DE4338770A1 - Indole-2-alkanoic acids and their derivatives as inhibitors of phospholipase A¶2¶ - Google Patents

Description

The invention relates to indole-2-alkanoic acids and their derivatives which contain the enzyme Phos Pholipase A₂ inhibit. The compounds are useful as drugs for prevention and for the treatment of diseases caused by increased activity of this enzyme caused or co-caused, such as inflammation, allergies, Asthma, psoriasis and endotoxin shock. The invention further relates to methods for Representation of these compounds as well as pharmaceutical agents containing these compounds contain.

Background of the invention

It is known that the phospholipase A₂ hydrolytically the ester bond in the 2-position of membrane phospholipids, using free fatty acids, mainly arachidon acid, and Iyso-phospholipids arise.

The released arachidonic acid becomes the Prosta via the cyclooxygenase pathway glandins and thromboxanes and via the lipoxygenase pathways to the leukotrienes and other hydroxylated fatty acids. The prostaglandins are at the Ent the onset of pain and fever and inflammatory reactions involved. Leukotrienes are important mediators in inflammatory processes and in ana phylactic and allergic processes (Forth et al., General and Special Pharma ecology and toxicology BI Wissenschaftsverlag Mannheim, Vienna, Zurich 1987).

The Iyso-phospholipids formed by the phospholipase A₂ possess cell-damaging Properties. Lysophosphatidylserine leads to the release of the allergic process involved histamine (Moreno et al., Agents Actions 1992, 36, 258). Lyso-phospha tidylcholine is also metabolised to platelet-activating factor (PAF), who is also an important mediator z. B. in inflammation.

Since the phospholipase A₂ is the key enzyme for the formation of said pathophy are siologically important mediators, can be inhibited by the En zyms disable these mediator effects.

The pathophysiological importance of phospholipase A₂ is also evident from the fact that their activity is significantly increased in different pathological conditions: so were the Example high phospholipase A₂ activities in the synovial fluid of patients with rheumatoid arthritis (Vadas et al., Life Sci., 1985, 36, 579), in serum from patients with endotoxin shock (Vadas J. Lab., Clin. Med. 1984, 104, 873) or pancreatitis (Ne  valainer scand. J. Gastroent. 1980,15, 641) as well as in the epidermis of patients with Psoriasis (Forster et al., Br. J. Derm., 1985, 112, 135) (see also Wong et al al. Adv. Exp. Med. Biol. 1990, Vol. 275 Phospholipase A₂: Role and Function in In Flammation, Plenum Press, New York).

Subject of the invention

It has now been found that certain indole compounds have potent phospholipase A₂- Inhibitors are and therefore for the prevention and treatment of diseases that caused by an increased activity of this enzyme, such as for example inflammation, allergies, asthma, psoriasis and endotoxin shock, are usable.

The invention therefore relates to indole compounds of the general formula:

wherein
R¹ is X, aryl or -X-aryl, wherein X is a C₁-C₁₉-alkyl or C₂-C₁₉ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl an aryl group or one with the radicals R⁶ and R⁷ are substituted aryl group;
R² is -COOH, -Y-COOH, -Tz, or -Y-Tz, wherein Y is a C₁-C₈-alkyl or C₂-C₈ alkenyl group, which may optionally be interrupted by an oxygen heteroatom, and Tz 1H- or 2H-tetrazol-5-yl;
R³ is a hydrogen atom; for a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom; an aryl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z-aryl, wherein Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl is an aryl group or an aryl group substituted by the radicals R⁸ and R⁹ ; for -Z- OR¹⁶, -Z-SR¹⁶ or -Z-NHR¹⁶, wherein Z is a C₂-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, means;
Q is CO, CH₂ and CHNHCOR¹⁰, wherein R¹⁰ is W, aryl or -W-aryl and W is a C₁-C₁₉-alkyl or C₂-C₁₉ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl represents an aryl group or an aryl group substituted with the radicals R¹¹ and R¹²; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently selected from:

• 1) hydrogen;
• 2) C₁-C₂₀-alkyl group, optionally substituted by an oxygen heteroatom under can be broken;
• 3) C₂-C₂₀ alkenyl optionally substituted by an oxygen heteroatom can be interrupted;
• 4) C₂-C₂₀ alkynyl group optionally substituted by an oxygen heteroatom can be interrupted;
• 5) halogen;
• 6) -CF₃;
• 7) -CN;
• 8) -NO₂;
• 9) -OR¹³;
• 10) -SR¹³;
• 11) -COOR¹³;
• 12) -COR¹⁴;
• 13) -COCH₂OH;
• 14) -NHCOR¹³;
• 15) -NR¹³R¹³;
• 16) -NHSO₂R¹⁵;
• 17) -SOR¹³;
• 18) -SO₂R¹³;
• 19) -CONR¹³R¹³;
• 20) -SO₂NR¹³R¹³;
• 21) -OOCR¹⁴;
• 22) -OOCNR¹³R¹³;
• 23) -OOCOR¹³;
• 24) - (CH₂) _r OR¹⁶;
• 25) - (CH₂) _r SR¹⁶;
• 26) - (CH₂) _r NHR¹⁶;
• 27) - (CH₂) _s R¹⁷;
• 28) perhalo-C₁-C₆ alkenyl;

Each of R¹³ independently represents hydrogen, a C₁-C₂₀ alkyl or C₂-C₁₉ alkenyl or alkynyl group which may optionally be interrupted by an oxygen heteroatom, or - (CH₂) _t R¹⁷;
Each of R¹⁴ independently represents R¹³, -CF₃, - (CH₂) _u COOH or - (CH₂) _u COOR¹⁹;
Each of R¹⁵ independently represents R¹³ or CF₃;
Each R¹⁶ is independently hydrogen or -COR¹⁹;
Each R¹⁷ independently represents aryl substituted with one or two R¹⁸ groups;
Each R¹⁸ is independently hydrogen, halogen, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ alkylcarbonyl, -CF₃, -CN or NO₂;
Each R¹⁹ is independently C₁-C₆ alkyl, benzyl or phenyl;
r is 1 to 20;
s and t are each independently 0 to 12;
u is 0 to 4.

The invention also includes the pharmaceutically acceptable salts and - in the case of carboxylic acids - also the esters of the compounds for use in pharmacy.

The pharmaceutically acceptable salts may be base addition salts. These include Salts of the compounds with inorganic bases, such as alkali hydroxides, alkaline earth metal droxiden or with organic bases, such as mono-, di- or triethanolamine.

The esters of the compounds include in particular physiologically readily hydrolyzed bare esters, for example alkyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, in danyl and methoxymethylene esters.

The term "alkyl" includes straight-chain, branched or cyclic alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, neopentyl, undecyl, dodecyl, pentadecyl, Hexadecyl, heptadecyl, octadecyl, cyclododecyl, etc.

The term "alkeny" includes straight, branched or cyclic alkenyl groups such as ethenyl, propenyl, butenyl, decenyl, heptadecinyl, cyclohexyl etc.

The term "alkynyl" includes straight-chain or branched alkynyl groups, such as Ethynyl, propynyl, butynyl, decynyl, heptadecinyl etc.

The term "cycloalkyl" means a hydrocarbon ring of 3 to 7 carbons atoms such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

The term "alkoxy" includes straight-chain, branched or cyclic alkoxy groups such as methoxy, ethoxy, propoxy, cyclohexyloxy etc.  

The term "alkylthio" includes straight-chain, branched or cyclic alkylthio groups, such as methylthio, ethylthio, propylthio, cycloheptylthio etc.

Aryl is preferably naphthyl or pyridyl and especially phenyl.

The term "halogen atom" includes a fluorine, chlorine, bromine or iodine atom and ins especially a fluorine or chlorine atom.

The compounds of the invention have as potent phospholipase A₂-Hem proved. The compounds are therefore useful as drugs for prevention and for the treatment of diseases caused by products or by-products of this Enzymes are caused or mituursacht, such as for the treatment of rheumatic forms and for the prevention and treatment of allergic indu graced diseases. The compounds of the invention thus provide u. a.wirksame Antiphlogistics, antipyretics, antiallergic drugs and broncholytics and are to Throm boseprophylaxe and for the prophylaxis of anaphylactic shock and for treatment dermatological diseases such as psoriasis, urticaria, acute and chronic Exanthema of allergic and non-allergic genesis, useful.

The compounds of the invention may be administered either as a single therapeutic Or administered as mixtures with other therapeutic agents become. They can be given alone, but in general they will be given in Form of pharmaceutical agents administered, that is, as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents. The connections or Agents may be administered orally, parenterally, by inhalation or topically (including dermal, transdermal, buccal and sublingual).

The nature of the pharmaceutical agent and the pharmaceutical carrier or diluent agent depends on the desired route of administration. Oral remedies may be included For example, as tablets or capsules, even in a retarded form, are present and can contain usual excipients, such as binding agents (eg syrup, acacia, gelatin, sorbitol, Tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, corn starch, calci umphosphate, sorbitol or glycine), lubricants (e.g., magnesium stearate, talcum, poly ethylene glycol or silica), disintegrating agent (eg starch) or wetting agent (eg, sodium lauryl sulfate). Oral liquid preparations may be in the form of aqueous or oily Suspensions, solutions, emulsions, syrups, elixirs or sprays, etc. or may be suitable as a dry powder for reconstitution with water or another Neten carrier present. Such liquid preparations may conventional additives, for example Wise suspending agents, flavorings, diluents or emulsifiers enthal  For parenteral administration, solutions or suspensions may be used use pharmaceutical carriers. For administration by inhalation, NEN the compounds are present in aqueous or partially aqueous solution in the form an aerosol can be applied. Agents for topical application may, for. B. as pharmaceutically acceptable powders, lotions, ointments, creams, gels or as thera peutische systems are present, the therapeutically effective amounts of the invention Contain connections.

The dosage required depends on the form of the pharmaceutical used remedy, the type of application, the severity of the symptoms and the specific ellen subject (human or animal) being treated. The treatment is usually two started at a dose below the optimal dose. After that, the Increases the dose until the optimal effect for the given conditions is achieved. In the all In general, the compounds of the invention are best in concentrations administered with which effective effects can be achieved without harmful or adverse effects occur. They can be in a single dose or in several Doses are administered.

The effectiveness of the compounds of the invention can be determined by the inhibition determine the phospholipase A₂. For this purpose, in intact bovine platelets, the phos pholipase A₂ with calcium ionophore A23 stimulates 187 and thereby the release of Arachidonic acid is released from the membrane phospholipids. To metabolize the Enzyme product arachidonic acid via the cyclooxygenase pathway and the 12-lipoxy In this process, the dual cyclooxygenase / 12-lipoxygenase inhi is prevented Bitor 5,8,11,14-Eikosatetrainsäure added. After purification by means of solid phase extract tion, the released arachidonic acid is determined by RP-HPLC with UV detection. The inhibition of the enzyme by a test substance results from the ratio of the arachidonic acid formed in the presence or in the absence of the test substance amounts. Further details on the test system are given in the example given below len.  

The compounds according to the invention can be prepared according to the following methods represent.

Method 1

Indole-2-carboxylic acid ester 1 can be treated with carboxylic acids in the presence of trifluoroacetic anhydride and polyphosphoric acid, optionally in a suitable solvent, such as. B. CH₂Cl₂ or nitrobenzene, or be reacted with carboxylic acid chlorides according to Friedel-Crafts to 3-acyl indole-2-carboxylic acid esters 2 (see Murakami et al., Chem. Pharm. Bull., 1985, 33, 4707-4716, Murakami et al. Heterocycles 1980, 14, 1939; Murakami et al Heterocycles 1984, 22, 241-244; Murakami et al., Chem. Pharm. Bull. 1988, 36, 2023-2035; Tani et al., Chem. Pharm. Bull. 38, 3261-3267). These esters can be alkylated on the indole nitrogen to the compounds 4 . The N-alkylation is carried out example, as usual using the corresponding alkyl halides in the presence of a base, eg. As alkali metal alkoxide, such as potassium t-butylate, in an inert solvent, such as DMSO or the like. The N-alkylation can also be heterogeneous with To luolsulfonsäurealkylestern or alkyl halides using Phasentrans pherkatalysatoren in an organic solvent such as ether, with the addition of ge powdered alkali hydroxide, such as sodium hydroxide perform. From 2 or 4 , the carboxylic acids 3 or 5 according to the invention are obtained by ester cleavage. The ester cleavage can hydrolytically, z. B. with alcoholic potassium hydroxide solution, or in the case of benzyl also hydrogenolysis, z. B. in THF with hydrogen in the presence of Pd / C occur. Letz tere method is especially indicated thin, if in addition to this ester group more hydro lyseempfindliche functions are included in the compounds.

