DE102007040336A1 - New inhibitors of 5-lipoxygenase and their uses - Google Patents

Abstract

The present invention relates to tricyclic thiazolone compounds and to imidazopyridine compounds as novel and effective inhibitors of 5-lipoxygenase and their influence on arachidonic acid metabolism. The compounds are useful in the treatment of diseases, especially leukotriene-mediated diseases such as inflammatory diseases, allergic diseases, cardiovascular diseases, osteoporosis, hair loss and others.

Description

The The present invention relates to tricyclic thiazolone compounds and on imidazopyridine compounds as novel and effective Inhibitors of 5-lipoxygenase and their influence on the Arachidonic acid metabolism. The compounds are suitable for the treatment of diseases, in particular of leukotriene-mediated Diseases, such as inflammatory diseases, allergic Diseases, cardiovascular diseases, osteoporosis, Hair loss and more.

Background of the invention

leukotrienes (LT) are bioactive lipid mediators that are involved in a variety of inflammatory diseases such as asthma, psoriasis, arthritis or allergic rhinitis are [1]. Furthermore, the increased formation and release plays of leukotrienes in the pathogenesis of diseases such as cancer, Osteoarthritis or atherosclerosis play a role [2].

5-Lipoxygenase (5-LO) is the enzyme responsible for the production of leukotriene A4 (LTA ₄ ) from arachidonic acid (AA). In cells, the 5-LO is located in the cytosol or in the soluble compartment of the cell nucleus. Upon stimulation, the enzyme migrates to the nuclear membrane and colocalizes with the cytosolic phospholipase A ₂ (cPLA ₂ ), the 5-LO activating protein (FLAP) and the leukotriene C4 (LTC ₄ ) synthase. At the nuclear membrane, the AA is released by means of the cPLA ₂ , presented by the helper protein FLAP 5-LO and then metabolized to LT (see 1 ) [3].

The stimulation of granulocytes leads, on the one hand, to an increase in the intracellular Ca ²⁺ concentration, to the formation of diacylglycerols via phospholipase C and, depending on the stimulus for the activation of the p38 MAP kinase and of the extracellular signal-regulated kinase (ERK). It could be shown that 5-LO is a substrate for ERK and MAPK-activated protein kinase 2/3 (MK-2/3) [4, 5]. The MK-2/3 is in turn phosphorylated and activated by p38. The addition of polyunsaturated fatty acids, such as AA or oleic acid, enhances the degree of phosphorylation of 5-LO [6]. According to current knowledge, 5-lipoxygenase can be activated either by high intracellular Ca ²⁺ concentrations and / or phosphorylation [7].

by virtue of The pathophysiological properties of LT is development of potential drugs that target the 5-LO possess, of considerable interest.

For the treatment of leukotriene-mediated diseases, there are already a number of approved drugs, eg. For example, the LT receptor antagonists pranlukast, montelukast, zafirlukast. The only 5-LO inhibitor currently on the market, Zileuton ^®, is approved for the treatment of asthma but has little therapeutic benefit in the treatment of the other diseases mentioned. Other candidates are being and have been tested in clinical trials, with many substances providing disappointing results in terms of clinical efficacy. One reason for this can be seen in that the known candidates mainly inhibit the Ca ²⁺ -dependent activation of the enzyme, whereas physiological stimuli of the 5-LO frequently act Ca ²⁺ independently via phosphorylation.

One Another new therapeutic approach is to use substances with "dual" inhibitory effect 5-LO and COX (cyclooxygenase) to develop the treatment of inflammatory Disease while avoiding side effects (concerning the Stomach).

WO 2007/012464 A1 discloses, for example, macrolide conjugates of pyrrolizine and indolizine derivatives with macrocyclic antibiotics and their derivatives. The macrolide conjugates are potent inhibitors of 5-lipoxygenase and cyclooxygenase and are therefore useful in the treatment of rheumatic-type diseases and for the prevention of allergic-induced diseases.

