EP0628047A1 - Therapeutische anwendung von pyridylpyrrolothiazol carboxamidderivaten - Google Patents

Therapeutische anwendung von pyridylpyrrolothiazol carboxamidderivaten

Info

Publication number
EP0628047A1
EP0628047A1 EP93905414A EP93905414A EP0628047A1 EP 0628047 A1 EP0628047 A1 EP 0628047A1 EP 93905414 A EP93905414 A EP 93905414A EP 93905414 A EP93905414 A EP 93905414A EP 0628047 A1 EP0628047 A1 EP 0628047A1
Authority
EP
European Patent Office
Prior art keywords
radical
pyrrolo
pyridyl
general formula
thiazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93905414A
Other languages
English (en)
French (fr)
Inventor
Anne Bousseau
Daniel Lave
Françoise Soler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0628047A1 publication Critical patent/EP0628047A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP93905414A 1992-02-25 1993-02-22 Therapeutische anwendung von pyridylpyrrolothiazol carboxamidderivaten Withdrawn EP0628047A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9202156 1992-02-25
FR9202156A FR2687574B1 (fr) 1992-02-25 1992-02-25 Nouvelle application therapeutique de derives du pyridylpyrrolothiazole carboxamide.
PCT/FR1993/000173 WO1993017027A1 (fr) 1992-02-25 1993-02-22 Nouvelle application therapeutique de derives du pyridylpyrrolothiazole carboxamide

Publications (1)

Publication Number Publication Date
EP0628047A1 true EP0628047A1 (de) 1994-12-14

Family

ID=9427000

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93905414A Withdrawn EP0628047A1 (de) 1992-02-25 1993-02-22 Therapeutische anwendung von pyridylpyrrolothiazol carboxamidderivaten

Country Status (6)

Country Link
EP (1) EP0628047A1 (de)
JP (1) JPH07503966A (de)
CA (1) CA2127545A1 (de)
FR (1) FR2687574B1 (de)
MX (1) MX9300899A (de)
WO (1) WO1993017027A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2470427C (en) 2001-12-21 2012-07-10 Cytokinetics, Incorporated Compositions and methods for treating heart failure
DK2666481T3 (en) * 2003-12-26 2019-02-25 Masatoshi Hagiwara A method for regulating the phosphorylation of SR protein and antiviral agents comprising an SR protein activity regulator as the active ingredient
TWI811428B (zh) 2018-08-21 2023-08-11 日商杏林製藥股份有限公司 雙環雜芳香環衍生物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601015B1 (fr) * 1986-07-04 1988-08-05 Rhone Poulenc Sante Nouveaux derives du 1h,3h-pyrrolo (1,2-c) thiazole, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2678834A1 (fr) * 1991-07-09 1993-01-15 Rhone Poulenc Rorer Sa Nouvelle application therapeutique du pyridylpyrrolothiazole carboxamide.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9317027A1 *

Also Published As

Publication number Publication date
JPH07503966A (ja) 1995-04-27
FR2687574A1 (fr) 1993-08-27
CA2127545A1 (fr) 1993-09-02
MX9300899A (es) 1993-09-01
FR2687574B1 (fr) 1995-05-05
WO1993017027A1 (fr) 1993-09-02

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