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FR2540115A1 - Pyridazine derivative having a psychotropic action, method for its preparation and the medicaments containing it - Google Patents

Pyridazine derivative having a psychotropic action, method for its preparation and the medicaments containing it Download PDF

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Publication number
FR2540115A1
FR2540115A1 FR8301366A FR8301366A FR2540115A1 FR 2540115 A1 FR2540115 A1 FR 2540115A1 FR 8301366 A FR8301366 A FR 8301366A FR 8301366 A FR8301366 A FR 8301366A FR 2540115 A1 FR2540115 A1 FR 2540115A1
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sep
product
action
preparation
cyano
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FR2540115B1 (en
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Jean-Paul Kan
Kathleen Biziere
Camille-Georges Wermuth
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Sanofi SA
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Sanofi SA
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Priority to FR8301366A priority Critical patent/FR2540115B1/en
Priority to CA000445482A priority patent/CA1218655A/en
Priority to US06/571,696 priority patent/US4565814A/en
Priority to PH30136A priority patent/PH21476A/en
Priority to DK025984A priority patent/DK159969C/en
Priority to IE148/84A priority patent/IE56750B1/en
Priority to GR73586A priority patent/GR81682B/el
Priority to ZA84500A priority patent/ZA84500B/en
Priority to IL70755A priority patent/IL70755A/en
Priority to PT77994A priority patent/PT77994B/en
Priority to AU23728/84A priority patent/AU566352B2/en
Priority to ES529108A priority patent/ES8500253A1/en
Priority to DE8484400157T priority patent/DE3469026D1/en
Priority to AT84400157T priority patent/ATE32220T1/en
Priority to EP84400157A priority patent/EP0116494B1/en
Priority to MA20240A priority patent/MA20019A1/en
Priority to OA58217A priority patent/OA07645A/en
Priority to SU843697653A priority patent/SU1274623A3/en
Priority to NO840329A priority patent/NO840329L/en
Priority to CS61484A priority patent/CS274405B2/en
Priority to PL1984245932A priority patent/PL143994B1/en
Priority to HU84378A priority patent/HU192975B/en
Priority to YU00141/84A priority patent/YU14184A/en
Priority to DD84259679A priority patent/DD215542A5/en
Priority to FI840349A priority patent/FI77453C/en
Priority to NZ206957A priority patent/NZ206957A/en
Priority to JP59014185A priority patent/JPS59141565A/en
Priority to KR1019840000387A priority patent/KR910000639B1/en
Publication of FR2540115A1 publication Critical patent/FR2540115A1/en
Priority to US06/735,580 priority patent/US4631280A/en
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Priority to SG93/89A priority patent/SG9389G/en
Priority to DK621589A priority patent/DK162218C/en
Priority to DK621689A priority patent/DK162219C/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

3-Morpholinoethylamino-4-cyano-6-phenylpyridazine and the salts of this product with the pharmaceutically acceptable acids, especially the hydrochloride of this product. The invention also relates to a process for the preparation of these products and to the medicaments which contain them.

Description

Dérivé de la pyridaine ayant une action psychotrope, son mode de préparation et les médicaments en contenant.Derived from pyridaine having a psychotropic action, its mode of preparation and the drugs containing it.

Depuis de nombreuses années des dérivés de la pyridazine ont été proposés en tant que médicaments. Dans un grand nombre de cas, il s'agit de substances actives sur le système cardiovasculaire et présentant en particulier un effet hypotenseur ou vasodilatateur. Plus rarement, on a mentionné parmi les dérivés de la pyridazine une action anti-inflammatoire et analgésique. Enfin le brevet français n 2 141 697 décrit une famille de produits répondant à la formule générale

Figure img00010001

où , R1 représente lthydrogène ou un groupe alkyle inférieur; , Ar représente un reste aromatique;; R R2 désigne un groupe
Figure img00010002

dans lequel n - 2 ou 3 et
Y et Z représentent un groupe alkyle inférieur ou bien
Figure img00010003
For many years, pyridazine derivatives have been proposed as drugs. In a large number of cases, these are substances that are active on the cardiovascular system and in particular have a hypotensive or vasodilatory effect. More rarely, pyridazine derivatives have been reported to have anti-inflammatory and analgesic activity. Finally, French Patent No. 2,141,697 describes a family of products corresponding to the general formula
Figure img00010001

wherein, R 1 is hydrogen or lower alkyl; Ar represents an aromatic residue; R2 means a group
Figure img00010002

in which n - 2 or 3 and
Y and Z represent a lower alkyl group or
Figure img00010003

constitue un radical hétérocyclique. constitutes a heterocyclic radical.

Ces composés sont caractérisés par une activité psychotrope de type psychostimulante. These compounds are characterized by psychotropic psychotropic activity.

La présente invention a pour objet la morpholinoéthylamino-3 cyano-4 phényl-6 pyidazine et ses sels avec les acides organiques ou minéraux pharmaceutiquement acceptables. Elle comprend également un procédé de préparation du composé et son application en thérapeutique.  The present invention relates to morpholinoethylamino-3-cyano-4-phenyl-6-pyidazine and its salts with pharmaceutically acceptable organic or inorganic acids. It also comprises a process for preparing the compound and its therapeutic application.