Method 1

a) carboxylic acid, trifluoroacetic anhydride, polyphosphoric acid, CH₂Cl₂; b) ethanolic potassium hydroxide or H₂, Pd / C, THF, when R¹⁹ = benzyl; (C) p-Toluolsulfonsäureester or alkyl halide, (C₄H₉) ₄NBr, NaOH powder, ether or ether / CH₂Cl₂ or alkyl halide, potassium t-butylate, DMSO.

Method 2

Alternatively, compounds of the formula 5 can also be prepared by method 2. The reactions correspond in principle to the reactions of method 1. However, the indole-2-carboxylic esters 1 are first N-alkylated and then acylated in position 3 of the indole.

Method 2

a) p-toluenesulfonic acid ester or alkyl halide, (C₄H₉) ₄NBr, NaOH powder, ether or ether / CH₂Cl₂ or alkyl halide, potassium t-butylate, DMSO; (b) carboxylic acid, trifluoroacetic anhydride, polyphosphoric acid, CH₂Cl₂; (c) ethanolic potassium hydroxide or H₂, Pd / C, THF, when R¹⁹ = benzyl.

Method 3

For the preparation of 3-acylindole-2-carboxylic acids homologous alkanoic acids 9 and 11 can be z. B. starting from the indole-2-alkansäureestern 2 . These are first acylated in position 3 of the indole by means of Vilsmeier or Friedel-Crafts synthesis. The he held ester 8 can be alkylated on the indole nitrogen to the compounds 10 . The N-alkylation can be carried out as described in Method 1. From 8 or 10 , the carboxylic acids 9 or 11 according to the invention are obtained by ester cleavage. The ester cleavage can hydrolytically, z. B. with alcoholic potassium hydroxide solution, or in the case of benzyl also hydrogenolysis, z. B. in THF with hydrogen in the presence of Pd / C occur. The latter method is especially indicated when in addition to this ester group more hydrolysis-sensitive functions are included in the compounds.

Method 3

a) Carbonsäuredimethylamid, POCl₃, benzene; (b) ethanolic potassium hydroxide or H₂, Pd / C, THF when R¹⁹ = benzyl; (C) p-Toluolsulfonsäureester or alkyl halide, (C₄H₉) ₄NBr, NaOH powder, ether or ether / CH₂Cl₂ or alkyl halide, potassium t-butylate, DMSO.

Method 4

Alternatively, compounds of the formula 11 can also be prepared according to method 4. The reactions correspond in principle to the reactions of method 3. However, the indole-2-carboxylic esters 7 are first N-alkylated and then acylated in position 3 of the indole.

Method 4

a) p-toluenesulfonic acid ester or alkyl halide, (C₄H₉) ₄NBr, NaOH powder, ether or ether / CH₂Cl₂ or alkyl halide, potassium t-butylate, DMSO; (b) carboxylic acid dimethylamide, POCl₃, benzene; c) ethanolic potassium hydroxide or H₂, Pd / C, THF, when R¹⁹ = benzyl.

Method 5

3- (1-Acylaminoalkyl) indole-2-alkanoic acids 15 and 17 can be prepared with the reaction sequence shown in Method 5. Starting compounds are the 3-acylindole-2-carboxylic acid esters 2 (s.Methode 1). These are first reductively aminated on the keto group; the amination is carried out for example by reaction with hydroxylamine hydrochloride, for. As in ethanol / pyridine or with ethanol / BaCO₃, to the oximes 13 and subsequent reduction of the oximes with zinc in sodium acetate / glacial acetic acid. Acylation of the resulting amine function, eg. B. with carboxylic acid chlorides in the presence of dimethylaminopyridine in triethylamine / chloroform, leads to the compounds 14th These can be alkylated on the indole nitrogen to the compounds 16 . The N-Alkylie tion can be carried out as described in Method 1. From 14 or 16 , the carboxylic acids 15 or 17 according to the invention are obtained by ester cleavage. The ester cleavage can hydrolytically, z. B. with alcoholic potassium hydroxide, or in the case of benzyl ester also hydrogenolysis, z. B. in THF with hydrogen in the presence of Pd / C, he follow. The latter method is especially indicated if, in addition to this ester group, further hydrolysis-sensitive functions are contained in the compounds.

Method 5

a) hydroxylamine hydrochloride, ethanol, pyridine; (b) zinc, sodium acetate, glacial acetic acid; (c) acyl chloride, 4-dimethylaminopyridine, triethylamine, CHCl₃; (d) ethanolic potassium hydroxide or H₂, Pd / C, THF when R¹⁹ = benzyl; (E) p-Toluolsulfonsäureester or alkyl halide, (C₄H₉) ₄NBr, NaOH powder, ether or ether / CH₂Cl₂ or alkyl halide, potassium t-butylate, DMSO.

Method 6

Compounds of the invention in which Q is CH₂ can be exemplified by the 3-acylindole derivatives 4 and 10, respectively. By reduction of the keto group z. B. with NaBH₄ / BF₃-ethyl ether complex in a suitable solvent or solvent mixture Lö, such as THF / methyl acetate, and subsequent ester cleavage gives the desired indole derivatives 18th The representation of these compounds from 4 or 10 is alternatively z. B. also possible by Wolff-Kishner reduction.

Method 6

a) NaBH₄, BF₃-ethyl ester complex, THF, methyl acetate; (b) ethanolic potassium hydroxide or H₂, Pd / C, THF, when R¹⁹ = benzyl.

Method 7

Compounds of the invention wherein R² is -Tz or -Y-Tz, where Y is a C₁-C₈-alkyl or C₂-C₈-alkenyl group, optionally substituted by an oxygen heteroatom can be interrupted, and Tz 1H or 2H-tetrazol-5-yl, let z. From analogous compounds where R² is -COOH or -Y-COOH, as known (see, eg, US Patent 4,808,608).  

Representative connections Tables 1 to 4 show representative compounds of the invention.

Table 1

Table 2

Table 3

Table 4

The following examples illustrate the invention.

The batches were carried out with the exclusion of atmospheric oxygen. To the column chro Silica gel 60 (70-230 mesh ASTM) from Merck, Darmstadt, used; the substances were ge for application to the columns in solvents ge dissolves, the elution strength was lower than the elution strength of each stated Eluent (usually toluene, CHCl₃ or CH₂Cl₂ or mixtures of these Lö with petroleum ether). All temperatures are uncorrected. At the Aufnah The mass spectra was chemically ionized with CH₄ gas or CH₅⁺ ions. The NMR spectra are 400 MHz spectra, which in CDCl₃ with tetramethylsilane (TMS) as internal standard were measured.

example 1 3-Octadecanovlindol-2-carboxylic acid A. Ethyl 3-octadecanoylindole-2-carboxylate

The mixture of 2.27 g (12 mmol) of indole-2-carboxylic acid ethyl ester, 5.12 g (18 mmol) of octadecanoic acid, 550 mg of polyphosphoric acid, 40 ml of absolute. CH₂Cl₂ and 2.6 ml of trifluoroacetic anhydride is stirred for 5 h at room temperature. Then it is mixed with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and filtered with suction after the addition of diatomaceous earth to remove the fallen octadecanoate. The ether phase is dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel first with CH₂Cl₂ / petroleum ether 3 + 1 and then with CH₂Cl₂. After concentrating the eluates, the product remains as a solid.
Yield: 2.28 g (42%)
M.p .: 65-68 ° C
C₂₉H₄₅NO₃ (455.7)
MS: m / z (rel.Int.) = 456 (71%), 428 (100%)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.13-1.41 (m, 28H, - (CH₂) ₁₄-), 1.43 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.74 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.07 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.45 (q , 2H, -O- CH₂- CH₃, J = 7 Hz), 7.24 (t, 1H, Arom., J = 8 Hz), 7.37 (t, 1H, Arom., J = 8 Hz), 7.42 (d, 1H, Arom., J = 8 Hz), 7.91 (d, 1H, Arom., J = 8 Hz), 9.05 (s, 1H, <NH)

B. 3-octadecanoylindole-2-carboxylic acid

The mixture of 456 mg (1 mmol) of ethyl 3-octadecanoylindole-2-carboxylate, 15 ml of ethanol and 5 ml of 10% strength aqueous KOH solution is refluxed for 1 h. Then it is mixed with water, acidified with 10% hydrochloric acid and ex trahiert twice with CH₂Cl₂. The organic phases are washed with dilute hydrochloric acid, dried over Na₂SO₄ and concentrated. The product is precipitated from methanol.
Yield: 200 mg (47%)
M.p .: 148-150 ° C
C₂₇H₄₁NO₃ (427.6)
H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1:12 to 1:48 (m, 28H, - (CH₂) _14-), 1.88 (quint, 2H, - CH₂ -CH₂ -CO-, J = 7Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7Hz), 7.42-7.52 (m, 2H, Arom.), 7.62 (d, 1H, Arom., J = 8 Hz), 8.00 (d, 1H, Arom., J = 8 Hz), 10.25 (s, 1H, <NH), 17.93 (s, 1H, -COOH)

Example 2 1-methyl-3-octadecanoylindol-2-carboxylic acid A. 1-Methyl-3-octadecanoylindole-2-carboxylic acid ethyl ester

The mixture of 456 mg (1 mmol) of ethyl 3-octadecanoylindole-2-carboxylate (see Example 1A), 205 mg (1.1 mmol) of p-toluenesulfonic acid methyl ester, 32 mg (0.1 mmol) of tetrabutylammonium bromide, 10 ml of ether and 48 mg (1.2 mmol) of pulverized NaOH is stirred at room temperature for 6 h. It is then mixed with water and extracted twice with ether, with NaCl being added for better phase separation. The extracts are dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 9 + 1. After a gene of the eluates, the product remains as a solid.
Yield: 350 mg (75%)
M .: 45-48 ° C
C₃₀H₄₇NO₃ (469.7)
MS: m / z (rel.Int.) = 470 (61%), 442 (100%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.07-1.39 (m, 28H, - (CH₂) _14- ), 1.42 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.75 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 2.90 (t, 2H, -CH₂-CO-, J = 7 Hz), 3.90 (s , 3H, <N-CH₃), 4.47 (q, 2H, -O- CH₂ -CH₃, J = 7Hz), 7.26-7.30 (m, 1H, Arom.), 7.35-7.40 (m, 2H, Arom. ), 7.94 (d, 1H, Arom., J = 8 Hz)

For example, 1-methyl-3-octadecanoylindole-2-carboxylic acid

164 mg (0.35 mmol) of ethyl 1-methyl-3-octadecanoylindole-2-carboxylate are saponified according to Example 1B. The product is precipitated from methanol.
Yield: 123 mg (80%)
M .: 108-111 ° C
C₂₈H₄₃NO₃ (441.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.14-1.43 (m, 26H, - (CH₂) ₁₃ ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 7.45 (t, 1H, Arom., J = 8 Hz), 7.51 (t, 1H, Arom., J = 8 Hz), 7.61 (d, 1H, Arom., J = 8 Hz) , 8.02 (d, 1H, Arom., J = 8 Hz), 16.70 (s, 1H, -COOH)

Example 3 1-methyl-3-octanoylindol-2-carboxylic acid A. 1-Methylindole-2-carboxylic acid ethyl ester

The mixture of 1.89 g (10 mmol) of ethyl indole-2-carboxylate, 2.05 g (11 mmol) of p-toluenesulfonate, 0.32 g (1 mmol) of tetrabutylammonium bromide, 100 ml of ether and 0.48 g (12 mmol) of pulverized NaOH is kept at room temperature for 12 h touched. The mixture is then filtered off with suction and the filter cake washed twice with ether nachge. The combined ether phases are concentrated and the residue is chromatographed on silica gel with petroleum ether / ethyl acetate 19 + 1. The oil remaining after evaporation of the eluates crystallizes after some time (see Johnson et al., J. Am. Chem. Soc., 1945, 67, 428).
Yield: 1.54g (76%)
Mp .: 63-64 ° C
C₁₂H₁₃NO₂ (203.2)
1 H-NMR: δ (ppm) = 1.41 (t, 3H, -O-CH₂- CH₃ , J = 7 Hz), 4.09 (s, 3H, <N-CH₃), 4.38 (q, 2H, -O- CH₂ 7.31 (s, 1H, Arom. 1H, Arom., J = 8 Hz)

