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WO2009117985A1 - Pirinixic acid derivatives as prostglandin e2 synthesis inhibitors for treating inflammatory diseases - Google Patents

Pirinixic acid derivatives as prostglandin e2 synthesis inhibitors for treating inflammatory diseases Download PDF

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Publication number
WO2009117985A1
WO2009117985A1 PCT/DE2009/000373 DE2009000373W WO2009117985A1 WO 2009117985 A1 WO2009117985 A1 WO 2009117985A1 DE 2009000373 W DE2009000373 W DE 2009000373W WO 2009117985 A1 WO2009117985 A1 WO 2009117985A1
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rule
pirinixic
pge
replacement blade
heteroaryl
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PCT/DE2009/000373
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German (de)
French (fr)
Inventor
Oliver Werz
Andreas Koeberle
Manfred Schubert-Zsilavecz
Laura Popescu
Yvonne Syha
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Medeon Pharmaceuticals Gmbh
Universität Tübingen
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Application filed by Medeon Pharmaceuticals Gmbh, Universität Tübingen filed Critical Medeon Pharmaceuticals Gmbh
Publication of WO2009117985A1 publication Critical patent/WO2009117985A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to derivatives of pirinixic acid (WY14643), in particular ⁇ -substituted pirinixic acids, pirinixic acid derivatives in which the ortho-xyloyl ring is replaced by other substituents, in particular a Aminomethylbiphenylring, and their structural derivatives, such as esters, and their use for the inhibition of inducible microsomal prostaglandin E 2 synthase-1, in particular for the production of a medicament for the treatment of prostaglandin E 2 -mediated diseases.
  • the present patent application claims the following priority: DE 102008 015432.6 (filing date: 22.03.2008).
  • Prostaglandin biosynthesis is initiated by the initial steps of converting arachidonic acid to prostaglandin (PG) H 2 through cyclooxygenase (COX) -I or -2 ( Figure 1).
  • Certain PGs, including PGE 2 are mediators in inflammation (especially rheumatoid arthritis), pain and fever, and are also involved in cancers (lung, colon, endometrium), other PGs 1 like PGI 2 but also PGE 2 itself , on the other hand, fulfill important physiological functions [1, 2].
  • Inhibitors of COX-1 and -2 thus prevent the synthesis of all PGs and have considerable side effects due to the lack of physiologically important PGs (such as PGF 2 ( X , PGI 2 , PGD 2 ) and due to the PGE 2 deficiency in the gastric mucosa (stomach, kidney , cardiovascular system) [3, 4].
  • the inducible microsomal prostaglandin E 2 synthase-1 (mPGES-1) is a member of the MAPEG family and catalyzes the conversion of PGH 2 to PGE 2 ( Figure 1) [5].
  • mPGES-1 mPGES-2 and cytosolic (c) PGES are known as PGE 2 synthases [6].
  • mPGES-1 is linked to COX-2 activity and expression of both enzymes is simultaneously induced by inflammation-relevant stimuli (interleukin-1 ⁇ , tumor microsphere factor ⁇ ) [7].
  • the COX-1 provides PGH 2 as substrate for the cPGES, and Both enzymes are constitutively expressed.
  • PGE 2 In contrast to the physiologically necessary PGs, PGE 2 , which is locally synthesized by COX-2 / mPGES-1, has pronounced pathophysiological properties (inflammation, pain, fever, cancers, angiogenesis, anorexia) [7]. In contrast, the gastric mucosal protective PGE 2 is produced by the COX-1 / cPGES directly in the stomach.
  • the object of the present invention is therefore to circumvent the disadvantages of the known processes (use of inhibitors of COX enzymes and their side effects), and to identify active substances and pharmaceutical preparations which are able to selectively inhibit the mPGES-1.
  • These agents are said to be used in the manufacture of a medicament for the therapeutic treatment of PGE 2 - mediated diseases, especially rheumatoid arthritis, are provided to have low side effects at high efficiency.
  • pirinixic acid derivatives in particular ⁇ -substituted pirinixic acids and pirinixic acid esters and their structural derivatives, as described in claim 1.
  • Preferred embodiments are mentioned in the dependent claims 2 to 10.
  • Pirinixic acid (Wy-14643, see FIG. 2) belongs structurally and functionally to the class of lipid-lowering fibrates which are used therapeutically, above all, in disorders of the lipid metabolism. Pirinixic acid has been identified as a potent ligand and activator of the peroxisome proliferator-activated receptor (PPAR) - ⁇ , to which other fibrates also bind and activate [10]. Pirinixic acid itself (up to 100 ⁇ M) has no significant inhibitory effect on mPGES-1 or PGE 2 synthesis.
  • PPAR peroxisome proliferator-activated receptor
  • pirinixic acid derivatives have been identified which are capable of inhibiting mPGES-1.
  • Pirinixinklare derivatives successfully tested which carry in ⁇ -position to the carboxyl function an n-alkyl radical, in particular an n-hexyl radical, or aryl radical. (For the synthesis of these pirinixic acid derivatives, see [11])
  • Table 1 contains some examples of the pirinixic acid derivatives for which an inhibitory effect on the PGE 2 synthesis could be demonstrated according to the invention.
  • Table 1 Examples of pirinixic acid derivatives which have an inhibiting effect on PGE 2 synthesis.
  • pirinixic acid derivatives intervene very strongly in the biosynthesis of the eicosanoids, in particular in the synthesis of the prostaglandin E 2 .
  • This is based on an inhibition of the catalytic activity of the human mPGES-1 (conversion of PGH 2 to PGE 2 ), as can be seen from the embodiments.
  • the IC 50 values are in the range of about 1-10 ⁇ M.
  • pirinixic acid derivatives in particular ⁇ -substituted pirinixic acids and their derivatives, should be regarded as direct inhibitors of mPGES-1 or inhibitors of PGE 2 synthesis.
  • ⁇ -alkyl substituted pirinixic acid derivatives are used to inhibit mPGES-1.
  • pirinixic acid derivatives are used for the inhibition of mPGES-1, in which the ortho-xyloyl ring is replaced by other substituents, in particular by a quinoline ring or by an amino (methyl) biphenyl radical.
  • the invention encompasses the use of preparations for inhibiting PGE 2 synthesis, in particular for inhibiting mPGES-1, which preparations comprise at least one derivative of pirinixic acid and / or one of its esters having the following structural formula:
  • R 1 is an aryl, heteroaryl, alkylaryl or alkylheteroaryl which is attached via a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or alkyl group to the remainder of the molecule, where the aryl, heteroaryl, alkylaryl or Alkylheteroaryl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, alkylaryl or alkylheteroaryl may be substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2 , NO 2, SH, (Ci-ioJAlkyl, (C 2-1 o) alkenyl, (C 2- io) alkynyl, OCF 3, (Ci-io) alkoxy, (Ci.ioJAlkylamin, (Ci-io) alkylthio, (C .io) alkylsilyl,
  • R 2 is a lipophilic radical which is greater than an ethyl radical and R 3 is a hydrogen or a lipophilic radical.
  • R3 may be a linear or branched (Ci-io) alkyl.
  • the lipophilicity of the compounds according to the invention can be represented by the K O w value (distribution coefficient in an octanol / water system at room temperature) or its decadic logarithm.
  • the radicals R2 and R3 are
  • Preferred embodiments of the invention have a log Kow greater than zero.
  • Particularly preferred embodiments of the invention have a log Kow greater than 2.
  • Very particularly preferred embodiments of the invention have a log Kow greater than 4.
  • R2 is an aryl, heteroaryl, alkylaryl, alkylheteroaryl, a linear or branched (Ci -10 ) AlkVl 1 C ( 2- io) alkenyl or C ( 2 -io) alkynyl, wherein a or several H atoms in these radicals can be eliminated or substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2 , NO 2 , SH, (C 1 -ol) AlCl yI, (C 2 - io) alkenyl, (C 2-10) alkynyl, (Ci-10) alkoxy, (Ci-10) alkylamino, (C -10) alkylthio, (C -10) alkylsilyl, (C 3 -io) cycloalkyl, (C 3 -io) ⁇ cycloalkenyl, (C 3-10
  • R 2 is an isopropyl, a phenyl, a naphthyl or a (C 5-10 ) alkyl radical.
