WO1993017027A1 - Novel therapeutical use of pyridylpyrrolothiazole carboxamide derivatives - Google Patents

Novel therapeutical use of pyridylpyrrolothiazole carboxamide derivatives Download PDF

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Publication number
WO1993017027A1
WO1993017027A1 PCT/FR1993/000173 FR9300173W WO9317027A1 WO 1993017027 A1 WO1993017027 A1 WO 1993017027A1 FR 9300173 W FR9300173 W FR 9300173W WO 9317027 A1 WO9317027 A1 WO 9317027A1
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Prior art keywords
radical
pyrrolo
pyridyl
general formula
thiazole
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PCT/FR1993/000173
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French (fr)
Inventor
Anne Bousseau
Daniel Lave
Françoise Soler
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Rhone-Poulenc Rorer S.A.
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Application filed by Rhone-Poulenc Rorer S.A. filed Critical Rhone-Poulenc Rorer S.A.
Priority to EP93905414A priority Critical patent/EP0628047A1/en
Priority to JP5514591A priority patent/JPH07503966A/en
Publication of WO1993017027A1 publication Critical patent/WO1993017027A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to a new therapeutic application of derivatives of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole carboxamide-7 of general formula:
  • R represents a radical of general formula:
  • X is an oxygen atom, a carbonyl, hydroxymethylene, carboxamido, methylenecarbonyl, carbonylvinylene or vinylenecarbonyl radical, and
  • Y is an aromatic carbocyclic or heterocyclic radical, in their stereoisomeric forms or their mixtures as well as their salts.
  • Products of general formula (I) or their analogs and their preparation have been previously described in European patents EP 115 979, EP 388 309 and American patents US 4,906,757 and US 4,783,472 for their usefulness in the treatment of allergies. , inflammation and inhibition of the aggregation of blood platelets, as well as in the treatment of conditions in which the physiological role of PAF-aceter is involved.
  • pyrrolo [1,2-c] thiazole carboxamide derivatives of general formula (I) in their stereoisomeric forms or their mixtures, as well as their salts, are useful for obtaining a medicament intended for prophylaxis and / or therapeutic treatment of retrovirus infections, and more particularly AIDS (acquired immunodeficiency syndrome) and associated syndromes [ARC (AIDS related complex)].
  • AIDS immunodeficiency syndrome
  • ARC AIDS related complex
  • prophylaxis we mean the treatment of subjects who have been exposed to HIVs (human immunodeficiency virus), in particular asymptomatic seropositive people, who present the risk of developing the disease in the months and years to come after the primary infection.
  • HIVs human immunodeficiency virus
  • Y represents an aromatic radical which can be advantageously chosen from phenyl, thienyl or pyridyl radicals.
  • the Tumor Necrosis Factor (TNF) is responsible for the activation of the HIV virus, especially in chronically infected cells.
  • U1 cell lines obtained after infection of the promonocytic line, U937, with the HIV-1 virus and selected according to the capacity to increase the viral production in response to Phorbol Myristate Acetate (PMA), to TNF and to are used.
  • PMA Phorbol Myristate Acetate
  • other mediators [Folks et al., Science, 238, 800 (1987)].
  • the activity of reverse transcriptase is used as an indicator of viral production.
  • the effect of increasing concentrations of the product to be studied is thus analyzed on stimulated cell lines.
  • the product to be studied is dissolved in dimethylformamide (DMF).
  • DMF dimethylformamide
  • the stock solutions are prepared on the day of the test and stored at a temperature of 4 ° C.
  • the dilutions are made in such a way that the DMF concentration is constant (0.1%).
  • the cell cultures are taken during the exponant growth phase and returned to culture at a final concentration of 2 ⁇ 10 5 cells / ml, in the presence of different concentrations of the product to be studied. 30 minutes later, all the cultures are supplemented with TNF ⁇ or PMA.
  • the pyrrolo [1,2-c] thiazole carboxamide derivatives are studied at concentrations of 1, 10 and 30 ⁇ M.
  • TNF ⁇ is added at the rate of 100, 10 or 1 Units / ml.
  • the present invention relates to obtaining a pharmaceutical composition containing a pyrrolothiazole carboxamide derivative of general formula (I) in its stereoisomeric forms or their mixtures, optionally in salt form, in the pure state or in the form of association with one or more compatible and pharmaceutically acceptable diluents or adjuvants.
  • compositions according to the invention are capable of inhibiting the replication of retroviruses and therefore of reducing the progression towards the disease or of decreasing its severity in infected subjects.
  • compositions according to the invention are capable of preventing or slowing down the development of subjects infected with retroviruses towards an aggravated stage of the disease.
  • preventive means the act of preventing progression in subjects with immunodeficiency and / or infected with retrovirus.
  • compositions will be adapted to the particular case of the digestive tract of the immunocompromised.
  • compositions can be used orally, parenterally or rectally.
  • the sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
  • These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating.
  • compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.
  • solid compositions for oral administration tablets, pills, powders or granules can be used.
  • the active product according to the invention (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • inert diluents or adjuvants such as sucrose, lactose or starch.
  • These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.
  • compositions for oral administration there may be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil.
  • emulsions solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil.
  • These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
  • the doctor will determine the dosage he considers most appropriate based on the age, weight and factors specific to the product and the subject to be treated. Generally in adults the doses are between 25 and 500 mg per day.
  • EXAMPLE 5 At about 60 ° C., 2 g of 7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) are added at about 60 minutes to a solution of 1.4 g of 3-benzoylmethylaniline and 1.9 cm 3 of triethylamine in 50. cm 3 of dioxane.
  • the reaction mixture is heated for 5 hours at 100 ° C., cooled to 25 ° C. and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 60 ° C. The residue is taken up in 200 cm 3 of dichloromethane and 80 cm 3 of water distilled.
