EP0973521A1 - Utilisation de derives de la cyclopentylxanthine dans le traitement de la mucoviscidose - Google Patents

Utilisation de derives de la cyclopentylxanthine dans le traitement de la mucoviscidose

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Publication number
EP0973521A1
EP0973521A1 EP97911336A EP97911336A EP0973521A1 EP 0973521 A1 EP0973521 A1 EP 0973521A1 EP 97911336 A EP97911336 A EP 97911336A EP 97911336 A EP97911336 A EP 97911336A EP 0973521 A1 EP0973521 A1 EP 0973521A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
cpt
cftr
medicament
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Withdrawn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
EP97911336A
Other languages
German (de)
English (en)
Inventor
Margaret Ann Mcpherson
Robert Leslie Dormer
Malcolm Martin Claude Pereire
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.)
University of Wales College of Medicine
Original Assignee
University of Wales College of Medicine
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 University of Wales College of Medicine filed Critical University of Wales College of Medicine
Publication of EP0973521A1 publication Critical patent/EP0973521A1/fr
Withdrawn legal-status Critical Current

Links

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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the present invention relates to the use of derivatives of theophylline for the preparation of medicaments suitable for the treatment of cystic fibrosis.
  • it relates to the use of 8-cyclopentyl theophylline (CPT) for the preparation of medicaments for the treatment of cystic fibrosis.
  • CPT 8-cyclopentyl theophylline
  • Such medicaments may be administered orally or directly to the lung, for example, in the form of an aerosol.
  • Cystic fibrosis is one of the most common lethal inherited disorders occurring in Caucasian populations. It is characterized as an exocrinopathy involving disturbances in mucin secretion, i.e. resulting in an altered composition of epithelial cell mucous secretions, and in electrolyte transport, in particular chloride transport. These manifestations of the disorder are caused by mutations in the cystic fibrosis (CF) gene, which encodes the cystic fibrosis transmembrane conductance regulator protein (CFTR) .
  • CF cystic fibrosis
  • R 1 and R 2 are the same or different and each represents an alkyl group having from 1 to 5 carbon atoms, provided that R 1 and R 2 are not both propyl groups, for the manufacture of a medicament for the treatment of cystic fibrosis .
  • the compound of formula (1) used for the manufacture of a medicament is 8-cyclopentyl-theophylline, where R 1 and R 2 in formula (1) are both methyl groups.
  • R 1 and R 2 are the same or different and each represents an alkyl group having from 1 to 5 carbon atoms, provided R 1 and R 2 are not both propyl groups, together with a pharmaceutically acceptable carrier therefor.
  • R 1 and R 2 are the same or different and each represents an alkyl group having from 1 to 5 carbon atoms, provided that R 1 and R 2 are not both methyl groups or propyl groups .
  • Figure 1 shows the structure of IBMX, DMPX and CPT
  • Figure 2 shows the effects of different concentrations of CPT and DMPX on mucin secretion from normal rat submandibular acini .
  • Figure 3 shows the effect of CPT on CFTR antibody inhibited ⁇ -adrenergic stimulation of mucin secretion.
  • the medicament or pharmaceutical formulation according to the invention which contains a compound of formula (1) may be presented in a form suitable for oral administration in a pharmaceutical vehicle convenient for that administrative route.
  • the medicament may be presented as tablets, capsules, ingestible liquid or a powder preparation.
  • Such formulations can include pharmaceutically acceptable carriers known to those skilled in the art.
  • Formulations suitable for oral administration further include lozenges, pastilles, aerosols and mouthwashes .
  • the medicament or pharmaceutical formulation may be administered direct to the lung via the nasal passage.
  • Formulations suitable for nasal administration where the carrier is a solid, include powders. Where the carrier is a liquid the formulation can be administered as a nasal spray or aerosol, or as drops.