Le chlorhydrate de ce composé est représenté par la formule chimique suivante

Figure img00020001
The hydrochloride of this compound is represented by the following chemical formula
Figure img00020001

NO de code : SR 95191
L'introduction du groupement cyano en position 4 de la pyridazine améliore sensiblement les propriétés thérapeutiques de ce produit par rapport à celles décrites pour la mQme famille de pyridazine substituées en 4 par un groupement méthyle dont l'exemple le plus connu est la minaprine (DCI).Code number: SR 95191
The introduction of the cyano group at the 4-position of pyridazine substantially improves the therapeutic properties of this product compared to those described for the same family of pyridazine substituted in 4 by a methyl group, the best-known example being minaprine (INN). ).

En effet, la comparaison de ces deux produits sur plusieurs tests pharmacologiques mettant en évidence leur activité psychotrope a montré que le produit selon l'invention a une dose efficace médiane comparable ou inférieure à celle de la minaprine alors que sa toxicité est notablement inférieure. Indeed, the comparison of these two products on several pharmacological tests demonstrating their psychotropic activity has shown that the product according to the invention has a median effective dose comparable to or less than that of minaprine while its toxicity is significantly lower.

Ainsi, le composé selon l'invention présente un coefficient thérapeutique très supérieur à celui de la minaprine.  Thus, the compound according to the invention has a therapeutic coefficient much higher than that of minaprine.

PROCEDE DE PREPARATION
Schéma réactionnel

Figure img00030001
PROCESS OF PREPARATION
Reaction scheme
Figure img00030001

Figure img00030002
Figure img00030002

Figure img00030003
Figure img00030003

Figure img00030004
Figure img00030004

Figure img00030005
Figure img00030005

Figure img00030006
Figure img00030006

Le procédé de préparation consiste tout d'abord à additionner le malonate d'éthyle au chlorure de phénacyle par chauffage dans un solvant anhydre, pour obtenir le phénacyl malonate d'éthyle (2). The process of preparation first consists in adding the ethyl malonate to the phenacyl chloride by heating in an anhydrous solvent, to obtain the phenacyl malonate of ethyl (2).

Le produit est cyclisé en présence d'hydrate d'hydrazine à 0 C puis l'éthoxycarbonyl-4 phényl-6 4,5-dihydro 2H-pyridazinone-3 (3) est réduite par action du brome en milieu acide pour obtenir la forme insaturée correspondante (4). par action de l'ammoniaque concentrée à température ambiante puis de l'oxychlorure de phosphore à température voisine de 800C, on prépare la chloro-3 cyano-4 phényl-6 pyridazine (7). The product is cyclized in the presence of hydrazine hydrate at 0 ° C., then 4-ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazinone-3 (3) is reduced by the action of bromine in acidic medium to obtain the form corresponding unsaturated (4). by the action of concentrated ammonia at room temperature and then phosphorus oxychloride at a temperature of about 800 ° C., 3-chloro-4-cyano-6-phenyl-pyridazine (7) is prepared.

L'addition de la N-(amino-2 éthyl)morpholine s'effectue ensuite dans un solvant alcoolique chauffé à reflux, on obtient ainsi le produit selon l'invention. Son chlorhydrate est formé par barbotage d'un courant d'acide chlorhydrique dans un solvant anhydre. The addition of N- (2-aminoethyl) morpholine is then carried out in an alcoholic solvent heated to reflux, thus obtaining the product according to the invention. Its hydrochloride is formed by bubbling a stream of hydrochloric acid in an anhydrous solvent.

a) Phénacyl malonate d'éthyle
On chauffe au reflux pendant une nuit 240,25 g de malonate d'éthyle, 138 g de carbonate de potassium, 5 g d'iodure de potassium et 154 g de chlorure de phénacyle dans 2 litres d'acétone anhydre.a) Phenacyl ethyl malonate
240.25 g of ethyl malonate, 138 g of potassium carbonate, 5 g of potassium iodide and 154 g of phenacyl chloride in 2 liters of anhydrous acetone are refluxed overnight.

Après avoir filtré les sels minéraux, on évapore à sec le filtrat puis on distille sous pression réduite le malonate d'éthyle en excès (pression : 0,5 mbar; température : environ 600C). After filtering off the inorganic salts, the filtrate is evaporated to dryness and the excess ethyl malonate is distilled off under reduced pressure (pressure: 0.5 mbar, temperature: approximately 600 ° C.).

Le résidu de distillation est chromatographié sur colonne de silice en utilisant comme éluant un mélange cyclohexane-acétate d'éthyle (9/1). Le cétoester attendu se présente sous forme d'une huile rouge.The distillation residue is chromatographed on a silica column using a cyclohexane-ethyl acetate mixture (9/1) as eluent. The expected ketoester is in the form of a red oil.

