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EP0000108B1 - Benzo(b)thieno pyridines, process for their preparation and therapeutical compositions containing them - Google Patents

Benzo(b)thieno pyridines, process for their preparation and therapeutical compositions containing them Download PDF

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Publication number
EP0000108B1
EP0000108B1 EP78400006A EP78400006A EP0000108B1 EP 0000108 B1 EP0000108 B1 EP 0000108B1 EP 78400006 A EP78400006 A EP 78400006A EP 78400006 A EP78400006 A EP 78400006A EP 0000108 B1 EP0000108 B1 EP 0000108B1
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Prior art keywords
formula
benzo
thieno
phenyl
methyl
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German (de)
French (fr)
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EP0000108A1 (en
Inventor
Daniel Frehel
Jean Pierre Maffrand
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Sanofi SA
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to new benzo [b] thienopyridine derivatives, to a process for their preparation and to their applications in human and veterinary medicine.
  • lower alkyl or “lower alkoxy” is meant groups having from 1 to 6 carbon atoms.
  • the invention also includes the addition salts of the derivatives of formula I with mineral or organic acids.
  • these derivatives are described as having tranquilizing properties, while the derivatives of the present invention exhibit sedative and inhibitory properties of platelet aggregation, which is completely different.
  • the subject of the invention is also a process for preparing the compounds of formula (I), characterized in that compounds of formula (II) are cyclized in which R 1 , R 2 , R 3 and R 4 have the meanings given for formula (I), by heating in polyphosphoric acid at temperatures between 60 and 80 ° C.
  • the cyclization is preferably carried out in the presence of an inert gas, in particular nitrogen.
  • the compounds of formulas (I) for which R 1 is different from hydrogen can also be obtained by condensation of the corresponding compounds of formula (I) in which R 1 is hydrogen, with a compound of formula R 1 X in which X is a halogen atom.
  • the reaction is normally carried out in an inert solvent such as ethanol or dimethylformamide, in the presence of a base such as an alkali metal carbonate, for example potassium carbonate.
  • a base such as an alkali metal carbonate, for example potassium carbonate.
  • X is chlorine or bromine
  • the halogenomethyl-2 or -3 benzo (b) thiophenes can be prepared according to: S. AVAKIAN, J. MOSS and G.J. MARTIN, J. amer. chem. Soc., 1948, 70, 3,075; N.B. CHAPMAN, K.CLARKE; B. GORE and S.N. SAWHNEY, J. chem. Soc. (C), 1968, 514; N.B. CHAPMAN, K. CLARKE and B. IDDON, J. chem. Soc. (C), 1965, 774.
  • Formyl-2 and -3 benzo (b) thiophenes can be prepared according to: D.A. SHIRLEY and M.J. DANZIG, J.
  • the addition salts are prepared with mineral acids (for example hydrochloric, sulfuric acid, etc.) or organic acids (for example methane sulfonic, maleic, tartaric, citric acid, etc.) by usual conventional methods.
  • mineral acids for example hydrochloric, sulfuric acid, etc.
  • organic acids for example methane sulfonic, maleic, tartaric, citric acid, etc.
  • N-methylation of 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1) is carried out by condensation with methyl iodide, in ethanol, in the presence of potassium carbonate, or by Leuckart reaction (heating in the presence of formaldehyde and formic acid).
  • Benzyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (Example 1) according to the process described in example 6.
  • Methanesulfonate white crystals, F> 260 ° C (acetonitrile), yield: 63%.
  • O-nitrobenzyl chloride is condensed with 8-chloro-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (example 3), according to the process described in l 'example 6.
  • O-cyanobenzyl bromide is condensed with 4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 4), according to the method of Example 6.
  • O-methoxycarbonylbenzyl bromide is condensed with 8-chloro-3-methylphenyl-1,2,3,4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (Example 1), according to the method described in Example 6.
  • Butyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1), according to the process described in 1 'example 6.
  • Phenethyl bromide is condensed with 3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 2), according to the process described in Example 6 .
  • a further subject of the invention is therefore a therapeutic composition having in particular activities which inhibit platelet aggregation and sedation, characterized in that it contains, as active principle, a derivative of formula (I) or a salt thereof. addition with a pharmaceutically acceptable acid thereof, in combination with a therapeutically administrable vehicle.
  • the compounds of the invention benefit from excellent tolerance and low toxicity.
  • the LD 50/24 h / kg of animal, determined in mice according to the Miller and Tainter method, for the oral route, is greater than 400 mg for all the derivatives.
  • a blood sample is taken from the jugular vein. From this citrated blood and after centrifugation, a plasma containing 600,000 ⁇ 20,000 platelets per mm 3 is reconstituted, which will be used in all aggregation measurements.
  • 0.4 ml of plasma is placed in a silicone tube provided with a magnetic bar itself silicone.
  • the tube is introduced into an aggregometer coupled to a device making it possible to record the variations in optical density.
  • 0.5 ml of a solution containing 10 ⁇ of ADP is introduced into the tube. (Adenosine-Di Phosphate).
  • the aggregation of platelets then causes an increase in light transmission followed a decrease following the disaggregation phase.
  • the maximum variation in optical density thus determined characterizes the intensity of the aggregation.
  • A.D.P.'s solution is replaced by a collagen solution (bovine tendon extract).
  • test products are administered to mice by the oral route at a dose of 100 mg / kg, thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological saline.
  • a solution of 300 mg of chloral in 20 ml of physiological saline was administered to mice by the oral route at a dose of 100 mg / kg, thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological saline.
  • the derivatives of the invention considerably potentiate the action of chloral, in particular with regard to the duration of the induced sleep and the number of sleeping mice.
  • mice which have received 100 mg of the derivative to be tested by the oral route. It is considered that the mice have undergone a sedative action when they do not manage, within thirty seconds, to effect a recovery which brings at least one of their hind legs on the wire.
  • the animals are tested before the test and those which fail to recover within thirty seconds are eliminated. We see during the tests that only 10%. 100 of the tested animals manage to recover.
  • a mouse placed in an enclosure containing 4 electrified plates, receives, with each passage of a plate towards another, an electrical stimulus causing a disorderly leak. After n electric shocks, the mouse no longer moves. It is considered that the degree of sedation obtained is proportional to the number n of electric shocks that the treated mouse will have received before it stops in a corner.
  • the derivatives of the invention produce an average percentage increase in the number of electric shocks n of the order of 60% after 15 minutes, of 62% after 30 minutes and 51% after ninety minutes.
  • the medicament of the invention can be presented, for oral administration, in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented, for rectal administration, in the form of suppositories and for parenteral administration, in the form of an injectable solution.
  • Each unit dose advantageously contains from 0.010 g to 0.500 g of active principle, the doses administered daily being able to vary from 0.010 g to 1.00 g of active principle depending on the age of the patient and the condition treated.
  • the medicament of the invention can thus be advantageously administered, as a preventive or curative treatment, in the treatment of diseases causing a pathological change in platelet aggregation such as diseases causing a pathological change in platelet aggregation such as diseases thromboembolic.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

La présente invention est relative à de nouveaux dérivés de benzo[b] thiénopyridines, à un procédé de préparation de ceux-ci et à leurs applications en médecine humaine et vétérinaire.The present invention relates to new benzo [b] thienopyridine derivatives, to a process for their preparation and to their applications in human and veterinary medicine.

