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WO2007009146A1 - Substituted 1-phenyl imidazoles as cox-i inhibitors - Google Patents

Substituted 1-phenyl imidazoles as cox-i inhibitors 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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cox
formula
mmol
inhibitors
aryl
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PCT/AT2006/000307
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German (de)
French (fr)
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Thomas Erker
Norbert Handler
Ingo Langhammer
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Universität Wien
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    • 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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Abstract

The invention relates to compounds of general formula (I), wherein R1 represents a radical of formula (IIa) or (IIb), in which n = 1, 2 or 3, and R2 represents hydrogen, C1-C4 alkyI, C1-C4 alkyloxy, C1-C4 alkylthio, or C1-C4 alkylsulfonyl. Said compounds act as selective COX-I inhibitors.

Description

SUBSTITUIERTE 1-PHENYL-IMIDAZOLE ALS COX-I-INHIBITORENSUBSTITUTED 1-PHENYL-IMIDAZOLE AS COX-I INHIBITORS
Die vorliegende Erfindung betrifft neuartige COX-I-Inhibitorverbindungen und deren Verwendung als Arzneimittel sowie zur Herstellung von Arzneimitteln.The present invention relates to novel COX-I inhibitor compounds and their use as medicaments and for the preparation of medicaments.
Anfang der 1990-er Jahre wurden zwei unterschiedliche Isoformen der Cyclooxygenase (COX) entdeckt, nämlich COX-I und COX-II. Diese beiden Enzyme werden von unterschiedlichen Genen codiert und katalysieren den limitierenden Schritt in der Bildung von Prostanoiden aus der Arachidonsäure.In the early 1990s, two different isoforms of cyclooxygenase (COX) were discovered, COX-I and COX-II. These two enzymes are encoded by different genes and catalyze the limiting step in the formation of arachidonic acid prostanoids.
COX-I zeigt die Eigenschaften eines „House-keeping"-Enzyms und wird konstitutiv in praktisch allen Geweben exprimiert. Hohe Expressionsraten von COX-I konnten sowohl in Blutplättchen als auch in der gastrointestinalen Mucosa festgestellt werden. Dieses Enzym hat eine schützende Wirkung auf die Magenschleimhaut und unterstützt die Blutgerinnung.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.
Im Unterschied dazu wird COX-II als Genantwort auf ein entzündliches und mitogenetisches Geschehen hin exprimiert. Dieses Enzym wird u.a. bei entzündlichen Prozessen sowie bei der Entstehung einiger Tumore, z.B. Kolonkarzinom, und neurodegenerativer Erkrankungen, wie Morbus Alzheimer, gebildet und bei diesen für das Auftreten von Schmerz etc. verantwortlich gemacht.In contrast, 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.
Selektive COX-II- Inhibitoren vermindern die Biosynthese von Prostacyclinen, wobei das Thromboxan-Geschehen unbeeinflusst bleibt. Aus diesem Grund sind selektive COX-II- Hemmer, wie z.B. Celecoxib, Rofecoxib und Valdecoxib, zur Behandlung von rheumatoider Arthritis, Osteoarthritis, zur Minderung von akuten Schmerzen bei Zahnbehandlungen und primärer Dysmenorrhoe zugelassen worden.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.
Dennoch hat dieses vereinfachte Modell von konstitutiver COX-I- und induzierbarer COX- II-Expression viele Ausnahmen. So kann die Bildung von COX-I während der Entwicklung eines Organismus reguliert werden. Dagegen wird COX-II u.a. konstitutiv im ZNS, in den für die Reproduktion wichtigen Geweben und in den Nieren gebildet und bedarf in dem oben gezeigten Sinn keiner besonderen Induktion.However, this simplified model of constitutive COX-I and inducible COX-II expression has many exceptions. Thus, the formation of COX-I during the development of an organism can be regulated. In contrast, COX-II u.a. constitutively formed in the CNS, in the tissues important for reproduction and in the kidneys, and requires no particular induction in the sense indicated above.
Des weiteren sind gerade in letzter Zeit die cardio-vaskulären Implikationen einer selektiven COX-II-Inhibition auf Basis der Ergebnisse der Vioxx Gastrointestinal Outsomes Research (VIGOR) - Studie ins Zentrum der Kritik geraten. Die akuten Myocard-Infarkt-Raten in dieser Studie erbrachten zwischen Rofecoxib und Naproxen (einem nichtselektiven NSAID) einen signifikanten Unterschied (0,4% und 0,1%).Furthermore, the cardio-vascular implications of selective COX-II inhibition based on the results of the Vioxx Gastrointestinal Outsomes Research (VIGOR) study have recently come under the spotlight. The acute myocardial infarction rates in of this study showed a significant difference between rofecoxib and naproxen (a nonselective NSAID) (0.4% and 0.1%).
