EP1622564A2 - Diazabicyclononen-derivate - Google Patents

Diazabicyclononen-derivate

Info

Publication number
EP1622564A2
EP1622564A2 EP04729414A EP04729414A EP1622564A2 EP 1622564 A2 EP1622564 A2 EP 1622564A2 EP 04729414 A EP04729414 A EP 04729414A EP 04729414 A EP04729414 A EP 04729414A EP 1622564 A2 EP1622564 A2 EP 1622564A2
Authority
EP
European Patent Office
Prior art keywords
lower alkyl
mixtures
compounds
diastereomers
general formula
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Withdrawn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
EP04729414A
Other languages
English (en)
French (fr)
Inventor
Olivier Bezencon
Daniel Bur
Walter Fischli
Lubos Remen
Sylvia Richard-Bildstein
Thomas Weller
Thierry Sifferlen
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.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of EP1622564A2 publication Critical patent/EP1622564A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to novel compounds of the general formula I.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula I and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.
  • these compounds can be regarded as inhibitors of other aspartyl proteases and might therefore be useful as inhibitors of plasmepsins to treat malaria and as inhibitors of Candida albicans secreted aspartyl proteases to treat fungal infections.
  • renin inhibitors The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645).
  • the only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin.
  • ACE can also cleave bradykinin besides Ang I and can be bypassed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%)) and potentially life-threatening angioneurotic edema (0.1-0.2%)) (Konili Z. H.
  • the present invention relates to novel compounds of the general formula I,
  • lower alkylenedioxy refers to a lower alkylene substituted at each end by an oxygen atom.
  • Examples of lower alkylenedioxy groups are preferably methylenedioxy and ethylenedioxy.
  • sp3-hybridized refers to a carbom atom and means that this carbon atom forms four bonds to four substituents placed in a tetragonal fashion around this carbon atom.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula I is acidic in nature
  • L represents H; -COR 3 "; -COOR 3 "; -CONR 2 "R 3 "; whereby R 2 " and R 3 " represent independently lower alkyl, lower cycloalkyl - lower alkyl, which lower alkyl and lower cycloalkyl - lower alkyl groups are unsubstituted or monosubstituted with halogen, cyano, hydroxy, -OCOCH 3 , -CONH 2 , -COOH, -NH 2 , with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3 -hybridized.
  • the compounds of general formula I can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
  • Suitable carrier materials for injections are, for example, water, alcohols, polyols, glycerols and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • the bicyclononene L (0.11 g, 0.11 mmol) was dissolved in THF (3 mL) and AcOH (0.3 mL) and treated with zinc (0.14 g, 2.2 mmol). The suspension was stirred for 2 h and filtered through a Titan® HPLC filter. The filtrate was evaporated under reduced pressure and the residue was used in the next step without further purification.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP04729414A 2003-05-02 2004-04-26 Diazabicyclononen-derivate Withdrawn EP1622564A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP0304622 2003-05-02
PCT/EP2004/004372 WO2004096116A2 (en) 2003-05-02 2004-04-26 Diazabicyclononene derivatives

Publications (1)

Publication Number Publication Date
EP1622564A2 true EP1622564A2 (de) 2006-02-08

Family

ID=33395698

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04729414A Withdrawn EP1622564A2 (de) 2003-05-02 2004-04-26 Diazabicyclononen-derivate

Country Status (10)

