WO2009117985A1 - Dérivés de l'acide pirinixique comme inhibiteurs de la synthèse de la prostaglandine e2 pour le traitement de maladies inflammatoires - Google Patents

Dérivés de l'acide pirinixique comme inhibiteurs de la synthèse de la prostaglandine e2 pour le traitement de maladies inflammatoires Download PDF

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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
replacement blade
pge
heteroaryl
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German (de)
English (en)
Inventor
Oliver Werz
Andreas Koeberle
Manfred Schubert-Zsilavecz
Laura Popescu
Yvonne Syha
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MEDEON PHARMACEUTICALS GmbH
Eberhard Karls Universitaet Tuebingen
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MEDEON PHARMACEUTICALS GmbH
Eberhard Karls Universitaet Tuebingen
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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

La présente invention concerne des dérivés de l'acide pirinixique, en particulier des acides pirinixiques et esters d'acides pirinixiques a-substitués ainsi que leurs dérivés structurels de formule développée. Les dérivés de l'acide pirinixique inhibent la synthèse de la PGE2, en particulier celle de la mPGES-1. L'invention concerne également l'utilisation de ces dérivés de l'acide pirinixique pour fabriquer un médicament destiné au traitement de maladies médiées par la prostaglandine E2, en particulier de maladies inflammatoires, d'états fébriles et douloureux, d'événements cardiovasculaires et de maladies cancéreuses associés à une activité accrue de la prostaglandine E2 synthase-1 microsomale (mPGES-1) inductible ou à une synthèse accrue de la prostaglandine E2.
PCT/DE2009/000373 2008-06-12 2009-03-23 Dérivés de l'acide pirinixique comme inhibiteurs de la synthèse de la prostaglandine e2 pour le traitement de maladies inflammatoires Ceased WO2009117985A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008015432A DE102008015432A1 (de) 2008-06-12 2008-06-12 Verwendung von Pirinixinsäure-Derivaten zur Hemmung der Prostaglandin E2 Synthese
DE102008015432.6 2008-06-12

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