  • the medicament may be presented in a formulation suitable for parenteral or intravenous administration, such as aqueous or non-aqueous sterile injectable solutions. Such solutions may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • the formulation for parenteral administration may be presented as an aqueous or non aqueous sterile suspension which may include suspending agents and thickening agents.
  • a therapeutically effective dose may typically comprise administering the active ingredient at the rate of 0.001 to 25 mg/kg body weight per day, and more preferably at a rate of from 0.01 to 0.5 mg/kg/day.
  • the medicament may contain from 0.001 to 0.01% w/w of the active ingredient.
  • CPT (8-cyclopentyl theophylline) may be prepared by mixing 5, 6-diamino-l , 3 -dimethyl uracil with 1 - 1.25M equivalent of cyclopentanecarboxylic acid followed by heating at 120 - 200°C for 1 to 4 hours to give the solid amide. The solid amide is then powdered and heated with 5 -
  • R 1 and R 2 are the same or different and each represents an alkyl group having from 1 to 5 carbon atoms provided that R 1 and R 2 are not both propyl groups .
  • KLH keyhole limpet haemocyanin
  • the peptide sequence was searched for in the Swissprot database (BLASTP and FASTA3_T, 1997) and only CFTR was found to contain a perfect match.
  • Antisera were prepared as described in C.
  • acini were pulse-chase labelled with [ 3 H] - glucosamine and suspended in TES-buffered saline (lOmM TES,
  • acini suspension 800 ⁇ l of either lOmM TES, pH 7.4 (swollen) or TES-buffered saline (unswollen) , each containing 5mM ATP and antibody (approx lmg IgG/ml) was added for 1.5 min at room temperature, followed by washing and resuspension in Krebs-Henseleit bicarbonate (KHB) buffer containing 20mg/ml BSA. Following a 15 min recovery incubation at 37°C in KHB buffer, acini were washed and incubated under experimental conditions at 37°C.
  • KHB Krebs-Henseleit bicarbonate
  • IBMX 3-isobutylmethylxanthine
  • cyclic AMP content Aliquots of acini suspensions (0.25ml) were added to an equal volume of ice cold trichloroacetic acid (20%) , extracted and assayed using a specific radioimmunoassay kit for cyclic AMP (Amersham) .
  • Fig. 1 shows the structure of CPT which is more selective for the Al receptor, and DMPX (3 , 7-dimethyl-1-propargylxanthine) which is more selective for the A2 receptor compared to that of IBMX.
  • Fig.2 shows the effects of different concentrations of CPT and DMPX on mucin secretion from normal rat submandibular acini, isolated as described in the Methods.
  • DMPX was the more effective stimulator, and at ImM increased mucin secretion to a similar degree to that obtained with isoproterenol or IBMX (Table 2) .
  • CPT was much less potent and at ImM gave a small but significant increase above basal levels.
  • Doses of CPT close to the K ⁇ for Al adenosine receptor antagonism did not stimulate mucin secretion (lOnM CPT; 104% basal) .
  • the data indicate that the effect of CPT in increasing mucin secretion is unlikely to be related to Al receptor antagonism.
  • IBMX was shown to correct defective CFTR function at a maximum concentration which did not significantly stimulate mucin secretion. Thus a concentration of CPT giving marginal stimulation (ImM) and a similar concentration of DMPX were tested for correction of defective CFTR function. Table 1 shows that the A2 adenosine receptor antagonist, DMPX did not correct defective ⁇ -adrenergic stimulation of mucin secretion in CFTR antibody containing cells. As shown previously, mucin secretion in response to isoproterenol from cells containing CFTR antibody, introduced by hypotonic swelling as described in the Methods, was significantly decreased compared to cells swollen in an equivalent amount of non-immune IgG.
  • Fig. 3 shows that the Al receptor antagonist CPT corrected the defective isoproterenol -stimulated mucin secretion in submandibular cells containing CFTR antibody, at mM concentrations.