  • the organic phase is decanted, washed with 180 cm 3 in total of 1N sodium hydroxide then 300 cm 3 of distilled water.
  • 0.5 g of bleaching black is added to the organic extracts, dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C.
  • the 2.9 g of resin obtained are dissolved in 300 cm 3 of ethyl acetate, filtered through a column 3 cm in diameter containing 25 g of silica (0.02-0.045 mm). The column is washed with 75 cm 3 in total of ethyl acetate.
  • the filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C.
  • the 2.5 g of solid cream obtained are dissolved for the first time in 25 cm 3 of boiling acetonitrile.
  • the solution obtained is filtered hot.
  • the filtrate is cooled to a temperature in the region of 10 ° C for 48 hours.
  • the crystals obtained are separated by filtration, washed with a total of 10 cm of ice-cold acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature in the region of 50 ° C.
  • 1.4 g of a beige solid are thus obtained which is redissolved hot in 200 cm 3 of ethyl acetate, and treated in the presence of 0.5 g of bleaching black, filtered hot. After evaporation of the solvent under reduced pressure
  • the 1.2 g obtained are dissolved one last time in 25 cm 3 of boiling acetonitrile.
  • the solution is filtered hot.
  • the filtrate is cooled to around 20 ° C for 48 hours.
  • the crystals obtained are separated by filtration, rinsed with 10 cm 3 in total of acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature in the region of 80 ° C.
  • the solution obtained is filtered hot.
  • the filtrate is cooled to a temperature in the region of 10 ° C for approximately 3 hours.
  • the crystals obtained are separated by filtration, washed with 20 cm 3 in total of ice-cold acetonitrile and dried under reduced pressure (13.5
  • 3-aminochalcone can be prepared as follows:
  • 3-aminochalcone in the form of a yellow solid, melting at around 156 ° C.
  • 3-nitrochalcone is prepared from Le Fevre and Pearson, J. Chem Soc., 2807 (1932).
  • a solution of 0.31 g of sodium borohydride in a mixture composed of 0.42 cm 3 of 2N sodium hydroxide and 4 cm 3 of distilled water is added dropwise, at a temperature in the region of 25 ° C. solution of 8.8 g of N- (3-benzoylphenyl) -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS) in 25 cm 3 of methanol.
  • 3 cm 3 of 4N acetic acid, 250 cm 3 of distilled water and 250 cm 3 of ethyl acetate are added.
  • the organic phase is decanted, the aqueous phase is extracted with 250 cm 3 of ethyl acetate.
  • the organic extracts are combined, washed with
  • the first 45 fractions are eliminated, the following 32 are combined and the solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C.
  • the 5.6 g of orange meringue obtained are dissolved in 90 cm 3 of boiling acetonitrile.
  • the solution is filtered hot.
  • the filtrate is cooled for 12 hours to 10 ° C.
  • the crystals are separated by filtration, washed with 10 cm 3 in total of acetonitrile and dried under reduced pressure (12.5 Pa) at a room temperature. sine of 60 ° C.
  • the organic phase is decanted, washed with 100 cm 3 of 1N sodium hydroxide and 500 cm 3 in total of distilled water.
  • the solid obtained above is added to the chloromethylenic phase and 100 cm 3 of a methylene chloride / methanol 90-10 mixture (by volume) are added to give a clear solution.
  • the solution is dried over anhydrous magnesium sulfate and filtered through 50 g of silica (0.063-0,200 mm).
  • the solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C.
  • the 8.5 g of solid obtained are dissolved in 150 cm 3 of boiling butanol.
  • the solution obtained is filtered hot.

Abstract

The use of 3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c]thiazole 7-carboxamide derivatives of general formula (I), wherein R is a radical of general formula (II), for which X is an oxygen atom, a carbonyl radical, hydroxymethylene, carboxamido or a -CH2?-CO-, _CH=CH-CO- or _CO-CH=CH- radical, and Y is an aromatic heterocyclic or carbocyclic radical, stereoisomeric forms or mixtures thereof, as well as salts thereof, for preparing a drug for the prevention and/or therapy of retroviral infections, is disclosed.

Description

NOUVELLE APPLICATION THERAPEU TIQUE DE DERIVES DU  NEW THERAPEUTIC APPLICATION OF DERIVATIVES OF
PYRIDYLPYRROLOTHIAZOLE CARBOXAMIDE  PYRIDYLPYRROLOTHIAZOLE CARBOXAMIDE
La présente invention concerne une nouvelle application thérapeutique de dérivés du (pyridyl-3)-3 1H,3H-pyrrolo [1,2-c] thiazole carboxamide-7 de formule générale : The present invention relates to a new therapeutic application of derivatives of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole carboxamide-7 of general formula:
Figure imgf000003_0001
Figure imgf000003_0001
dans laquelle R représente un radical de formule générale :
Figure imgf000003_0002
in which R represents a radical of general formula:
Figure imgf000003_0002
pour lequel X est un atome d'oxygène, un radical carbonyle, hydroxyméthylene, carboxamido, méthylènecarbonyle, carbonylvinylêne ou vinylènecarbonyle, et for which X is an oxygen atom, a carbonyl, hydroxymethylene, carboxamido, methylenecarbonyl, carbonylvinylene or vinylenecarbonyl radical, and
Y est un radical carbocyclique ou heterocyclique aromatique, sous leurs formes stéréoisomères ou leurs mélanges ainsi que leurs sels. Des produits de formule générale (I) ou leurs analogues ainsi que leur préparation, ont été précédemment décrits dans les brevets européens EP 115 979, EP 388 309 et américains US 4 906 757 et US 4 783 472 pour leur utilité dans le traitement des allergies, de l'inflammation et de l'inhibition de l'agrégation des plaquettes sanguines, ainsi que dans le traitement des affections dans les-quelles est impliqué le rôle physiologique du PAF-acéter.  Y is an aromatic carbocyclic or heterocyclic radical, in their stereoisomeric forms or their mixtures as well as their salts. Products of general formula (I) or their analogs and their preparation, have been previously described in European patents EP 115 979, EP 388 309 and American patents US 4,906,757 and US 4,783,472 for their usefulness in the treatment of allergies. , inflammation and inhibition of the aggregation of blood platelets, as well as in the treatment of conditions in which the physiological role of PAF-aceter is involved.