Rendement 80,3X.Yield 80.3X.

b) Ethoxycarbonyl-4 phényl-6 4,5-dihydro 2H-pyridazinone-3
On dissout 40,5 g du produit précédemment obtenu dans 70 ml d'éthanol absolu et on ajoute au milieu réactionnel, à une température voisine de OOC, goutte à goutte et sous agitation, 7,25 g d'hydrate d'hydrazine. Lorsque le milieu réactionnel est revenu à température ambiante, on agite pendant 24 heures puis on filtre le précipité beige obtenu correspondant à la pyridazinone attendue (3). b) Ethoxycarbonyl-4-phenyl-4,5-dihydro-2H-pyridazinone-3
40.5 g of the product obtained above are dissolved in 70 ml of absolute ethanol and 7.25 g of hydrazine hydrate are added dropwise with stirring to the reaction medium at a temperature in the region of OOC. When the reaction medium has returned to ambient temperature, the mixture is stirred for 24 hours and then the beige precipitate obtained corresponding to the expected pyridazinone (3) is filtered off.

Le filtrat est traité par 3,62 g d'hydrate d'hydrazine. The filtrate is treated with 3.62 g of hydrazine hydrate.

Après 24 heures d'agitation, une quantité supplémentaire de pyridazinone peut Entre filtrée. La meme opération est encore répétée une fois sur le filtrat.After stirring for 24 hours, additional pyridazinone can be filtered. The same operation is repeated once more on the filtrate.

Après purification par passage sur colonne de silice en utilisant comme éluant le mélange cyclohexane-acétate d'éthyle (volume/volume : 1/1), on obtient le composé obtenu avec un rendement de 37%. After purification by passage through a silica column using the cyclohexane-ethyl acetate mixture (volume / volume: 1/1) as eluent, the compound obtained is obtained in a yield of 37%.

c) Ethoxycarbonyl-4 phényl-6 2H-pyridazinone-3 (4)
On dissout 9 g de (3) dans 200 ml d'acide acétique puis on ajoute 11,18 g de brome 8 la solution, sous agitation. Une décoloration du milieu se produit au bout de 5 min. Après 2 h à température ambiante et sous agitation on verse dans 200 ml d'eau puis on extrait au chlorure de méthylène, évapore à sec la phase organique.c) 4-Ethoxycarbonyl-6-phenyl-2H-pyridazinone-3 (4)
9 g of (3) are dissolved in 200 ml of acetic acid and then 11.18 g of bromine are added to the solution, with stirring. Discoloration of the medium occurs after 5 min. After 2 h at room temperature and stirring is poured into 200 ml of water and then extracted with methylene chloride, evaporated to dryness the organic phase.

Le résidu est repris trois fois avec du cyclohexane. The residue is taken up three times with cyclohexane.

La poudre beige obtenue est chromatographiée sur colonne de silice en utilisant comme éluant un mélange cyclohexane-acétate d'éthyle (volume/volume : 1/1). La pyridazinone attendue est obtenue avec un rendement de 51%, F. 150 0C. The beige powder obtained is chromatographed on a silica column using a cyclohexane-ethyl acetate mixture (volume / volume: 1/1) as eluent. The expected pyridazinone is obtained with a yield of 51%, F. 150 ° C.

d) Amido-4 phényl-6 2H-pyridazinone-3 (5)
Dans 40 ml d'ammoniaque concentrée, on ajoute 2 g de (4), puis on laisse une nuit sous agitation et à température ambiante. Après filtration, le précipité blanc obtenu est séché pour obtenir (5). d) 4-Amido-6-phenyl-2H-pyridazinone-3 (5)
In 40 ml of concentrated ammonia, 2 g of (4) are added, followed by stirring overnight at room temperature. After filtration, the white precipitate obtained is dried to obtain (5).

Rendement 86%; F. > 300"C. Yield 86%; F.> 300 ° C.

e) Chloro-3 cyano-4 phényl-6 pyridazine (6)
On dissout 1,5 g du produit précédent dans 20 ml d'oxychlorure de phosphore. On chauffe à environ 800C pendant 5 h puis on verse dans 50 ml d'eau. Un précipité beige apparait, il est filtré et séché, Readement 58,3%; F. 206 C.e) 3-Chloro-4-cyano-6-phenyl pyridazine (6)
1.5 g of the above product are dissolved in 20 ml of phosphorus oxychloride. The mixture is heated at approximately 800 ° C. for 5 hours and then poured into 50 ml of water. A beige precipitate appears, it is filtered and dried, Read 58.3%; F. 206 C.

f) Morpholino éthylamino-3 cyano-4 phényl-6 pyridazine (7)
On dissout 0,73 g de (6) dans 60 ml de butanol normal.f) Morpholino 3-ethylamino-4-cyano-6-phenyl pyridazine (7)
0.73 g of (6) are dissolved in 60 ml of normal butanol.