  • R1 is a (indan-4-ylamino) -, a (2,3-dimethyl-phenylamino) -, a (quinolin-6-ylamino) -, a (quinolin-6-yloxo ), a (quinolin-6-yl-methylamino) or a [3,5-bis (2,2,2-trifluoro-ethoxy) -phenylamino] radical.
  • the compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form.
  • stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the invention may be present, which are also subject of the invention.
  • the above-mentioned substances are generally used for the inhibition of PGE 2 synthesis, in particular for the inhibition of mPGES-1, for example in cell cultures.
  • the above-mentioned pirinixic acid derivatives are used for the preparation of a medicament for the treatment of PGE 2 -mediated Used diseases.
  • the PGE 2 -mediated diseases are, in particular, inflammations and cancers.
  • the medicament may further contain a pharmaceutical carrier material.
  • the present invention therefore teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way.
  • Free carboxylic acid groups can also be used in the form of their salts with physiologically acceptable counterions, e.g. Mg ++, Ca ++, Na +, K +, Li + or ammonium derivatives such as cyclohexylammonium.
  • Amino-containing compounds may also be in the form of an ammonium salt, e.g. as chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate, fumarate or tartrate.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), forms of preparation for Dry powder inhalation, transdermal systems as well as preparations with sustained-release release, in the production of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used.
  • excipients examples include magnesium carbonate, titanium dioxide, lactose, manidine and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and to the desired dosage form is prepared.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • this dose may be from 0.1 to 1000 mg, preferably from 10 to 50 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 10 to 40 mg.
  • the preparation of infusion solutions is another preferred embodiment.
  • daily doses for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active substance, preferably 10-500 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
  • plasma concentrations of about 0.5 - 10 uM pirinixic acid derivative are desirable, which could be about the po dose of about 25 - 500 mg / day.
  • the advantage of the present invention is that basic structures have been identified for the drug target mPGES-1 with pirinixic acid derivatives, which lead to the inhibition of the activity of mPGES-1.
  • the synthesis of PGE 2 can be selectively inhibited by COX-2 / mPGES-1, without inhibiting, as previously by inhibitors of COX-1 and -2, the synthesis of other (physiologically important) PGs.
  • the therapy of PGE 2 -mediated diseases by means of pirinixic acid derivatives has fewer side effects compared to COX-1/2 inhibitors. Because COX 2 inhibitors are withdrawn from the market because of their side effects (rofecoxib) or not approved was (etoricoxib) can be used by the method presented here representatively and also advantageous.
  • the present invention has the advantage that due to the mPGES-1 inhibition, pirinixic acid derivatives can be used specifically for inflammatory diseases that are attributable to an increased formation of PGE 2 .
  • Another advantage compared to the use of other inhibitors of mPGES-1 or PGE 2 synthesis in general is that the Pirinixinkladerivate additionally activate PPAR ⁇ and thus synergistic effects are expected in terms of anti-inflammatory.
  • the use or the dose of non-steroidal anti-inflammatory drugs (COX inhibitors) can be reduced and the duration of administration can be shortened, which leads to considerable side effects because of their unspecific blockade of the synthesis of all PGs.
  • the invention can be used to treat all forms of diseases associated with increased production of PGE 2 . These are primarily pain of all kinds (mild, moderate and severe pain, inflammatory diseases (especially rheumatoid arthritis and osteoarthritis), feverish and painful conditions, cardiovascular events, anorexia, multiple sclerosis and cancers in which PGE 2 plays a role ,
  • FIG. 1 Biosynthetic pathway of PGE 2 ; FIG.
  • Fig. 2 Structures of selected pirinixic acid derivatives
  • A549 cells were incubated with interleukin-1 ⁇ (1 ng / ml) for 72 hours. After harvesting and cell count determination, the pelleted cells were flash-frozen on dry ice / ethanol, thawed again by adding 1 ml of homogenization buffer (4 ° C.) and homogenized by means of ultrasound. After centrifugation (10,000 g for 10 min at 4 0 C) of the resulting supernatant at 174.000g and 4 0 C was for 1 h hour centrifuged to obtain microsomes. The pellet (microsomes) was dissolved in the homogenization buffer and preincubated with the test substances (pirinixic acid derivatives or DMSO) for 10 min at 4 ° C. in 96-well plates.
  • test substances pirinixic acid derivatives or DMSO
  • PGH 2 was added as a substrate and the reaction after 1 min at 4 0 C by means of stop solution (containing, inter alia, Fe 2+ , citric acid and 11 -B-PGE 2 as a standard) ended.
  • stop solution containing, inter alia, Fe 2+ , citric acid and 11 -B-PGE 2 as a standard
  • a batch is added to the stop solution before the start of the reaction to detect PGE 2 already contained in the PGH 2 solution.
  • solid phase extraction RP-18 columns and acetonitrile as eluent
  • the sample was analyzed by HPLC (RP-18, UV detection at 190 nm).

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Abstract

The invention relates to pirinixic acid derivatives, especially α-substituted pirinixic acids and pirinixic acid esters, and the structural derivatives thereof with the following structural formula. The pirinixic acid derivatives inhibit the PGE2 synthesis, especially that of the mPGES-1. The invention also relates to the use of said pirinixic acid derivatives for producing a medicament for treating prostaglandin E2-mediated diseases, especially inflammatory diseases, painful and feverish conditions, cardiovascular events and cancerous diseases associated with an increased inducible microsomal prostaglandin E2 synthesis-1 (mPGES-1) activity or increased prostaglandin E2 synthesis.

Description

PIRINIXINSÄURE-DERIVATE ALS PROSTAGLANDIN E2 SYNTHESE INHIBITOREN ZUR BEHANDLUNG VON ENTZÜNDLICHEN ERKRANKUNGEN PIRINIXIC ACID DERIVATIVES AS PROSTAGLANDIN E2 SYNTHESIS INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES
Beschreibungdescription
Die vorliegende Erfindung betrifft Derivate der Pirinixinsäure (WY14643), insbesondere α-substituierte Pirinixinsäuren, Pirinixinsäure-Derivate, bei denen der ortho-Xyloyl-Ring durch andere Substituenten, insbesondere einen Aminomethylbiphenylring, ersetzt ist, sowie deren strukturelle Abkömmlinge, wie z.B. Ester, und deren Anwendung zur Hemmung der induzierbaren mikrosomalen Prostaglandin E2 Synthase-1 , insbesondere zur Herstellung eines Arzneimittels zur Behandlung von Prostaglandin E2-vermittelten Erkrankungen. Die vorliegende Patentanmeldung nimmt folgende Priorität in Anspruch: DE 102008 015432.6 (Anmeldetag:22.03.2008).The present invention relates to derivatives of pirinixic acid (WY14643), in particular α-substituted pirinixic acids, pirinixic acid derivatives in which the ortho-xyloyl ring is replaced by other substituents, in particular a Aminomethylbiphenylring, and their structural derivatives, such as esters, and their use for the inhibition of inducible microsomal prostaglandin E 2 synthase-1, in particular for the production of a medicament for the treatment of prostaglandin E 2 -mediated diseases. The present patent application claims the following priority: DE 102008 015432.6 (filing date: 22.03.2008).
Die Prostaglandinbiosynthese wird durch die initialen Schritte der Umwandlung von Arachidonsäure zu Prostaglandin (PG)H2 durch die Cyclooxygenase (COX)-I oder -2 eingeleitet (Fig. 1). Gewisse PGs, dazu gehörend das PGE2, sind Mediatorstoffe bei Entzündungen (v.a. rheumatoide Arthritis), Schmerz und Fieber, und sind des Weiteren bei Krebserkrankungen (Lunge, Kolon, Endometrium) beteiligt, andere PGs1 wie PGI2 aber auch das PGE2 selbst, erfüllen dagegen wichtige physiologische Funktionen [1 , 2]. Hemmstoffe der COX-1 und -2 unterbinden damit die Synthese aller PGs und weisen aufgrund des Mangels physiologisch wichtiger PGs (wie PGF2(X, PGI2, PGD2) und aufgrund des PGE2 Mangels in der Magenmucosa beträchtliche Nebenwirkungen (Magen, Niere, kardiovaskuläres System) auf [3, 4].Prostaglandin biosynthesis is initiated by the initial steps of converting arachidonic acid to prostaglandin (PG) H 2 through cyclooxygenase (COX) -I or -2 (Figure 1). Certain PGs, including PGE 2 , are mediators in inflammation (especially rheumatoid arthritis), pain and fever, and are also involved in cancers (lung, colon, endometrium), other PGs 1 like PGI 2 but also PGE 2 itself , on the other hand, fulfill important physiological functions [1, 2]. Inhibitors of COX-1 and -2 thus prevent the synthesis of all PGs and have considerable side effects due to the lack of physiologically important PGs (such as PGF 2 ( X , PGI 2 , PGD 2 ) and due to the PGE 2 deficiency in the gastric mucosa (stomach, kidney , cardiovascular system) [3, 4].
