EP0389607A1 - Derives de chromone - Google Patents

Derives de chromone

Info

Publication number
EP0389607A1
EP0389607A1 EP19890910594 EP89910594A EP0389607A1 EP 0389607 A1 EP0389607 A1 EP 0389607A1 EP 19890910594 EP19890910594 EP 19890910594 EP 89910594 A EP89910594 A EP 89910594A EP 0389607 A1 EP0389607 A1 EP 0389607A1
Authority
EP
European Patent Office
Prior art keywords
thε
compound
oxo
allyl
nhr
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.)
Ceased
Application number
EP19890910594
Other languages
German (de)
English (en)
Inventor
Laurence Mark Von Itzstein
Hume Forrest White
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.)
Biota Scientific Management Pty Ltd
Original Assignee
Biota Scientific Management Pty Ltd
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 Biota Scientific Management Pty Ltd filed Critical Biota Scientific Management Pty Ltd
Publication of EP0389607A1 publication Critical patent/EP0389607A1/fr
Ceased legal-status Critical Current

Links

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
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 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 in position 2

Definitions

  • CHROMONE DERIVATIVES This invention relates to compounds capable of inhibiting allergic release of histamine and other autacoids, and in particular to novel chromone derivatives and methods of synthesis thereof.
  • Asthma is a wide-spread condition which affects a considerable proportion of the population, and makes a major contribution to morbidity and mortality. It is a condition characterised by narrowing and inflammation of the respiratory passages, which causes difficulty in breathing. Paroxysmal attacks of bronchospasm may occur. Asthmatic subjects are believed to have hyper-reactive airways, so that they respond more readily to stimuli.
  • Asthmatic attacks may be precipitated by one or more of a large range of stimuli which include allergens, exercise, infection, and certain chemical irritants, such as sulphur dioxide. Emotional upset may possibly be a contributory factor. Sufferers usually experience their first asthma attack at an early age, and attacks, particularly in allergic people, may be associated with other manifestations of hypersensitivity, such as eczema and hayfev ⁇ r.
  • Treatment of asthma involves the use of powerful drugs such as corticosteroids and their derivatives, as well as sympathomimetic agents related to adrenaline. Avoidance of known allergens may also be of assistance. Desensitization to allergens is of dubious benefit only.
  • Histamine is only one of a large number of substances, generically known as autacoids, which are released or formed during immediate hypersensitivity reaction and which cause bronchospas and other symptoms of asthma. Consequently, antihistamines are frequently ineffective. Therefore, prophylactic treatment which prevents the production or release of autacoids by inhibiting the response of sensitized mast cells and basophils to specific antigens is especially useful. Adrenergic drugs and theophylline are useful in this respect. More recently, a much more specific inhibition of these responses has been made possible by the use of agents which inhibit the antigen-induced secretion of histamine and other autacoids from human pulmonary mast cells and from mast cells at some other sites.
  • the bis-chromones represent one group of drugs having such activity.
  • the best known of these is cromolyn, also known as cromoglycic acid, whose preparation is disclosed in British Patent No. 1,114,906 to Fisons.
  • the disodium salt of this compound is very widely used as a prophylactic anti-asthmatic, under the trade name, among others, of Intal (trade mark of Fisons Pty. Ltd.).
  • Cromolyn has the following structure:
  • nedocromil sodium Another drug used for similar purposes is nedocromil sodium. Both nedocromil sodium and cromolyn protect atopic asthmatic subjects against antigen-induced bronchospasm, exercise- or sulphur dioxide-induced bronchoconstriction, and prevent the late response which occurs in some subjects. Both sodium cromoglycate and nedocromil sodium have been shown to inhibit the IgE-mediated release of histamine from mast cells isolated from human lung, having an IC30 of 50 and 5um respectively (Cromwell et. al. 1986). In this test nedocromil sodium had greater inhibitory potency than sodium cromyglycate, but in other test systems the two drugs were equipotent.
  • nedocromil sodium inhibits the antigen-induced release of sulphidopeptide leukotrienes C , f D . , and E_. which comprise the slow reacting substance of anaphylaxis (SRS-A), and of histamine, from passively-sensitized human lung in vitro.
  • SRS-A anaphylaxis
  • histamine histamine
  • Cromolyn does not inhibit either the binding of IgE to mast cells or the interaction between cell-bound IgE and specific antigen; it specifically suppresses the secretory response to this interaction.
  • the mechanism of the suppression is not clear.
  • the effect is not limited to the response to the antigen-antibody reaction, although this response may be preferentially effected. Marked tissue differences in responsiveness to cromolyn have been observed. Further problems with the use of cromolyn have been presented by the fact that this compound cannot be administered orally, and must be given by inhalation, and by the fact that on withdrawal of cromolyn, symptoms of asthma may recur.
  • cromolyn be administered before the onset of signs and symptoms of an acute asthmatic attack; thus it is of no utility in the treatment of an attack once it has commenced, nor in the treatment of status asthmaticus, which is the immediately life-threatening manifestation of asthma. Furthermore, for reasons which are unclear, the drug is ineffective in some patients.
  • Figure 1 represents a reaction scheme for synthesis of compounds according to the invention
  • Et ethyl
  • Figure 2 represents an alternative reaction scheme for synthesis of a sub-class of these compounds.
  • R is H, Na, or the appropriate corresponding methyl or ethyl esters
  • R 2 is OH, NHR 3 , * CH 2 OH, CH 2 NHR 3 , CHXCH 2 OH, CHXCH 2 NHR 3 , CH 2 CHXCH 2 OH, or CH 2 CH CH 2 HR 3
