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WO1988005775A1 - Nouveaux derives de xanthine - Google Patents

Nouveaux derives de xanthine Download PDF

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Publication number
WO1988005775A1
WO1988005775A1 PCT/EP1987/000610 EP8700610W WO8805775A1 WO 1988005775 A1 WO1988005775 A1 WO 1988005775A1 EP 8700610 W EP8700610 W EP 8700610W WO 8805775 A1 WO8805775 A1 WO 8805775A1
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WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
formula
hydroxy
treatment
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
PCT/EP1987/000610
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English (en)
Inventor
Zoltan Kis
John Morley
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.)
Novartis Pharma GmbH Austria
Sandoz AG
Original Assignee
Sandoz Erfindungen Verwaltungs GmbH
Sandoz AG
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
Priority claimed from GB878702129A external-priority patent/GB8702129D0/en
Priority claimed from GB878703435A external-priority patent/GB8703435D0/en
Application filed by Sandoz Erfindungen Verwaltungs GmbH, Sandoz AG filed Critical Sandoz Erfindungen Verwaltungs GmbH
Publication of WO1988005775A1 publication Critical patent/WO1988005775A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine

Definitions

  • the present invention relates to novel xanthine derivatives having pharmaceutical utility, processes for their production, pharmaceutical compositions comprising them and their use as pharmaceuticals.
  • R 1 is C 1-4 alkyl, C 3 -4alkenyl or (C 3-5 cycloalkyl)-methyl,
  • R 2 is C 1-4 alkyl, [hydroxy- or (C 1-4 alkoxy)-substituted
  • R 3 and R 4 are each hydrogen, hydroxymethyl, methoxymethyl or
  • R 5 is hydroxy or methoxy
  • R 6 is hydrogen, hydroxy, methoxy or halogen and R 7 is in the 2- or 3-position and is hydroxy, methoxy or halogen, or together with R 5 is 3,4-methylenedioxy, or together with R 6 is 2,3-methylenedioxy, or physiologically-hydrolysable and -acceptable ester thereof.
  • Alkyl and alkenyl groups as R 1 , as well as alkyl groups and the alkoxy and/or alkyl moieties of (hydroxy- and alkoxy-alkyl)-methyl groups as R 2 may each be branched or straight chain.
  • [Hydroxy- and alkoxy-substituted alkyl]-methyl groups as R 2 may be mono-, di- or poly-substituted. Preferably they are monosubstituted.
  • Preferred [hydroxy- and alkoxy-substituted alkyl]-methyl groups as R 2 are thus (C 1-3 hydroxyalkyl)-methyl and (C 1-4 alkoxy-C 1-3 alkyl)-methyl.
  • R 1 is alkenyl
  • the double bond thereof is preferably separated from the nitrogen atom to which it is attached by at least two carbon atoms.
  • R 1 is cycloalkylmethyl, this is suitably cyclopropylmethyl.
  • R 2 is a group of formula A this is tetrahydrofuran-2-yl-methyl or 1,3-dioxolan-2-yl-methyl.
  • halogen is meant fluorine, chlorine or bromine, especially fluorine or chlorine and, most especially fluorine.
  • R 1 is suitably methyl.
  • R 2 to R 7 inclusive are preferred, individually, collectively or in any combination or sub-combination:
  • R 2 is C 1-4 alkyl, (C 1-3 hydroxyalkyl)-methyl, (C 1-4 alkoxy- C 1-3 alkyl)-methyl, (C 3-5 cycloalkyl)-methyl or a group of formula A.
  • R 2 is (C 1 -3 hydroxyalkyl)-methyl this is preferably 2-hydroxyethyl.
  • R 2 is (C 1-4 alkoxy- C 1-3 alkyl)-methyl this is preferably 2-(C 1-2 alkoxy)- ethyl, e.g. 2-methoxyethyl.
  • R 3 is hydrogen
  • R 4 is hydrogen, hydroxymethyl, methoxymethyl or N,N-dimethylcarbamoyloxymethyl, especially hydroxymethyl or methoxy-methyl.
  • R 5 is methoxy
  • R 6 is hydrogen, hydroxy or methoxy, especially hydrogen. 4b. When R 6 is other than hydrogen: R 6 is preferably in the 5-position.
  • R 7 is hydroxy or methoxy, especially methoxy. 5b. R 7 is in the 3-position.