Apres avoir ajouté 0,8 g de N-(amino-2 éthyl)morpholine, on chauffe au reflux pendant 3 h puis on verse dans 100 ml d'eau. Après extraction à l'éther, on extrait la phase éthérée avec l'acide sulfurique normal puis on neutralise avec une solution de carbonate de sodium à 10%. Après une nouvelle extraction à l'éther, on sèche sur sulfate de magnésium puis on évapore sous pression réduite à siccité. After adding 0.8 g of N- (2-aminoethyl) morpholine, the mixture is refluxed for 3 hours and then poured into 100 ml of water. After extraction with ether, the ether phase is extracted with normal sulfuric acid and then neutralized with a 10% sodium carbonate solution. After further extraction with ether, dried over magnesium sulfate and evaporated under reduced pressure to dryness.

Le produit attendu se présente sous forme d'un précipité jaune. Rendement 81,3%; F. 1380C. The expected product is in the form of a yellow precipitate. Yield 81.3%; F. 1380C.

g) Dichlorhydrate de la (morpholino éthylamino)-3 cyano-4 phényl-6
pyridazine (I)
Eyridazine (1)
On dissout 0,68 g de (7) dans 10 cm de méthanol anhydre puis on fait barboter un courant d'acide chlorhydrique gazeux et on évapore le méthanol. Le résidu obtenu est repris par de l'éther. Il se forme un précipité qui est recristallisé deux fois dans l'isopropanol. (g) (Morpholino ethylamino) -3-cyano-4-phenyl-6-dihydrochloride
pyridazine (I)
Eyridazine (1)
0.68 g of (7) are dissolved in 10 cm 3 of anhydrous methanol, then a stream of gaseous hydrochloric acid is bubbled through and the methanol is evaporated off. The residue obtained is taken up in ether. A precipitate is formed which is recrystallized twice from isopropanol.

F. 144 C (avec décomposition).F. 144 C (with decomposition).

L'activité psychotrope du produit a été mesurée sur 3 tests de pharmacologie en comparaison avec la minaprine et 1'imipramine antidépresseur très utilisé. De même, la toxicité du produit a été comparée avec celle des produits de référence. The psychotropic activity of the product was measured on 3 pharmacological tests in comparison with minaprine and the widely used anti-depressant imipramine. Similarly, the toxicity of the product was compared with that of the reference products.

Comportement de désespoir
Ce test a été réalisé chez la souris femelle CDI (Charles
River) pesant 18 à 23 g selon la méthode décrite par PORSOLT (Archives
Internationales de Pharmacodynamie, 1977, 229, 327-336).Behavior of despair
This test was performed in CDI female mice (Charles
River) weighing 18 to 23 g according to the method described by PORSOLT (Archives
International Pharmacodynamics, 1977, 229, 327-336).

Le principe de ce test est le suivant : lorsqu'une souris est placée dans un récipient étroit, rempli d'eau, elle se débat puis, au bout de 2 à 4 min, elle s'immobilise et flotte sur le ventre, le dos arrondi, les pattes postérieures ramenées sous le corps et elle ne fait que quelques mouvements nécessaires pour se maintenir la tete hors de l'eau. C'est la réaction dite de désespoir (despair reaction)
Certains psychotropes, notamment les antidépresseurs, allongent le temps pendant lequel la souris se débat.The principle of this test is as follows: when a mouse is placed in a narrow container, filled with water, it struggles and, after 2 to 4 min, it stops and floats on the stomach, the back rounded, the hind legs brought under the body and it makes only a few movements necessary to keep the head out of the water. This is the so-called despair reaction
Some psychotropic drugs, including antidepressants, lengthen the time during which the mouse struggles.

Le protocole suivant a été choisi
Les produits à étudier ont été administrés i.p. 1 h avant le test. Pour le test, les animaux sont placés dans un récipient étroit (10 x 10 x 10 cm) > rempli d'eau, sur une hauteur de 6 cm; la température de l'eau étant de 240Ct20 C. Les animaux sont laissés 6 min dans l'eau et on mesure le temps où l'animal reste immobile entre la 2e et la 6e minute. Plus ce temps est court, plus la substance est active.The following protocol was chosen
The products to be studied were administered ip 1 h before the test. For the test, the animals are placed in a narrow container (10 x 10 x 10 cm)> filled with water, to a height of 6 cm; the temperature of the water being 240Ct20 C. The animals are left for 6 minutes in the water and the time is measured when the animal remains motionless between the 2nd and 6th minute. The shorter this time, the more active the substance is.

Chaque substance a été étudiée sur un lot de 10 souris. Each substance was studied on a batch of 10 mice.

Les résultats sont la moyenne d'au moins deux expériences. The results are the average of at least two experiments.

Antagonisme de la ptôse induite par la réserpine
Ce test, décrit par GOURET (Journal de Pharmacologie
Paris, 1973, 4 (1), 105-128), a été réalisé chez la souris femelle CDI (Charles River) pesant 20+1 g. La réserpine entraîne un ptôsis 1 heure après son administration intraveineuse; certains antidépresseurs s'opposent à ce ptôsis.Antagonism of ptosis induced by reserpine
This test, described by GOURET (Journal of Pharmacology
Paris, 1973, 4 (1), 105-128), was performed in CDI female mice (Charles River) weighing 20 + 1 g. Reserpine causes ptosis 1 hour after intravenous administration; some antidepressants oppose this ptosis.

