WO2009146696A1 - Use of indole-3-carboxylic esters for inhibiting microsomal prostaglandin e2 synthase - Google Patents

Use of indole-3-carboxylic esters for inhibiting microsomal prostaglandin e2 synthase Download PDF

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WO2009146696A1
WO2009146696A1 PCT/DE2009/000809 DE2009000809W WO2009146696A1 WO 2009146696 A1 WO2009146696 A1 WO 2009146696A1 DE 2009000809 W DE2009000809 W DE 2009000809W WO 2009146696 A1 WO2009146696 A1 WO 2009146696A1
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Prior art keywords
indole
mmol
aryl
ethyl
carboxylic acid
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PCT/DE2009/000809
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German (de)
French (fr)
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Oliver Werz
Andreas Koeberle
Reinhard Troschütz
Eva-Maria Karg
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Universität Tübingen
Friedrich-Alexander Universität Erlangen-Nürnberg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 the use of derivatives of 3-carboxy-indole, in particular of 2-aryl- and 2-alkylaryl-indole-3-carboxylic acid esters and their structural derivatives for the inhibition of inducible microsomal prostaglandin E 2 synthase-1 (mPGES- 1) and 5-lipoxygenase (5-LO).
  • the invention relates to the use of derivatives of 3-carboxy-aryl [g] indole, in particular 2-aryl- and 2-arylalkyl-aryl [g] indole-3-carboxylic acid ester, for inhibiting mPGES-1 and the 5- LO.
  • the invention relates to the use of indole-3-carboxylic acid esters for the manufacture of a medicament for the treatment of prostaglandin (PG) E 2 and / or 5-LO-mediated diseases and pathological conditions.
  • Acute and chronic inflammatory diseases are associated with increased activity of inflammation-relevant cells such as monocytes, granulocytes, lymphocytes and endothelial cells, which release more PGE 2 and / or 5-LO products (mainly leukotrienes (LTs)).
  • 5-LO products and the PGE 2 are significantly responsible for the development and maintenance of inflammatory symptoms (pain, swelling, redness, overheating and loss of function) responsible or have a promotional effect on it.
  • 5-LO products promote allergic asthma and allergic rhinitis, are involved in the development and progression of arteriosclerosis and thus play an important role in the pathology of cardiovascular diseases (eg angina pectoris, stroke, heart attack, etc.).
  • PGE 2 and 5-LO products play an important role in the proliferation of different cells and are responsible for the development and maintenance of cancer.
  • PG biosynthesis is initiated by the catalytic conversion of arachidonic acid to PGH 2 by cyclooxygenase (COX) -I or -2 ( Figure 1).
  • COX cyclooxygenase
  • Certain PGs, including the PGE 2 are mediators in inflammation (especially rheumatoid arthritis), pain and fever, and are also involved in cancers (lung, colon, endometrium).
  • Other PGs fulfill important physiological functions [1, 2].
  • Inhibitors of COX-1 and -2 thus prevent the synthesis of all PGs and have considerable side effects (stomach, kidney) due to the lack of physiologically important PGs [3].
  • the inducible mPGES-1 is a member of the MAPEG family and catalyzes the transformation of PGH 2 into PGE 2 [4].
  • PGE 2 mediates its effects via four G protein-coupled receptors (so-called EP receptors) on corresponding target cells and, in contrast to the physiologically necessary PGs pronounced pathophysiological properties (inflammation, pain, fever, cancer, angiogenesis) on.
  • EP receptors G protein-coupled receptors
  • pathophysiological properties inflammation, pain, fever, cancer, angiogenesis
  • PGE 2 contributes to homeostasis in the stomach and kidney.
  • 5-lipoxygenase is the key enzyme in leukotriene biosynthesis, which catalyzes the reaction of free arachidonic acid with molecular oxygen to form 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) ( Figure 2) [6].
  • 5-HPETE can be reduced by peroxidases to the corresponding alcohol 5-hydroxyeicosatetraenoic acid (5-HETE) or converted again to the LTA 4 with catalysis of the 5-LO.
  • the unstable LTA 4 is then enzymatically converted to LTB 4 or to the cysteinyl LTs C 4 , D 4 and E 4 . All 5-LO products bind and act via specific G-protein coupled receptors on different target cells, thus mediating their effect.
  • 5-LO product formation or LT receptor antagonists as well as 5-LO knockout mice, it is believed that excessive, non-physiological 5-LO product formation on the Emergence and maintenance of diseases and pathological conditions is involved, such as inflammatory skin diseases (psoriasis, atopic dermatitis), asthma, allergic rhinitis, osteoarthritis, rheumatoid arthritis, osteoporosis, cardiovascular diseases (arteriosclerosis, stroke, heart attack, etc.) and also in cancer (eg, pancreatic carcinoma, prostate carcinoma, mummy carcinoma, etc.) [7].
  • diseases and pathological conditions such as inflammatory skin diseases (psoriasis, atopic dermatitis), asthma, allergic rhinitis, osteoarthritis, rheumatoid arthritis, osteoporosis, cardiovascular diseases (arteriosclerosis, stroke, heart attack, etc.) and also in cancer (eg, pancreatic carcinoma, prostate carcinoma, mummy carcinoma, etc.) [7].
  • 5-LO inhibitors are subdivided into (I) redox-active substances, (II) iron-ligand inhibitors, and (III) non-redox-active (competitive) 5-LO inhibitors [8].
  • Another approach to inhibiting 5-LO product formation is the blockade of 5-LO activating protein (FLAP) by small molecule inhibitors.
  • FLAP 5-LO activating protein
  • the leukotriene receptor antagonists e.g., montelukast, zafirlukast, and pranlukast
  • 5-LO inhibitor zileuton
  • the object of the present invention is therefore to identify substances which potently inhibit PGE 2 synthesis and which are additionally capable of producing the 5-LO inhibit and thus block inflammatory, allergic and neoplastic processes in an additive and / or synergistic manner.
  • the disadvantages of the known methods are to be circumvented and drugs identified for the preparation of a drug for the therapeutic treatment of 5-LO product and / or PGE 2 mediated diseases, in particular chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, cardiovascular system disorders, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis, and cancer, and morbid conditions, in particular Pain and fever, can be used to have low side effects at high efficiency.
  • indole-3-carboxylic acid esters in particular of 2-aryl and 2-arylalkyl-indole-3-carboxylic acid esters and their structural derivatives, as described in claim 1 and dependent claims 2 to 7.
  • the compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers. Subject of the present
  • stereoisomers are all possible stereoisomers both as racemates, as well as in enantiomerically pure form.
  • stereoisomers also includes all possible ones
  • Diastereomers and regioisomers and tautomers e.g., keto-enol tautomers
  • tautomers e.g., keto-enol tautomers
  • indole-3-carboxylic acid esters are effective inhibitors of mPGES-1 and PGE 2 synthesis, respectively (Table 1 and 2). Therefore, starting from indole-3-carboxylic acid esters, derivatives have been developed which are capable of potently inhibiting mPGES-1. Indole-3-carboxylic acid esters which have a [6,7] -annulated aromatic have proven to be particularly potent. In addition, C2 and C5 of the indole-3-carboxylic acid ester has been substituted, in particular by substituted benzyl or anilino substituents on C2 and by aryl, hydroxyl or chlorine substituents on C5.
  • indole-3-carboxylic acid esters have a high potential for the treatment of inflammatory and / or neoplastic diseases and disease states associated with increased PGE 2 formation. This could be treated by the use of indole-3-carboxylic acid esters PGE 2 -mediated diseases, in contrast to previous methods (COX inhibition) fewer side effects are likely to occur.
  • preparations containing indole-3-carboxylic acid esters can be used in the present invention to inhibit mPGES-1.
  • Formulations may also be used for the manufacture of a medicament for inhibiting the
  • PGE 2 synthesis in particular for the inhibition of mPGES-1, can be used.
  • these preparations can be used for the manufacture of a medicament for a patient.
  • PGE 2 -mediated diseases and morbid conditions can be used. These can include chronic inflammation such as rheumatoid arthritis, and
  • indole-3-carboxylic acid esters can additionally inhibit the 5-LO potent.
  • the aryl [g] indole-3-carboxylic esters synthesized for the first time showed a particularly effective inhibition of 5-LO (Table 2).
  • the biological activity of these aryl [g] indole-3-carboxylic acid esters was hitherto unknown.
  • these Substances not only inhibit 5-LO product formation in intact neutrophils, but also interfere with 5-LO activity in cell-free systems (Table 2, Figs. 5 and 6). The latter suggests that the compounds directly inhibit 5-LO.
  • preparations containing indole-3-carboxylic acid esters can be used for the dual inhibition of mPGES-1 and 5-LO.
  • aryl [g] indole-3-carboxylic acid esters can be used for the dual inhibition of mPGES-1 and 5-LO.
  • 2-aryl and 2-arylalkyl derivatives of the aryl [g] indole-3-carboxylic acid esters are used which show the best inhibitory activity against mPGES-1 and 5-LO.
  • preparations may also be used for the manufacture of a medicament for the simultaneous inhibition of PGE 2 synthesis and 5-LO production become.
  • These preparations may preferably be used for the preparation of a medicament for the therapeutic treatment of PGE 2 and 5-LO-mediated diseases and pathological conditions, in particular chronic inflammations such as rheumatoid arthritis, osteoarthritis, cardiovascular system disorders, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases , Osteoporosis, and cancer, and morbid conditions, especially pain and fever.
  • the invention comprises the use of preparations for inhibiting PGE 2 synthesis, in particular for inhibiting mPGES-1 and / or for inhibiting 5-LO, which preparations comprise at least one indole-3-carboxylic acid ester and / or one of its derivatives with the following Structural formulas contain:
  • X is a fused aryl or heteroaryl ring having a total of 3 to 8 ring atoms
  • R 1 is an aryl, heteroaryl, arylalkyl or heteroarylalkyl which has a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or
  • Alkyl group is attached to the remainder of the molecule, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, arylalkyll or heteroarylalkyl may be substituted by one or more groups selected from the substance class halogen, O, N, S, OH, NH 2, NO 2, SH, (C 1-10) alkyl, (C 2- I 0) alkenyl, (C 2-10) alkynyl, OCF 3 , (C 1-
  • R 2 forms the alcohol component of the carboxylic ester on C 2 and in particular represents an alkyl, aryl or alkylaryl radical, and
  • R 3 is H or any polar or lipophilic radical, in particular an OH group or halogen,
  • R 4 is H or is also substituted by an alkyl, aryl or arylalkyl radical.
  • indole-3-carboxylic acid ester is a 2-aryl or 2-arylalkyl-indole-3-carboxylic acid ester or a structural derivative thereof.
  • Another particular embodiment of the invention are compounds in which the indole-3-carboxylic acid ester is an aryl [g] indole-3-carboxylic acid ester.
  • Another particular embodiment of the invention are compounds wherein X is an annelated phenyl or pyridinyl ring.
  • the fused phenyl or pyridinyl ring is mono- or disubstituted by C 1 -C 4 -alkoxy groups, preferably twice with methoxy groups.
  • R1 is selected from the group
  • R2 is selected from the group
  • R3 is selected from the group
  • R4 is selected from the group -H
  • a further particular embodiment of the invention are compounds in which R5 and R6 are independently selected from the group -H -OCH. 3
  • Another particular embodiment of the invention are compounds in which substituted benzyl or anilino substituents are introduced at C2 position of the indole-3-carboxylic acid ester.
  • Another particular embodiment of the invention are compounds in which the indole-3-carboxylic acid ester is substituted at C5-position by aryl, hydroxyl or chlorine radicals.
  • the invention further comprises a pharmaceutical composition comprising an indole-3-carboxylic acid ester according to one of the above-mentioned.
  • Structural formulas and optionally contains a pharmaceutical carrier material are also included.
  • plasma concentrations of about 0.1 - 10 uM indole-3-carboxylic acid esters are desirable. This could be achieved, for example, by administering about 5 - 500 mg / day.
  • indole-3-carboxylic acid esters or pharmaceutical compositions containing them for the treatment of diseases can be oral or parenteral.
  • the present invention therefore teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or excipients 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 may also be present in the form of their salts with physiologically acceptable counterions such as Mg ++, Ca ++, Na +, K +, Li + or ammonium derivatives such as cyclohexylammonium.
  • Amino-containing compounds may also be present in the form of an ammonium salt, for example 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 retarded Release of active substances, in the preparation of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
  • adjuvants are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol 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 prepared to the desired dosage form is.
  • 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.
  • One advantage of the present invention is that drug targets mPGES-1 and 5-LO G have been identified as having structures that result in the inhibition of mPGES-1 and 5-LO activity.
  • the synthesis of PGE 2 could be selectively inhibited by COX-2 / mPGES-1, without, as previously by inhibitors of COX-1 and -2, the synthesis of other (physiologically important) Inhibit PGs.
  • the formation of 5-LO products can be prevented.
  • This has the consequence that the treatment of corresponding diseases and pathological conditions by means of indole-3-carboxylic acid esters compared to COX-1/2 inhibitors should have fewer side effects.
  • the method presented here can be used as a representative and also more advantageously.
  • indole-3-carboxylic acid esters can be used specifically for inflammatory diseases that are attributable to an increased formation of PGE 2 and / or 5-LO products.
  • indole-3-carboxylic acid ester the use or the dose of steroidal (glucocorticoids) and non-steroidal anti-inflammatory drugs (COX inhibitors) can be reduced and the duration of ingestion can be shortened.
  • COX inhibitors lead, as mentioned, because of their unspecific blockade of the synthesis of all PGs to significant side effects.
  • the invention can be used to treat all forms of diseases and pathological conditions associated with increased production of PGE 2 and / or 5-LO products. These are primarily chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, cardiovascular diseases, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis and cancer, pain and fever in which PGE 2 and / or 5-LO products have one Role-play.
  • diseases and pathological conditions associated with increased production of PGE 2 and / or 5-LO products are primarily chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, cardiovascular diseases, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis and cancer, pain and fever in which PGE 2 and / or 5-LO products have one Role-play.
  • Fig. 1 Biosyntheseweg of PGE2.
  • Fig. 2 Biosynthetic pathway of the leukotrienes and other 5-LO products.
  • 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 centrifuged for 1 h hour to obtain microsomes.
  • the pellet (microsomes) was dissolved in Homogenstechnikspuffer and preincubated with the test substances (indole-3-carboxylic acid ester or DMSO) for 15 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-ß-PGE 2 as standard) ended.
  • stop solution containing, inter alia, Fe 2+ , citric acid and 11-ß-PGE 2 as standard
  • One approach is added before the start of the reaction with the stop solution to determine already contained in the PGH 2 solution PGE 2 . After solid phase extraction (RP-18 columns and acetonitrile as eluent), the sample was analyzed by HPLC (RP-18, UV detection at 195 nm).
  • A549 cells were incubated with interleukin-1 ⁇ (1 ng / ml) for 72 hours. After harvesting and cell count determination, the cells (2 ⁇ 10 6 ) were resuspended in CaCl 2 -containing PBS buffer. After preincubation with the test substances for 10 min at 37 0 C, the PGE 2 formation is induced by the addition of A23187 (2.5 uM), AA (1 uM) and [3 H] AA (18.4 kBq). The reaction is stopped after 15 min at 37 ° C by cooling to 4 ° C.
  • indole-3-carboxylic acid esters appear as potent inhibitors of the PGE 2 synthesis and show IC 50 values of about 5 ⁇ M for compounds 89a and 135a (FIG. 4).
  • E. coli strain MV1190
  • plasmid pT3-5LO plasmid pT3-5LO
  • Lysate of E. coli ⁇ a 100,000 g centrifugation are subjected. Aliquots of the 100-OOO ⁇ g supernatant is then pre-incubated with the inhibitors on ice for 5 min and preheated in a water bath (37 ° C) for 30 sec.
  • 20 ⁇ M arachidonic acid and 1 mM Ca 2+ are added.
  • PMNL are isolated from fresh human leukocyte concentrates according to a standard protocol [11], resuspended in PBS in the presence of 1 mM CaCb, and preincubated with inhibitors accordingly. After stimulus addition (2.5 ⁇ M ionophore plus 20 ⁇ M arachidonic acid) is incubated for 10 min at 37 ° C. The incubation is stopped with methanol, the formed 5-LO metabolites (trans-LTB 4l epi-trans-LTB 4 , LTB 4 , 5-H (P) ETE) was isolated by solid-phase extraction, and then qualitatively and quantitatively analyzed by automated RP-HPLC system (see above).
  • Figure 6 shows that preincubation of PMNL with compounds 89a, 13Od, 135a, and 141d also results in potent and concentration- dependent inhibition of 5-LO product formation in cellular systems, with IC 50 values at 0.65, 0.5, 0.3 and 0.4 ⁇ M lie.
  • reaction mixture is then allowed to stand for 2 h at RT and washed successively with 10% NaHCO 3 solution, 1 molar HCl and water.
  • CH 2 Cl 2 phase is dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the product is isolated from unreacted starting materials by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 v / v).
  • Methyl 2- (3-chlorophenylamino) -5-hydroxy-1H-indole-3-carboxylate (91 b) Preparation According to Preparation Procedure C 1 from 226.7 mg (1, 0 mmol) of methyl (2EZ) -3-amino- 3 - [(3-chlorophenyl) amino] acrylate (91aMe) and 129.7 mg (1.2 mmol) of 1,4-benzoquinone. Yield: 107.6 mg (34%) grayish-luster powder. Note: To avoid the risk of transesterification, MeOH is the preferred solvent.
