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EP1776120A1 - Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle - Google Patents

Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle

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Publication number
EP1776120A1
EP1776120A1 EP05764196A EP05764196A EP1776120A1 EP 1776120 A1 EP1776120 A1 EP 1776120A1 EP 05764196 A EP05764196 A EP 05764196A EP 05764196 A EP05764196 A EP 05764196A EP 1776120 A1 EP1776120 A1 EP 1776120A1
Authority
EP
European Patent Office
Prior art keywords
methyl
treatment
propyl
imidazo
phenyl
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Withdrawn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
EP05764196A
Other languages
German (de)
English (en)
Inventor
Helmut Haning
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.)
Bayer AG
Original Assignee
Bayer Healthcare 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
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1776120A1 publication Critical patent/EP1776120A1/fr
Withdrawn legal-status Critical Current

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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Definitions

  • the present invention relates to the use of PDE 5 inhibitors in general and ins ⁇ particular of known 2-phenyl-substituted imidazotriazinone derivatives for the preparation of medicaments for the treatment of diseases that are treatable by increasing cGMP levels in certain tissues, such as for example, acute myocardial infarction and reperfusion damage, - various clinical pictures of the female and male reproductive system and genitourinary tract, gastrointestinal diseases, diabetes damage and kidney failure.
  • cyclic nucleotide cGMP cyclic guanosine monophosphate
  • PDEs phosphodiesterases
  • PDE 5 is found mainly in vascular smooth muscle cell tissue, less in the kidney, lung and platelets. Due to their vasorelaxing effect PDE 5 inhibitors are proposed for the treatment of angina and hypertension, but mainly for the treatment of erectile dysfunction.
  • WO 99/24433 describes 2-phenyl-substituted imidazotriazinones, their cGMP-PDE-inhibiting action and their use for the treatment of vascular diseases, in particular for the treatment of erectile dysfunction.
  • WO 02/089808 and WO 03/011262 uses of 2-phenyl-substituted imidazotriazinones are disclosed.
  • phosphodiesterases with different specificity towards the cyclic nucleotides cAMP and cGMP are described in the literature [cf. Fawcett et al., Proc. Nat. Acad. Be. 97 (7), 3072-3077 (2000)].
  • Cyclic guanosine-3 ', 5'-monophosphate-rnetabol is the PDE 1, 2, 5, 6, 9, 10 and 11.
  • 2-phenyl-substituted imidazotriazinones are potent inhibitors of phosphodiesterase 5.
  • the differentiated expression of phosphodiesterases in various cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with selective inhibitors allow a selective increase of cGMP concentration in specific cells, tissues and organs and thereby allow the addressing of various processes regulated by cGMP so that PDE 5 inhibitors are therapeutically applicable in a number of conditions that may be affected by the increase in cGMP levels.
  • PDE 5 inhibitors which inhibit PDE 5 with an IC 50 value of less than 1 ⁇ M, preferably of less than 0.1 ⁇ M, in the test listed below.
  • the PDE 5 inhibitors used according to the invention are also selective to cAMP-PDEs, in particular to PDE 4. Particularly preferred is an at least 10-fold stronger inhibition of PDE 5.
  • EP-A-0 347 146 EP-A-0 349 239
  • EP-A-0 351 058 EP-A-0 352 960
  • EP-A-0 371 731 EP-A-0 371 731
  • One aspect of the present invention relates to the use of compounds of the general formula (I)
  • R 1 is methyl or ethyl
  • R 2 is ethyl or propyl
  • R 3 and R 4 are identical or different and represent a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally substituted identically or differently by hydroxy or methoxy up to two times,
  • R 3 and R 4 together with the nitrogen atom, a piperidinyl, morpholinyl, Thiomorpholinyl- ring or a radical of the formula
  • R 6 denotes hydrogen, formyl, acyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
  • straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- to disubstituted, identical or different, by hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by groups of the formulas - (CO) r NR 7 R 8 or
  • f is a number 0 or 1
  • R 7 and R 8 are identical or different and denote hydrogen or methyl
  • R 9 and R 10 are the same or different and denote hydrogen, methyl or ethyl
  • R 6 denotes cyclopentyl
  • R 11 and R 12 are the same or different and denote hydrogen, methyl or ethyl
  • i is a number 0 or 1
  • R 13 and R 14 are the same or different and denote hydrogen or methyl