Les dérives de pyrrolo[1,2-c]thiazole carboxamide de formule générale (I) sous leurs formes stéréoisomères ou leurs mélanges, ainsi que leurs sels, sont utiles pour l'obtention d'un médicament destiné à la prophylaxie et/ou au traitement thérapeutique des infections à rétrovirus, et plus particulièrement du SIDA (syndrome d'immuno-déficience acquise) et de syndromes associés [ARC (AIDS related complex)]. The pyrrolo [1,2-c] thiazole carboxamide derivatives of general formula (I) in their stereoisomeric forms or their mixtures, as well as their salts, are useful for obtaining a medicament intended for prophylaxis and / or therapeutic treatment of retrovirus infections, and more particularly AIDS (acquired immunodeficiency syndrome) and associated syndromes [ARC (AIDS related complex)].
Par prophylaxie nous sous entendons le traitement des sujets qui ont été exposés aux virus HIVs (human immunodeficiency virus), en particulier les séropositifs asymptomatiques, qui présentent le risque de développer la maladie dans les mois et les années à venir après la primo-infection. By prophylaxis we mean the treatment of subjects who have been exposed to HIVs (human immunodeficiency virus), in particular asymptomatic seropositive people, who present the risk of developing the disease in the months and years to come after the primary infection.
Dans la formule générale (I) le symbole Y représente un radical aromatique qui peut être avantageusement choisi parmi les radicaux phényle, thiényle ou pyridyle. In the general formula (I) the symbol Y represents an aromatic radical which can be advantageously chosen from phenyl, thienyl or pyridyl radicals.
Les produits de formule générale (I) pour lesquels X est un radical carboxamido ou hydroxyméthylène sont des produits nouveaux. Ces dérivés du pyrrolo[1,2-c] thiazole carboxamide peuvent être préparés par analogie avec les méthodes décrites dans les références citées ci-dessus. The products of general formula (I) for which X is a carboxamido or hydroxymethylene radical are new products. These pyrrolo [1,2-c] thiazole carboxamide derivatives can be prepared by analogy with the methods described in the references cited above.
L'activité des produits de formule générale (I) a été mise en évidence de la manière suivante : The activity of the products of general formula (I) was highlighted in the following way:
Le Tumour Necrosis Factor (TNF) est responsable de l'activation du virus HIV notamment dans les cellules chroniquement infectées. The Tumor Necrosis Factor (TNF) is responsible for the activation of the HIV virus, especially in chronically infected cells.
Les effets des dérivés du pyrrolo[1,2-c] thiazole carboxamide sur l'induction du virus HIV-1 ont été étudiés sur des lignées cellulaires chroniquement infectées. The effects of pyrrolo [1,2-c] thiazole carboxamide derivatives on the induction of the HIV-1 virus have been studied in chronically infected cell lines.
On utilise des lignées cellulaires U1 obtenues après infection de la lignée promonocytaire, U937, par le virus HIV-1 et sélection-née selon la capacité a augmenter la production virale en réponse au Phorbol Myristate Acétate (PMA), au TNF et à d'autres médiateurs [Folks et al., Science, 238, 800 (1987)]. L'activité de la reverse transcriptase est utilisée comme un indicateur de la production virale. On analyse ainsi l'effet de concentrations croissantes du produit à étudier sur des lignées cellulaires stimulées. Etude expérimentale U1 cell lines obtained after infection of the promonocytic line, U937, with the HIV-1 virus and selected according to the capacity to increase the viral production in response to Phorbol Myristate Acetate (PMA), to TNF and to are used. other mediators [Folks et al., Science, 238, 800 (1987)]. The activity of reverse transcriptase is used as an indicator of viral production. The effect of increasing concentrations of the product to be studied is thus analyzed on stimulated cell lines. Experimental study
Le produit à étudier est mis en solution dans le diméthylformamide (DMF). Les solutions mères sont préparées le jour de l'essai et conservées à une température de 4°C. Les dilutions sont réalisées de telle manière que la concentration en DMF soit constante (0,1%). The product to be studied is dissolved in dimethylformamide (DMF). The stock solutions are prepared on the day of the test and stored at a temperature of 4 ° C. The dilutions are made in such a way that the DMF concentration is constant (0.1%).
Les cultures cellulaires sont prélevées en phase de croissance exponantielle et remises en culture à raison d'une concentration finale de 2×105 cellules/ml, en présence de différentes concentrations du produit à étudier. 30 minutes après, l'ensemble des cultures est additionné de TNFα ou de PMA. The cell cultures are taken during the exponant growth phase and returned to culture at a final concentration of 2 × 10 5 cells / ml, in the presence of different concentrations of the product to be studied. 30 minutes later, all the cultures are supplemented with TNFα or PMA.
Chaque essai est fait en triple, excepté les contrôles qui sont faits en quadruple. Trois jours après, une fraction de surnageant des cultures est prélevée, et congelée en vue de la mesure de la reverse transcriptase. Each test is carried out in triplicate, except for the controls which are carried out in quadruple. Three days later, a fraction of culture supernatant is removed, and frozen for the measurement of reverse transcriptase.
