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WO1996018400A1 - Thioxanthines trisubstituees - Google Patents

Thioxanthines trisubstituees Download PDF

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Publication number
WO1996018400A1
WO1996018400A1 PCT/US1995/016724 US9516724W WO9618400A1 WO 1996018400 A1 WO1996018400 A1 WO 1996018400A1 US 9516724 W US9516724 W US 9516724W WO 9618400 A1 WO9618400 A1 WO 9618400A1
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WO
WIPO (PCT)
Prior art keywords
thioxanthine
isopropyl
group
ethyl
compound
Prior art date
Application number
PCT/US1995/016724
Other languages
English (en)
Inventor
David J. Cavalla
Peter Hofer
Mark Chasin
Original Assignee
Euro-Celtique, S.A.
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 Euro-Celtique, S.A. filed Critical Euro-Celtique, S.A.
Priority to AU45279/96A priority Critical patent/AU4527996A/en
Priority to DE69531555T priority patent/DE69531555T2/de
Priority to CA002206804A priority patent/CA2206804C/fr
Priority to US08/860,674 priority patent/US6025361A/en
Priority to JP51932796A priority patent/JP2001523213A/ja
Priority to AT95943950T priority patent/ATE247655T1/de
Priority to EP95943950A priority patent/EP0799040B1/fr
Publication of WO1996018400A1 publication Critical patent/WO1996018400A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C07D473/38—Sulfur atom attached in position 6
    • 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
    • C07D473/20—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two sulfur atoms

Definitions

  • Asthma is a complex disease involving the concerted actions of multiple inflammatory and immune cells, spasmogens, inflammatory mediators, cytokines and growth factors.
  • bronchodilators e.g., beta- adrenoceptor agonists
  • anti-inflammatory agents e.g., corticosteroids
  • prophylactic anti-allergic agents e.g., cromolyn sodium
  • xanthines e.g., theophylline
  • Theophylline has been a preferred drug of first choice in the treatment of asthma. Although it has been advocated for its direct bronchodilatory action, theophyliine's therapeutic value is now believed to also stem from anti-inflammatory activity. Its mechanism of action remains unclear. However, it is believed that several of its cellular activities are important in its activity as an anti-asthmatic, including cyclic nucleotide phosphodiesterase inhibition, adenosine receptor antagonism, stimulation of catecholamine release, and its ability to increase the number and activity of suppressor T-lymphocytes. While all of these actually may contribute to its activity, only PDE inhibition may account for both the anti- inflammatory and bronchodilatory components. However, theophylline is known to have a narrow therapeutic index, and a wide range of untoward side effects which are considered problematic.
  • Cyclic nucleotide phosphodiesterases PDEs
  • Cyclic 3',5'-adenosine monophosphate (cA P) and cyclic 3',5'-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids.
  • At least two therapeutically important effects could result from phosphodiesterase inhibition, and the consequent rise in intracellular (cAMP) or (cG P) in key cells in the pathophysiology of asthma. These . re smooth muscle relaxation (resulting in bronchodilation) and anti- inflammatory activity.
  • the structure-activity relationships (SAR) of isozyme-selective inhibitors has been discussed in detail, e.g., in the article of Theodore J. Torphy, et al., "Novel Phosphodiesterase Inhibitors For The Therapy Of Asthma", Drug News & Prospectives, 6(4) May 1993, pages 203-214.
  • the PDE enzymes can be grouped into five families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds.
  • PDE I is stimulated by Ca 2 /calmodulin
  • PDE II is cGMP-stimulated, and is found in the heart and adrenals.
  • PDE III is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity.
  • PDE IV is cAMP specific, and its inhibition causes airway relaxation, anti- inflammatory and antidepressant activity.
  • PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity. While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited. Analogues of rolipram, which following structural formula:
  • Rolipram which was initially studied because of its activity as an antidepressant has been shown to selectively inhibit the PDE IV enzyme and this compound has since become a standard agent in the classification of PDE enzyme subtypes. There appears to be considerable therapeutic potential for PDE IV inhibitors. Besides initial work suggesting an antidepressant action, rolipram has been investigated for its anti-inflammatory effects, particularly in asthma. In-vitro, rolipram, Ro-20-1724 and other PDE IV inhibitors have been shown to inhibit (1) mediator synthesis/release in mast cells, basophils, monocytes and eosinophils; (2) respiratory burst, chemotaxis and degranulation in neutrophils and eosinophils; and
  • lymphocytes The PDE IV Family Of Calcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al., Drugs of the Future 1992, 17(9) 799-807).