For example, 1-methyl-3-octanoylindole-2-carboxylic acid

The mixture of 122 mg (0.6 mmol) of ethyl 1-methylindole-2-carboxylate, 130 mg (0.9 mmol) of octanoic acid, 27 mg of polyphosphoric acid, 3 ml of absol. CH₂Cl₂ and 0.13 ml of trifluoroacetic anhydride is stirred for 4 h at room temperature. Then it is mixed with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and dried over Na₂SO₄. The solvent is distilled off, the residue chromatographed on silica gel with petroleum ether / ethyl acetate 9 + 1 chromatography and the resulting 1-methyl-3-octanoylindol-2-carboxylic acid ethyl ester according to Example 1 B saponified, being used for the extraction of the carboxylic acid formed ether instead of CH₂Cl₂. The product is precipitated from petroleum ether.
Yield: 71 mg (38%)
M .: 113-114 ° C
C₁₈H₂₃NO₃ (311.5)
¹H-NMR: δ (ppm) = 0.90 (t, 3H, -CH₃, J = 7 Hz), 1.23-1.52 (m, 6H, - (CH₂) _3- ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 7.43-7.53 (m, 2H, Arom.), 7.61 (d, 1H, Arom., J = 8Hz), 8.01 (d, 1H, Arom., J = 8Hz), 16.73 ( s, 1H, -COOH)

Example 4 3-decanoyl-1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 155 mg (0.9 mmol) of decanoic acid instead of octanoic acid.
Yield: 46 mg (23%)
M .: 114-116 ° C
C₂₀H₂₇NO₃ (329.4)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.23-1.41 (m, 10H, - (CH₂) _5- ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 7.43-7.53 (m, 2H, Arom.), 7.61 (d, 1H, Arom., J = 9Hz), 8.02 (d, 1H, Arom., J = 8Hz), 16.71 ( s, 1H, -COOH)

Example 5 3-dodecanoyl-1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 182 mg (0.9 mmol) of dodecanoic acid instead of octanoic acid. In the case of column chromatography, it is different from petroleum ether / ethyl acetate 19 + 1 eluted.
Yield: 49 mg (23%)
M .: 116-117 ° C
C₂₂H₃₁NO₃ (357.5)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.43 (m, 14H, - (CH₂) _7- ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 7.43-7.53 (m, 2H, Arom.), 7.61 (d, 1H, Arom., J = 8Hz), 8.02 (d, 1H, Arom., J = 9Hz), 16.72 ( s, 1H, -COOH)

Example 6 1-methyl-3-tetradecanoylindol-2-carboxylic acid

Preparation according to Example 3 B with 206 mg (0.9 mmol) of tetradecanoic acid instead of octanoic acid. Deviating from the isolation of the 1-methyl-3-tetradecanoylindol-2-carboxylic acid ethyl ester according to Example 1 B; in the column chromatography is eluted with petrol ether / ethyl acetate 19 + 1.
Yield: 33mg (14%)
M .: 118-119 ° C
C₂₄H₃₅NO₃ (385.5)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.43 (m, 18H, - (CH₂) _9- ), 1.47 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 7.43-7.53 (m, 2H, Arom.), 7.61 (d, 1H, Arom., J = 8Hz), 8.02 (d, 1H, Arom., J = 9Hz), 16.72 ( s, 1H, -COOH)

Example 7 1-methyl-3- (10-undecenol) indole-2-carboxylic acid

Preparation according to Example 3 B with 166 mg (0.9 mmol) of 10-undecenoic acid instead of octanoic acid. In the case of column chromatography, this is eluted differently from petroleum ether / ethyl acetate 19 + 1.
Yield: 54 mg (26%)
M .: 93-95 ° C
C₂₁H₂₇NO₃ (341.5)
¹H-NMR: δ (ppm) = 1.23-1.43 (m, 8H, - (CH₂) ₄-), 1.48 (quint, 2H, -CH₂, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂ -CO-, J = 7 Hz), 2.05 (q, 2H, - CH₂- CH = CH₂, J = 7 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.27 (s , 3H, <N-CH₃), 4.92-5.02 (m, 2H, -CH = CH₂), 5.76-5.86 (m, 1H, - CH = CH₂), 7:43 to 7:53 (m, 2H, arom), 7.61. (d, 1H, Arom., J = 9Hz), 8.01 (d, 1H, Arom., J = 9Hz), 16.72 (s, 1H, -COOH)

Example 8 3- (4-hexylbenzoyl) -1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 206 mg (0.9 mmol) of 4-hexylbenzoic acid instead of octanoic acid. In the column chromatography is different from eluting with petroleum ether / ethyl acetate 19 + 1; the final product is precipitated from ethanol / water.
Yield: 32 mg (15%)
M .: 114-116 ° C
C₂₃H₂₅NO₃ (363.5)
1 H-NMR: δ (ppm) = 0.90 (t, 3H, -CH₃, J = 7 Hz), 1.24-1.46 (m, 6H, - (CH₂) _3- ), 1.46-1.66 (m, 2H, -CH₂ -), 1.68 (quint, 2H, phenyl-CH₂- CH₂ -, J = 7 Hz), 2.73 (t, 2H, phenyl-CH₂-, J = 7 Hz), 4.26 (s, 3H, <N-CH₃) , 6.98 (d, 1H, Arom., J = 8 Hz), 7.11 (t, 1H, Arom., J = 8 Hz), 7.31 (d, 2H, Arom., J = 8 Hz), 7.41 ( t, 1H, Arom., J = 8 Hz), 7.54 (d, 1H, Arom., J = 8 Hz), 7.73 (d, 2H, Arom., J = 8 Hz), 14.58 (broad, 1H, - COOH)

Example 9 3- (2-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 276 mg (0.9 mmol) of 2-dodecyloxybenzoic acid instead of octanoic acid. In the column chromatography, it is different from with triol ether / ethyl acetate 19 + 1 eluted.
Yield: 79 mg (28%)
M .: 63-65 ° C
C₂₉H₃₇NO₄ (463.6)
1 H-NMR: δ (ppm) = 0.72 (quint, 2H, -CH₂-, J = 7 Hz), 0.88 (t, 3H, -CH₃, J = 7 Hz), 0.92-1.04 (m, 4H, -CH₂ - and -CH₂-), 1.04-1.15 (m, 2H, -CH₂-), 1.15-1.32 (m, 12H, - (CH₂) ₆-), 3.75 (t, 2H, -O-CH₂-, J = 6 Hz), 4.28 (s, 3H, <N-CH₃), 6.65 (d, 1H, Arom., J = 7 Hz), 6.98 (d, 1H, Arom., J = 8 Hz), 7.05 (t, 1H, Arom., J = 8Hz), 7.12 (t, 1H, Arom., J = 7Hz), 7.36 (t, 1H, Arom., J = 7Hz), 7.47 (d, 1H, Arom., J = 7 Hz), 7.50 (d, 1H, Arom., J = 8 Hz), 7.57 (t, 1H, Arom., J = 8 Hz), 16.06 (s, 1H, -COOH)

Example 10 3- (3-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 276 mg (0.9 mmol) of 3-dodecyloxybenzoic acid instead of octanoic acid. In the column chromatography, it is different from with triol ether / ethyl acetate 19 + 1 eluted.
Yield: 18 mg (6%)
M.p .: 118-120 ° C
C₂₉H₃₇NO₄ (463.6)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.18-1.37 (m, 16H, - (CH₂) _8- ), 1.43 (quint, 2H, -CH₂-, J = 7 Hz), 1.77 (quint, 2H, -O-CH₂- CH₂ -, J = 7 Hz), 3.97 (t, 2H, -O-CH₂-, J = 7 Hz), 4.27 (s, 3H, <N-CH₃), 6.96 (d, 1H, Arom., J = 8Hz), 7.11 (t, 1H, Arom., J = 8Hz), 7.19-7.22 (m, 1H, Arom.), 7.30- 7.32 (m, 2H, Arom.), 7.37-7.42 (m, 2H, Arom.), 7.54 (d, 1H, Arom., J = 8 Hz), 14.92 (broad, 1H, -COOH)

Example 11 3- (4-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid

Preparation according to Example 3 B with 276 mg (0.9 mmol) of 4-dodecyloxybenzoic acid instead of octanoic acid. In the column chromatography, it is different from with triol ether / ethyl acetate 19 + 1 eluted.
Yield: 95 mg (34%)
M .: 90-92 ° C
C₂₉H₃₇NO₄ (463.6)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.18-1.41 (m, 16H, - (CH₂) _8- ), 1.49 (quint, 2H, -CH₂-, J = 7 Hz), 1.84 (quint, 2H, -O-CH₂- CH₂ -, J = 7 Hz), 4.07 (t, 2H, -O-CH₂-, J = 7 Hz), 4.25 (s, 3H, <N-CH₃), 6.96 (d, 2H, Arom., J = 9Hz), 7.11-7.15 (m, 2H, Arom.), 7.39-7.43 (m, 1H, Arom.), 7.53 (d, 1H , Arom., J = 9 Hz), 7.82 (d, 2H, Arom., J = 9 Hz), 14.75 (broad, 1H, -COOH)

Example 12 1-hexyl-3-octadecanoylindol-2-carboxylic acid

The mixture of 189 mg (1 mmol) of indole-2-carboxylic acid ethyl ester, 135 mg (1.2 mmol) of potassium t-butoxide and 4 ml of absol. DMSO is stirred for 15 min in an oil bath at 110.degree. At closing, are added to 198 mg (1.2 mmol) of 1-bromohexane and the mixture is heated for a further 15 min. After cooling, water is added and extracted with ether. The or ganic phase is dried over Na₂SO₄ and the solvent is distilled off. To the residue 427 mg (1.5 mmol) of octadecanoic acid, 67 mg of polyphosphoric acid, 6 ml absol. CH₂Cl₂ and 0.33 ml trifluoroacetic anhydride added. The mixture is stirred for 4 h at room temperature, then treated with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and filtered with suction after addition of diatomaceous earth to remove the precipitated octadecanoate. The ether phase is dried over Na₂SO₄ and the solvent is distilled off. The residue was chromatographed on silica gel with petroleum ether / ethyl acetate 29 + 1 and he saponified 1-alkyl-3-octadecanoylindol-2-carboxylic acid ethyl ester according to Example 1 B saponified, being used for the extraction of the carboxylic acid formed ether instead of CH₂Cl₂. The product is precipitated from petroleum ether.
Yield: 66mg (13%)
M .: 75-77 ° C
C₃₃H₅₃NO₃ (511.8)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 0.89 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.55 (m, 34H, - (CH₂ ) ₃- and - (CH₂) ₁₄-), 1.86 (quint, 4H, - CH₂- CH₂- CO- and - CH₂- CH₂-N <, J = 7 Hz), 3.27 (t, 2H, -CH₂-CO -, J = 7 Hz), 4.79 (t, 2H, -CH₂-N <, J = 7 Hz), 7.44 (t, 1H, Arom., J = 8 Hz), 7.49 (t, 1H, Arom., J = 8Hz), 7.59 (d, 1H, Arom., J = 8Hz), 8.01 (d, 1H, Arom., J = 8Hz), 16.67 (broad, 1H, -COOH)

Example 13 1 -dodecyl-3-octadecanoylindole-2-carboxylic acid

Preparation according to Example 12 with 299 mg (1.2 mmol) of 1-bromododecane instead of 1-bromohexane. In column chromatography, it is different from petroleum ether / ethyl acetate 200 + 3 eluted.
Yield: 135 mg (23%)
M .: 74-76 ° C
C₃₉H₆₅NO₃ (596.0)
1 H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.11-1.52 (m, 46H, - (CH₂) ₉- and - (CH₂) 14-), 1.86 (quint, 4H, - CH₂- CH₂-CO- and - CH₂- CH₂- N <, J = 7 Hz), 3.27 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.79 (t, 2H, -CH₂-N <, J = 7Hz), 7.44 (t, 1H, Arom., J = 8Hz), 7.49 (t, 1H, Arom., J = 8Hz), 7.59 (d, 1H, Arom., J = 8 Hz), 8.01 (d, 1H, Arom., J = 8 Hz), 16.73 (broad, 1H, -COOH)