  • Methyl 2 - [(3-trifluoromethyl) phenylamino] -1H-indole-3-carboxylate (115) Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 377.0 mg ( 2.34 mmol) of 3-trifluoromethylaniline. Yield: 210.4 mg (53%) of white powder.
  • Variant a Preparation according to Preparation Procedure C 1 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 129.7 mg (1 , 2 mmol) 1, 4-benzoquinone. Yield: 94.6 mg (29%) of white powder.
  • Variant b Preparation according to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 108.1 mg (1, 0 mmol ) 1,4-benzoquinone. Yield: 135.1 mg (41%) of white powder.
  • Variant b Preparation according to preparation procedure C 2 from 240.7 mg (1, 0 mmol) of ethyl (2EZ) - 3-amino-3 - [(3-chlorophenyl) amino] acrylate (91aEt) and 158.2 mg (1, 0 mmol) 1, 4-naphthoquinone. Yield: 133.3 mg (35%) of light green powder.
  • Preparation according to Preparation Procedure C 1 from 239.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 189.8 mg (1, 2 mmol ) 1,4-naphthoquinone. Yield: 77.7 mg (20%) of light brown powder.
  • Variant b Preparation according to Preparation Procedure C 2 from 239.7 mg (1.0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 158.2 mg (1 , 0 mmol) 1, 4-naphthoquinone. Yield: 197.2 mg (52%) of light brown powder.
  • Ethyl 2- (3-chlorobenzyl) -5-phenyl-1H-benzo [g] indole-3-carboxylate (176b) A mixture of 112.2 mg (0.55 mmol) phenyl boronic acid pinacol ester, 256.0 mg (0, 50 mmol) ethyl 5 - [[(trifluoromethyl) sulfonyl] oxy] -2- (3-chlorobenzyl) -1H-benzo [g] indole-3-carboxylate (176a), 3.4 mg (0.015 mmol) PdOAc 2 , 3.9 mg (0.015 mmol) of PPh 3 , aqueous Na 2 CO 3 solution and DMF is boiled under reflux for 2 h.

Abstract

The present invention relates to the use of indole-3-carboxylic esters and derivatives thereof for inhibiting inducible microsomal prostaglandin E2 synthase-1 and/or for inhibiting 5-lipoxygenase. More particularly, the invention relates to the use of derivatives of 3‑carboxyaryl[g]indole, in particular of 2-aryl- and 2-arylalkyl­aryl[g]indole-3-carboxylic esters and structural derivatives thereof for inhibiting inducible microsomal prostaglandin E2 synthase-1 and/or for inhibiting 5-lipoxygenase. The invention further relates to the use of indole-3-carboxylic esters for producing a medicament for treatment of PGE2- and/or 5-LO-mediated disorders and pathological states, especially of inflammatory chronic inflammations such as rheumatoid arthritis, osteoarthritis, disorders of the cardiovascular system, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin disorders, osteoporosis and cancer, pain and fever, in which PGE2 and/or 5-LO products are involved.

Description

Verwendung von lndol-3-carbonsäureestern zur Hemmung der mikrosomalen Use of indole-3-carboxylic acid esters for the inhibition of microsomal
Prostaglandin E2 SynthaseProstaglandin E2 synthase
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von Derivaten des 3-Carboxy- indols, vor allem von 2-Aryl- und 2-Alkylaryl-indol-3-carbonsäureestern sowie deren strukturellen Abkömmlinge zur Hemmung der induzierbaren mikrosomalen Prostaglandin E2 Synthase-1 (mPGES-1 ) und der 5-Lipoxygenase (5-LO). Insbesondere betrifft die Erfindung die Verwendung von Derivaten des 3-Carboxy- aryl[g]indols, vor allem 2-Aryl- und 2-Arylalkyl-Aryl[g]indol-3-carbonsäureester, zur Hemmung der mPGES-1 und der 5-LO. Ferner betrifft die Erfindung die Verwendung von lndol-3-carbonsäureestern zur Herstellung eines Arzneimittels zur Behandlung von Prostaglandin (PG)E2- und / oder 5-LO-vermittelter Erkrankungen und krankhafter Zustände.The present invention relates to the use of derivatives of 3-carboxy-indole, in particular of 2-aryl- and 2-alkylaryl-indole-3-carboxylic acid esters and their structural derivatives for the inhibition of inducible microsomal prostaglandin E 2 synthase-1 (mPGES- 1) and 5-lipoxygenase (5-LO). In particular, the invention relates to the use of derivatives of 3-carboxy-aryl [g] indole, in particular 2-aryl- and 2-arylalkyl-aryl [g] indole-3-carboxylic acid ester, for inhibiting mPGES-1 and the 5- LO. Furthermore, the invention relates to the use of indole-3-carboxylic acid esters for the manufacture of a medicament for the treatment of prostaglandin (PG) E 2 and / or 5-LO-mediated diseases and pathological conditions.
Akute und chronische entzündliche Erkrankungen gehen mit einer erhöhten Aktivität von entzündungsrelevanten Zellen wie z.B. Monozyten, Granulozyten, Lymphozyten und endothelialen Zellen einher, die vermehrt PGE2 und/oder 5-LO Produkte (hauptsächlich Leukotriene (LTs)) freisetzen. Diese 5-LO Produkte und das PGE2 sind maßgeblich für die Entstehung und Aufrechterhaltung entzündlicher Symptomatik (Schmerz, Schwellung, Rötung, Überwärmung und Funktionsverlust) verantwortlich bzw. wirken fördernd darauf ein. Daneben fördern 5-LO Produkte allergisches Asthma und allergische Rhinitis, sind an der Entstehung und Progression der Arteriosklerose beteiligt und spielen damit eine wichtige Rolle bei der Pathologie kardiovaskulärer Erkrankungen (z.B. Angina pectoris, Schlaganfall, Herzinfarkt etc.). Weiterhin haben PGE2 und 5-LO Produkte eine wichtige Funktion bei der Proliferation verschiedener Zellen und sind für die Entstehung und Aufrechterhaltung von Krebserkrankungen verantwortlich.Acute and chronic inflammatory diseases are associated with increased activity of inflammation-relevant cells such as monocytes, granulocytes, lymphocytes and endothelial cells, which release more PGE 2 and / or 5-LO products (mainly leukotrienes (LTs)). These 5-LO products and the PGE 2 are significantly responsible for the development and maintenance of inflammatory symptoms (pain, swelling, redness, overheating and loss of function) responsible or have a promotional effect on it. In addition, 5-LO products promote allergic asthma and allergic rhinitis, are involved in the development and progression of arteriosclerosis and thus play an important role in the pathology of cardiovascular diseases (eg angina pectoris, stroke, heart attack, etc.). Furthermore, PGE 2 and 5-LO products play an important role in the proliferation of different cells and are responsible for the development and maintenance of cancer.
Die PG-Biosynthese wird durch die katalytische Umsetzung von Arachidonsäure zu PGH2 durch die Cyclooxygenase (COX)-I oder -2 eingeleitet (Figur 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 PGs dagegen erfüllen 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 beträchtliche Nebenwirkungen (Magen, Niere) auf [3]. Die induzierbare mPGES-1 ist Mitglied der MAPEG Familie und katalysiert die Umwandlung von PGH2 zu PGE2 [4]. PGE2 vermittelt seine Effekte über vier G- Protein-gekoppelte Rezeptoren (sog. EP-Rezeptoren) auf entsprechenden Zielzellen und weist im Gegensatz zu den physiologisch notwendigen PGs ausgeprägte pathophysiologische Eigenschaften (Entzündung, Schmerz, Fieber, Krebserkrankungen, Angiogenese) auf. Im Magen und in der Niere trägt PGE2 allerdings zur Homöostase bei.PG biosynthesis is initiated by the catalytic conversion of arachidonic acid to PGH 2 by cyclooxygenase (COX) -I or -2 (Figure 1). Certain PGs, including the PGE 2 , are mediators in inflammation (especially rheumatoid arthritis), pain and fever, and are also involved in cancers (lung, colon, endometrium). Other PGs, 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 (stomach, kidney) due to the lack of physiologically important PGs [3]. The inducible mPGES-1 is a member of the MAPEG family and catalyzes the transformation of PGH 2 into PGE 2 [4]. PGE 2 mediates its effects via four G protein-coupled receptors (so-called EP receptors) on corresponding target cells and, in contrast to the physiologically necessary PGs pronounced pathophysiological properties (inflammation, pain, fever, cancer, angiogenesis) on. However, PGE 2 contributes to homeostasis in the stomach and kidney.
Seit Entdeckung der induzierbaren mPGES-1 im Jahre 1999 ist man bestrebt, potente und selektive Hemmstoffe gegen die mPGES-1 zu entwickeln, um die entzündliche PGE2 Synthese selektiv zu inhibieren, ohne dabei die Bildung der physiologisch wichtigen PGs zu unterdrücken [4, 5]. Dies macht die mPGES-1 zu einem interessanten Arzneistoff-Target, v.a. bei chronisch entzündlichen Erkrankungen (rheumatoide Arthritis), die mit Schmerz oder auch mit Fieber einhergehen, aber auch bei diversen Krebserkrankungen. Allerdings ist bislang kein Hemmstoff der mPGES-1 als Arzneimittel zur Therapie zugelassen. Nur eine geringe Anzahl an Hemmstoffen (wie z.B. MK-886) ist derzeit verfügbar und die Substanzen befinden sich noch in klinischer Prüfung. Die Motivation der pharmazeutischen Forschung sichere und selektive Hemmstoffe der mPGES-1 zu finden ist enorm.Since the discovery of inducible mPGES-1 in 1999, efforts have been made to develop potent and selective inhibitors of mPGES-1 to selectively inhibit inflammatory PGE 2 synthesis without suppressing the formation of physiologically important PGs [4, 5 ]. This makes the mPGES-1 an interesting drug target, especially in chronic inflammatory diseases (rheumatoid arthritis), which are associated with pain or with fever, but also in various cancers. However, so far no inhibitor of mPGES-1 is approved as a drug for therapy. Only a small number of inhibitors (such as MK-886) are currently available and the substances are still under clinical review. The motivation of pharmaceutical research to find safe and selective inhibitors of mPGES-1 is enormous.
Die 5-Lipoxygenase ist das Schlüsselenzym der Leukotrienbiosynthese, welches die Umsetzung der freien Arachidonsäure mit molekluarem Sauerstoff zur 5-Hydro- peroxy-eikosatetraensäure (5-HPETE) katalysiert (Fig. 2) [6]. 5-HPETE kann durch Peroxidasen zum korrespondierenden Alkohol 5-Hydroxyeikosatetraensäure (5-HETE) reduziert oder erneut unter Katalyse der 5-LO zum LTA4 umgesetzt werden. Das instabile LTA4 wird dann enzymatisch zu LTB4 oder zu den Cysteinyl- LTs C4, D4 und E4 umgesetzt. Sämtliche 5-LO Produkte binden und agieren über spezifische G-Protein-gekoppelte Rezeptoren auf verschiedenen Zielzellen und vermitteln so ihre Wirkung. Diese biologischen Wirkungen reichen u.a. von der Chemotaxis und Chemokinese von Leukozyten, Aktivierung funktioneller Prozesse von Phagozyten, Erhöhung der Kapillarpermeabilität und Plasmaexudation, Konstriktion glatter Muskelzellen, insbesondere der Bronchiolen, bis hin zur Stimulation der Proliferation verschiedener Zelltypen [7]. Aufgrund der Kenntnis dieser Wirkungen und aufgrund von Studienergebnissen unter Verwendung von Hemmstoffen der 5-LO Produktbildung oder von LT Rezeptorantagonisten sowie von 5-LO knock-out-Mäusen, geht man davon aus, dass eine überschießende, nicht physiologische 5-LO Produktbildung an der Entstehung und Aufrechterhaltung von Erkrankungen und krankhaften Zuständen beteiligt ist, wie z.B. an entzündlichen Hauterkrankungen (Psoriasis, Neurodermitis), Asthma, allergische Rhinitis, Osteoarthritis, Rheumatoide Arthritis, Osteoporose, kardiovaskulären Erkrankungen (Arteriosklerose, Schlaganfall, Herzinfarkt, etc.) und auch bei Krebs (z.B. Pankreaskarziom, Prostatakarzinom, Mamakarzinom etc.) [7].5-lipoxygenase is the key enzyme in leukotriene biosynthesis, which catalyzes the reaction of free arachidonic acid with molecular oxygen to form 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) (Figure 2) [6]. 5-HPETE can be reduced by peroxidases to the corresponding alcohol 5-hydroxyeicosatetraenoic acid (5-HETE) or converted again to the LTA 4 with catalysis of the 5-LO. The unstable LTA 4 is then enzymatically converted to LTB 4 or to the cysteinyl LTs C 4 , D 4 and E 4 . All 5-LO products bind and act via specific G-protein coupled receptors on different target cells, thus mediating their effect. These biological effects range from the chemotaxis and chemokinesis of leukocytes, activation of functional processes of phagocytes, increase of capillary permeability and plasma exudation, constriction of smooth muscle cells, especially bronchioles, to the stimulation of the proliferation of different cell types [7]. Based on the knowledge of these effects and on study results using inhibitors of 5-LO product formation or LT receptor antagonists as well as 5-LO knockout mice, it is believed that excessive, non-physiological 5-LO product formation on the Emergence and maintenance of diseases and pathological conditions is involved, such as inflammatory skin diseases (psoriasis, atopic dermatitis), asthma, allergic rhinitis, osteoarthritis, rheumatoid arthritis, osteoporosis, cardiovascular diseases (arteriosclerosis, stroke, heart attack, etc.) and also in cancer (eg, pancreatic carcinoma, prostate carcinoma, mummy carcinoma, etc.) [7].
Bislang wurden zahlreiche 5-LO Inhibitoren und Leukotrienrezeptorantagonisten entwickelt. 5-LO Inhibitoren unterteilen sich gemäß dem molekularen Wirkungsmechanismus in (I) redoxaktive Substanzen, (II) Eisenligandinhibitoren, und (III) nicht-redoxaktive (kompetitive) 5-LO inhibitoren [8]. Ein weiterer Ansatz die 5-LO Produktbildung zu hemmen, besteht in der Blockade des 5-LO-aktivierenden Proteins (FLAP) durch niedermolekulare Inhibitoren. Während die Leukotrienrezeptorantagonisten (z.B. Montelukast, Zafirlukast und Pranlukast) fester Bestandteil der Asthmatherapie sind, ist derzeit nur ein 5-LO Inhibitor (Zileuton) als Arzneimittel zugelassen. Der Grund liegt an der geringen Wirksamkeit am Patient und/oder and den zahlreichen und schweren Nebenwirkungen der Wirkstoffe, insbesondere von redoxaktiven 5-LO Inhibitoren.So far, numerous 5-LO inhibitors and leukotriene receptor antagonists have been developed. According to the molecular mechanism of action, 5-LO inhibitors are subdivided into (I) redox-active substances, (II) iron-ligand inhibitors, and (III) non-redox-active (competitive) 5-LO inhibitors [8]. Another approach to inhibiting 5-LO product formation is the blockade of 5-LO activating protein (FLAP) by small molecule inhibitors. While the leukotriene receptor antagonists (e.g., montelukast, zafirlukast, and pranlukast) are an integral part of asthma therapy, only a 5-LO inhibitor (zileuton) is currently approved as a drug. The reason is the low efficacy on the patient and / or the numerous and severe side effects of the drugs, especially redox-active 5-LO inhibitors.
Zusammenfassend spielen also sowohl die mPGES-1 als auch die 5-LO Schlüsselrollen bei entzündlichen bzw. allergischen Erkrankungen, die jedoch sowohl hinsichtlich der unterschiedlichen Angriffspunkte des PGE2 (EP-Rezeptoren) und der 5-LO Produkte (LT-Rezeptoren) als auch der Wirkungsweisen sehr unterschiedlich sind. Dies impliziert, dass die kombinierte / gleichzeitige Unterdrückung beider Enzyme zu einem additiven oder auch synergistischen Effekt führen kann.In summary, both the mPGES-1 and the 5-LO key roles in inflammatory and allergic diseases, however, both in terms of the different targets of PGE 2 (EP receptors) and the 5-LO products (LT receptors) as well the modes of action are very different. This implies that the combined / simultaneous suppression of both enzymes can lead to an additive or even synergistic effect.
Die Aufgabe der vorliegenden Erfindung ist es daher, Substanzen zu identifizieren, die die PGE2 Synthese potent hemmen und die zusätzlich in der Lage sind, die 5-LO zu inhibieren und somit entzündliche, allergische und neoplastische Prozesse in einer additiven und / oder synergistischen Weise blockieren. Dabei sollen die Nachteile der bekannten Verfahren (Einsatz von steroidalen Antirheumatika (Glukokorticoide), NSAIDs, COX-2-selektiven Hemmstoffen, redoxaktive 5-LO Inhibitoren, und Leukotrienrezeptorantagonisten) umgangen werden und Wirkstoffe identifiziert werden, die zur Herstellung eines Arzneistoffes zur therapeutischen Behandlung von 5-LO Produkt- und/oder PGE2-vermittelten Erkrankungen, insbesondere von chronischen Entzündungen wie rheumatoide Arthritis, Osteoarthritis, Erkrankungen des kardiovaskulären Systems, Asthma, allergische Rhinitis, Multiple Sklerose, entzündliche Hauterkrankungen, Osteoporose, und Krebs, und krankhafter Zustände, insbesondere Schmerz und Fieber, verwendet werden können, um bei einer hohen Effizienz geringe Nebenwirkungen aufzuweisen.The object of the present invention is therefore to identify substances which potently inhibit PGE 2 synthesis and which are additionally capable of producing the 5-LO inhibit and thus block inflammatory, allergic and neoplastic processes in an additive and / or synergistic manner. The disadvantages of the known methods (use of steroidal anti-inflammatory drugs (glucocorticoids), NSAIDs, COX-2-selective inhibitors, redox-active 5-LO inhibitors, and leukotriene receptor antagonists) are to be circumvented and drugs identified for the preparation of a drug for the therapeutic treatment of 5-LO product and / or PGE 2 mediated diseases, in particular chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, cardiovascular system disorders, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis, and cancer, and morbid conditions, in particular Pain and fever, can be used to have low side effects at high efficiency.