  • PDE-IV inhibitors are 3,8-alkyl-disubstituted-6-thioxanthines disclosed by U.S. Patent No. 4,925,847, issued May 15, 1990 to Hofer, the disclosure of which is incorporated by reference herein in its entirety.
  • PDE IV is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down-regulation of cellular activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent.
  • Theophylline a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation.
  • French Patent No. 188M also discloses trisubstituted 6-thioxanthines (Formula I of the 188M patent) having at the 1 and 3 positions an alcohol or alkyl (C,. 6 ), straight or branched and H or an alcohol (C, ⁇ ) at the 8 position.
  • disease states such as asthma, allergies, inflammation, depression, dementia, a disease caused by Human Immunodeficiency Virus and disease states associated with abnormally high physiological levels of cytokines.
  • R 1 , R 3 and R* are independently selected from alkyl, aryl and aralkyl moieties,
  • R 2 and R 6 are independently S or O; with the exception that R 2 and R 6 are not both O.
  • R 1 and R J are aralkyl; and R 8 is optionally cycloalkyl, aryl, aralkyl or an alkyl which is either straight or branched, such as methyl, ethyl, isopropyl, n-propyl, cyclopropyl, butyl and pentyl; and one of R 1 and R 3 is benzyl.
  • the aryl groups can be substituted or unsubstituted.
  • Some particularly preferred compounds in accordance with the present invention include:
  • the invention also comprises pharmaceutical compositions including an effective amount of a compound according to Formula (I), or a salt thereof, together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is suitable for administration of the pharmaceutical composition orally, topically, by suppository, inhalation, insufflation, and parenterally and any other suitable method for administering a medication.
  • the invention also provides methods for selectively inhibiting PDE IV and/or PDE V enzyme activity in a patient requiring the same by administering a compound according to the invention by administering an effective amount of a pharmaceutically acceptable compound according to the invention.
  • the invention provides methods for treating a patient suffering from a disease or disorder such as asthma, allergies, inflammation, depression, dementia, atopic diseases, rhinitis and disease states associated with abnormally high physiological levels of cytokine by administering an effective amount of a pharmaceutically acceptable compound according to the invention.
  • a disease or disorder such as asthma, allergies, inflammation, depression, dementia, atopic diseases, rhinitis and disease states associated with abnormally high physiological levels of cytokine by administering an effective amount of a pharmaceutically acceptable compound according to the invention.
  • Both methods comprise administering an effective amount of the compound according to Formula (I) in a pharmaceutically acceptable form as described above to a patent in need of such treatment
  • the method includes administering one of the following compounds: l,3,8-triethyl-2,6-dithioxanthine;
  • An alternative aspect of the invention includes a method of treatment which involves administering an effective amount of a pharmaceutically acceptable compound according to the invention having anti-inflammatory and/or immunosuppressant activity, to a patient in need of such treatment.
  • the method of treatment according to the invention involves administering the compound to a patient in need of such treatment.
  • Figure 1 provides reaction scheme 1 exemplifying preparation of certain compounds according to the invention.
  • the compounds of the present invention are effective in the mediation or inhibition of PDE IV enzyme activity in need of such treatment. Further, these compounds are selective PDE IV inhibitors which possess bronchodilatory, anti-inflammatory and other properties characteristic of PDE IV inhibitors substantially without undesirable cardiovascular stimulation caused by PDE III inhibition. Many of these compounds have a substantially equal or superior PDE IV inhibitory effect as compared to theophylline, disubstituted 6-thioxanthines and other previously known PDE IV inhibitors.
  • the present invention provides novel compounds having unexpectedly superior PDE IV inhibitory activity and novel methods for treating diseases or disorders related to PDE IV enzyme activity.
  • the compounds according to the invention mainly comprise compounds of Formula I below:
  • R ⁇ R 3 and R 8 are independently selected from alkyl, aryl and aralkyl moieties,
  • R 2 and R 6 are independently S or O; with the exception that R 2 and R 6 are not both O.