Le protocole suivant a été choisi
Les substances à étudier ont été administrées i.p. La réserpine est administrée simultanément par voie intraveineuse à la dose de 2 mg/kg. 1 h après l'administration de réserpine, on note le nombre d'animaux ne présentant pas de ptbsis. The following protocol was chosen
The substances to be studied were administered ip. Reserpine is administered simultaneously intravenously at the dose of 2 mg / kg. 1 hour after the administration of reserpine, we note the number of animals not exhibiting ptbsis.

Ce test a été réalisé sur des lots de 10 souris, les résultats sont exprimés en pourcentage d'animaux ne présentant pas de ptôsis et sont la moyenne de, au moins, deux expériences. This test was carried out on batches of 10 mice, the results are expressed as a percentage of animals not exhibiting ptosis and are the average of at least two experiments.

Comportement rotatoire
Ce test est décrit par PROTAIS et coll. dans le Journal de Pharmacologie, 1976, 7, 251-255.Rotatory behavior
This test is described by PROTAIS et al. in the Journal of Pharmacology, 1976, 7, 251-255.

Des souris femelles Charles River CDI pesant de 20 à 24 g font préalablement l'objet d'une lésion unilatérale du striatum par injection stéréotaxique de 6-hydroxydopamine à raison de 81ug par animal. Charles River CDI female mice weighing 20 to 24 g are previously subject to unilateral striatum injury by stereotactic injection of 6-hydroxydopamine at 81 μg per animal.

Une semaine après cette opération, le produit est administré par voie i.p. à des groupes de 7 souris. Le nombre de rotations est évalué pendant 2 min, 1 h après l'administration du produit. Les rotations ipsilatérales à la lésion sont comptées positivement, celles contrala térales sont comptées négativement. La somme algébrique des rotations pour un groupe d'animaux traités est comparée à celle du groupe d'animaux témoins n'ayant reçu que le véhicule (sérum physiologique).One week after this operation, the product is administered i.p. to groups of 7 mice. The number of rotations is evaluated for 2 min, 1 h after administration of the product. Rotations ipsilateral to the lesion are counted positively, and contralateral ones are counted negatively. The algebraic sum of the rotations for a group of treated animals is compared with that of the group of control animals that received only the vehicle (physiological saline).

Toxicité aiguë
Les produits à étudier ont été administrés par voie intrapéritonéale à doses croissantes à des lots de 10 souris. La mortalité provoquée par les produits étudiés a été notée pendant les 24 h ayant suivi l'administration du produit.acute toxicity
The products to be studied were administered intraperitoneally in increasing doses to batches of 10 mice. Mortality caused by the products studied was noted during the 24 hours following the administration of the product.

A partir des résultats obtenus, on détermine pour chacun des produits étudiés la dose létale 50, c'est-à-dire la dose provoquant la mort de 50% des animaux étudiés.  From the results obtained, for each of the products studied, the lethal dose 50, that is to say the dose causing the death of 50% of the animals studied, was determined.

PROFIL PHARMACOLOGIQUE DU SR 95191
Comparation avec la minaprine et l'imipramine

Figure img00080001
PHARMACOLOGICAL PROFILE OF SR 95191
Comparison with minaprine and imipramine
Figure img00080001

<SEP> Test <SEP> de <SEP> l'antagonisme <SEP> Test <SEP> du <SEP> comportement <SEP> Comportement <SEP> rota
Produits <SEP> Toxicité <SEP> de <SEP> la <SEP> ptoso <SEP> à <SEP> la <SEP> de <SEP> déserpoir <SEP> toire <SEP> chez <SEP> la <SEP> souris
<tb> <SEP> voie <SEP> i.p. <SEP> réserpine <SEP> voie <SEP> i.p. <SEP> voie <SEP> i.p.
<tb><SEP> Test <SEP> of <SEP><SEP> SEP <SEP> Antagonism <SEP> Behavior <SEP> Behavior <SEP> rota
Products <SEP> Toxicity <SEP> from <SEP><SEP> ptoso <SEP> to <SEP><SEP> from <SEP> desperation <SEP> to <SEP> from <SEP><SEP> mouse
<tb><SEP> lane <SEP> ip <SEP> reserpine <SEP> lane <SEP> ip <SEP> lane <SEP> ip
<Tb>

<SEP> voie <SEP> imp. <SEP> voie <SEP> p.o.
<tb><SEP> way <SEP> imp. <SEP> lane <SEP> in
<Tb>