Dies und die folgenden Befunde lassen den Einsatz von selektiven COX-I-Inhibitoren gerechtfertigt erscheinen: Kürzlich zeigten experimentelle und klinische Ergebnisse eine mögliche Rolle von COX-I in der Schmerz- und Krebsentwicklung. Tatsächlich ergaben Tierversuche, dass das Enzym COX-I eine wichtige Rolle bei der Entwicklung von intestinalen Polypen und Hautkrebs spielt, was mit den Ergebnissen aus epidemiologischen Studien konform geht, welche zeigten, dass die regelmäßige Einnahme von geringen Dosen Aspirin, das nur die Plättchen-COX-I- Aktivität hemmt, das Auftreten von Darmkrebs und die Mortalität reduzieren kann.This and the following findings justify the use of selective COX-I inhibitors: Recently, experimental and clinical results have demonstrated a possible role for COX-I in the development of pain and cancer. In fact, animal studies have shown that the enzyme COX-I plays an important role in the development of intestinal polyps and skin cancer, in line with the results of epidemiological studies, which showed that the regular intake of low doses of aspirin, which is only the platelet COX-I activity inhibits the occurrence of colon cancer and can reduce mortality.
Auch bei Ovarialkarzinomen wird COX-I überexprimiert und verstärkt daher die Produktion des angiogenen Wachstumfaktors. Weiters wird vermutet, dass COX-I eine wichtige Rolle bei der Schmerzverarbeitung und vor allem der Schmerzsensibilisierung in den afferenten Bahnen der Wirbelsäule und des Nucleus gracilis spielt.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.
Selektive COX-I-Inhibitoren könnten somit eine wichtige und nützliche Rolle als analgetisch und chemopräventiv wirkende Substanzen in der Therapie verschiedenster Erkrankungen spielen. Als mögliche Einsatzgebiete von selektiven COX-I-Inhibitoren seien genannt: Behandlung und Vorbeugung von Krankheiten wie Arteriosklerose, Myokardinfarkt, Schlaganfall, Embolien, Thrombosen, Angina pectoris, periphere Durchblutungsstörungen und ähnliches (siehe auch 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)). Eine gastrale Schädigung durch COX-I-Inhibitoren ist hier nicht zu befürchten, da für diese Wirkung offensichtlich die Hemmung beider Cyclooxygenase-Isoformen notwendig ist (Steinhilber, D. et al., Pharmazie in unserer Zeit 33(6):500-501 (2004)).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)). Gastric damage by COX-I inhibitors is not to be feared here, since the inhibition of both cyclooxygenase isoforms is obviously necessary for this action (Steinhilber, D. et al., Pharmacy in Our Time 33 (6): 500-501 ( 2004)).
Selektive COX-I-Inhibitorverbindungen, z.B. auf Basis von Resveratrol sowie Imidazol- und Triazolderivate, sind beispielsweise aus 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); der WO 04/060367 A, WO 03/040110 A, WO 02/076951 A, EP 1122243 A und der WO 03/040110 A bekannt. Die Erfindung stellt sich daher die Aufgabe, neuartige Verbindungen bereit zu stellen, die als selektive, zum Teil hoch selektive, COX-I-Inhibitoren wirken. Vorzugsweise sollten diese Verbindungen gegenüber COX-II jedoch keine oder kaum hemmende Wirkung zeigen.Selective 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.
Diese Aufgabe wird erfmdungsgemäß durch Verbindungen der allgemeinen Formel I gelöst,This object is achieved according to the invention by compounds of general formula I,
Figure imgf000005_0001
Figure imgf000005_0001
wobei R1 ein Rest gemäß Formel IIa oder IIb ist, wobei n = 1, 2 oder 3,where R 1 is a radical according to formula IIa or IIb, where n = 1, 2 or 3,
Figure imgf000005_0002
Figure imgf000005_0002
und R2 Wasserstoff, Ci-C4-Alkyl, C1-C4-AuCyIoXy, C1-C4-Alkylthio oder C1-C4- Alkylsulfonyl ist.and 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.
Diese Verbindungen erwiesen sich, wie weiter unten gezeigt wird, als selektive, zum Teil hoch selektive COX-I-Inhibitoren mit geringer bzw. vernachlässigbarer Hemmungswirkung für COX-II. Diese Verbindungen sind somit für die Herstellung eines Arzneimittels zur Behandlung von Zustandsbildern und Erkrankungen verwendbar, bei deren Entstehung und/oder Symptomatik COX-I beteiligt ist.These compounds have been shown, as shown below, to be selective, sometimes highly selective COX-I inhibitors with little or negligible COX-II inhibitory activity. These compounds are thus useful for the manufacture of a medicament for the treatment of condition patterns and diseases in whose formation and / or symptomatology COX-I is involved.