  • the present invention provides: a compound of formula I as illustrated above wherein R1 is C 1-4 alkyl, C 3-4 alkenyl or cyclopropylmethyl, R 2 is C 1-4 alkyl, [hydroxy- or (C 1-4 alkoxy)-substituted
  • R 5 , R 6 and R 7 have the meanings given for formula I, or physiologically-hydrolysable and -acceptable ester thereof.
  • physiologically-hydrolysable and -acceptable ester is meant an ester which is hydrolysable under physiological conditions to yield an acid which is itself physiologically acceptable, i.e. which exhibits no undesirable side effects at desired dosage levels.
  • esters may be derived e.g. by acylation of free hydroxy groups in the substituents R 2 , R 3 and R 4 .
  • Appropriate esters include e.g.
  • the present invention provides: a compound of formula I as illustrated above wherein R 1 , R 2 , R 5 , R 6 and R 7 have the meanings hereinbefore given and -C(R 3 )R 4 - is (R) -CH(CH 2 OH)-, (R) -CH(CH 2 OCH 3 )- or (R) -CH[CH 2 O-CO-N(CH 3 ) 2 ]-, or a physiologically- hydrolysable and -acceptable ester thereof.
  • R 3 to R 7 have the meanings given above, whereby any hydroxy group present in the compound of formula II or III may be in free or protected form and, when required, carrying out process step a),
  • Process step a) may be carried out in accordance with means known in the art for the removal of hydroxy protecting groups, e.g. for the deprotection of benzyl-protected hydroxy groups, by ether cleavage, for example via hydrogenation in the presence of a Pd/charcoal catalyst.
  • Process step b) above can be carried out in accordance with means generally known in the art, for example by reaction of a compound of formula II with a compound of formula III at a temperature of from ca. 20 to 180 oC in the presence of an inert solvent or diluent, suitably in the presence of an acid binding agent such as triethylamine.
  • Suitable leaving groups as Z include e.g. halogen atoms, in particular chlorine or bromine atoms.
  • Process step c) is also conventional and may be performed e.g. by esterification employing an appropriate acid halide or acid anhydride, suitably in the presence of an acid binding agent such as pyridine, e.g. at a temperature of from 20 to 100 oC.
  • an acid binding agent such as pyridine
  • hydroxy groups are present in the starting materials of formula I, II or III which might otherwise be susceptible to undesired side reaction, these may be in protected form.
  • Suitable hydroxy-protecting groups include any of those known and commonly employed in the art including e.g. benzyl. Such protecting groups are the removed subsequent to the main defined reaction in accordance with process step a).
  • optically active starting materials for process steps a) through c) will lead directly to optically active compounds of formula I or esters thereof.
  • individual optically active isomers may be recovered from initially obtained mixtures, e.g. racemic or diastereomeric mixtures, thereof in accordance with process step d) and employing any of the techniques known and commonly practiced in the art.
  • the compounds of examples 12, 13 and 16 above are prepared by acetylation of the compounds of examples 7, 18 and 9 respectively employing acetic acid anhydride.
  • the reaction is performed in conventional manner in the presence of pyridine and CH 2 CI 2 as solvent at a temperature of ca. 20 oC.
  • the compound of example 19 is prepared by debenzylatio ⁇ of the corresponding compound in which R 2 is in 0-benzyl protected form, this being in turn produced anlogously to example 1 employing 7-benzyloxy-ethyl-bromotheophylline. in place of 8-chlorocaffeine.
  • Debenzylation is effected by hydrogenation at latm, and 20 oC in ethanol emplyoing a 10 % Pd/C catalyst.
  • the R-isomer product of example 20 is obtained employing R-( ⁇ -hydroxymethyl- 3,4-dimethoxy benzyl)amine as starting material hereinafter described for example 22.
  • the R-isomer product of example 21 is obtained from the product of example 22 hereinafter by reaction with dimethyl carbonyl- chloride in dioxane as solvent in the presence of sodium hydride at a temperature of ca. 20 oC.
  • the trachea is excised from freshly sacrificed guinea-pigs and transected in the transverse plane to give rings of tissue of ca. 2 mm.
  • Individual rings are mounted vertically on stainless steel supports, one of which is fixed at the base of an organ bath, the other being attached to a tension transducer.
  • the rings are bathed in modified Tyrode solution at 37oC and gassed with O 2 /CO 2 (95:5, v/v). Rings prepared in this manner, preloaded with 1 g, generate spontaneous tone and, after a period of equilibration, relax on addition of spasmolytic drugs.