  • R 1 and R 3 are independently an aralkyl, substituted or unsubstituted
  • R* is optionally cycloalkyl, aryl, aralkyl or an alkyl which is either straight or branched, such as methyl, ethyl, isopropyl, n-propyl, cyclopropyl, butyl and pentyl; and one of R 1 and R 3 is benzyl.
  • R ⁇ R 3 and R 8 are optionally substituted by halogen, hydroxy, hydroxy, C,-C 4 alkoxy, C 3 -C 7 cycloalkoxy, oxo, oximido, carbamido or hydroxycarbimido.
  • R 1 , R 3 and R 8 cycloalkylalkyl, preferably, in this embodiment, both R 1 and R 3 are cycloalkylalkyl moieties.
  • the alkyl moieties can be straight, branched or cyclic.
  • R 1 , R 3 and R 8 may have substituents such as halogen, hydroxy, C,-C 4 alkoxy, C 3 -C 7 cycloalkoxy, oxo, oximido, carbamido or hydroxycarbimido.
  • Preferable alkyl moieties include straight or branched lower alkyls such as methyl, ethyl, isopropyl, n-propyl, cyclopropyl, butyl and pentyl.
  • the alkyl portion of the aralkyl moieties is preferably a lower alkyl.
  • the term "lower alkyl" is defined for purposes of the present invention as straight or branched chain radicals having from 1 to 8 carbon atoms.
  • R 8 is propyl and, preferably is isopropyl.
  • a compound of the present invention is one of the following: 1 ,3-Di-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine;
  • the invention also provides for methods of selectively inhibiting the enzymes PDE IV and/or PDE V in a patient, in order to treat a disease or disorder related to elevated PDE IV and/or PDE V activity in a patient as enumerated above.
  • the method of treatment comprises administering to a patient in need thereof an effective dose of a pharmacologically active compound having PDE IV and/or PDE
  • R 1 is a C,_ 3 alkyl, straight or branched
  • R 3 is a C,_ 5 alky!
  • R 8 is an ethyl or propyl, including cyclopropyl and isopropyl, moiety
  • R 1 and R 3 are aralkyl, substituted or unsubstituted
  • R 2 and R 6 are S or O, but R ? and R 6 are not both O and R 8 is alkyl or cycloalkyi, aryl or aralkyl, substituted or unsubstituted.
  • R 8 is propyl and more preferably, isopropyl.
  • the present invention is further related to a method for the treatment of allergic and inflammatory disease which comprises administering to a patient in need thereof an effective amount of the compounds of the present invention able to selectively inhibit PDE IV.
  • the compounds of the present invention may find use in the treatment of other diseases or disorders, such as, for example, in the treatment of disease states associated with a physiologically detrimental excess of tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • TNF activates monocytes, macrophages and T-lymphocytes. This activation has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection and other disease states related to the production of TNF and other cytokines modulated by TNF.
  • HIV Human Immunodeficiency Virus
  • the method of treatment involves administering compounds of the present invention having anti-inflammatory and/or immunosuppressants to a patient in need of such treatment.
  • the method of treatment involves administering a compound of the present invention, wherein R 1 and R 2 are independently aryl or arylalkyl, to a patient in need of such treatment.
  • the following compounds are particularly preferred: l,3,8-triethyl-2,6-dithioxanthine; l,3,8-triethyl-2-thioxanthine;
  • the compounds of the present invention have been found to be highly effective PDE IV inhibitors, the inhibition of which is in fact significantly and surprisingly greater than that of, for example, theophylline or disubstituted 6- thioxanthines.
  • Example 14 there is provided a comparison of analogous disubstituted and trisubstituted xanthines which illustrate the advantages of trisubstituted xanthines.
  • the trisubstituted compounds according to the invention have substantially lower PDE IV IC 5 values, indicating that these compounds will have increased potency and/or selectivity in the treatment of PDE IV related diseases or disorder.
  • Steps (4) through (7) provide closuie of the second aromatic ring to produce a xanthine where R 6 is O.
  • Reactions producing compounds (7) through (8) provide a 6-thioxanthine as compound (8).
  • thioxanthines can be prepared, for example, by two different routes, either starting with a N, N'-disubstituted (thio)urea, which can be used for R' ⁇ R 3 or starting with a monosubstituted (thio)urea followed by alkylation of compounds of type (4) or (6) where R'is H, which can be applied in all cases, including R'>R 3 .