Bevorzugte Ausführungsformen der vorliegenden Erfindung sind Verbindungen, bei denen:Preferred embodiments of the present invention are compounds in which:
• Ri ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methoxygruppe ist (Formel III)Ri is a radical according to formula IIa, where n = 2, and R 2 is a methoxy group (formula III)
• Ri ein Rest gemäß Formel IIa ist, wobei n = 1 , und R2 eine Methoxygruppe ist (Formel IV) • R1 ein Rest gemäß Formel IIa ist, wobei n = 3, und R2 eine Methoxygruppe ist (Formel V)Ri is a radical according to formula IIa, where n = 1, and R 2 is a methoxy group (formula IV) R 1 is a radical according to formula IIa, where n = 3, and R 2 is a methoxy group (formula V)
• R1 ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methylsulfanylgruppe ist (Formel VI)• R 1 is a radical according to formula IIa, where n = 2, and R 2 is a methylsulfanyl group (formula VI)
• Ri ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methylsulfonylgruppe ist (Formel VII)Ri is a radical according to formula IIa, where n = 2, and R 2 is a methylsulfonyl group (formula VII)
• R1 ein Rest gemäß Formel IIb ist, wobei n = 2, und R2 eine Methylsulfonylgruppe ist (Formel VIII)R 1 is a radical according to formula IIb, where n = 2, and R 2 is a methylsulfonyl group (formula VIII)
Ein weiterer Aspekt der Erfindung betrifft die Verbindungen der allgemeinen Formel I als Arzneimittel. Ferner betrifft die Erfindung die Verwendung der Verbindungen der allgemeinen Formel I zur Herstellung eines Arzneimittels mit COX-I-Inhibitorwirkung. Medizinische Indikationen sind u.a. die Behandlung und Vorbeugung von Krankheiten wie Arteriosklerose, Myokardinfarkt, Schlaganfall, Embolien, Thrombosen, Angina pectoris, peripheren Durchblutungsstörungen und Malignomen. Außerdem kann das erfindungsgemäße Arzneimittel in Kombination mit einer Strahlentherapie und mit Chemotherapeutika verwendet werden. Es kann ferner verwendet werden zur Reduktion der Invasivität und des metastatischen Potentials von Tumoren, zur Induktion der Apoptose. Es hat darüber hinaus auch antiangiogenetische Wirkung und kann zur Behandlung und Vorbeugung von Tumoren wie Hautkrebs, Ovarialkarzinom, Darmkrebs, intestinalen Polypen und anderen Tumoren, bei denen das COX-I-Enzym überexprimiert wird, eingesetzt werden.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. In addition, 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.
Die Erfindung wird nachfolgend anhand von Beispielen näher erläutert.The invention will be explained in more detail by way of examples.
Beispiele:Examples:
Allgemeine Arbeitsvorschrift zur Herstellung von 1,2-disubstituierten Imidazolen:General procedure for the preparation of 1,2-disubstituted imidazoles:
2 mmol entsprechend substituiertes 1-Phenyl-lH-imidazol wurde in einem trockenen Dreihalskolben in absolutem THF gelöst. Die Lösung wurde unter Inertgas auf -78 °C gekühlt und 2,2 mmol (1,4 ml 1,6 M-Lösung in Hexan-Fraktion) Butyllithiurn langsam zugetropft. Nach 15 Minuten Rühren wurden 2,4 mmol zyklisches Keton hinzugefügt, für weitere 30 Minuten gerührt und schließlich bei Raumtemperatur zu Ende reagieren gelassen. Die Reaktionsmischung wurde mit 70 ml gesättigter Ammonchloridlösung gewaschen, die wässrige