  • the actions of CPT in increasing the CFTR antibody-inhibited response were almost as effective as that of mM cpt-cyclic AMP (8- (4-chlorophenylthio) -cyclic AMP) which has been previously shown to restore secretory responsiveness to approx: 75% of that seen in cells containing similar amount of non-immune IgG.
  • CPT at high concentration, corrected the CFTR antibody-inhibited mucin secretory response suggesting that a mechanism other than Al receptor antagonism was operating.
  • CPT is a less effective stimulator of mucin secretion than IBMX; but it induces greater increases in cyclic AMP.
  • DMPX which did not correct CFTR function, increases mucin secretion to a greater degree than CPT (Fig. 2) and induces increases in cyclic AMP greater than those induced by isoproterenol alone
  • IBMX also acts as a non-selective cyclic nucleotide phosphodiesterase inhibitor which increases cyclic AMP levels in submandibular acini and potentiates the cyclic AMP rise induced by isoproterenol. Furthermore, since the correction of CFTR-mediated mucin secretion was mimicked by cpt-cyclic AMP, it was postulated that excessive increase in cellular cyclic AMP could be a mechanism by which CFTR activity is restored. This hypothesis was tested by investigating the effects of the adenosine receptor antagonist on cyclic AMP levels in the presence or absence of isoproterenol. It is clear from the results in Table 3 that CFTR function could be corrected without potentiating the isoproterenol induced cyclic AMP rise although CPT increased cyclic AMP levels alone.
  • Mucin release was measured at 30 min and cyclic AMP at
  • a solution suitable for use as nasal drops is prepared by dissolving CPT (0.2 mg/ml) in isotonic saline containing hypromellose, with the optional addition of a suitable buffer.
  • a solution suitable for intravenous injection is prepared by dissolving CPT (0.2 mg/ml) in isotonic saline containing sodium EDTA, with the optional addition of a suitable buffer.
  • Example 5 Aerosol Formulation A solution suitable for aerosolisation into the lungs is prepared by mixing CPT (0.2 mg/ml) with oleic acid and priolene, which mixture can then be delivered to the lungs using the following propellents - 11 (trichlorofluoromethane) 12 (dichloro difluoromethane) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur l'utilisation de dérivés de la théophylline dans la préparation de médicaments utiles pour le traitement de la mucoviscidose. L'invention porte en particulier sur l'utilisation de 8-cyclopentyl-théophylline (CPT) dans la préparation de médicaments utiles pour le traitement de la mucoviscidose. De tels médicaments peuvent être administrés par voie orale ou directement dans les poumons, par exemple sous la forme d'un aérosol.
EP97911336A 1996-11-05 1997-11-05 Utilisation de derives de la cyclopentylxanthine dans le traitement de la mucoviscidose Withdrawn EP0973521A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9622981.0A GB9622981D0 (en) 1996-11-05 1996-11-05 Cystic fibrosis medicaments
GB9622981 1996-11-05
PCT/GB1997/003036 WO1998019679A1 (fr) 1996-11-05 1997-11-05 Derives de la cyclopentylxanthine pouvant etre utilises dans le traitement de la mucoviscidose

Publications (1)

Publication Number Publication Date
EP0973521A1 true EP0973521A1 (fr) 2000-01-26

Family

ID=10802439

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97911336A Withdrawn EP0973521A1 (fr) 1996-11-05 1997-11-05 Utilisation de derives de la cyclopentylxanthine dans le traitement de la mucoviscidose

Country Status (5)

Country Link
EP (1) EP0973521A1 (fr)
AU (1) AU4875197A (fr)
CA (1) CA2270355A1 (fr)
GB (1) GB9622981D0 (fr)
WO (1) WO1998019679A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037345A1 (fr) * 2001-10-26 2003-05-08 Sciclone Pharmaceuticals, Inc. Preparations pharmaceutiques comprenant des composes de xanthine substituee

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8729714D0 (en) * 1987-12-21 1988-02-03 Lee P F Compositions & method
GB9321083D0 (en) * 1993-10-13 1993-12-01 Univ Mcgill Phosphatase inhibitors in channel diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9819679A1 *

Also Published As

Publication number Publication date
AU4875197A (en) 1998-05-29
GB9622981D0 (en) 1997-01-08
CA2270355A1 (fr) 1998-05-14
WO1998019679A1 (fr) 1998-05-14

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