  • compound (1 ) where X is O or S
  • compound (2) where R 1 is H or other substituents
  • Steps (4) to (7) provide closure of the second ring to produce a xanthine where R 6 is O.
  • Reactions producing compound (8) provide a 6-thioxanthine.
  • the present invention also encompasses, where appropriate, all pharmaceutically acceptable salts of the foregoing compounds.
  • amine, alkali and alkaline earth metal salts are prepared by reaction of the compounds of the invention with the appropriate base via a variety of known methods.
  • the compounds of the present invention can be administered to anyone requiring PDE IV inhibition. Administration may be orally, topically, by suppository, inhalation or insufflation, or parenterally.
  • Various oral dosage forms can be used, including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders and liquid forms such as emulsions, solution and suspensions.
  • the compounds of the present invention can be administered alone or can be combined with various pharmaceutically acceptable carriers and excipients known to those skilled in the art, including but not limited to diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, coloring agents, lubricants and the like.
  • Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavorings agents.
  • the compounds of the present invention are to b" injected parenterally, they may be, e.g., in the form of an isotonic sterile solution.
  • the compounds of the present invention when the compounds of the present invention are to be inhaled, they may be formulated into a dry aerosol or may be formulated into an aqueous or partially aqueous solution.
  • dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the gastrointestinal tract.
  • controlled and/or sustained release formulations are well known to those skilled in the art, and are contemplated for use in connection with the formulations of the present invention.
  • the controlled and/or sustained release may be provided by, e.g., a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix.
  • the formulation for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such formulations may further comprise pharmaceutically necessary additives such as stabilizing agents, suspending agents, dispersing agents, and the like.
  • the compounds of the invention may also be in the form of a powder for reconstitution as an injectable formulation.
  • the dose of the compounds of the present invention is dependent upon the affliction to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things.
  • PDE IV inhibitory compounds of the present invention may be examined for their PDE IV inhibitory effects via the techniques scl forth in the following examples, wherein the ability of the compounds to inhibit PDE IV isolated from bovine tracheal smooth muscle is set forth. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • EXAMPLE 3 l-(4-CI-lorobenzyl)-3-ethyl-8-isopropyl-6-thioxanthine
  • 1 -(4-Chlorobenzyl)-3-ethyl-8-isopropyl-xanthine 3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to a solution of 6.1 1 g (27.5 mM) of 6-amino-l-ethyl-5-isobutyrylamino-uracil. At 0° C, 4.90 g (30.4 mM) of 4-chlorobenzylchloride were added.
  • the isopropanol was distilled off with addition of water and the solid collected, washed and dried to give 2.60 g (89.7%) of crude thioxanthine, which was dissolved in 40 ml of dichloromethane and filtered through 30 g of silica gel: 1.91 g (65.9%) of 6- thioxanthine were recovered, mp 153-4 C°.
  • EXAMPLE 4 l,3-8-Triethyl-2.6-dithioxanthine and K3,8-trieth ⁇ l-2-thioxanthine Using a process an o, gous to that used for Example 1, l,3,8-triethyI-2,6- dithioxanthine and l,3,8-triethyl-2-thioxanthine were prepared. A recrystallized sample from ether for the first compound had m.p. 144-6°C while the second compound had a m.p. of 255-6°C. Elemental analysis for CnH ⁇ N ⁇ S, calc. C 49.22 H 6.01 N 20.87 S 23.89 found C 49.55 H 6. l l N 20.92 S 23.83 EXAMPLE 5
  • the product was redissolved in 30 ml NaOH, treated twice with 0.5 g of charcoal, filtered, and acidified with 5N HCI to pH 3. At 5°C, the solid was collected, washed and dried. The compound had a mp of 168-70 °C.
  • 6-thioxanthines were prepared: a) 3-Ethyl-8-isopropyl-l-methyl-6-thioxanthine; m.p.230-40°C
  • Protocols for PDE IV inhibition activity are set forth below: Type IV Phosphodiesterase Enzyme Isolation Protocol
  • Type IV PDE is isolated from bovine tracheal smooth muscle using a procedure similar to that previously described by Silver, P.J. et al., Eur. J.
  • Enzyme activity is assessed by measuring the hydrolysis of [ 3 H]-cyclic AMP, as described by Thompson, W.J. et al., Adv. Cyclic Nucleotide Res. 10:69, 1979.
