EP1368353A1 - Imidazotriazinones 2-alcoxyphenyl-substituees - Google Patents

Imidazotriazinones 2-alcoxyphenyl-substituees

Info

Publication number
EP1368353A1
EP1368353A1 EP02710833A EP02710833A EP1368353A1 EP 1368353 A1 EP1368353 A1 EP 1368353A1 EP 02710833 A EP02710833 A EP 02710833A EP 02710833 A EP02710833 A EP 02710833A EP 1368353 A1 EP1368353 A1 EP 1368353A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
mmol
compound
diseases
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Withdrawn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
EP02710833A
Other languages
German (de)
English (en)
Inventor
Ulrich Niewöhner
Helmut Haning
Martin Radtke
Dietrich Seidel
Erwin Bischoff
Wolfgang Karl
Maria Teresa. Niewöhner
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 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 AG filed Critical Bayer AG
Publication of EP1368353A1 publication Critical patent/EP1368353A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to 2-alkoxyphenyl-substituted. Imidazotriazinones, ner process for their preparation and their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
  • WO 94/28902 describes pyrazolopyrimidinones which are suitable for the treatment of impotence.
  • WO 99/24433 and WO 99/67244 describe imidazotriazinones which are suitable for the treatment of impotence.
  • Cyclic guanosine 3 ', 5'-monophosphate metabolizing phosphodiesterases are PDE-1, 2, 5, 6, 9, 10, 11.
  • the compounds according to the invention are potent inhibitors of Phosphodiesterase 5.
  • the differentiated expression of the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with the selective inhibitors according to the invention enable a selective increase in the cGMP_ concentration in specific cells, tissues and organs and thereby enable addressing various processes regulated by cGMP. This is particularly to be expected if the synthesis of cGMP is increased under certain physiological conditions. For example, during sexual stimulation, nitrogen monoxide is released in the vessels of the corpus cavernosum by neuronal means, thereby increasing the synthesis of cGMP. This leads to a strong expansion of the vessels that supply the corpus cavernosum with blood, and thus to an erection. Therefore inhibitors of cGMP metabohsive PDEs should be particularly suitable for the treatment of erectile dysfunction.
  • An increase in the cGMP concentration can lead to curative, antiaggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilating, natriuretic and diuretic effects and can influence the conduction of excitation in the central nervous system and thus affect memory. It can affect short or long-term modulation of vascular and cardiac inotropy, cardiac rhythm and cardiac conduction (JC Stoclet, T. Keravis, N. Komas and C. Lugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
  • the present invention relates to the compounds of the general formula (I)
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid , Toluenesulfonic acid or naphthalenedisulfonic acid.
  • inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • sodium, potassium, magnesium or calcium salts and ammonium salts which are derived from ammonia or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, are particularly preferred , Lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention, in particular the salts can also be present as hydrates. In the context of the invention, hydrates are understood to mean those compounds which contain water in the crystal. Such compounds may contain one or more, typically 1 to 5, equivalents of water. Hydrates can be prepared, for example, by removing the compound in question
  • the compounds of the invention can be prepared by using compounds of the formula (II)
  • L represents straight-chain or branched alkyl having up to 4 carbon atoms
  • organic solvents which do not change under the reaction conditions are suitable as solvents for the individual steps.
  • solvents preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichlorethylene or chlorobenzene Dimethylformamide, hexamethylphosphoric triamide, acetonitrile, Acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the solvents mentioned. Ethanol is particularly preferred for the first step and dichloroethane for the second step.
  • the reaction temperature can generally be varied within a substantial range. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to 70 ° C.
  • the process steps according to the invention are generally carried out at normal pressure. However, it is also possible to carry them out at overpressure or underpressure (e.g. in a range from 0.5 to 5 bar).
  • the conversion to the compounds of the general formula (V) takes place in a temperature range from 0 ° C. to room temperature and normal pressure.
  • reaction with the corresponding amines is carried out in one of the chlorinated hydrocarbons listed above, preferably in dichloromethane.
  • the reaction temperature can generally be varied within a substantial range. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to room temperature.
  • the reaction is generally carried out at normal pressure. However, it is also possible to carry them out at overpressure or underpressure (e.g. in a range from 0.5 to 5 bar).
  • the compounds of formula (II) can be prepared by:
  • T represents halogen, preferably chlorine
  • organic solvents which do not change under the reaction conditions are suitable as solvents for the individual steps of the process.