Example 14 1-octadecyl-3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 12 with 398 mg (1.2 mmol) of 1-bromooctadecane instead of 1-bromohexane. In column chromatography, it is different from petroleum ether / ethyl acetate 200 + 3 eluted.
Yield: 174mg (26%)
M .: 83-84 ° C
C₄₅H₇₇NO₃ (680.1)
1 H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.14-1.52 (m, 58H, - (CH₂) ₁₅- and - (CH₂) ₁₄-), 1.86 (quint, 4H, - CH₂- CH₂-CO- and - CH₂- CH₂- N <, J = 7 Hz), 3.27 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.79 (t, 2H, -CH₂-N <, J = 7Hz), 7.44 (t, 1H, Arom., J = 8Hz), 7.49 (t, 1H, Arom., J = 8Hz), 7.59 (d, 1H, Arom., J = 8 Hz), 8.01 (d, 1H, Arom., J = 8 Hz), 16.71 (broad, 1H, -COOH)

Example 15 3-octadecanoyl-1- (3-phenylpropyl) indole-2-carboxylic acid

Preparation according to Example 12 with 239 mg (1.2 mmol) of 1-bromo-3-phenylpropane instead of 1-bromohexane.
Yield: 156 mg (29%)
M .: 73-74 ° C
C₃₆H₅₁NO₃ (545.8)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.14-1.41 (m, 26H, - (CH₂) _13- ), 1.47 (quint, 2H, -CH₂-, J = 7 Hz), 1.85 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 2.22 (quint, 2H, - CH₂- CH₂-N <, J = 7 Hz), 2.79 (t, 2H, phenyl-CH₂-, J = 7 Hz), 3.26 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.81 (t, 2H, -CH₂-N <, J = 7 Hz), 7.20 -7.43 (m, 8H, Arom.), 7.98-8.00 (m, 1H, Arom.), 16.72 (broad, 1H, -COOH)

Example 16 1-Benzyl-3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 12 with 205 mg (1.2 mmol) of benzyl bromide instead of 1-bromohexane. In the case of column chromatography, this is eluted differently from petroleum ether / ethyl acetate 19 + 1.
Yield: 50mg (10%)
M .: from 87 ° C
C₃₄H₄₇NO₃ (517.8)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.43 (m, 26H, - (CH₂) _13- ), 1.49 (quint, 2H, -CH₂-, J = 7 Hz), 1.88 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.31 (t, 2H, -CH₂-CO-, J = 7 Hz), 6.13 (s, 2H, -CH₂-N <), 7.09 (d, 2H, Ar., J = 7 Hz), 7.21-7.30 (m, 3H, Arom.), 7.42-7.46 (m, 2H, Arom.), 7.52-7.57 ( m, 1H, Arom.), 8.03-8.06 (m, 1H, Arom.), 16.57 (broad, 1H, -COOH)

Example 17 1- (4-chlorobenzyl) -3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 12 with 193 mg (1.2 mmol) of 4-chlorobenzyl chloride instead of 1-bromohexane. In the case of column chromatography, this is eluted differently from petroleum ether / ethyl acetate 19 + 1.
Yield: 18mg (3%)
M .: 101-102 ° C
C₃₄H₄₆ClNO₃ (552.2)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.21-1.44 (m, 26H, - (CH₂) _13- ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.88 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.31 (t, 2H, -CH₂-CO-, J = 7 Hz), 6.07 (s, 2H, -CH₂-N <), 7.04 (d, 2H, Arom., J = 9 Hz), 7.24 (d, 2H, Arom., J = 9 Hz), 7.43-7.48 (m, 2H, Arom.), 7.50 -7.53 (m, 1H, Arom.), 8.04-8.06 (m, 1H, Arom.)

Example 18 1- (4-methylbenzyl) -3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 12 with 169 mg (1.2 mmol) of 4-methylbenzyl chloride instead of 1-bromohexane. In the column chromatography is different from eluting with petroleum ether / ethyl acetate 19 + 1.
Yield: 109 mg (20%)
M .: 102-103 ° C
C₃₅H₄₉NO₃ (531.8)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7Hz), 1.16-1.43 (m, 26H, - (CH ₁₃ ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.88 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 2.28 (s, 3H, phenyl-CH₃), 3.30 (t, 2H, -CH₂-CO-, J = 7Hz), 6.09 (s, 2H, -CH₂-N <), 7.00 (d, 2H, Arom., J = 8Hz), 7.06 (d, 2H, Arom., J = 8Hz), 7.41-7.45 (m, 2H, Arom.), 7.55-7.60 (m, 1H, Arom.), 8.01-8.05 (m, 1H, Arom.), 16.54 (broad, 1H, -COOH).

Example 19 1- (4-carbamoylbenzyl) -3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 12 with 169 mg (1.2 mmol) 4-cyanobenzyl bromide instead of 1-bromohexane. In the column chromatography is different from eluting with petroleum ether / ethyl acetate 9 + 1. After saponification is further not extracted with ether, but with ether / CH₂Cl₂ 3 + 1; the product is precipitated from ether.
Yield: 39 mg (7%)
Mp .: 158-160 ° C
C₃₅H₄₈N₂O₄ (560.8) Ber. C 74.96 H 8.63 N 5.00
Gef. C 74.91 H 8.34 N 5.29
IR (KBr): V max = 3400 (NH), 1690 (C = O), 1630 (C = O) cm ^-1
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.14-1.45 (m, 26H, - (CH₂) _13- ), 1.49 (quint, 2H, -CH₂-, J = 7 Hz), 1.89 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.33 (t, 2H, -CH₂-CO-, J = 7 Hz), 5.56 (broad, 1H, <NH), 5.98 (broad, 1H, <NH), 6.15 (s, 2H, -CH₂-N <), 7.15 (d, 2H, Arom., J = 8 Hz), 7.43-7.52 (m, 3H, Arom.), 7.71 (d, 2H, Arom., J = 8 Hz), 8.05-8.08 (m, 1H, Arom.), 16.56 (broad, 1H, -COOH)

Example 20 1- (4-methoxybenzyl) -3-octadecanoylindol-2-carboxylic acid

The mixture of 182 mg (0.4 mmol) of ethyl 3-octadecanoylindole-2-carboxylate (see Example 1A), 49 mg (0.44 mmol) of potassium t-butylate, 3 ml of absol. DMSO and 69 mg (0.44 mmol) 4-methoxybenzyl chloride are heated in an oil bath at 110 ° C for 15 min. After cooling off, water is added and extracted with ether. The organic phase is dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 19 + 1 and the resulting 1- (4-methoxybenzyl) -3-octadecanoylindol-2-carboxylic acid ethyl ester according to Example 1 B saponified, being used for the extraction of the carboxylic acid formed ether instead of CH₂Cl₂. The product is precipitated from petroleum ether.
Yield: 57mg (10%)
M .: 110-113 ° C
C₃₅H₄₉NO₄ (547.8)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.43 (m, 26H, (CH₂) ₁₃), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.87 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.30 (t, 2H, -CH₂-CO-, J = 7 Hz), 3.75 (s, 3H, -O -CH₃), 6.06 (s, 2H, -CH₂-N <), 6.79 (d, 2H, Arom., J = 9 Hz), 7.08 (d, 2H, Arom., J = 9 Hz), 7.41-7.46 (m, 2H, Arom.), 7.59-7.62 (m, 1H, Arom.), 8.01-8.04 (m, 1H, Arom.), 16.59 (broad, 1H, -COOH).

Example 21 1- (3-pyridylmethyl) -3-octadecanoylindol-2-carboxylic acid

The mixture of 182 mg (0.4 mmol) of ethyl 3-octadecanoylindole-2-carboxylate (see Example 1A), 99 mg (0.88 mmol) of potassium t-butylate, 3 ml of absol. DMSO and 69 mg (0.44 mmol) of 3-picolyl chloride hydrochloride are heated in an oil bath at 110 ° C for 15 minutes. After cooling, saturated NaCl solution is added and the mixture is extracted with ether. The organic phase is dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 1. 7 + 3 and 2. 1 + 1 chromatographed. The resulting 1- (3-pyridylmethyl) -3-octadecanoylindole-2-carboxylic acid ethyl ester is refluxed with 15 ml of ethanol and 5 ml of 10% aqueous KOH solution for 1 h. After cooling, the mixture is diluted with phosphate buffer pH 4 and extracted twice with ether. The organic phases are washed with phosphate buffer pH 4 ge, dried over Na₂SO₄ and concentrated. The product is precipitated from ethyl acetate.
Yield: 22 mg (4%)
M .: 132-133 ° C
C₃₃H₄₆N₂O₃ (518.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.20-1.43 (m, 26H, - (CH₂) ₁₃-), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.88 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.31 (t, 2H, -CH₂-CO-, J = 7 Hz), 6.12 (see 2H, -CH₂-N <), 7.18- 7.22 (m, 1H, Arom.), 7.43-7.49 (m, 3H, Arom.), 7.52-7.59 (m, 1H, Arom.), 8.05-8.07 (m, 1H , Arom.), 8.48-8.51 (m, 2H, Arom.)

Example 22 1- (4-cyanobenzyl) -3-octadecanoylindol-2-carboxylic acid A. Benzyl 3-octadecanoylindole-2-carboxylate

The mixture of 302 mg (1.2 mmol) of benzyl indole-2-carboxylate, 512 mg (1.8 mmol) of octadecanoic acid, 55 mg of polyphosphoric acid, 8 ml of absol. CH₂Cl₂ and 0.26 ml of tri fluoroacetic anhydride is stirred for 10 h at room temperature. Then it is mixed with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and filtered with suction after addition of diatomaceous earth to remove the precipitated octadecanoate. The ether phase is dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 1.19 + 1 and 2.9 + 1. After concentrating the eluates, the product remains as a solid.
Yield: 218 mg (35%)
M .: 82-85 ° C
C₃₄H₄₇NO₃ (517.8)
MS: m / z (rel.Int.) = 518 (37%), 490 (62%), 234 (35%), 91 (100%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.13-1.37 (m, 28H, - (CH₂) _14- ), 1.64 (quint, 2H, - CH₂- CH₂ -CO-, J = 7 Hz), 2.99 (t, 2H, - CH₂- CO-, J = 7 Hz), 5.40 (s, 2H, -COO-CH₂-), 7.22-7.25 (m, 1H, Arom .), 7.34-7.48 (m, 7H, Arom.), 7.90 (d, 1H, Arom., J = 9 Hz), 9.02 (s, 1H, <NH)

B. 1- (4-cyanobenzyl) -3-octadecanoylindole-2-carboxylic acid

The mixture of 52 mg (0.1 mmol) of benzyl 3-octadecanoylindole-2-carboxylate, 22 mg (0.11 mmol) of 4-cyanobenzyl bromide, 32 mg (0.1 mmol) of tetrabutylammonium bromide, 10 ml of ether and 40 mg (1 mmol ) powdered NaOH is heated to reflux for 1 h with stirring. The mixture is then filtered off with suction and the filter cake washed twice with ether / CH₂Cl₂ 1 + 1. The filtrate is concentrated and the residue on silica gel with petroleum ether / ethyl acetate. 9 + 1 and 2. 17 + 3 chromatographed. The obtained 1- (4-cyanobenzyl) -3-octadecanoylindol-2-carboxylic acid benzyl is dissolved in 5 ml of THF ge and hydrogenated after addition of a spatula tip Pd / C at room temperature and atmospheric pressure under a hydrogen atmosphere and with vigorous stirring for 1.5 h. After adding some diatomaceous earth is filtered, the solvent was distilled off and the product was precipitated from petroleum ether.
Yield: 15 mg (28%)
M .: 122-124 ° C
C₃₅H₄₆N₂O₃ (542.8)
IR (KBr): V max = 2240 (CN), 1705 (C = O) cm ^-1
H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.05-1.61 (m, 28H, - (CH₂) _14-), 1.89 (quint, 2H, - CH₂ -CH₂ -CO-, J = 7 Hz), 3.33 (t, 2H, -CH₂-CO-, J = 7 Hz), 6.16 (s, 2H, -CH₂-N <), 7.16 (d, 2H, Arom., J = 8Hz), 7.46-7.49 (m, 3H, Arom.), 7.57 (d, 2H, Ar., J = 8Hz), 8.07-8.09 (m, 1H, Arom.), 16.58 (broad, 1H , -COOH)