La mesure de l'activité de la reverse transcriptase est faite par les techniques connues, en double exemplaire [Strebel et al., Nature, 328, 728 (1987)]. The measurement of the reverse transcriptase activity is made by known techniques, in duplicate [Strebel et al., Nature, 328, 728 (1987)].
Les dérivés du pyrrolo[1,2-c] thiazole carboxamide sont étudiés aux concentrations de 1, 10 et 30 μM. The pyrrolo [1,2-c] thiazole carboxamide derivatives are studied at concentrations of 1, 10 and 30 μM.
Le TNFα est additionné à raison de 100, 10 ou 1 Unités/ml. TNFα is added at the rate of 100, 10 or 1 Units / ml.
Certains contrôles ne reçoivent pas l'activateur. D'autres contrôles ne reçoivent pas le produit à étudier. D'autres ne reçoivent ni le produit ni l'activateur. Résultats : Some controls do not receive the activator. Other controls do not receive the product to be studied. Others receive neither the product nor the activator. Results:
La diminution de la production virale par les dérivés du pyrrolo[1,2-c] thiazole carboxamide-7 est significative et dose-dépendante dans le cas de cellules U1 traitées par le TNFα ou par le PMA. Le jour 3, on observe une diminution d'au moins 50% de l'acti vité. de la reverse transcriptase pour les cellules U1 traitées par 10 Unités/ml de TNFα et additionnées d'une concentration de 10μM des produits. The decrease in viral production by pyrrolo [1,2-c] thiazole carboxamide-7 derivatives is significant and dose-dependent in the case of U1 cells treated with TNFα or with PMA. On day 3, there is a decrease of at least 50% in the activity quickly. reverse transcriptase for U1 cells treated with 10 Units / ml of TNFα and added with a concentration of 10 μM of the products.
Par ailleurs les dérivés de pyrrolo[1,2-c] thiazole carboxamide de formule générale (I) sont sans effet sur la viabilité des cellules quelque soit la concentration utilisée. Furthermore, the pyrrolo [1,2-c] thiazole carboxamide derivatives of general formula (I) have no effect on the viability of the cells whatever the concentration used.
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000006_0001
Figure imgf000007_0001
La présente invention concerne l'obtention d'une composition pharmaceutique contenant un dérivé de pyrrolothiazole carboxamide de formule générale (I) sous ses formes stéréoisomères ou leur mélanges, éventuellement sous forme de sel, à l'état pur ou sous forme d'association avec un ou plusieurs diluants ou adjuvants compatibles et pharmaceutiquement acceptables.  The present invention relates to obtaining a pharmaceutical composition containing a pyrrolothiazole carboxamide derivative of general formula (I) in its stereoisomeric forms or their mixtures, optionally in salt form, in the pure state or in the form of association with one or more compatible and pharmaceutically acceptable diluents or adjuvants.
Les compositions pharmaceutiques selon l'invention sont capables d'inhiber la réplication des rétrovirus et donc de réduire la progression vers la maladie ou de diminuer sa gravité chez les sujets infectés. The pharmaceutical compositions according to the invention are capable of inhibiting the replication of retroviruses and therefore of reducing the progression towards the disease or of decreasing its severity in infected subjects.
Notamment dans le cas des infections par le HIV, en inhibant la replication de ce virus, elles sont capables de réduire la progression vers le SIDA ou de diminuer sa gravité chez les sujets infectés. Les compositions pharmaceutiques selon l'invention sont susceptibles d'empécher ou de ralentir l'évolution des sujets infectés par rétrovirus vers un stade aggravé de la maladie. Particularly in the case of HIV infections, by inhibiting the replication of this virus, they are capable of reducing the progression to AIDS or of reducing its severity in infected subjects. The pharmaceutical compositions according to the invention are capable of preventing or slowing down the development of subjects infected with retroviruses towards an aggravated stage of the disease.
Elles peuvent être utilisées à titre préventif ou curatif. ParThey can be used for preventive or curative purposes. Through
"préventif" on entend le fait de prévenir l'évolution chez des sujets présentant une immunodéficience et/ou infectés par rétrovirus. Bien entendu, la constitution de ces compositions sera adaptée au cas particulier du tractus digestif des immunodéprimés. "preventive" means the act of preventing progression in subjects with immunodeficiency and / or infected with retrovirus. Of course, the constitution of these compositions will be adapted to the particular case of the digestive tract of the immunocompromised.
Les compositions peuvent être utilisées par voie orale, parentérale ou rectale. Les compositions stériles pour administration parentérale peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'éthyle ou d'autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, isotonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorporant à la composition des agents stérilisants, par irradiation ou par chauffage. Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans un milieu stérile injectable. Comme compositions solides pour l'administration orale peuvent être utilisés des comprimés, des pilules, des poudres ou des granulés. Dans ces compositions, le produit actif selon l'invention (éventuellement associé à un autre produit pharmaceutiquement compatible) est mélangé à un ou plusieurs diluants ou adjuvants inertes, tels que saccharose, lactose ou amidon. Ces compositions peuvent également comprendre des substances autres que des diluants, par exemple un lubrifiant tel que le stéarate de magnésium. The compositions can be used orally, parenterally or rectally. The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium. As solid compositions for oral administration, tablets, pills, powders or granules can be used. In these compositions, the active product according to the invention (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.