  • Tension can be enhanced by addition of carbachol (10 -6 M) or histamine (10 -4 M).
  • test substances are dissolved in physiological saline and added in increasing quantities to the organ bath at 5 min. intervals to provide a cumulative concentration-effect curve.
  • Rings of bronchus (ca.2mm depth) are dissected from samples of human lung, resected from patients with lung carcinoma but grossly free of disease. Activity is determined employing the methodology of example A.1.1.
  • Guinea pigs are anaesthetised with pentobarbital (30 mg/kg i.p.) and phenobarbital (100 mg/kg i.p.) and ventilated via a trachea! cannula (10 ml/kg, 1Hz). Ventilation is monitored either by a pressure transducer measuring air-flow (Konzett-Rossler method), or by a Fleisch flow transducer in line with the inspiratory circuit. When making measurements of flow, coincident pressure changes in the thorax are monitored directly via an intrathoracic trochar, permitting display of differential pressure relative to the trachea. From this information resistance and compliance are calculated at each inspiration.
  • Intravenous injection of bombesin (ca. 500 ug/kg) as a bolus, induces increased airways resistance which is sustained over a period of several minutes.
  • Capacity of test-substance to reverse response when administered i.v. at the height of bombesin-induced bronchospasm serves as a measure of efficacy in reversing established bronchospasm.
  • compounds and esters of the invention are found to effect dose related abrogation of bronchospasm at dosages of from about 0.01 to about 1.0 mg/kg i.v.
  • Conscious guinea-pigs are. subjected to inhalation of test substance or placebo (vehicle) 10 mins. prior to explosure to a 0.3% mist of acetylcholine.
  • Test substance is administered as a mist generated from aerosol preparations at concentrations of from 1 mg/ml to 0.001 mg/ml. Prolongation of time prior to collapse in treated groups as compared with placebo groups is taken as a measure of bronchodilator efficacy.
  • EXAMPLE B SUPPRESSION OF AIRWAYS HYPERREACTIVITY
  • Guinea pigs are anaesthetised and airways resistance and compliance recorded as described under example A.2.1. above.
  • Intravenous injection of histamine (1 - 1.8 ⁇ g/kg) is used to define airways sensitivity.
  • Allergic reaction is initiated by i.v. injection of preformed immune complexes (bovine ⁇ -globulin/anti-bovine ⁇ -globulin), using a dose that is scarcely sufficient to induce bronchospasm at the first injection.
  • This dose of immune complexes is repeated at regular (10 min.) intervals. Following the last dose of immune complexes, the dose-effect relationship to histamine is re-defined. In animals so treated, induction of airways hyperreactivity is consistently observed.
  • PAF platelet activating factor
  • Test-substance is conveniently determined by measurement of influence on PAF-induced eosinophil accumulation in the guinea-pig peritoneal cavity in vivo.
  • the guinea-pig there is a substantial (up to 40%) resident population of eosinophils in the peritoneal cavity and eosinophil accumulation in the peritoneal cavity relative to control animals ca. 24 - 48 hrs. following injection of PAF i.p. at dosages of ca. 10 ⁇ g/kg serves to establish the influence of test substance on eosinophil accumulation.
  • test animals receive 10 ⁇ g/kg PAF i.p., 2 days prior. to sacrifice.
  • Smears from the peritoneal cavity are prepared employing Leishman's Stain after fixation with 95% methanol. At least 500 white cells are differentiated for each estimation.
  • Test substance is administered s.c. via a mini pump for four days prior to sacrifice.
  • bronchodilators e.g. for the treatment, e.g. symptomatic treatment of obstructive or inflammatory airways disease, for example asthma, pneumoconiosis or bronchitis.
  • obstructive or inflammatory airways disease for example asthma, pneumoconiosis or bronchitis.
  • compounds and esters of the invention are indicated for use in the prophylactic treatment of obstructive or inflammatory airways disease, for example the prophylactic treatment of pneumoconiosis and, in particular, asthma.
  • compounds and esters of the invention may be used to abort or restrict bronchoconstrictor attack consequential to obstructive or inflammatory airways disease, e.g. asthma (symptomatic treatment).