Die induzierbare mikrosomale Prostaglandin E2 Synthase-1 (mPGES-1) ist Mitglied der MAPEG Familie und katalysiert die Umwandlung von PGH2 zu PGE2 (Fig. 1) [5]. Neben der mPGES-1 sind die mPGES-2 und die cytosolische (c)PGES als PGE2 Synthasen bekannt [6]. Interessanterweise ist die mPGES-1 an die Aktivität der COX-2 gekoppelt und die Expression beider Enzyme wird durch entzündungsrelevante Stimuli (lnterleukin-1ß, Tumomekrosisfaktor α) zeitgleich induziert [7]. Die COX-1 dagegen stellt PGH2 als Substrat für die cPGES bereit und beide Enzyme werden konstitutiv exprimiert. Das von der COX-2/mPGES-1 lokal synthetisierte PGE2 weist im Gegensatz zu den physiologisch notwendigen PGs ausgeprägte pathophysiologische Eigenschaften (Entzündung, Schmerz, Fieber, Krebserkrankungen, Angiogenese, Anorexie) auf [7]. Dagegen wird das für die Magenmucosa protektive PGE2 von der COX-1/cPGES direkt im Magen produziert.The inducible microsomal prostaglandin E 2 synthase-1 (mPGES-1) is a member of the MAPEG family and catalyzes the conversion of PGH 2 to PGE 2 (Figure 1) [5]. In addition to mPGES-1, mPGES-2 and cytosolic (c) PGES are known as PGE 2 synthases [6]. Interestingly, mPGES-1 is linked to COX-2 activity and expression of both enzymes is simultaneously induced by inflammation-relevant stimuli (interleukin-1β, tumor microsphere factor α) [7]. The COX-1, on the other hand, provides PGH 2 as substrate for the cPGES, and Both enzymes are constitutively expressed. In contrast to the physiologically necessary PGs, PGE 2 , which is locally synthesized by COX-2 / mPGES-1, has pronounced pathophysiological properties (inflammation, pain, fever, cancers, angiogenesis, anorexia) [7]. In contrast, the gastric mucosal protective PGE 2 is produced by the COX-1 / cPGES directly in the stomach.
Seit Entdeckung der mPGES-1 im Jahre 1999 ist man bestrebt, potente und selektive Hemmstoffe gegen die mPGES-1 zu entwickeln, um die PGE2 Synthese bei entzündlichen Vorgängen selektiv zu inhibieren, ohne dabei die Bildung der physiologisch wichtigen PGs und des im Magen protektiven PGE2 zu unterdrücken [8]. Weiterhin könnte dadurch im Gegensatz zu selektiven COX-2 Inhibitoren (sog. Coxibe wie z.B. Rofecoxib oder Celecoxib) die Suppression des vasodilatorischen PGI2 durch selektiven pharmakologischen Angriff an der mPGES-1 vermieden werden. So führen selektive COX-2 Inhibitoren in Langzeitstudien (> 18 Monate) zu kardiovaskulären Schäden, einhergehend mit erhöhter Mortalitätsrate. Rofecoxib (VIOXX®) wurde deshalb vom Markt genommen, die Zulassung von Etoricoxib ist gescheitert. Im Gegensatz dazu weisen Forschungsergebnisse mit mPGES-1 knockout Mäusen auf positive Effekte hinsichtlich kardiovaskulärer Ereignisse hin [9]. Zu begründen ist dieser vorteilhafte Effekt damit, dass durch die selektive Verminderung der PGE2-Bildung die Prostacyclinsynthese (im Gegensatz zur COX-Hemmung) nicht negativ beeinflusst wird und somit die vasodilatorische Komponente der PGs aufrechterhalten bleibt. Dies macht die mPGES-1 zu einem hochinteressanten Arzneistoff-Target, v.a. bei entzündlichen Erkrankungen (z.B. rheumatoide Arthritis), die mit Schmerz oder auch mit Fieber einhergehen, aber auch bei diversen Krebserkrankungen. Zudem sind kardiovaskuläre Nebenwirkungen durch mPGES-1 Inhibitoren nicht zu erwarten. Allerdings ist bislang kein Inhibitor der mPGES-1 als Arzneimittel zur Therapie zugelassen, und die Anzahl verfügbarer Hemmstoffe (wie z.B. MK-886) ist derzeit äußerst gering und sie stehen noch am Anfang der klinischen Prüfung. Die Motivation der pharmazeutischen Forschung sichere und selektive Hemmstoffe der mPGES-1 zu finden ist enorm.Since the discovery of mPGES-1 in 1999, efforts have been made to develop potent and selective mPGES-1 inhibitors to selectively inhibit PGE 2 synthesis in inflammatory processes, without the formation of physiologically important PGs and gastric protective agents Suppress PGE 2 [8]. Furthermore, in contrast to selective COX-2 inhibitors (so-called coxibs such as rofecoxib or celecoxib), the suppression of the vasodilatory PGI 2 could be avoided by selective pharmacological attack on the mPGES-1. For example, selective COX-2 inhibitors in long-term studies (> 18 months) lead to cardiovascular damage, accompanied by an increased mortality rate. Rofecoxib (VIOXX ® ) was therefore withdrawn from the market, the approval of etoricoxib has failed. In contrast, research results with mPGES-1 knockout mice indicate positive effects on cardiovascular events [9]. This beneficial effect is justified by the fact that the selective reduction of PGE 2 formation does not adversely affect the prostacyclin synthesis (in contrast to the COX inhibition) and thus the vasodilatory component of the PGs is maintained. This makes the mPGES-1 to a highly interesting drug target, especially in inflammatory diseases (eg rheumatoid arthritis), which are associated with pain or with fever, but also in various cancers. In addition, cardiovascular side effects caused by mPGES-1 inhibitors are not expected. However, no inhibitor of mPGES-1 is currently approved as a drug for therapy, and the number of available inhibitors (such as MK-886) is currently extremely low and they are still at the beginning of the clinical trial. The motivation of pharmaceutical research to find safe and selective inhibitors of mPGES-1 is enormous.
Die Aufgabe der vorliegenden Erfindung ist es daher, die Nachteile der bekannten Verfahren (Einsatz von Hemmstoffen der COX Enzyme und deren Nebenwirkungen) zu umgehen, und Wirkstoffe und pharmazeutische Zubereitungen zu identifizieren, die in der Lage sind, die mPGES-1 selektiv zu hemmen. Diese Wirkstoffe sollen zur Herstellung eines Arzneimittels zur therapeutischen Behandlung von PGE2- vermittelten Erkrankungen, insbesondere rheumatoider Arthritis, bereitgestellt werden, um bei einer hohen Effizienz geringe Nebenwirkungen aufzuweisen.The object of the present invention is therefore to circumvent the disadvantages of the known processes (use of inhibitors of COX enzymes and their side effects), and to identify active substances and pharmaceutical preparations which are able to selectively inhibit the mPGES-1. These agents are said to be used in the manufacture of a medicament for the therapeutic treatment of PGE 2 - mediated diseases, especially rheumatoid arthritis, are provided to have low side effects at high efficiency.
Diese Aufgabe wird durch den Einsatz von Pirinixinsäurederivaten, insbesondere α-substituierte Pirinixinsäuren und Pirinixinsäureester sowie deren strukturellen Derivaten, gelöst, wie es im Anspruch 1 beschrieben ist. Bevorzugte Ausführungen sind in den abhängigen Ansprüchen 2 bis 10 genannt.This object is achieved by the use of pirinixic acid derivatives, in particular α-substituted pirinixic acids and pirinixic acid esters and their structural derivatives, as described in claim 1. Preferred embodiments are mentioned in the dependent claims 2 to 10.