Country Link
EP (1) EP1622564A2 (de)
JP (1) JP2006525259A (de)
KR (1) KR20060015573A (de)
CN (1) CN1780838A (de)
AU (1) AU2004233577A1 (de)
BR (1) BRPI0409882A (de)
CA (1) CA2521898A1 (de)
MX (1) MXPA05011711A (de)
RU (1) RU2005137571A (de)
WO (1) WO2004096116A2 (de)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867568A (zh) * 2003-10-13 2006-11-22 埃科特莱茵药品有限公司 二氮杂二环壬烯衍生物及其作为血管紧张肽原酶抑制剂的用途
WO2005040173A1 (en) * 2003-10-23 2005-05-06 Actelion Pharmaceuticals Ltd Diazabicyclononene and tetrahydropyridine derivatives as renin inhibitors
AU2004295092A1 (en) * 2003-12-05 2005-06-16 Actelion Pharmaceuticals Ltd. Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain
AU2005276624B2 (en) 2004-08-25 2011-09-29 Actelion Pharmaceuticals Ltd. Bicyclononene derivatives as renin inhibitors
WO2006021403A1 (en) * 2004-08-25 2006-03-02 Actelion Pharmaceuticals Ltd Bicyclononene derivatives
WO2006058546A1 (en) * 2004-12-01 2006-06-08 Actelion Pharmaceuticals Ltd Novel lactame derivatives as renin inhibitors
WO2006063610A1 (en) * 2004-12-17 2006-06-22 Actelion Pharmaceuticals Ltd Heteroaryl substituted diazabicyclononene derivatives
GB0428526D0 (en) 2004-12-30 2005-02-09 Novartis Ag Organic compounds
JP4111533B1 (ja) 2005-01-28 2008-07-02 アクテリオン ファーマシューティカルズ リミテッド 高血圧症の治療のためのレニンの阻害剤としての７−｛４−［２−（２，６−ジクロロ−４−メチルフェノキシ）エトキシ］フェニル｝−３，９−ジアザビシクロ［３．３．３１］ノン−６−エン−６−カルボン酸シクロプロピル−（２，３−ジメチルベンジル）アミド
WO2006131884A2 (en) * 2005-06-07 2006-12-14 Actelion Pharmaceuticals Ltd Thiazole substituted diazabicyclononane or-nonene derivatives as renin inhibitors
GB0514203D0 (en) 2005-07-11 2005-08-17 Novartis Ag Organic compounds
EP1968940B1 (de) 2005-12-30 2014-04-02 Novartis AG 3,5-substituierte piperidinverbindungen als renininhibitoren
EP2007725A2 (de) * 2006-03-16 2008-12-31 Nicox S.A. Nichtpeptidische nitroderivate als renininhibitoren
EP2162436A4 (de) 2007-05-24 2010-08-04 Merck Frosst Canada Ltd Neuer fall von renininhibitoren
EP2527338B1 (de) 2007-06-25 2015-05-06 Novartis AG N5-(2-ethoxyethyl)-n3-(2-pyridinyl) -3,5-piperidinedicarboxamide derivate als renin inhibitoren
US8334308B2 (en) 2007-08-20 2012-12-18 Merck Sharp & Dohme Corp. Renin inhibitors
JP4790871B2 (ja) 2008-05-05 2011-10-12 メルク フロスト カナダ リミテツド レニン阻害剤としての３，４−置換ピペリジン誘導体
WO2013038936A1 (ja) * 2011-09-13 2013-03-21 タカラバイオ株式会社 ペルオキシダーゼ反応の停止方法及び反応停止剤

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3509161A (en) * 1967-07-10 1970-04-28 Boehringer & Soehne Gmbh 3-phenyl-granatene-(2)-derivatives
ATE242213T1 (de) * 1995-09-07 2003-06-15 Hoffmann La Roche Neue 4-(oxyalkoxyphenyl)-3-oxy-piperidine zur behandlung von herz- und niereninsuffizienz
BR0309498A (pt) * 2002-04-29 2005-02-15 Actelion Pharmaceuticals Ltd Compostos, composições farmacêuticas, método para o tratamento ou profilaxia de doenças que são relacionadas com o ras, e, uso de compostos
US20060009497A1 (en) * 2002-06-27 2006-01-12 Actelion Pharmaceuticals, Ltd. Novel tetrahydropyridine derivatives as renin inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004096116A2 *

Also Published As

Publication number Publication date
WO2004096116A3 (en) 2005-03-24
BRPI0409882A (pt) 2006-05-23
CN1780838A (zh) 2006-05-31
MXPA05011711A (es) 2006-01-23
WO2004096116A2 (en) 2004-11-11
AU2004233577A1 (en) 2004-11-11
RU2005137571A (ru) 2006-05-10
CA2521898A1 (en) 2004-11-11
KR20060015573A (ko) 2006-02-17
JP2006525259A (ja) 2006-11-09

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Inventor name: BUR, DANIEL

Inventor name: BEZENCON, OLIVIER

Inventor name: WELLER, THOMAS

Inventor name: SIFFERLEN, THIERRY

Inventor name: REMEN, LUBOS

Inventor name: RICHARD-BILDSTEIN, SYLVIA

Inventor name: FISCHLI, WALTER

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