Les dérivés de l'invention répondent à la formule

Figure imgb0001
dans laquelle :

  • R1 représente l'hydrogène ou un groupe alcoyle inférieur ; phényl-C1-2 alcoyle éventuellement substitué sur le noyau phényle par au moins un atome d'halogène ou un groupe hydroxy, nitro, amino, cyano, carboxy, carboxamido, alcoxycarbonyle, alcoyle inférieur, alcoxy inférieur ou trifluorométhyle ; (pyridyl-2)méthyle ; (pyridyl-3)méthyle ou (pyridyl-4)méthyle ;
  • R2 représente l'hydrogène ou un radical alcoyle inférieur ; et
  • R 3 et R4 représentent chacun l'hydrogène, un atome d'halogène ou un groupe hydroxy, alcoyle inférieur ou alcoxy inférieur.
The derivatives of the invention correspond to the formula
Figure imgb0001
 in which :
  • R 1 represents hydrogen or a lower alkyl group; phenyl-C 1-2 alkyl optionally substituted on the phenyl ring with at least one halogen atom or a hydroxy, nitro, amino, cyano, carboxy, carboxamido, alkoxycarbonyl, lower alkyl, lower alkoxy or trifluoromethyl group; (2-pyridyl) methyl; (3-pyridyl) methyl or (4-pyridyl) methyl;
  • R 2 represents hydrogen or a lower alkyl radical; and
  • R 3 and R 4 each represent hydrogen, a halogen atom or a hydroxy, lower alkyl or lower alkoxy group.

Par « alcoyle inférieur » ou « alcoxy inférieur » on veut désigner des groupes ayant de 1 à 6 atomes de carbone.By "lower alkyl" or "lower alkoxy" is meant groups having from 1 to 6 carbon atoms.

L'invention comprend aussi les sels d'addition des dérivés de formule I avec des acides minéraux ou organiques.The invention also includes the addition salts of the derivatives of formula I with mineral or organic acids.

On connaît déjà par le brevet US 3 752 820 des dérivés de benzo[b] thiéno pyridine du type (3,2-c), mais ces dérivés ne portent pas, comme les dérivés de la présente invention, de substituant phényle sur les atomes de carbone du cycle pyridinique.Already known from US Pat. No. 3,752,820 derivatives of benzo [b] thieno pyridine of the type (3,2-c), but these derivatives do not carry, like the derivatives of the present invention, a phenyl substituent on the atoms carbon from the pyridine cycle.

De plus, ces dérivés sont décrits comme possédant des propriétés tranquillisantes, alors que les dérivés de la présente invention présentent des propriétés sédative et inhibitrice de l'agrégation plaquettaire, ce qui est complètement différent.In addition, these derivatives are described as having tranquilizing properties, while the derivatives of the present invention exhibit sedative and inhibitory properties of platelet aggregation, which is completely different.

Quant à la demande FR 2 358 150 déposée le 13 juillet 1976 mais publiée le 10 février 1978, elle décrit des dérivés de thiéno (2,3-c) et (3,2-c) pyridines et non pas des benzo(b) thiénopyridines.As for application FR 2 358 150 filed on July 13, 1976 but published on February 10, 1978, it describes thieno derivatives (2,3-c) and (3,2-c) pyridines and not benzo (b) thienopyridines.

L'invention a également pour objet un procédé de préparation des composés de formule (I), caractérisé en ce qu'on cyclise des composés de formule (II)

Figure imgb0002
dans laquelle R1, R2, R3 et R4 ont les significations données pour la formule (I), par chauffage dans l'acide polyphosphorique à des températures comprises entre 60 et 80 °C.The subject of the invention is also a process for preparing the compounds of formula (I), characterized in that compounds of formula (II) are cyclized
Figure imgb0002
 in which R 1 , R 2 , R 3 and R 4 have the meanings given for formula (I), by heating in polyphosphoric acid at temperatures between 60 and 80 ° C.

La cyclisation est effectuée de préférence en présence d'un gaz inerte, notamment l'azote.The cyclization is preferably carried out in the presence of an inert gas, in particular nitrogen.

Les composés (II) utilisés à titre d'intermédiaires sont des composés nouveaux qui peuvent être préparés par des procédés classiques. On peut obtenir, par exemple, les composés de formule (II) comme suit :

  • On fait réagir un phényl-1 éthanolamine de formule (III) ci-dessous dans laquelle R2 et R3 ont les mêmes significations que ci-dessus, soit avec un formyl-3 benzo(b) thiophène et on fait suivre d'une réduction, soit avec un halogénométhyl-3 benzo(b)thiophène, pour obtenir le composé de formule (Ila) ci-dessous, qui est ensuite le cas échéant condensé avec un halogénure de formule R1X dans lequel R1 a la même signification que précédemment et X est un atome d'halogène (chlore, brome ou iode), si on désire que R1 soit autre qu'un atome d'hydrogène.
The compounds (II) used as intermediates are new compounds which can be prepared by conventional methods. The compounds of formula (II) can be obtained, for example, as follows:
  • A 1-phenylethanolamine of formula (III) below is reacted in which R 2 and R 3 have the same meanings as above, either with a 3-formyl benzo (b) thiophene and followed by a reduction, either with a 3-halogenomethyl benzo (b) thiophene, to obtain the compound of formula (Ila) below, which is then optionally condensed with a halide of formula R 1 X in which R 1 has the same meaning as above and X is a halogen atom (chlorine, bromine or iodine), if we want R 1 to be other than a hydrogen atom.

Le schéma réactionnel est le suivant :

Figure imgb0003
The reaction scheme is as follows:
Figure imgb0003

Les composés de formules (I) pour lesquels R1 est différent de l'hydrogène peuvent aussi être obtenus par condensation des composés de formule (I) correspondants dans lesquels R1 est de l'hydrogène, avec un composé de formule R1X dans lequel X est un atome d'halogène. La réaction est effectuée normalement dans un solvant inerte tel que l'éthanol ou le diméthylformamide, en présence d'une base telle qu'un carbonate de métal alcalin, par exemple le carbonate de potassium. Lorsque X est le chlore ou le brome, on peut avantageusement ajouter une quantité catalytique d'un iodure minéral tel que l'iodure de potassium.The compounds of formulas (I) for which R 1 is different from hydrogen can also be obtained by condensation of the corresponding compounds of formula (I) in which R 1 is hydrogen, with a compound of formula R 1 X in which X is a halogen atom. The reaction is normally carried out in an inert solvent such as ethanol or dimethylformamide, in the presence of a base such as an alkali metal carbonate, for example potassium carbonate. When X is chlorine or bromine, it is advantageous to add a catalytic amount of a mineral iodide such as potassium iodide.