  • X is halogen, NHR , or OH
  • R is H, acetyl, benzyl, or a linear or cyclic alkyl group having 1-6 carbon atoms.
  • X is Cl, or R 2 is OH.
  • a method of synthesis of a desired compound of general formula I comprising the steps of: (a) reacting 2-hydroxyacetophenone with an allyl halide or dihalide, in the presence of sodium iodide or potassium iodide and an anhydrous alkali metal carbonate to form an allyloxyacetophenone; (b) subjecting the allyloxyacetophenone to thermal rearrangement and reacting the product thereof with an alkali metal alkoxide;
  • step (c) reacting the product of step (b) with a dialkyloxalate in a dry alkane solvent to give an
  • step (a) there is a possibility that direct nucleophilic substitution may be effected on the allyl side chain in step (d) .
  • the alkali metal alkoxide is sodium methoxide
  • the dialkyloxalate is diethyloxalate.
  • step (d) is an epoxidation step.
  • the alkali metal alkoxide is sodium ethoxide, and/or the dialkyloxalate is diethyloxalate.
  • the organic acid is acetic acid.
  • a pharmaceutical composition comprising a compound of general formula I together with a phar aceutically-acceptable diluent, carrier or excipient.
  • a method of treatment or prophylaxis of a hypersensitivity reaction in a mammal in need of such treatment comprising the step of administering to that mammal a therapeutically-effective amount of a compound according to general formula I.
  • the compound according to general formula I is either 8- (2-chloro-3-hydroxypropyl)-2-carboxy-4-oxo-2-chromene (8-CHPC) or 8-hydroxy-2-carboxy-4-oxo-2-chromene(8HC) .
  • the starting material is 2-hydroxyacteophenone.
  • Treatment of this starting material with allyl halide or allyl dihalide in dry acetone for circa 16h in the presence of potassium iodide and anhydrous sodium carbonate results in the formation of (1) or corresponding analogue.
  • Thermal rearrangement and further reaction with sodium methoxide followed by addition of diethyloxalate in dry hexane results in the formation of 8-allyl-2-ethoxycarbonyl-4-oxo-2-chromene (3) or corresponding analogue.
  • the starting material is 3-methoxy-2- hydroxyacetophenone
  • a solution of sodium ethoxide is added the starting material and diethyloxalate. This mixture is heated for circa 20 minutes followed by refluxing in acetic acid and cone HCl for circa 2h. After isolation of the free acid the product is then treated with acetic acid and HBr at reflux for approx. 2h.
  • the product isolated after purification is compound (7). This is illustrated in Fig. 2.
  • Sodium methoxide was generated in the usual manner by addition of metallic sodium (4.1g) to dry methanol (20 ml) with stirring at room temperature followed by heating to dissolve all of the sodium. After dry hexane (150 ml) was added a mixture of diethyloxalate (9.32 g) and 3-allyl-2-hydroxyacetophenone (10.25 g) in 100 ml of diethyl ether was introduced. The reaction mixture was refluxed for 120 min. The precipitate was filtered and was dissolved in a mixture of acetic acid (50 ml) and 33% HCl solution (0.75 ml) and heated on a steam bath for 90 min. The cooled solution was poured on to water (300 ml) and the precipitate was collected and recrystallised from aqueous methanol.
  • the lung fragments were washed free of serum, and divided into a large number of 250 mg replicat ⁇ s, which were suspended in Tyrode's solution with or without test compound, and treated in duplicate for fifteen minutes with an extract of P. pteronyssinus to give a final volume of 3 ml.
  • duplicate samples were incubated for fifteen minutes prior to antigen treatment with 1, 10 or 100 uM of compounds.
  • Controls for drug-induced or spontaneous release of mediators contained no antigen solution.
  • An appropriate concentration range for the compounds was establish ⁇ d in pr ⁇ liminary experiments. The reaction was stopped by chilling the tubes in ice, and the supernatant solution was decanted and assayed for released SRS-A leukotrienes and for histamine.
  • Leukotrienes were bioassayed using a cascade of four strips of longitudinal muscle from guinea pig ileum, which was sup ⁇ rfus ⁇ d at 37°C with Tyrode's solution containing an antihistamine and an anticholinergic, • mepyramine and hyoscine respectively, each at 1 uM.
  • Muscle contractions were measured in quadruplicate for each supernatant solution, and these measurements were ⁇ calibrat ⁇ d against those for contractions produced by standard solutions of leukotriene C. , and characterized using the leukotriene antagonist FPL 55712.
  • Histamine was assayed using an automated fluorimetric method (Evans et. al, 1973) and histamine content was expr ⁇ ssed as a proportion of total tissue histamine. The latter was determined by adding each valu ⁇ for released histamine to that for residual histamine, which was measured after boiling each . remaining 250 g aliquot of luhg in normal saline solution in order to releas ⁇ r ⁇ sidual histamine.
  • SRS-A sulfidopeptide leukotrien ⁇ s
  • Histamine r ⁇ l ⁇ ase from twelve lung samples was 13. 8 + 2.7 perc ⁇ nt of total tissu ⁇ histamin ⁇ , which is ⁇ quivalent to 2.53 + 0.90 ug histamine per gram of lung. Results from exp ⁇ rim ⁇ nts wh ⁇ re histamine rel ⁇ as ⁇ was l ⁇ ss than 5% of total tissue histamine, or 1 ug p ⁇ r g lung, w ⁇ r ⁇ ⁇ xclud ⁇ d from furth ⁇ r consid ⁇ ration.
  • a small lung sampl ⁇ from a subj ⁇ ct who was all ⁇ rgic to D ⁇ rmatophagoides farinae was tr ⁇ at ⁇ d as d ⁇ scribed above, but passive sensitization was omitt ⁇ d, and a Dermatophagoides farinae extract was us ⁇ d for antig ⁇ n challenge.
  • the compound 8-CHPC at concentration of 1.0 and 10.0 ⁇ M was used in this experiment. This sample releas ⁇ d no m ⁇ asurabl ⁇ SRS-A, and only 5.4% of th ⁇ total tissu ⁇ histamin ⁇ .
  • thes ⁇ compounds may hav ⁇ us ⁇ ful therap ⁇ utic effects in allergic diseas ⁇ s such as asthma, in which immunologically-stimulat ⁇ d releas ⁇ of mediators such as leukotri ⁇ n ⁇ s and histamin ⁇ occurs.
  • Butchers P.R., J.R. Fullarton, I.F. Skidmore, L.E. Thompson, C.J. Vardey & A. Wheeler, (1979), Br. J. Pharmacol, 61_, 23-32.