  • solvents preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetic acid triamide, dimethyl acetonitrile,
  • Suitable bases are generally alkali metal hydrides or alcoholates, such as, for example, sodium hydride or potassium tert-butylate, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C 1 -C 4 -alkylamines, such as, for example, triethylamine. Triethylamine, pyridine and / or dimethylaminopyridine are preferred.
  • 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 compound of the formula (X).
  • the reaction temperature can generally be varied within a substantial range. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to 100 ° C.
  • the compound of formula (III) can be prepared by the compound of formula (XI)
  • ammonium chloride in toluene and in the presence of trimethylaluminum in hexane in a temperature range from -20 ° C to room temperature, preferably at 0 ° C and normal pressure and the resulting amidine, _ optionally in situ, is reacted with hydrazine hydrate.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • cGMP-metabolizing phosphodiesterase 5 They inhibit cGMP-metabolizing phosphodiesterase 5. This leads to an increase in cGMP.
  • the compounds according to the invention enhance the action of substances such as EDRF (Endothelium derived relaxing factor), ANP
  • the compounds of the general formula (I) according to the invention are therefore suitable for the prophylaxis and / or treatment of diseases in which an increase in the cGMP concentration is beneficial, i.e. Diseases associated with cGMP-regulated processes (usually simply referred to as 'cGMP-related diseases' in English). These include cardiovascular diseases, diseases of the genitourinary system and cerebrovascular diseases.
  • cardiovascular diseases in the context of the present invention includes diseases such as, for example, high blood pressure, pulmonary hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic diseases and ischemia such as myocardial infarction, stroke, transistor and ischemic attacks, angina pectoris, peripheral circulatory disorders, prevention of restenosis after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass.
  • PTA percutaneous transluminal angioplasty
  • PTCA percutaneous transluminal coronary angioplasty
  • the compounds of the general formula (I) according to the invention can also have significance for cerebrovascular diseases. These include, for example, cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cerebral thrombosis, dementia, reduced memory and Alzheimer's disease.
  • the relaxing effect on smooth muscles makes them suitable for the treatment of motility disorders in the digestive tract such as gastroparesis and diseases of the genitourinary system such as prostate hypertrophy, BPH, incontinence and especially for the treatment of erectile dysfunction and female sexual dysfunction.
  • PDE phosphorus diesterases
  • the inhibition of phosphodiesterase 5 leads to an increase in the cGMP concentration. This makes the compounds interesting for all therapies in which an increase in the cGMP concentration can be assumed to be beneficial.
  • the new active ingredients and their physiologically acceptable salts 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 acceptable carriers 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, i.e. in amounts 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 them of 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, for example perlingually, buccally, intravenously, nasally, rectally or by inhalation.
  • doses of 0.001 to 50 mg / kg are expediently administered in the case of oral administration.
  • parenteral administration e.g. A dose of 0.001 mg / kg - 0.5 mg / kg is advisable via mucous membranes nasally, buccally, or by inhalation.
  • the compounds according to the invention are also suitable for use in veterinary medicine.
  • the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practices.
  • the veterinarian can determine the type of application and the dosage according to the type of animal to be treated. starting compounds
  • reaction mixture is refluxed for 3 hours. It is poured onto ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated.
  • Example 2 The preparation was carried out analogously to Example 1 from 2.2 g (5.35 mmol) of the sulfonic acid chloride from Example 5A and 3.22 g (53.5 mmol) of ethylenediamine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des imidazotriazinones 2-phényl-substituées à restes alkyle courts et non ramifiés en position 9, qui sont produites à partir des 2-phényl-imidazotriazinones correspondantes par chlorosulfonation puis réaction consécutive avec des amines. Ces composés inhibent des phosphodiestérases métabolisant le cGMP et conviennent comme principes actifs dans des médicaments pour le traitement d'affections cardiovasculaires et cérébrovasculaires ou d'affections de l'appareil urogénital, notamment pour le traitement du dysfonctionnement érectile.
EP02710833A 2001-02-15 2002-02-04 Imidazotriazinones 2-alcoxyphenyl-substituees Withdrawn EP1368353A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10107639A DE10107639A1 (de) 2001-02-15 2001-02-15 2-Alkoxyphenyl-substituierte Imidazotriazinone
DE10107639 2001-02-15
PCT/EP2002/001100 WO2002064593A1 (fr) 2001-02-15 2002-02-04 Imidazotriazinones 2-alcoxyphenyl-substituees