Les halogénométhyl-2 ou -3 benzo(b)thiophènes peuvent être préparés selon : S. AVAKIAN, J. MOSS et G.J. MARTIN, J. amer. chem. Soc., 1948, 70, 3 075 ; N.B. CHAPMAN, K.CLARKE ; B. GORE et S.N. SAWHNEY, J. chem. Soc. (C), 1968, 514 ; N.B. CHAPMAN, K. CLARKE et B. IDDON, J. chem. Soc. (C), 1965, 774. Les formyl-2 et -3 benzo(b)thiophènes peuvent être préparés selon : D.A. SHIRLEY et M.J. DANZIG, J. amer. chem. Soc., 1952, 74, 2 935 ; K. CLARKE, C.G. HUGUES, A.J. HUMPHRIES et R.M. SCROWSTON, J. chem. Soc. (C), 1970, 1 013 ; M.S. EL SHANTA et R.M. SCROWSTON, J. chem. Soc. (C), 1967, 2 085 ; E. CAMPAIGNE et E.S. NEISS, J. HET. Chem., 1966, 3, 46.The halogenomethyl-2 or -3 benzo (b) thiophenes can be prepared according to: S. AVAKIAN, J. MOSS and G.J. MARTIN, J. amer. chem. Soc., 1948, 70, 3,075; N.B. CHAPMAN, K.CLARKE; B. GORE and S.N. SAWHNEY, J. chem. Soc. (C), 1968, 514; N.B. CHAPMAN, K. CLARKE and B. IDDON, J. chem. Soc. (C), 1965, 774. Formyl-2 and -3 benzo (b) thiophenes can be prepared according to: D.A. SHIRLEY and M.J. DANZIG, J. amer. chem. Soc., 1952, 74, 2,935; K. CLARKE, C.G. HUGUES, A.J. HUMPHRIES and R.M. SCROWSTON, J. chem. Soc. (C), 1970, 1013; M.S. EL SHANTA and R.M. SCROWSTON, J. chem. Soc. (C), 1967, 2085; E. CAMPAIGNE and E.S. NEISS, J. HET. Chem., 1966, 3, 46.

Les produits de départ de formule (III) sont des produits disponibles dans le commerce ou bien sont décrits dans la littérature.The starting products of formula (III) are commercially available products or are described in the literature.

On prépare les sels d'addition avec des acides minéraux (par exemple l'acide chlorhydrique, sulfurique, etc...) ou organiques (par exemple l'acide méthane sulfonique, maléique, tartrique, citrique, etc...) par les procédés classiques usuels.The addition salts are prepared with mineral acids (for example hydrochloric, sulfuric acid, etc.) or organic acids (for example methane sulfonic, maleic, tartaric, citric acid, etc.) by usual conventional methods.

Les exemples non limitatifs suivants illustrent l'invention:The following nonlimiting examples illustrate the invention:

Exemple 1Example 1

Chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = R3 = H, R2 = CH3, R4 = CI).8-chloro-3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = R 3 = H, R 2 = CH 3 , R 4 = CI ).

a) préparation de l'amino-alcool de formule Ila) preparation of the amino alcohol of formula II

On chauffe à 70 °C, pendant 14 heures, sous atmosphère d'azote, un mélange de 40 g (0,153 mole) de bromométhyl-3 chloro-5 benzo(b)thiophène, 28,7 g (0,153 mole) de chlorhydrate de noréphédrine, 42 g (0,306 mole) de carbonate de potassium sec et 400 cm3 de diméthylformamide. On filtre les sels minéraux et on évapore le solvant à sec sous bon vide. L'huile résiduelle est reprise par du chlorure de méthylène. Les extraits organiques sont lavés à l'eau, séchés sur sulfate de sodium sec et filtrés sur lit de silice. L'évaporation laisse des cristaux que l'on recristallise dans le cyclohexane : cristaux blanchâtres, F = 83 °C, rdt : 71 %.Heated to 70 ° C for 14 hours, under a nitrogen atmosphere, a mixture of 40 g (0.153 mole) of 3-bromomethyl-5-chloro benzo (b) thiophene, 28.7 g (0.153 mole) of hydrochloride norephedrine, 42 g (0.306 mole) of dry potassium carbonate and 400 cm 3 of dimethylformamide. The mineral salts are filtered and the solvent is evaporated to dryness under good vacuum. The residual oil is taken up in methylene chloride. The organic extracts are washed with water, dried over dry sodium sulfate and filtered through a bed of silica. Evaporation leaves crystals which are recrystallized from cyclohexane: whitish crystals, mp 83 ° C, mdt: 71%.

b) cyclisation de l'amino-alcoolb) cyclization of the amino alcohol

On chauffe à 70 °C pendant 1 heure 30, sous atmosphère d'azote, un mélange agité mécaniquement de 16,7 g (0,05 mole) de l'aminoalcool précédent dans 55 g d'acide polyphosphorique commercial. Après refroidissement le milieu réactionnel est versé sur de la glace, rendu basique avec de l'ammoniaque concentrée et extrait au chlorure de méthylène. Les extraits organiques sont séchés sur sulfate de sodium, filtrés sur lit de silice et évaporés à sec.Heated to 70 ° C for 1 hour 30 minutes, under a nitrogen atmosphere, a mechanically stirred mixture of 16.7 g (0.05 mole) of the above amino alcohol in 55 g of commercial polyphosphoric acid. After cooling, the reaction medium is poured onto ice, made basic with concentrated ammonia and extracted with methylene chloride. The organic extracts are dried over sodium sulfate, filtered through a silica bed and evaporated to dryness.

Les cristaux obtenus sont recristallisés dans un mélange isopropanol-éthanol : cristaux blancs, F = 174 °C, rdt : 97%.The crystals obtained are recrystallized from an isopropanol-ethanol mixture: white crystals, mp = 174 ° C., mdt: 97%.

Exemple 2Example 2

Méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = R3 = R4 = H, R2 = CH3).3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = R 3 = R 4 = H , R 2 = CH 3 ).

a) préparation de l'amino-alcool de formule IIa) preparation of the amino alcohol of formula II

Elle est réalisée à partir du chlorométhyl-3 benzo(b) thiophène et de noréphédine selon le mode opératoire de l'exemple 1 (partie a). Base : cristaux blancs, F = 104 °C (cyclohexane) ; rdt : 67 %.It is carried out using 3-chloromethyl benzo (b) thiophene and norephedine according to the procedure of Example 1 (part a). Base: white crystals, F = 104 ° C (cyclohexane); rdt: 67%.

b) cyclisation de l'amino-alcoolb) cyclization of the amino alcohol

Elle est réalisée selon le mode opératoire décrit à l'exemple 1 (partie b).It is carried out according to the procedure described in Example 1 (part b).