Landscapes

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

Abstract

Le nouveau dérivé de chromone décrit est représenté par la formule générale (I) où R1 représente H, Na ou les esters méthyles ou éthyle correspondant; R2 représente OH, NHR3, CH2OH, CH2NHR3, CHXCH2OH, CHXCH2NHR3, CH2CHXCH2OH ou CH2CHXCH2NHR3 où X représente halogène, NHR3 ou OH et R3 représente H, acétyle, benzyle ou un groupe alkyle linéaire ou cyclique comprenant 1 à 6 atomes de carbone. Des procédés de synthèse, des préparations pharmaceutiques et des procédés de traitement utilisant de tels composés sont également décrits et revendiqués.
EP19890910594 1988-09-14 1989-09-14 Derives de chromone Ceased EP0389607A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPJ041988 1988-09-14
AU419/88 1988-09-14

Publications (1)

Publication Number Publication Date
EP0389607A1 true EP0389607A1 (fr) 1990-10-03

Family

ID=3773370

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890910594 Ceased EP0389607A1 (fr) 1988-09-14 1989-09-14 Derives de chromone

Country Status (4)

Country Link
EP (1) EP0389607A1 (fr)
DK (1) DK116990A (fr)
FI (1) FI902400A0 (fr)
WO (1) WO1990002741A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU209245B (en) * 1991-12-20 1994-04-28 Richter Gedeon Vegyeszet Process for producing new cimetidine derivatives, as well as new gastric acid secretion inhibiting and gastrocytoprotective pharmaceuitcal compositions
DE59604811D1 (de) * 1995-12-08 2000-04-27 Martin Raithel Verfahren und vorrichtung zur in-vitro diagnose allergischer erkrankungen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1340512A (en) * 1970-01-21 1973-12-12 Fisons Ltd Production of esters of chromone-2-carboxylic acids
AU477982B2 (en) * 1973-01-16 1974-07-18 Fisons Limited Phenoxyalkoxy-4-oxo-benzopyran-2-carboxylic acids and-2-tetrazoles
CA1261835A (fr) * 1984-08-20 1989-09-26 Masaaki Toda Benz(thio) amides fusionnes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9002741A1 *

Also Published As

Publication number Publication date
WO1990002741A1 (fr) 1990-03-22
FI902400A0 (fi) 1990-05-14
DK116990D0 (da) 1990-05-10
DK116990A (da) 1990-07-12

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