Comme compositions liquides pour l'administration orale, on peut utiliser des émulsions pharmaceutiquement acceptables, des solutions, des suspensions, des sirops, des élixirs contenant des diluants inertes tels que l'eau ou l'huile de paraffine. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants ou aromatisants. As liquid compositions for oral administration, there may be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil. These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
Les compositions pour administration rectale sont les suppositoires ou les capsules rectales, qui contiennent outre le principe actif, des excipients tels que le beurre de cacao, des glycérides semi-synthétiques ou des polyéthylèneglycols. The compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
D'une manière générale, le médecin déterminera la posologie qu'il estime la plus appropriée en fonction de l'âge, du poids et des facteurs propres au produit et au sujet à traiter. Généralement chez l'adulte les doses sont comprises entre 25 et 500 mg par jour. In general, the doctor will determine the dosage he considers most appropriate based on the age, weight and factors specific to the product and the subject to be treated. Generally in adults the doses are between 25 and 500 mg per day.
L'exemple suivant donné à titre non limitatif illustre une composition selon l'invention. The following example, given without implied limitation, illustrates a composition according to the invention.
Exemple Example
- N-(phénoxy-3 phényl) (pyridyl-3)-3 1H,3H-pyrrolo  - N- (phenoxy-3 phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo
[1,2-c]thiazolecarboxamide-7...................... 5 mg [1,2-c] thiazolecarboxamide-7 ...................... 5 mg
- Stéarate de magnésium : 1 %.................... 2 mg- Magnesium stearate: 1% .................... 2 mg
- ACDISOL : 1 %................................... 2 mg- ACDISOL: 1% ................................... 2 mg
- Silice colloïdale : 0,5%...................... 1 mg- Colloidal silica: 0.5% ...................... 1 mg
- Lactose ....................................... 199 mg Les dérivés de pyrrolo[1,2-c] thiazole carboxamide peuvent être préparés comme décrit dans les références citées précédemment. A titre d'exemple les produits des exemples 5 à 8 peuvent être préparés comme décrit ci après : - Lactose ....................................... 199 mg Pyrrolo derivatives [1, 2-c] thiazole carboxamide can be prepared as described in the references cited above. By way of example, the products of Examples 5 to 8 can be prepared as described below:
Exemple 5 On ajoute, vers 60°C, en 10 minutes environ, 2 g de 7-chloroformyl-3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c]thiazole-(RS) à une solution de 1,4 g de 3-benzoylméthylaniline et de 1,9 cm3 de triéthylamine dans 50. cm3 de dioxane. Le mélange réactionnel est chauffé 5 heures à 100°C, refroidi vers 25°C et le solvant est éliminé sous pression réduite (2,7 kPa) à une température voisine de 60°C. Le résidu est repris par 200 cm3 de dichlorométhane et 80 cm3 d'eau distillée. La phase organique est dé-cantée, lavée par 180 cm3 au total de soude 1N puis 300 cm3 d'eau distillée. Les extraits organiques sont additionnés de 0,5 g de noir décolorant, séchés sur sulfate de magnésium anhydre, filtrés et le solvant est évaporé sous pression réduite (2,7 kPa) à une température voisine de 45°C. Les 2,9 g de résine obtenus sont dissous dans 300 cm3 d'acétate d'éthyle, filtrés sur une colonne de 3 cm de diamètre contenant 25 g de silice (0,02-0,045 mm). La colonne est lavée par 75 cm3 au total d'acétate d'éthyle. Les filtrats sont rassemblés et concentrès à sec sous pression réduite (2,7 kPa) à une température voisine de 50°C. Les 2,5 g de solide crème obtenus sont dissous une première fois dans 25 cm3 d'acétonitrile bouillant. La solution obtenue est filtrée à chaud. Le filtrat est refroidi à une température voisine de 10°C pendant 48 heures. Les cristaux obtenus sont séparés par filtration, lavés par 10 cm au total d'acetonitrile glacé et séchés sous pression réduite (13,5 Pa) à une température voisine de 50°C. On obtient ainsi 1,4 g d'un solide beige qui est redissous à chaud dans 200 cm3 d acétate d'éthyle, et traité en présence de 0,5 g de noir décolorant, filtré à chaud. Après évaporation du solvant sous pression réduiteEXAMPLE 5 At about 60 ° C., 2 g of 7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) are added at about 60 minutes to a solution of 1.4 g of 3-benzoylmethylaniline and 1.9 cm 3 of triethylamine in 50. cm 3 of dioxane. The reaction mixture is heated for 5 hours at 100 ° C., cooled to 25 ° C. and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 60 ° C. The residue is taken up in 200 cm 3 of dichloromethane and 80 cm 3 of water distilled. The organic phase is decanted, washed with 180 cm 3 in total of 1N sodium hydroxide then 300 cm 3 of distilled water. 0.5 g of bleaching black is added to the organic extracts, dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 45 ° C. The 2.9 g of resin obtained are dissolved in 300 cm 3 of ethyl acetate, filtered through a column 3 cm in diameter containing 25 g of silica (0.02-0.045 mm). The column is washed with 75 cm 3 in total of ethyl acetate. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The 2.5 g of solid cream obtained are dissolved for the first time in 25 cm 3 of boiling acetonitrile. The solution obtained is filtered hot. The filtrate is cooled to a temperature in the region of 10 ° C for 48 hours. The crystals obtained are separated by filtration, washed with a total of 10 cm of ice-cold acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature in the region of 50 ° C. 1.4 g of a beige solid are thus obtained which is redissolved hot in 200 cm 3 of ethyl acetate, and treated in the presence of 0.5 g of bleaching black, filtered hot. After evaporation of the solvent under reduced pressure
(2,7 kPa), à une température voisine de 50°C, les 1,2 g obtenus sont dissous une dernière fois dans 25 cm3 d'acetonitrile bouillant- La solution est filtrée à chaud. Le filtrat est refroidi vers 20°C pendant 48 heures. Les cristaux obtenus sont séparés par filtration, rincés par 10 cm3 au total d'acétonitrile et séchés sous pression réduite (13,5 Pa) à une température voisine de 80°C.(2.7 kPa), at a temperature in the region of 50 ° C, the 1.2 g obtained are dissolved one last time in 25 cm 3 of boiling acetonitrile. The solution is filtered hot. The filtrate is cooled to around 20 ° C for 48 hours. The crystals obtained are separated by filtration, rinsed with 10 cm 3 in total of acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature in the region of 80 ° C.