• – Gruppe 1: Redoxaktive Inhibitoren, wie Cumarine oder Flavonoide, welche jedoch eine niedrige Selektivität gegenüber 5-LO aufweisen und erhebliche Nebenwirkungen mit sich bringen.
• – Gruppe 2: Chelatoren des Eisenions im aktiven Zentrum, wozu u. a. Zileuton^® zählt. Weitere Kandidaten dieser Gruppe befinden sich in klinischer Prüfung.
• – Gruppe 3: Nicht-redoxaktive Inhibitoren, umfassend eine Reihe von Methoxyalkylthiazol- und Methoxytetrahydropyran-Verbindungen. Tests mit diesen Verbindungen zeigten, dass die inhibitorische Wirkung der Substanzen von der Art des Stimulus (Ca²⁺ bzw. Phosphorylierung) abhängig ist. Während bei der Ca²⁺-abhängigen Stimulierung von intakten PMNL (polymorphonuklearen Leukocyten) eine hohe Wirksamkeit gefunden wurde, ist diese unter Bedingungen mit erhöhten Peroxid-Konzentrationen in zellfreien Assays deutlich erniedrigt. Ursprünglich wurden Nonredox-5-LO-Inhibitoren als kompetitive Wirkstoffe entwickelt, die mit der AA um die Bindung an die katalytische Domäne der 5-LO konkurrieren. Vertreter dieser Inhibitoren, wie ZM230487 und L-739,010, zeigen eine potente Hemmung der LT-Biosynthese in verschiedenen Testsystemen, waren aber aus verschiedenen Gründen (Pharmakokinetik etc.) beim Menschen nicht einsetzbar bzw. unwirksam [8].

The known inhibitors of 5-LO can be divided into three groups:

• - Group 1: redox-active inhibitors, such as coumarins or flavonoids, which, however, have a low selectivity to 5-LO and bring significant side effects.
• - Group 2: chelators of iron ion in the active site, which includes Zileuton ^® . Other candidates in this group are undergoing clinical trials.
• Group 3: non-redox active inhibitors comprising a series of methoxyalkylthiazole and methoxytetrahydropyran compounds. Tests with these compounds showed that the inhibitory effect of the substances depends on the type of stimulus (Ca ²⁺ or phosphorylation). While in the Ca ²⁺ ab has been found to be highly effective in stimulating intact PMNL (polymorphonuclear leukocytes), it is markedly decreased under conditions of elevated peroxide concentrations in cell-free assays. Originally, nonredox 5-LO inhibitors were developed as competitive agents that compete with AA for binding to the catalytic domain of 5-LO. Representatives of these inhibitors, such as ZM230487 and L-739,010, show a potent inhibition of LT biosynthesis in various test systems, but were for various reasons (pharmacokinetics, etc.) in humans not applicable or ineffective [8].

JP 2005-063833 describes tricyclic thiazolone compounds as photoelectric conversion materials.

McMillan et al., 1991 [9, see also 10] disclose methoxyalkylthiazoles as enantioselective 5-LO inhibitors, such as compound ICI211965 (1- [3- (naphth-2-yl-methoxy) phenyl] -1- (thiazol-2-yl) propyl) 1-methyl ether) and the conformation-restricted chiral analog ICI216800 (1-methoxy-6- (naphth-2-yl-methoxy) -1- (thiazol-2-yl) indane).

WO 2006/114263 A1 discloses imidazo [1,2-a] pyridine derivatives as inhibitors of peptide deformylase (PDF), which are useful as antibiotics.

WO 2006/101455 A1 discloses imidazo [1,2-a] pyridine derivatives as inhibitors of histone deacetylase (HDAC), which can be used to treat diseases involving enzymes with histone deacetylase activities.

It Thus, there is a need in the art for 5-lipoxygenase inhibitors with new basic structures that are the already known inhibitors improve.

task The present invention was therefore 5-lipoxygenase inhibitors to provide with new basic structures that improve the already known in the art inhibitors of 5-lipoxygenase or as an alternative to these in the treatment of diseases and / or can be used for cosmetic treatment.

The The object is achieved by the available provide compounds of the formula I for the treatment of diseases solved.

links of the formula I according to the invention have a tricyclic Backbone with a central thiazolone group and up to three substituents.

Verbindungen, wobei
R₁ Wasserstoff,
Alkyl-, Alkenyl-, Alkoxy-,
Aryl-,
ein annelierter Aryl-Rest,
ein Heterozyklus oder
Halogen
ist,
R₂ Wasserstoff,
Hydroxy-,
Alkyl-, Alkenyl-, Alkoxy-,
Cycloalkyl-,
ein substituierter oder unsubstituierter Aryl-Rest,
ein annelierter Aryl-Rest oder
ein Heterozyklus
ist,
R₃ Wasserstoff,
Alkyl-, Alkenyl-, Alkoxy-,
Cycloalkyl-,
ein substituierter oder unsubstituierter Aryl-Rest,
ein annelierter Aryl-Rest oder
ein Heterozyklus
ist,
m 0 oder 1 ist und aus CH₂, NH oder O ausgewählt ist.
n Alkyl- oder Alkenyl-Linker ist, bevorzugt mit 1 bis 4 C-Atomen ist, der N, S, O oder P als Heteroatome enthalten kann.According to the invention, compounds of the formula I

Compounds, wherein
R _{1 is} hydrogen,
Alkyl, alkenyl, alkoxy,
aryl,
a fused aryl radical,
a heterocycle or
halogen
is
R _{2 is} hydrogen,
hydroxy,
Alkyl, alkenyl, alkoxy,
cycloalkyl,
a substituted or unsubstituted aryl radical,
a fused aryl radical or
a heterocycle
is
R _{3 is} hydrogen,
Alkyl, alkenyl, alkoxy,
cycloalkyl,
a substituted or unsubstituted aryl radical,
a fused aryl radical or
a heterocycle
is
m is 0 or 1 and is selected from CH ₂ , NH or O.
n is alkyl or alkenyl linker, preferably having 1 to 4 carbon atoms, which may contain N, S, O or P as heteroatoms.