SR <SEP> 95191 <SEP> DL50 <SEP> DE50 <SEP> DE50 <SEP> 5 <SEP> mg/kg <SEP> : <SEP> -26% <SEP> ** <SEP> 0,1 <SEP> mg/kg <SEP> : <SEP> -605**
<tb> <SEP> > 250 <SEP> mg/kg <SEP> = <SEP> 3,9 <SEP> mg/kg <SEP> = <SEP> 2,7 <SEP> mg/kg <SEP> 2 <SEP> mg/kg <SEP> : <SEP> -107%**
<tb> Minaprine <SEP> DL50 <SEP> DE50 <SEP> DE50 <SEP> 5 <SEP> mg/kg <SEP> : <SEP> -31% <SEP> ** <SEP> 0,125 <SEP> mg/kg <SEP> : <SEP> -53%**
<tb> <SEP> = <SEP> 63 <SEP> mg/kg <SEP> = <SEP> 5 <SEP> mg/kg <SEP> = <SEP> 8 <SEP> mg/kg <SEP> 2 <SEP> mg/kg <SEP> : <SEP> -82%**
<tb> Imipramine <SEP> DL50 <SEP> D@50 <SEP> 10 <SEP> mg/kg <SEP> : <SEP> -38%** <SEP> 3 <SEP> mg/kg <SEP> :<SEP> -6;NS
<tb> <SEP> = <SEP> 89 <SEP> mg/kg <SEP> = <SEP> 2,4 <SEP> mg/kg
<tb> ** : p < 0,01, test de Student
NS : non significatif
Le produit selon l'invention et la minaprine, administrés par voie i.p., ont une activité comparable sur le test de comportement de désespoir et sur le- test d'antagonisme de la ptôse à la réserpine, tandis que l'imipramine est moins active sur le premier test et légèrement plus active sur le second. Par contre, administré par voie per os, le produit selon l'invention a une dose efficace 50 nettement inférieure (d'un facteur 3 environ) à celle de la minaprine.SR <SEP> 95191 <SEP> LD50 <SEP> DE50 <SEP> DE50 <SEP> 5 <SEP> mg / kg <SEP>: <SEP> -26% <SEP> ** <SEP> 0.1 <SEP > mg / kg <SEP>: <SEP> -605 **
<tb><SEP>> 250 <SEP> mg / kg <SEP> = <SEP> 3.9 <SEP> mg / kg <SEP> = <SEP> 2.7 <SEP> mg / kg <SEP> 2 <SEP> mg / kg <SEP>: <SEP> -107% **
<tb> Minaprine <SEP> LD50 <SEP> DE50 <SEP> DE50 <SEP> 5 <SEP> mg / kg <SEP>: <SEP> -31% <SEP> ** <SEP> 0.125 <SEP> mg / kg <SEP>: <SEP> -53% **
<tb><SEP> = <SEP> 63 <SEP> mg / kg <SEP> = <SEP> 5 <SEP> mg / kg <SEP> = <SEP> 8 <SEP> mg / kg <SEP> 2 <MS> mg / kg <SEP>: <SEP> -82% **
<tb> Imipramine <SEP> LD50 <SEP> D @ 50 <SEP> 10 <SEP> mg / kg <SEP>: <SEP> -38% ** <SEP> 3 <SEP> mg / kg <SEP>: <SEP> -6 NS
<tb><SEP> = <SEP> 89 <SEP> mg / kg <SEP> = <SEP> 2.4 <SEP> mg / kg
<tb> **: p <0.01, Student's test
NS: not significant
The product according to the invention and minaprine, administered ip, have a comparable activity on the despair behavior test and on the reserpine ptosis antagonism test, while the imipramine is less active on the test. the first test and slightly more active on the second. On the other hand, if administered orally, the product according to the invention has a significantly lower effective dose (about a factor of 3) than that of minaprine.

A faibles doses (0,1 et 2 mg/kg, i.p.), le produit selon l'invention et la minaprine diminuent significativement le nombre de rotations ipsilatérales présentées par des souris dont un des stiata a été lésé par la 6-hydroxy dopamine (comportement rotatoire). Ces résultats distinguent nettement les deux produits à noyaux pyridazine de l'imipramine qui, elle, est inactive à une dose comparable (3 mg/kg). At low doses (0.1 and 2 mg / kg, ip), the product according to the invention and minaprine significantly reduce the number of ipsilateral rotations presented by mice, one of whose stiata was injured by 6-hydroxy dopamine ( rotational behavior). These results clearly distinguish the two pyridazine ring products from imipramine, which is inactive at a comparable dose (3 mg / kg).

L'iatéret particulier du produit selon l'invention réside dans sa faible toxicité. Administré par voie i.p., il a en effet une dose létale 50 environ 5 fois supérieure à celle de la minaprine. The particular nature of the product according to the invention lies in its low toxicity. Administered i.p., it has indeed a lethal dose 50 approximately 5 times higher than that of minaprine.

Ainsi, le produit selon l'invention présente des propriétés antidépressives alliées à un coefficient thérapeutique particulièrement favorable. Thus, the product according to the invention has antidepressant properties combined with a particularly favorable therapeutic coefficient.

En particulier, le produit selon l'invention peut etre utilisé dans diverses affections neurologiques et psychiatriques traitement des troubles de l'humeur et du comportement, dépressions névrotiques et endogènes2 troubles de la mémoire chez les sujets agés, hyperkinésie infantile, autisme, insuffisance sexuelle d'origine psychogène. In particular, the product according to the invention can be used in various neurological and psychiatric disorders treatment of mood and behavior disorders, neurotic and endogenous depressions2 memory disorders in elderly subjects, infant hyperkinesia, autism, sexual incompetence psychogenic origin.