Base : cristaux blancs rosés, F = 164 °C (isopropanol) ; rdt : 72,5 %.Base: pinkish white crystals, F = 164 ° C (isopropanol); rdt: 72.5%.

Exemple 3Example 3

Chloro-8 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = R2 = R3 = H, R4 = CI).Chloro-8 phenyl-4 tétrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = R 2 = R 3 = H, R 4 = CI).

a) préparation de l'amino-alcool de formule Ila) preparation of the amino alcohol of formula II

Elle est réalisée à partir du bromométhyl-3 chloro-5 benzo(b) thiophène et de l'amino-2 phényl-1 éthanol, selon le mode opératoire décrit à l'exemple 1 (partie a).It is carried out using 3-bromomethyl-5-chloro benzo (b) thiophene and 2-amino-1-phenyl ethanol, according to the procedure described in Example 1 (part a).

Base : cristaux blanchâtres, F = 95 °C (cyclohexane) ; rdt : 40 %.Base: whitish crystals, F = 95 ° C (cyclohexane); rdt: 40%.

b) cyclisation de l'amino-alcoolb) cyclization of the amino alcohol

Elle est réalisée selon le mode opératoire décrit à l'exemple 1 (partie b).It is carried out according to the procedure described in Example 1 (part b).

Méthanesulfonate : cristaux blancs, F = 234 °C (éthanol), rdt : 77 %.Methanesulfonate: white crystals, F = 234 ° C (ethanol), yield: 77%.

Exemple 4Example 4

Phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = R2 = R3 = R4 = H)4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = R 2 = R 3 = R 4 = H)

a) préparation de l'amino-alcool Ila) preparation of the amino alcohol II

Elle est réalisée à partir du chlorométhyl-3 benzo(b) thiophène et de l'amino-2 phényl-1 éthanol, selon le mode opératoire décrit à l'exemple 1 (partie a). Base : cristaux blancs, F = 108 °C (cyclohexane) ; rdt : 34%It is carried out using 3-chloromethyl benzo (b) thiophene and 2-amino-1-phenyl ethanol, according to the procedure described in Example 1 (part a). Base: white crystals, F = 108 ° C (cyclohexane); rdt: 34%

b) cyclisation de l'amino-alcoolb) cyclization of the amino alcohol

Elle est réalisée selon le mode opératoire décrit à l'exemple 1 (partie b).It is carried out according to the procedure described in Example 1 (part b).

Méthanesulfonate : cristaux beiges, F = 215 °C (éthanol), rdt : 69%.Methanesulfonate: beige crystals, M = 215 ° C (ethanol), yield: 69%.

Exemple 5Example 5

Chloro-8 diméthyl-2,3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = R2 = méthyl ; R 3 = H, R4 = CI)8-chloro-2,3-dimethyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = R 2 = methyl; R 3 = H, R 4 = THIS)

On effectue la N-méthylation de la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno [3,2-c]pyridine (exemple 1), par condensation avec de l'iodure de méthyle, dans l'éthanol, en présence de carbonate de potassium, ou par réaction de Leuckart (chauffage en présence de formol et d'acide formique).N-methylation of 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1) is carried out by condensation with methyl iodide, in ethanol, in the presence of potassium carbonate, or by Leuckart reaction (heating in the presence of formaldehyde and formic acid).

Chlorhydrate : cristaux blancs, F = 229 °C (isopropanol), rdt : 100 % (réaction de Leuckart).Hydrochloride: white crystals, M = 229 ° C (isopropanol), rdt: 100% (Leuckart reaction).

Exemple 6Example 6

Chloro-8 o-chlorobenzyl-2 méthyl-3 phényi-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = o.chlorobenzyl ; R2 = méthyl ; R3 = H ; R4 = CI)8-Chloro-2-chlorobenzyl-3-methyl-4-phenyi-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = o.chlorobenzyl; R 2 = methyl; R 3 = H; R 4 = CI)

On chauffe à 70 °C, pendant 12 heures, un mélange de 6 g (0,019 mole) de chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1), 3,1 g (0,019 mole) de chlorure d'o-chlorobenzyle et 2,6 g (0,019 mole) de carbonate de potassium sec dans 80 cm3 de diméthylformamide. Après refroidissement les sels minéraux sont filtrés et le solvant est évaporé sous pression réduite. Le résidu est repris par de l'eau et extrait au chlorure de méthylène. Les extraits organiques sont lavés à l'eau, séchés sur sulfate de sodium, filtrés sur lit de silice et évaporés à sec. Le résidu est transformé en chlorhydrate que l'on recristallise dans le méthanol : cristaux blancs, F = 175 °C ; rdt : 55%.Heated to 70 ° C for 12 hours, a mixture of 6 g (0.019 mole) of 8-chloro-3-methyl-4-phenyl-1,2,3,4 tetrahydro benzo (b) thieno [3,2-c ] pyridine (Example 1), 3.1 g (0.019 mole) of o-chlorobenzyl chloride and 2.6 g (0.019 mole) of dry potassium carbonate in 80 cm 3 of dimethylformamide. After cooling the mineral salts are filtered and the solvent is evaporated off under reduced pressure. The residue is taken up in water and extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sulfate, filtered through a silica bed and evaporated to dryness. The residue is transformed into the hydrochloride which is recrystallized from methanol: white crystals, mp 175 ° C; rdt: 55%.

Exemple 7Example 7

Benzyl-2 chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = benzyl ; R2 = méthyl ; R3 = H ; R4 = CI)Benzyl-2 chloro-8 methyl-3 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = benzyl; R 2 = methyl; R 3 = H; R 4 = CI)

On condense du bromure de benzyle avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1) selon le procédé décrit à l'exemple 6.Benzyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (Example 1) according to the process described in example 6.

Méthanesulfonate : cristaux blancs, F > 260 °C (acétonitrile), rdt : 63%.Methanesulfonate: white crystals, F> 260 ° C (acetonitrile), yield: 63%.

Exemple 8Example 8

Phényl-4 p-tolyl-2 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = p-tolyle ; R2 = R3 = R4 = H) On condense du bromure de. p-tolyle avec la phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c] pyridine (exemple 4) selon le procédé à l'exemple 6.Phenyl-4 p-tolyl-2 tétrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = pt ol yle; R 2 = R 3 = R 4 = H) On condense of bromide. p-tolyl with 4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (example 4) according to the method in example 6.

Chlorhydrate : cristaux blancs, F = 200 °C (acétate d'éthyle-méthanol), rdt : 99 %.Hydrochloride: white crystals, F = 200 ° C (ethyl acetate-methanol), yield: 99%.

Exemple 9Example 9

Méthyl-3 m-méthoxybenzyl-2 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = m-méthoxybenzyle : R3 = R4 = H ; R2 = CH3)Methyl-3 m-methoxybenzyl-2 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = m- methox y benz y le: R3 = R4 = H ; R 2 = CH 3 )

On condense du bromure de m-méthoxybenzyle avec la méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 2), selon le procédé décrit à l'exemple 6.Condensing m-methoxybenzyl bromide with 3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 2), according to the process described in example 6.

