WO2007009146A1 - 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i - Google Patents

1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i Download PDF

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Publication number
WO2007009146A1
WO2007009146A1 PCT/AT2006/000307 AT2006000307W WO2007009146A1 WO 2007009146 A1 WO2007009146 A1 WO 2007009146A1 AT 2006000307 W AT2006000307 W AT 2006000307W WO 2007009146 A1 WO2007009146 A1 WO 2007009146A1
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WO
WIPO (PCT)
Prior art keywords
cox
formula
mmol
inhibitors
aryl
Prior art date
Application number
PCT/AT2006/000307
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German (de)
English (en)
Inventor
Thomas Erker
Norbert Handler
Ingo Langhammer
Original Assignee
Universität Wien
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.)
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Publication date
Application filed by Universität Wien filed Critical Universität Wien
Publication of WO2007009146A1 publication Critical patent/WO2007009146A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to novel COX-I inhibitor compounds and their use as medicaments and for the preparation of medicaments.
  • COX-I cyclooxygenase
  • COX-I shows the properties of a "house-keeping" enzyme and is constitutively expressed in virtually all tissues.High levels of COX-I expression have been reported in both platelets and gastrointestinal mucosa, which has a protective effect on the human body Gastric mucosa and supports blood clotting.
  • COX-II is expressed as a gene response to an inflammatory and mitogenetic event.
  • This enzyme is used i.a. in inflammatory processes as well as in the development of some tumors, e.g. Colon carcinoma, and neurodegenerative diseases, such as Alzheimer's disease, formed and in these responsible for the occurrence of pain, etc.
  • selective COX-II inhibitors reduce the biosynthesis of prostacyclin, while the thromboxane event is unaffected. For this reason, selective COX-II inhibitors, e.g. Celecoxib, rofecoxib and valdecoxib, have been approved for the treatment of rheumatoid arthritis, osteoarthritis, acute pain relief in dental care and primary dysmenorrhea.
  • selective COX-II inhibitors e.g. Celecoxib, rofecoxib and valdecoxib
  • COX-I is also overexpressed in ovarian carcinomas and therefore increases the production of the angiogenic growth factor. Furthermore, it is believed that COX-I plays an important role in pain processing and, above all, pain sensitization in the afferent pathways of the spine and the gracilis nucleus.
  • Selective COX-I inhibitors could thus play an important and useful role as analgesic and chemopreventive substances in the therapy of various diseases.
  • Possible uses of selective COX-I inhibitors include: treatment and prevention of diseases such as arteriosclerosis, myocardial infarction, stroke, embolisms, thromboses, angina pectoris, peripheral circulatory disorders and the like (see also Graupera, M. et al., J. of Hepatology 39 (4): 515-521 (2003); Ito, Y. et al., European Surgical Research 35 (5): 408-416 (2003); Candelario-Jalil, E. et al., J. of Neurochemistry 86 (3): 545-555 (2003)).
  • COX-I inhibitor compounds for example based on resveratrol and imidazole and triazole derivatives, are known, for example, from Hsu et al., J. Med. Chem. 47 (20): 4875-80 (2004); Szewczuk et al., J. Biol. Chem. 279 (21): 22727-22737 (2004); Leblanc et al., Bioorganic & Medicinal Chemistry Letters 5 (18): 2123-8 (1995); WO 04/060367 A, WO 03/040110 A, WO 02/076951 A, EP 1122243 A and WO 03/040110 A known.
  • the invention therefore has as its object to provide novel compounds which act as selective, sometimes highly selective, COX-I inhibitors. Preferably, however, these compounds should show little or no inhibitory effect on COX-II.
  • R 2 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -acryloxy, C 1 -C 4 -alkylthio or C 1 -C 4 -alkylsulfonyl.
  • Another aspect of the invention relates to the compounds of general formula I as a medicament. Furthermore, the invention relates to the use of the compounds of the general formula I for the preparation of a medicament with COX-I inhibitor activity. Medical indications are i.a. the treatment and prevention of diseases such as arteriosclerosis, myocardial infarction, stroke, embolism, thrombosis, angina pectoris, peripheral circulatory disorders and malignancies.
  • the medicament of the invention may be used in combination with radiotherapy and with chemotherapeutic agents. It can also be used to reduce the invasiveness and metastatic potential of tumors, to induce apoptosis. It also has antiangiogenic activity and can be used to treat and prevent tumors such as skin cancer, ovarian carcinoma, colon cancer, intestinal polyps, and other tumors that overexpress the COX-I enzyme.
  • the compound of the formula III was prepared from 2 mmol (0.348 g) of 1- (4-methoxyphenyl) -1H-imidazole, 2.2 mmol (1.4 ml of 1.6 M solution) of butyllithium and 2.4 mmol (0, 25 ml) of cyclohexanone.
  • the compound of formula IV was prepared from 2 mmol (0.348 g) of 1- (4-methoxyphenyl) -1H-imidazole, 2.2 mmol (1.4 ml of 1.6 M solution) of butyllithium and 2.4 mmol (0, 21 ml) of cyclopentanone.
  • the compound of formula V was prepared from 2 mmol (0.348 g) of 1- (4-methoxyphenyl) -1-imidazole, 2.2 mmol (1.4 ml of 1.6 M solution) of butyl lithium and 2.4 mmol (0 , 28 ml) of cycloheptanone.
  • the starting material l- [2- (methylsulfanyl) phenyl] -1H-imidazole was prepared as follows. In a tipped flask, 5 mmol (0.711 g) 2-fluorothioanisole, 10 mmol (0.680 g) imidazole, 0.050 g copper powder and 11 mmol (1.520 g) freshly annealed K 2 CO 3 were weighed and covered with N-methyl pyrolidinone. The reaction mixture was refluxed at 200 ° C on an oil bath for one week; After cooling, the mixture was extracted with ethyl acetate / water, the organic phase was dried and concentrated by rotary evaporation.
  • the compound of formula VI was prepared from 2 mmol (0.380 g) of 1- [2- (methylsulfanyl) phenyl] -1-imidazole, 2.2 mmol (1.4 ml of 1.6 M solution) of butyl lithium and 2, 4 mmol (0.25 ml) of cyclohexanone.
  • the precursor l- [l- [4- (methylsulfanyl) phenyl] -lH "-2-imidazolyl] -l-cyclohexanol was prepared from 2 mmol (0.380 g) l- (4-methylsulfanyl) ⁇ henyl-lH-imidazol [1] , 2.2 mmol (1.4 ml of 1.6 M solution) of butyllithium and 2.4 mmol (0.25 ml) of cyclohexanone, the crude product is recrystallized from ethanol Yield: 0.288 g (50%); 122-143 ° C 1 H-NMR (200 MHz, CDCl3).
  • COX-I and COX-II were indicated as so-called IC 50, 50% enzyme inhibition, ie the substance concentration which inhibits 50% of the measured isoenzyme.
  • Table 1 COX inhibitors - IC50 [ ⁇ M]
  • the compounds according to the invention show a good to high selectivity for COX-I and hardly any inhibitory effects on COX-II.