Preferably, R ₁ , R ₂ and R _{3 are} not each hydrogen.

Preferably, the cyclic substituent carrying the substituent R ₁ taken together with R _{1 is} an aminoaryl, heteroaryl, cycloalkyl, alkenylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl.

Preferably, R _{1 is} selected from methyl, in particular p-methyl, hydrogen and naphthyl.

Preferably, R _{2 is} selected from methoxy, in particular p-methoxy or o-methoxy, methyl, hydroxy, in particular o-hydroxy. Hydrogen and 9-anthrazyl.

Preferably, R _{3 is} selected from methoxy, in particular m-methoxy and hydrogen.

Prefers the linker n is selected from methyl or prop-1-enyl.

Prefers is the bridging atom or the bridging group m 0 (i.e., missing) or is NH.

Preferred embodiments of the compounds of the formula I according to the invention are compounds wherein
R _{1 is} methyl,
R ₂ methoxy,
R ₃ H and
m 0,
n is methyl,
or
R _{1 is} methyl,
R ₂ hydroxy,
R _{3 is} methoxy and
m 0,
n is methyl,
or
R _{1 is} methyl,
R ₂ methoxy,
R _{3 is} methoxy and
m 0,
n is methyl,
or
R _{1 is} methyl,
R ₂ H,
R ₃ H and
m 0,
n is prop-1-enyl,
or
R ₁ H,
R ₂ anthracyl,
R ₃ H and
m 0,
n is methyl.

In particular, compounds of the formula I are selected from

For Preferred compounds of the formula I see also Table 1.

The Task is further according to the invention by the provide compounds of formula II to Treatment of diseases solved.

links of the formula II have an imidazopyridine skeleton with up to three substituents.

In the compounds of the formula II, the substituents R ₁ , R ₂ and / or R ₃ according to the invention are in particular lipophilic groups / radicals.

Compounds of formula II are inventively preferred compounds, wherein
R _{1 is} hydrogen,
Alkyl, alkenyl, alkoxy radical, preferably in each case from C1 to C6,
a substituted or unsubstituted aryl radical,
a substituted or unsubstituted alkylaryl radical,
a heterocycle,
Halogen or
an amino group
is
R _{2 is} hydrogen,
an unbranched or branched alkyl, alkenyl, alkoxy radical, preferably in each case from C1 to C6,
cycloalkyl,
a substituted or unsubstituted aryl radical,
a substituted or unsubstituted alkylaryl radical or
a heterocycle
is
R _{3 is} hydrogen,
Alkyl, alkenyl, alkoxy radical, preferably in each case from C1 to C6,
cycloalkyl,
a substituted or unsubstituted aryl radical,
a substituted or unsubstituted alkylaryl radical,
a heterocycle or
halogen
is.

Preferably, R ₁ , R ₂ and R _{3 are} not each hydrogen.

Preferably, R ₁ , R ₂ and / or R _{3 are} selected from substituted and unsubstituted aryl radicals, more preferably substituted and unsubstituted alkylaryl radicals.

Preferably, R _{1 is} selected from phenyl, chlorophenyl, methylphenyl, dimethylaminophenyl and thiophenyl.

Preferably, R _{2 is} selected from isopropyl, isobutyl, isopentyl, benzyl, cyclopentyl, cyclohexyl and methylfuranyl.

Preferably, R _{3 is} selected from hydrogen, methyl, in particular 6-methyl and 7-methyl, and chlorine, in particular 6-chloro.

Preferred embodiments of the compounds of formula II according to the invention are compounds wherein
R _{1 is} phenyl,
R ₂ isopropyl and
R _{3 is} H,
or
R _{1 is} chlorophenyl,
R ₂ isobutyl and
R _{3 is} methyl,
or
R _{1 is} methylphenyl,
R ₂ isobutyl and
R _{3 is} methyl,
or
R _{1 is} dimethylaminophenyl,
R ₂ isopropyl and
R _{3 is} methyl,
or
R _{1 is} methylphenyl,
R ₂ isopropyl and
R _{3 is} chlorine,
or
R _{1 is} phenyl,
R _{2 is} benzyl and
R _{3 is} H,
or
R _{1 is} phenyl,
R ₂ isopentyl and
R _{3 is} methyl,
or
R _{1 is} phenyl,
R _{2 is} cyclohexyl and
R _{3 is} methyl,
or
R _{1 is} phenyl,
R _{2 is} cyclohexyl and
R _{3 is} H,
or
R _{1 is} thiophenyl,
R _{2 is} benzyl and
R _{3 is} methyl,
or
R _{1 is} methylphenyl,
R ₂ cyclopentyl and
R _{3 is} methyl,
or
R _{1 is} phenyl,
R _{2 is} methylfuranyl and
R _{3 is} methyl.