Diese Aufgabe wird durch den Einsatz von lndol-3-carbonsäureestern, insbesondere von 2-Aryl- und 2-Arylalkyl-indol-3-carbonsäureestern sowie deren strukturellen Derivaten, gelöst, wie sie im Anspruch 1 und abhängigen Ansprüchen 2 bis 7 beschrieben sind.This object is achieved by the use of indole-3-carboxylic acid esters, in particular of 2-aryl and 2-arylalkyl-indole-3-carboxylic acid esters and their structural derivatives, as described in claim 1 and dependent claims 2 to 7.
Die erfindungsgemäßen Verbindungen können durch das Vorhandensein von Asymmetriezentren als Stereoisomere vorliegen. Gegenstand der vorliegendenThe compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers. Subject of the present
Erfindung sind alle möglichen Stereoisomere sowohl als Racemate, als auch in enantiomerenreiner Form. Der Begriff Stereoisomere umfaßt auch alle möglichenInvention are all possible stereoisomers both as racemates, as well as in enantiomerically pure form. The term stereoisomers also includes all possible ones
Diastereomere und Regioisomere und Tautomere (z.B. Keto-Enol-Tautomere), in denen die erfindungsgemäßen Verbindungen vorliegen können, die damit ebenfalls Gegenstand der Erfindung sind.Diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the present invention may be present, which are also objects of the invention.
Es hat sich in der vorliegenden Erfindung herausgestellt, dass lndol-3- carbonsäureester effektive Inhibitoren der mPGES-1 bzw. der PGE2-Synthese sind (Tabelle 1 und 2). Daher wurden ausgehend von lndol-3-carbonsäureestem Derivate entwickelt, die in der Lage sind, die mPGES-1 potent zu hemmen. Als besonders potent haben sich lndol-3-carbonsäureester erwiesen, die einen [6,7]-annelierten Aromaten aufweisen. Zudem wurde C2 und C5 des lndol-3-carbonsäureesters substituiert, insbesondere durch substituierte Benzyl- oder Anilinosubstituenten an C2 und durch Aryl-, Hydroxyl- oder Chlorsubstituenten an C5. Überraschenderweise greifen diese Verbindungen sehr potent in die Biosynthese des PGE2 ein. Dem liegt eine Hemmung der katalytischen Aktivität der humanen mPGES-1 (Umwandlung von PGH2 zu PGE2 im zellfreien System) zugrunde, wie aus den Ausführungsbeispielen ersichtlich ist (Tabelle 1 und 2, Abb. 3). Die IC50 Werte liegen bei diesen Substanzen im Bereich von ca. 0.5 - 10 μM. Damit wurden in der vorliegenden Erfindung lndol-3- carbonsäureester zum ersten Mal als direkte Hemmstoffe der mPGES-1 bzw. Hemmstoffe der PGE2 Synthese identifiziert.It has been found in the present invention that indole-3-carboxylic acid esters are effective inhibitors of mPGES-1 and PGE 2 synthesis, respectively (Table 1 and 2). Therefore, starting from indole-3-carboxylic acid esters, derivatives have been developed which are capable of potently inhibiting mPGES-1. Indole-3-carboxylic acid esters which have a [6,7] -annulated aromatic have proven to be particularly potent. In addition, C2 and C5 of the indole-3-carboxylic acid ester has been substituted, in particular by substituted benzyl or anilino substituents on C2 and by aryl, hydroxyl or chlorine substituents on C5. Surprisingly These compounds are very potent in the biosynthesis of PGE 2 . This is based on an inhibition of the catalytic activity of human mPGES-1 (conversion of PGH 2 to PGE 2 in the cell-free system), as can be seen from the exemplary embodiments (Table 1 and 2, FIG. 3). The IC 50 values for these substances are in the range of about 0.5-10 μM. Thus, in the present invention, indole-3-carboxylic acid esters were identified for the first time as direct inhibitors of mPGES-1 and inhibitors of PGE 2 synthesis, respectively.
Tabelle 1 umfasst einige Beispiele für strukturelle Modifikationen von lndol-3- carbonsäureestem und deren Hemmwirkung auf mPGES-1. n.i. = keine Hemmung.Table 1 includes some examples of structural modifications of indole-3-carboxylic acid esters and their inhibitory effect on mPGES-1. n.i. = no inhibition.
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Die Befunde lassen den Schluss zu, dass lndol-3-carbonsäureester ein hohes Potential zur Therapie entzündlicher und/oder neoplastischer Erkrankungen und krankhafter Zustände haben, die mit einer erhöhten Bildung von PGE2 einhergehen. Damit könnten durch Einsatz von lndol-3-carbonsäureestern PGE2-vermittelte Erkrankungen behandelt werden, wobei im Gegensatz zu bisherigen Verfahren (COX-Hemmung) weniger Nebenwirkungen auftreten dürften.The findings suggest that indole-3-carboxylic acid esters have a high potential for the treatment of inflammatory and / or neoplastic diseases and disease states associated with increased PGE 2 formation. This could be treated by the use of indole-3-carboxylic acid esters PGE 2 -mediated diseases, in contrast to previous methods (COX inhibition) fewer side effects are likely to occur.
Somit können Zubereitungen, die lndol-3-carbonsäureester enthalten, erfindungsgemäß zur Hemmung der mPGES-1 verwendet werden. DieseThus, preparations containing indole-3-carboxylic acid esters can be used in the present invention to inhibit mPGES-1. These
Zubereitungen können ferner zur Herstellung eines Arzneimittels zur Hemmung derFormulations may also be used for the manufacture of a medicament for inhibiting the
PGE2 Synthese, insbesondere zur Hemmung der mPGES-1 , verwendet werden.PGE 2 synthesis, in particular for the inhibition of mPGES-1, can be used.
Insbesondere können diese Zubereitungen zur Herstellung eines Arzneimittels zurIn particular, these preparations can be used for the manufacture of a medicament for
Behandlung PGE2-vermittelter Erkrankungen und krankhafter Zustände verwendet werden. Diese können z.B. chronische Entzündungen wie rheumatoide Arthritis, undTreatment of PGE 2 -mediated diseases and morbid conditions can be used. These can include chronic inflammation such as rheumatoid arthritis, and
Krebs, Schmerz und Fieber sein.Cancer, pain and fever.
Es hat sich ferner herausgestellt, dass lndol-3-carbonsäureester zusätzlich die 5-LO potent hemmen können. Dabei zeigten die erstmals synthetisierten Aryl[g]indol-3- carbonsäureester eine besonders effektive Hemmung der 5-LO (Tabelle 2). Über die biologische Wirksamkeit dieser Aryl[g]indol-3-carbonsäureester war bislang nichts bekannt. In der vorliegenden Erfindung konnte gezeigt werden, dass diese Substanzen nicht nur die 5-LO Produktbildung in intakten Neutrophilen hemmen, sondern auch mit der 5-LO Aktivität in zellfreien Systemen interferieren (Tabelle 2, Abb. 5 und 6). Letzteres lässt den Schluss zu, dass die Verbindungen die 5-LO direkt hemmen.It has also been found that indole-3-carboxylic acid esters can additionally inhibit the 5-LO potent. The aryl [g] indole-3-carboxylic esters synthesized for the first time showed a particularly effective inhibition of 5-LO (Table 2). The biological activity of these aryl [g] indole-3-carboxylic acid esters was hitherto unknown. In the present invention it could be shown that these Substances not only inhibit 5-LO product formation in intact neutrophils, but also interfere with 5-LO activity in cell-free systems (Table 2, Figs. 5 and 6). The latter suggests that the compounds directly inhibit 5-LO.
Tabelle 2 umfasst einige Beispiele für strukturelle Modifikationen von Aryl[g]indol-3- carbonsäureester und deren Hemmwirkung auf mPGES-1 bzw. 5-LO. n.i. = keine Hemmung; n.d. = nicht bestimmt.Table 2 includes some examples of structural modifications of aryl [g] indole-3-carboxylic acid ester and their inhibitory effect on mPGES-1 and 5-LO, respectively. n.i. = no inhibition; n.d. = not determined.
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Erfindungsgemäß können Zubereitungen, die lndol-3-carbonsäureester, insbesondere Aryl[g]indol-3-carbonsäureester enthalten, zur dualen Hemmung der mPGES-1 und der 5-LO verwendet werden. In einer bevorzugten Ausführung der Erfindung werden 2-Aryl- und 2-Arylalkyl-Derivate der Aryl[g]indol-3- carbonsäureester verwendet, welche die beste Hemmwirkung gegenüber mPGES-1 und 5-LO zeigen.According to the invention, preparations containing indole-3-carboxylic acid esters, in particular aryl [g] indole-3-carboxylic acid esters, can be used for the dual inhibition of mPGES-1 and 5-LO. In a preferred embodiment of the invention, 2-aryl and 2-arylalkyl derivatives of the aryl [g] indole-3-carboxylic acid esters are used which show the best inhibitory activity against mPGES-1 and 5-LO.
Diese Zubereitungen können ferner zur Herstellung eines Arzneimittels zur gleichzeitigen Hemmung der PGE2 Synthese und der 5-LO Produktion verwendet werden. Bevorzugt können diese Zubereitungen zur Herstellung eines Arzneimittels zur therapeutischen Behandlung von PGE2- und 5-LO vermittelten Erkrankungen und krankhafter Zustände, insbesondere von chronischen Entzündungen wie rheumatoide Arthritis, Osteoarthritis, Erkrankungen des kardiovaskulären Systems, Asthma, allergische Rhinitis, Multiple Sklerose, entzündliche Hauterkrankungen, Osteoporose, und Krebs, und krankhafter Zustände, insbesondere Schmerz und Fieber.These preparations may also be used for the manufacture of a medicament for the simultaneous inhibition of PGE 2 synthesis and 5-LO production become. These preparations may preferably be used for the preparation of a medicament for the therapeutic treatment of PGE 2 and 5-LO-mediated diseases and pathological conditions, in particular chronic inflammations such as rheumatoid arthritis, osteoarthritis, cardiovascular system disorders, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases , Osteoporosis, and cancer, and morbid conditions, especially pain and fever.
Die Erfindung umfasst die Verwendung von Zubereitungen zur Hemmung der PGE2 Synthese, insbesondere zur Hemmung der mPGES-1 und / oder zur Hemmung der 5-LO, wobei diese Zubereitungen mindestens einen lndol-3-carbonsäureester und / oder eines seiner Derivate mit den folgenden Strukturformeln enthalten:The invention comprises the use of preparations for inhibiting PGE 2 synthesis, in particular for inhibiting mPGES-1 and / or for inhibiting 5-LO, which preparations comprise at least one indole-3-carboxylic acid ester and / or one of its derivatives with the following Structural formulas contain:
Figure imgf000012_0001
Figure imgf000012_0001
wobei X für einen annelierten Aryl- oder Heteroarylring mit insgesamt 3 bis 8 Ringatomen,where X is a fused aryl or heteroaryl ring having a total of 3 to 8 ring atoms,
R1 für einen Aryl, Heteroaryl, Arylalkyl oder Heteroarylalkyl steht, das über ein Stickstoff-, Sauerstoff- oder Kohlenstoffatom oder eine Aminoalkyl-, Oxoalkyl- oderR 1 is an aryl, heteroaryl, arylalkyl or heteroarylalkyl which has a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or
Alkylgruppe an das Restmolekül geknüpft ist, wobei das Aryl-, Heteroaryl-, Arylalkyl- bzw. Heteroarylalkyl mit einem weiteren Ringsystem kondensiert sein kann, und ein oder mehrere H-Atome im Aryl, Heteroaryl, Arylalkyll bzw. Heteroarylalkyl substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (C1-10)Alkyl, (C2-i0)Alkenyl, (C2-10)Alkinyl, OCF3, (C1- Alkyl group is attached to the remainder of the molecule, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, arylalkyll or heteroarylalkyl may be substituted by one or more groups selected from the substance class halogen, O, N, S, OH, NH 2, NO 2, SH, (C 1-10) alkyl, (C 2- I 0) alkenyl, (C 2-10) alkynyl, OCF 3 , (C 1-
10)Alkoxy, (C1-10)Alkylamin, (C1-10)Alkylthio, (C1-10)Alkylsilyl, Cycloalkyl, Cycloalkenyl, 10 ) alkoxy, (C 1-10 ) alkylamine, (C 1-10 ) alkylthio, (C 1-10 ) alkylsilyl, cycloalkyl, cycloalkenyl,
Cycloheteroalkyl, oder Cycloheteroalkenyl, R2 die Alkoholkomponente des Carbonsäureesters an C2 bildet und insbesondere einen Alkyl-, Aryl- oder Alkylarylrest darstellt, undCycloheteroalkyl, or cycloheteroalkenyl, R 2 forms the alcohol component of the carboxylic ester on C 2 and in particular represents an alkyl, aryl or alkylaryl radical, and
R3 für H oder einen beliebigen polaren oder lipophilen Rest, insbesondere eine OH- Gruppe oder Halogen, steht,R 3 is H or any polar or lipophilic radical, in particular an OH group or halogen,
R4 für H steht oder auch durch einen Alkyl-, Aryl- oder Arylalkylrest substituiert ist.R 4 is H or is also substituted by an alkyl, aryl or arylalkyl radical.
Besondere Ausführungsformen der Erfindung sind insbesondere solche, bei denen der lndol-3-carbonsäureester ein 2-Aryl- oder 2-Arylalkyl-indol-3-carbonsäureester oder ein strukturelles Derivat davon ist.Particular embodiments of the invention are in particular those in which the indole-3-carboxylic acid ester is a 2-aryl or 2-arylalkyl-indole-3-carboxylic acid ester or a structural derivative thereof.
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen der lndol-3-carbonsäureester ein Aryl[g]indol-3-carbonsäureester ist.Another particular embodiment of the invention are compounds in which the indole-3-carboxylic acid ester is an aryl [g] indole-3-carboxylic acid ester.
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen X für einen anneliierten Phenyl- oder Pyridinylring steht. In einer weiteren besonderen Ausführungsform ist der annellierte Phenyl- oder Pyridinylring ein- oder zweifach mit CrC4-Alkoxygruppen substituiert, bevorzugt zweifach mit Methoxygruppen.Another particular embodiment of the invention are compounds wherein X is an annelated phenyl or pyridinyl ring. In a further particular embodiment, the fused phenyl or pyridinyl ring is mono- or disubstituted by C 1 -C 4 -alkoxy groups, preferably twice with methoxy groups.
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen R1 ausgewählt ist aus der GruppeAnother particular embodiment of the invention are compounds in which R1 is selected from the group
-NH-C6H5 -NH-C6H4-CI-NH-C 6 H 5 -NH-C 6 H 4 -CI
-NH-C6H4-F-NH-C 6 H 4 -F
-NH-C6H4-CF3 -NH-C 6 H 4 -CF 3
-NH-C6H3-CI2 -NH-C 6 H 3 -CI 2
-NH-C5H3N-CI -0-C6H4-Cl-NH-C 5 H 3 N-Cl-O-C 6 H 4 -Cl
-N(CH3)-C6H4-CI-N (CH 3 ) -C 6 H 4 -CI
-CH2-CH2-C6H4-CI-CH 2 -CH 2 -C 6 H 4 -CI
-NH-CH2-C6H4-CI-NH-CH 2 -C 6 H 4 -CI
-NH-CH2-C6H5 -CH2-C6H4-CI -CH2-CH2-C6H5 .-NH-CH 2 -C 6 H 5 -CH 2 -C 6 H 4 -CI -CH 2 -CH 2 -C 6 H 5 .
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen R2 ausgewählt ist aus der GruppeAnother particular embodiment of the invention are compounds in which R2 is selected from the group
-CH3 -CH 3
-C2H5 -C 2 H 5
-CH2-C6H5.-CH 2 -C 6 H 5 .
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen R3 ausgewählt ist aus der GruppeAnother particular embodiment of the invention are compounds in which R3 is selected from the group
-OH-OH
-CH2-C6H5 -CH 2 -C 6 H 5
-Cl -0-C6H5 -Cl-O-C 6 H 5
-O-CH2-C6H5.-O-CH 2 -C 6 H 5 .
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen R4 ausgewählt ist aus der Gruppe -HAnother particular embodiment of the invention are compounds in which R4 is selected from the group -H
-CH2-C6H5.-CH 2 -C 6 H 5 .