  • compounds and esters of the invention may, by continued administration, be used to provide advance protection against recurrence of bronchoconstrictor attack consequential to obstructive or inflammatory airways disease, e.g. asthma, or for the control, restriction or reversal of basal status of such disease, e.g. for the control, restriction or reversal of basal causes of asthma and asthma attack.
  • treatment and “treating” as used throughout the present specification and claims are accordingly to be understood as including prophylactic as well as symptomatic modes, unless otherwise specified.
  • the present invention accordingly also provides:
  • a method for the treatment of obstructive or inflammatory airways disease in a subject in need thereof comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined or a physiol ogical ly-hydrolysabl e and -acceptable ester thereof for example;
  • a method of effecting bronchodilatation in a subject in need thereof comprises administering to said subject a bronchodilatorily effective amount of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof or
  • a method for the prophylactic treatment of obstructive or, more particularly, inflammatory airways disease e.g. for advance protective treatment against acute airways obstruction, for example bronchospasm, e.g. as occurring in the symptomatology of diseases, disorders or conditions as herein set forth
  • the present invention provides: II.
  • the method of the present invention as defined under I to lb above is, in particular, applicable to the treatment of asthma of whatever type or genesis. It is applicable to both intrinsic and, especially, extrinsic asthma. It is especially applicable to the treatment of allergic asthma, whether atopic, (i.e. IgE-mediated) or non-atopic, as well as e.g. bronchitic asthma, thymic asthma, excercise induced asthma, occupational asthma, asthma induced following bacterial infection and other non-allergic asthmas. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g.
  • whez-infant syndrome an established patient category of major medical concern and now more correctly identified as incipient or early-phase asthmatics.
  • the present invention thus provides for treatment of asthma, in particular allergic asthma (for example allergic atopic asthma), exercise induced asthma and whez-infant syndrome, including symptomatic treatment of asthma (e.g. bronchodilator treatment of asthma exacerbation or attack) as well as prophylactic treatment of asthma (e.g. prophylactic treatment of asthma exacerbation or attack), comprising use of or administration of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof.
  • allergic asthma for example allergic atopic asthma
  • exercise induced asthma and whez-infant syndrome including symptomatic treatment of asthma (e.g. bronchodilator treatment of asthma exacerbation or attack) as well as prophylactic treatment of asthma (e.g. prophylactic treatment of asthma exacerbation or attack), comprising use of or administration of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof.
  • the method of the present invention as defined under I to lb above is also applicable to the treatment of pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of
  • the present invention thus also provides for the treatment of pneumoconiosis, in particular byssinosis, including symptomatic treatment of airways obstruction (e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea or bronchospasm) attributable thereto, as well as prophylactic treatment of airways obstruction (e.g. advance protective treatment of acute airways obstruction, e.g. bronchospasm) attributable thereto, comprising use or administration of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof.
  • airways obstruction e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea or bronchospasm
  • prophylactic treatment of airways obstruction e.g. advance protective treatment of acute airways obstruction, e.g. bronchospasm
  • the method of the present invention as defined under I or, especially, la above, is also applicable to the treatment of bronchitis or, more especially, the treatment of chronic or acute airways obstruction, for example, dyspnea, associated therewith.
  • the present invention is applicable to the treatment of bronchitis of whatever type or genesis, including, for example, acute bronchitis, arachidic bronchitis, catarrhal bronchitis, chronic bronchitis, croupous bronchitis, phthinoid bronchitis and so forth.
  • the present invention accordingly provides for the treatment of bronchitis or, more especially, the symptomatic treatment of airways obstruction (e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea) attributable thereto, comprising use or administration of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof.
  • airways obstruction e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea
  • a method for the suppression of eosinophil accumulation and/or activation e.g. for the treatment of disease characterised by or having an aetiology comprising morbid eosinophil accumulation and/or activation, in a subject in need of such treatment which method comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof;
  • Diseases as defined under III above include, in particular, hypereosinophilia and the eosinophil related disorders.
  • Hypereosinophilia is a distinct condition or status of varied aetiology characterised by chronic, morbid eosinophil presence in the body tissues generally.
  • the eosinophil-related disorders comprise a distinct and extensively documented indication group, commonly occurring concomitant to another, primary disease or condition.
  • Schatz et al. Medical Clinics of North America, 65, (5), 1055-1071 (1981) and Ottesen et al., "Allergy, Principles and Practice", Eds.E. Middleton, C. Reed and S. Ellis, 584-632, (1987)].