Example 23 1- (4-hydroxybenzyl) -3-octadecanoylindol-2-carboxylic acid

The solution of 27 mg (0.05 mmol) of 1- (4-methoxybenzyl) -3-octadecanoylindole-2-carboxylic acid (see Example 20) in 5 ml of absol. CH₂Cl₂ is absolute at -20 ° C with the solution of 0.025 ml BBr₃ in 1 ml. CH₂Cl₂ added. The mixture is stirred for 1 h at -20 ° C and then allowed to warm for 1 h to room temperature. After addition of dilute hydrochloric acid is extracted twice with ether. The ether phases are dried over Na₂SO₄ and concentrated to a few ml. After addition of petroleum ether and renewed concentration of the product precipitates.
Yield: 25 mg (94%)
M.p .: 119-122 ° C
C₃₄4H₄₇NO₄ (533.8)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.17-1.43 (m, 26H, - (CH₂) _13- ), 1.48 (quint, 2H, -CH₂-, J = 7 Hz), 1.87 (quint, 4H, - CH₂- CH₂-CO-, J = 7 Hz), 3.30 (t, 2H, -CH₂-CO-, J = 7 Hz), 6.03 (s, 2H, -CH₂-N <, 6.70 (d, 2H, Arom., J = 9Hz), 7.01 (d, 2H, Arom., J = 9Hz), 7.42-7.48 (m, 2H, Arom.), 7.60 -7.62 (m, 1H, Arom.), 8.02-8.04 (m, 1H, Arom.), 16.70 (broad, 1H, -COOH)

Example 24 1- (3-hydroxypropyl) -3-octadecanoylindol-2-carboxylic acid A. 1- (3-Acetoxy-propyl) -3-octadecanoylindole-2-carboxylic acid ethyl ester

The mixture of 114 mg (0.6 mmol) of indole-2-carboxylic acid ethyl ester, 67 mg (0.6 mmol) of potassium t-butoxide and 3 ml of absol. DMSO is stirred for 15 min in an oil bath at 110.degree. Then the solution of 109 mg (0.6 mmol) of acetic acid (3-bromopropyl) ester is added and the batch is heated for a further 15 min. After cooling, water is added and extracted with ether. The organic phase is dried over Na₂SO₄ and the solvent is distilled off. To the residue are 228 mg (0.8 mmol) of octadecanoic acid, 35 mg of polyphosphoric acid, 3 ml absol. CH₂Cl₂ and 0.17 ml give trifluoroacetic anhydride ge. The mixture is stirred for 4 h at room temperature, then treated with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and filtered with suction after addition of diatomaceous earth to remove the precipitated octadecanoate. The ether phase is dried over Na₂SO₄ and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 9 + 1. The product remains as a waxy substance after removal of the eluent.
Yield: 97 mg (3%)
C₃₄H₅₃NO₅ (555.8)
MS: m / z (rel.Int.) = 556 (56%), 528 (100%), 331 (40%)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.17-1.43 (m, 28H, - (CH₂) _14- ), 1.41 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.75 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 2.05 (s, 3H, -CO-CH₃), 2.17 (quint, 2H, - CH₂ - CH₂-N <, J = 6.4 Hz), 2.90 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.09 (t, 2H, -CH₂-, J = 6 Hz), 4.45 (q, 2H , -O- CH₂- CH₃, J = 7 Hz), 4.45 (t, 2H, -CH₂-, J = 7 Hz), 7.27-7.30 (m, 1H, Arom.), 7.35-7.41 (m, 2H, Arom.), 7.90 (d, 1H, Arom., J = 8 Hz)

B. 1- (3-hydroxypopyl) -3-octadecanoylindole-2-carboxylic acid

The mixture of 83 mg (0.15 mmol) ethyl 1- (3-acetoxypropyl) -3-octadecanoylindole-2-carboxylate, 15 ml of ethanol and 5 ml of 10% aqueous KOH solution is refluxed for 1.5 h. Then added to the solution of 4. 1 g Na₂HPO₄ · H₂O in 80 ml of water and extracted with ether. The organic phase is dried over Na₂SO₄ and concentrated. The product is precipitated from petroleum ether.
Yield: 36 mg (49%)
Mp .: 77-80 ° C
C₃₀H₄₇NO₄ (485.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.42 (m, 26H, - (CH₂) _13- ), 1.47 (quint, 2H, -CH₂-, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 2.15 (quint, 2H, - CH₂- CH₂-N <, J = 6 Hz), 3.28 (t, 2H, -CH₂-CO-, J = 7 Hz), 3.66 (t, 2H, -CH₂-, J = 6 Hz), 4.90-5.00 (m, 2H, -CH₂-), 7.45 (t, 1H, Arom , J = 8 Hz), 7.50 (t, 1H, Arom., J = 8 Hz), 7.69 (d, 1H, Arom., J = 8 Hz), 8.01 (d, 1H, Arom., J = 8 Hz)

Example 25 4-chloro-1-methyl-3-octadecanoylindol-2-carboxylic acid

The mixture of 224 mg (1 mmol) of 4-chloroindole-2-carboxylic acid ethyl ester, 205 mg (1. 1 mmol) of p-toluenesulfonate, 32 mg (0. 1 mmol) of tetrabutylammonium bromide, 10 ml of ether and 48 mg (1.2 mmol) of powdered NaOH is stirred for 8 h at room temperature. The mixture is then filtered off with suction, the filter cake washed with ether / CH₂Cl₂ 1 + 1 and distilled off the solvent. To the residue 427 mg (1.5 mmol) of octadecanoic acid, 67 mg of polyphosphoric acid, 6 ml absol. CH₂Cl₂ and 0.33 ml trifluoroacetic anhydride added. The mixture is stirred for 4 h at room temperature, then treated with saturated NaCl solution and extracted with ether. The organic phase is washed with NaCl-containing 1 M NaOH and filtered with suction after addition of diatomaceous earth to remove the precipitated octadecanoate. The ether phase is dried over Na₂SO₄ and concentrated. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 19 + 1 and the resulting 3-acylindole-2-carboxylic acid ester according to Example 1 B saponified, being used for the extraction of the carboxylic acid formed ether instead of CH₂Cl₂. The product is precipitated from petroleum ether.
Yield: 130 mg (27%)
M.p .: 130-132 ° C
C₂₈H₄₂ClNO₃ (476.1)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.13-1.45 (m, 28H, - (CH₂) _14- ), 1.80 (quint, 2H, - CH₂- CH₂ -CO-, J = 7 Hz), 3.02 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.08 (s, 3H, <N-CH₃), 7.18-7.34 (m, 3H, Arom. )

Example 26 5-chloro-1-methyl-3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 25 with ethyl 5-chloroindole-2-carboxylate instead of ethyl 4-chloroindole-2-carboxylate.
Yield: 112 mg (24%)
Mp .: 97-99 ° C
C₂₈H₄₂ClNO₃ (476.1)
H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1:16 to 1:42 (m, 26H, - (CH₂) _13-), 1:48 (quint, 2H, - CH₂ -, J = 7 Hz), 1.86 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.22 (t, 2H, -CH₂-CO-, J = 7 Hz), 4.25 (s, 3H, <N-CH₃), 7.47 (dd, 1H, Arom., J = 2Hz and 9Hz), 7.54 (d, 1H, Arom., J = 9Hz), 7.98 (d, 1H, Arom., J = 2 Hz)

Example 27 5-methoxy-1-methyl-3-octadecanoylindol-2-carboxylic acid

Preparation according to Example 25 with 219 mg (1 mmol) of ethyl 5-methoxyindole-2-carboxylate instead of ethyl 4-chloroindole-2-carboxylate. However, the reaction time in the N-methylation is 15 h. The final product is precipitated from petroleum ether and then from methanol for further purification.
Yield: 42 mg (%)
Mp .: 97-99 ° C
C₂₉H₄₅NO₄ (471.7)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.18-1.69 (m, 28H, - (CH₂) _14- ), 1.86 (quint 2H- CH₂- CH₂-CO -, J = 7 Hz), 3.21 (t, 2H, -CH₂-CO-, J = 7 Hz), 3.93 (s, 3H, -CH₃), 4.25 (s, 3H, -CH₃), 7.16 (dd, 1H, Arom., J = 2 Hz and 9 Hz), 7.35 (s, 1H, Arom.), 7.51 (d, 1H, Arom., J = 9 Hz)

Example 28 3-Octadecanoylindol-2-yl-acetic acid A. 3. Octadecanoylindol-2-yl-acetic acid ethyl ester

To the boiling solution of 374 mg (1.2 mmol) Octadecansäuredimethylamid and 153 mg (1 mmol) of POCl₃ in 10 ml of absolute. Benzene is added 203 mg (0.4 mmol) of indol-2-yl-acetic acid ethyl ester (Capuano et al., Chem. Ber. 1986, 19, 2069-2074), dissolved in 3 ml absol. Benzene, and refluxed for 3 h. After adding the solution of 1 g Natriuinace did in 4 ml of water, the mixture is heated for a further 15 min with vigorous stirring under reflux. The batch is diluted after cooling with water and extracted twice with ether. The organic phases are dried over Na₂SO₄ and concentrated. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 1.9 + 1 and 2. 8 + 2 chroma and the product is precipitated from petroleum ether.
Yield: 222 mg (47%)
M .: 86-97 ° C
C₃₀H₄₇NO₃ (469.7)
MS: m / z (relative int) = 470 (100%), 468 (16%), 424 (8%), 245 (9%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.43 (m, 26H, - (CH₂) _13- ), 1.32 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.44 (quint, 2H, -CH₂-, J = 7 Hz), 1.78 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.03 (t, 2H , -CH₂-CH₂- CO-, J = 7 Hz), 4.26 (q, 2H, -O- CH₂- CH₃, J = 7 Hz), 4.40 (s, 2H, -CH₂-COO-), 7.23-7.29 (m, 2H, Arom.), 7.42-7.44 (m, 1H, Arom.), 7.88-7.90 (m, 1H, Arom.), 10.09 (s, 1H, <NH).

3-octadecanoylindol-2-yl-acetic acid

80 mg (0.17 mmol) of ethyl 3-octadecanoylindol-2-yl-acetate are saponified according to example 1 B. The reaction time is only 15 minutes; In addition, for the extraction of the carboxylic acid formed ether instead of CH₂Cl₂ used and precipitated the product of petroleum instead of methanol.
Yield: 59 mg (79%)
M .: 134-136 ° C
C₂₈H₄₃NO₃ (441.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.41 (m, 26H, - (CH₂) _13- ), 1.45 (quint, 2H, -CH₂-, J = 7 Hz), 1.83 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.15 (t, 2H, -CH₂- CH₂- CO-, J = 7 Hz), 4.12 (s, 2H, -CH₂-COO-), 7.28-7.35 (m, 2H, Arom.), 7.45-7.47 (m, 1H, Arom.), 7.81-7.83 (m, 1H, Arom.), 10.17 (s, 1H , <NH)

Example 29 1-methyl-3-octadecanoylindol-2-yl-acetic acid

The mixture of 80 mg (0.1 mmol) of ethyl 3-octadecanoylindol-2-yl-acetate (see Example 28A), 32 mg (0.19 mmol) of p-toluenesulfonic acid methyl ester, 22 mg (0.07 mmol) of tetrabutylammonium bromide, 10 ml of ether, 5 ml CH₂Cl₂ and 105 mg (2.6 mmol) of powdered NaOH NaOH is stirred for 20 h at room temperature. The mixture is then filtered off with suction and the filter cake washed twice with ether / CH₂Cl₂ 1 + 1. The filtrate is concentrated and the residue is chromatographed on silica gel with petroleum ether / ethyl acetate 17 + 3. The resulting 1-methyl-3-octadecanoylindol-2-yl-acetic acid ethyl ester is then saponified according to Example 28 B.
Yield: 22 mg (28%)
M .: 119-121 ° C
C₂₉H₄₅NO₃ (455.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.09-1.39 (m, 26H, - (CH₂) _13- ), 1.45 (quint, 2H, -CH₂-, J = 7 Hz), 1.83 (quint, 2H, - CH₂- CH₂-CO-, J = 7 Hz), 3.15 (t, 2H, -CH₂- CH₂- CO-, J = 7 Hz), 3.91 (s, 3H, <N-CH₃), 4.09 (s, 2H, -CH₂-COO-), 7.33-7.44 (m, 3H, Arom.), 7.82-7.85 (m, 1H, Arom.), 13.05 (s, 1H , -COOH)