  • R 3 and R 4 are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which may optionally be mono- to disubstituted, identical or different Substituted hydroxy, carboxyl or by a radical of the formula -P (O) OR 15 OR 16 ,
  • R 15 and R 16 are the same or different and denote hydrogen, methyl or ethyl
  • R 3 and R 4 are optionally substituted by N-linked piperidinyl or pyrrolidinyl,
  • R 5 is ethoxy or propoxy
  • the compounds used according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the use of the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds used according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds used according to the invention.
  • Physiologically acceptable salts of the compounds used according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic acids , Citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic acids , Citric acid, fumaric acid, maleic acid and be
  • Physiologically acceptable salts of the compounds used according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16C Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salt
  • solvates are those forms of the compounds used according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules.
  • Hydrates are a special form of solvates that coordinate with water.
  • hydrates are preferred in the context of the present invention. Hydrates can be prepared, for example, by crystallizing the compound in question from water or an aqueous solvent.
  • the present invention also includes prodrugs of the compounds used in the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body to the compounds used according to the invention (for example metabolically or hydrolytically).
  • acyl radical having 1 to 3 carbon atoms in the context of the invention is, for example, formyl, acetyl or propionyl.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms in the context of the invention is, for example, methoxy, ethoxy, n-propoxy or isopropoxy.
  • alkoxycarbonyl radical having 1 to 3 carbon atoms in the context of the invention is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.
  • a straight-chain or branched alkyl radical having 1 to 5 or 1 to 3 carbon atoms in the context of the invention is, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl or n-pentyl.
  • Straight-chain or branched alkyl radicals having 1 to 4 or 1 to 3 carbon atoms are preferred.
  • Another embodiment of the invention relates to the use according to the invention of compounds of the general formula (I) in which the radicals R 5 and -SO 2 NR 3 R 4 in the para position each other on the phenyl ring and R 1 , R 2 , R 3 , R 4 and R 5 are each as defined above.
  • a further embodiment of the invention relates to the use according to the invention of compounds of the general formula (Ia)
  • R 1 , R 2 , R 3 , R 4 and R s are each as defined above,
  • a further embodiment of the invention relates to the use of the compounds of the general formulas (T) and (Ia) for the preparation of a medicament for the treatment of cardiac ischemia, for achieving or improving a preconditioning effect, for the treatment of an acute myocardial infarction and for reperfusion damage, especially after a myocardial infarction, for the treatment of male infertility, Raynaud's syndrome, Claudicatio intermittens, Peyronie's disease, for the treatment of f ⁇ brotic diseases, atherosclerosis, for the improvement of sperm motility, for the treatment of depression, leukemia (eg lymphocytic leukemia), for the treatment of priapism, for the treatment of platelet adhesion and aggregation in renal ischemia, for the promotion and promotion of liver regeneration after surgical liver resection or in liver cancer, for the inhibition of Contraction of the esophageal musculature (eg in nutcracker esophagus or es
  • the compounds used according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds used according to the invention can be administered in suitable administration forms.
  • functioning fast and / or modified delivery forms which contain the compounds used in accordance with the invention in crystalline and / or amorphized and / or dissolved form, such as eg Tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound used according to the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (For example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound used according to the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity
  • films / lyophilisates films (For example, hard or soft gelatin capsules), dragees, granules, pellets, powders
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Intravenous administration is particularly preferred for the treatment of acute myocardial infarction and reperfusion damage, for example; Intravenous administration can also take place creeping in here.
