortality in 8 days.

Le produit de l'exemple 1 a une DLo supérieure à 400 mg/Eg par voie intrapéritonéale et par voie orale.  The product of Example 1 has a DLo greater than 400 mg / Eg intraperitoneally and orally.

Claims (10)

REVENDICATIONS 1. - Le N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide ainsi que ses sels d'addition avec les acides minéraux ou organiques.1. - N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide as well as its addition salts with mineral or organic acids. 2. - Les sels d'addition avec les acides minéraux du N-(4,5 dihydro 2 -thiazolyl) 4-hydroxy 3-quinoléine carboxamide.2. - The addition salts with mineral acids of N- (4,5 dihydro 2 -thiazolyl) 4-hydroxy 3-quinoline carboxamide. 3. - Le chlorhydrate du N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide.3. - The hydrochloride of N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide. 4. - Procédé de préparation des dérivés tels que définis à la revendication 1, caractérisé en ce que l'on fait réagir un produit de formule (II)4. - Process for the preparation of derivatives as defined in claim 1, characterized in that a product of formula (II) is reacted
Figure img00080001
Figure img00080001
 dans laquelle R représente un atome de chlore ou de brome, un radical hydroxy ou un radical alcoxy renfermant de 1 à 5 atomes de carbone, avec la 2-aminothiazoline, pour obtenir le produit attendu, que l'on isole et, si désiré, salifie. in which R represents a chlorine or bromine atom, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms, with 2-aminothiazoline, to obtain the expected product, which is isolated and, if desired, salifies. 5. - Procédé de préparation, selon la revendication 4,caractérisé en ce que l'on opère à partir d'un dérivé de formule (II) dans laquelle R représente un radical alcoxy renfermant de i à 5 atomes de carbone en présence d'un dérivé alcoylé de l'aluminium.5. - Preparation process according to claim 4, characterized in that one operates from a derivative of formula (II) in which R represents an alkoxy radical containing i to 5 carbon atoms in the presence of an alkylated aluminum derivative. 6. - Procédé de préparation selon la revendication 5, carac- térisé en ce que lton opère en présence de trtisobutylalumi- nium.6. - Preparation process according to claim 5, characterized in that lton operates in the presence of trtisobutylaluminium. 7. - Médicaments, notamment anxiolytiques, caractérisés en ce qu'ils sont constitués par le N-(4,5-dihydro 2-thiazolyl) 4hydroxy 3-quinoléine carboxamide, ainsi que par ses sels d'addition avec les acides pharmaceutiquement acceptables.7. - Drugs, in particular anxiolytics, characterized in that they consist of N- (4,5-dihydro 2-thiazolyl) 4hydroxy 3-quinoline carboxamide, as well as by its addition salts with pharmaceutically acceptable acids. 8. - Médicaments, notamment anxiolytiques, caractérisés en ce qu'ils sont constitués par les sels d'addition avec les acides pharmaceutiquement acceptables du N-(4 , 5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide.8. - Drugs, in particular anxiolytics, characterized in that they consist of addition salts with pharmaceutically acceptable acids of N- (4, 5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide. 9. - Médicament, notamment anxiolytique, caractérisé en ce qutil est constitué par le chlorhydrate du N-(4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoléine carboxamide.9. - Medicine, in particular anxiolytic, characterized in that it is constituted by the hydrochloride of N- (4,5-dihydro 2-thiazolyl) 4-hydroxy 3-quinoline carboxamide. 10. - Compositions pharmaceutiques, caractérisées en ce quelles renferment, à titre de principe actif, l'un au moins des médicaments, tels que définis à l'une des revendications 7, 8 ou 9.  10. - Pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicaments, as defined in one of claims 7, 8 or 9.
FR8111607A 1981-06-12 1981-06-12 N-4,5-di:hydro-2-thiazolyl 4-hydroxy 3-quinoline-carboxamide derivs. - anxiolytics having strong affinity for benzodiazepine receptors, opt. used in association with neuroleptics or antidepressants Granted FR2507602A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
FR8111607A FR2507602A1 (en) 1981-06-12 1981-06-12 N-4,5-di:hydro-2-thiazolyl 4-hydroxy 3-quinoline-carboxamide derivs. - anxiolytics having strong affinity for benzodiazepine receptors, opt. used in association with neuroleptics or antidepressants
HU821657A HU190796B (en) 1981-06-12 1982-05-24 Process for producing n-dihydrothiazolyl-3-quinoline-carboxamide derivatives
MA19695A MA19488A1 (en) 1981-06-12 1982-05-26 PROCESS FOR THE PREPARATION OF NEW D-DERIVATIVES OF N-DIHYDROTHIAZOLYL 3-QUINOLEINE CARBOXAMIDE
IL65943A IL65943A (en) 1981-06-12 1982-06-01 Derivatives of n-dihydrothiazolyl-4-hydroxy quinoline-3-carboxamide and their salts,process for preparing them and compositions containing them
ES512852A ES512852A0 (en) 1981-06-12 1982-06-04 "A PROCEDURE FOR PREPARING NEW DERIVATIVES OF N-DIHYDROTIAZOLYL-3-QUINOLEIN-CARBOXAMIDE".
ZA823982A ZA823982B (en) 1981-06-12 1982-06-07 Derivatives of n-dihydrothiazolyl-3-quinoline carboxamide,their salts,process for preparing them,their use as medicaments and the compositions containing them
PT75023A PT75023B (en) 1981-06-12 1982-06-08 PROCESS FOR THE PREPARATION OF NOVEL N-DIHYDROTHIAZOLYL 3-QUINOLINE CARBOXAMIDE DERIVATIVES
US06/386,597 US4450166A (en) 1981-06-12 1982-06-09 N-(4,5-Dihydro-thiazol-2-yl)-3-quinoline-carboxamides having anxiolytic activity
EG32982A EG15915A (en) 1981-06-12 1982-06-09 Process for preparing new derivatives of n-dihydronouveau derive dihydrothiazole de la quinoleine,sethiazolyl-3-quinoline carboxamide s sels,procede de preparation application a titre de medicament
MX794482A MX155120A (en) 1981-06-12 1982-06-10 PROCEDURE FOR PREPARING DERIVATIVES OF N-DIHYDROTIAZOLYL-3-QUINOLEINCARBOXAMIDE
FI822067A FI78087C (en) 1981-06-12 1982-06-10 FOERFARANDE FOER FRAMSTAELLNING AV NYA N-DIHYDROTIAZOLYL-3-KINOLINKARBOXAMIDDERIVAT, VILKA HAR ANXIOLYTISK AKTIVITET.
GR68384A GR77201B (en) 1981-06-12 1982-06-10
JP57098602A JPS57212181A (en) 1981-06-12 1982-06-10 Novel derivatives of n-dihydrothiazolyl-3- quinoline carboxamides and their salts, manufacture, use as drug and composition containing them
IE1394/82A IE53520B1 (en) 1981-06-12 1982-06-11 N-(4,5-dihydrothiazol-2-yl)-3-quinoline carboxamide derivatives
AU84827/82A AU552029B2 (en) 1981-06-12 1982-06-11 Derivatives of n-dihydrothiazolyl-3-quinoline
AT82401062T ATE12111T1 (en) 1981-06-12 1982-06-11 N-DIHYDROTHIAZOLYL-3-QUINOLINE CARBOXIAMIDE DERIVATIVES, THEIR SALTS, PROCESSES FOR THEIR PREPARATION, THEIR USE AS MEDICINAL PRODUCTS AND MEDICATIONS CONTAINING THEM.
NZ200931A NZ200931A (en) 1981-06-12 1982-06-11 N-dihydrothiazolyl-3-quinoline carboxamide derivatives and pharmaceutical compositions containing such
DE8282401062T DE3262536D1 (en) 1981-06-12 1982-06-11 N-dihydrothiazolyl-3-quinoleine carboxyamide derivatives, their salts, their preparation and use as pharmaceutical preparations, and pharmaceutical preparations containing them
CA000405006A CA1216795A (en) 1981-06-12 1982-06-11 Pharmaceutical compositions having a tranquillizing effect and comprising as an active ingredient at least one n-dihydrothiazolyl-3-quinolein carboxamide derivative
DK262782A DK150070C (en) 1981-06-12 1982-06-11 ANALOGY PROCEDURE FOR PREPARING N-DIHYDROTHIAZOLYL-3-QUINOLINCARBOXAMIDE DERIVATIVES
KR8202613A KR880000808B1 (en) 1981-06-12 1982-06-11 Process for preparing derivatives of n-dihydro thiazolyly-3-quinoline carboxamide
EP82401062A EP0067772B1 (en) 1981-06-12 1982-06-11 N-dihydrothiazolyl-3-quinoleine carboxyamide derivatives, their salts, their preparation and use as pharmaceutical preparations, and pharmaceutical preparations containing them