Example 30 3-Octadecanoylindol-2-yl-propionic acid A. 3-octadecanoylindol-2-yl-propionic acid methyl ester

To the boiling solution of 137 mg (0.44 mmol) Octadecansäuredimethylamid and 61 mg (0.4 mmol) POCl₃ in 8 ml absol. Benzene is added to 81 mg (0.4 mmol) of indol-2-yl-propionic acid methyl ester (Capuano et al., Chem. Ber. 1986, 119, 2069-2074), dissolved in 2 ml of absolute. Benzene, and refluxed for 3 h. After addition of the solution of 1 g Na triumacetat in 4 ml of water, the mixture is heated for a further 15 min with vigorous stirring under reflux. The batch is diluted after cooling with water and extracted twice with ether. The organic phases are dried over Na₂SO₄ and concentrated. The product is precipitated from petroleum ether.
Yield: 126 mg (67%)
M .: 91-93 ° C
C₃₀H₄₇NO₃ (469.7)
MS: m / z (rel.Int.) = 470 (80%), 438 (100%)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.16-1.37 (m, 26H, - (CH₂) _13- ), 1.43 (quint, 2H, -CH₂-, J = 7 Hz), 1.78 (quint, 2H, - CH₂- CH₂-CO-aryl, J = 7 Hz), 2.83 (t, 2H, -CH₂-, J = 6 Hz), 3.02 (t, 2H, - CH₂-CO-, J = 7 Hz), 3.46 (t, 2H, -CH₂-, J = 6 Hz), 3.67 (s, 3H, -O-CH₃), 7.21-7.25 (m, 2H, Arom.) , 7.37-7.40 (m, 1H, Arom.), 7.86-7.88 (m, 1H, Arom.), 9.22 (s, 1H, <NH).

3-octadecanoylindol-2-yl-propionic acid

70 mg (0.15 mmol) of methyl 3-octadecanoylindol-2-yl-propionate are saponified in accordance with Example 28B.
Yield: 42 mg (61%)
M .: 134-136 ° C
C₂₉H₄₅NO₃ (455.7)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.21-1.37 (m, 26H, - (CH₂) _13- ), 1.44 (quint, 2H, -CH₂-, J = 7 Hz), 1.78 (quint, 2H, - CH₂- CH₂-CO-aryl, J = 7 Hz), 2.90 (t, 2H, -CH₂-, J = 6 Hz), 3.03 (t, 2H, - CH₂-CO-, J = 7 Hz), 3.44 (t, 2H, -CH₂-, J = 6 Hz), 7.21-7.28 (m, 2H, Arom.), 7.37-7.39 (m, 1H, Arom.) , 7.86-7.88 (m, 1H, Arom.)

Example 31 1-methyl-3-octadecanoylindol-2-yl-propionic acid

The mixture of 46 mg (0.1 mmol) of methyl 3-octadecanoylindol-2-yl-propionate (see Example 30A), 20 mg (0.11 mmol) of p-toluenesulfonic acid methyl ester, 13 mg (0.04 mmol) of tetrabutylammonium bromide, 5 ml Ether, 2 ml of CH₂Cl₂ and 60 mg (1.5 mmol) of powdered NaOH is stirred for 5 h at room temperature. The batch is then filtered off with suction and the filter cake washed twice with ether / CH₂Cl₂ (1 + 1). The filtrate is concentrated and the resulting 1-methyl-3-octadecanoylindol-2-yl-pro pionsäuremethylester precipitated from methanol. This is then saponified according to Example 28 B.
Yield: 22 mg (47%)
Mp .: 106-108 ° C
C₂₃H₄₇NO₃ (469.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.17-1.38 (m, 26H, - (CH₂) _13- ), 1.43 (quint, 2H, -CH₂-, J = 7 Hz), 1.79 (quint, 2H, CH₂- CH₂-CO-aryl, J = 7 Hz), 2.83 (t, 2H, -CH₂-, J = 7 Hz), 3.05 (t, 2H, -CH₂ -CO-, J = 7 Hz), 3.47 (t, 2H, -CH₂-, J = 7 Hz), 3.80 (s, 3H, <N-CH₃), 7.28-7.32 (m, 2H, Arom.), 7.36-7.40 (m, 1H, Arom.), 7.86-7.91 (m, 1H, Arom.)

Example 32 3- (1-Octadecanoylaminooctadecyl) indole-2-carboxylic acid A. 3- (1-Hydroxyiminooctadecyl) indole-2-carboxylic acid ethyl ester

The mixture of 2.28 g (5 mmol) of ethyl 3-octadecanoylindole-2-carboxylate (see example 1 A), 850 mg of hydroxylamine hydrochloride, 40 ml of absolute. Ethanol and 13 ml absolute. Pyridine is refluxed for 2 hours. After cooling, it is diluted with water, acidified with dil. H₃PO₄ and extracted twice with ether / CH₂Cl₂ 3 + 1. The organic phases are washed with water, dried over Na₂SO₄ and concentrated. The residue is treated with petroleum ether and allowed to stand for a short time. The precipitating substance is sucked off; from the filtrate, the product is isolated by column chromatography (silica gel, eluting rapidly with petroleum ether / ethyl acetate 1. 9 + 1 and 2. 7 + 3). Concentration of the product fractions leaves an oil which crystallizes after a certain time.
Yield: 0.78g (33%)
M .: 71-74 ° C
C₂₉H₄₆N₂O₃ (470.7)
MS: m / z (rel.Int.) = 471 (45%), 427 (100%), 215 (62%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.08-1.35 (m, 28H, - (CH₂) _14- ), 1.39 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.44 (quint, 2H, - CH₂ , -CH₂-CNOH-, J = 8 Hz), 2.87 (t, 2H, -CH₂-CNOH-, J = 8 Hz), 4.40 ( g, 2H, -O- CH₂ -CH₃, J = 7Hz), 7.14-7.18 (m, 1H, Arom.), 7.28-7.33 (m, 2H, Arom.), 7.68 (d, 1H, Arom., J = 8 Hz), 9.16 (s, 1H, <CNOH)

B. 3- (1-Octadecanoylaminooctadecyl) indole-2-carboxylic acid ethyl ester

235 mg (0.5 mmol) of ethyl 3- (1-hydroxyiminooctadecyl) indole-2-carboxylate and 1.7 g of sodium acetate are dissolved in 30 ml of glacial acetic acid. After addition of 1 g of zinc dust is stirred for 45 min at room temperature. The batch is poured into 350 ml of ice-cold 2 M NaOH and extracted with ether. The organic phase is dried over Na₂SO₄ and concentrated. The residue is treated with the solution of 86 mg (0.7 mmol) of 4-dimethylamino pyridine and 1 ml of absolute. Triethylamine in 5 ml of CHCl₃ and immediately thereafter with the solu tion of 182 mg (0.6 mmol) Octadecansäurechlorid in 5 ml of CHCl₃. The mixture is stirred for 15 minutes, then dilute hydrochloric acid and extracted twice with ether. The organic phase is washed with saturated NaHCO solution, dried over Na₂SO₄ and concentrated. The residue is chromatographed on silica gel with petroleum ether / ethyl acetate 1. 8.5 + 1.5 and 2. 8 + 2 and the product recrystallized from petroleum ether.
Yield: 203 g (56%)
M .: 84-86 ° C
C₄₇H₈₂N₂O₃ (723.2)
MS: m / z (rel.Int.) = 724 (10%), 695 (20%), 483 (9%), 412 (38%), 391 (90), 284 (79%), 149 (100 %), 113 (41%)
1 H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.08-1.39 (m, 58H, - (CH₂) ₁₄- and - (CH₂) ₁₅-), 1.46 (t, 3H, -O-CH₂- CH₃ , J = 7 Hz), 1.57-1.65 (m, 2H, - CH₂- CH₂-CO-), 1.76-1.94 (m, 2H, - CH₂- CH <) , 2.17 (t, 2H, -CH₂-CO-, J = 8 Hz), 4.46 (g, 2H, -O- CH₂- CH₃, J = 7 Hz), 5.73-5.79 (m, 1H, -CH₂- CH <), 7.15-7.19 (m, 1H, Arom.), 7.32-7.37 (m, 2H, Arom.), 7.65 (d, 1H, <CH- NH- CO-, J = 9Hz), 7.84 (i.e. , 1H, Arom., J = 8 Hz), 8.74 (s, 1H, 3 <NH)

C. 3- (1-Octadecanoylaminooctadecyl) indole-2-carboxylic acid

The mixture of 72 mg (0. 1 mmol) 3- (1-Octadecanoylaminooctadecyl) indole-2-carboxylic acid ethyl ester, 15 ml of ethanol and 5 ml of 10% aqueous KOH solution is heated to boiling for 30 min under reflux. Then it is mixed with water, acidified with 10% hydrochloric acid and extracted with ether. The organic phase is washed with dil. Hydrochloric acid, dried over Na₂SO₄ and concentrated. The product is precipitated from methanol.
Yield: 33 mg (47%)
M .: 56-58 ° C
C₄₅H₇₈N₂O₃ (695.1)
¹H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.03-1.38 (m, 58H, - (CH₂) ₁₄- and - (CH₂) ₁₅-), 1.52-1.64 (m 2H - CH₂- CH₂-CO-), 1.97-2.07 (m, 2H, - CH₂- CH <), 2.20 (t, 2H, -CH₂-CO-, J = 8 Hz), 5.47- 5.53 (m, 1H, -CH₂- CH <), 6.96 (broad, 1H, <CH- NH- CO-), 7.15 (t, 1H, Arom., J = 8 Hz), 7.33 (t, 1H, Arom , J = 8 Hz), 7.39 (d, 1H, Arom., J = 8 Hz), 7.76 (d, 1H, Arom., J = 8 Hz), 8.92 (s, 1H, <NH)

Example 33 3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylic acid A. 3- [1- (3-Phenylpropionylamino) octadecyl] indole-2-carboxylic acid ethyl ester

Representation according to Example 32 B with 101 mg (0.6 mmol) of 3-Phenylpropionsäurechlorid instead of Octadecansäurechlorid. In the column chromatography is eluted with petroleum ether / ethyl acetate 1. 7.5 + 2.5 and 2. 7 + 3. The product remains as a waxy substance after removal of the eluent.
Yield: 153 mg (52%)
C₃₈H₅₆N₂O₃ (588.9)
MS: m / z (rel.Int.) = 589 (66%), 561 (100%), 412 (99%), 349 (53%), 150 (65%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.00-1.37 (m, 30H, - (CH₂) _15- ), 1.44 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.70-1.87 (m, 2H, - CH₂- CH <), 2.40-2.55 (m, 2H, -CH₂-), 2.88-3.01 (m, 2H, -CH₂-), 4.41 (q, 2H, -O- CH₂- CH3, J = 7Hz), 5.70-5.76 (m, 1H, -CH₂- CH <), 7.11-7.22 (m, 6H, Arom.), 7.33-7.39 ( m, 2H, Arom.), 7.62 (d, 1H, <CH- NH- CO-, J = 9Hz), 7.82 (d, 1H, Arom., J = 8Hz), 8.75 (s, 1H, < NH)

B. 3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylic acid

Preparation of 3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylic acid ethyl ester according to Example 32 C. The product remains after removal of the solvent as a wax-like substance.
Yield: 41 mg (73%)
C₃₆H₅₂N₂O₃ (560.8)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.00-1.37 (m, 30H, - (CH₂) _15- ), 1.87-2.00 (m, 2H, -CH₂ -CH <), 2.44-2.57 (m, 2H, -CH₂-), 2.87-2.98 (m, 2H, -CH₂-), 5.45-5.51 (m, 1H, -CH₂- CH <), 6.84 (m, 1H, <CH- NH -CO-), 7.08-7.15 (m, 6H, Arom.), 7.34 (t, 1H, Arom., J = 8Hz), 7.40 (d, 1H, Arom., J = 8 Hz), 7.67 (d, 1H, Arom., J = 8 Hz), 8.89 (s, 1H, <NH)

