Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
  • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
  • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
  • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

• the present invention relates to a new medicament useful more particularly as a bronchodilator, as well as the methods for its preparation.
• Theophylline is one of the most widely used bronchodilator drugs, particularly in the treatment of asthma attacks as well as in the background treatment of asthmatic disease.
• Theophylline acts by increasing the intracellular level of cyclic AMP by inhibiting its degradation by phosphodiesterase. It is this increase which is responsible for the relaxation of the smooth muscle fiber, and in particular of the bronchial fiber, base of the broncho-dilator effect of the drug.
• theophylline inhibits the degranulation of mast cells, thus preventing the release of chemical mediators from broncho-spasm.
• theophylline causes a relaxation of the smooth digestive fiber, an analeptic effect on the heart, arterial vasodilatation, a diuretic effect, a psycho-analeptic action, a stimulation of the respiratory centers.
• One of the major drawbacks of theophylline is that the margin existing between the effective therapeutic doses and the toxic doses is relatively small, this obviously hinders the prescription.
• theophylline has many undesirable effects, in particular in the event of an overdose, namely nausea, vomiting, headache, excitement, insomnia, tachycardia, which are closely related to the ancillary activities of this product.
• this product remains the treatment of choice in asthma attacks and the basic treatment of asthmatic diseases.
• the subject of the present invention is a new pharmaceutical product which can be used as a bronchodilator and in particular in the treatment of asthma, both at the level of the crisis and as a basic treatment, possibly used as a replacement for theophylline in its other applications. of the same type.
• the present invention is based on the demonstration of the bronchodilator activity of the compound called Hispidulin of formula:
• the present invention relates to the preceding compounds as medicaments, the pharmaceutical compositions containing them and their use, in particular, in the preparation of bronchodilator compositions, in particular anti-asthmatic ones.
• the compounds according to the invention have other pharmacological properties, in particular local anti-inflammatory properties. Hispidulin and its derivatives mentioned above are also useful in compositions for external topical application, whether cosmetic or dermatological.
• Hispidulin in itself is known and has already been isolated from plants, but it has not been possible to demonstrate the pharmacological activity which will be described below.
• Hispidulin can be obtained in different ways. First of all, it is possible to synthesize it by methods which have already been described or by adapting methods which are also known.
• the examples below will give an idea of the methods which can be used for the synthesis of Hispidulin.
• the product can, moreover, be prepared by extraction from different plants in which it is known that there are varying amounts of Hispidulin.
• a first extract with alcohol, ether or ketone is then treated with a chlorinated solvent.
• This chlorinated solvent extract contains Hispidulin which can be separated by chromatography.
• Hispidulin like theophylline, can be used in pharmaceutical compositions applicable by different routes, in particular Hispidulin can be administered orally, rectally or even by injection.
• Galenic shaping of Hispidulin can be carried out by known processes and with excipients adapted to each of the routes used, taking into account the solubility properties of Hispidulin.
• the dosages used will depend, of course, on the patient's condition and the type of disease to be treated and on the nature of the treatment, basic treatment, treatment of paroxysmal attacks.
• the dosage to be used will be less restrictive than with products such as theophylline.
• the extract is then treated with a mixture of water and dichloromethane (400 1 CH 2 Cl 2/200 1 H 2 O). The extraction is carried out by 6 kg.
• the CH 2 Cl 2 phase representing approximately 1.7 kg, that is to say 3.4% of the total weight of the plant, contains the active fraction Hispidulin. This CH 2 Cl 2 phase will be fractionated by chromatography in order to isolate the Hispidulin.
• the product is fixed on the silica by pulping with it.
• Hispidulin is found in the ether fraction, both by chromatography and by measurement of the inhibition of platelet aggregation on rabbit platelets (which is proportional to the Hispidulin content).
• Hispidulin a bronchodilator of choice superior to theophylline with which it will be compared in the examples which follow.
• the measurements were carried out as follows:
• the tracheae used come from male albino guinea pigs or are samples of lung tissue from surgical procedures on human patients.
• the human lung trachea or smooth muscle is prepared and cut into a spiral.
• the spirals are fixed at their ends so as to obtain a force of 8 g for the guinea pig trachea and 2 to 8 g for the human bronchus. They are each stored in an insulated organ tank filled with 10 ml of oxygenated Tyrode buffer (95% O 2 , 5% CO 2 ) and thermostatically controlled at 37 ° C. After 90 minutes of equilibration the length of the spirals is measured. Isometric sensors and physiographers are used to record changes in force.
• Relaxation of the basic tone The relaxing effect of a molecule on the basic tone has been observed by adding it to the preparation of the previously balanced muscle.
• the relaxation of an induced contraction is carried out by stimulating the preparations with the maximum dose of agonist, in this case histamine.
• the molecules to be studied are added to the bath at increasing concentrations every 5 minutes.
• the preparations are convtracted with one of the agonists chosen at the maximum or submaximal dose, then washed. They are preincubated for 30 minutes with the molecule to be studied and contracted under the same conditions as above. The heights of the agonist contacts, before and after incubation, are measured.
• the responses obtained are expressed in g / mm 2 , after dividing the response measured in g by the wet weight / length ratio.
• the contraction after incubation is expressed as a% of the first contraction which expresses a percentage of inhibition.
• Relaxation is expressed as a percentage of the maximum contraction obtained with the agonist used.
• concentration making it possible to obtain 50% of the maximum response (EC50) characterizes the sensitivity of the preparation to the molecule studied and is measured by interpolation of the curve obtained (percentage of relaxation as a function of the decimal logarithm of the concentration). The results observed were as follows: RELAXATION OF THE BASIC MUSCLE TONUS - COBAYA TRACHEA
• PRODUCTS RESPONSE (g / mm 2 ) SEM) (N) REPORT
• a virtually pure mast cell culture is constituted from bone marrow cells of mouse femurs.
• the mast cells suspended in gelatin tyrode buffer (TG), after counting, are distributed so as to have 1 ⁇ 10 6 cells / tube in 100 ⁇ l.
• the tubes are centrifuged at 300 g for 5 minutes at 4 ° C.
• the supernatants are recovered and the pellets taken up in 500 ⁇ l of TG BSA and sonicated 3 times 5 seconds. Determination of the release of ⁇ -hexosaminidase
• the supernatants are tested directly on the aggregation of the rabbit washed platelets and treated with aspirin (0.1 mM for 15 minutes).
• the measurement is carried out in an aggregameter in the presence of the CP / CPK complex.
• the amount of Paf. controls, cells stimulated in physiological saline, is maximum in these tubes and will be the 0% inhibition of the release of Paf.
• the inhibition percentage of the other tubes can thus be deducted.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=9324708

Family Applications (1)

Country Status (3)

Families Citing this family (7)

Family Cites Families (1)

• 1985
  • 1985-11-12 FR FR8516692A patent/FR2598414B1/fr not_active Expired
• 1986
  • 1986-11-07 EP EP19860906358 patent/EP0245333A1/de not_active Withdrawn
  • 1986-11-07 WO PCT/FR1986/000379 patent/WO1987002981A1/fr not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events