Ces produit peuvent etre administrés par voie orale ou par voie injectable. Les compositions pharmaceutiques peuvent entre solides ou liquides et se présenter, par exemple, sous forme de comprimés, gélules, granulés, suppositoires ou préparations injectables. These products can be administered orally or by injection. The pharmaceutical compositions can be between solids or liquids and can be, for example, in the form of tablets, capsules, granules, suppositories or injectable preparations.

La posologie peut varier dans de larges proportions, en particulier suivant le type et la gravité de l'affection d traiter et suivant le mode d'administration. Le plus souvent, chez l'adulte par voie orale, elle est comprise entre 1 mg et 500 mg par jour, éventuellement répartie en plusieurs prises. The dosage may vary widely, particularly depending on the type and severity of the condition to be treated and the mode of administration. Most often, in the adult oral, it is between 1 mg and 500 mg per day, possibly divided into several doses.

A titre d'exemple, on peut indiquer la préparation galénique suivante
Gélules
SR 95191 50 mg
Aérosil 0,5mg
Stéarate de magnésium 1,5 mg
Amidon STA RX 1500 48 mg
100 mg By way of example, it is possible to indicate the following galenical preparation
capsules
SR 95191 50 mg
Aerosil 0.5mg
Magnesium stearate 1.5 mg
Starch STA RX 1500 48 mg
100 mg

Claims (4)

REVENDICATIONS 1. Morphoîinoéthylamino-3 cyano-4 phényl-6 pyridazine et les sels de ce produit avec les acides pharmaceutiquement acceptables, notamment le chlorhydrate de ce produit. 1. Morpho-aminoethyl-3-amino-4-cyano-6-phenyl pyridazine and the salts of this product with pharmaceutically acceptable acids, including the hydrochloride of this product. 2. Procédé de préparation du produit selon la revendication 1, caractérisé en ce que l'on effectue les réactions successives suivantes :2. Process for the preparation of the product according to claim 1, characterized in that the following successive reactions are carried out: - addition du malonate d'éthyle sur le chlorure de - addition of ethyl malonate to the chloride of phénacyle, phenacyl, - cyclisation du produit obtenu par action de l'hydrate cyclization of the product obtained by the action of the hydrate d'hydrazine, hydrazine, - réduction du produit obtenu par action du brome en - reduction of the product obtained by action of bromine in milieu acide pour obtenir le dérivé insaturé correspon dant  acid medium to obtain the corresponding unsaturated derivative - puis réactions successives avec l'ammoniaque concentrée - then successive reactions with concentrated ammonia puis 1'oxychlorure de phosphore de façon à obtenir then phosphorus oxychloride so as to obtain la chloro-3 cyano-4 phényl-6 pyridazine, 3-chloro-4-cyano-6-phenylpyridazine, - et réaction sur ce dernier produit de la N"(amino-2  - and reaction on the latter product of N "(amino-2 éthyl)morpholine dans un solvant alcoolique à chaud, ethyl) morpholine in a hot alcoholic solvent, le produit obtenu pouvant etre traité par un acide the product obtained which can be treated with an acid pharmaceutiquement acceptable pour obtenir le sel pharmaceutically acceptable for obtaining salt correspondant. corresponding. 3. Médicaments ayant notamment une action psychotrope, caractérisés en ce qu'ils contiennent un produit selon la revendication 1.3. Medicaments having in particular a psychotropic action, characterized in that they contain a product according to claim 1. 4. Médicaments selon la revendication 3, caractérisés en ce qu'ils sont conditionnés en vue d'une administration orale et contiennent 1 à 500 mg de produit selon la revendication 1. 4. Medicaments according to claim 3, characterized in that they are packaged for oral administration and contain 1 to 500 mg of product according to claim 1.
FR8301366A 1983-01-28 1983-01-28 PYRIDAZINE DERIVATIVE HAVING PSYCHOTROPIC ACTION, METHOD OF PREPARATION THEREOF AND MEDICAMENTS CONTAINING SAME Expired FR2540115B1 (en)

Priority Applications (32)