Chlorhydrate : cristaux blancs, F = 160 °C (acétonitrile-méthanol), rdt : 92 %.Hydrochloride: white crystals, M = 160 ° C (acetonitrile-methanol), yield: 92%.

Exemple 10Example 10

Chloro-8 (triméthoxy-3,4,5 benzyl)-2 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c] pyridine (R1 = triméthoxy-3,4,4 benzyle ; R3 = R4 = H ; R2 = méthyl)Chloro-8 (trimethoxy-3,4,5 benzyl) -2 methyl-3 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = trimethoxy-3 , 4.4 benzyl; R 3 = R 4 = H; R 2 = methyl)

On condense le chlorure de triméthoxy-3,4,5 benzyle avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1), selon le procédé décrit à l'exemple 6.The 3,4,5-trimethoxy benzyl chloride is condensed with the 8-chloro-3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (example 1) , according to the method described in Example 6.

Base : cristaux blancs, F = 172 °C, rdt : 78,5 %.Base: white crystals, M = 172 ° C, yield: 78.5%.

Exemple 11Example 11

Chloro-8 o-nitrobenzyl-2 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = o-nitrobenzyl; R2 = R3 = H; R4 = Cl)Chloro-8 o-nitrobenzyl-2 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = o-nitrobenzyl; R 2 = R 3 = H; R 4 = Cl)

On condense du chlorure d'o-nitrobenzyle avec la chloro-8 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 3), selon le procédé décrit à l'exemple 6.O-nitrobenzyl chloride is condensed with 8-chloro-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (example 3), according to the process described in l 'example 6.

Chlorhydrate : cristaux jaunes, F = 150 °C (acétonitrile) ; rdt : 45 %.Hydrochloride: yellow crystals, F = 150 ° C (acetonitrile); rdt: 45%.

Exemple 12Example 12

o-cyanobenzyl-2 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = o-cyanobenzyl ; R2 = R3 = R4 = H)o-cyanobenzyl-2 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = o-cyanobenzyl; R 2 = R 3 = R 4 = H)

On condense du bromure d'o-cyanobenzyle avec la phényl-4 tétrahydro-1,2,3,4 benzo (b) thiéno [3,2-c] pyridine (exemple 4), selon le procédé de l'exemple 6.O-cyanobenzyl bromide is condensed with 4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 4), according to the method of Example 6.

Base : cristaux blanchâtres, F = 143 °C, rdt : 69 %.Base: whitish crystals, M = 143 ° C, yield: 69%.

Exemple 13Example 13

chloro-8 méthyl-3 o-méthoxycarbonylbenzyl-2 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c] pyridine (R1 = o-méthoxycarbonylbenzyl ; R2 = CH3 ; R3 = H ; R4 = CI)chloro-8 methyl-3 o-methoxycarbonylbenzyl-2 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = o-methoxycarbonylbenzyl; R 2 = CH 3 ; R 3 = H; R 4 = CI)

On condense du bromure d'o-méthoxycarbonylbenzyle avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1), selon le procédé décrit à l'exemple 6.O-methoxycarbonylbenzyl bromide is condensed with 8-chloro-3-methylphenyl-1,2,3,4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (Example 1), according to the method described in Example 6.

Chlorhydrate : cristaux blanchâtres, F = 155 °C (acétonitriie), rdt : 86 %.Hydrochloride: whitish crystals, M = 155 ° C (acetonitrile), yield: 86%.

Exemple 14Example 14

o-carboxybenzyl-2 chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = o-carboxybenzyl ; R2 = CH3 : R3 = H ; R4 = CI.o-carboxybenzyl-2 chloro-8 methyl-3 phenyl-4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = o-carboxybenzyl; R 2 = CH 3 : R 3 = H; R 4 = CI.

Ce dérivé est obtenu par hydrolyse basique du composé décrit à l'exemple 13.This derivative is obtained by basic hydrolysis of the compound described in Example 13.

Base : cristaux blancs, F = 258 °C (méthanol-diméthylformamide), rdt : 100 %.Base: white crystals, F = 258 ° C (methanol-dimethylformamide), yield: 100%.

Exemple 15Example 15

.Butyl-2 chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = butyl ; R2 = CH3 ; R3 = H ; R4 = Cl).-2-Butyl-8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (R 1 = butyl; R 2 = CH 3 ; R 3 = H; R 4 = Cl)

On condense du bromure de butyle avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1), selon le procédé décrit à l'exemple 6.Butyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1), according to the process described in 1 'example 6.

Méthanesulfonate : cristaux blancs, F = 210 °C (acétonitrile), rdt = 58 %.Methanesulfonate: white crystals, F = 210 ° C (acetonitrile), rdt = 58%.

Exemple 16Example 16

Méthyl-3 phénéthyl-2 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = phénéthyl ; R2 = CH3; R3 = R4 = H)3-methyl-2-phenethyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = phenethyl; R 2 = CH 3 ; R 3 = R 4 = H )

On condense du bromure de phénéthyle avec la méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 2), selon le procédé décrit à l'exemple 6.Phenethyl bromide is condensed with 3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 2), according to the process described in Example 6 .

Chlorhydrate : cristaux blancs, F = 210 °C (isopropanol-méthanol), rdt : 72 %.Hydrochloride: white crystals, M = 210 ° C (isopropanol-methanol), rdt: 72%.

Exemple 17Example 17

Chloro-8 méthyl-3 phényl-4(pyridyl-3) méthyl-2 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = (pyridyl-3) méthyl ; R2 = CH3 ; R3 = H ; R4 = CI)8-chloro-3-methyl-phenyl-4 (3-pyridyl) 2-methyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = (3-pyridyl) methyl; R 2 = CH3 ; R 3 = H; R 4 = CI)

On condense du chlorhydrate de chlorométhyl-3 pyridine avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1) selon le procédé décrit à l'exemple 6.Condensing chloromethyl-3 pyridine hydrochloride with chloro-8 methyl-3-phenyl-4,3-tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (Example 1) according to the method described in example 6.

Dichlorhydrate : cristaux roses, F = 260 °C (méthanoldiméthylformamide), rdt : 69 %.Dihydrochloride: pink crystals, M = 260 ° C (methanoldimethylformamide), yield: 69%.

Exemple 18Example 18

Méthyl-3 phényi-4 (pyridyl-2) méthyl-2 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = (pyridyl-2) méthyl ; R2 = CH3 ; R3 = R 4 = H).3-methylpheny-4 (2-pyridyl) 2-methyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (R 1 = (2-pyridyl) methyl; R 2 = CH3 ; R 3 = R 4 = H ).

On condense du chlorhydrate de chlorométhyl-2 pyridine avec la méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 2), selon le procédé décrit à l'exemple 6.Condensing 2-chloromethyl pyridine hydrochloride with 3-methyl-4-phenyl tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (example 2), according to the process described in 1 'example 6.