Phase mit Ethylacetat zweimal extrahiert und die organische Phase getrocknet und einrotiert. Nach Umkristallisation erhielt man die gewünschten Imidazole. Beispiel 12 mmol of appropriately substituted 1-phenyl-1H-imidazole was dissolved in absolute dry THF in a dry three-necked flask. The solution was cooled under inert gas to -78 ° C and 2.2 mmol (1.4 ml of 1.6 M solution in hexane fraction) Butyllithiurn slowly added dropwise. After stirring for 15 minutes, 2.4 mmol of cyclic ketone was added, stirred for a further 30 minutes, and finally allowed to react to completion at room temperature. The reaction mixture was washed with 70 ml of saturated ammonium chloride solution, the aqueous phase was extracted twice with ethyl acetate and the organic phase was dried and concentrated by rotary evaporation. After recrystallization, the desired imidazoles were obtained. example 1
l-[l-(4-Methoxyphenyl)-ljff-2-imidazolyl]-l-cyclohexaπoll- [l- (4-methoxyphenyl) -ljff-2-imidazolyl] -l-cyclohexaπol
Die Verbindung der Formel III wurde aus 2 mmol (0,348 g) l-(4-Methoxyphenyl)-lH- imidazol, 2,2 mmol (1,4 ml 1,6 M-Lösung) Butyllithium und 2,4 mmol (0,25 ml) Cyclohexanon hergestellt. Das Rohprodukt wurde aus Ethanol umkristallisiert. Ausbeute: 0,220 g (39,7%); Fp = 135-137°C. 1H-NMR (200 MHz, CDCl3): δ 7,32-7,26 (m, 2H, Aryl- H), 7,00-6,87 (m, 4H, Aryl-H), 3,87 (s, 3H, OCH3), 2,75 (s, IH, OH), 1,89-1,07 (m, 10H, Cyclohexanol). 13C-NMR (50 MHz, CDCl3): δ 159,6, 153,0, 131,9, 128,7, 125,9, 124,2, 113,9, 71,7, 55,5, 37,3, 25,2, 21,8. MS: m/z 272 (M+, 31%), 254 (100%).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 crude product was recrystallized from ethanol. Yield: 0.220 g (39.7%); Mp = 135-137 ° C. 1 H-NMR (200 MHz, CDCl 3): δ 7.32-7.26 (m, 2H, aryl H), 7.00 to 6.87 (m, 4H, aryl-H), 3.87 (s, 3H, OCH 3 ), 2.75 (s, IH, OH), 1.89-1.07 (m, 10H, cyclohexanol). 13 C-NMR (50 MHz, CDCl 3): δ 159.6, 153.0, 131.9, 128.7, 125.9, 124.2, 113.9, 71.7, 55.5, 37 , 3, 25, 2, 21, 8. MS: m / z 272 (M + , 31%), 254 (100%).
Beispiel 2Example 2
l-[l-(4-Methoxyphenyl)-lÄ-2-imidazolyl]-l-cyclopentanoll- [l- (4-methoxyphenyl) -lÄ-2-imidazolyl] -l-cyclopentanol
Die Verbindung der Formel IV wurde aus 2 mmol (0,348 g) l-(4-Methoxyphenyl)-lH- imidazol, 2,2 mmol (1,4 ml 1,6 M-Lösung) Butyllithium und 2,4 mmol (0,21 ml) Cyclopentanon hergestellt. Das Rohprodukt wurde aus 40%-igem Ethanol umkristallisiert. Ausbeute: 0,190 g (36,8%); Fp = 137-141°C. 1H-NMR (200 MHz, CDCl3): δ 7,36 (AB- System, A-Teil, JAB = 8,9 Hz, 2H, Phenyl-H), 7,00-6,89 (m, 4H, Aryl-H), 3,85 (s, 3H, OCH3), 3,20 (s, breit, IH, OH), 2,07-1,53 (m, 8H, Cyclopentanol). 13C-NMR (50 MHz, CDCl3): δ 159,5, 152,1, 131,5, 128,5, 125,9, 123,7, 113,8, 79,6, 55,4, 39,6, 23,4. MS: m/z 258 (M+, 6%), 201 (100%).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 crude product was recrystallized from 40% ethanol. Yield: 0.190 g (36.8%); Mp = 137-141 ° C. 1 H-NMR (200 MHz, CDCl 3 ): δ 7.36 (AB system, A part, J AB = 8.9 Hz, 2H, phenyl-H), 7.00-6.89 (m, 4H, aryl-H), 3.85 (s, 3H, OCH 3 ), 3.20 (s, broad, IH, OH), 2.07-1.53 (m, 8H, cyclopentanol). 13 C-NMR (50 MHz, CDCl 3): δ 159.5, 152.1, 131.5, 128.5, 125.9, 123.7, 113.8, 79.6, 55.4, 39 , 6, 23,4. MS: m / z 258 (M + , 6%), 201 (100%).