In particular, compounds of the formula II are selected from

For Preferred compounds of the formula II see also Table 2.

Pharmaceutical compositions

The Task is further according to the invention by the providing pharmaceutical compositions solved, the one or more of the invention Compounds or their pharmaceutically acceptable salts and optionally acceptable carriers and / or excipients.

Prefers For example, a pharmaceutical composition comprises one or more compounds of formula I as defined herein and / or one or more compounds of formula II as defined herein, as well as pharmaceutically acceptable Carriers and / or auxiliaries.

preferably, these pharmaceutical compositions have a unit dosage form, like tablets, pills, capsules, powder, granules, sterile parenteral Solutions or suspensions. Other dosage forms are known to the skilled person.

One A pharmaceutical or a pharmaceutical composition comprises a therapeutically active amount of the active substance or of several active substances, d. H. a therapeutically active amount of one or more of the invention Links. A person skilled in the art is capable of being treated Disease and taking into account the condition of Patients to determine the therapeutically active amount. A medicine or a pharmaceutical composition may suitably be between about 0.1 and 1000 mg, preferably about 1 to 500 mg of a compound of the invention include.

Of the pharmaceutically acceptable carrier and / or excipient a great variety of forms depending from the desired route of administration (e.g., oral, parenteral). Suitable carriers and excipients are known in the art and can be obtained by a person skilled in the art to be selected. Vehicles include inert pharmaceutical excipients, such as binders, suspending agents, Lubricants, flavorings, sweeteners, preservatives, Dyes and coatings, a.

The pharmaceutical compositions according to the invention are further characterized in that the compound (s) is / are present in an amount such that a concentration range of preferably 0.001 to 100 μM, more preferably of 0.01 to 10 μM in in vivo treatment.

Further uses of the compounds and compositions

The Task is further solved according to the invention by the use of a compound of the invention of the formula I as defined herein or a compound of the invention A compound of the formula II as defined herein or a compound of the invention pharmaceutical composition for the treatment of 5-lipoxygenase products mediated diseases.

These Diseases are selected from inflammatory diseases, allergic diseases, cardiovascular diseases, Hypertension, osteoporosis, osteosclerosis, osteoarthritis, hair loss, Atherosclerosis, cancers, multiple sclerosis, Parkinson's disease and Alzheimer's disease.

The Inflammatory diseases are selected from asthma, Psoriasis, rheumatoid arthritis, allergic rhinitis and chronic inflammatory bowel disease.

The Task is further solved according to the invention by the use of a compound of the invention of the formula I as defined herein or a compound of the invention A compound of the formula II as defined herein or a compound of the invention pharmaceutical composition as an inhibitor of arachidonic acid metabolism.

The Task is further solved according to the invention by the use of a compound of the invention of the formula I as defined herein or a compound of the invention A compound of the formula II as defined herein or a compound of the invention pharmaceutical composition as an arachidonic acid-binding inhibitor Enzymes.

at the arachidonic acid-binding enzymes are Lipoxygenases, cyclooxygenase and phospholipases, preferably 5-lipoxygenase (5-LO).

Administration of the compounds and compositions

The Administration of the compounds of the invention and compositions are preferably carried out locally or systemically.

The Administration of the compounds of the invention and compositions are further preferably oral, nasal, subcutaneous, intracutaneous, parenteral, transdermal, topical, intravenous, intraarterial, intramuscular, intraperitoneal or in Combinations of it.

Prefers Transdermal or topical administration is particularly preferred the transdermal administration.

The transdermal administration of the invention Compounds and compositions in a dosage form takes place selected from the group comprising: spray; Plaster; Ointment; semi-solid cream; Liquid, like a solution; Solid, like a powder; Gel; Emulsion or suspension.

The Compounds of the invention and compositions are administered in a therapeutically effective amount, preferably in an amount of 0.01 mg to 1 g per kg of body or so in that a concentration range of preferably 0.001 to 100 μM, more preferably from 0.01 to 10 μM in a treatment in vivo is present.

Of the The practitioner or the administering physician will be able to in each case to determine or determine sufficient therapeutic amount.

Cosmetic treatment

The Task is further solved according to the invention by the use of a compound of the invention of the formula I as defined herein or a compound of the invention A compound of formula II as defined herein for the cosmetic Treatment, especially of skin.