Dichlorhydrate : cristaux blanchâtres ; F = 155 °C (acétate d'éthyle-méthanol) ; rdt : 63 %.Hydrochloride: whitish crystals; Mp 155 ° C (ethyl acetate-methanol); rdt: 63%.

Exemple 19Example 19

Chloro-8 méthyl-3 phényl-4 (pyridyl-4) méthyl-2-tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (R1 = (pyridyl-4) méthyl ; R2 = CH3 ;R3 = H ; R4 = CI)Chloro-8 methyl-3-phenyl-4 (pyridyl-4) methyl-2-tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (R 1 = (pyridyl-4) methyl ; R 2 = CH 3 ; R 3 = H; R 4 = CI)

On condense du chlorhydrate de chlorométhyl-4 pyridine avec la chloro-8 méthyl-3 phényl-4 tétrahydro-1,2,3,4 benzo(b) thiéno[3,2-c]pyridine (exemple 1), selon le procédé décrit à l'exemple 6.4-chloromethyl pyridine hydrochloride is condensed with 8-chloro-3 methyl-4-phenyl 1,2,3,4 tetrahydro benzo (b) thieno [3,2-c] pyridine (example 1), according to the method described in Example 6.

Dichlorhydrate : cristaux marron clair, F = 258 °C, rdt : 41 %.Dihydrochloride: light brown crystals, M = 258 ° C, yield: 41%.

Les résultats des essais toxicologiques et pharmacologiques qui sont rapportés ci-après, ont mis en évidence les intéressantes activités des dérivés de l'invention, notamment inhibitrice de l'agrégation plaquettaire et sédative.The results of the toxicological and pharmacological tests which are reported below, have highlighted the interesting activities of the derivatives of the invention, in particular inhibiting platelet aggregation and sedative.

L'invention a donc encore pour objet une composition thérapeutique présentant en particulier des activités inhibitrice de l'agrégation plaquettaire et sédative, caractérisé en ce qu'elle contient, à titre de principe actif, un dérivé de formule (I) ou un sel d'addition avec un acide pharmaceutiquement acceptable de celui-ci, en association avec un véhicule thérapeutiquement administrable.A further subject of the invention is therefore a therapeutic composition having in particular activities which inhibit platelet aggregation and sedation, characterized in that it contains, as active principle, a derivative of formula (I) or a salt thereof. addition with a pharmaceutically acceptable acid thereof, in combination with a therapeutically administrable vehicle.

1 - Etude toxicologique1 - Toxicological study

Les composés de l'invention bénéficient d'une excellente tolérance et d'une faible toxicité. Ainsi, la DL50/24 h/kg d'animal, déterminée chez la souris selon la méthode de Miller et Tainter, pour la voie orale, est supérieure à 400 mg pour tous les dérivés.The compounds of the invention benefit from excellent tolerance and low toxicity. Thus, the LD 50/24 h / kg of animal, determined in mice according to the Miller and Tainter method, for the oral route, is greater than 400 mg for all the derivatives.

En outre, les essais effectués sur la toxicité aiguë, chronique, sub-chronique et retardée, chez diverses espèces animales, n'ont mis en évidence aucune réaction locale ou générale, aucune perturbation dans les contrôles biologiques régulièrement effectués, aucune anomalie dans les examens microscopiques et macroscopiques chez les animaux sacrifiés et autopsiés en fin d'expérimentation.In addition, the tests carried out on acute, chronic, sub-chronic and delayed toxicity, in various animal species, did not highlight any local or general reaction, no disturbance in the biological controls regularly carried out, no abnormality in the examinations microscopic and macroscopic in animals sacrificed and autopsied at the end of the experiment.

Il - Etude pharmacologiqueIt - Pharmacological study 1. Action inhibitrice de l'agrégation plaquettaire1. Inhibitory action on platelet aggregation

Chez des rats de souche Wistar, on effectue un prélèvement sanguin dans la veine jugulaire. A partir de ce sang citraté et après centrifugation, on reconstitue un plasma contenant 600 000 ± 20 000 plaquettes par mm3, qui servira dans toutes les mesures d'agrégation.In rats of Wistar strain, a blood sample is taken from the jugular vein. From this citrated blood and after centrifugation, a plasma containing 600,000 ± 20,000 platelets per mm 3 is reconstituted, which will be used in all aggregation measurements.

a) Mesure de l'agrégation plaquettaire à l'A.D.P.a) Measurement of platelet aggregation at the A.D.P.

On place 0,4 ml de plasma dans un tube siliconé pourvu d'une barre aimantée elle-même siliconée. Le tube est introduit dans un agrégomètre couplé à un appareil permettant d'enregistrer les variations de densité optique. Lorsque la transmission de la lumière a atteint une valeur stable, on introduit dans le tube 0,5 ml d'une solution contenant 10 µ d'A.D.P. (Adénosine-Di Phosphate).0.4 ml of plasma is placed in a silicone tube provided with a magnetic bar itself silicone. The tube is introduced into an aggregometer coupled to a device making it possible to record the variations in optical density. When the light transmission has reached a stable value, 0.5 ml of a solution containing 10 μ of ADP is introduced into the tube. (Adenosine-Di Phosphate).

L'agrégation des plaquettes provoque alors une augmentation de la transmission lumineuse suivie d'une diminution consécutive à la phase de désagrégation.The aggregation of platelets then causes an increase in light transmission followed a decrease following the disaggregation phase.

La variation maximale de densité optique ainsi déterminée caractérise l'intensité de l'agrégation.The maximum variation in optical density thus determined characterizes the intensity of the aggregation.

b) Mesure de l'agrégation plaquettaire au collagèneb) Measurement of collagen platelet aggregation

La solution d'A.D.P. est remplacée par une solution de collagène (extrait de tendons bovins).A.D.P.'s solution is replaced by a collagen solution (bovine tendon extract).

c) Résultatsc) Results

Différents lots de 20 rats sont utilisés, chaque lot recevant un dérivé à tester par la voie orale, à la dose de 100 mg/kg. Les résultats obtenus au cours de ces 2 essais sont rapportés dans le tableau I suivant qui indique le pourcentage d'inhibition de l'agrégation plaquettaire obtenu, par rapport au témoin, 3 heures après le traitement par le médicament de l'invention, dans le test de l'A.D.P. et au collagène.

Figure imgb0004
Different batches of 20 rats are used, each batch receiving a derivative to be tested by the oral route, at a dose of 100 mg / kg. The results obtained during these 2 tests are reported in the following Table I which indicates the percentage of inhibition of platelet aggregation obtained, relative to the control, 3 hours after treatment with the medicament of the invention, in the ADP and collagen test.
Figure imgb0004

2. Action sédative2. Sedative action

L'action sédative des composés de l'invention a été étudiée selon plusieurs méthodes.The sedative action of the compounds of the invention has been studied according to several methods.