Pirinixinsäure (Wy-14643, siehe Fig. 2) gehört strukturell und funktionell zur Klasse der Lipid-senkenden Fibrate, die v.a. bei Störungen des Lipidstoffwechsels therapeutisch eingesetzt werden. Pirinixinsäure wurde als potenter Ligand und Aktivator des Peroxisomen Proliferator-aktivierten Rezeptors (PPAR)-α identifiziert, an den auch andere Fibrate binden und aktivieren [10]. Pirinixinsäure selbst (bis 100 μM) hat keinen signifikanten Hemmeffekt auf die mPGES-1 bzw. die PGE2- Synthese.Pirinixic acid (Wy-14643, see FIG. 2) belongs structurally and functionally to the class of lipid-lowering fibrates which are used therapeutically, above all, in disorders of the lipid metabolism. Pirinixic acid has been identified as a potent ligand and activator of the peroxisome proliferator-activated receptor (PPAR) -α, to which other fibrates also bind and activate [10]. Pirinixic acid itself (up to 100 μM) has no significant inhibitory effect on mPGES-1 or PGE 2 synthesis.
In der vorliegenden Erfindung wurden Pirinixinsäure-Derivate identifiziert, die in der Lage sind, die mPGES-1 zu hemmen. Es wurden z.B. Pirinixinsäure-Derivate erfolgreich getestet, die in α-Stellung zur Carboxylfunktion einen n-Alkyl-Rest, insbesondere einen n-Hexyl-Rest, oder Aryl-Rest tragen. (Zur Synthese dieser Pirinixinsäure-Derivate s. [11])In the present invention, pirinixic acid derivatives have been identified which are capable of inhibiting mPGES-1. For example, Pirinixinsäure derivatives successfully tested, which carry in α-position to the carboxyl function an n-alkyl radical, in particular an n-hexyl radical, or aryl radical. (For the synthesis of these pirinixic acid derivatives, see [11])
Zudem wurden weitere Pirinixinsäure-Derivate identifiziert, die die Synthese der mPGES-1 hemmen. Bei diesen Pirinixinsäure-Derivaten ist der ortho-Xyloyl-Ring durch andere Substituenten, insbesondere einen Chinolin-Ring, ersetzt. (Zur Synthese dieser Pirinixinsäure-Derivate s. [11])In addition, other pirinixic acid derivatives have been identified that inhibit the synthesis of mPGES-1. In these pirinixic acid derivatives, the ortho-xyloyl ring is replaced by other substituents, in particular a quinoline ring. (For the synthesis of these pirinixic acid derivatives, see [11])
Tabelle 1 umfasst einige Beispiele der Pirinixinsäure-Derivate, für die erfindungsgemäß ein Hemmeffekt auf die PGE2-Synthese gezeigt werden konnte. Table 1 contains some examples of the pirinixic acid derivatives for which an inhibitory effect on the PGE 2 synthesis could be demonstrated according to the invention.
Tabelle 1: Beispiele der Pirinixinsäure-Derivate, die einen Hemmeffekt auf die PGE2- Synthese aufweisen.
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Table 1: Examples of pirinixic acid derivatives which have an inhibiting effect on PGE 2 synthesis.
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0001
In der vorliegenden Erfindung konnte gezeigt werden, dass Verbindungen dieser Pirinixinsäure-Derivate sehr potent in die Biosynthese der Eikosanoide, insbesondere in die Synthese des Prostaglandin E2 eingreifen. Dem liegt eine Hemmung der katalytischen Aktivität der humanen mPGES-1 (Umwandlung von PGH2 zu PGE2) zugrunde, wie aus den Ausführungsbeispielen ersichtlich ist. Die IC50 Werte liegen im Bereich von ca. 1 - 10 μM. Damit sind Pirinixinsäure-Derivate, insbesondere α-substituierte Pirinixinsäuren sowie deren Abkömmlinge, als direkte Hemmstoffe der mPGES-1 bzw. Hemmstoffe der PGE2 Synthese zu betrachten. Bislang sind weder Pirinixinsäure noch deren Derivate als Hemmstoffe der PGE2-Synthese beschrieben worden. Diese Befunde lassen den Schluss zu, dass Pirinixinsäure-Derivate ein hohes Potential zur Therapie entzündlicher Erkrankungen haben, vorzugsweise Entzündungen, die mit einer erhöhten Bildung von PGE2 einhergehen. Damit könnten durch Einsatz von Pirinixinsäurederivaten PGE2-vermittelte Erkrankungen behandelt werden, wobei im Gegensatz zu bisherigen Verfahren (COX-Hemmung) weniger Nebenwirkungen auftreten.In the present invention it has been possible to show that compounds of these pirinixic acid derivatives intervene very strongly in the biosynthesis of the eicosanoids, in particular in the synthesis of the prostaglandin E 2 . This is based on an inhibition of the catalytic activity of the human mPGES-1 (conversion of PGH 2 to PGE 2 ), as can be seen from the embodiments. The IC 50 values are in the range of about 1-10 μM. Thus, pirinixic acid derivatives, in particular α-substituted pirinixic acids and their derivatives, should be regarded as direct inhibitors of mPGES-1 or inhibitors of PGE 2 synthesis. So far, neither pirinic acid nor its derivatives have been described as inhibitors of PGE 2 synthesis. These findings suggest that pirinixic acid derivatives have a high potential for the treatment of inflammatory diseases, preferably inflammations associated with increased formation of PGE 2 . This could be treated by the use of Pirinixinsäurederivaten PGE 2 -mediated diseases, in contrast to previous methods (COX inhibition) fewer side effects occur.
In einer Ausführung der Erfindung werden α-Alkyl-substituierte Pirinixinsäure- Derivate zur Hemmung der mPGES-1 verwendet. In einer weiteren Ausführung der Erfindung werden Pirinixinsäure-Derivate zur Hemmung der mPGES-1 verwendet, bei denen der ortho-Xyloyl-Ring durch andere Substituenten, insbesondere durch einen Chinolin-Ring oder durch einen Amino(methyl)-biphenylrest, ersetzt ist.In one embodiment of the invention, α-alkyl substituted pirinixic acid derivatives are used to inhibit mPGES-1. In a further embodiment of the invention, pirinixic acid derivatives are used for the inhibition of mPGES-1, in which the ortho-xyloyl ring is replaced by other substituents, in particular by a quinoline ring or by an amino (methyl) biphenyl radical.
Die Erfindung umfasst die Verwendung von Zubereitungen zur Hemmung der PGE2 Synthese, insbesondere zur Hemmung der mPGES-1 , wobei diese Zubereitungen mindestens ein Pirinixinsäure-Derivat und / oder einen seiner Ester mit der folgenden Strukturformel enthalten:The invention encompasses the use of preparations for inhibiting PGE 2 synthesis, in particular for inhibiting mPGES-1, which preparations comprise at least one derivative of pirinixic acid and / or one of its esters having the following structural formula:
Figure imgf000012_0001
wobei R1 für ein Aryl, Heteroaryl, Alkylaryl oder Alkylheteroaryl steht, das über ein Stickstoff-, Sauerstoff- oder Kohlenstoffatom oder eine Aminoalkyl-, Oxoalkyl- oder Alkylgruppe an das Restmolekül geknüpft ist, wobei das Aryl-, Heteroaryl-, Alkylaryl- bzw. Alkylheteroaryl mit einem weiteren Ringsystem kondensiert sein kann, und ein oder mehrere H-Atome im Aryl, Heteroaryl, Alkylaryl bzw. Alkylheteroaryl substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (Ci-ioJAlkyl, (C2-1o)Alkenyl, (C2-io)Alkinyl, OCF3, (Ci-io)Alkoxy, (Ci.ioJAlkylamin, (Ci-io)Alkylthio, (Ci.io)Alkylsilyl, Cycloalkyl, Cycloalkenyl, Cycloheteroalkyl, Cycloheteroalkenyl, COOH, oder das korrespondierende Säureadditionssalz dieser Verbindung,
Figure imgf000012_0001
where R 1 is an aryl, heteroaryl, alkylaryl or alkylheteroaryl which is attached via a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or alkyl group to the remainder of the molecule, where the aryl, heteroaryl, alkylaryl or Alkylheteroaryl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, alkylaryl or alkylheteroaryl may be substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2 , NO 2, SH, (Ci-ioJAlkyl, (C 2-1 o) alkenyl, (C 2- io) alkynyl, OCF 3, (Ci-io) alkoxy, (Ci.ioJAlkylamin, (Ci-io) alkylthio, (C .io) alkylsilyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, COOH, or the corresponding acid addition salt of this compound,
R2 für einen lipophilen Rest steht, der größer als ein Ethyl-Rest ist, und R3 für einen Wasserstoff oder einen lipophilen Rest steht.R 2 is a lipophilic radical which is greater than an ethyl radical and R 3 is a hydrogen or a lipophilic radical.