Prefers be the compounds of the invention for general cosmetic treatment of inflammatory skin diseases used.

To they can be used in cosmetic compositions which include suitable carriers and / or excipients. Suitable carriers and excipients are known in the art known and can be selected by a professional become. Carriers include binders, suspending agents, Lubricants, flavorings, sweeteners, preservatives, Dyes and coatings, a.

There a great need for 5-LO inhibitors with new basic structures There have been various commercial substance databases computer-based procedures initially screened virtually and then the identified substances in intact Granulocytes and S100 supernatants tested.

As a simple cellular test system granulocyte offer (PMNL), which are stimulated with the Ca ^{2 +} ionophore A23187 in the presence of arachidonic acid. Arachidonic acid addition prevents the identification of substances or compounds which inhibit the biosynthesis of leukotrienes by cPLA ₂ inhibition. Using this test system, FLAP and 5-LO inhibitors can be identified [11]. The subsequent testing of the substances with cell homogenates and 100,000 g supernatants was used to check whether a direct 5-LO inhibition is present. FLAP inhibitors are ineffective in these two test systems.

It Two new molecular backbones were found, type 1 (compounds of the formula I) and type 2 (compounds of the formula II), showing significant nanomolar binding to 5-LO and inhibition 5-LO catalyzed reactions and arachidonic acid metabolism exhibit.

Table 1 Preferred substitution patterns for compounds of the formula I.

Table 2 Preferred Substitution Patterns for Compounds of Formula II

The present invention will be further clarified in the following figures and examples without, however, being limited thereto. The cited references are hereby fully incorporated by reference accepted.

characters

1 , Regulation of cellular 5-lipoxygenase activity.

Representation of the regulation of the 5-lipoxygenase activity in the cell, including the influence of Ca ²⁺ concentration and phosphorylation.

2 - 8th , Inhibitory activity of compounds of the formula I.

Shown The results are the direct inhibition of 5-lipoxygenase (S100) by compounds of the formula I and the functional activity Compounds in a Cellular Test System (PMNL).

9 - 20 , Inhibitory activity of compounds of the formula II.

Shown The results are the direct inhibition of 5-lipoxygenase (S100) by compounds of the formula II and the functional activity Compounds in a Cellular Test System (PMNL).

Examples

Example 1. Virtual screening after new 5-LO inhibitors

At the virtual screening for 5-LO inhibitors using a computerized method were commercial substance databases with a total of 364,062 organic Searches connections. Each of the molecules became this into a vector representation of the pharmacophore properties. The different variants of the CATS algorithm were used [12, 13]. The COX / LOX present in the data collection COBRA 4.6 [14] Dual inhibitors served as reference substances for the carried out similarity searches.

wobei A und B zwei Moleküldeskriptoren darstellen. Je kleiner die Distanz D zwischen einem Anfragemolekül (Referenzsubstanz) A und einem Datenbankmolekül B ist, desto ähnlicher sind deren Pharmakophore.The Manhattan distance D (Equation 1) served as a similarity metric.

where A and B represent two molecular descriptors. The smaller the distance D between a query molecule (reference substance) A and a database molecule B, the more similar are the pharmacophores thereof.

The with the Manhattan distance calculated best structures from the virtual hit list for each reference molecule, and the averaged one List of all reference substances have become biological Activity determination selected.

Example 2. Determination of the 5-LO activity in intact granulocytes (PMNL)

PMNL cells (5 x 10 ⁶ ) are resuspended in 1 ml of PBS-glucose (pH 7.4, 1 mg / ml glucose). The following concentrations of the test substances were used, see also 2 - 20 : 0.03-10 μM (C03, A07) 0.1-10 μM (C06, A03, C05, A01, B01, A05, A04, B07, B02) 1-10 μM (C01, B06) 1-30 μm A02, C02, B05, B03, B04, A06)

After preincubation with the test substances for 15 min at RT, 5-lipoxygenase (5-LO) product formation is started by addition of 2.5 μM calcium ionophore A23187 (Sigma) plus 20 μM arachidonic acid. Incubate for 10 min at 37 ° C and quench with methanol (1 mL). After addition of 30 .mu.l 1 N HCl, 200 ng prostaglandin B ₁ (internal standard) and 500 ul of PBS, the formed 5-LO metabolites by solid phase extraction on an RP18 column (Clean-Up ^® Extraction Columns, United Chemical Technologies) , which was preconditioned with 1 ml each of methanol and water, isolated from the mixture. After loading the sample, the column is washed with 1 ml of water and 1 ml of 25% methanol, and the 5-LO metabolites are extracted with 300 μl of methanol.

