Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to 4-hydroxy-2-quinolinone-3-carboxylic acids and their salts.
• the invention provides pharmaceutical compositions comprising compounds of formula Ip
• the compounds of formula I p possess pharmacological activity. In particular they possess disodium chromoglycate (DSCG)-like actiivity, in particular histamine release inhibiting activity, and are therefore indicated for use in the prophylactic treatment of allergic conditions, such as allergic asthma, as indicated in the passive cutaneous anaphylaxis test in the rat.
• Female rats (180-200 g) are sensitised by subcutaneous administration of 1 mg of egg albumin (Merck Nr. 967) and 200 mg Al(OH) 3 in 1 ml of physiological saline and 0.5 ml of Haemophiluspertussis vaccine (Schwei- zerisches Serum and Impfinstitut, Bern; Nr.
• egg albumin (5 mg/ml i.v.) dissolved in physiological saline containing 0.25% Evans Blue dye (Merck Nr. 3169).
• the egg albumin elicits a cutaneous anaphylatic reaction, the intensity of which is proportional to the extent to which the Evans Blue dye diffuses into the tissue surrounding each of the four 'sensitisation sites.
• the rats are killed with ether, the underside of the skin of the back of each animal is exposed and the diameter of the areas of blue dye surrounding each of the four sensitisation sites are measured.
• Each dose of test compound is investigated in between four and six rats and the mean diameter compared with the mean value obtained in four solvent-treated control rats. The percentage inhibition is taken as the percentage of the mean diameter in the test animals relative to the mean diameter in the controls.
• the DSCG-like activity in particular histamine release inhibiting activity, can be confirmed by inhibition of histamine release fn the rat peritoneal mast cell test, basically as described by Kusner et al., J. Pharmacol. Exp. Therap. 184, 41-46 (1973), with the following modification: after sedimentation of the mast cells by centrifugation at 350 x g and 4°C, the sediments are taken up in 1 ml of Hank's balanced salt solution (HBSS) (buffered to a pH of 6.9) and pooled. The resulting suspension is centrifuged, washed again with HBSS and sedimented. The thus purified mast cells are prepared as 2 ml suspensions in HBSS.
• HBSS Hank's balanced salt solution
• the 48/80 induced histamine release minus the spontaneous histamine release is taken as 100% histamine release.
• the 48/80 induced histamine release in the presence of the test compound minus the spontaneous histamine release is then compared with the 100% value to determine the percentage inhibition by the test compound.
• the histamine determination is effected in conventional manner, for example as described in the above-mentioned Kusner et al. article, or in Kusner and Herzig, Advances in Automated Analysis, 429 (1971).
• An indicated suitable daily dosage is from 20 to 800 mg preferably administered in divided dosages of from 5 to 400 mg 2 to 4 times a day, or in retard form.
• the compounds may be used in free acid form or in the form of their pharmaceutically acceptable mono- or di-base salts, which salt forms have the same order of activity as the free acid forms.
• Suitable salts include the sodium, potassium and lithium mono- and disalts.
• the compounds of formula I may be admixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients, and administered in such forms as tablets or capsules.
• novel compounds within the scope of formula I p above.
• novel compounds are those of formula I in which either
• R° are hydrogen, alkyl or alkenyl, more preferably alkyl or alkenyl, particularly allyl.
• Preferred significances of R 1 and R 2 are dialkoxy, more preferably 6,7-dialkoxy, particularly 6,7-dimethoxy. Combinations of these preferred significances are especially advantageous.
• the compounds of formula I are in the free acid or disalt form, more preferably the free acid form.
• the invention also provides a process for the preparation of compounds of formula I, characterised by hydrolysing a compound of formula II
• a suitable procedure is alkaline hydrolysis of the compound of formula II in an aqueous medium at a temperature of 40-150°C, preferably 80-120°C, followed by recovery under conditions avoiding acidification, which can lead to decarboxylation of the product.
• M is hydrogen and at least 2 mole equivalents of base are used, preferably sodium or potassium hydroxide to give the disodium or dipotassium salt.
• base preferably sodium or potassium hydroxide
• a suitable procedure is mild acid hydrolysis of a compound of formula II in which R is an acid-labile group such as t-butyl.
• the temperature is suitably from -20° to 60°C, preferably from -10° to 35°C in order to avoid decarboxylation of the product.
• Suitable acid catalysts are sulphuric acid, hydrochloric acid and perchloric acid, preferably the latter.
• the reaction medium is suitably a water-miscible non-hydroxylic organic solvent, for example acetonitrile.
• Example 1 (1-allyl-6,7-dimethoxy-4-hydroxy-7-quinolinone-3-carboxylic acid) (3.0 g) and 800 mg of sodium hydroxide are placed in 75 ml of water and the resulting suspension heated to 50°C until a solution is formed. The water is then evaporated in vacuo and the resulting residue oven dried under high vacuum to obtain 1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid disodium salt, m.p. 320°C with decomposition.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)

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ID=25197418

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Cited By (5)

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Citations (2)

Family Cites Families (8)

• 1977
  • 1977-06-20 US US05/807,914 patent/US4187309A/en not_active Expired - Lifetime
• 1978
  • 1978-06-12 DK DK262678A patent/DK262678A/da not_active Application Discontinuation
  • 1978-06-13 FI FI781885A patent/FI781885A/fi not_active Application Discontinuation
  • 1978-06-15 EP EP78100168A patent/EP0000153A1/en not_active Ceased
  • 1978-06-19 PT PT68192A patent/PT68192B/pt unknown
  • 1978-06-19 ES ES470916A patent/ES470916A1/es not_active Expired
  • 1978-06-19 JP JP7332878A patent/JPS5495578A/ja active Pending
  • 1978-06-19 IL IL54949A patent/IL54949A/xx unknown
  • 1978-06-19 NZ NZ187618A patent/NZ187618A/xx unknown
  • 1978-06-19 AT AT0443078A patent/AT367403B/de not_active IP Right Cessation
  • 1978-06-19 IT IT7849938A patent/IT7849938A0/it unknown
  • 1978-06-19 AU AU37251/78A patent/AU521418B2/en not_active Expired
  • 1978-06-19 CA CA305,757A patent/CA1105462A/en not_active Expired
  • 1978-06-20 ZA ZA783515A patent/ZA783515B/xx unknown

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