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WO1998032755A1 - Diones de purine s'utilisant comme inhibiteurs de phosphodiesterase - Google Patents

Diones de purine s'utilisant comme inhibiteurs de phosphodiesterase Download PDF

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Publication number
WO1998032755A1
WO1998032755A1 PCT/EP1998/000176 EP9800176W WO9832755A1 WO 1998032755 A1 WO1998032755 A1 WO 1998032755A1 EP 9800176 W EP9800176 W EP 9800176W WO 9832755 A1 WO9832755 A1 WO 9832755A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
substituted
branched
Prior art date
Application number
PCT/EP1998/000176
Other languages
German (de)
English (en)
Inventor
Ulrich Rosentreter
Helmut Haning
Ulrich Niewöhner
Thomas Schenke
Jörg Keldenich
Erwin Bischoff
Karl-Heinz Schlemmer
Helmuth Schütz
Günter Thomas
Original Assignee
Bayer Aktiengesellschaft
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 Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU62093/98A priority Critical patent/AU6209398A/en
Publication of WO1998032755A1 publication Critical patent/WO1998032755A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the present invention relates to new cyclic urea derivatives, a process for their preparation and their use in medicaments, in particular for the treatment of cardiovascular and cerebrovascular diseases, peripheral vascular diseases and diseases of the genitourinary system.
  • R4 and R ⁇ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
  • R ⁇ represents aryl having 6 to 10 carbon atoms, which may be up to 3 times the same or different by halogen, hydroxy, trifluoromethyl, trifluromethoxy or by straight-chain or mixed branched alkyl or alkoxy, each having up to 8 carbon atoms,
  • the substances according to the invention can also be present as salts.
  • Physiologically acceptable salts are preferred in the context of the invention
  • the compounds of the general formula (I) according to the invention can occur in various stereochemical forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the antipodes and the racemic forms as well the mixtures of diastereomers
  • the racemic forms, like the diastereomers, can be uniformly standardized into the stereoisomers
  • R 3 represents phenyl, which is optionally substituted up to 2 times the same or different by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
  • A stands for a straight-chain or branched alkylene chain with up to 3 carbon atoms
  • R ⁇ represents straight-chain or branched alkoxy or acyl each having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy each having up to 3 carbon atoms, or represents phenyl, which is optionally by hydroxyl, fluorine, chlorine, bromine or by straight-chain or branched alkoxy or alkyl, each with up to 3
  • R- is phenyl, which is optionally up to 2-fold identical or different by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluromethoxy or by straight-chain or branched alkyl or alkoxy, each with up to 3
  • R 1 represents phenyl, which is optionally substituted up to 2 times by the same or different means by methyl, methoxy or amino,
  • R 2 represents methyl or the solid of the formula OH .
  • A represents straight-chain or branched alkyl is up to 3 carbon atoms
  • Rl has the meaning given above
  • R6 represents straight-chain or branched alkyl having up to 6 carbon atoms
  • R-, R6 and A have the meaning given above,
  • R7 represents straight-chain or branched alkyl having up to 3 carbon atoms
  • Inert organic solvents which do not change under the reaction conditions are suitable for process [A] and for the cyclization steps.
  • These include preferably alcohols such as methanol, ethanol, propanol, isopropanol, butanol or t-butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide.
  • Alcohols such as ethanol, propanol, isopropanol or t-butanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned
  • Suitable solvents for the first step of process [B] are cyclic hydrocarbons such as toluene or benzene, preferably toluene.
  • bases are suitable as bases. These preferably include
  • Alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali alcoholates such as sodium methanolate, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium tert-butoxide.
  • the base is generally used in an amount of 1 mol to 4 mol, preferably from 1.2 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (II), (III) and (VI)
  • the reaction temperature can generally be varied within a substantial range. In general, a range from -20 ° C. to 200 ° C., preferably from 0 ° C. to 100 ° C.
  • the cyclization is generally carried out under normal pressure. However, it is also possible to carry out the process under positive or negative pressure (for example in a range from 0.5 to 5 bar).
  • the enantiomerically pure compounds can be obtained by customary methods, for example by chromatography of the racemic compounds of the general formula (I) accessible on chiral phases or through the use of chiral starting compounds.