Of the Extract is diluted with 120 μl of water and 100 μl of the diluted extract are analyzed by HPLC. The detection takes place in the first 8 minutes at 280 nm and at 235 nm for another 22 minutes. As stationary Phase is a Novapak C-18 Radial Pack column (100 mm 5 mm I.D., 4 μm particle size, Waters) used, the flow agent is a mixture of methanol / water / trifluoroacetic acid (72/28 / 0.007 v / v), the flow is 1.2 ml / min.

The 5-LO product formation is reported in ng 5-LO metabolites per 10 ⁶ cells and comprises the sum of LTB ₄ , the all-trans isomers of LTB ₄ (5 (S), 12 (S) -di-hydroxy -6,10-trans-8,14-cis-eicosatetraenoic acid (5 (S), 12 (S) -dihetone) and 5 (S) -hydro (pero) xy-6-trans-8,11,14- cis-eicosatetraenoic acid (5-H (p) ETE) Each substance was tested three times and averages and standard deviation were determined.

The results are in the 2 - 21 and Tables 3 and 4.

Example 3. Determination of the 5-LO activity in 100,000 g cell supernatants (S100)

PMNL (7.5 x 10 ⁶ ) are resuspended in 1 ml PBS (pH 7.4) with 1 mM EDTA, chilled on ice for 5 min and after addition of soybean trypsin inhibitor (60 μg / ml), 1 mM phenylmethylsulphonyl fluoride (PMSF), leupeptin and lysozyme (500 μg / ml) were homogenized by sonic ultrasound (3 x 10 seconds). After centrifugation at 100,000 x g for 70 min at 4 ° C, the pellet is removed and the supernatant (S100) used for the 5-LO assay.

The samples are preincubated with the test substances in the appropriate concentrations as indicated in Example 2. After addition of 1 mM ATP, the samples are preheated for 30 seconds at 37 ° C and the reaction started by adding 2 mM CaCl ₂ and 20 μM arachidonic acid. Incubate for 10 min at 37 ° C and quench with methanol (1 mL). The subsequent determination of the 5-LO products is carried out as described for the intact cells (vide supra) (see Example 2). Each substance is tested three times and the mean and standard deviation are determined.

The results are in the 2 - 21 and Tables 3 and 4. Table 3 Compounds of formula I and their experimentally observed activity (direct inhibition of 5-LO (S100), and functional activity in the cellular assay system (PMNL)). connection substitution m Left, n activity R ₁ R ₂ R ₃ intact PMNL 5-LO (S100) C06 p-methyl p-methoxy H 0 Methyl n = 1 0.17 μM 0.15 μM A03 p-methyl o-hydroxy m-methoxy 0 Methyl n = 1 0.8 μM 1.3 μM C05 p-methyl o-methoxy m-methoxy 0 Methyl n = 1 0.35 μM 0.13 μM C03 p-methyl H H 0 Prop-1-enyl n = 3 0.4 μM 0.23 μM A01 H 9-Anthrazyl H 0 Methyl n = 1 4.3 μM 0.3 μM

Table 4 Compounds of formula II and their experimentally observed activity (direct inhibition of 5-LO (S100), and functional activity in the cellular assay system (PMNL)).

references

• 1. Werz, O., Steinhilber, D. (2006) Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol. Ther. 112, 701-718 ,
• Second Mehrabian, M., Allayee, H. (2003) 5-lipoxygenase and atherosclerosis. Curr Opin Lipidol 14, 447-457 ,
• Third Rådmark, O., Samuelsson, B. (2005) Regulation of 5-lipoxygenase enzyme activity. Biochem. Biophys. Res. Commun. 338, 102-110 ,
• 4th Werz, O., Klemm, J., Samuelsson, B., Rådmark, 0. (2000) 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc. Natl. Acad. Sci. USA 97, 5261-5266 ,
• 5th Werz, O., Burkert, E., Fischer, L., Szellas, D., Dishart, D., Samuelsson, B., Rådmark, O., Steinhilber, D. (2002) Extracellular signal-regulated kinases phosphorylate 5- lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. FASEB J. 16, 1441-1443 ,
• 6th Werz, O., Szellas, D., Steinhilber, D., Rådmark, O. (2002) Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J. Biol. Chem. 277, 14793-14800 ,
• 7th Werz, O., Burkert, E., Rådmark, O., Steinhilber, D. (2002) Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes. Blood 99, 1044-1052 ,
• 8th. Werz, O., Steinhilber, D. (2005) Development of 5-lipoxygenase inhibitors - lessons from cellular enzyme regulation. Biochem. Pharmacol. 70, 327-333 ,
• 9th McMillan, RM, Bird, TG, Crawley, GC, Edwards, MP, Girodeau, JM, Kingston, JF, Foster, SJ (1991) Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase. Agents Action. 34 (1-2), 110-112 ,
• 10th Bird, TGC, Bruneau, P., Crawley, PC, Edwards, MP, Foster, SJ, Girodeau, JM, Kingston, JF and McMillan, RM (1991) (methoxyalkyl) thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity. J. Med. Chem. 34 (7), 2176-2186 ,
• 11th Miller, DK, Gillard, JW, Vickers, PJ, Sadowski, S., Léveillé, C., Mancini, JA, Charleson, P., Dixon, RAF, Ford-Hutchinson, AW, Fortin, R., Gauthier, JY, Rodkey, J., Rosen, R., Rouzer, C., Sigal, IS, Strader, CD, Evans, JF (1990) Identification and isolation of a membrane protein necessary for leukotriene production. Nature 343, 278-281 ,
• 12th Schneider, G., Neidhart, W., Giller, T., Schmid, G. (1999) "Scaffold hopping" by topological pharmacophore search: A contribution to virtual screening Angew. Chemie 111, 3068-3070, Angew Int. Ed. 38, 2894-2896 ,
• 13th Fechner, U., Franke, L., Renner, S., Schneider, P., Schneider, G. (2003) Comparison of correlation vector methods for ligand-based similarity searching. J. Comput. Aided Mol. Des. 17, 687-698 ,
• 14th Schneider, P., Schneider, G. (2003) Collection of bioactive reference compounds for focused library design. QSAR Comb. Sci. 22, 713-718 ,