  • the compounds used according to the invention can be converted into the stated forms of application. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others.
  • Carrier materials for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example Antioxi - Dantien such as ascorbic acid
  • dyes eg, inorganic pigments such as example, iron oxides
  • flavor and / or odoriferous include, among others.
  • Carrier materials for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds used in the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • parenterally administered amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 mg / kg of body weight to achieve effective results.
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.1 to 30 mg / kg and most preferably 0.1 to 10 mg / kg body weight.
  • Embodiment 1 is 2- [2-ethoxy-5 ⁇ (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] [l, 2,4] triazin-4-one; this compound is prepared according to Example 16 in WO 99/24433.
  • Embodiment 2 is 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3 ⁇ -imidazole [5, 1-fj [l, 2,4 ] triazm-4-one hydrochloride trihydrate; This compound is prepared according to Example 336 in WO 99/24433.
  • the PDE or PDE 5 -inhibiting effect of the compounds used according to the invention can be determined as follows:
  • the "phosphodiesterase [ 3 H] cGMP-SPA enzyme assay" from Amersham Life Science is used. The test is carried out according to the test protocol specified by the manufacturer. Human recombinant PDE 5 expressed in a bacculovirus system is used. The substance concentration is measured at which the reaction rate is reduced by 50%.
  • Exemplary embodiments 1 and 2 show IC 50 values of 0.6 and 0.7 nM in this test.
  • PDELA Generic / EMBL Accession Number: NMJH6953, Fawcett et al., Proc Natl Acad., 2000, 9 ⁇ , 3702-3707
  • GibcoBRL pFASTBAC baculovirus expression system
  • test substances are dissolved in 100% DMSO to determine their in vitro effect on PDE9A and serially diluted.
  • serial dilutions 200 ⁇ M to 1.6 ⁇ M are prepared (resulting final concentrations in the assay: 4 ⁇ M to 0.032 ⁇ M).
  • 2 ⁇ L each of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate, Wallac Inc., Atlanta, GA). Subsequently, 50 ⁇ l of a dilution of the above-described PDE9A preparation are added.
  • the dilution of the PDE9A preparation is chosen such that during the later incubation less than 70% of the substrate is reacted (typical dilution: 1: 10,000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA, 0.2% BSA).
  • the substrate, [8- 3 H] guanosine 3 ', 5-cyclic phosphate (1 ⁇ Ci / ⁇ L, Amersham Pharmacia Biotech., Piscataway, NJ) is assayed 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA) to a concentration of 0.0005 ⁇ Ci / ⁇ L. By adding 50 ⁇ L (0.025 ⁇ Ci) of the diluted substrate, the enzyme reaction is finally started.
  • assay buffer 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA
  • test mixtures are incubated for 60 min at room temperature and the reaction is stopped by addition of 25 ⁇ l of a PDE9A inhibitor dissolved in assay buffer (eg compound from Example 1 in WO 2004/026286, 10 ⁇ M final concentration). Immediately thereafter, 25 ⁇ l of a suspension containing 18 mg / ml of Yttrium Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ) is added. The microtiter plates are sealed with a foil and left for 60 min at room temperature. The plates are then measured for 30 seconds per well in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA). IC 50 values are determined by plotting the concentration of the substance against the percent inhibition.
  • a PDE9A inhibitor dissolved in assay buffer (eg compound from Example 1 in WO 2004/026286, 10 ⁇ M final concentration).
  • the in vz ⁇ ro-effect of test substances on recombinant PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDEIlA is determined by the method described above for PDE9A test protocol with the following adaptations:
  • the addition of an inhibitor solution to stop the reaction is not necessary. Instead, following the incubation of substrate and PDE, the addition of the Yttrium Scintillation Proximity Beads is continued as described above, thereby stopping the reaction.
  • PDE2A and PDE5A becomes the protocol Additionally adjusted as follows:
  • PDE1C calmodulin 10 "7 M and CaCk 3 mM are added to the reaction mixture
  • PDE2A is stimulated by addition of cGMP 1 ⁇ M and tested with a BSA concentration of 0.01% substrate [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphate (1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ.), for PDE5A [8- 3 H] guanosine 3 ', 5'- cyclic phosphates (1 ⁇ Ci / ⁇ L; Amersham Pharmacia Biotech., Piscataway, NJ).