  • Suitable solvents are preferably ethers, for example tetrahydrofuran or diethyl ether. Tetrahydrofuran is particularly preferred
  • Suitable dehydrating reagents are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phen 2-oxazohum-3-sulfonate or propanephosphoric anhydride or isobutylchloroformate or benzotriazolyloxy tris (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid di-phenyl ester amide or methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine or N-ethylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide
  • the reaction temperature can generally
  • the process is generally carried out under normal pressure. However, it is also possible to carry out the process under positive or negative pressure (for example in a range from 0.5 to 5 bar).
  • the compounds of the general formula (V) are known per se or can be reacted from the corresponding alkylhydroxy compounds firstly with tert-butyl pyrocarbonate in ethers, preferably tetrahydrofuran and then with acetanehyd ⁇ d in the presence of a base, preferably 4-dimethylamino-nopyridine at room temperature and normal pressure, followed by cleavage of the tert-butoxycarbonyl group by treatment with acids, preferably hydrochloric acid, in one of the inert solvents listed above at room temperature and normal pressure
  • the compounds of the general formula (I) according to the invention have an unforeseeable, valuable pharmacological spectrum of action They either inhibit one or more of the c-GMP metabolizing phosphodiesterases (PDE I, PDE II and PDE V). This leads to a differentiated increase in c-GMP. An increase in the c-GMP level can lead to an antithrombotic, vasodilatory and / or antiarrhythmic effect. The differentiating effect is determined by the distribution of the isoenzymes in the tissue
  • the compounds according to the invention intensify the action of substances, such as EDRF (Endothe um de ⁇ ved relaxing factor) and ANP (at ⁇ al nat ⁇ uretic peptide), which increase the cGMP level
  • cardiovascular diseases such as for the treatment of high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transistoric and ischemic
  • PDE phosphorus diesterases
  • the c-GMP stimulable PDE II, the c-GMP inhibitable PDE III and the cAMP-specific PDE IV were isolated from either porcine or bovine myocardium specific PDE V was preferred from pig small intestine, pig aorta, human blood platelets and
  • Bovine aorta obtained The purification was carried out by anion exchange chromatography on MonoQ ⁇ Pharmacia, essentially using the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al. Biochemical Pharmacology Vol. 35 1743-1751 (1986).
  • the enzyme activity is determined in a test mixture of 100 ⁇ l in 20 mM Tris / HCl buffer pH 7.5 which contains 5 mM MgCi2, 0.1 mg / ml bovine serum albumin and either 800 Bq -1HcAMP or -1HcGMP.
  • the final concentration of the corresponding nucleotides is 10 ⁇ 6 mol / 1.
  • the reaction is started by adding the enzyme; the amount of enzyme is such that about 50% of the substrate is converted during the incubation period of 30 minutes.
  • -1HcAMP is used as the substrate and 10.6 mol / 1 unlabeled cGMP is added to the batch.
  • the reaction batch is additionally CaCl2 1 ⁇ M and Calmodulin 0.
  • the reaction is stopped by adding 100 ⁇ l of acetonitrile, which contains 1 mM cAMP and 1 mM AMP, 100 ⁇ l of the reaction mixture are separated on the HPLC and the cleavage products “online” are quantified using a flow scintillation counter Substance concentration measured at which the reaction rate is reduced by 50%
  • the "Phosphodiesterase [ 3 H] cAMP-SPA enzyme assay” and the “Phosphodiesterase [ 3 H] cGMP-SPA enzyme assay” from Amersham Life Science were used for testing The test was carried out according to the test protocol specified by the manufacturer The [-1H] cAMP SPA assay was used to determine the activity of the PDE2 z 10 ⁇ 6 M cGMP was added to activate the enzyme.
  • the compounds were examined for antihypertensive activity in the anesthetized pig.
  • the substances were administered in doses of 0.03 to 10 mg / kg directly into the cavernous corpus, intraduodenally, rectally, orally, transdermally or intravenously.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, where, for example, if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously
  • Chloroformic acid tetrichloromethyl ester was added and the mixture was stirred at 90 ° C. for 1 hour. After cooling, the activated carbon was filtered off and the filtrate was washed with saturated sodium bicarbonate solution. The organic phase was dried with magnesium sulfate and evaporated IV. The evaporation pressure was dissolved in 60 ml of methanol and 4.32 g 2-Am ⁇ no-2-cyanoacetam ⁇ d mixed After 1 h stirring at approx. 20 ° C, i V is evaporated and the evaporation pressure is mixed with 167 ml in sodium hydroxide solution and a few ml isopropanol. The reaction mixture is stirred for 2 h at approx.