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - WO 2007/012464 A1 [0008]
• JP 2005-063833 [0010]
• WO 2006/114263 A1 [0012]
• WO 2006/101455 A1 [0013]

Cited non-patent literature

• McMillan et al., 1991 [0011]
• - Werz, O., Steinhilber, D. (2006) Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol. Ther. 112, 701-718 [0079]
• - Mehrabian, M., Allayee, H. (2003) 5-lipoxygenase and atherosclerosis. Curr Opin Lipidol 14, 447-457 [0079]
• - Rådmark, O., Samuelsson, B. (2005) Regulation of 5-lipoxygenase enzyme activity. Biochem. Biophys. Res. Commun. 338, 102-110 [0079]
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Claims (28)

Compound of formula I

wherein R _{1 is} hydrogen, alkyl, alkenyl, alkoxy, aryl, a fused aryl radical, a heterocycle or halogen, R _{2 is} hydrogen, hydroxy, alkyl, alkenyl, alkoxy, cycloalkyl, a substituted or unsubstituted aryl radical, a fused aryl radical or a heterocycle, R _{3 is} hydrogen, alkyl, alkenyl, alkoxy, cycloalkyl, a substituted or unsubstituted aryl radical, an annelated aryl radical or a heterocycle, m is 0 or 1 and selected from CH ₂ , NH and O. n is alkyl or alkenyl linker, preferably having 1 to 4 carbon atoms, which may contain N, S, O or P as heteroatoms, for the treatment of diseases. A compound according to claim 1, wherein R _{1 is} selected from methyl, especially p-methyl, hydrogen and naphthyl. A compound according to claim 1 or 2, wherein R _{2 is} selected from methoxy, in particular p-methoxy or o-methoxy, methyl, hydroxy, in particular o-hydroxy. Hydrogen and 9-anthrazyl. A compound according to any one of claims 1 to 3, wherein R _{3 is} selected from methoxy, especially m-methoxy and hydrogen. A compound according to any one of the claims 1 to 4, wherein the linker n is methyl or prop-1-enyl. A compound according to any one of claims 1 to 5, wherein R _{1 is} methyl, R _{2 is} methoxy, R _{3 is} H and m is 0, n is methyl, or R _{1 is} methyl, R _{2 is} hydroxy, R _{3 is} methoxy and m is 0, n is methyl, or R _{1 is} methyl, R _{2 is} methoxy, R _{3 is} methoxy and m is 0, n is methyl, or R _{1 is} methyl, R _{2 is} H, R _{3 is} H and m is 0, n is prop-1-enyl, or R _{1 is} H, R _{2 is} anthrazyl, R _{3 is} H and m is 0, n is methyl. A compound according to any one of claims 1 to 6, wherein the compound is selected from