Erfindungsgemäß werden insbesondere Substanzen mit einem lipophilen R3 Rest verwendet, damit die Substanzen für die Zelle eine ausreichende Membranpermeabilität aufweisen. Insbesondere kann R3 für ein lineares oder verzweigtes (Ci-io)Alkyl stehen.According to the invention, in particular substances with a lipophilic R 3 radical are used so that the substances for the cell have sufficient membrane permeability. In particular, R3 may be a linear or branched (Ci-io) alkyl.
Die Lipophilie der erfindungsgemäßen Verbindungen kann durch den KOw -Wert (Verteilungskoeffizient in einem Octanol/Wasser System bei Raumtemperatur) bzw. dessen dekadischen Logarithmus dargestellt werden. Die Reste R2 und R3 sindThe lipophilicity of the compounds according to the invention can be represented by the K O w value (distribution coefficient in an octanol / water system at room temperature) or its decadic logarithm. The radicals R2 and R3 are
ERSATZBLATT (REGEL 26) lipophil im Sinne dieser Patentanmeldung wenn der log Kow größer ist als -2. Bevorzugte Ausführungsformen der Erfindung weisen einen log Kow von größer 0 auf. Besonders bevorzugte Ausführungsformen der Erfindung weisen einen log Kow von größer 2 auf. Ganz besonders bevorzugte Ausführungsformen der Erfindung weisen einen log Kow von größer 4 auf.Replacement Blade (RULE 26) lipophilic in the sense of this patent application if the log Kow is greater than -2. Preferred embodiments of the invention have a log Kow greater than zero. Particularly preferred embodiments of the invention have a log Kow greater than 2. Very particularly preferred embodiments of the invention have a log Kow greater than 4.
In einer bevorzugten Ausführung werden Substanzen verwendet, bei denen R2 für ein Aryl, Heteroaryl, Alkylaryl Alkylheteroaryl, ein lineares oder verzweigtes (Ci-10)AIkVl1 C(2-io)Alkenyl oder C(2-io)Alkinyl steht, wobei ein oder mehrere H-Atome in diesen Resten eliminiert oder substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (Ci-Io)AIlCyI, (C2-io)Alkenyl, (C2-10)Alkinyl, (Ci-10)Alkoxy, (Ci-10)Alkylamin, (Ci-10)Alkylthio, (Ci-10)Alkylsilyl, (C3-io)Cycloalkyl, (C3-io)~Cycloalkenyl, (C3-10)-Cycloheteroalkyl, (C3-io)-Cycloheteroalkenyln COOH oder das korrespondierende Säureadditionssalz dieser Verbindung, und das Aryl, Heteroaryl, Alkylaryl bzw. Alkylheteroaryl mit einem weiteren Ringsystem kondensiert sein kann.In a preferred embodiment, substances are used in which R2 is an aryl, heteroaryl, alkylaryl, alkylheteroaryl, a linear or branched (Ci -10 ) AlkVl 1 C ( 2- io) alkenyl or C ( 2 -io) alkynyl, wherein a or several H atoms in these radicals can be eliminated or substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2 , NO 2 , SH, (C 1 -ol) AlCl yI, (C 2 - io) alkenyl, (C 2-10) alkynyl, (Ci-10) alkoxy, (Ci-10) alkylamino, (C -10) alkylthio, (C -10) alkylsilyl, (C 3 -io) cycloalkyl, (C 3 -io) ~ cycloalkenyl, (C 3-10 ) -cycloheteroalkyl, (C 3 -io) -cycloheteroalkenyl n COOH or the corresponding acid addition salt of this compound, and the aryl, heteroaryl, alkylaryl or alkylheteroaryl may be condensed with another ring system ,
Besonders bevorzugt steht R2 für einen Isopropyl-, einen Phenyl-, einen Naphtyl- oder einen (C5-10)Alkyl-Rest.Particularly preferably, R 2 is an isopropyl, a phenyl, a naphthyl or a (C 5-10 ) alkyl radical.
Insbesondere werden Substanzen verwendet, bei denen R1 für einen (lndan-4-yl- amino)-, einen (2,3-Dimethyl-phenylamino)-, einen (Chinolin-6-ylamino)-, einen (Chinolin-6-yloxo)-, einen (Chinolin-6-yl-methylamino)- oder einen [3,5-Bis(2,2,2- trifluoro-ethoxy)-phenylamino]-Rest steht.In particular, substances are used in which R1 is a (indan-4-ylamino) -, a (2,3-dimethyl-phenylamino) -, a (quinolin-6-ylamino) -, a (quinolin-6-yloxo ), a (quinolin-6-yl-methylamino) or a [3,5-bis (2,2,2-trifluoro-ethoxy) -phenylamino] radical.
Die erfindungsgemäßen Verbindungen können durch das Vorhandensein von Asymmetriezentren als Stereoisomere vorliegen. Gegenstand der vorliegenden Erfindung sind alle möglichen Stereoisomere sowohl als Racemate, als auch in enantiomerenreiner Form. Der Begriff Stereoisomere umfaßt auch alle möglichen Diastereomere und Regioisomere und Tautomere (z.B. Keto-Enol-Tautomere), in denen die erfindungsgemäßen Verbindungen vorliegen können, die damit ebenfalls Gegenstand der Erfindung sind.The compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form. The term stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the invention may be present, which are also subject of the invention.
In einer Ausführung der Erfindung werden die o.g. Substanzen allgemein zur Hemmung der PGE2 Synthese, insbesondere zur Hemmung der mPGES-1 verwendet, z.B. in Zellkulturen.In one embodiment of the invention, the above-mentioned substances are generally used for the inhibition of PGE 2 synthesis, in particular for the inhibition of mPGES-1, for example in cell cultures.
In einer speziellen Ausführung der Erfindung werden die o.g. Pirinixinsäure-Derivate zur Herstellung eines Arzneimittels zur Behandlung von PGE2-vermittelten Erkrankungen verwendet. Bei den PGE2-vermittelten Erkrankungen handelt es sich insbesondere um Entzündungen und Krebserkrankungen. Das Arzneimittel kann ferner ein pharmazeutisches Trägermaterial enthalten.In a specific embodiment of the invention, the above-mentioned pirinixic acid derivatives are used for the preparation of a medicament for the treatment of PGE 2 -mediated Used diseases. The PGE 2 -mediated diseases are, in particular, inflammations and cancers. The medicament may further contain a pharmaceutical carrier material.