Applications Claiming Priority (1)

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FR8111607A FR2507602A1 (en) 1981-06-12 1981-06-12 N-4,5-di:hydro-2-thiazolyl 4-hydroxy 3-quinoline-carboxamide derivs. - anxiolytics having strong affinity for benzodiazepine receptors, opt. used in association with neuroleptics or antidepressants

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FR2507602B1 FR2507602B1 (en) 1984-02-17

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1364605A (en) * 1962-03-01 1964-06-26 Process for the preparation of amides of carboxylic acids
FR2281761A1 (en) * 1974-08-13 1976-03-12 Roussel Uclaf NEW DERIVATIVES OF 3-QUINOLEINE CARBOXYLIC ACID, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT
FR2324304A2 (en) * 1975-09-22 1977-04-15 Roussel Uclaf Analgesic (4)-hydroxy-quinoline-(3)-amides - prepd. from a quinoline-(3)-carboxyl chloride and an amine
FR2340735A1 (en) * 1976-02-11 1977-09-09 Roussel Uclaf NEW DERIVATIVES OF 3-QUINOLEINE CARBOXYLIC ACID, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT
FR2377400A2 (en) * 1977-01-18 1978-08-11 Roussel Uclaf Analgesic hydroxy:quinoline carboxamide cpds. - esp. N-(2-thiazolyl)-carboxamide cpds. with 8-tri:fluoro:methyl substit.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1364605A (en) * 1962-03-01 1964-06-26 Process for the preparation of amides of carboxylic acids
FR2281761A1 (en) * 1974-08-13 1976-03-12 Roussel Uclaf NEW DERIVATIVES OF 3-QUINOLEINE CARBOXYLIC ACID, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT
FR2324304A2 (en) * 1975-09-22 1977-04-15 Roussel Uclaf Analgesic (4)-hydroxy-quinoline-(3)-amides - prepd. from a quinoline-(3)-carboxyl chloride and an amine
FR2340735A1 (en) * 1976-02-11 1977-09-09 Roussel Uclaf NEW DERIVATIVES OF 3-QUINOLEINE CARBOXYLIC ACID, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT
FR2377400A2 (en) * 1977-01-18 1978-08-11 Roussel Uclaf Analgesic hydroxy:quinoline carboxamide cpds. - esp. N-(2-thiazolyl)-carboxamide cpds. with 8-tri:fluoro:methyl substit.

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