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen R5 und R6 unabhängig voneinander ausgewählt sind aus der Gruppe -H -OCH3.A further particular embodiment of the invention are compounds in which R5 and R6 are independently selected from the group -H -OCH. 3
Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen an C2-Position des lndol-3-carbonsäureesters substituierte Benzyl- oder Anilinosubstituenten eingeführt sind. Eine weitere besondere Ausführungsform der Erfindung sind Verbindungen, bei denen der lndol-3-carbonsäureester an C5-Position durch Aryl-, Hydroxyl- oder Chlor-Reste substituiert ist.Another particular embodiment of the invention are compounds in which substituted benzyl or anilino substituents are introduced at C2 position of the indole-3-carboxylic acid ester. Another particular embodiment of the invention are compounds in which the indole-3-carboxylic acid ester is substituted at C5-position by aryl, hydroxyl or chlorine radicals.
Die Erfindung umfasst ferner eine pharmazeutische Zusammensetzung, die einen lndol-3-carbonsäureester nach einer der o.g. Strukturformeln und gegebenenfalls ein pharmazeutisches Trägermaterial enthält.The invention further comprises a pharmaceutical composition comprising an indole-3-carboxylic acid ester according to one of the above-mentioned. Structural formulas and optionally contains a pharmaceutical carrier material.
Zur therapeutischen Behandlung von PGE2- und / oder 5-LO-vermittelten Erkrankungen sind Plasmakonzentrationen von ca. 0,1 - 10 μM lndol-3- carbonsäureester erstrebenswert. Das könnte etwa durch die p.o. Gabe von etwa 5 - 500 mg/Tag erreicht werden.For the therapeutic treatment of PGE 2 - and / or 5-LO-mediated diseases plasma concentrations of about 0.1 - 10 uM indole-3-carboxylic acid esters are desirable. This could be achieved, for example, by administering about 5 - 500 mg / day.
Die Verabreichung von lndol-3-carbonsäureestern oder diese enthaltenden pharmazeutischen Zusammensetzungen zur Therapie von Erkrankungen kann oral oder parenteral erfolgen.The administration of indole-3-carboxylic acid esters or pharmaceutical compositions containing them for the treatment of diseases can be oral or parenteral.
Die vorliegende Erfindung lehrt daher eine pharmazeutische Zusammensetzung enthaltend mindestens eine erfindungsgemäße Verbindung. Optional können ein oder mehrere physiologisch verträgliche Hilfsstoffe und/oder Trägerstoffe 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., i.m., 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, Mannit 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 excipients 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 may also be present in the form of their salts with physiologically acceptable counterions such as Mg ++, Ca ++, Na +, K +, Li + or ammonium derivatives such as cyclohexylammonium. Amino-containing compounds may also be present in the form of an ammonium salt, for example 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 retarded Release of active substances, in the preparation of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. As adjuvants are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol 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 Substanzkombination 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. 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.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 prepared to the desired dosage form is. 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. 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.
Ein Vorteil der vorliegenden Erfindung liegt darin, dass für die Arzneistofftargets mPGES-1 und 5-LO G rund Strukturen identifiziert wurden, die zur Hemmung der Aktivität der mPGES-1 und der 5-LO führen. Damit könnte 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. Parallel dazu kann die Bildung von 5-LO Produkten unterbunden werden. Dies hat zur Folge, dass die Therapie entsprechender Erkrankungen und krankhafter Zustände mittels lndol-3-carbonsäureestern im Vergleich zu COX-1/2 Inhibitoren weniger Nebenwirkungen aufweisen dürfte. Da selektive COX-2- Inhibitoren wegen ihrer Nebenwirkungen vom Markt genommen (Rofecoxib) oder ihnen die Zulassung nicht erteilt wurde (Etoricoxib), kann das hier vorgestellte Verfahren stellvertretend und zudem vorteilhafter eingesetzt werden.One advantage of the present invention is that drug targets mPGES-1 and 5-LO G have been identified as having structures that result in the inhibition of mPGES-1 and 5-LO activity. Thus, the synthesis of PGE 2 could be selectively inhibited by COX-2 / mPGES-1, without, as previously by inhibitors of COX-1 and -2, the synthesis of other (physiologically important) Inhibit PGs. In parallel, the formation of 5-LO products can be prevented. This has the consequence that the treatment of corresponding diseases and pathological conditions by means of indole-3-carboxylic acid esters compared to COX-1/2 inhibitors should have fewer side effects. As selective COX-2 inhibitors have been withdrawn from the market because of their side effects (rofecoxib) or the approval has not been granted (etoricoxib), the method presented here can be used as a representative and also more advantageously.
Da nun die duale Hemmung der mPGES-1 und der 5-LO hinsichtlich der therapeutischen Anwendung bei Erkrankungen oder krankhaften Zuständen zu einer additiven oder sogar synergistischen Wirkung führen und geringere Nebenwirkungen aufweisen kann, ist darin ein Vorteil gegenüber anderen Verfahren (Monotherapie) zu sehen. Aufgrund der mPGES-1/5-LO-Hemmung können lndol-3-carbonsäureester gezielt bei entzündlichen Erkrankungen eingesetzt werden, die auf eine erhöhte Bildung von PGE2 und/oder von 5-LO Produkten zurückzuführen sind.Since the dual inhibition of mPGES-1 and 5-LO with respect to the therapeutic use in diseases or pathological conditions to an additive or even synergistic effect and may have fewer side effects, this is an advantage over other procedures (monotherapy) to see. Due to the mPGES-1/5-LO inhibition, indole-3-carboxylic acid esters can be used specifically for inflammatory diseases that are attributable to an increased formation of PGE 2 and / or 5-LO products.
Desweiteren kann durch Verwendung von lndol-3-carbonsäureester der Einsatz bzw. die Dosis von steroidalen (Glucocortikoide) und nicht-steroidalen Antiphlogistika (COX Inhibitoren) reduziert und die Dauer der Einnahme verkürzt werden. COX Inhibitoren führen wie erwähnt wegen ihrer unspezifischen Blockade der Synthese aller PGs zu erheblichen Nebenwirkungen.Furthermore, by using indole-3-carboxylic acid ester, the use or the dose of steroidal (glucocorticoids) and non-steroidal anti-inflammatory drugs (COX inhibitors) can be reduced and the duration of ingestion can be shortened. COX inhibitors lead, as mentioned, because of their unspecific blockade of the synthesis of all PGs to significant side effects.
Die Erfindung kann genutzt werden, um alle Formen von Erkrankungen und krankhafter Zustände, die mit einer erhöhten Produktion von PGE2 und / oder 5-LO Produkten einhergehen, zu behandeln. Dabei handelt es sich primär um chronische Entzündungen wie rheumatoide Arthritis, Osteoarthritis, Erkrankungen des kardiovaskulären Systems, Asthma, allergische Rhinitis, Multiple Sklerose, entzündliche Hauterkrankungen, Osteoporose und Krebs, Schmerz und Fieber, bei denen PGE2 und/oder 5-LO Produkte eine Rolle spielen.The invention can be used to treat all forms of diseases and pathological conditions associated with increased production of PGE 2 and / or 5-LO products. These are primarily chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, cardiovascular diseases, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis and cancer, pain and fever in which PGE 2 and / or 5-LO products have one Role-play.
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: Biosyntheseweg of PGE2.
Fig. 2: Biosyntheseweg der Leukotriene und anderer 5-LO Produkte.Fig. 2: Biosynthetic pathway of the leukotrienes and other 5-LO products.
Fig. 3: Konzentrations-Wirkungskurven von 89a, 132b und 135a bezüglich der Hemmung der mPGES-1 -vermittelten Synthese von PGE2 (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in der mikrosomalen Fraktion von lnterleukin-1 ß-stimulierten A549 Zellen (Mittelwert + Standardfehler, n = 3).Figure 3: Concentration-action curves of 89a, 132b and 135a for the inhibition of 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 = 3).
Fig. 4: Hemmung der Synthese von PGE2 (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in intakten lnterleukin-1 ß-stimulierten A549 Zellen nach Aktivierung mit Ca2+-inophore A23187 und AA (Mittelwert + Standardfehler, n = 3). Konzentrations-Wirkungskurven von 89a und 135a.FIG. 4: Inhibition of the synthesis of PGE 2 (percentage activity against the control with DMSO as solvent) in intact interleukin-1β-stimulated A549 cells after activation with Ca 2+ -inophores A23187 and AA (mean + standard error, n = 3 ). Concentration-activity curves of 89a and 135a.
Fig. 5: Konzentrations-Wirkungskurven bezüglich der Hemmung der 5-LO Produktbildung (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in zellfreien Präparationen (100.000χg Überstände von Lysaten aus 5-LO- eprimierenden E.coli). Die Ergebnisse sind als Mittelwert + Standardfehler, n = 3 angegeben.FIG. 5 shows concentration-response curves for inhibition of 5-LO product formation (percent activity versus the control with DMSO as solvent) in cell-free preparations (χ 100,000 g supernatants of lysates of 5-LO eprimierenden E.coli). The results are given as mean + standard error, n = 3.
Fig. 6: Konzentrations-Wirkungskurven bezüglich der Hemmung der 5-LO Produktbildung (Prozentuale Aktivität gegenüber der Kontrolle mit DMSO als Solvent) in isolierten humanen PMNL, stimuliert mit 2.5 μM lonophor plus 20 μM Arachidonsäure. Die Ergebnisse sind als Mittelwert + Standardfehler, n = 3 angegeben.Figure 6: Concentration-action curves for inhibition of 5-LO product formation (percent activity versus control with DMSO as solvent) in isolated human PMNL stimulated with 2.5 μM lonophor plus 20 μM arachidonic acid. The results are given as mean + standard error, n = 3.
Ausführungsbeispieleembodiments
a) Einfluss von lndol-3-carbonsäureester auf die Aktivität der mPGES-1 1. Bestimmung der Aktivität der mPGES-1 in der mikrosomalen Fraktion von A549- Zellen:a) Influence of indole-3-carboxylic acid ester on the activity of mPGES-1 1. Determination of the activity of mPGES-1 in the microsomal fraction of A549 cells:
A549 Zellen wurden mit lnterleukin-1 ß (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 (lndol-3- carbonsäureester bzw. DMSO) für 15 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+, Zitronensäure und 11-ß-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 195 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 centrifuged for 1 h hour to obtain microsomes. The pellet (microsomes) was dissolved in Homogensierungspuffer and preincubated with the test substances (indole-3-carboxylic acid ester or DMSO) for 15 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-ß-PGE 2 as standard) ended. One approach is added before the start of the reaction with the stop solution to determine already contained in the PGH 2 solution PGE 2 . After solid phase extraction (RP-18 columns and acetonitrile as eluent), the sample was analyzed by HPLC (RP-18, UV detection at 195 nm).
Es zeigt sich, dass die Vorinkubation der mikrosomalen Fraktion von lnterleukin-1 ß- stimulierten A549 Zellen mit konkreten lndol-3-carbonsäureestern zu einer potenten Hemmung der mPGES-1 Aktivität führt, indem beispielsweise 10 μM Verbindung 135a die PGE2-Synthese aus PGH2 zu ca. 90 % hemmt, der IC50-WeIi liegt bei ca. 1 μM (Abb. 3).It has been found that preincubation of the microsomal fraction of interleukin-1β-stimulated A549 cells with specific indole-3-carboxylic acid esters results in potent inhibition of mPGES-1 activity, for example, by adding 10 μM compound 135a to PGE 2 synthesis from PGH 2 to about 90% inhibits, the IC 50 -WeIi is about 1 uM (Fig. 3).
2. Bestimmung der PGE?-Svnthese in intakten A549-Zellen:2. Determination of the PGE? Sness in Intact A549 Cells:
A549 Zellen wurden mit lnterleukin-1 ß (1 ng/ml) für 72 Stunden inkubiert. Nach Ernte und Zellzahlbestimmung wurden die Zellen (2 x 106) in CaCI2-haltigem PBS-Puffer resuspendiert. Nach Vorinkubation mit den Testsubstanzen für 10 min bei 370C, wird die PGE2-Bildung durch Zugabe von A23187 (2,5 μM), AA (1 μM) and [3H]AA (18,4 kBq) induziert. Die Reaktion wird nach 15 min bei 37°C durch Abkühlen auf 4°C gestoppt. Nach Zentrifugation (800χg, 5 min, 4°C) wird der Überstand durch Zitronensäure angesäuert (pH 3) und mit dem internen Standard 11ß-PGE2 versehen. Das radiomarkierte PGE2 wird durch Festphasenextraktion (RP-18-Säulen und Acetonitril als Elutionsmittel) und RP-HPLC (RP-18, UV-Detektion des Standards bei 195 nm) abgetrennt und mittels Flüssigszintillationszählung quantifiziert (LKB Wallac 1209 Rackbeta Liquid Scintillation Counter).A549 cells were incubated with interleukin-1β (1 ng / ml) for 72 hours. After harvesting and cell count determination, the cells (2 × 10 6 ) were resuspended in CaCl 2 -containing PBS buffer. After preincubation with the test substances for 10 min at 37 0 C, the PGE 2 formation is induced by the addition of A23187 (2.5 uM), AA (1 uM) and [3 H] AA (18.4 kBq). The reaction is stopped after 15 min at 37 ° C by cooling to 4 ° C. After centrifugation (800χg, 5 min, 4 °C) the supernatant is acidified by citric acid (pH 3) and with the internal standard 11β-PGE 2 Mistake. The radiolabelled PGE 2 is separated by solid phase extraction (RP-18 columns and acetonitrile as eluent) and RP-HPLC (RP-18, UV detection of the standard at 195 nm) and quantified by liquid scintillation counting (LKB Wallac 1209 Rackbeta Liquid Scintillation Counter). ,
Auch im zellulären System treten lndol-3-carbonsäureester als potente Inhibitoren der PGE2-Synthese auf und zeigen ICso-Werte von ca. 5 μM für Verbindung 89a und 135a (Abb. 4)Also in the cellular system, indole-3-carboxylic acid esters appear as potent inhibitors of the PGE 2 synthesis and show IC 50 values of about 5 μM for compounds 89a and 135a (FIG. 4).
b) Einfluss von Arylfgiindol-3-carbonsäureester auf die Aktivität der 5-LOb) Influence of arylfgiindole-3-carboxylic acid ester on the activity of 5-LO
1. Bestimmung der Aktivität der 5-LO in zellfreien Systemen:1. Determination of the activity of 5-LO in cell-free systems:
Zur Gewinnung rekombinanter 5-LO, werden E. coli (Stamm MV1190) mit dem Plasmid pT3-5LO transformiert, nach erfolgter 5-LO Expression geerntet und lysiert [9]. Lysate von E.coli werden einer 100.000χg-Zentrifugation unterworfen. Aliquote des 100-OOOχg Überstands werden dann mit den Inhibitoren auf Eis für 5 min vorinkubiert und für 30 sec im Wasserbad (37°C) vorgewärmt. Zur Induktion der 5-LO Produktbildung wird 20 μM Arachidonsäure und 1 mM Ca2+ zugegeben. Nach 10 min bei 37°C wird die Inkubation mit Methanol gestoppt, die gebildeten 5-LO Metabolite (trans-LTB4, epi-trans-LTB4, 5-H(P)ETE) mittels Festphasenextraktion isoliert und dann mittels automatisiertem RP-HPLC-System qualitativ und quantitativ analysiert [10].To obtain recombinant 5-LO, E. coli (strain MV1190) are transformed with the plasmid pT3-5LO, harvested after 5-LO expression and lysed [9]. Lysate of E. coli χ a 100,000 g centrifugation are subjected. Aliquots of the 100-OOO χ g supernatant is then pre-incubated with the inhibitors on ice for 5 min and preheated in a water bath (37 ° C) for 30 sec. To induce 5-LO product formation, 20 μM arachidonic acid and 1 mM Ca 2+ are added. After 10 min at 37 ° C., the incubation with methanol is stopped, the formed 5-LO metabolites (trans-LTB 4 , epi-trans-LTB 4 , 5-H (P) ETE) are isolated by solid-phase extraction and then purified by means of automated RP- HPLC system qualitatively and quantitatively analyzed [10].
Es zeigt sich (Abb. 5), dass die Verbindungen 89a, 13Od, 135a und 141d zu einer potenten und konzentrationsabhängigen Hemmung der 5-LO Aktivität führt, mit IC50 Werten von 0.25, 0.07, 0.09, und 0.12 μM.It can be seen (Figure 5) that compounds 89a, 13Od, 135a, and 141d result in potent and concentration-dependent inhibition of 5-LO activity, with IC 50 values of 0.25, 0.07, 0.09, and 0.12 μM.
2. Bestimmung der Aktivität der 5-LO in intakten PMNL:2. Determination of the activity of 5-LO in intact PMNL:
PMNL werden aus frischen menschlichen Leukozytenkonzentraten gemäß einem Standardprotokoll isoliert [11], in PBS in Gegenwart von 1 mM CaCb resuspendiert und entsprechend mit Inhibitoren vorinkubiert. Nach Stimuluszugabe (2.5 μM lonophor plus 20 μM Arachidonsäure) wird für 10 min bei 37°C inkubiert. Die Inkubation wird mit Methanol gestoppt, die gebildeten 5-LO Metabolite (trans-LTB4l epi-trans-LTB4, LTB4, 5-H(P)ETE) mittels Festphasenextraktion isoliert, und dann mittels automatisiertem RP-HPLC-System qualitativ und quantitativ analysiert (s.o.).PMNL are isolated from fresh human leukocyte concentrates according to a standard protocol [11], resuspended in PBS in the presence of 1 mM CaCb, and preincubated with inhibitors accordingly. After stimulus addition (2.5 μM ionophore plus 20 μM arachidonic acid) is incubated for 10 min at 37 ° C. The incubation is stopped with methanol, the formed 5-LO metabolites (trans-LTB 4l epi-trans-LTB 4 , LTB 4 , 5-H (P) ETE) was isolated by solid-phase extraction, and then qualitatively and quantitatively analyzed by automated RP-HPLC system (see above).