Beispiel 3Example 3
l-[l-(4-Methoxyphenyl)-lif-2-imiazolyl]-l-cycloheptanoll- [l- (4-methoxyphenyl) -lif-2-imiazolyl] -l-cycloheptanol
Die Verbindung der Formel V wurde aus 2 mmol (0,348 g) l-(4-Methoxyphenyl)-l#- imidazol, 2,2 mmol (1,4 ml 1,6 M-Lösung) Butyllithium und 2,4 mmol (0,28 ml) Cycloheptanon hergestellt. Das Rohprodukt wurde mittels Säulenchromatographie (Laufmittel: Toluol/ Ethylacetat = 2 + 8) gereinigt. Ausbeute: 0,150 g (26,6%); Fp = 90- 97°C. 1H-NMR (200 MHz, CDCl3): δ 7,29 (AB-System, A-Teil, JAB = 8,9 Hz, 2H, Phenyl- H), 6,98-6,86 (m, 4H, Aryl-H), 3,86 (s, 3H, OCH3), 2,81 (s, breit, IH, OH), 2,15-2,03 (m, 2H, Cycloheptanol), 1,83-1,25 (m, 10H, Cycloheptanol). 13C-NMR (50 MHz, CDCl3): δ 159,6, 154,1, 131,9, 128,9, 125,5, 124,3, 113,8, 75,4, 55,5, 41,2, 28,7, 22,1. MS: m/z 286 (M+, 26%), 229 (100%). Beispiel 4The 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 crude product was purified by column chromatography (eluent: toluene / ethyl acetate = 2 + 8). Yield: 0.150 g (26.6%); Mp = 90-97 ° C. 1 H-NMR (200 MHz, CDCl 3): δ 7.29 (AB-System, A part, J AB = 8.9 Hz, 2H, phenyl H), 6.98 to 6.86 (m, 4H , aryl-H), 3.86 (s, 3H, OCH 3), 2.81 (s, broad, IH, OH), 2.15 to 2.03 (m, 2H, cycloheptanol), 1,83- 1.25 (m, 10H, cycloheptanol). 13 C-NMR (50 MHz, CDCl 3): δ 159.6, 154.1, 131.9, 128.9, 125.5, 124.3, 113.8, 75.4, 55.5, 41 , 2, 28, 7, 22, 1. MS: m / z 286 (M + , 26%), 229 (100%). Example 4
l-[l-[2-(MethyIsulfanyl)phenyl]-liϊ-2-iinidazolyl]-l-cyclohexanoIl- [l- [2- (MethyIsulfanyl) phenyl] -liϊ-2-iinidazolyl] -l-cyclohexanoI
Zuerst wurde das Edukt l-[2-(Methylsulfanyl)phenyl]-lH-imidazol wie folgt hergestellt. In einem Spitzkolben wurden 5 mmol (0,711 g) 2-Fluorthioanisol, 10 mmol (0,680 g) Imidazol, 0,050 g Kupferpulver und 11 mmol (1,520 g) frisch geglühtes K2CO3 eingewogen und mit N-Methylpyrolidinon bedeckt. Die Reaktionsmischung wurde bei 200 °C am Ölbad eine Woche refluxiert; nach dem Abkühlen wurde mit Ethylacetat/ Wasser extrahiert, die organische Phase getrocknet und einrotiert. Das erhaltene Rohprodukt wurde über eine präparative Säule (Laufmittel Toluol/ Ethylacetat = 4 + 6) gereinigt. Ausbeute: 0,370 g (38,9 %); Öl. 1H-NMR (200 MHz, CDCl3): δ 7,65 (s, IH, Aryl-H), 7,47-7,29 (m, 2H5 Aryl-H), 7,27-7,21 (m, 3H, Aryl-H), 7,13 (s, IH, Aryl-H), 2,36 (s, 3H, SCH3). 13C-NMR (50 MHz, CDCl3): δ 136,1, 129,3, 129,2, 126,8, 126,4, 125,4, 120,4, 15,2. MS: m/z 190 (M+, 100%).First, 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 resulting crude product was purified via a preparative column (eluent toluene / ethyl acetate = 4 + 6). Yield: 0.370 g (38.9%); Oil. 1 H-NMR (200 MHz, CDCl 3): δ 7.65 (s, IH, aryl-H), 7.47 to 7.29 (m, 2H 5 aryl-H), 7.27-7.21 (m, 3H, aryl-H), 7.13 (s, IH, aryl-H), 2.36 (s, 3H, SCH 3 ). 13 C-NMR (50 MHz, CDCl 3): δ 136.1, 129.3, 129.2, 126.8, 126.4, 125.4, 120.4, 15.2. MS: m / z 190 (M + , 100%).