Example 34 3- (1-Acetylaminooctadecyl) indole-2-carboxylic acid A. 3- (1-acetylaminooctadecyl) indole-2-carboxylic acid ethyl ester

Preparation according to Example 32 B with 47 mg (0.6 mmol) of acetyl chloride instead of octa decanoic acid chloride. For column chromatography, elute with petroleum ether / ethyl acetate 1. 7 + 3 and 2. 1 + 1. The remaining after concentration of the product fractions oil crystallized after some time.
Yield: 95 mg (38%)
Mp .: 98-101 ° C
C₃₁H₅₀N₂O₃ (498.9)
MS: m / z (rel.Int.) = 499 (76%), 471 (90%), 440 (73%), 412 (93%), 259 (100%)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.09-1.41 (m, 30H, - (CH₂) _15- ), 1.47 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.75-1.94 (m, 2H, - CH₂- CH <), 1.97 (s, 3H, -CO-CH₃), 4.46 (q, 2H, -O- CH₂ -CH₃, J = 7Hz), 5.71-5.77 (m, 1H, -CH₂- CH <), 7.16-7.20 (m, 1H, Arom.), 7.33-7.38 (m, 2H, Arom.), 7.70 (d, 1H < CH- NH- CO-, J = 9 Hz), 7.85 (d, 1H, Arom., J = 9 Hz), 8.76 (s, 1H, <NH)

B. 3- (1-Acetylaminooctadecyl) indole-2-carboxylic acid

The mixture of 50 mg (0.1 mmol) of ethyl 3- (1-acetylaminooctadecyl) indole-2-carboxylate, 15 ml of ethanol and 5 ml of 10% aqueous KOH solution is refluxed for 30 minutes. Then it is mixed with 2.5% Na₂CO₃ solution and washed with ether. The aqueous phase is carefully acidified with dil. Hydrochloric acid and extracted with ether. The organic phase is dried over Na₂SO₄ and concentrated. The product remains as oil.
Yield: 22 mg (73%)
M .: from 65 ° C
C₂₉H₄₆N₂O₃ (470.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.08-1.38 (m, 30H, - (CH₂) _15- ), 1.93-2.05 (m, 2H, - CH₂ -CH <), 2.02 (s, 3H, -CO-CH₃), 5.54-5.60 (m, 1H, -CH₂- CH <), 7.15 (t, 1H, Arom., J = 8 Hz), 7.33 (t , 1H, Arom., J = 8Hz), 7.40 (d, 1H, Arom., J = 8Hz), 7.78 (d, 1H, Arom., J = 8Hz), 8.96 (s, 1H, <NH )

Example 35 1-Methyl-3- (1-octadecanoylaminooctadecyl) indole-2-carboxylic acid A. 1-Methyl-3- (1-octadecanoylaminooctadecyl) indole-2-carboxylic acid ethyl ester

The mixture of 108 mg (0.15 mmol) of ethyl 3- (1-octadecanoylaminooctadecyl) indole-2-carboxylate (see Example 32 B), 32 mg (0.17 mmol) of p-toluenesulfonate, 13 mg (0.04 mmol) of tetrabutylammonium bromide, 5 ml of ether, 5 ml of CH₂Cl₂ and 16 mg (0.4 mmol) of powdered NaOH is stirred for 7 h at room temperature. Then it is mixed with water and extracted with ether. The ether phase is washed twice with dil. Na₂CO₃ solution, dried over Na₂SO₄ and concentrated. The product is precipitated from methanol.
Yield: 82 mg (74%)
M.p .: 78-80 ° C
C₄₈H₈₄N₂O₃ (737.2)
1 H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.04-1.41 (m, 58H, - (CH₂) _14- and - (CH₂) _15- ), 1.49 (t, 3H, -O-CH₂- CH₃ , J = 7 Hz), 1.53-1.67 (m, 2H, - CH₂- CH₂-CO-), 1.75-1.97 (m, 2H, - CH₂- CH <) , 2.14 (t, 2H, -CH₂-CO-, J = 8 Hz), 3.97 (s, 3H, <N-CH₃), 4.48 (q, 2H, -O- CH₂ -CH₃, J = 7 Hz), 5.77-5.83 (m, 1H, -CH₂- CH <), 7.15-7.19 (m, 2H <CH- NH -CO- and Arom.), 7.33-7.39 (m, 2H, Arom.), 7.85 (d, 1H, Arom., J = 8Hz)

For example, 1-methyl-3- (1-octadecanoylaminooctadecyl) indole-2-carboxylic acid

Preparation of 1-methyl-3- (1-octadecanoylaminooctadecyl) indole-2-carboxylic acid ethyl ester-r according to Example 32 C. The product remains after solidification of the ether phase as a solid to back.
Yield: 32 mg (45%)
M .: 110-113 ° C
C₄₆H₈₀N₂O₃ (709.2)
1 H-NMR: δ (ppm) = 0.88 (t, 6H, -CH₃ and -CH₃, J = 7 Hz), 1.07-1.34 (m, 58H, - (CH₂) ₁₄- and - (CH₂) _15- ), 1.46-1.66 (m 2H - CH₂- CH₂-CO-), 2.07-2.23 (m, 4H, - CH₂- CH <and -CH₂-CO-), 3.92 (s, 3H, <N-CH₃), 5.08- 5.14 (m, 1H, -CH₂- CH <), 6.33 (d, 1H, <CH- NH- CO-, J = 6 Hz), 7.13 (t, 1H, Arom., J = 8 Hz), 7.33 ( t, 1H, Arom., J = 8 Hz), 7.39 (d, 1H, Arom., J = 8 Hz), 7.66 (d, 1H, Arom., J = 8 Hz)

Example 36 1-methyl-3- [1- (3-phenyl-propionylamino) octadecyl] indole-2-carboxylic acid A. 1-Methyl-3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylic acid ethyl ester

Preparation of ethyl 3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylate (see Example 33A) according to Example 35 A. The product, however, is purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1.9 + 1 and 2. 8 + 2). After removal of the eluent, the product remains as a waxy substance.
Yield: 71 mg (79%)
C₃₉H₅₈N₂O₃ (602.9)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.05-1.37 (m, 30H, - (CH₂) _15- ), 1.46 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.69-1.89 (m, 2H, - CH₂- CH <), 2.38-2.50 (m, 2H, -CH₂-), 2.86-3.00 (m, 2H, -CH₂-), 3.97 (s, 3H, -CO-CH₃), 4.43 (q, 2H, -O- CH₂ -CH₃, J = 7 Hz), 5.75-5.81 (m, 1H, -CH₂- CH <), 7.08 (d, 1H, <CH- NH- CO-, J = 9.5Hz), 7.10-7.18 (m, 6H, Arom.), 7.29-7.40 (m, 2H, Arom.), 7.79 (d, 1H, Arom., J = 8 Hz)

For example, 1-methyl-3- [1- (3-phenylpropionylamino) octadecyl] indole-2-carboxylic acid

Preparation according to Example 32 C. The product remains after concentration of the ether phase as a waxy substance.
Yield: 42 mg (73%)
C₃₇H₅₄N₂O₃ (574.8)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.03-1.37 (m, 30H, - (CH₂) _15- ), 1.89-2.08 (m, 2H, - CH₂ -CH <), 2.43-2.55 (m, 2H, -CH₂-), 2.88 (t, 2H, -CH₂-, J = 7 Hz), 3.92 (s, 3H, -CO-CH₃), 5.04-5.10 ( m, 1H, -CH₂- CH <), 6.26 (d, 1H, <CH- NH- CO-, J = 6 Hz), 7.04-7. 14 (m, 6H, Arom.), 7.34 (t, 1H, Arom., J = 8Hz), 7.39 (d, 1H, Arom., J = 8Hz), 7.51 (d, 1H, Arom., J = 8Hz)

Example 37 1-methyl-3- (1-acetylaminooctadecyl) indole-2-carboxylic acid A. 1-Methyl-3- (1-acetylamino-octadecyl) -indole-2-carboxylic acid ethyl ester

Preparation of 3- (1-acetylaminooctadecyl) indole-2-carboxylic acid ethyl ester (see Example 34 A) according to Example 35 A. However, the product is purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1. 8 + 2 and 2. 9 + 1 ) cleaned. After removal of the eluent, the product remains as a waxy substance. Yield: 70 mg (91%)
C₃₂H₅₂N₂O₃ (512.8)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.03-1.42 (m, 30H, - (CH₂) _15- ), 1.49 (t, 3H, -O-CH₂ - CH₃ , J = 7 Hz), 1.74-1.97 (m, 2H, - CH₂- CH <), 1.95 (s, 3H, -CO-CH₃), 3.97 (s, 3H, <N-CH₃), 4.49 ( q, 2H, -O- CH₂- CH₃, J = 7 Hz), 5.76-5.82 (m, 1H, -CH₂- CH <), 7.15-7.20 (m, 2H, <CH- NH - CO- and Arom. ), 7.33-7.40 (m, 2H, Arom.), 7.85 (d, 1H, Arom., J = 8Hz)

For example, 1-methyl-3 (1-acetylaminooctadecyl) indole-2-carboxylic acid

Preparation according to Example 32 C. The product remains after concentration of the ether phase as a solid.
Yield: 33 mg (68%)
M .: 134-137 ° C
C₃₀H₄₈N₂O₃ (484.7)
1 H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.05-1.36 (m, 30H, - (CH _15- ), 1.99 (s, 3H, -CO-CH₃) , 2:04 to 2:19 (m, 2H, - CH₂ -CH <), 3.92 (s, 3H, <N-CH₃), 5:10 to 5:16 (m, 1H, -CH₂- CH <), 6:41 (d, 1H, < CH- NH- CO-, J = 6 Hz), 7.14 (t, 1H, Arom., J = 8 Hz), 7.35 (t, 1H, Arom., J = 8 Hz), 7.40 (d, 1H, Arom , J = 8 Hz), 7.68 (d, 1H, Arom., J = 8 Hz)

Example 38 1-methyl-3-octadecylindol-2-carboxylic acid

The mixture of 94 mg (0.2 mmol) of ethyl 1-methyl-3-octadecanoylindole-2-carboxylate (see Example 2 A), 2 ml of absol. THF, 3 ml absolute. Methyl acetate, 40 mg NaBH₄ and 0.2 ml BF₃-ethyl ether complex is stirred for 1 h at room temperature. After addition of 2 ml of methanol (50%), the mixture is stirred for a further 15 min, then diluted with water and extracted twice with ether. The organic phases are concentrated by evaporation and the resulting ethyl 1-methyl-3-octadecylindole-2-carboxylate is saponified according to Example 1 B, ether being used instead of CH₂Cl₂ to extract the carboxylic acid formed. The product is precipitated from methanol.
Yield: 24 mg (26%)
M .: 87-90 ° C
C₃₀H₄₉NO₂ (455.7)
¹H-NMR: δ (ppm) = 0.88 (t, 3H, -CH₃, J = 7 Hz), 1.11-1.39 (m, 28H, - (CH₂) _14- ), 1.41 (quint, 2H, -CH₂-, J = 7 Hz), 1.68 (quint, 2H, - CH₂ -CH₂-indolyl, J = 7 Hz), 3.15 (t, 2H, -CH₂-CO-indolyl, J = 7 Hz), 4:05 (s, 3H, <N-CH₃), 7.13-7.17 (m, 1H, Arom.), 7.36-7.41 (m, 2H, Arom.), 7.70 (d, 1H, Arom., J = 8Hz)

Example 39

The effectiveness of the compounds of the invention can be determined by the inhibition determine the phospholipase A₂. The test method used has already been described (see Lehr Matthias: In-vitro assay for the evaluation of phospholipase A₂ inhibitors using bovine platelets and HPLC with UV detection. Pharm. Pharmacol. Lett. 1992, 2, 176-179).

The test substances were usually dissolved in DMSO, if necessary with heating. at Substances that did not dissolve in this solvent became the solvent  Mixture of DMSO / 0.05M ethanolic NaOH (1 + 1) used. In the latter case was deviating from the above cited rule not the platelet suspension to Test substance solution but, conversely, the test substance solution to thrombocytes pension zupipettiert.