Aus Abb. 6 wird ersichtlich, dass die Vorinkubation der PMNL mit den Verbindungen 89a, 13Od, 135a, und 141d auch in zellulären Systemen zu einer potenten und konzentrationsabhängigen Hemmung der 5-LO Produktbildung führt, wobei die IC5O Werte bei 0.65, 0.5, 0.3 und 0.4 μM liegen.Figure 6 shows that preincubation of PMNL with compounds 89a, 13Od, 135a, and 141d also results in potent and concentration- dependent inhibition of 5-LO product formation in cellular systems, with IC 50 values at 0.65, 0.5, 0.3 and 0.4 μM lie.
Synthese und Darstellung der Verbindungen: Allgemeine HerstellungsvorschriftenSynthesis and Preparation of Compounds: General manufacturing instructions
Herstellungsvorschrift AManufacturing Specification A
Die Lösung von 1 ,19 mmol eines lndol-3-carbonsäureesters in 5 ml CH2CI2 wird auf 0 0C gekühlt. Danach werden 75,0 mg (0,66 mmol) Λ/,/V-Dimethylpiperazin und 175,0 mg (1 ,31 mmol) Λ/-Chlorsuccinimid zugegeben und der Ansatz weitere 2 h lang bei 0 0C stehengelassen. Anschließend wird eine Lösung von 50,0 mg (0,31 mmol) Trichloressigsäure und 2.34 mmol eines Anilin-, Amin- oder Phenolderivates in 5 ml CH2CI2 zugegeben. Das Reaktionsgemisch wird nun 2 h bei RT stehengelassen und nacheinander mit 10 %iger NaHCO3-Lösung, 1 molarer HCl und Wasser gewaschen. Die CH2CI2-Phase wird über Na2SO4 getrocknet, filtriert und im Vakuum eingeengt. Die Isolierung des Produkts von nicht umgesetzten Edukten erfolgt mittels Flashchromatographie an Kieselgel (Cyclohexan/Ethylacetat 9:1 v/v).The solution of 1, 19 mmol of an indole-3-carbonsäureesters in 5 ml CH 2 CI 2 is cooled to 0 0 C. Thereafter, 75.0 mg (0.66 mmol) Λ /, / V-dimethylpiperazine and 175.0 mg (1, 31 mmol) Λ / chlorosuccinimide are added and the mixture allowed to stand at 0 0 C for a further 2 h. Subsequently, a solution of 50.0 mg (0.31 mmol) of trichloroacetic acid and 2.34 mmol of an aniline, amine or phenol derivative in 5 ml of CH 2 Cl 2 is added. The reaction mixture is then allowed to stand for 2 h at RT and washed successively with 10% NaHCO 3 solution, 1 molar HCl and water. The CH 2 Cl 2 phase is dried over Na 2 SO 4 , filtered and concentrated in vacuo. The product is isolated from unreacted starting materials by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 v / v).
Herstellungsvorschrift BManufacturing instructions B
3,0 mmol ß-Ketoester und die δfache molare Menge an NH4OAc (bzw. die doppelte Menge eines entsprechenden Amins) werden in 10 ml abs. Toluol unter Zusatz von 4 Tropfen Eisessig (bzw. Ameisensäure bei Aminen als Edukt) unter Rückfluss zum Sieden erhitzt. Das während der Reaktion entstehende Wasser wird durch azeotrope Destillation am Wasserabscheider aus dem Ansatz entfernt. Nach Beendigung der Wasserabscheidung (ca. 6 h) wird der abgekühlte Ansatz nacheinander mit gesättigter NaHCXVLösung und Wasser gewaschen. Die organische Phase wird über Na2SO4 getrocknet, filtriert und im Vakuum eingeengt. Die Isolierung des Produkts von nicht umgesetztem Edukt erfolgt mittels Flashchromatographie an Kieselgel (Cyclohexan/Ethylacetat 9:1 v/v).3.0 mmol of β-ketoester and the δfache molar amount of NH 4 OAc (or twice the amount of a corresponding amine) are abs in 10 ml. Toluene with the addition of 4 drops of glacial acetic acid (or formic acid in amines as starting material) heated to reflux under reflux. The water formed during the reaction is removed from the batch by azeotropic distillation on a water separator. After completion of the water separation (about 6 h), the cooled batch is washed successively with saturated NaHCXV solution and water. The organic phase is dried over Na 2 SO 4 , filtered and concentrated in vacuo. The isolation of the Product of unreacted educt is carried out by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 v / v).
Herstellungsvorschrift C 1 1 ,2 mmol des entsprechenden 1 ,4-Chinons werden unter Rühren über einen Zeitraum von 5 min zu einer Lösung des jeweiligen Enamins oder Ketenaminals (1 ,0 mmol) in 4 ml EtOH gegeben. Nach Rühren bei RT über eine Stunde wird das Lösungsmittel im Vakuum abdestilliert und das Produkt aus dem verbleibenden schwarzen Rückstand via präparativer MPLC oder Flashchromatographie an Kieselgel isoliert (Cyclohexan/Ethylacetat 95:5 v/v).Preparation Procedure C 1 1.2 mmol of the corresponding 1, 4-quinone are added with stirring over a period of 5 min to a solution of the respective enamine or ketenaminal (1, 0 mmol) in 4 ml of EtOH. After stirring at RT for one hour, the solvent is distilled off in vacuo and the product is isolated from the remaining black residue via preparative MPLC or flash chromatography on silica gel (cyclohexane / ethyl acetate 95: 5 v / v).
Herstellungsvorschrift C 2Manufacturing instructions C 2
Zu einer Lösung des entsprechenden 1 ,4-Chinons (1 ,0 mmol) in 3 ml CH2CI2 werden 32,0 mg (0,1 mmol) ZnI2 gegeben und die Temperatur bis zum Rückfluss erhöht. Anschließend wird eine Lösung von 1 ,0 mmol des jeweiligen Enamins oder Ketenaminals in 2 ml CH2CI2 über einen Zeitraum von 5-10 min unter Rühren zugetropft. Nach Weiterrühren unter Refluxbedingungen über ca. 40 min wird die Mischung 2-3 h lang bei 0-5 0C stehengelassen. Der gebildetete Niederschlag wird abfiltriert und entsprechend kristallisiert bzw. umkristallisiert.To a solution of the corresponding 1, 4-quinone (1, 0 mmol) in 3 ml of CH 2 Cl 2 are added 32.0 mg (0.1 mmol) ZnI 2 and the temperature is increased to reflux. Then a solution of 1, 0 mmol of the respective enamine or Ketenaminals in 2 ml CH 2 CI 2 is added dropwise over a period of 5-10 min under stirring. After further stirring under reflux conditions for about 40 minutes, the mixture is allowed to stand at 0-5 0 C for 2-3 h. The precipitate formed is filtered off and crystallized or recrystallized accordingly.
Spezielle HerstellungsvorschriftenSpecial manufacturing instructions
Methyl 2-[(3-Chlorphenyl)amino]-1H-indol-3-carboxylat (76c)Methyl 2 - [(3-chlorophenyl) amino] -1H-indole-3-carboxylate (76c)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 298,5 mg (2,34 mmol) 3-Chloranilin. Ausbeute: 222,3 mg (62 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 298.5 mg (2.34 mmol) of 3-chloroaniline. Yield: 222.3 mg (62%) of white powder.
Methyl 2-[(4-Chlorphenyl)amino]-1H-indol-3-carboxylat (76a)Methyl 2 - [(4-chlorophenyl) amino] -1H-indole-3-carboxylate (76a)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 298,5 mg (2,34 mmol) 4-Chloranilin. Ausbeute: 219,2 mg (61 %) weißes Pulver. Methyl 2-[(2-Chlorphenyl)amino]-1H-indol-3-carboxylat (76e)Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 298.5 mg (2.34 mmol) of 4-chloroaniline. Yield: 219.2 mg (61%) of white powder. Methyl 2 - [(2-chlorophenyl) amino] -1H-indole-3-carboxylate (76e)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 298,5 mg (2,34 mmol) 2-Chloranilin. Ausbeute: 152,9 mg (43 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 298.5 mg (2.34 mmol) of 2-chloroaniline. Yield: 152.9 mg (43%) of white powder.
Methyl 2-(3-Chlorphenylamino)-5-hydroxy-1 H-indol-3-carboxylat (91 b) Darstellung gemäß Herstellungsvorschrift C 1 aus 226,7 mg (1 ,0 mmol) Methyl (2EZ)-3-Amino-3-[(3-chlorphenyl)amino]acrylat (91aMe) und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 107,6 mg (34 %) grauglänzendes Pulver. Anmerkung: Um die Gefahr einer Umesterung zu vermeiden, ist MeOH als Lösungsmittel vorzuziehen.Methyl 2- (3-chlorophenylamino) -5-hydroxy-1H-indole-3-carboxylate (91 b) Preparation According to Preparation Procedure C 1 from 226.7 mg (1, 0 mmol) of methyl (2EZ) -3-amino- 3 - [(3-chlorophenyl) amino] acrylate (91aMe) and 129.7 mg (1.2 mmol) of 1,4-benzoquinone. Yield: 107.6 mg (34%) grayish-luster powder. Note: To avoid the risk of transesterification, MeOH is the preferred solvent.
Methyl (2£Z)-3-Amino-3-[(3-chlorphenyl)amino]acrylat (91aMe)Methyl (2 lb Z) -3-amino-3 - [(3-chlorophenyl) amino] acrylate (91aMe)
Eine Mischung aus 330,4 mg (2,52 mmol) Methyl (2E)-3-Amino-3-methoxyacrylat und 321 ,5 mg (2,52 mmol) 3-Chloranilin in 4 ml MeOH wird 48 h lang unter Rϋckfluss gekocht. Nach Entfernung des Lösungsmittels im Vakuum wird der verbleibende Rückstand mittels Flashchromatographie an Kieselgel aufgereinigt (Cyclohexan/Ethylacetat 7:3 v/v). Ausbeute: 337,7 mg (59 %) transparenter Lack.A mixture of 330.4 mg (2.52 mmol) of methyl (2E) -3-amino-3-methoxyacrylate and 321.5 mg (2.52 mmol) of 3-chloroaniline in 4 ml of MeOH is boiled under reflux for 48 h , After removal of the solvent in vacuo, the remaining residue is purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 7: 3 v / v). Yield: 337.7 mg (59%) of transparent varnish.
Methyl 2-[(3-Chlorphenyl)amino]-5-chlor-1 H-indol-3-carboxylat (111) Darstellung gemäß Herstellungsvorschrift A aus 249,5 mg (1 ,19 mmol) Methyl 5-Chlor-1 H-indol-3-carboxylat und 298,5 mg (2,34 mmol) 3-Chloranilin. Ausbeute: 172,0 mg (43 %) weißes, kristallines Pulver.Methyl 2 - [(3-chlorophenyl) amino] -5-chloro-1H-indole-3-carboxylate (III) Preparation according to Preparation Procedure A from 249.5 mg (1.19 mmol) of methyl 5-chloro-1 H indole-3-carboxylate and 298.5 mg (2.34 mmol) of 3-chloroaniline. Yield: 172.0 mg (43%) of white, crystalline powder.
Methyl 2-[(3-Fluorphenyl)amino]-1H-indol-3-carboxylat (121c) Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 260,0 mg (2,34 mmol) 3-Fluoranilin. Ausbeute: 195,3 mg (58 %) weiße Kristalle.Methyl 2 - [(3-fluorophenyl) amino] -1H-indole-3-carboxylate (121c) Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 260.0 mg (2 , 34 mmol) of 3-fluoroaniline. Yield: 195.3 mg (58%) of white crystals.
Methyl 2-[(3-Trifluormethyl)phenylamino]-1 H-indol-3-carboxylat (115) Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 377,0 mg (2,34 mmol) 3-Trifluormethylanilin. Ausbeute: 210,4 mg (53 %) weißes Pulver. Methyl 2-[(3,5-Dichlorphenyl)amino]-1H-indol-3-carboxylat (120a)Methyl 2 - [(3-trifluoromethyl) phenylamino] -1H-indole-3-carboxylate (115) Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 377.0 mg ( 2.34 mmol) of 3-trifluoromethylaniline. Yield: 210.4 mg (53%) of white powder. Methyl 2 - [(3,5-dichlorophenyl) amino] -1H-indole-3-carboxylate (120a)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 379,1 mg (2,34 mmol) 3,5-Dichloranilin. Ausbeute: 155,1 mg (39 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 379.1 mg (2.34 mmol) of 3,5-dichloroaniline. Yield: 155.1 mg (39%) of white powder.
Methyl 2-[(3,4-Dichlorphenyl)amino]-1 H-indol-3-carboxylat (120b)Methyl 2 - [(3,4-dichlorophenyl) amino] -1H-indole-3-carboxylate (120b)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 379,1 mg (2,34 mmol) 3,4-Dichloranilin. Ausbeute: 165,0 mg (41 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 379.1 mg (2.34 mmol) of 3,4-dichloroaniline. Yield: 165.0 mg (41%) of white powder.
Methyl 2-[(2,6-Dichlorphenyl)amino]-1 H-indol-3-carboxylat (120c)Methyl 2 - [(2,6-dichlorophenyl) amino] -1H-indole-3-carboxylate (120c)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 379,1 mg (2,34 mmol) 2,6-Dichloranilin. Ausbeute: 169,1 mg (42 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 379.1 mg (2.34 mmol) of 2,6-dichloroaniline. Yield: 169.1 mg (42%) of white powder.
Methyl 2-(1-Pyridin-2-chlor-3-yl-amino)-1H-indol-3-carboxylat (80c)Methyl 2- (1-pyridine-2-chloro-3-ylamino) -1H-indole-3-carboxylate (80c)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 300,8 mg (2,34 mmol) 2-Chlorpyridin-3-amin. Ausbeute: 196,9 mg (55 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 300.8 mg (2.34 mmol) of 2-chloropyridin-3-amine. Yield: 196.9 mg (55%) of white powder.
Methyl 2-(3-Chlorphenoxy)-1H-indol-3-carboxylat (118)Methyl 2- (3-chlorophenoxy) -1H-indole-3-carboxylate (118)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 300,8 mg (2,34 mmol) 3-Chlorphenol. Ausbeute: 169,6 mg (47 %) weißes Pulver.Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 300.8 mg (2.34 mmol) of 3-chlorophenol. Yield: 169.6 mg (47%) of white powder.
Methyl 2-[(3-Chlorphenyl)(methyl)amino]-1 H-indol-3-carboxylat (115b)Methyl 2 - [(3-chlorophenyl) (methyl) amino] -1H-indole-3-carboxylate (115b)
Darstellung gemäß Herstellungsvorschrift A aus 208,5 mg (1 ,19 mmol) Methyl Indol- 3-carboxylat und 331 ,3 mg (2,34 mmol) 3-Chlor-Λ/-methylanilin. Ausbeute: 187,3 mg (50 %) weißes Pulver. Ethyl 2-[2-(3-Chlorphenyl)ethyl]-5-hydroxy-1 H-indol-3-carboxylat (113c)Preparation according to Preparation Procedure A from 208.5 mg (1.19 mmol) of methyl indole-3-carboxylate and 331.3 mg (2.34 mmol) of 3-chloro-Λ / -methylaniline. Yield: 187.3 mg (50%) of white powder. Ethyl 2- [2- (3-chlorophenyl) ethyl] -5-hydroxy-1H-indole-3-carboxylate (113c)
Variante a:Option A:
Darstellung gemäß Herstellungsvorschrift C 1 aus 253,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-5-(3-chlorphenyl)pent-2-enoat (113b) und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 102,7 mg (30 %) weißes Pulver. Variante b:Preparation according to Preparation Procedure C 1 from 253.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-5- (3-chlorophenyl) pent-2-enoate (113b) and 129.7 mg (1, 2 mmol ) 1,4-benzoquinone. Yield: 102.7 mg (30%) of white powder. Variant b:
Darstellung gemäß Herstellungsvorschrift C 2 aus 253,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-5-(3-chlorphenyl)pent-2-enoat (113b) und 108,1 mg (1 ,0 mmol) 1 ,4-Benzochinon. Ausbeute: 141 ,8 mg (41 %) weißes Pulver. Ethyl (2Z)-3-Amino-5-(3-chlorphenyl)pent-2-enoat (113b)Preparation according to Preparation Procedure C 2 from 253.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-5- (3-chlorophenyl) pent-2-enoate (113b) and 108.1 mg (1, 0 mmol ) 1,4-benzoquinone. Yield: 141.8 mg (41%) of white powder. Ethyl (2Z) -3-amino-5- (3-chlorophenyl) pent-2-enoate (113b)
Darstellung gemäß Herstellungsvorschrift B aus 761 ,1 mg (3,0 mmol) Ethyl 5-(3-Chlorphenyl)-3-oxopentanoat (113a) und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 566,3 mg (74 %) farbloses Öl.Preparation according to Preparation Procedure B from 761, 1 mg (3.0 mmol) of ethyl 5- (3-chlorophenyl) -3-oxopentanoate (113a) and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 566.3 mg (74%) of colorless oil.