Die Verbindung der Formel VI wurde aus 2 mmol (0,380 g) l-[2-(Methylsulfanyl)phenyl]- 1/i-imidazol, 2,2 mmol (1,4 ml 1,6 M-Lösung) Butyllithium und 2,4 mmol (0,25 ml) Cyclohexanon hergestellt. Das Rohprodukt wurde aus 40%-igem Ethanol umkristallisiert. Ausbeute: 0,150 g (26,0%); Fp = 131-136°C. 1H-NMR (200 MHz, CDCl3): δ 7,56-7,01 (m, 5H, Aryl-H), 6,69-6,72 (m, IH, Aryl-H), 2,84 (s, breit, IH, OH), 2,41 (s, 3H, SCH3), 1,98- 0,95 (m, 10H, Cyclohexanol). 13C-NMR (50 MHz, CDCl3): δ 129,5, 128,6, 126,7, 124,7, 124,6, 122,9, 72,0, 37,2, 25,2, 21,7, 14,4. MS: m/z 288 (M+, 20%), 241 (100%).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 crude product was recrystallized from 40% ethanol. Yield: 0.150 g (26.0%); Mp = 131-136 ° C. 1 H-NMR (200 MHz, CDCl 3): δ 7.56 to 7.01 (m, 5H, aryl-H), 6.69 to 6.72 (m, IH, aryl-H), 2.84 (s, broad, IH, OH), 2.41 (s, 3H, SCH 3), 1,98- 0.95 (m, 10H, cyclohexanol). 13 C-NMR (50 MHz, CDCl 3): δ 129.5, 128.6, 126.7, 124.7, 124.6, 122.9, 72.0, 37.2, 25.2, 21 , 7, 14,4. MS: m / z 288 (M + , 20%), 241 (100%).
Beispiel 5Example 5
l-[l-[4-(Methylsulfonyl)phenyl]-lÄ-2-imidazolyl]-l-cyclohexanoll- [l- [4- (methylsulfonyl) phenyl] -lÄ-2-imidazolyl] -l-cyclohexanol
Die Vorstufe l-[l-[4-(Methylsulfanyl)phenyl]-lH"-2-imidazolyl]-l-cyclohexanol wurde aus 2 mmol (0,380 g) l-(4-Methylsulfanyl)ρhenyl-lH-imidazol [1], 2,2 mmol (1,4 ml 1,6 M- Lösung) Butyllithium und 2,4 mmol (0,25 ml) Cyclohexanon hergestellt. Das Rohprodukt wird aus Ethanol umkristallisiert. Ausbeute: 0,288 g (50%); Fp = 122-143°C. 1H-NMR (200 MHz, CDCl3): δ 7,36-7,17 (m, 4H, Aryl-H), 7,03-6,93 (m, IH, Aryl-H), 6,90-6,80 (m, IH, Aryl-H), 2,74 (s, IH, OH), 2,53 (s, 3H, S-CH3), 1,96-1,02 (m, 10H, Cyclohexanol). 13C- NMR (50 MHz, CDCl3): δ 152,7, 139,7, 136,1 , 127,9, 126,0, 123,9, 71,7, 37,3, 25,2, 21,8, 15,4. MS: m/z 288 (M+, 53%), 245 (100%).The precursor l- [l- [4- (methylsulfanyl) phenyl] -lH "-2-imidazolyl] -l-cyclohexanol was prepared from 2 mmol (0.380 g) l- (4-methylsulfanyl) ρhenyl-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). δ 7.36-7.17 (m, 4H, aryl-H), 7.03 to 6.93 (m, IH, aryl H), 6.90-6.80 (m, IH, aryl-H), 2.74 (s, IH, OH), 2.53 (s, 3H, S-CH 3), 1.96 to 1 02 (m, 10H, cyclohexanol) 13 C NMR (50 MHz, CDCl 3). δ 152.7, 139.7, 136.1, 127.9, 126.0, 123.9, 71.7 , 37.3, 25.2, 21.8, 15.4 MS: m / z 288 (M + , 53%), 245 (100%).