On obtient ainsi 0,75 g de N-(3-phénacylphényl)-3-(3-pyridyl)0.75 g of N- (3-phenacylphenyl) -3- (3-pyridyl) are thus obtained
1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide-(RS), sous la forme d'un solide crème fondant vers 165°C. La 3-benzoylméthylaniline est préparée d'après G.G.I. MOORE, J.K. HARRINGTON, J. Med. Chenu , 18, 386 (1975). Exemple 6 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS), in the form of a cream solid, melting at around 165 ° C. 3-Benzoylmethylaniline is prepared according to GGI MOORE, JK HARRINGTON, J. Med. Chenu, 18, 386 (1975). Example 6
On ajoute, vers 60°C environ, en 10 minutes environ, 8,8 g deAt about 60 ° C., 8.8 g of
7-chloroformyl-3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c]thiazole-(RS) à une solution de 6 , 6 g de 3-aminochalcone et de 8,3 cm3 de triéthylamine dans 165 cm3 de dioxane. Le mélange réactionnel est chauffé 6 heures 30 minutes à 100°C, refroidi vers 25°C et le solvant est éliminé sous pression réduite (2,7 kPa) à une température voisine de 50°C. Le résidu est repris par 500 cm3 de dichlorométhane et 200 cm3 d'eau distillée. La phase organique est décantée, lavée par 450 cm3 au total d'eau distillée, séchée sur sulfate de magnésium anhydre et le solvant est évaporé sous pression réduite7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) to a solution of 6.6 g of 3-aminochalcone and 8.3 cm 3 of triethylamine in 165 cm 3 of dioxane. The reaction mixture is heated 6 hours 30 minutes to 100 ° C, cooled to 25 ° C and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The residue is taken up in 500 cm 3 of dichloromethane and 200 cm 3 of distilled water. The organic phase is decanted, washed with a total of 450 cm 3 of distilled water, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure
(2,7 kPa) à une température voisine de 40°C. Les 13,9 g de meringue obtenus sont dissous dans 300 cm3 d'acétonitrile bouillant.(2.7 kPa) at a temperature close to 40 ° C. The 13.9 g of meringue obtained are dissolved in 300 cm 3 of boiling acetonitrile.
La solution obtenue est filtrée à chaud. Le filtrat est refroidi à une température voisine de 10°C pendant 3 heures environ. Les cristaux obtenus sont séparés par filtration, laves par 20 cm3 au total d'acétonitrile glacé et séchés sous pression réduite (13,5The solution obtained is filtered hot. The filtrate is cooled to a temperature in the region of 10 ° C for approximately 3 hours. The crystals obtained are separated by filtration, washed with 20 cm 3 in total of ice-cold acetonitrile and dried under reduced pressure (13.5
Pa) à une température voisine de 50°C. On obtient ainsi 6,6 g dePa) at a temperature close to 50 ° C. This gives 6.6 g of
N-[3-(3-phényl-3-oxo-propényl)phényl]-3-(3-pyridyl) 1H,3H-pyrrolo [1,2-c]thiazole-7-carboxamide-(RS), sous la forme d'un solide crème fondant vers 180°C. N- [3- (3-phenyl-3-oxo-propenyl) phenyl] -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS), under the form of a solid cream, melting around 180 ° C.
La 3-aminochalcone peut être préparée de la manière suivante: 3-aminochalcone can be prepared as follows:
Une solution de 42,5 g de chlorure stanneux dans un mélange de 40 cm3 d'éthanol absolu et 16 cm3 d'acide chlorhydrique 12N est ajoutée goutte à goutte, en 50- minutes environ, à une suspension de 15 g de 3-nitrochalcone dans 50 cm3 d'éthanol absolu, en maintenant la température vers 45°C. Le mélange réactionnel est alors chaufféA solution of 42.5 g of stannous chloride in a mixture of 40 cm 3 of absolute ethanol and 16 cm 3 of 12N hydrochloric acid is added dropwise, in about 50 minutes, to a suspension of 15 g of 3 -nitrochalcone in 50 cm 3 of absolute ethanol, maintaining the temperature around 45 ° C. The reaction mixture is then heated
2 heures 30 au reflux, puis refroidi vers 20°C. Le précipité est séparé par filtration, lavé par 100 cm3 environ d'éthanol et mis. en solution dans 25 cm3 d'ammoniaque 10N. On ajoute 200 cm3 d'eau distillée et 200 cm3 d'acétate d' éthyle. La phase organique est décantée et la phase aqueuse est extraite par 800 cm3 au total d'acétate d'éthyle. Les extraits organiques sont rassemblés, lavés par 300 cm3 au total d'eau distillée, séchés sur du sulfate de magnésium anhydre et concentrés à sec sous pression réduite (2,7 kPa) à une température voisine de 40°C. On obtient ainsi 9,5 g de2 hours 30 minutes at reflux, then cooled to around 20 ° C. The precipitate is separated by filtration, washed with approximately 100 cm 3 of ethanol and put. dissolved in 25 cm 3 of 10N ammonia. 200 cm 3 of distilled water and 200 cm 3 of ethyl acetate are added. The organic phase is decanted and the aqueous phase is extracted with 800 cm 3 in total of ethyl acetate. The organic extracts are collected, washed per 300 cm 3 in total of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 9.5 g of
3-aminochalcone, sous la forme d'un solide jaune, fondant vers 156°C. 3-aminochalcone, in the form of a yellow solid, melting at around 156 ° C.