Publications (1)

Publication Number Publication Date
EP1368353A1 true EP1368353A1 (fr) 2003-12-10

Family

ID=7674515

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02710833A Withdrawn EP1368353A1 (fr) 2001-02-15 2002-02-04 Imidazotriazinones 2-alcoxyphenyl-substituees

Country Status (6)

Country Link
US (1) US20060160810A1 (fr)
EP (1) EP1368353A1 (fr)
JP (1) JP2004521907A (fr)
CA (1) CA2438113A1 (fr)
DE (1) DE10107639A1 (fr)
WO (1) WO2002064593A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10063108A1 (de) * 2000-12-18 2002-06-20 Bayer Ag Verfahren zur Herstellung von Sulfonamid-substituierten Imidazotriazinonen
DE10135815A1 (de) * 2001-07-23 2003-02-06 Bayer Ag Verwendung von 2-Alkoxyphenyl-substituierten Imidazotriazinonen
JP2006219374A (ja) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Ｐｄｅ７阻害作用を有するイミダゾトリアジノン誘導体
KR20080016531A (ko) * 2005-02-18 2008-02-21 서피스 로직스, 인크. 약동학적으로 개선된 화합물
US20100324037A1 (en) * 2006-08-24 2010-12-23 Surface Logix, Inc. Pharmacokinetically improved compounds
CN102382129B (zh) * 2010-08-19 2014-02-26 山东轩竹医药科技有限公司 螺环取代的磷酸二酯酶抑制剂
CN102372730B (zh) * 2010-08-19 2014-03-26 山东轩竹医药科技有限公司 桥环取代的磷酸二酯酶抑制剂
CN103086920A (zh) * 2011-11-04 2013-05-08 山东科技大学 一种邻乙氧基苯甲脒盐酸盐的新合成方法
CN103374002B (zh) * 2012-04-19 2015-07-15 山东轩竹医药科技有限公司 磷酸二酯酶-5抑制剂
CN106008524A (zh) * 2016-06-01 2016-10-12 合肥创新医药技术有限公司 一种伐地那非杂质的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9301192D0 (en) * 1993-06-09 1993-06-09 Trott Francis W Flower shaped mechanised table
HU230154B1 (hu) * 1997-11-12 2015-09-28 Bayer Intellectual Property Gmbh Eljárás 2-es helyzetben fenil-szubszituenst hordozó imidazo-triazinon-származékok előállítására
DE19827640A1 (de) * 1998-06-20 1999-12-23 Bayer Ag 7-Alkyl- und Cycloalkyl-substituierte Imidazotriazinone
DE10063108A1 (de) * 2000-12-18 2002-06-20 Bayer Ag Verfahren zur Herstellung von Sulfonamid-substituierten Imidazotriazinonen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02064593A1 *

Also Published As

Publication number Publication date
CA2438113A1 (fr) 2002-08-22
DE10107639A1 (de) 2002-08-22
US20060160810A1 (en) 2006-07-20
WO2002064593A1 (fr) 2002-08-22
JP2004521907A (ja) 2004-07-22

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