Zur Herstellung der Verbindung der Formel VII wurden in einem 100 ml Birnenkolben 1 mmol (0,288 g) l-[l-[4-(Methylsulfanyl) phenyl]-l/f-2-imidazolyl]-l-cyclohexanol in 15 ml Methanol gelöst. Danach wurden 2 mmol (1,23 g) Oxone®, gelöst in 10 ml Wasser, zugetropft. Nach einer Stunde Rühren wurden 13 ml 10%-ige NH3 -Lösung zugegeben und eine weitere Stunde gerührt. Das Methanol wurde am Rotavapor abdestilliert, die wässrige Phase mehrmals mit Ethylacetat extrahiert, dann die vereinigten organischen Phasen getrocknet und schließlich einrotiert. Das Rohprodukt wurde noch aus Ethanol umkristallisiert. Ausbeute: 0,292 g (91%); Fp = 148-163°C. 1H-NMR (200 MHz, CDCl3): δ 8,07-7,96 (m, 2H, Aryl-H), 7,74-7,62 (m, 2H, Aiyl-H), 7,02 (s, IH, Aryl-H), 6,91 (s, IH, Aryl-H), 3,13 (s, 3H, SO2-CH3), 2,71 (s, IH, OH), 2,03-1,11 (m, 10H, Cyclohexanol). 13C- NMR (50 MHz, CDCl3): δ 152,4, 144,1, 140,1, 128,4, 127,4, 126,3, 123,7, 70,6, 43,3, 37,3, 25,1, 21,6. MS: m/z 320 (M+, 23%), 277 (100%). Beispiel 6To prepare the compound of the formula VII, 1 mmol (0.288 g) of 1- [1- [4- (methylsulfanyl) phenyl] -1 / 2-imidazolyl] -1-cyclohexanol was dissolved in a 100 ml pear-shaped flask Dissolved 15 ml of methanol. Thereafter, 2 mmol (1.23 g) of Oxone® dissolved in 10 ml of water was added dropwise. After one hour of stirring, 13 ml of 10% NH 3 solution was added and stirred for an additional hour. The methanol was distilled off on a rotary evaporator, the aqueous phase was extracted several times with ethyl acetate, then the combined organic phases were dried and finally concentrated by rotary evaporation. The crude product was recrystallized from ethanol. Yield: 0.292 g (91%); Mp = 148-163 ° C. 1 H-NMR (200 MHz, CDCl 3): δ 8.07 to 7.96 (m, 2H, aryl-H), 7.74 to 7.62 (m, 2H, Aiyl-H), 7.02 (s, IH, aryl-H), 6.91 (s, IH, aryl-H), 3.13 (s, 3H, SO 2 -CH 3 ), 2.71 (s, IH, OH), 2 , 03-1.11 (m, 10H, cyclohexanol). 13 C-NMR (50 MHz, CDCl 3 ): δ 152.4, 144.1, 140.1, 128.4, 127.4, 126.3, 123.7, 70.6, 43.3, 37 , 3, 25, 1, 21.6. MS: m / z 320 (M + , 23%), 277 (100%). Example 6
2-(l-Cyclohexenyl)-l-[4-(methylsulfonyl)phenyl]-li?-imidazol2- (l-cyclohexenyl) -l- [4- (methylsulfonyl) phenyl] -li? -Imidazole
Zur Herstellung der Verbindung der Formel VIII wurden in einem Dreihalskolben 1 mmol (0,320 g) l-[l-[4-(Methylsulfonyl)phenyl]-lH-2-imidazolyl]-l-cyclohexanol in einer Mischung aus 7,5 ml Acetanhydrid und 15 ml Eisessig gelöst und eine Stunde bei 130°C gerührt. Das Lösungsmittel wurde abdestilliert und der Rückstand aus Ethanol umkrstallisiert. Ausbeute: 0,209 g (69%); Fp = 140-142°C. 1H-NMR (200 MHz, CDCl3): δ 8,14-7,94 (m, 2H, Aryl-H), 7,64-7,44 (m, 2H, Aryl-H), 7,20-7,10 (m, IH, Aryl-H), 7,09-6,97 (m, IH, Aryl-H), 5,83-5,70 (m, IH, Olefm-H), 3,13 (s, 3H, CH3), 2,38-2,18 (m, 2H, Cyclohexenyl-CH2), 2,12-1,93 (m, 2H, Cyclohexenyl-CH2), 1,76-1,48 (m, 4H, Cyclohexenyl-CH2). 13C-NMR (50 MHz, CDCl3): δ 148,7, 143,4, 139,5, 132,7, 128,9, 128,8, 127,8, 125,8, 121,1, 44,4, 27,3, 25,4, 22,3, 21,5. MS: m/z 302 (M+, 81%), 301 (100%).To prepare the compound of the formula VIII, 1 mmol (0.320 g) of 1- [1- [4- (methylsulfonyl) phenyl] -1H-2-imidazolyl] -1-cyclohexanol in a three-necked flask was dissolved in a mixture of 7.5 ml of acetic anhydride and 15 ml of glacial acetic acid and stirred at 130 ° C for one hour. The solvent was distilled off and the residue was recrystallized from ethanol. Yield: 0.209 g (69%); Mp = 140-142 ° C. 1 H-NMR (200 MHz, CDCl 3): δ 8.14 to 7.94 (m, 2H, aryl-H), 7.64 to 7.44 (m, 2H, aryl-H), 7.20 -7.10 (m, IH, aryl-H), 7.09-6.97 (m, IH, aryl-H), 5.83-5.70 (m, IH, Olefm-H), 3, 13 (s, 3H, CH 3), 2.38 to 2.18 (m, 2H, cyclohexenyl-CH 2), 2.12 to 1.93 (m, 2H, cyclohexenyl-CH 2), 1,76- 1.48 (m, 4H, cyclohexenyl CH 2 ). 13 C-NMR (50 MHz, CDCl 3): δ 148.7, 143.4, 139.5, 132.7, 128.9, 128.8, 127.8, 125.8, 121.1, 44 , 4, 27, 3, 25, 4, 22, 3, 21, 5. MS: m / z 302 (M + , 81%), 301 (100%).