(R) Ethyl 5-Hydroxy-2-[(1 -phenylethyl)amino]-1 H-indol-3-carboxylat (56a/?)(R) ethyl 5-hydroxy-2 - [(1-phenylethyl) amino] -1H-indole-3-carboxylate (56a /?)
Darstellung gemäß Herstellungsvorschrift C 1 aus 234,1 mg (1 ,0 mmol) Rohprodukt (R) Ethyl (2EZ)-3-Amino-3-[(1-phenylethyl)amino]acrylat und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 121 ,2 mg (37 %) graue Kristalle.Preparation according to Preparation Procedure C 1 from 234.1 mg (1.0 mmol) of crude product (R) ethyl (2EZ) -3-amino-3 - [(1-phenylethyl) amino] acrylate and 129.7 mg (1, 2 mmol ) 1,4-benzoquinone. Yield: 121.2 mg (37%) of gray crystals.
(S) Ethyl 5-Hydroxy-2-[(1 -phenylethyl)amino]-1 H-indol-3-carboxylat (56aS)(S) ethyl 5-hydroxy-2 - [(1-phenylethyl) amino] -1H-indole-3-carboxylate (56aS)
Darstellung gemäß Herstellungsvorschrift C 1 aus 234,1 mg (1 ,0 mmol) Rohprodukt (S) Ethyl (2EZ)-3-Amino-3-[(1-phenylethyl)amino]acrylat und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 111 ,0 mg (34 %) graue Kristalle. Anmerkung: Die Darstellung von (R) und (S) Ethyl (2EZ)-3-Amino-3-[(1-phenylethyl)amino]acrylat erfolgt gemäß Herstellungsvorschrift der literaturbekannten racemischen Verbindung.Preparation according to Preparation Procedure C 1 from 234.1 mg (1.0 mmol) of crude product (S) ethyl (2EZ) -3-amino-3 - [(1-phenylethyl) amino] acrylate and 129.7 mg (1.2 mmol ) 1,4-benzoquinone. Yield: 111.0 mg (34%) of gray crystals. Note: The preparation of (R) and (S) ethyl (2EZ) -3-amino-3 - [(1-phenylethyl) amino] acrylate is carried out according to the preparation procedure of the literature-known racemic compound.
Ethyl 2-(3-Chlorbenzyl)-5-hydroxy-1H-indol-3-carboxylat (105a)Ethyl 2- (3-chlorobenzyl) -5-hydroxy-1H-indole-3-carboxylate (105a)
Variante a: Darstellung gemäß Herstellungsvorschrift C 1 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)-3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 94,6 mg (29 %) weißes Pulver. Variante b: Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)-3- Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 108,1 mg (1 ,0 mmol) 1 ,4-Benzochinon. Ausbeute: 135,1 mg (41 %) weißes Pulver.Variant a: Preparation according to Preparation Procedure C 1 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 129.7 mg (1 , 2 mmol) 1, 4-benzoquinone. Yield: 94.6 mg (29%) of white powder. Variant b: Preparation according to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 108.1 mg (1, 0 mmol ) 1,4-benzoquinone. Yield: 135.1 mg (41%) of white powder.
Ethyl (2Z)-3-Amino-4-(3-chlorphenyl)but-2-enoat (103a)Ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a)
Darstellung gemäß Herstellungsvorschrift B aus 722,0 mg (3,0 mmol) Ethyl 4-(3-Chlorphenyl)-3-oxobutanoat und 1.16 g (15.0 mmol) Ammoniumacetat. Ausbeute: 616,3 mg (86 %) hellgelbes Harz.Preparation according to Preparation Procedure B from 722.0 mg (3.0 mmol) of ethyl 4- (3-chlorophenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 616.3 mg (86%) of light yellow resin.
Ethyl 5-Hydroxy-2-phenylethyl-benzofuran-3-carboxylat (101)Ethyl 5-hydroxy-2-phenylethyl-benzofuran-3-carboxylate (101)
1 ,65 g (7,5 mmol) Ethyl 5-Phenyl-3-oxopentanoat in 4 ml Diethylether werden tropfenweise zu einer 85-90 0C heißen Lösung aus 1 ,05 g ZnCb 99.99% in wenig Ethanol gegeben. 811 mg (7,5 mmol) 1 ,4-Benzochinon in 25 ml Diethylether werden tropfenweise hinzugegeben und die Mischung unter Rühren 19 h bei ca. 85 °C gehalten. Nach Abkühlen des Ansatzes auf r.t. wird die braune pastenartige Masse mit Wasser gewaschen und getrocknet. Das Produkt wird mittels Flashchromatographie an Kieselgel isoliert (Cyclohexan/Ethylacetat 9:1 v/v). Ausbeute: 834,3 mg (36 %) weißes Pulver.1, 65 g (7.5 mmol) of ethyl 5-phenyl-3-oxopentanoate in 4 ml of diethyl ether was added dropwise to a hot 85-90 0 C solution of 1, 05 g ZnCl 99.99% in a little ethanol are added. 811 mg (7.5 mmol) of 1,4-benzoquinone in 25 ml of diethyl ether are added dropwise and the mixture is kept at about 85 ° C. with stirring for 19 h. After cooling the batch to rt, the brown paste-like mass is washed with water and dried. The product is isolated by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 v / v). Yield: 834.3 mg (36%) of white powder.
Ethyl 1 -Benzyl-2-(4-chlorphenyl)-5-hydroxy-1 H-indol-3-carboxylat (134b)Ethyl 1 -benzyl-2- (4-chlorophenyl) -5-hydroxy-1H-indole-3-carboxylate (134b)
Variante a:Option A:
Darstellung gemäß Herstellungsvorschrift C 1 aus 329,8 mg (1 ,0 mmol) Rohprodukt Ethyl (2Z)-3-(benzylamino)-4-(4-chlorphenyl)but-2-enoat (134a) und 129,7 mg (1 ,2 mmol) 1 ,4-Benzochinon. Ausbeute: 54,0 mg (13 %) weißes Pulver. Variante b:Preparation according to Preparation Procedure C 1 from 329.8 mg (1.0 mmol) of crude product ethyl (2Z) -3- (benzylamino) -4- (4-chlorophenyl) but-2-enoate (134a) and 129.7 mg (1 , 2 mmol) 1, 4-benzoquinone. Yield: 54.0 mg (13%) of white powder. Variant b:
Darstellung gemäß Herstellungsvorschrift C 2 aus 329,8 mg (1 ,0 mmol) Rohprodukt Ethyl (2Z)-3-(benzylamino)-4-(4-chlorphenyl)but-2-enoat (134a) und 108,1 mg (1 ,0 mmol) 1 ,4-Benzochinon. Ausbeute: 118,3 mg (28 %) weißes Pulver. Anmerkung: Darstellung von 134a gemäß Herstellungsvorschrift B aus 722,0 mg (3,0 mmol) Ethyl 4-(4-Chlorphenyl)-3-oxobutanoat und 645,0 mg (6,0 mmol) Benzylamin ohne Aufreinigung via Flashchromatographie.Preparation according to Preparation Procedure C 2 from 329.8 mg (1.0 mmol) of crude product ethyl (2Z) -3- (benzylamino) -4- (4-chlorophenyl) but-2-enoate (134a) and 108.1 mg (1 , 0 mmol) 1, 4-benzoquinone. Yield: 118.3 mg (28%) of white powder. Note: Preparation of 134a according to Preparation B from 722.0 mg (3.0 mmol) of ethyl 4- (4-chlorophenyl) -3-oxobutanoate and 645.0 mg (6.0 mmol) of benzylamine without purification via flash chromatography.
Ethyl 2-(3-Chlorphenylamino)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (89a)Ethyl 2- (3-chlorophenylamino) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (89a)
Variante a: Darstellung gemäß Herstellungsvorschrift C 1 aus 240,7 mg (1 ,0 mmol) Ethyl (2EZ)- 3-Amino-3-[(3-chlorphenyl)amino]acrylat (91aEt) und 189,8 mg (1 ,2 mmol) 1 ,4-Naphthochinon. Ausbeute: 84,3 mg (22 %) hellgrünes Pulver. Variante b: Darstellung gemäß Herstellungsvorschrift C 2 aus 240,7 mg (1 ,0 mmol) Ethyl (2EZ)- 3-Amino-3-[(3-chlorphenyl)amino]acrylat (91aEt) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 133,3 mg (35 %) hellgrünes Pulver.Option A: Preparation According to Preparation Procedure C 1 from 240.7 mg (1.0 mmol) of ethyl (2EZ) -3-amino-3 - [(3-chlorophenyl) amino] acrylate (91aEt) and 189.8 mg (1.2 mmol) 1,4-naphthoquinone. Yield: 84.3 mg (22%) of light green powder. Variant b: Preparation according to preparation procedure C 2 from 240.7 mg (1, 0 mmol) of ethyl (2EZ) - 3-amino-3 - [(3-chlorophenyl) amino] acrylate (91aEt) and 158.2 mg (1, 0 mmol) 1, 4-naphthoquinone. Yield: 133.3 mg (35%) of light green powder.
Ethyl (2EZ)-3-Amino-3-[(3-chlorphenyl)amino]acrylat (91aEt) Darstellung und Aufreinigung analog 91aMe mit 401 ,2 mg (2,52 mmol) Ethyl (2E)- 3-Amino-3-ethoxyacrylat und 321 ,5 mg (2,52 mmol) 3-Chloranilin unter Verwendung von EtOH als Lösungsmittel. Ausbeute: 353,7 mg (58 %) transparenter Lack.Ethyl (2EZ) -3-amino-3 - [(3-chlorophenyl) amino] acrylate (91aEt) Preparation and purification analogous to 91aMe with 401.2 mg (2.52 mmol) of ethyl (2E)-3-amino-3- ethoxyacrylate and 321.5 mg (2.52 mmol) of 3-chloroaniline using EtOH as solvent. Yield: 353.7 mg (58%) of transparent varnish.
Ethyl 2-(3-Chlorbenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (135a) Variante a:Ethyl 2- (3-chlorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (135a) Variant a:
Darstellung gemäß Herstellungsvorschrift C 1 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 189,8 mg (1 ,2 mmol) 1 ,4-Naphthochinon. Ausbeute: 77,7 mg (20 %) hellbraunes Pulver. Variante b: Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 197,2 mg (52 %) hellbraunes Pulver.Preparation according to Preparation Procedure C 1 from 239.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 189.8 mg (1, 2 mmol ) 1,4-naphthoquinone. Yield: 77.7 mg (20%) of light brown powder. Variant b: Preparation according to Preparation Procedure C 2 from 239.7 mg (1.0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 158.2 mg (1 , 0 mmol) 1, 4-naphthoquinone. Yield: 197.2 mg (52%) of light brown powder.
Ethyl 2-(4-Chlorbenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (132b) Variante a:Ethyl 2- (4-chlorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (132b) variant a:
Darstellung gemäß Herstellungsvorschrift C 1 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(4-chlorphenyl)but-2-enoat (103b) und 189,8 mg (1 ,2 mmol) 1 ,4-Naphthochinon. Ausbeute: 63,8 mg (17 %) weißes Pulver. Variante b: Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(4-chlorphenyl)but-2-enoat (103b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 162,3 mg (43 %) weißes Pulver. Ethyl (2Z)-3-Amino-4-(4-chlorophenyl)but-2-enoat (103b)Preparation according to Preparation Procedure C 1 from 239.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (4-chlorophenyl) but-2-enoate (103b) and 189.8 mg (1, 2 mmol ) 1,4-naphthoquinone. Yield: 63.8 mg (17%) of white powder. Variant b: Preparation according to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (4-chlorophenyl) but-2-enoate (103b) and 158.2 mg (1 , 0 mmol) 1, 4-naphthoquinone. Yield: 162.3 mg (43%) of white powder. Ethyl (2Z) -3-amino-4- (4-chlorophenyl) but-2-enoate (103b)
Darstellung gemäß Herstellungsvorschrift B aus 722,0mg (3,00 mmol) EthylPreparation according to Preparation Procedure B from 722.0 mg (3.00 mmol) of ethyl
4-(4-Chlorphenyl)-3-oxobutanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat.4- (4-chlorophenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate.
Ausbeute: 613,0 mg (85 %) hellgelbes Harz.Yield: 613.0 mg (85%) of light yellow resin.
Ethyl 1-Benzyl-2-(4-chlorbenzyl)-5-hydroxy-1H-benzo[g]indol-3-carboxylatEthyl 1-benzyl-2- (4-chlorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate
(134c)(134c)
Variante a:Option A:
Darstellung gemäß Herstellungsvorschrift C 1 aus 329,8 mg (1 ,0 mmol) Rohprodukt Ethyl (2Z)-3-(benzylamino)-4-(4-chlorphenyl)but-2-enoat (134a) und 189,8 mgPreparation according to Preparation Procedure C 1 from 329.8 mg (1.0 mmol) of crude product ethyl (2Z) -3- (benzylamino) -4- (4-chlorophenyl) but-2-enoate (134a) and 189.8 mg
(1 ,2 mmol) 1 ,4-Naphthochinon. Ausbeute: 56,3 mg (12 %) weißes Pulver.(1.2 mmol) 1, 4-naphthoquinone. Yield: 56.3 mg (12%) of white powder.
Variante b:Variant b:
Darstellung gemäß Herstellungsvorschrift C 2 aus 329,8 mg (1 ,0 mmol) RohproduktPreparation according to preparation procedure C 2 from 329.8 mg (1, 0 mmol) of crude product
Ethyl (2Z)-3-(benzylamino)-4-(4-chlorphenyl)but-2-enoat (134a) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 123,6 mg (26 %) weißes Pulver.Ethyl (2Z) -3- (benzylamino) -4- (4-chlorophenyl) but-2-enoate (134a) and 158.2 mg (1, 0 mmol) of 1,4-naphthoquinone. Yield: 123.6 mg (26%) of white powder.
Ethyl 2-(3-Chlorphenyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (130D)Ethyl 2- (3-chlorophenyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (130D)
Variante a:Option A:
Darstellung gemäß Herstellungsvorschrift C 1 aus 225,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-3-(3-chlorphenyl)acrylat (130b) und 189,8 mg (1 ,2 mmol)Preparation According to Preparation Procedure C 1 from 225.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-3- (3-chlorophenyl) acrylate (130b) and 189.8 mg (1, 2 mmol)
1 ,4-Naphthochinon. Ausbeute: 70,5 mg (19 %) weißes Pulver.1,4-naphthoquinone. Yield: 70.5 mg (19%) of white powder.
Variante b:Variant b:
Darstellung gemäß Herstellungsvorschrift C 2 aus 225,7 mg (1 ,0 mmol) Ethyl (2Z)-Preparation According to Preparation Procedure C 2 from 225.7 mg (1, 0 mmol) of ethyl (2Z) -
3-Amino-3-(3-chlorphenyl)acrylat (130b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 139,9 mg (38 %) weißes Pulver.3-Amino-3- (3-chlorophenyl) acrylate (130b) and 158.2 mg (1.0 mmol) of 1,4-naphthoquinone. Yield: 139.9 mg (38%) of white powder.
Ethyl (2Z)-3-Amino-3-(3-chlorphenyl)acrylat (130b)Ethyl (2Z) -3-amino-3- (3-chlorophenyl) acrylate (130b)
Darstellung gemäß Herstellungsvorschrift B aus 680,0 mg (3,0 mmol) Ethyl 3-(3-Chlorphenyl)-3-oxopropanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 562,9 mg (83 %) farblose Kristalle.Preparation according to Preparation B from 680.0 mg (3.0 mmol) of ethyl 3- (3-chlorophenyl) -3-oxopropanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 562.9 mg (83%) of colorless crystals.
Benzyl 2-(4-Chlorbenzyl)-5-hydroxy-1H-benzo[g]indol-3-carboxylat (141d) Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Benzyl (2Z)- 3-Amino-4-(4-chlorphenyl)but-2-enoat (141b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 128,5 mg (29 %) weißes Pulver.Benzyl 2- (4-chlorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (141d) Preparation according to preparation procedure C 2 from 239.7 mg (1, 0 mmol) of benzyl (2Z) - 3-amino-4- (4-chlorophenyl) but-2-enoate (141b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 128.5 mg (29%) of white powder.
Benzyl (2Z)-3-Amino-4-(4-chlorphenyl)but-2-enoat (141b)Benzyl (2Z) -3-amino-4- (4-chlorophenyl) but-2-enoate (141b)
Darstellung gemäß Herstellungsvorschrift B aus 908,3 mg (3,0 mmol) Benzyl 4-(4-Chlorphenyl)-3-oxobutanoat (141a) und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 771 ,6 mg (85 %) farbloses Öl.Preparation according to Preparation Procedure B from 908.3 mg (3.0 mmol) of benzyl 4- (4-chlorophenyl) -3-oxobutanoate (141a) and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 771.6 mg (85%) of colorless oil.
Benzyl 4-(4-Chlorphenyl)-3-oxobutanoat (141a)Benzyl 4- (4-chlorophenyl) -3-oxobutanoate (141a)
2,33 g (12,0 mmol) 3-(Benzyloxy)-3-oxopropansäure werden in 15 ml trockenem THF gelöst. Nach Zugabe von 686,6 mg (6,0 mmol) Magnesiumethylat wird 4 h lang bei RT gerührt und anschließend das Lösungsmittel im Vakuum abdestilliert. Das entstandene Magnesiumsalz wird gut mit Ether gewaschen, abfiltriert und erneut im Vakuum getrocknet.2.33 g (12.0 mmol) of 3- (benzyloxy) -3-oxopropanoic acid are dissolved in 15 ml of dry THF. After addition of 686.6 mg (6.0 mmol) of magnesium ethylate is stirred for 4 h at RT and then the solvent is distilled off in vacuo. The resulting magnesium salt is washed well with ether, filtered off and dried again in vacuo.