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

Abstract

L'invention concerne des composés de formule (I), R<SUB>1</SUB> étant un groupe selon la formule (IIa) ou (IIb), sachant que n = 1, 2 ou 3 et R<SUB>2</SUB> désigne hydrogène, alkyle C<SUB>1</SUB>-C<SUB>4</SUB>, alkyloxy C<SUB>1</SUB>-C<SUB>4</SUB>, alkylthio C<SUB>1</SUB>-C<SUB>4</SUB> ou alkylsulfonyle C<SUB>1</SUB>-C<SUB>4</SUB>. Ces composés agissent comme inhibiteurs sélectifs de COX-I.
PCT/AT2006/000307 2005-07-22 2006-07-20 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i WO2007009146A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA1237/2005 2005-07-22
AT0123705A AT502258B1 (de) 2005-07-22 2005-07-22 Cox-i-inhibitorverbindungen

Publications (1)

Publication Number Publication Date
WO2007009146A1 true WO2007009146A1 (fr) 2007-01-25

Family

ID=36968184

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT2006/000307 WO2007009146A1 (fr) 2005-07-22 2006-07-20 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i

Country Status (2)

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AT (1) AT502258B1 (fr)
WO (1) WO2007009146A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025047A1 (fr) * 1996-01-11 1997-07-17 Smithkline Beecham Corporation Nouveaux imidazoles cycloalkyle-substitues
WO2004060367A1 (fr) * 2002-12-30 2004-07-22 Fujisawa Pharmaceutical Co., Ltd. Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2733466A1 (de) * 1977-07-25 1979-02-22 Basf Ag Verfahren zur herstellung von imidazolen
ES2183140T3 (es) * 1996-02-13 2003-03-16 Searle & Co Combinaciones, que tienen efectos inmunosupresores, que contienen un inhibidor de ciclooxigenasa-2 y un inhibidor de leucotrieno a4 hidrolasa.
PE20030547A1 (es) * 2001-09-24 2003-08-18 Bayer Corp Derivados de imidazol para el tratamiento de la obesidad
AU2003249977A1 (en) * 2002-07-05 2004-01-23 Axxima Pharmaceuticals Ag Imidazole compounds for the treatment of hepatitis c virus infections
US7112601B2 (en) * 2003-09-11 2006-09-26 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis C virus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025047A1 (fr) * 1996-01-11 1997-07-17 Smithkline Beecham Corporation Nouveaux imidazoles cycloalkyle-substitues
WO2004060367A1 (fr) * 2002-12-30 2004-07-22 Fujisawa Pharmaceutical Co., Ltd. Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HANDLER N ET AL: "Cyclooxygenase-1 and cyclooxygenase-2 inhibition of novel 1,2-disubstituted imidazoles", ARCHIV DER PHARMAZIE, vol. 338, no. 12, December 2005 (2005-12-01), pages 602 - 604, XP002399693 *
LANGHAMMER I ET AL: "Synthesis of 1,2-disubstituted imidazoles via cross-coupling and substitution reactions", HETEROCYCLES, vol. 65, no. 11, November 2005 (2005-11-01), pages 2721 - 2728, XP001208078 *

Also Published As

Publication number Publication date
AT502258A1 (de) 2007-02-15
AT502258B1 (de) 2007-09-15

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