  • the cyclic AMP concentration used in this assay is 0.2 mM, which approximates the K m value. Protein concentration is adjusted to ensure that no more than 15% of the available substrate is hydrolyzed during the incubation period.
  • test compounds are dissolved in dimethyl sulfoxide (final concentration of 2.5%). This concentration of dimethyl sulfoxide inhibits enzyme activity by approximately 10%.
  • Example 13 The procedures of Example 13 were used to measure PDE IV activity for exemplary compounds and for some analogous disubstituted thioxanthine compounds in order to demonstrate the improved PDE IV IC 50 activity for the compounds according to the invention.
  • the results, wherein a lower PDE IV IC 50 number indicates a superior activity, are provided below.
  • Type V Phosphodiesterase Enzyme Isolation Protocol Enzyme Isolation Procedure.
  • the Type V PDE is isolated using a procedure similar to that previously described by Weishaar et al., Hypertension 15:528, (1990). Briefly, 1-2 units of platelets are suspended in an equal volume of buffer A (20 mM Tris-HCl, pH 7.5, containing 2 mM magnesium acetate, 1 mM dithiothreitol, and 5 mM Na 2 EDTA) using a polytron. The proteinase inhibitor phenylmethylsulfonyl fluoride (PMSF) are also included in this buffer at a final concentration of 200 ⁇ M.
  • PMSF proteinase inhibitor phenylmethylsulfonyl fluoride
  • the homogenate is then centrifuged at lOO.OOOrp for 60 minutes.
  • the supernatant is then removed and filtered through four layers of gauze and applied to a DEAE-Trisacryl M column.
  • the column is washed with several bed volumes of buffer B (20 mM Tris- HCI, pH 7.5, containing 2 mM magnesium acetate, 1 mM diothiothreitol, and 200 ⁇ M PMSF) and eluted by two successive linear NaCl gradients (0.05-0.15 M, 300 ml total; 0.15-0.40 M, 200 ml total).
  • PDE V is then concentrated to 10% of the original volume, diluted to 50% with ethylene glycol monoethyl ether and stored at -20 C. PDE V can typically be retained for up to four weeks with little or no loss of activity.
  • Enzyme activity are assessed by measuring the hydrolysis of [ 3 H]-cyclic GMP, as described by Thompson et al.
  • the cyclic GMP concentration used in this assay is 0.2 uM, which approximates to the K m value. Protein concentration is adjusted to ensure that no more than 15% of the available substrate is hydrolyzed during the incubation period.
  • test compounds are dissolved in dimethyl sulfoxide (final concentration of 2.5%). This concentration of dimethyl sulfoxide inhibits enzyme activity by approximately 10%.
  • compositions of the present invention are also potent inhibitors of PDE V in mammals.
  • Such activity is useful in the medical arts to reduce smooth muscle cell proliferation and increase pulmonary vasodilation.
  • the compounds demonstrate a combination of selective PDE IV and PDE V inhibition and can be used in diseases such as restenosis and related diseases.
  • Such aspects include administering an effective amount of a compound of the present invention possessing said combination of PDE IV and V inhibitory activities to a mammal in need of such therapy.

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

Abstract

On décrit des composés de la formule (I), où R?1, R3 et R8¿ sont indépendamment alkyle, aryle ou aralkyle; R2 est choisi dans le groupe qui comprend S et O, et R6 est choisi dans le groupe qui comprend S et O, à condition que R2 et R6 ne soient pas O. Les composés sont des inhibiteurs efficaces de phosphodiestérases (PDE) IV et offrent à la fois une capacité d'inhibition améliorée des PDE IV et une sélectivité améliorée par rapport à l'inhibition des PDE III. On décrit également des méthodes de traitement qui reposent sur les composés en question.