  • the group includes eosinophil-related disorders of the airways (involving morbid eosinophilic infiltration of pulmonary tissues) as well as of other organs and tissues including, for example, the skin, eye, nasal passages and the gastro-intestinal and urinary tracts.
  • Eosinopil-related disorders to which the present invention is applicable include those concomitant to atopy or atopic reactions in general (e.g. atopic conditions such as rhinitis, conjunctivitis etc... as set forth below) as well as non-atopic eosinophil-related disorders.
  • disorders of the airways to which the present invention is applicable include hypereosinophilia as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome) as well as eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • hypereosinophilia as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome) as
  • eosinophil-related disorders include eosinophilia consequential or concomitant to eosinophilic gastroenteritis, Heiner's syndrome, atopic dermatitis, urticaria or angioderma (allergic, recurrent or prolonged), ichthyosis, exfoliative dermatitis or pityriasisrubra, urticaria pigmentosa or mastocytoma, toxic epidermal necrolysis (drug related), dermatitis herpetiformis, allergic rhinitis, hyperplastic sinusitis, interstitial nephritis (drug related), interstitial cystitis, choleostatic hepatotoxicity (drug related), allergic conjunctivitis, vernal conjunctivitis, eosinophilic fascitis, hypersensitivity angiitis, serous myocarditis or endomyocardi al fibrosis, Wiscott-A
  • the present invention is directed primarily to the treatment of hypereosinophilia or eosinophil- related disorders as such.
  • eosinophil -related disorders are concomitant to atopy, for example to any of the atopic diseases or conditions specifically recited above including atopic or allergic forms of dermatitis, urticaria, angioderma, rhinitis, conjunctivitis and gastro-intestinal allergies
  • the present invention may equally be applicable to the treatment of eosinophil-related disorder as an integral or basal component thereof.
  • the present invention thus also provides means for the treatment (e.g.
  • atopy including each of the said recited atopic diseases or conditions, as such.
  • the compound and esters of the invention will more commonly be administered together with other medication for treatment of the disease or condition with which eosinophilia is associated.
  • use will generally be in conjunction with other, anti-parasitic drug therapy.
  • compounds and esters of the invention are employed in accordance with the method of the invention for the treatment of eosinophil-related disorders of the airways, e.g.
  • hypereosinophilia for the treatment of hypereosinophilia as it affects the lungs or for the treatment of pulmonary eosinophilia associated with eosinophilic pneumonia, and the disorder is accompanied by symptoms of airways obstruction
  • they may be employed either as symptomatic or prophylactic therapy, e.g. either to alleviate or abort, or to provide advance protection against recurrence of, obstruction.
  • compounds and esters of the invention will be employed symptomatically, e.g. as a means for the treatment of hypereosinophilia or eosinophil-related disorder, i.e. in accordance with methods defined under III above.
  • eosinophil-related disorders including treatment in accordance with the methods defined under III above, including, in the case of eosinophil-related disorders of the airways associated with airways obstruction, symptomatic treatment of airways obstruction (e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea or bronchospasm) and prophylactic treatment of airways obstruction (e.g. advance protective treatment of acute airways obstruction, e.g.
  • symptomatic treatment of airways obstruction e.g. bronchodilator treatment of acute or chronic airways obstruction, e.g. dyspnea or bronchospasm
  • prophylactic treatment of airways obstruction e.g. advance protective treatment of acute airways obstruction, e.g.
  • bronchospasm attributable thereto, comprising use or administration of a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof; as well as ii) for the treatment of atopy, for example for the treatment of any of the atopic diseases or conditions causal to or associated with eosinophil-related disorder as hereinbefore set forth, comprising use or administration of a compound of formula I as hereinbefore defined or a physiologically- hydrolysable and -acceptable ester thereof.
  • an indicated daily dosage for oral administration in particular for the symptomatic and/or prophylactic treatment of obstructive or inflammatory airways disease, for example asthma is in the range of from about 50 to about 500 mg per day, in particular from about 100-300 mg per day, conveniently administered in divided doses 2 to 4x/day or in sustained release form.
  • Unit dosage forms for oral administration thus suitably comprise from about 12 to about 500, in particular from about 25 to about 150 or 300 mg compound or ester of the invention, together with a pharmaceutically acceptable diluent or carrier therefor.