Die vorliegende Erfindung lehrt daher eine pharmazeutische Zusammensetzung enthaltend mindestens eine erfindungsgemäße Verbindung. Optional können ein oder mehrere physiologisch verträgliche Hilfsstoffe und/oder Trägersstoffe mit der Verbindung gemischt und die Mischung galenisch zur lokalen oder systemischen Gabe, insbesondere oral, parenteral, zur Infusion, zur Injektion hergerichtet sein. Die Auswahl der Zusatz- und/oder Hilfsstoffe wird von der gewählten Darreichungsform abhängen. Die galenische Herrichtung der erfindungsgemäßen pharmazeutischen Zusammensetzung erfolgt in fachüblicher Weise. Freie Carbonsäuregruppen können auch in Form ihrer Salze mit physiologisch verträglichen Gegenionen, wie z.B. Mg++, Ca++, Na+, K+, Li+ oder Ammoniumderivaten, wie Cyclohexylammonium vorliegen. Aminogruppenhaltige Verbindungen können auch in Form eines Ammoniumsalzes vorliegen, z.B. als Chlorid, Bromid, Mesylat, Tosylat, Oxalat, Orotat, Maleat, Fumarat oder als Tartrat. Geeignete feste oder flüssige galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, Mikrokapseln, Suppositorien, Sirupe, Säfte, Suspensionen, Emulsionen, Tropfen oder Lösungen zur Injektion (i.V., i.p., im, s.c.) oder Vernebelung (Aerosole), Zubereitungsformen zur Trockenpulverinhalation, transdermale Systeme sowie Präparate mit retardierter Wirkstofffreigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Süßungsmittel und Lösungsvermittler Verwendung finden. Als Hilfsstoffe seien beispielsweise Magnesiumkarbonat, Titandioxyd, Laktose, Manid und andere Zucker, Talkum, Milcheiweiß, Gelatine, Stärke, Zellulose und ihre Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesamöl, Polyethylenglykole und Lösungsmittel wie etwa steriles Wasser und ein- oder mehrwertige Alkohole, beispielsweise Glyzerin genannt.The present invention therefore teaches a pharmaceutical composition containing at least one compound of the invention. Optionally, one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection. The choice of additives and / or adjuvants will depend on the chosen dosage form. The galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way. Free carboxylic acid groups can also be used in the form of their salts with physiologically acceptable counterions, e.g. Mg ++, Ca ++, Na +, K +, Li + or ammonium derivatives such as cyclohexylammonium. Amino-containing compounds may also be in the form of an ammonium salt, e.g. as chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate, fumarate or tartrate. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), forms of preparation for Dry powder inhalation, transdermal systems as well as preparations with sustained-release release, in the production of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used. Examples of excipients which may be mentioned are magnesium carbonate, titanium dioxide, lactose, manidine and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.
Eine erfindungsgemäße pharmazeutische Zusammensetzung ist dadurch herstellbar, dass mindestens eine erfindungsgemäß verwendete Substanz-kombination in definierter Dosis mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und ggf. weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen mit definierter Dosis gemischt und zu der gewünschten Darreichungs^form hergerichtet ist. Als Verdünnungsmittel kommen Polyglykole, Ethanol, Wasser und Pufferlösungen in Frage. Geeignete Puffersubstanzen sind beispielsweise N,N-Dibenzylethylen-diamin, Diethanolamin, Ethylendiamin, N-Methylglukamin, N-Benzylphenethylamin, Diethylamin, Phosphat, Natriumbikarbonat und Natriumkarbonat. Es kann aber auch ohne Verdünnungsmittel gearbeitet werden.A pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and to the desired dosage form is prepared. Suitable diluents are polyglycols, ethanol, water and buffer solutions. Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate. However, it is also possible to work without a diluent.
Vorzugsweise wird die pharmazeutische Zusammensetzung in Dosierungseinheiten herstellt und verabreicht, wobei jede Einheit als aktiven Bestandteil eine definierte Dosis der erfindungsgemäßen Verbindung gemäß Formel I enthält. Bei festen Dosierungseinheiten wie Tabletten, Kapseln, Dragees oder Suppositorien kann diese Dosis 0,1 - 1.000 mg, bevorzugt 10 - 50 mg, und bei Injektionslösungen in Ampullenform 0,01 - 1.000 mg, vorzugsweise 10 - 40 mg, betragen.Preferably, the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, this dose may be from 0.1 to 1000 mg, preferably from 10 to 50 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 10 to 40 mg.
Für die klinische Anwendung ist die Herstellung von Infusionslösungen eine weitere bevorzugte Ausführungsform.For clinical use, the preparation of infusion solutions is another preferred embodiment.
Für die Behandlung eines Erwachsenen, 50 - 100 kg schweren, beispielsweise 70 kg schweren, Patienten sind beispielsweise Tagesdosen von 0,1 - 1.000 mg Wirkstoff, vorzugsweise 10 - 500 mg, indiziert. Unter Umständen können jedoch auch höhere oder niedrigere Tagesdosen angebracht sein. Die Verabreichung der Tagesdosis kann sowohl durch Einmalgabe in Form einer einzelnen Dosierungseinheit oder aber mehrerer kleinerer Dosierungseinheiten als auch durch Mehrfachgabe unterteilter Dosen in bestimmten Intervallen erfolgen.For example, for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active substance, preferably 10-500 mg, are indicated. However, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
Zur therapeutischen Behandlung von PGE2-vermittelten Erkrankungen sind Plasmakonzentrationen von ca. 0,5 - 10 μM Pirinixinsäure-Derivat erstrebenswert, das könnte etwa die p.o. Gabe von etwa 25 - 500 mg/Tag sein.For therapeutic treatment of PGE 2 -mediated diseases plasma concentrations of about 0.5 - 10 uM pirinixic acid derivative are desirable, which could be about the po dose of about 25 - 500 mg / day.
Der Vorteil der vorliegenden Erfindung liegt darin, dass für das Arzneistoff-Target mPGES-1 mit Pirinixinsäure-Derivaten Grundstrukturen identifiziert wurden, die zur Hemmung der Aktivität der mPGES-1 führen. Damit kann nun selektiv die Synthese des PGE2 durch COX-2/mPGES-1 gehemmt werden, ohne dabei, wie bislang mittels Inhibitoren der COX-1 und -2, auch die Synthese anderer (physiologisch wichtiger) PGs zu hemmen. Dies hat zur Folge, dass die Therapie PGE2-vermittelter Erkrankungen mittels Pirinixinsäure-Derivaten im Vergleich zu COX-1/2 Inhibitoren weniger Nebenwirkungen aufweisen. Da COX2-lnhibitoren wegen ihrer Nebenwirkungen vom Markt genommen (Rofecoxib) oder die Zulassung nicht erteilt wurde (Etoricoxib) kann durch das hier vorgestellte Verfahren stellvertretend und zudem vorteilhafter eingesetzt werden.The advantage of the present invention is that basic structures have been identified for the drug target mPGES-1 with pirinixic acid derivatives, which lead to the inhibition of the activity of mPGES-1. Thus, the synthesis of PGE 2 can be selectively inhibited by COX-2 / mPGES-1, without inhibiting, as previously by inhibitors of COX-1 and -2, the synthesis of other (physiologically important) PGs. As a result, the therapy of PGE 2 -mediated diseases by means of pirinixic acid derivatives has fewer side effects compared to COX-1/2 inhibitors. Because COX 2 inhibitors are withdrawn from the market because of their side effects (rofecoxib) or not approved was (etoricoxib) can be used by the method presented here representatively and also advantageous.
Ferner hat die vorliegende Erfindung den Vorteil, dass aufgrund der mPGES-1- Hemmung, Pirinixinsäurederivate gezielt bei entzündlichen Erkrankungen eingesetzt werden können, die auf eine erhöhte Bildung von PGE2 zurückzuführen sind. Ein weiterer Vorteil im Vergleich zur Anwendung anderer Hemmstoffe der mPGES-1 oder der PGE2 Synthese allgemein liegt darin, dass die Pirinixinsäurederivate zusätzlich PPARα aktivieren und damit synergistische Effekte hinsichtlich der Entzündungshemmung zu erwarten sind. Des Weiteren kann durch Verwendung von Pirinixinsäure-Derivaten der Einsatz bzw. die Dosis von nicht-steroidalen Antiphlogistika (COX Inhibitoren) reduziert und die Dauer der Einnahme verkürzt werden, die wegen ihrer unspezifischen Blockade der Synthese aller PGs zu erheblichen Nebenwirkungen führen.Furthermore, the present invention has the advantage that due to the mPGES-1 inhibition, pirinixic acid derivatives can be used specifically for inflammatory diseases that are attributable to an increased formation of PGE 2 . Another advantage compared to the use of other inhibitors of mPGES-1 or PGE 2 synthesis in general is that the Pirinixinsäurederivate additionally activate PPARα and thus synergistic effects are expected in terms of anti-inflammatory. Furthermore, by using pirinixic acid derivatives, the use or the dose of non-steroidal anti-inflammatory drugs (COX inhibitors) can be reduced and the duration of administration can be shortened, which leads to considerable side effects because of their unspecific blockade of the synthesis of all PGs.