1 ,78 g (11 ,0 mmol) Λ/,Λ/'-Carbonyldiimidazol werden portionsweise zu einer Lösung von 1 ,71 g (10,0 mmol) 4-Chlorphenylessigsäure in 20 ml trockenem DMF gegeben. Nach einstündigem Rühren der Mischung unter Stickstoff wird das Magnesiumsalz zugegeben und der Ansatz ca. 4 h lang weitergerührt. Zur Aufarbeitung wird mit 2N HCl angesäuert, das Produkt dreimal mit EtOAc extrahiert, die vereinigten Phasen nacheinander mit gesättigter NaHCO3-Lösung und Wasser gewaschen und über Na2SO4 getrocknet. Ausbeute: 2,52 g (83 %) farbloses Öl.1, 78 g (11, 0 mmol) Λ /, Λ / '- carbonyldiimidazole are added in portions to a solution of 1, 71 g (10.0 mmol) of 4-chlorophenylacetic acid in 20 ml of dry DMF. After stirring the mixture under nitrogen for one hour, the magnesium salt is added and the mixture is stirred for about 4 hours. For working up, it is acidified with 2N HCl, the product is extracted three times with EtOAc, and the combined phases are washed successively with saturated NaHCO 3 solution and water and dried over Na 2 SO 4 . Yield: 2.52 g (83%) of colorless oil.
Benzyl 2-(3-Chlorbenzyl)-5-hydroxy-1H-benzo[g]indol-3-carboxylat (142d)Benzyl 2- (3-chlorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (142d)
Darstellung gemäß Herstellungsvorschrift C 2 aus 302,8 mg (1 ,0 mmol) Benzyl (2Z)- 3-Amino-4-(3-chlorphenyl)but-2-enoat (142b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 128,7 mg (29 %) weißes Pulver.Preparation according to preparation procedure C 2 from 302.8 mg (1, 0 mmol) of benzyl (2Z) - 3-amino-4- (3-chlorophenyl) but-2-enoate (142b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 128.7 mg (29%) of white powder.
Benzyl (2Z)-3-Amino-4-(3-chlorphenyl)but-2-enoat (EKV142b)Benzyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (EKV142b)
Darstellung gemäß Herstellungsvorschrift B aus 908,3 mg (3,0 mmol) Benzyl 4-(3-Chlorphenyl)-3-oxobutanoat (142a) und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 752,5 mg (83 %) farbloses Öl. Benzyl 4-(3-Chlorphenyl)-3-oxobutanoat (142a)Preparation according to Preparation Procedure B from 908.3 mg (3.0 mmol) of benzyl 4- (3-chlorophenyl) -3-oxobutanoate (142a) and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 752.5 mg (83%) of colorless oil. Benzyl 4- (3-chlorophenyl) -3-oxobutanoate (142a)
Darstellung und Aufreinigung analog 141a mit 2,33 g (12,0 mmol) 3-(Benzyloxy)- 3-oxopropansäure und 1 ,71 g (10,0 mmol) 3-Chlorphenylessigsäure. Ausbeute: 2,51 g (83 %) transparentes Öl.Preparation and purification analogous to 141a with 2.33 g (12.0 mmol) of 3- (benzyloxy) -3-oxopropanoic acid and 1.71 g (10.0 mmol) of 3-chlorophenylacetic acid. Yield: 2.51 g (83%) of transparent oil.
Ethyl 5-Hydroxy-2-phenylpropyl-1 H-benzo[g]indol-3-carboxylat (144d) Darstellung gemäß Herstellungsvorschrift C 1 aus 233,3 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-6-phenylhex-2-enoat (144b) und 189,8 mg (1 ,2 mmol) 1 ,4-Naphthochinon. Ausbeute: 64,3 mg (17 %) hellgraues Pulver.Ethyl 5-hydroxy-2-phenylpropyl-1H-benzo [g] indole-3-carboxylate (144d) Preparation according to Preparation Procedure C 1 from 233.3 mg (1, 0 mmol) of ethyl (2Z)-3-amino-6 phenylhex-2-enoate (144b) and 189.8 mg (1.2 mmol) of 1,4-naphthoquinone. Yield: 64.3 mg (17%) of light gray powder.
Ethyl (2Z)-3-Amino-6-phenylhex-2-enoat (EKV144b)Ethyl (2Z) -3-amino-6-phenylhex-2-enoate (EKV144b)
Darstellung gemäß Herstellungsvorschrift B aus 702,9 mg (3,0 mmol) Ethyl 3-Oxo- 6-phenylhexanoat (144a) und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 506,6 mg (74 %) farblose Kristalle.Preparation according to Preparation B from 702.9 mg (3.0 mmol) of ethyl 3-oxo-6-phenylhexanoate (144a) and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 506.6 mg (74%) of colorless crystals.
Ethyl 2-(3-Chlorbenzyl)-7,8-dimethoxy-5-hydroxy-1H-benzo[g]indol-3-carboxylatEthyl 2- (3-chlorobenzyl) -7,8-dimethoxy-5-hydroxy-1H-benzo [g] indole-3-carboxylate
(139b)(139b)
Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)-Preparation According to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -
3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 218,2 mg (1 ,0 mmol) 6,7-Dimethoxy-1 ,4-naphthochinon. Ausbeute: 123,7 mg (28 %) hellgraues Pulver.3-Amino-4- (3-chlorophenyl) but-2-enoate (103a) and 218.2 mg (1.0 mmol) 6,7-dimethoxy-1,4-naphthoquinone. Yield: 123.7 mg (28%) of light gray powder.
Ethyl 7-Biphenyl-4-yl-(3-chlorbenzyl)-5-hydroxy-1 H-indol-3-carboxylat (157b)Ethyl 7-biphenyl-4-yl- (3-chlorobenzyl) -5-hydroxy-1H-indole-3-carboxylate (157b)
Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 260,3 mg (1 ,0 mmol) 2-Biphenyl- 1 ,4-benzochinon. Ausbeute: 134,4 mg (28 %) weißes, kristallines Pulver.Preparation according to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 260.3 mg (1, 0 mmol ) 2-biphenyl-1,4-benzoquinone. Yield: 134.4 mg (28%) of white, crystalline powder.
Ethyl 2-(3-Chlorbenzyl)-5-hydroxy-6-phenyl-1 H-indol-3-carboxylat (155c)Ethyl 2- (3-chlorobenzyl) -5-hydroxy-6-phenyl-1H-indole-3-carboxylate (155c)
Darstellung gemäß Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)-3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 184,2 mg (1 ,0 mmol) 2-Phenyl-1 ,4-benzochinon. Ausbeute: 132,7 mg (33 %) weißes, kristallines Pulver.Preparation according to preparation procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 184.2 mg (1, 0 mmol ) 2-phenyl-1,4-benzoquinone. Yield: 132.7 mg (33%) of white, crystalline powder.
Ethyl 2-(2-Chlor-6-fluorbenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (158d) Darstellung gemäß Herstellungsvorschrift C 2 mit 257,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(2-chlor-6-fluorphenyl)but-2-enoat (158b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 149,0 mg (37 %) hellbraunes Pulver.Ethyl 2- (2-chloro-6-fluorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (158d) Preparation according to Preparation Procedure C 2 with 257.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (2-chloro-6-fluorophenyl) but-2-enoate (158b) and 158.2 mg ( 1, 0 mmol) 1, 4-naphthoquinone. Yield: 149.0 mg (37%) of light brown powder.
Ethyl (2Z)-3-Amino-4-(2-chlor-6-fluorphenyl)but-2-enoat (158b)Ethyl (2Z) -3-amino-4- (2-chloro-6-fluorophenyl) but-2-enoate (158b)
Darstellung gemäß Herstellungsvorschrift B aus 776,0 mg (3,0 mmol) Ethyl 4-(2-Chlor-6-fluorphenyl)-3-oxobutanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 677,2 mg (88 %) farbloses Harz.Preparation according to Preparation B from 776.0 mg (3.0 mmol) of ethyl 4- (2-chloro-6-fluorophenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 677.2 mg (88%) of colorless resin.
Ethyl 2-(2-Chlorpyridin-3-yl)-5-hydroxy-1H-benzo[g]indol-3-carboxylat (160c)Ethyl 2- (2-chloropyridin-3-yl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (160c)
Darstellung gemäß Herstellungsvorschrift C 2 aus 226,7 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-3-(2-chlorpyridin-3-yl)acrylat (160b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 168,1 mg (46 %) rötlich-braunes Pulver.Preparation according to preparation procedure C 2 from 226.7 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-3- (2-chloropyridin-3-yl) acrylate (160b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 168.1 mg (46%) reddish-brown powder.
Ethyl (2Z)-3-Amino-3-(2-chlorpyridin-3-yl)acrylat (160b)Ethyl (2Z) -3-amino-3- (2-chloropyridin-3-yl) acrylate (160b)
Darstellung gemäß Herstellungsvorschrift B aus 682,9 mg (3,0 mmol) Ethyl 3-(2-Chlorpyridin-3-yl)-3-oxopropanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 546,2 mg (80 %) weißes flockiges Pulver.Preparation according to Preparation B from 682.9 mg (3.0 mmol) of ethyl 3- (2-chloropyridin-3-yl) -3-oxopropanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 546.2 mg (80%) of white fluffy powder.
Ethyl 2-[2-(te/t-Butoxycarbonylamino)ethyl]-5-hydroxy-1 H-benzo[g]indol-Ethyl 2- [2- (te / t-butoxycarbonylamino) ethyl] -5-hydroxy-1H-benzo [g] indole
3-carboxylat (162d)3-carboxylate (162d)
Darstellung gemäß Herstellungsvorschrift C 2 mit 258,3 mg (1 ,0 mmol) Rohprodukt Ethyl (2Z)-3-Amino-5-(ferf-butoxycarbonylamino)pent-2-enoat (162b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon in 40 ml EtOH. Ausbeute: 139,0 mg (35 %) weißes Pulver.Preparation according to Preparation Procedure C 2 with 258.3 mg (1, 0 mmol) of crude product ethyl (2Z) -3-amino-5- (ferf-butoxycarbonylamino) pent-2-enoate (162b) and 158.2 mg (1, 0 mmol) 1, 4-naphthoquinone in 40 ml EtOH. Yield: 139.0 mg (35%) of white powder.
Anmerkung:Annotation:
Darstellung von 162b gemäß Herstellungsvorschrift B aus 567,6 mg (3,0 mmol) Ethyl 5-[(ferf-Butoxycarbonyl)amino]-3-oxopentanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat ohne Aufreinigung via Flashchromatographie.Preparation of 162b according to Preparation Procedure B from 567.6 mg (3.0 mmol) of ethyl 5 - [(ferf-butoxycarbonyl) amino] -3-oxopentanoate and 1.16 g (15.0 mmol) of ammonium acetate without purification via flash chromatography.
Ethyl 2-(3-Brombenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (166c) Darstellung gemäß Herstellungsvorschrift C 2 mit 284,2 mg (1 ,0 mmol) Ethyl (2Z)-3- Amino-4-(3-bromphenyl)but-2-enoat (166b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 187,2 mg (44 %) hellbraunes Pulver. Ethyl (2Z)-3-Amino-4-(3-bromphenyl)but-2-enoat (166b)Ethyl 2- (3-bromobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (166c) Preparation according to Preparation Procedure C 2 with 284.2 mg (1, 0 mmol) of ethyl (2Z) -3 - Amino-4- (3-bromophenyl) but-2-enoate (166b) and 158.2 mg (1, 0 mmol) of 1,4-naphthoquinone. Yield: 187.2 mg (44%) of light brown powder. Ethyl (2Z) -3-amino-4- (3-bromophenyl) but-2-enoate (166b)
Darstellung gemäß Herstellungsvorschrift B aus 855,4 mg (3,0 mmol) Ethyl 4-(3-Bromphenyl)-3-oxobutanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 709,4 mg (83 %) farbloses Harz.Preparation according to Preparation Procedure B from 855.4 mg (3.0 mmol) of ethyl 4- (3-bromophenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 709.4 mg (83%) of colorless resin.
Ethyl 2-(3-Methoxybenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (167c)Ethyl 2- (3-methoxybenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (167c)
Darstellung gemäß Herstellungsvorschrift C 2 mit 235,3 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(3-methoxyphenyl)but-2-enoat (167b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 147,2 mg (39 %) hellbraunes Pulver.Preparation according to Preparation Procedure C 2 with 235.3 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (3-methoxyphenyl) but-2-enoate (167b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 147.2 mg (39%) of light brown powder.
Ethyl (2Z)-3-Amino-4-(3-methoxyphenyl)but-2-enoat (167b)Ethyl (2Z) -3-amino-4- (3-methoxyphenyl) but-2-enoate (167b)
Darstellung gemäß Herstellungsvorschrift B aus 708,8 mg (3,0 mmol) Ethyl 4-(3-Methoxyphenyl)-3-oxobutanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 605,5 mg (86 %) farbloses Harz.Preparation according to Preparation Procedure B from 708.8 mg (3.0 mmol) of ethyl 4- (3-methoxyphenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 605.5 mg (86%) of colorless resin.
Ethyl 2-(4-Fluorbenzyl)-5-hydroxy-1 H-benzo[g]indol-3-carboxylat (168c)Ethyl 2- (4-fluorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (168c)
Darstellung gemäß Herstellungsvorschrift C 2 mit 223,3 mg (1 ,0 mmol) Ethyl (2Z)-3- Amino-4-(4-fluorphenyl)but-2-enoat (168b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 119,2 mg (33 %) hellbraunes Pulver.Preparation according to Preparation Procedure C 2 with 223.3 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (4-fluorophenyl) but-2-enoate (168b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 119.2 mg (33%) of light brown powder.
Ethyl 2-(3-Chlorbenzyl)-5-hydroxy-1H-pyrrolo[2,3-/]chinolin-3-carboxylat (170)Ethyl 2- (3-chlorobenzyl) -5-hydroxy-1H-pyrrolo [2,3- /] quinoline-3-carboxylate (170)
Darstellung nach Herstellungsvorschrift C 2 aus 239,7 mg (1 ,0 mmol) Ethyl (2Z)-3-Amino-4-(3-chlorphenyl)but-2-enoat (103a) und 159,1 mg (1 ,0 mmol) Chinolin- 5,8-dion. Ausbeute: 70,0 mg (18 %) graues Pulver.Preparation according to Preparation Procedure C 2 from 239.7 mg (1, 0 mmol) of ethyl (2Z) -3-amino-4- (3-chlorophenyl) but-2-enoate (103a) and 159.1 mg (1, 0 mmol ) Quinoline-5,8-dione. Yield: 70.0 mg (18%) of gray powder.
Ethyl 2-(3-Fluorbenzyl)-5-hydroxy-1H-benzo[g]indol-3-carboxylat (171c)Ethyl 2- (3-fluorobenzyl) -5-hydroxy-1H-benzo [g] indole-3-carboxylate (171c)
Darstellung gemäß Herstellungsvorschrift C 2 mit 223,3 mg (1 ,0 mmol) Ethyl (2Z)- 3-Amino-4-(3-fluorphenyl)but-2-enoat (171b) und 158,2 mg (1 ,0 mmol) 1 ,4-Naphthochinon. Ausbeute: 152,2 mg (42 %) hellbraunes Pulver. Ethyl (2Z)-3-Amino-4-(3-fluorphenyl)but-2-enoat (171b)Preparation according to Preparation Procedure C 2 with 223.3 mg (1, 0 mmol) of ethyl (2Z) - 3-amino-4- (3-fluorophenyl) but-2-enoate (171b) and 158.2 mg (1, 0 mmol ) 1,4-naphthoquinone. Yield: 152.2 mg (42%) of light brown powder. Ethyl (2Z) -3-amino-4- (3-fluorophenyl) but-2-enoate (171b)
Darstellung gemäß Herstellungsvorschrift B aus 855,4 mg (3,0 mmol) Ethyl 4-(3-Fluorphenyl)-3-oxobutanoat und 1 ,16 g (15,0 mmol) Ammoniumacetat. Ausbeute: 597,4 mg (89 %) farbloses Harz.Preparation according to Preparation Procedure B from 855.4 mg (3.0 mmol) of ethyl 4- (3-fluorophenyl) -3-oxobutanoate and 1.16 g (15.0 mmol) of ammonium acetate. Yield: 597.4 mg (89%) colorless resin.