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Abstract

L'invention concerne l'utilisation en général d'inhibiteurs de la PDE 5 et en particulier de dérivés connus d'imidazotriazinones substituées par 2-phényle pour produire des médicaments servant à traiter des syndromes qui peuvent être soignés par élévation des taux de cGMP dans certains tissus, par exemple l'infarctus aigu du myocarde et les lésions de reperfusion, différents syndromes de l'appareil reproducteur et de l'appareil génito-urinaire chez la femme et chez l'homme, les infections gastro-intestinales, les lésions diabétiques et les défaillances rénales.
EP05764196A 2004-08-06 2005-07-23 Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle Withdrawn EP1776120A1 (fr)

Applications Claiming Priority (2)

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DE102004038328A DE102004038328A1 (de) 2004-08-06 2004-08-06 Neue Verwendungen von 2-Phenyl-substituierten Imidazotriazinon-Derivaten
PCT/EP2005/008057 WO2006015715A1 (fr) 2004-08-06 2005-07-23 Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle

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AU (1) AU2005270446A1 (fr)
BR (1) BRPI0514123A (fr)
CA (1) CA2575907A1 (fr)
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KR20090042863A (ko) * 2006-08-24 2009-04-30 서피스 로직스, 인크. 약물동력학적으로 향상된 화합물
EP2346872B1 (fr) * 2008-10-08 2015-11-25 Bristol-Myers Squibb Company Antagonistes de récepteur-1 d hormone de mélano-concentration d azolotriazinone
ES2549979T3 (es) * 2010-05-26 2015-11-03 Adverio Pharma Gmbh El uso de estimuladores de la sGC, activadores de la sGC, solos y en combinaciones con inhibidores de la PDE5 para el tratamiento de esclerosis sistémica (EcS)
US8465413B2 (en) 2010-11-25 2013-06-18 Coloplast A/S Method of treating Peyronie's disease
AP2013007070A0 (en) * 2011-02-23 2013-08-31 Pfizer Imidazo[5,1-f][1,2,4] triazines for the treatment of neurological disorders
RU2497203C2 (ru) * 2012-02-13 2013-10-27 Государственное бюджетное образовательное учреждение высшего профессионального образования "Курский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации Способ фармакологической коррекции ишемии скелетной мышцы силденафилом, в том числе при l-name-индуцированном дефиците оксида азота

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DE19812462A1 (de) * 1998-03-23 1999-09-30 Bayer Ag 2-[2-Ethoxy-5(4-ethyl-piperazin-1-sulfonyl) -phenyl]-5-methyl-7-prophyl-3H-imidazo[5,1-f][1,2,4]triazin-4-on Dihydrochlorid
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DE10135815A1 (de) * 2001-07-23 2003-02-06 Bayer Ag Verwendung von 2-Alkoxyphenyl-substituierten Imidazotriazinonen
AU2003286555A1 (en) * 2002-10-22 2004-05-13 Harbor-Ucla Research And Education Institute Phosphodiester inhibitors and nitric oxide modulators for treating peyronie's disease, arteriosclerosis and other fibrotic diseases
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CA2575907A1 (fr) 2006-02-16
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JP2008509101A (ja) 2008-03-27
WO2006015715A1 (fr) 2006-02-16
DE102004038328A1 (de) 2006-03-16
AU2005270446A1 (en) 2006-02-16
CN101035539A (zh) 2007-09-12
US20070299088A1 (en) 2007-12-27
NO20071231L (no) 2007-05-03
KR20070041613A (ko) 2007-04-18
MA28811B1 (fr) 2007-08-01
RU2007108078A (ru) 2008-09-20
BRPI0514123A (pt) 2008-05-27
ECSP077224A (es) 2007-03-29

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