Die Erfindung kann genutzt werden, um alle Formen von Erkrankungen, die mit einer erhöhten Produktion von PGE2 einhergehen, zu behandeln. Dabei handelt es sich primär um Schmerzen aller Art (leichte, mittelstarke und starke Schmerzen, entzündliche Erkrankungen (v.a. rheumatoide Arthritis und Osteoarthritis), fiebrige und schmerzhafte Zustände, kardiovaskuläre Ereignisse, Anorexie, Multiple Sklerose, sowie Krebserkrankungen, bei denen PGE2 eine Rolle spielt.The invention can be used to treat all forms of diseases associated with increased production of PGE 2 . These are primarily pain of all kinds (mild, moderate and severe pain, inflammatory diseases (especially rheumatoid arthritis and osteoarthritis), feverish and painful conditions, cardiovascular events, anorexia, multiple sclerosis and cancers in which PGE 2 plays a role ,
Weitere Vorteile, Merkmale und Anwendungsmöglichkeiten der Erfindung werden nachstehend anhand der Ausführungsbeispiele mit Bezug auf die Zeichnungen beschrieben. Die Zeichnungen zeigen:Further advantages, features and possible applications of the invention are described below with reference to the embodiments with reference to the drawings. The drawings show:
Fig. 1: Biosyntheseweg des PGE2;FIG. 1: Biosynthetic pathway of PGE 2 ; FIG.
Fig. 2: Strukturen ausgesuchter Pirinixinsäurederivate;Fig. 2: Structures of selected pirinixic acid derivatives;
Fig. 3: Hemmung der mPGES-1 -vermittelten Synthese von PGE2 (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in der mikrosomalen Fraktion von lnterleukin~1ß-stimulierten A549 Zellen (Mittelwert + Standardfehler, n = 4) durch die erfindungsgemäßen Substanzen bei einer Konzentration von 10 μM;FIG. 3: Inhibition of the mPGES-1-mediated synthesis of PGE 2 (percent activity versus control with DMSO as solvent) in the microsomal fraction of interleukin-1β-stimulated A549 cells (mean + standard error, n = 4) by the invention Substances at a concentration of 10 μM;
Fig. 4: Hemmung der mPGES-1 -vermittelten Synthese von PGE2 (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in der mikrosomalen Fraktion von lnterleukin~1ß-stimulierten A549 Zellen (Mittelwert + Standardfehler, n = 4) durch die Substanzen YS121 und LP105 bei unterschiedlichen Konzentrationen. AusführunqsbeispieleFIG. 4: Inhibition of the mPGES-1-mediated synthesis of PGE 2 (percent activity versus control with DMSO as solvent) in the microsomal fraction of interleukin-1β-stimulated A549 cells (mean + standard error, n = 4) by the substances YS121 and LP105 at different concentrations. EXEMPLARY EMBODIMENTS
Einfluss von Pirinixinsäurederivaten auf die Aktivität der mPGES-1Influence of pirinixic acid derivatives on the activity of mPGES-1
A549 Zellen wurden mit lnterleukin-1ß (1 ng/ml) für 72 Stunden inkubiert. Nach Ernte und Zellzahlbestimmung wurden die pelletierten Zellen auf Trockeneis/Ethanol schockgefroren, durch Zugabe von 1 ml Homogenisierungspuffer (4 0C) wieder aufgetaut und mittels Ultraschall homogenisiert. Nach Zentrifugation (10.000g für 10 min bei 4 0C) wurde der erhaltene Überstand bei 174.000g und 4 0C für 1 h Stunde zentrifugiert um Mikrosomen zu gewinnen. Das Pellet (Mikrosomen) wurde im Homogensierungspuffer gelöst und mit den Testsubstanzen (Pirinixinsäurederivate bzw. DMSO) für 10 min bei 4°C in 96-well Platten vorinkubiert. Dann wurde PGH2 als Substrat zugegeben und die Reaktion nach 1 min bei 4 0C mittels Stopplösung (enthält u.a. Fe2+, Citronensäure und 11 -B-PGE2 als Standard) beendet. Ein Ansatz wird vor Reaktionsbeginn mit der Stopplösung versetzt um bereits in der PGH2- Lösung enthaltenes PGE2 zu ermitteln. Nach Festphasenextraktion (RP-18-Säulen und Acetonitril als Elutionsmittel) wurde die Probe mittels HPLC (RP-18, UV- Detektion bei 190 nm) analysiert.A549 cells were incubated with interleukin-1β (1 ng / ml) for 72 hours. After harvesting and cell count determination, the pelleted cells were flash-frozen on dry ice / ethanol, thawed again by adding 1 ml of homogenization buffer (4 ° C.) and homogenized by means of ultrasound. After centrifugation (10,000 g for 10 min at 4 0 C) of the resulting supernatant at 174.000g and 4 0 C was for 1 h hour centrifuged to obtain microsomes. The pellet (microsomes) was dissolved in the homogenization buffer and preincubated with the test substances (pirinixic acid derivatives or DMSO) for 10 min at 4 ° C. in 96-well plates. Then, PGH 2 was added as a substrate and the reaction after 1 min at 4 0 C by means of stop solution (containing, inter alia, Fe 2+ , citric acid and 11 -B-PGE 2 as a standard) ended. A batch is added to the stop solution before the start of the reaction to detect PGE 2 already contained in the PGH 2 solution. After solid phase extraction (RP-18 columns and acetonitrile as eluent), the sample was analyzed by HPLC (RP-18, UV detection at 190 nm).
Es zeigt sich, dass die Vorinkubation der mikrosomalen Fraktion von lnterleukin-1ß- stimulierten A549 Zellen mit jeweils 10 μM Pirinixinsäurederivaten zu einer potenten Hemmung der mPGES-1 Aktivität führt (Fig. 3), indem die PGE2-Synthese aus PGH2 gehemmt wird (beispielsweise hemmt Verbindung YS121 die PGE2-Synthese zu ca. 60-70% und Verbindung LP105 zu ca. 50-60%). Die IC50-Werte der konzentrationsabhängigen Hemmung der PGE2-Synthese liegen für Verbindung YS121 und für Verbindung LP105 bei ca. 3 μM (Fig. 4).It has been found that preincubation of the microsomal fraction of interleukin-1β-stimulated A549 cells with 10 μM each of pirinixic acid derivatives results in potent inhibition of mPGES-1 activity (Figure 3) by inhibiting PGE 2 synthesis from PGH 2 (For example, compound YS121 inhibits PGE 2 synthesis by about 60-70% and compound LP105 by about 50-60%). The IC 50 values of the concentration-dependent inhibition of the PGE 2 synthesis are approximately 3 μM for compound YS121 and for compound LP105 (FIG. 4).
Literaturliterature
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Claims

Patentansprüche claims
1) Pirinixinsäure-Derivat, mit der Strukturformel1) Pirinixic acid derivative, having the structural formula
Figure imgf000019_0001
wobei R1 für ein Aryl, Heteroaryl, Alkylaryl oder Alkylheteroaryl steht, das über ein Stickstoff-, Sauerstoff- oder Kohlenstoffatom oder eine Aminoalkyl-, Oxoalkyl- oder Alkylgruppe an das Restmolekül geknüpft ist, wobei das Aryl-, Heteroaryl-, Alkylaryl- bzw. Alkylheteroaryl mit einem weiteren Ringsystem kondensiert sein kann, und ein oder mehrere H-Atome im Aryl, Heteroaryl, Alkylaryl bzw. Alkylheteroaryl substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (C1-10)Alkyl, (C2-io)Alkenyl, (C2-io)Alkinyl, OCF3, (C1-10)Alkoxy, (Ci-10)- Alkylamin, (Ci-10)Alkylthio, (Ci-iO)Alkylsilyl, (C3-io)Cycloalkyl, (C3-io)-Cyclo- alkenyl, (Cs-ioJ-Cycloheteroalkyl, (C3-i0)-Cycloheteroalkenyl, COOH, oder das korrespondierende Säureadditionssalz dieser Verbindung,
Figure imgf000019_0001
where R 1 is an aryl, heteroaryl, alkylaryl or alkylheteroaryl which is attached via a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or alkyl group to the remainder of the molecule, where the aryl, heteroaryl, alkylaryl or Alkylheteroaryl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, alkylaryl or alkylheteroaryl may be substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2 , NO 2, SH, (C 1-10) alkyl, (C 2- io) alkenyl, (C 2- io) alkynyl, OCF 3, (C 1-10) alkoxy, (C -10) - alkylamine, (Ci - 10) alkylthio, (C-i O) alkylsilyl, (C 3- io) cycloalkyl, (C 3- io) cyclo- alkenyl, (Cs-iOJ cycloheteroalkyl, (C 3 i 0) -Cycloheteroalkenyl, COOH, or the corresponding acid addition salt of this compound,
R2 für einen lipophilen Rest steht, der größer als ein Ethyl-Rest ist,R2 is a lipophilic radical greater than an ethyl radical,
und R3 für einen Wasserstoff oder einen lipophilen Rest steht.and R3 is a hydrogen or a lipophilic radical.