La 3-nitrochalcone est préparée d'après Le Fevre et Pearson, J. Chem Soc., 2807 (1932). 3-nitrochalcone is prepared from Le Fevre and Pearson, J. Chem Soc., 2807 (1932).
Exemple 7 Example 7
On ajoute goutte à goutte, à une température voisine de 25°C, une solution de 0,31 g de borohydrure de sodium dans un mélange composé de 0,42 cm3 de soude 2N et 4 cm3 d'eau distillée, à une solution de 8,8 g de N-(3-benzoylphényl)-3-(3-pyridyl) 1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide-(RS) dans 25 cm3 de méthanol. Après 48 heures sous agitation, on ajoute 3 cm3 d'acide acétique 4N, 250 cm3 d'eau distillée et 250 cm3 d'acétate d'éthyle. La phase organique est décantée, la phase aqueuse est extraite par 250 cm3 d'acétate d'éthyle. Les extraits organiques sont réunis, lavés parA solution of 0.31 g of sodium borohydride in a mixture composed of 0.42 cm 3 of 2N sodium hydroxide and 4 cm 3 of distilled water is added dropwise, at a temperature in the region of 25 ° C. solution of 8.8 g of N- (3-benzoylphenyl) -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS) in 25 cm 3 of methanol. After 48 hours with stirring, 3 cm 3 of 4N acetic acid, 250 cm 3 of distilled water and 250 cm 3 of ethyl acetate are added. The organic phase is decanted, the aqueous phase is extracted with 250 cm 3 of ethyl acetate. The organic extracts are combined, washed with
200 cm3 au total d'eau distillée, puis par 100 cm3 d'une solution saturée de bicarbonate de sodium et par 100 cm3 d'eau distillée. On ajoute 0,5 g de noir décolorant, sèche sur du sulfate de magnésium anhydre, et évaporé le solvant sous pression réduite (2,7 kPa) à une température voisine de 40°C. Les 8,2 g de meringue orange obtenus sont chromatographiés sur une colonne de 8,5 cm de diamètre contenant 800 g de silice (0,02-0,045 mm), éluée avec un mélange de cyclohexane et d'acétate d'éthyle 20-80 (en volumes) en recueillant des fractions de 80 cm3. Les 45 premières fractions sont éliminées, les 32 suivantes sont rassemblées et le solvant est évaporé sous pression réduite (2,7 kPa) a une température voisine de 40°C. Les 5,6 g de meringue orange obtenus sont dissous dans 90 cm3 d'acetonitrile bouillant. La solution est filtrée à chaud. Le filtrat est refroidi 12 heures à 10°C. Les cristaux sont séparés par filtration, lavés par 10 cm3 au total d'acétonitrile et séchés sous pression réduite (12,5 Pa) à une température voi sine de 60°C. On obtient ainsi 1,4 g de N-[3-(α-hydroxybenzyl)phényl]-3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c] thiazole-7-carboxamide- (RS), sous la forme d'un solide blanc, fondant vers 182°C. 200 cm 3 in total of distilled water, then per 100 cm 3 of a saturated sodium bicarbonate solution and per 100 cm 3 of distilled water. 0.5 g of bleaching black is added, dried over anhydrous magnesium sulfate, and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The 8.2 g of orange meringue obtained are chromatographed on a column of 8.5 cm in diameter containing 800 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 20- 80 (by volume) by collecting 80 cm 3 fractions. The first 45 fractions are eliminated, the following 32 are combined and the solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The 5.6 g of orange meringue obtained are dissolved in 90 cm 3 of boiling acetonitrile. The solution is filtered hot. The filtrate is cooled for 12 hours to 10 ° C. The crystals are separated by filtration, washed with 10 cm 3 in total of acetonitrile and dried under reduced pressure (12.5 Pa) at a room temperature. sine of 60 ° C. 1.4 g of N- [3- (α-hydroxybenzyl) phenyl] -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS) are thus obtained, as a white solid, melting at around 182 ° C.
Exemple 8 On ajoute, vers 60°C, en 15 minutes environ, 6 g deEXAMPLE 8 At around 60 ° C., 6 g of
7-chloroformyl-3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c]thiazole-(RS) à une solution de 4,2 g de 3-aminobenzanilide, 5,6 cm3 de triéthylamine dans 100 cm3 de dioxane. Le mélange réactionnel est chauffé 6 heures au reflux, refroidi vers 25°C et le solvant est éliminé sous pression réduite (2,7 kPa) à une température voisine de 60°C. Le résidu est repris par 500 cm3 de dichlorométhane, l'insoluble est séparé par filtration, lavé par 60 cm3 au total de dichlorométhane et 200 cm3 d'eau distillée. La phase organique est décantée, lavée par 100 cm3 de soude 1N et 500 cm3 au total d'eau distillée. On ajoute le solide obtenu précédemment à la phase chlorométhylènique et ajoute 100 cm3 d'un mélange chlorure de méthylène/méthanol 90-10 (en volumes) pour avoir une solution limpide. La solution est séchée sur sulfate de magnésium anhydre et filtrée sur 50 g de silice (0,063-0,200 mm). Le solvant est évaporé sous pression réduite (2,7 kPa) à une température voisine de 50°C. Les 8,5 g de solide obtenus sont dissous dans 150 cm3 de butanol bouillant. La solution obtenue est filtrée à chaud. Le filtrat est refroidi à une température voisine de 10°C pendant 24 heures. Les cristaux obtenus sont séparés par filtration, lavés par 30 cm3 au total de butanol et 40 cm3 d'éther ethylique et séchés sous pression réduite (13,5 Pa) à une température voisine de 100°C. On obtient ainsi 5,3 g de N-(3-phénylcarbamoylphényl)-3-(3-pyridyl) 1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide-(RS), sous la forme d'un solide crème fondant vers 206°C. 7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) to a solution of 4.2 g of 3-aminobenzanilide, 5.6 cm 3 of triethylamine in 100 cm 3 of dioxane. The reaction mixture is heated for 6 hours at reflux, cooled to 25 ° C. and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 60 ° C. The residue is taken up in 500 cm 3 of dichloromethane, the insoluble material is separated by filtration, washed with 60 cm 3 in total of dichloromethane and 200 cm 3 of distilled water. The organic phase is decanted, washed with 100 cm 3 of 1N sodium hydroxide and 500 cm 3 in total of distilled water. The solid obtained above is added to the chloromethylenic phase and 100 cm 3 of a methylene chloride / methanol 90-10 mixture (by volume) are added to give a clear solution. The solution is dried over anhydrous magnesium sulfate and filtered through 50 g of silica (0.063-0,200 mm). The solvent is evaporated under reduced pressure (2.7 kPa) at a temperature in the region of 50 ° C. The 8.5 g of solid obtained are dissolved in 150 cm 3 of boiling butanol. The solution obtained is filtered hot. The filtrate is cooled to a temperature in the region of 10 ° C for 24 hours. The crystals obtained are separated by filtration, washed with 30 cm 3 in total of butanol and 40 cm 3 of ethyl ether and dried under reduced pressure (13.5 Pa) at a temperature in the region of 100 ° C. 5.3 g of N- (3-phenylcarbamoylphenyl) -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS) are thus obtained, in the form of a solid cream, melting at around 206 ° C.