A) Etude du comportementA) Behavioral study

Cette étude a été effectuée selon la méthode de SAMUEL IRWIN (Ph. D. animal and clinical Pharmacology Technics in drug evaluation). Les dérivés de l'invention sont administrés par la voie orale à des souris à la dose de 100 mg/Kg. L'étude du comportement des animaux traités, pendant les 4 heures suivantes, ainsi que la mesure des différents paramètres physiologiques, température, vitesse cardiaque et respiratoire, met en évidence la nette action sédative des dérivés de l'invention.This study was carried out according to the method of SAMUEL IRWIN (Ph. D. animal and clinical Pharmacology Technics in drug evaluation). The derivatives of the invention are administered orally to mice at a dose of 100 mg / kg. The study of the behavior of the animals treated, during the following 4 hours, as well as the measurement of the various physiological parameters, temperature, cardiac and respiratory speed, highlights the clear sedative action of the derivatives of the invention.

B) Action vis-à-vis des hypnotiquesB) Action against hypnotics

Les produits à tester sont administrés à des souris par la voie orale à la dose de 100 mg/kg, trente minutes avant l'injection intrapéritonéale d'une solution de 300 mg de chloral dans 20 ml de sérum physiologique. On note le nombre de souris endormies, le temps d'endormissement et la durée du sommeil, par rapport aux souris témoins qui n'ont reçu que l'injection du chloral. On constate que les dérivés de l'invention potentialisent considérablement l'action du chloral, notamment en ce qui concerne la durée du sommeil induit et le nombre de souris endormies.The test products are administered to mice by the oral route at a dose of 100 mg / kg, thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological saline. We note the number of sleeping mice, the time to fall asleep and the duration of sleep, compared to the control mice which received only the injection of chloral. It is found that the derivatives of the invention considerably potentiate the action of chloral, in particular with regard to the duration of the induced sleep and the number of sleeping mice.

C) Test de la tractionC) Traction test

Ce test consiste à suspendre sur un fil, par les pattes antérieures, des souris qui ont reçu 100 mg du dérivé à tester par la voie orale. On considère que les souris ont subi une action sédative quand elles ne parviennent pas, en trente secondes, à effectuer un rétablissement qui amène au moins une de leurs pattes postérieures sur le fil.This test consists in suspending on a wire, by the front legs, mice which have received 100 mg of the derivative to be tested by the oral route. It is considered that the mice have undergone a sedative action when they do not manage, within thirty seconds, to effect a recovery which brings at least one of their hind legs on the wire.

Les animaux sont testés avant l'essai et ceux qui n'arrivent pas à se rétablir dans le temps de trente secondes sont éliminés. On constate au cours des essais que seulement 10 p. 100 des animaux testés réussissent à se rétablir.The animals are tested before the test and those which fail to recover within thirty seconds are eliminated. We see during the tests that only 10%. 100 of the tested animals manage to recover.

D) Test des 4 plaques (Boissier, Simon et Aron, Europ. J. of Pharmacol. 4, 1968, 145-151)D) Test of the 4 plates (Boissier, Simon and Aron, Europ. J. of Pharmacol. 4, 1968, 145-151)

Une souris, placée dans une enceinte contenant 4 plaques électrifiées, reçoit, à chaque passage d'une plaque vers une autre, un stimulus électrique provoquant une fuite désordonnée. Au bout de n chocs électriques, la souris ne bouge plus. On considère que le degré de sédation obtenu est proportionnel au nombre n de secousses électriques que la souris traitée aura reçu avant qu'elle ne s'immobilise dans un coin.A mouse, placed in an enclosure containing 4 electrified plates, receives, with each passage of a plate towards another, an electrical stimulus causing a disorderly leak. After n electric shocks, the mouse no longer moves. It is considered that the degree of sedation obtained is proportional to the number n of electric shocks that the treated mouse will have received before it stops in a corner.

On détermine ainsi qu'administrés par la voie orale à la dose de 100 mg/Kg, les dérivés de l'invention produisent un pourcentage moyen d'accroissement du nombre de secousses électriques n de l'ordre de 60 % après 15 minutes, de 62 % après 30 minutes et de 51 % après quatre vingt dix minutes.It is thus determined that administered by the oral route at a dose of 100 mg / kg, the derivatives of the invention produce an average percentage increase in the number of electric shocks n of the order of 60% after 15 minutes, of 62% after 30 minutes and 51% after ninety minutes.

Les résultats de ces études mettent en évidence la bonne tolérance et les intéressantes propriétés inhibitrices de l'agrégation plaquettaire et sédatives des dérivés de l'invention qui les rendent très utiles en médecine humaine et vétérinaire.The results of these studies demonstrate the good tolerance and the interesting inhibitory properties of platelet aggregation and sedatives of the derivatives of the invention which make them very useful in human and veterinary medicine.

Le médicament de l'invention peut être présenté, pour l'administration orale, sous forme de comprimés, comprimés dragéifiés, capsules, gouttes et sirop. Il peut aussi être présenté, pour l'administration rectale, sous forme de suppositoires et pour l'administration parentérale, sous forme de soluté injectable.The medicament of the invention can be presented, for oral administration, in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented, for rectal administration, in the form of suppositories and for parenteral administration, in the form of an injectable solution.

Chaque dose unitaire contient avantageusement de 0,010 g à 0,500 g de principe actif, les doses administrabes journellement pouvant varier de 0,010 g à 1,00 g de principe actif selon l'âge du patient et l'affection traitée.Each unit dose advantageously contains from 0.010 g to 0.500 g of active principle, the doses administered daily being able to vary from 0.010 g to 1.00 g of active principle depending on the age of the patient and the condition treated.

On donnera ci-après, à titre d'exemples non limitatifs, quelques formulations pharmaceutiques du médicament de l'invention.

  • 1) Comprimés
    • dérivé de l'Ex. 2............0,050 g
    • excipient : amidon de maïs, stéarate de magnésium, aérosil, talc, amaranthe, tartrazine.
  • 2) Comprimés dragéifiés
    • dérivé de l'Ex. 6............0,075 g
    • excipient : talc, amidon de maïs, gomme arabique, gomme laque, sucre, glucose, cire blanché, cire de carnauba, blanc de baleine, lactose, jaune orangé S, oxyde de titane.
  • 3) Capsules
    • dérivé de l'Ex. 9............0,100 g
    • excipient : stéarate de magnésium, amidon de maïs, saccharose.
  • 4) Ampoules injectables
    • dérivé de l'Ex. 14...........0,050 g
    • excipient : solvant isotonique q.s.p...5 ml
  • 5) Suppositoires
    • dérivé de l'Ex. 18...........0,100 g
    • excipient : triglycérides semi-synthétiques
  • 6) Sirop
    • dérivé de l'Ex: 2............1,00 g
    • excipient aromatisé q.s.p. 100 ml
A few pharmaceutical formulations of the medicament of the invention will be given below, by way of nonlimiting examples.
  • 1) Tablets
    • derived from Ex. 2 ............ 0.050 g
    • excipient: corn starch, magnesium stearate, aerosil, talc, amaranth, tartrazine.
  • 2) sugar-coated tablets
    • derived from Ex. 6 ............ 0.075 g
    • excipient: talc, corn starch, gum arabic, shellac, sugar, glucose, white wax, carnauba wax, whale white, lactose, orange yellow S, titanium oxide.
  • 3) Capsules
    • derived from Ex. 9 ............ 0.100 g
    • excipient: magnesium stearate, corn starch, sucrose.
  • 4) Injectable ampoules
    • derived from Ex. 14 ........... 0.050 g
    • excipient: isotonic solvent qsp..5 ml
  • 5) Suppositories
    • derived from Ex. 18 ........... 0.100 g
    • excipient: semi-synthetic triglycerides
  • 6) Syrup
    • derived from Ex: 2 ............ 1.00 g
    • flavored excipient qs 100 ml