2) Verbindung nach Anspruch 1 , wobei R1 für einen (lndan-4-yl-amino)-, einen (2,3-Dimethyl-phenylamino)-, einen (Chinolin-6-ylamino)-, einen (Chinolin-6-yloxo)-, einen (Chinolin-6-yl- methylamino)- oder einen [3,5-Bis(2,2,2-trifluoro-ethoxy)-phenylamino]-Rest steht.2) A compound according to claim 1, wherein R 1 is a (indan-4-yl-amino) -, a (2,3-dimethyl-phenylamino) -, a (quinolin-6-ylamino) -, a (quinoline-6-) yloxo), a (quinolin-6-yl-methylamino) or a [3,5-bis (2,2,2-trifluoro-ethoxy) -phenylamino] radical.
ERSATZBLATT (REGEL 26) 3) Verbindung nach Anspruch 1 , wobei R2 für ein Aryl, Heteroaryl, (Ci-io)-Alkylaryl, (Ci-io)-Alkylheteroaryl, ein lineares oder verzweigtes (CMO)- Alkyl, C(2-io)Alkenyl oder C(2-io)Alkinyl steht, wobei ein oder mehrere H-Atome in diesen Resten eliminiert oder substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (Ci-10)Alkyl, (C2-io)Alkenyl, (C2-io)Alkinyl, (C1-10)Alkoxy, (d-ioJAlkylamin, (C1.io)Alkylthio, (C1-10)Alkylsilyl, (C3-io)Cycloalkyl, (C3-io)-Cycloalkenyl, (C3- io)-Cycloheteroalkyl, (C3-i0)-Cycloheteroalkenyl, COOH oder das korrespondierende Säureadditionssalz dieser Verbindung, wobei das Aryl, Heteroaryl, Alkylaryl bzw. AI kyl heteroaryl mit einem weiteren Ringsystem kondensiert sein kann.Replacement Blade (RULE 26) 3) A compound according to claim 1, wherein R 2 is an aryl, heteroaryl, (Ci-io) -alkylaryl, (Ci-io) -alkyl heteroaryl, a linear or branched (CMO) - alkyl, C ( 2 -io) alkenyl or C ( 2- ω) alkynyl, where one or more H atoms in these radicals can be eliminated or substituted by one or more groups from the substance class halogen, O, N, S, OH, NH 2, NO 2, SH, (C 1 -) 10) alkyl, (C 2- io) alkenyl, (C 2- io) alkynyl, (C 1-10) alkoxy, (d-ioJAlkylamin, (C 1 .io) alkylthio, (C 1-10) alkylsilyl, ( C 3- io) cycloalkyl, (C 3- io) cycloalkenyl, (C 3- io) cycloheteroalkyl, (C 3 i 0) -Cycloheteroalkenyl, COOH or the corresponding acid addition salt of this compound, wherein the aryl, heteroaryl, alkylaryl or Al kyl heteroaryl may be condensed with another ring system.
4) Verbindung nach Anspruch 1 , wobei R2 für einen Isopropyl-, einen Phenyl-, einen Naphtyl- oder einen (C5-io)Alkyl-Rest steht.4) A compound according to claim 1, wherein R 2 is an isopropyl, a phenyl, a naphthyl or a (C 5-10 ) alkyl radical.
5) Verbindung nach Anspruch 1 , wobei R3 für ein lineares oder verzweigtes (C1-10)Alkyl steht.5) A compound according to claim 1, wherein R 3 is a linear or branched (C 1-10 ) alkyl.
6) Verbindung nach Anspruch 1 , gekennzeichnet durch folgende Kombination der Substituenten R 1 , R2 und R3:6) A compound according to claim 1, characterized by the following combination of the substituents R 1, R 2 and R 3:
Figure imgf000020_0001
Figure imgf000020_0001
ERSATZBLATT (REGEL 26)
Figure imgf000021_0001
Replacement Blade (RULE 26)
Figure imgf000021_0001
ERSATZBLATT (REGEL 26) Replacement Blade (RULE 26)
Figure imgf000022_0001
Figure imgf000022_0001
ERSATZBLATT (REGEL 26)
Figure imgf000023_0001
Replacement Blade (RULE 26)
Figure imgf000023_0001
ERSATZBLATT (REGEL 26) Replacement Blade (RULE 26)
1515
Figure imgf000024_0001
Figure imgf000024_0001
ERSATZBLATT (REGEL 26)
Figure imgf000025_0001
Replacement Blade (RULE 26)
Figure imgf000025_0001
ERSATZBLATT (REGEL 26) 7) Verbindungen nach Anspruch 1 , nämlich:Replacement Blade (RULE 26) 7) Compounds according to claim 1, namely:
Figure imgf000026_0001
oder
Figure imgf000026_0001
or
Figure imgf000026_0002
Figure imgf000026_0002
8) Verbindung nach Anspruch 1 und 6, gekennzeichnet durch folgende Kombination der Substituenten R 1 , R2 und R3:8) A compound according to claim 1 and 6, characterized by the following combination of the substituents R 1, R 2 and R 3:
Figure imgf000026_0003
Figure imgf000026_0003
ERSATZBLATT (REGEL 26) Replacement Blade (RULE 26)
Figure imgf000027_0001
Figure imgf000027_0001
ERSATZBLATT (REGEL 26)
Figure imgf000028_0001
Replacement Blade (RULE 26)
Figure imgf000028_0001
9) Pharmazeutische Zubereitungen enthaltend mindestens ein Pirinixinsäure- Derivat gemäß mindestens einem der Ansprüche 1-8 mit einem pharmazeutisch unbedenklichem Träger.9) Pharmaceutical compositions containing at least one derivative of pirinixic according to any one of claims 1-8 with a pharmaceutically acceptable carrier.
ERSATZBLATT (REGEL 26) 10) Verwendung von mindestens einem Pirinixinsäure-Derivat gemäß mindestens einem der Ansprüche 1-8 zur Herstellung eines Arzneimittels.Replacement Blade (RULE 26) 10) Use of at least one pirinixic acid derivative according to any one of claims 1-8 for the manufacture of a medicament.
11)Verwendung von mindestens einem Pirinixinsäure-Derivat gemäß mindestens einem der Ansprüche 1-8 zur Herstellung eines Arzneimittels zur Hemmung der PGE2 Synthese, insbesondere zur Hemmung der mPGES-1.11) Use of at least one pirinixic acid derivative according to any one of claims 1-8 for the manufacture of a medicament for inhibiting the PGE 2 synthesis, in particular for the inhibition of mPGES-1.
12) Verwendung nach Anspruch 11 zur Herstellung eines Arzneimittels zur Behandlung PGE2-vermittelter Erkrankungen.12) Use according to claim 11 for the preparation of a medicament for the treatment of PGE 2 -mediated diseases.
13) Verwendung nach Anspruch 12, dadurch gekennzeichnet, dass die PGE2- vermittelte Erkrankungen entzündliche Erkrankungen, insbesondere Schmerzen aller Art, rheumatoide Arthritis, Osteoarthritis, fiebrige und schmerzhafte Zustände, Multiple Sklerose, kardiovaskuläre Ereignisse und / oder Krebserkrankungen sind.13) Use according to claim 12, characterized in that the PGE 2 - mediated diseases are inflammatory diseases, in particular pain of all kinds, rheumatoid arthritis, osteoarthritis, feverish and painful conditions, multiple sclerosis, cardiovascular events and / or cancers.
14) Verwendung nach einem der vorgehenden Ansprüche, dadurch gekennzeichnet, dass die Plasmakonzentrationen von mindestens einem Pirinixinsäure-Derivat nach der Applikation des Arzneimittels etwa 0,5 - 10 μM beträgt. 14) Use according to one of the preceding claims, characterized in that the plasma concentrations of at least one pirinixic acid derivative after the application of the medicament is about 0.5 to 10 μM.
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