Application Number Priority Date Filing Date Title
FR8301366A FR2540115B1 (en) 1983-01-28 1983-01-28 PYRIDAZINE DERIVATIVE HAVING PSYCHOTROPIC ACTION, METHOD OF PREPARATION THEREOF AND MEDICAMENTS CONTAINING SAME
CA000445482A CA1218655A (en) 1983-01-28 1984-01-18 Process for the preparation of pyridazine derivatives having a psychotropic action
US06/571,696 US4565814A (en) 1983-01-28 1984-01-18 Pyridazine derivatives having a psychotropic action and compositions
DK025984A DK159969C (en) 1983-01-28 1984-01-20 PYRIDAZINE DERIVATIVES WHICH HAVE PSYCHOTROPIC EFFECTS AND MEDICINALS CONTAINING THEM
PH30136A PH21476A (en) 1983-01-28 1984-01-20 4-cyano pyridazine derivatives having a psychotrophic action and pharmaceutical composition containing them
GR73586A GR81682B (en) 1983-01-28 1984-01-23
IE148/84A IE56750B1 (en) 1983-01-28 1984-01-23 Pyridazine derivatives having a psychotropic action,process for their preparation;intermediates and medicaments in which they are present
ZA84500A ZA84500B (en) 1983-01-28 1984-01-23 Pyridazine derivatives process for their preparation,intermediates and medicaments in which they are present
IL70755A IL70755A (en) 1983-01-28 1984-01-23 3-amino-4-cyano-pyridazine derivatives,their preparation and pharmaceutical compositions containing them
PT77994A PT77994B (en) 1983-01-28 1984-01-23 PROCESS FOR OBTAINING PYRIDAZINE DERIVATIVES HAVING PSYCHOTROPIC ACTION
AU23728/84A AU566352B2 (en) 1983-01-28 1984-01-24 Pyridazine derivatives
ES529108A ES8500253A1 (en) 1983-01-28 1984-01-24 PROCEDURE FOR OBTAINING PIRIDAZINE DERIVATIVES WITH PSYCHOTROPIC ACTION
AT84400157T ATE32220T1 (en) 1983-01-28 1984-01-25 PYRIDAZINE DERIVATIVES WITH PSYCHOTROPIC ACTIVITIES, METHOD OF MANUFACTURE, INTERMEDIATE PRODUCTS AND MEDICINES CONTAINING THEM.
EP84400157A EP0116494B1 (en) 1983-01-28 1984-01-25 Pyridazine derivatives with a psychotrope activity, process for their preparation, intermediates and medicines containing them
DE8484400157T DE3469026D1 (en) 1983-01-28 1984-01-25 Pyridazine derivatives with a psychotrope activity, process for their preparation, intermediates and medicines containing them
OA58217A OA07645A (en) 1983-01-28 1984-01-26 Pyridazine derivatives having psychotropic action, process for obtaining them, intermediates and medicaments containing them.
MA20240A MA20019A1 (en) 1983-01-28 1984-01-26 Method for obtaining pyridazine derivatives having a psychotropic action.
NZ206957A NZ206957A (en) 1983-01-28 1984-01-27 4-cyano-pyridazines; intemediates and pharmaceutical compositions
CS61484A CS274405B2 (en) 1983-01-28 1984-01-27 Method of 4-cyanopyridazines preparation
PL1984245932A PL143994B1 (en) 1983-01-28 1984-01-27 Process for manufacturing 4-cyanopyridazines
HU84378A HU192975B (en) 1983-01-28 1984-01-27 Process for preparing pyridazine derivatives with psychotropic activity
YU00141/84A YU14184A (en) 1983-01-28 1984-01-27 Process for making new derivatives of cyano-4-pyridiazine
DD84259679A DD215542A5 (en) 1983-01-28 1984-01-27 PROCESS FOR THE PREPARATION OF 4-CYANO-PYRIDAZINES
FI840349A FI77453C (en) 1983-01-28 1984-01-27 Process for the preparation of 3- (2-morpholinoethylamino) -4-cyanopyridine zine derivatives which have psychotropic activity.
NO840329A NO840329L (en) 1983-01-28 1984-01-27 PROCEDURE FOR THE PREPARATION OF 4-CYANOPYRIDAZINE DERIVATIVES.
SU843697653A SU1274623A3 (en) 1983-01-28 1984-01-27 Method of producing 4-cyanopyridazines or pharmaceutically compatible salts thereof
JP59014185A JPS59141565A (en) 1983-01-28 1984-01-28 Psychotropic pyridazine derivative, manufacture and drug
KR1019840000387A KR910000639B1 (en) 1983-01-28 1984-01-28 Method for preparing 4-cyanopyridazine
US06/735,580 US4631280A (en) 1983-01-28 1985-05-20 Pyridazine derivatives having a psychotropic action, and medicaments in which they are present
SG93/89A SG9389G (en) 1983-01-28 1989-02-14 Pyridazine derivatives with a psychotrope activity,process for their preparation,intermediates and medicines containing them
DK621589A DK162218C (en) 1983-01-28 1989-12-08 3-OXO-4-CARBOXAMIDOPYRIDAZINES FOR THE SYNTHESIS OF HIS UNKNOWN 4-CYANO-PYRIDAZINES
DK621689A DK162219C (en) 1983-01-28 1989-12-08 3-CHLOR-4-CYANOPYRIDAZINES FOR THE SYNTHESIS OF HIS UNKNOWN 4-CYANOPYRIDAZINES

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WO2011133920A1 (en) 2010-04-23 2011-10-27 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
AR081626A1 (en) * 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
AR081331A1 (en) 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME

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FR2141697A1 (en) * 1971-06-18 1973-01-26 Cepbepe

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Publication number Priority date Publication date Assignee Title
FR2141697A1 (en) * 1971-06-18 1973-01-26 Cepbepe

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Title
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CHEMICAL ABSTRACTS, vol. 76, no. 7, 14 février 1972, page 22, no. 41974h, Columbus Ohio (USA); *

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