Les études toxicologiques et pharmacologiques qui viennent d'être rapportées ont mis en évidence la bonne tolérance des dérivés de l'invention ainsi que leurs activités inhibitrice de l'agrégation plaquettaire et sédative.The toxicological and pharmacological studies which have just been reported have highlighted the good tolerance of the derivatives of the invention as well as their activities which inhibit platelet aggregation and sedation.

Le médicament de l'invention peut ainsi être administré avec profit, à titre préventif ou curatif, dans le traitement des maladies provoquant une modification pathologique de l'agrégation plaquettaire telles que les maladies provoquant une modification pathologique de l'agrégation plaquettaire telles que les maladies thromboembolliques.The medicament of the invention can thus be advantageously administered, as a preventive or curative treatment, in the treatment of diseases causing a pathological change in platelet aggregation such as diseases causing a pathological change in platelet aggregation such as diseases thromboembolic.

Il peut aussi être administré en tant que sédatif et régulateur du système nerveux, dans l'éréthisme nerveux, la neurotonie, les états d'excitation avec insomnie et les troubles de la dentition.It can also be administered as a sedative and regulator of the nervous system, in nervous erethism, neurotonia, states of excitement with insomnia and disorders of dentition.

Claims (7)

1. Compounds having the formula
Figure imgb0007
in which :
R1 represents hydrogen or a C1-6 alkyl group ; a phenyl-C1-2 alkyl group optionally substituted on the phenyl nucleus with at least a halogen atom or a hydroxy, nitro, amino, cyano, carboxy, carboxamido, alkoxycarbonyl, C1-6 alkyl, C1-6 alkoxy or trifluoromethyl group ; a (2-pyridyl)-methyl group ; a (3-pyridyl)-methyl group or a (4-pyridyl)-methyl group,
R2 represents hydrogen or a C1-6 alkyl radical, and
R3 and R4 represent each hydrogen, a halogen atom or a hydroxy, C1-6 alkyl or C1-6 alkoxy group, and their addition salts with inorganic or organic acids.
2. Process for the preparation of compounds as defined in claim 1, characterized in that compounds of the formula (II) :
Figure imgb0008
in which R1, R2, R3 and R4 are as defined in claim 1, are cyclized by heating in polyphosphoric acid at a temperature of 60-80 °C.
3. Process as claimed in claim 2, characterized in that the cyclization is effected in the presence of an inert gas.
4. Process as claimed in claim 2 or 3, characterized in that, to prepare compounds of the formula (I) in which R1 is other than hydrogen, a corresponding compound of the formula (I) in which R1 is hydrogen is condensed with a compound of the formula R1X in which R1 is as defined in claim 1 and X is a halogen atom.
5. Process as claimed in claim 4, characterized in that the condensation is effected within an inert solvent, in the presence of a base.
6. Therapeutic composition having in particular a sedative and a blood-platelet aggregation inhibiting activity, characterized in that it contains, as active ingredient, a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a therapeutically administrable carrier.
7. Therapeutic composition as claimed in claim 6, characterized in that it is in unit dosage form, each unit dose containing 0.010-0.500 g active ingredient.
EP78400006A 1977-06-02 1978-06-01 Benzo(b)thieno pyridines, process for their preparation and therapeutical compositions containing them Expired EP0000108B1 (en)

Applications Claiming Priority (2)

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FR7716878A FR2423494A1 (en) 1977-06-02 1977-06-02 BENZO (B) THIENO PYRIDINES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS
FR7716878 1977-06-02

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EP0000108B1 true EP0000108B1 (en) 1981-08-19

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US4282227A (en) * 1980-05-22 1981-08-04 Smithkline Corporation Renal vasodilating 3,4-dihydroxyphenyltetrahydrothienopyridines
JPS5939349A (en) * 1982-08-31 1984-03-03 杉　晤夫 Method of hulling rice and rice-cleaning machine
JP2570692B2 (en) * 1986-06-20 1997-01-08 株式会社豊田自動織機製作所 Variable displacement rotary compressor
JPH0771637B2 (en) * 1986-06-30 1995-08-02 株式会社佐竹製作所 Vertical axis rice milling equipment
JPS63182041A (en) * 1987-01-21 1988-07-27 株式会社　サタケ Vertical type grain refiner
JPS63218258A (en) * 1987-03-06 1988-09-12 株式会社　サタケ Cereal grain feeder for vertical shaft type cereal-cleaning machine
JPH0822389B2 (en) * 1987-07-27 1996-03-06 株式会社佐竹製作所 Vertical type friction cutting type rice milling machine
JPH01262949A (en) * 1988-04-14 1989-10-19 Satake Eng Co Ltd Vertical shaft-type grain polishing mill by wearing and grinding
JP3266167B2 (en) * 1993-08-06 2002-03-18 株式会社サタケ Resistor adjustment device for vertical grinding type grain mill
JPH0775741A (en) * 1993-09-07 1995-03-20 Satake Eng Co Ltd Perforated cylindrical body for bran removal of grinding type vertical grain milling machine

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GB1210106A (en) * 1967-03-08 1970-10-28 Colgate Palmolive Co Derivatives of 1,2,3,4-tetrahydrobenzothieno [2,3-c]pyridine and of 1,2,3,4-tetrahydro-5h-benzothieno[2,3-c]azepine
US3704237A (en) * 1971-04-29 1972-11-28 Colgate Palmolive Co Certain 2-amidino-1,2,3,4-tetrahydrobenzothiene(2,3-c)pyridines
US3752820A (en) * 1972-03-20 1973-08-14 Colgate Palmolive Co Substituted-1,2,3,4-tetrahydrobenzothieno(3,2-c)pyridine derivatives
FR2358150A1 (en) * 1976-07-13 1978-02-10 Parcor NEW THIENO (2,3-C) AND (3,2-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION

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DK152130B (en) 1988-02-01
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FR2423494B1 (en) 1980-10-17
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ES470274A1 (en) 1979-09-16
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