Ethyl 2-(3-Chlorbenzyl)-5-phenyl-1 H-benzo[g]indol-3-carboxylat (176b) Eine Mischung aus 112,2 mg (0,55 mmol) Phenylboronsäurepinakolester, 256,0 mg (0,50 mmol) Ethyl 5-[[(Trifluormethyl)sulfonyl]oxy]-2-(3-chlorbenzyl)-1H- benzo[g]indol-3-carboxylat (176a), 3,4 mg (0,015 mmol) PdOAc2, 3,9 mg (0,015 mmol) PPh3, wässriger Na2CO3-Lösung und DMF wird 2 h lang unter Rückfluss gekocht. Anschließend wird der Ansatz in Wasser aufgenommen und das Produkt mittels EtOAc extrahiert. Das nach Abdestillieren des Lösungsmittels erhaltene Rohprodukt wird via Flashchromatographie an Kieselgel isoliert (Cyclohexan/Ethylacetat 9:1 v/v). Ausbeute: 75,1 mg (34 %) weißes Pulver.Ethyl 2- (3-chlorobenzyl) -5-phenyl-1H-benzo [g] indole-3-carboxylate (176b) A mixture of 112.2 mg (0.55 mmol) phenyl boronic acid pinacol ester, 256.0 mg (0, 50 mmol) ethyl 5 - [[(trifluoromethyl) sulfonyl] oxy] -2- (3-chlorobenzyl) -1H-benzo [g] indole-3-carboxylate (176a), 3.4 mg (0.015 mmol) PdOAc 2 , 3.9 mg (0.015 mmol) of PPh 3 , aqueous Na 2 CO 3 solution and DMF is boiled under reflux for 2 h. The mixture is then taken up in water and the product extracted with EtOAc. The crude product obtained after distilling off the solvent is isolated by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 v / v). Yield: 75.1 mg (34%) of white powder.
Ethyl 5-[[(Trifluormethyl)sulfonyl]oxy]-2-(3-chlorbenzyl)-1H-benzo[g]indol- 3-carboxylat (176a)Ethyl 5 - [[(trifluoromethyl) sulfonyl] oxy] -2- (3-chlorobenzyl) -1H-benzo [g] indole-3-carboxylate (176a)
949,6 mg (2,5 mmol) Ethyl 2-(3-Chlorbenzyl)-5-hydroxy-1H-benzo[gr]indol- 3-carboxylat (135a) werden in 5 ml CH2CI2 gelöst. Nach Zugabe von 506,0 mg (5,0 mmol) Triethylamin werden unter Eiskühlung 1 ,76 g (6,25 mmol) Trifluormethansulfonsäureanhydrid (TfO2) zugesetzt und die Reaktionsmischung 4 h lang bei 0 0C gerührt. Anschließend wird das Lösungsmittel im Vakuum abdestilliert und das Produkt mittels Flashchromatographie an Kieselgel isoliert (Cyclohexan/Ethylacetat 4:1 v/v). Ausbeute: 1 ,04 g (81 %) weißes Pulver.949.6 mg (2.5 mmol) of ethyl 2- (3-chlorobenzyl) -5-hydroxy-1H-benzo [gr] indole-3-carboxylate (135a) are dissolved in 5 ml of CH 2 Cl 2 . After the addition of 506.0 mg (5.0 mmol) of triethylamine under ice-cooling 1, 76 g (6.25 mmol) of trifluoromethanesulfonic anhydride (TfO 2) was added and the reaction mixture stirred for 4 h at 0 0 C. The solvent is then distilled off in vacuo and the product isolated by flash chromatography on silica gel (cyclohexane / ethyl acetate 4: 1 v / v). Yield: 1.04 g (81%) of white powder.
Ethyl 2-(3-Chlorbenzyl)-5-(4-chlorphenyl)-1 H-benzo[g]indol-3-carboxylat (176c) Darstellung und Aufreinigung analog 176b mit 131 ,2 mg (0,55 mmol) 4-Chlorphenylboronsäurepinakolester und 256,0 mg (0,50 mmol) Ethyl 5-[[(Trifluormethyl)sulfonyl]oxy]-2-(3-chlorbenzyl)-1/-/-benzo[g]indol-3-carboxylat (176a). Ausbeute: 67,1 mg (28 %) weißes Pulver.Ethyl 2- (3-chlorobenzyl) -5- (4-chlorophenyl) -1H-benzo [g] indole-3-carboxylate (176c) Preparation and purification analogous to 176b with 131.2 mg (0.55 mmol) 4- Chlorophenylboronic acid pinacol ester and 256.0 mg (0.50 mmol) of ethyl 5 - [[(trifluoromethyl) sulfonyl] oxy] -2- (3-chlorobenzyl) -1 / - / - benzo [g] indole-3-carboxylate (176a) , Yield: 67.1 mg (28%) of white powder.
Ethyl 2-(3-Chlorbenzyl)-5-(4-cyanophenyl)-1H-benzo[g]indol-3-carboxylat (176d)Ethyl 2- (3-chlorobenzyl) -5- (4-cyanophenyl) -1H-benzo [g] indole-3-carboxylate (176d)
Darstellung und Aufreinigung analog 176b mit 126,0 mg (0.55 mmol) 4-Cyanophenylboronsäurepinakolester und 256,0 mg (0,50 mmol) Ethyl 5-[[(Trifluormethyl)sulfonyl]oxy]-2-(3-chlorbenzyl)-1/-/-benzo[g]indol-3-carboxylat (176a). Ausbeute: 77,4 mg (33 %) weißes Pulver.Preparation and purification analogous to 176b with 126.0 mg (0.55 mmol) of 4-cyanophenylboronic acid pinacol ester and 256.0 mg (0.50 mmol) of ethyl 5 - [[(trifluoromethyl) sulfonyl] oxy] -2- (3-chlorobenzyl) -1 / - / - benzo [g] indole-3-carboxylate (176a). Yield: 77.4 mg (33%) of white powder.
Literaturliterature
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Biochem J 1989;259:315-24. [2] Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology.Biochem J 1989; 259: 315-24. [2] Radio CD. Prostaglandins and leukotrienes: advances in eicosanoid biology.
Science 2001 ;294:1871-5. [3] Rainsford KD. Anti-inflammatory drugs in the 21 st Century. Subcell BiochemScience 2001; 294: 1871-5. [3] Rainsford KD. Anti-inflammatory drugs in the 21st Century. Subcell Biochem
2007;42:3-27. [4] Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane Prostaglandin E synthase-1 : a novel therapeutic target. Pharmacol Rev 2007;59:207-24. [5] Jachak SM. PGE synthase inhibitors as an alternative to COX-2 inhibitors. Curr Opin Investig Drugs 2007;8:411-5.2007; 42: 3-27. [4] Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 2007; 59: 207-24. [5] Jachak SM. PGE synthase inhibitors as an alternative to COX-2 inhibitors. Curr Opin Investig Drugs 2007; 8: 411-5.
[6] Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sei 2007:32:332-41.[6] Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sei 2007: 32: 332-41.
[7] Werz O, Steinhilber D. Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 2006:112:701-18.[7] Werz O, Steinhilber D. Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 2006: 112: 701-18.
[8] Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors-lessons from cellular enzyme regulation. Biochem Pharmacol 2005;70:327-33. [9] Fischer L, Szellas D, Radmark O, Steinhilber D, Werz O. Phosphorylation- and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox- type inhibitors. Faseb J 2003; 17:949-51.[8] Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors-lessons from cellular enzyme regulation. Biochem Pharmacol 2005; 70: 327-33. [9] Fischer L, Szellas D, Radmark O, Steinhilber D, Werz O. Phosphorylation and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox-type inhibitors. Faseb J 2003; 17: 949-51.
[10] Werz O, Steinhilber D. Selenium-dependent peroxidases suppress 5- lipoxygenase activity in B-lymphocytes and immature myeloid cells - the presence of peroxidase-insensitive 5-lipoxygenase activity in differentiated myeloid cells. Eur J Biochem 1996;242:90-7. [11] Werz O, Klemm J, Samuelsson B, Radmark O. Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in Mono Mac 6 cells and human polymorphonuclear leukocytes. Blood 2001 ;97:2487-95. [10] Werz O, Steinhilber D. Selenium-dependent peroxidases suppress 5-lipoxygenase activity in B-lymphocytes and immature myeloid cells - the presence of peroxidase-insensitive 5-lipoxygenase activity in differentiated myeloid cells. Eur J Biochem 1996; 242: 90-7. [11] Werz O, Klemm J, Samuelsson B, Radmark O. Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in monocytes Mac 6 cells and human polymorphonuclear leukocytes. Blood 2001; 97: 2487-95.

Claims

Patentansprüche: claims:
1 ) lndol-3-carbonsäureester gemäß einer der folgenden Strukturformeln1) indole-3-carboxylic acid ester according to one of the following structural formulas
Figure imgf000035_0001
Figure imgf000035_0001
worin X für einen anellierten Aryl- oder Heteroarylring mit insgesamt 3 bis 8 Ringatomen steht, der seinerseits mit 1-2 CrC-rAlkoxygruppen oder 1-2 Fluor-, Chlor- oder Bromatomen oder 1-2 Trifluormethylgruppen substituiert sein kann,wherein X is a fused aryl or heteroaryl ring having a total of 3 to 8 ring atoms, which in turn may be substituted with 1 to 2 CrC-r alkoxy groups or 1 to 2 fluorine, chlorine or bromine atoms or 1 to 2 trifluoromethyl groups,
R1 für einen Aryl, Heteroaryl, Arylalkyl oder Heteroarylalkyl steht, das über ein Stickstoff-, Sauerstoff- oder Kohlenstoffatom oder eine Aminoalkyl-, Oxoalkyl- oder Alkylgruppe an das Restmolekül geknüpft ist, wobei das Aryl-, Heteroaryl-, Arylalkyl- bzw. Heteroarylalkyl mit einem weiteren Ringsystem kondensiert sein kann, und ein oder mehrere H-Atome im Aryl, Heteroaryl, Arylalkyl bzw. Heteroarylalkyl substituiert sein können durch eine oder mehrere Gruppen aus der Substanzklasse Halogen, O, N, S, OH, NH2, NO2, SH, (C1-10)Alkyl, (C2-10)Alkenyl, (C2-10)Alkinyl, OCF3, (Ci-10)Alkoxy, (C1-i0)Alkylamin, (C1.10)Alkylthio,(Ci.i0)Alkylsilyl> Cycloalkyl, Cycloalkenyl, Cycloheteroalkyl, oder Cycloheteroalkenyl,R 1 is an aryl, heteroaryl, arylalkyl or heteroarylalkyl which is attached to the remainder of the molecule via a nitrogen, oxygen or carbon atom or an aminoalkyl, oxoalkyl or alkyl group, where the aryl, heteroaryl, arylalkyl or heteroarylalkyl may be condensed with another ring system, and one or more H atoms in the aryl, heteroaryl, arylalkyl or heteroarylalkyl 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 2-10) alkenyl, (C 2-10) alkynyl, OCF 3, (Ci-10) alkoxy, (C 1- i 0) alkylamine, (C. 1 10 ) alkylthio, (Ci.i 0 ) alkylsilyl > cycloalkyl, cycloalkenyl, cycloheteroalkyl, or cycloheteroalkenyl,
R2 die Alkoholkomponente des Carbonsäureesters an C2 bildet und insbesondere einen Alkyl-, Aryl- oder Alkylarylrest darstellt, undR 2 forms the alcohol component of the carboxylic ester on C 2 and in particular represents an alkyl, aryl or alkylaryl radical, and
R3 für H oder einen beliebigen polaren oder lipophilen Rest, insbesondere eine OH-Gruppe oder Halogen, steht, R4 für H oder einen Alkyl-, Aryl- oder Arylalkylrest steht.R 3 is H or any polar or lipophilic radical, in particular an OH group or halogen, R 4 is H or an alkyl, aryl or arylalkyl radical.
2) Verbindung gemäß Anspruch 1 , wobei der lndol-3-carbonsäureester ein 2- Aryl- oder 2-Arylalkyl-indol-3-carbonsäureester oder ein strukturelles Derivat davon ist.2) A compound according to claim 1, wherein the indole-3-carboxylic acid ester is a 2-aryl or 2-arylalkyl-indole-3-carboxylic acid ester or a structural derivative thereof.
3) Verbindung gemäß Anspruch 1 , wobei der lndol-3-carbonsäureester ein Aryl[g]indol-3-carbonsäureester ist.3) A compound according to claim 1, wherein the indole-3-carboxylic acid ester is an aryl [g] indole-3-carboxylic acid ester.
4) Verbindung gemäß Anspruch 1 , wobei X für einen anneliierten Phenyl- oder4) A compound according to claim 1, wherein X is an annelated phenyl or
Pyridinylring steht, welcher mit 1-2 Ci-C4-Alkoxygruppen substituiert sein kann.Pyridinylring is, which may be substituted by 1-2 Ci-C 4 alkoxy.
5) Verbindung gemäß Anspruch 1 , wobei R1 ausgewählt ist aus der Gruppe -NH-C6H5 5) A compound according to claim 1, wherein R 1 is selected from the group -NH-C 6 H 5
-NH-C6H4-CI-NH-C 6 H 4 -CI
-NH-C6H4-F-NH-C 6 H 4 -F
-NH-C6H4-CF3 -NH-C 6 H 4 -CF 3
-NH-C6H3-CI2 -NH-C5H3N-CI-NH-C 6 H 3 -CI 2 -NH-C 5 H 3 N-CI
-0-C6H4-Cl-0-C 6 H 4 -Cl
-N(CHa)-C6H4-CI-N (CHa) -C 6 H 4 -CI
-CH2-CH2-C6H4-CI-CH 2 -CH 2 -C 6 H 4 -CI
-NH-CH2-C6H4-CI -NH-CH2-C6H5 -NH-CH 2 -C 6 H 4 -CI -NH-CH 2 -C 6 H 5
-CH2-C6H4-CI-CH 2 -C 6 H 4 -CI
-CH2-CH2-C6H5 -CH 2 -CH 2 -C 6 H 5
oder wobei R2 ausgewählt ist aus der Gruppeor where R2 is selected from the group
-CH3 -C2H5 -CH2-C6H5 oder wobei R3 ausgewählt ist aus der Gruppe -OH -C6H5 -CH2-C6H5 -CH 3 -C 2 H 5 -CH 2 -C 6 H 5 or wherein R3 is selected from the group -OH -C 6 H 5 -CH 2 -C 6 H 5
-Cl-Cl
-0-C6H5 -0-CH2-C6H5 -O-C 6 H 5 -O-CH 2 -C 6 H 5
oder wobei R4 ausgewählt ist aus der Gruppeor where R4 is selected from the group
-H-H
-C6H5 -C 6 H 5
-CH2-C6H5 -CH 2 -C 6 H 5
oder wobei R5 und R6 unabhängig voneinander ausgewählt sind aus der Gruppeor wherein R5 and R6 are independently selected from the group
-H-H
-OCH3.-OCH 3 .
6) Verbindung nach einem der vorgehenden Ansprüche, wobei an C2-Position des lndol-3-carbonsäureesters substituierte Benzyl- oder Anilinosubstituenten eingeführt sind.6) A compound according to any one of the preceding claims, wherein at C2-position of the indole-3-carboxylic acid ester substituted benzyl or anilino substituents are introduced.
7) Verbindung nach einem der vorgehenden Ansprüche, wobei der lndol-3- carbonsäureester an C5-Position durch Aryl-, Hydroxyl- oder Chlor-Reste substituiert ist.7) A compound according to any one of the preceding claims, wherein the indole-3-carboxylic acid ester is substituted at C5-position by aryl, hydroxyl or chlorine radicals.
8) Verwendung einer Substanz gemäß mindestens einem der Ansprüche 1-7 zur8) Use of a substance according to any one of claims 1-7 to
Herstellung eines Arzneimittels.Production of a drug.
9) Verwendung einer Substanz gemäß mindestens einem der Ansprüche 1-7 zur Herstellung eines Arzneimittels zur Hemmung der PGE2 und / oder der 5-LO. 10)Verwendung nach Anspruch 8 oder 9, dadurch gekennzeichnet, dass das Arzneimittel ferner ein pharmazeutisches Trägermaterial enthält.9) Use of a substance according to any one of claims 1-7 for the manufacture of a medicament for inhibiting PGE 2 and / or 5-LO. 10) Use according to claim 8 or 9, characterized in that the medicament further contains a pharmaceutical carrier material.
11 )Verwendung nach einem der Ansprüche 8-10 zur Herstellung eines11) Use according to one of claims 8-10 for the preparation of a
Arzneimittels zur Behandlung PGE2- und / oder 5-LO-vermittelter Erkrankungen oder krankhafter Zustände.Medicament for the treatment of PGE 2 - and / or 5-LO-mediated diseases or morbid conditions.
12)Verwendung nach Anspruch 11 , dadurch gekennzeichnet, dass die PGE2- und/oder 5-LO-vermittelte Erkrankungen chronische Entzündungen wie rheumatoide Arthritis, Osteoarthritis, Erkrankungen des kardiovaskulären Systems, Asthma, allergische Rhinitis, Multiple Sklerose, entzündliche Hauterkrankungen, Osteoporose und Krebs oder krankhafte Zustände, insbesondere Schmerz und Fieber, sind.12) Use according to claim 11, characterized in that the PGE 2 - and / or 5-LO-mediated diseases include chronic inflammations such as rheumatoid arthritis, osteoarthritis, cardiovascular diseases, asthma, allergic rhinitis, multiple sclerosis, inflammatory skin diseases, osteoporosis and Cancer or morbid conditions, especially pain and fever, are.
13)Verwendung nach einem der Ansprüche 8 bis 12, dadurch gekennzeichnet, dass die Plasmakonzentrationen der Verbindung gemäß mindestens einem der Ansprüche 1-7 nach der Applikation des Arzneimittels 0,1 - 10 μM beträgt. 13) Use according to one of claims 8 to 12, characterized in that the plasma concentrations of the compound according to any one of claims 1-7 after the application of the drug is 0.1 - 10 uM.
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