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

Abstract

L'invention concerne de dérivés cycliques d'urée obtenus par constitution desdits dérivés cycliques par réactions de condensation progressives. Les nouveaux dérivés cycliques d'urées s'utilisent comme principes actifs dans des médicaments, notamment dans des médicaments servant à traiter des affections cardio-vasculaires et cérébro-vasculaires, des vasculopathies périphériques et des affections de l'appareil génito-urinaire.
PCT/EP1998/000176 1997-01-27 1998-01-14 Diones de purine s'utilisant comme inhibiteurs de phosphodiesterase WO1998032755A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62093/98A AU6209398A (en) 1997-01-27 1998-01-14 Purine diones as phosphodiesterase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1997102785 DE19702785A1 (de) 1997-01-27 1997-01-27 Neue cyclische Harnstoffderivate
DE19702785.7 1997-01-27

Publications (1)

Publication Number Publication Date
WO1998032755A1 true WO1998032755A1 (fr) 1998-07-30

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PCT/EP1998/000176 WO1998032755A1 (fr) 1997-01-27 1998-01-14 Diones de purine s'utilisant comme inhibiteurs de phosphodiesterase

Country Status (3)

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AU (1) AU6209398A (fr)
DE (1) DE19702785A1 (fr)
WO (1) WO1998032755A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089953A1 (fr) * 2003-03-04 2004-10-21 Altana Pharma Ag Derives de purine-6-one
WO2015106032A1 (fr) 2014-01-08 2015-07-16 Intra-Cellular Therapies, Inc. Produits et compositions pharmaceutiques
US10105349B2 (en) 2014-12-06 2018-10-23 Intra-Cellular Therapies, Inc. Organic compounds
US10300064B2 (en) 2014-12-06 2019-05-28 Intra-Cellular Therapies, Inc. Organic compounds

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9924020D0 (en) 1999-10-11 1999-12-15 Pfizer Ltd Pharmaceutically active compounds
CN100439370C (zh) 2001-02-08 2008-12-03 记忆药物公司 作为磷酸二酯酶4抑制剂的三氟甲基嘌呤
WO2004014913A2 (fr) 2002-08-08 2004-02-19 Memory Pharmaceuticals Corporation Inhibiteurs de la phosphodiesterase 4
JP2005538133A (ja) 2002-08-08 2005-12-15 メモリー・ファーマシューティカルズ・コーポレイション ホスホジエステラーゼ４阻害剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4548820A (en) * 1982-07-28 1985-10-22 Adir Xanthine compounds
EP0352960A2 (fr) * 1988-07-25 1990-01-31 Smith Kline & French Laboratories Limited Composés purines, leur procédé de préparation et compositions pharmaceutiques
EP0447324A1 (fr) * 1990-03-15 1991-09-18 Sanofi Dérivés de pyrimidinedione-2,4 et médicaments les contenant
WO1994000453A1 (fr) * 1992-06-26 1994-01-06 Pfizer Limited Purinones utilises comme antiangineux

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4548820A (en) * 1982-07-28 1985-10-22 Adir Xanthine compounds
EP0352960A2 (fr) * 1988-07-25 1990-01-31 Smith Kline & French Laboratories Limited Composés purines, leur procédé de préparation et compositions pharmaceutiques
EP0447324A1 (fr) * 1990-03-15 1991-09-18 Sanofi Dérivés de pyrimidinedione-2,4 et médicaments les contenant
WO1994000453A1 (fr) * 1992-06-26 1994-01-06 Pfizer Limited Purinones utilises comme antiangineux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. BELTMAN ET AL.: "Characterization of Cyclic Nucleotide Phosphodiesterases with Cyclic GMP Analogs: Topology of the Catalytic Domains", MOL. PHARMACOL., vol. 47, no. 2, 1995, pages 330 - 339, XP002062684 *
S. MURESAN ET AL.: "Comparative QUASAR study with electronic and steric parameters for cAMP derivatives with large substituents in positions 2, 6 and 8", JOURNAL OF MOLECULAR STRUCTURE (THEOCHEM), vol. 342, 1995, pages 161 - 171, XP002062683 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089953A1 (fr) * 2003-03-04 2004-10-21 Altana Pharma Ag Derives de purine-6-one
WO2015106032A1 (fr) 2014-01-08 2015-07-16 Intra-Cellular Therapies, Inc. Produits et compositions pharmaceutiques
US10105349B2 (en) 2014-12-06 2018-10-23 Intra-Cellular Therapies, Inc. Organic compounds
US10300064B2 (en) 2014-12-06 2019-05-28 Intra-Cellular Therapies, Inc. Organic compounds
US10543194B2 (en) 2014-12-06 2020-01-28 Intra-Cellular Therapies, Inc. Organic compounds

Also Published As

Publication number Publication date
AU6209398A (en) 1998-08-18
DE19702785A1 (de) 1998-07-30

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