Messung der Inhibitorwirkung der Verbindungen der allgemeinen Formel IMeasurement of the inhibitory effect of the compounds of general formula I.
COX (humaner) Inhibitor Screening Assay:COX (Human) Inhibitor Screening Assay:
Es wurde ein Immunoassay der Firma IBL Produkte, Hamburg, Deutschland, für die Bestimmung der COX-I und COX-II- Aktivitäten verwendet. Der Assay bestimmt quantitativ die Prostaglandine F, E und D sowie Thromboxan B-artige Prostaglandine, die durch die Cyclooxygenase-Reaktion gebildet werden. COX-I und COX-II wurden als sogenannte IC50, 50% Enzym-Hemmung, d.h. die Substanzkonzentration, welche 50% des gemessenen Isoenzyms hemmt, angegeben. Tabelle 1 : COX-Inhibitoren - IC50 [μM]An immunoassay from IBL Products, Hamburg, Germany, was used for the determination of COX-I and COX-II activities. The assay quantifies prostaglandins F, E and D as well as thromboxane B-like prostaglandins formed by the cyclooxygenase reaction. 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 [μM]
Figure imgf000010_0001
Figure imgf000010_0001
Wie aus der Tabelle ersichtlich, zeigen die erfindungsgemäßen Verbindungen eine gute bis hohe Selektivität für COX-I und kaum hemmende Wirkungen gegenüber COX-II. As can be seen from the table, the compounds according to the invention show a good to high selectivity for COX-I and hardly any inhibitory effects on COX-II.

Claims

Patentansprüche : Claims:
1. Verbindung der allgemeinen Formel I1. Compound of general formula I.
Figure imgf000011_0001
Figure imgf000011_0001
wobei R1 ein Rest gemäß Formel IIa oder IIb ist, wobei n = 1, 2 oder 3,where R 1 is a radical according to formula IIa or IIb, where n = 1, 2 or 3,
Figure imgf000011_0002
Figure imgf000011_0002
und R2 Wasserstoff, Ci-C4-Alkyl, CrC4-Alkyloxy, CrC4-Alkylthio oder C1-C4- Alkylsulfonyl ist.alkylsulfonyl - and R 2 is hydrogen, Ci-C 4 alkyl, C r C 4 alkyloxy, C r C 4 alkylthio or C 1 -C 4 alkyl.
2. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass R1 ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methoxygruppe ist (Formel III).2. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIa, where n = 2, and R 2 is a methoxy group (formula III).
Figure imgf000011_0003
Figure imgf000011_0003
3. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass R1 ein Rest gemäß Formel IIa ist, wobei n = 1, und R2 eine Methoxygruppe ist (Formel IV).3. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIa, where n = 1, and R 2 is a methoxy group (formula IV).
Figure imgf000012_0001
Figure imgf000012_0001
4. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass R1 ein Rest gemäß Formel IIa ist, wobei n = 3, und R2 eine Methoxygruppe ist (Formel V).4. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIa, where n = 3, and R 2 is a methoxy group (formula V).
Figure imgf000012_0002
Figure imgf000012_0002
5. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass R1 ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methylsulf anylgruppe ist (Formel VI).5. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIa, where n = 2, and R 2 is a methylsulfanyl group (formula VI).
Figure imgf000012_0003
Figure imgf000012_0003
6. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass R1 ein Rest gemäß Formel IIa ist, wobei n = 2, und R2 eine Methylsulfonylgruppe ist (Formel VII).6. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIa, where n = 2, and R 2 is a methylsulfonyl group (formula VII).
Figure imgf000013_0001
Figure imgf000013_0001
7. Verbindung nach Anspruch 1, dadurch gekennzeichnet, däss R1 ein Rest gemäß Formel IIb ist, wobei n = 2, und R2 eine Methylsulfonylgruppe ist (Formel VIII).7. A compound according to claim 1, characterized in that R 1 is a radical according to formula IIb, where n = 2, and R 2 is a methylsulfonyl group (formula VIII).
Figure imgf000013_0002
Figure imgf000013_0002
8. Verbindung gemäß einem der Ansprüche 1 bis 7 als Arzneimittel.8. A compound according to any one of claims 1 to 7 as a medicament.
9. Verwendung einer Verbindung gemäß einem der Ansprüche 1 bis 7 zur Herstellung eines Arzneimittels mit COX-I-Inhibitorwirkung. 9. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament with COX-I inhibitor activity.
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