Compound of the formula II

wherein R _{1 is} hydrogen, alkyl, alkenyl, alkoxy, preferably each of C ₁ to C 6, a substituted or unsubstituted aryl, a substituted or unsubstituted alkylaryl, a heterocycle, halogen or an amino group, R _{2 is} hydrogen unbranched or branched alkyl, alkenyl, alkoxy, preferably in each case C1 to C6, cycloalkyl, a substituted or unsubstituted aryl radical, a substituted or unsubstituted alkylaryl radical or a heterocycle, R _{3 is} hydrogen, alkyl, alkenyl , Alkoxy radical, preferably each C1 to C6, cycloalkyl, a substituted or unsubstituted aryl radical, a substituted or unsubstituted alkylaryl radical, a heterocycle or halogen, for the treatment of diseases. A compound according to claim 8, wherein R ₁ , R ₂ and / or R _{3 are} selected from substituted and unsubstituted aryl radicals, in particular substituted and unsubstituted alkylaryl radicals. A compound according to claim 8 or 9, wherein R _{1 is} selected from phenyl, chlorophenyl, methylphenyl, dimethylaminophenyl and thiophenyl. A compound according to any one of claims 8 to 10, wherein R _{2 is} selected from isopropyl, isobutyl, isopentyl, benzyl, cyclopentyl, cyclohexyl and methylfuranyl. A compound according to any one of claims 8 to 11, wherein R _{3 is} selected from hydrogen, methyl, especially 6-methyl and 7-methyl, and chlorine, especially 6-chloro. A compound according to any one of claims 8 to 12, wherein R _{1 is} phenyl, R _{2 is} isopropyl and R _{3 is} H, or R _{1 is} chlorophenyl, R _{2 is} isobutyl and R _{3 is} methyl, or R _{1 is} methylphenyl, R ₂ isobutyl and R _{3 is} methyl, or R _{1 is} dimethylaminophenyl, R _{2 is} isopropyl and R _{3 is} methyl, or R _{1 is} methylphenyl, R _{2 is} isopropyl and R _{3 is} chloro, or R _{1 is} phenyl, R _{2 is} benzyl and R _{3 is} H, or R _{1 is} phenyl, R ₂ isopentyl and R _{3 is} methyl , or R _{1 is} phenyl, R _{2 is} cyclohexyl and R _{3 is} methyl, or R _{1 is} phenyl, R _{2 is} cyclohexyl and R _{3 is} H, or R _{1 is} thiophenyl, R _{2 is} benzyl and R _{3 is} methyl, or R _{1 is} methylphenyl, R _{2 is} cyclopentyl and R _{3 is} methyl, or R _{1 is} phenyl, R _{2 is} methylfuranyl and R _{3 is} methyl. A compound according to any one of claims 8 to 13, wherein the compound is selected from

A pharmaceutical composition comprising a or several compounds of the formula I according to one of the claims 1 to 7 and / or one or more compounds of the formula II one of claims 8 to 14 and pharmaceutically acceptable Carriers and / or auxiliaries. Use of a compound of the formula I according to one of claims 1 to 7 or a compound of the formula II according to any one of claims 8 to 14 or a pharmaceutical A composition according to claim 15 for the treatment of 5-lipoxygenase products mediated diseases. Use according to claim 16, wherein the diseases are selected from inflammatory diseases, allergic diseases, cardiovascular diseases, Hypertension, osteoporosis, osteosclerosis, osteoarthritis, hair loss, Atherosclerosis, cancers, multiple sclerosis, Parkinson's disease and Alzheimer's disease. Use according to claim 17, wherein the inflammatory diseases are selected from asthma, psoriasis, rheumatoid arthritis, allergic rhinitis and inflammatory bowel disease. Use of a compound of the formula I according to one of claims 1 to 7 or a compound of the formula II according to any one of claims 8 to 14 or a pharmaceutical A composition according to claim 15 as an inhibitor of arachidonic acid metabolism. Use of a compound of the formula I according to one of claims 1 to 7 or a compound of the formula II according to any one of claims 8 to 14 or a pharmaceutical A composition according to claim 15 as an arachidonic acid-binding inhibitor Enzymes. Use according to claim 20, wherein arachidonic acid-binding enzymes are selected are from lipoxygenases, cyclooxygenase and phospholipases. Use according to claim 21, wherein the arachidonic acid-binding enzyme 5-lipoxygenase is. Use according to one of the claims 16 to 22, wherein a compound of formula I according to any one of claims 1 to 7 or a compound of formula II according to any one of claims 8 to 14 or a pharmaceutical composition according to claim 15 administered locally or systemically. Use according to claim 23, the administration being oral, nasal, subcutaneous, intracutaneous, parenteral, transdermal, topical, intravenous, intraarterial, intramuscular, intraperitoneally or in combinations thereof. Use according to claim 24, wherein the administration is a transdermal or topical administration, preferred is transdermal administration. Use according to claim 25, wherein the transdermal administration is in a dosage form selected from the group comprising spray; Plaster; Ointment; semi-solid cream; Liquid, like a solution; Solid, like a powder; Gel; Emulsion or suspension. Use of a compound of the formula I according to one of claims 1 to 7 or a compound of the formula II according to any one of claims 8 to 14 for cosmetic treatment, especially of skin. Use according to claim 27, where inflammatory skin diseases are treated cosmetically become.