The results obtained in the testing of compounds of the invention are shown in listed in Table 5 below. For the already known PLA₂ inhibitor N- (S) - Hexadecyl-2-pyrrolidinecarboxamide (McGregor et al., U.S. Patent No. 4,795,555) was used with the used test system given in Table 6 inhibitory value.

Compound of Example No. % Inhibition of PLA₂ at 10 μM 2 61 5 62 6 63 9 82 10 79 11 76 12 75

connection % Inhibition of PLA₂ at 10 μM N- (S) -hexadecyl-2-pyrrole 00160 00070 552 001000280000000200012000285910004900040 0002004338770 00004 00041idincarboxamide 42

Claims (12)

1. Substituted indole compounds of the general formula: wherein
R¹ is X, aryl or -X-aryl, wherein X is a C₁-C₁₉-alkyl or C₂-C₁₉ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl an aryl group or one with the radicals R⁶ and R⁷ are substituted aryl group;
R² is -COOH, -Y-COOH, -Tz, or -Y-Tz, wherein Y is a C₁-C₈-alkyl or C₂-C₈ alkenyl group, which may optionally be interrupted by an oxygen heteroatom, and Tz 1H- or 2H-tetrazol-5-yl;
R³ is a hydrogen atom; for a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom; an aryl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z-aryl, wherein Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl is an aryl group or an aryl group substituted by the radicals R⁸ and R⁹ ; for -Z- OR¹⁶, -Z-SR¹⁶ or -Z-NHR¹⁶, wherein Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, means;
Q is CO, CH₂ and CHNHCOR¹⁰, wherein R¹⁰ is W, aryl or -W-aryl and W is a C₁-C₁₉-alkyl or C₂-C₁₉ alkenyl or alkynyl group, which may optionally be interrupted by an oxygen heteroatom, and aryl represents an aryl group or an aryl group substituted with the radicals R¹¹ and R¹²; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently selected from:

• 1) hydrogen;
• 2) C₁-C₂₀ alkyl group, which may optionally be interrupted by an oxygen heteroatom interrupted;
• 3) C₂-C₂₀ alkenyl group, which may optionally be interrupted by an oxygen heteroatom;
• 4) C₂-C₂₀ alkynyl group, which may optionally be interrupted by an oxygen heteroatom;
• 5) halogen;
• 6) -CF₃;
• 7) -CN;
• 8) -NO₂;
• 9) -OR¹³;
• 10) -SR¹³;
• 11) -COOR¹³;
• 12) -COR¹⁴;
• 13) -COCH₂OH;
• 14) -NHCOR¹³;
• 15) -NR³R¹³;
• 16) -NHSO₂R¹⁵;
• 17) -SOR¹³;
• 18) -SO₂R¹³;
• 19) -CONR¹³R¹³;
• 20) -SO₂NR¹³R¹³;
• 21) -OOCR¹⁴;
• 22) -OOCNR¹³R¹³;
• 23) -OOCOR¹³;
• 24) - (CH₂) _r OR¹⁶;
• 25) - (CH₂) _r SR¹⁶;
• 26) - (CH₂) _r NHR¹⁶;
• 27) - (CH₂) _s R¹⁷;
• 28) perhalo-C₁-C₆ alkenyl;

Each of R¹³ independently represents hydrogen, a C₁-C₂₀ alkyl or C₂-C₁₉ alkenyl or alkynyl group which may optionally be interrupted by an oxygen heteroatom, or - (CH₂) _t R¹⁷;
Each of R¹⁴ independently represents R¹³, -CF₃, - (CH₂) _u COOH or - (CH₂) _u COOR¹⁹;
Each of R¹⁵ independently represents R¹³ or CF₃;
Each R¹⁶ is independently hydrogen or -COR¹⁹;
Each R¹⁷ independently represents aryl substituted with one or two R¹⁸ groups;
Each R¹⁸ is independently hydrogen, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ alkylcarbonyl, CF₃, CN or NO₂;
Each R¹⁹ is independently C₁-C₆ alkyl, benzyl or phenyl;
r is 1 to 20;
s and t are each independently 0 to 12;
u is 0 to 4;
and their pharmaceutically acceptable salts and esters for use in the Phar mazie. 2. Compounds according to claim 1 of the general formula: wherein
R¹ is X, aryl or -X-aryl, wherein X is a C₁-C₁₉-alkyl or C₂-C₁₉-alkenyl group and aryl is an aryl group or an aryl group substituted by the radicals R⁶ and R⁷;
R² is -COOH, -Y-COOH, -Tz, or -Y-Tz, wherein Y is a C₁-C₈ alkyl or C₂-C₈ alkenyl group and Tz is 1H- or 2H-tetrazol-5-yl;
R³ is a hydrogen atom; for a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl group;
for an allyl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z- aryl, wherein Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl group and aryl is an aryl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z-OR¹⁶, -Z- SR¹⁶ or -Z-NHR¹⁶, wherein Z is a C₁-C₂₀ alkyl or C₂-C₂₀ alkenyl group meaning tet;
Q is CO, CH₂ and CHNHCOR¹⁰, wherein R¹⁰ is W, aryl or -W-aryl and W is a C₁-C₁₉ alkyl or C₂-C₁₉ alkenyl group and aryl is an aryl group or one substituted by the radicals R¹¹ and R¹² Aryl group means;
R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently selected from:

• 1) hydrogen;
• 2) C₁-C₂₀ alkyl group;
• 3) C₂-C₂₀ alkenyl group;
• 4) C₂-C₂₀ alkynyl group;
• 5) halogen;
• 6) -CF₃;
• 7) -CN;
• 8) -NO₂;
• 9) -OR¹³;
• 10) -SR¹³;
• 11) -COOR¹³;
• 12) -COR¹⁴;
• 13) -COCH₂OH;
• 14) -NHCOR¹³;
• 15) -NR¹³R¹³;
• 16) -NHSO₂R¹⁵;
• 17) -SOR¹³;
• 18) -SO₂R¹³;
• 19) -CONR¹³R¹³;
• 20) -SO₂NR¹³R¹³;
• 21) -OOCR¹⁴;
• 22) -OOCNR¹³R¹³;
• 23) -OOCOR¹³;
• 24) - (CH₂) _r OR¹⁶;
• 25) - (CH₂) _r SR¹⁶;
• 26) - (CH₂) _r NHR¹⁶;
• 27) - (CH₂) _s R¹⁷;
• 28) perhalo-C₁-C₆ alkenyl;

Each of R¹³ independently represents hydrogen, a C₁-C₂₀ alkyl or C₂-C₁₉ alkenyl group or - (CH₂) _t R⁷;
Each R¹⁴ is independently hydrogen, R¹³, -CF₃, - (CH₂) _u COOH or - (CH₂) _u COOR¹⁹;
Each of R¹⁵ independently represents R¹³ or CF₃;
Each R¹⁶ is independently hydrogen or -COR¹⁹;
Each R¹⁷ independently represents aryl substituted with one or two R¹⁸ groups;
Each R¹⁸ is independently hydrogen, halogen, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ alkylcarbonyl, -CF₃, -CN or NO₂;
Each R¹⁹ is independently C₁-C₆ alkyl, benzyl or phenyl;
r is 1 to 20;
s and t are each independently 0 to 12;
u is 0 to 4;
and their pharmaceutically acceptable salts and esters for use in the Phar mazie. 3. Compounds according to claim 1 of the general formula: wherein R¹ is X, aryl or -X-aryl, wherein X is a C₁-C₁₉-alkyl or C₂-C₁₉ alkenyl group and aryl is an aryl group or an aryl group substituted by the radicals R⁶ and R⁷;
R² is -COOH or -Y-COOH, wherein Y is a C₁-C₈ alkyl group;
R³ is a hydrogen atom; for a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl group; an aryl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z- aryl, wherein Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl group and aryl is an aryl group or an aryl group substituted by the radicals R⁸ and R⁹; for -Z-OR¹⁶, where Z is a C₁-C₂₀-alkyl or C₂-C₂₀ alkenyl group;
Q is CO, CH₂ and CHNHCOR¹⁰, wherein R¹⁰ is W, aryl or -W-aryl and W is a C₁-C₁₉ alkyl or C₂-C₁₉ alkenyl group and aryl is an aryl group or one substituted by the radicals R¹¹ and R¹² Aryl group means;
R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently selected from:

• 1) hydrogen;
• 2) C₁-C₂₀ alkyl group;
• 3) C₂-C₂₀ alkenyl group;
• 4) halogen;
• 5) -CF₃;
• 6) -CN;
• 7) -NO₂;
• 8) -OR¹³;
• 9) -SR¹³;
• 10) -COOR¹³;
• 11) -COR¹⁴;
• 12) -COCH₂OH;
• 13) -NHCOR¹³;
• 14) -NR¹³R¹³;
• 15) -NHSO₂R¹⁵;
• 16) -SOR¹³;
• 17) -SO₂R¹³;
• 18) -CONR¹³R¹³;
• 19) -SO₂NR¹³R¹³;
• 20) -OOCR¹⁴;
• 21) -OOCNR¹³R¹³;
• 22) -OOCOR¹³;
• 23) - (CH₂) _r OR¹⁶;
• 24) - (CH₂) _s R¹⁷;
• 25) perhalo-C₁-C₆ alkenyl;

Each of R¹³ independently represents hydrogen, a C₁-C₂₀ alkyl or C₂-C₁₉ alkenyl group or - (CH₂) _t R¹⁷;
Each of R¹⁴ independently represents R¹³, -CF₃, - (CH₂) _u COOH or - (CH₂) _u COOR¹⁹;
Each of R¹⁵ independently represents R¹³ or CF₃;
Each R¹⁶ is independently hydrogen or -COR¹⁹;
Each R¹⁷ independently represents aryl substituted with one or two R¹⁸ groups;
Each R¹⁸ is independently hydrogen, halo, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ alkylcarbonyl, CF₃, CN or NO₂;
Each R¹⁹ is independently C₁-C₆ alkyl, benzyl or phenyl;
r is 1 to 20;
s and t are each independently 0 to 12;
u is 0 to 4;
and their pharmaceutically acceptable salts and esters for use in the Phar mazie. 4. Compounds according to claim 1, namely:
1-methyl-3-octanoylindol-2-carboxylic acid
1-methyl-3-decanoylindol-2-carboxylic acid
1-methyl-3-dodecanoylindol-2-carboxylic acid
1-methyl-3-tetradecanoylindol-2-carboxylic acid
1-methyl-3-octadecanoylindol-2-carboxylic acid
3- (2-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid
3- (3-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid
3- (4-dodecyloxybenzoyl) -1-methylindole-2-carboxylic acid
1-hexyl-3-octadecanoylindol-2-carboxylic acid. 5. A process for the preparation of substituted indole compounds according to claim 1, which are characterized in that

• A) in a compound of the general formula: in which R³ is a hydrogen atom and in which R¹, R², R⁴, R⁵ and Q are as defined in claim 1, in an optionally multistage reaction, introduces a radical R³ which corresponds to the meanings given in claim 1 for R³. Optionally, this reaction may be followed by ester cleavage.
• B) in a compound of the general formula: in which Q-R¹ is a hydrogen atom and in which R², R³, R⁴ and R⁵ have the meanings given in claim 1, in an optionally multi-step reaction introduces a radical Q-R¹ which has the meanings given in claim 1 for Q-R¹ equivalent. Optionally, this reaction may be followed by ester cleavage.

6. Pharmaceutical agent containing at least one compound according to one of the Claims 1 to 4, optionally together with customary pharmaceutically acceptable Auxiliaries and / or additives. 7. Pharmaceutical agent according to claim 6 for use as an inhibitor of Phospholipase A₂. 8. Use of at least one compound according to one of claims 1 to 4 for the preparation of a pharmaceutical composition for the prevention and treatment of Diseases caused by increased activity of phospholipase A₂ or be caused, such as inflammation, allergies, asthma, psoriasis and Endotoxin shock. 9. A process for the preparation of the pharmaceutical agent according to claim 8, characterized characterized in that at least one compound according to one of claims 1 to 4 in a form suitable for administration, optionally using conventional pharmaceutical carriers and / or additives.