  • the compounds and esters of the invention may be administered in similar manner to known standards, e.g. theophylline, for use in the recited indications, e.g. orally in oral unit dosage form, e.g. in the form of tablets or capsules. They exhibit a low degree of side effects such as psychostimul ation as compared with other clinically employed xanthi ⁇ e bronchodilator drugsubstances, for example theophylline or aminophylline.
  • the present invention also provides: a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as hereinbefore defined or a physiologically-hydrolysable and -acceptable ester thereof, together with a pharmaceutically acceptable diluent carrier therefor.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le composé décrit est représenté par la formule (I), où R1 représente un alkyle C1-4, un alkényle C3-4 ou un (cycloalkyle C3-5)-méthyle, R2 représente un alkyle C1-4, un [alkyle C1-3 à substitution hydroxy ou (alkoxy C1-4)]-méthyle, un cycloalkyle C3-5)-méthyle, un tétrahydrofuran-2-yl-méthyle ou un 1,3-dioxolan-2-yl-méthyle, R3 et R4 représentent chacun un hydrogène, un hydroxyméthyle, un méthoxyméthyle ou un N,N-diéthylcarbamoyloxyméthyle, R5 représente un hydroxy ou un méthoxy, R6 représente un hydrogène, un hydroxy, un méthoxy ou un halogène et R7, qui se trouve dans la position 2 ou 3, représente un hydroxy, un méthoxy ou un halogène ou, avec R5, un 3,4 méthylènedioxy ou avec R6, un 2,3-méthylènedioxy. Ledit composé ainsi que ces esters physiologiquement hydrolysables et acceptables sont utiles dans le traitement (symptomatique et prophylactique) de maladies obstructives ou inflammatoires des voies respiratoires, telles que l'asthme, et de maladies se caractérisant par une étiologie ou comportant une étiologie dans laquelle se manifestent une accumulation ou une activation d'éosinophyles morbides, telle que l'hyperéosinophilie.
PCT/EP1987/000610 1987-01-30 1987-10-16 Nouveaux derives de xanthine Ceased WO1988005775A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB878702129A GB8702129D0 (en) 1987-01-30 1987-01-30 Organic compounds
GB8702129 1987-01-30
GB8703435 1987-02-13
GB878703435A GB8703435D0 (en) 1987-02-13 1987-02-13 Organic compounds

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005175A1 (fr) * 1990-09-26 1992-04-02 Beecham Group Plc Derives de xanthine
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1024968B (de) * 1956-03-31 1958-02-27 Asal Fabrik Biolog Und Pharmaz Verfahren zur Herstellung von 7-Ketonyl-8-amino-theophyllinen
FR2157727A1 (en) * 1971-10-29 1973-06-08 Brun Lab Sa Le !,#dimethyl-8-aminopurines - with analgesicantitussive and other theophylline-like activities
AT361944B (de) * 1978-10-04 1981-04-10 Chinoin Gyogyszer Es Vegyeszet Verfahren zur herstellung von neuen 7-(halogen- hydroxypropyl)-8-benzylaminotheophyllinen

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AT212847B (de) * 1959-08-13 1961-01-10 Hans Dr Med Voigt Verfahren zur Herstellung des neuen Coffeino-(8)-(β-Phenyl-isopropyl)-amin
CH505276A (de) * 1970-08-27 1971-03-31 Zenhaeusern Heinrich In einem Mauerwerk verankerte Steigeinrichtung
AT364921B (de) * 1979-03-05 1981-11-25 Edarco Europ Dev & Res Zuganker zur verankerung von bauteilen in einem grundkoerper

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Publication number Priority date Publication date Assignee Title
DE1024968B (de) * 1956-03-31 1958-02-27 Asal Fabrik Biolog Und Pharmaz Verfahren zur Herstellung von 7-Ketonyl-8-amino-theophyllinen
FR2157727A1 (en) * 1971-10-29 1973-06-08 Brun Lab Sa Le !,#dimethyl-8-aminopurines - with analgesicantitussive and other theophylline-like activities
AT361944B (de) * 1978-10-04 1981-04-10 Chinoin Gyogyszer Es Vegyeszet Verfahren zur herstellung von neuen 7-(halogen- hydroxypropyl)-8-benzylaminotheophyllinen

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Publication number Priority date Publication date Assignee Title
WO1992005175A1 (fr) * 1990-09-26 1992-04-02 Beecham Group Plc Derives de xanthine
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism

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AT392968B (de) 1991-07-25
ATA903787A (de) 1990-12-15

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