Claims

Revendications  Claims
1 - Application de dérivés du (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c]thiazole carboxamide-7 de formule générale : 1 - Application of derivatives of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole carboxamide-7 of general formula:
Figure imgf000014_0001
Figure imgf000014_0001
dans laquelle R représente un radical de formule générale
Figure imgf000014_0002
pour lequel X est un atome d'oxygène, un radical carbonyle, hydroxyméthylène, carboxamido, méthylènecarbonyle, carbonylvinylène ou vinylènecarbonyle, et in which R represents a radical of general formula
Figure imgf000014_0002
for which X is an oxygen atom, a carbonyl, hydroxymethylene, carboxamido, methylenecarbonyl, carbonylvinylene or vinylenecarbonyl radical, and
Y est un radical carbocyclique ou heterocyclique aromatique, sous leurs formes stéréoisomères ou leurs mélanges, ainsi que leurs sels, pour l'obtention d'un médicament destiné à la prophylaxie et/ou au traitement thérapeutique des infections à rétrovirus. Y is an aromatic carbocyclic or heterocyclic radical, in their stereoisomeric forms or their mixtures, as well as their salts, for obtaining a medicament intended for the prophylaxis and / or the therapeutic treatment of retrovirus infections.
2 - Application selon la revendication 1, caractérisée en ce que le médicament est destiné à la prophylaxie et/ou au traitement du2 - Application according to claim 1, characterized in that the medicament is intended for the prophylaxis and / or the treatment of
SIDA. AIDS.
3 - Application selon l'une des revendications 1 ou 2, caractérisée en ce que le symbole Y du dérivé du (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c]thiazole carboxamide-7 représente un radical phényle, thiényle ou pyridyle. 3 - Application according to one of claims 1 or 2, characterized in that the symbol Y of the derivative of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole carboxamide-7 represents a phenyl radical , thienyl or pyridyl.
4 - Procédé de préparation d'une composition pharmaceutique destinée au traitement préventif et/ou curatif des infections à rétrovirus caractérisé en ce que l'on mélange un produit selon la revendication 1 ou 3 avec un ou plusieurs diluants ou adjuvants compatibles et pharmaceutiquement acceptables. 4 - Process for the preparation of a pharmaceutical composition intended for the preventive and / or curative treatment of retrovirus infections characterized in that a product is mixed according to the claim 1 or 3 with one or more compatible and pharmaceutically acceptable diluents or adjuvants.
5 - Un nouveau dérivé du (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c]thiazole carboxamide-7 selon la revendication 1, pour lequel X est un radical carboxamido ou hydroxymethylene et Y est défini comme dans la revendication 1. 5 - A new derivative of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole carboxamide-7 according to claim 1, for which X is a carboxamido or hydroxymethylene radical and Y is defined as in claim 1.
PCT/FR1993/000173 1992-02-25 1993-02-22 Novel therapeutical use of pyridylpyrrolothiazole carboxamide derivatives WO1993017027A1 (en)

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AU2004308825B2 (en) * 2003-12-26 2011-03-10 Masatoshi Hagiwara Method of regulating phosphorylation of SR protein and antiviral agents comprising SR protein activity regulator as the active ingredient
US8338362B2 (en) 2003-12-26 2012-12-25 Masatoshi Hagiwara Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
EP2666481A3 (en) * 2003-12-26 2014-01-01 HAGIWARA, Masatoshi Method of regulating phosphorylation of sr protein and antiviral agents comprising sr protein activity regulator as the active ingredient
US8816089B2 (en) 2003-12-26 2014-08-26 Masatoshi Hagiwara Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
RU2798838C2 (en) * 2018-08-21 2023-06-28 Керин Фармасьютикал Ко., Лтд. Bicyclic heteroaromatic ring derivative
US11952387B2 (en) 2018-08-21 2024-04-09 Kyorin Pharmaceutical Co., Ltd Bicyclic heteroaromatic ring derivative

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MX9300899A (en) 1993-09-01
EP0628047A1 (en) 1994-12-14
FR2687574A1 (en) 1993-08-27
JPH07503966A (en) 1995-04-27
FR2687574B1 (en) 1995-05-05
CA2127545A1 (en) 1993-09-02

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