PCT/US1995/016724 1994-12-13 1995-12-12 Thioxanthines trisubstituees WO1996018400A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU45279/96A AU4527996A (en) 1994-12-13 1995-12-12 Trisubstituted thioxanthines
DE69531555T DE69531555T2 (de) 1994-12-13 1995-12-12 Dreifachsubstituierte thioxanthine
CA002206804A CA2206804C (fr) 1994-12-13 1995-12-12 Thioxanthines trisubstituees
US08/860,674 US6025361A (en) 1994-12-13 1995-12-12 Trisubstituted thioxanthines
JP51932796A JP2001523213A (ja) 1994-12-13 1995-12-12 三置換チオキサンチン類
AT95943950T ATE247655T1 (de) 1994-12-13 1995-12-12 Dreifachsubstituierte thioxanthine
EP95943950A EP0799040B1 (fr) 1994-12-13 1995-12-12 Thioxanthines trisubstituees

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/354,664 1994-12-13
US47626295A 1995-06-07 1995-06-07
US08/476,262 1995-06-07

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248746B1 (en) * 1998-01-07 2001-06-19 Euro-Celtique S.A. 3-(arylalkyl) xanthines
WO2003089430A1 (fr) 2002-04-19 2003-10-30 Astrazeneca Ab Derives de thioxanthine utilises comme inhibiteurs de la myeloperoxydase
WO2005037835A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux derives de thioxanthine utiles comme inhibiteurs de la mpo
WO2006062465A1 (fr) * 2004-12-06 2006-06-15 Astrazeneca Ab Nouveaux derives de pyrrolo [3, 2-d] pyrimidin-4-one et leur utilisation dans une therapie
US7943625B2 (en) 2006-06-05 2011-05-17 Astrazeneca Ab 2 thioxanthine derivatives acting as MPO-inhibitors
KR101172638B1 (ko) * 2008-12-30 2012-08-08 조선대학교산학협력단 신규한 티아졸리딘디온 유도체 및 그의 용도
US12187729B2 (en) 2018-12-06 2025-01-07 Korea Research Institute Of Chemical Technology Compounds having PDE9A inhibitory activity, and pharmaceutical uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710503A (en) * 1985-02-07 1987-12-01 Euroceltique S.A. 6-thioxanthine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710503A (en) * 1985-02-07 1987-12-01 Euroceltique S.A. 6-thioxanthine derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRIT. J. PHARMACOL., Volume 17, issued 1961, A.K. ARMITAGE et al., "Structure-Activity Relationships in a Series of 6-Thioxanthines with Bronchodilator and Coronary Dilator Properties", pages 196-207. *
See also references of EP0799040A4 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248746B1 (en) * 1998-01-07 2001-06-19 Euro-Celtique S.A. 3-(arylalkyl) xanthines
EP2332541A1 (fr) * 2002-04-19 2011-06-15 AstraZeneca AB Utilisation de dérivés de thioxanthines comme inhibiteurs de MPO
US8236951B2 (en) 2002-04-19 2012-08-07 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
WO2003089430A1 (fr) 2002-04-19 2003-10-30 Astrazeneca Ab Derives de thioxanthine utilises comme inhibiteurs de la myeloperoxydase
US7425560B2 (en) 2002-04-19 2008-09-16 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
AU2003224548B2 (en) * 2002-04-19 2010-01-21 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
KR101064092B1 (ko) * 2002-04-19 2011-09-08 아스트라제네카 아베 미엘로퍼옥시다제 억제제로서의 티오크산틴 유도체
AU2010200345B2 (en) * 2002-04-19 2011-07-07 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
WO2005037835A1 (fr) * 2003-10-17 2005-04-28 Astrazeneca Ab Nouveaux derives de thioxanthine utiles comme inhibiteurs de la mpo
US7829707B2 (en) 2004-12-06 2010-11-09 Astrazeneca Ab Pyrrolo [3,2-d]pyrimidin-4-one derivatives and their use in therapy
WO2006062465A1 (fr) * 2004-12-06 2006-06-15 Astrazeneca Ab Nouveaux derives de pyrrolo [3, 2-d] pyrimidin-4-one et leur utilisation dans une therapie
US8859568B2 (en) 2004-12-06 2014-10-14 Astrazeneca Ab Pyrrolo[3,2-D]pyrimidin-4-one derivatives and their use in therapy
US9580429B2 (en) 2004-12-06 2017-02-28 Astrazeneca Ab Pyrrolo[3,2-D]pyrimidin-4-one derivatives and their use in therapy
US7943625B2 (en) 2006-06-05 2011-05-17 Astrazeneca Ab 2 thioxanthine derivatives acting as MPO-inhibitors
KR101172638B1 (ko) * 2008-12-30 2012-08-08 조선대학교산학협력단 신규한 티아졸리딘디온 유도체 및 그의 용도
US12187729B2 (en) 2018-12-06 2025-01-07 Korea Research Institute Of Chemical Technology Compounds having PDE9A inhibitory activity, and pharmaceutical uses thereof

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