DE19963177A1 - substance library - Google Patents

Abstract

The invention relates to a substance library, a method for the production thereof, and the use of said substance library in the detection of active ingredients.

Description

The invention relates to a substance library, to a method for the production thereof, and the use of this substance library for finding active ingredients.

There is a worldwide need for effective therapies for Treatment / control of pain, inflammatory and allergic Reactions, drug and / or alcohol abuse, diarrhea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock, Migraine, narcolepsy, obesity, asthma, glaucoma and / or hyperkinetic Syndrome.

With the help of modern, automated synthesis methods it is possible To produce substance libraries, which consist of a multiplicity of different Consist of compounds suitable for screening Active ingredients, in particular pharmaceutical agents, can be identified.

Object of the present invention was a variety of compounds, d. H. a so-called substance library, which can be used as active ingredients, in particular pharmaceutically active substances.

The subject of the present invention is therefore a substance library which is obtainable by the reaction of aromatic aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic Aldehyde compounds which have no acidic proton in α-position, in solution, preferably in organic solvents, more preferably in toluene, in Presence of a base, preferably potassium carbonate or boric anhydride, preferably at a temperature of -10 to + 110 ° C, with secondary amines too Aminal compounds, implementation of these aminal compounds without further Purification with acid chlorides, preferably with acetyl chloride in absolute Solvent, preferably in diethyl ether to iminium salts and their implementation without further purification in an organic solvent, preferably in Dimethyl sulfoxide and / or acetonitrile and / or toluene, particularly preferably in  Acetonitrile and / or toluene, with unsubstituted or substituted naphthol, Pyrrole and / or indole compounds, purification and isolation of the thus obtained Compounds according to the usual methods and, where appropriate, implementation of the so obtained naphthol and / or indole compounds in solution, preferably in Dimethylformamide and / or dimethyl sulfoxide, with organic halogen compounds in the presence of a base, preferably potassium tert-butylate, triethylamine or Potassium hydroxide, preferably at a temperature of 10 to 190 ° C and if appropriate, purification of the naphthol and / or indole Compounds by filtration, preferably by filtration through a scavenger Resin, more preferably by filtration over polymer-bound tris (2) aminoethyl) amine (Novablochem, Bad Soden) and / or 3- (3-mercaptophenyl) - Propanamidomethylpolystyrene (Argonaut, Muttenz, Switzerland) and isolation according to the usual methods.

Preference is given to a substance library obtainable by the reaction of aromatic aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic aldehyde compounds of the general formula 1,

in which the radical R ^{9 is} an aryl radical, a heteroaryl radical or an alkyl radical without an acidic proton in the α-position, preferably an unsubstituted or substituted phenyl, thiophene-pyrrolyl or furfuryl radical or a C _1-6 -alkyl radical Rest without acidic proton in α-position means
in solution, preferably in organic solvents, more preferably in toluene, in the presence of a base, preferably potassium carbonate or
Boric acid anhydride, preferably at a temperature of -10 to + 110 ° C with secondary amines of general formula II,

wherein
the radicals R ¹⁰ and R ¹¹ , identical or different, represent a C _1-10 -alkyl, an -aryl or an aryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl -, a phenyl or bonded via a C _1-2 alkylene group aryl radical
or the radicals R ¹⁰ and R ¹¹ together with (CH ₂ ) ₂ O (CH ₂ ) ₂ or (CH ₂ ) _n with
n = an integer from 3 to 6,
to aminal compounds of general formula III,

Reaction of these aminal compounds of general formula III without further purification with an acid chloride, preferably with acetyl chloride in absolute solvent, preferably in diethyl ether to give iminium salts of general formula IV,

and reaction of these iminium salts of general formula IV without further purification in solution, preferably in acetonitrile and / or toluene and / or dimethyl sulfoxide, particularly preferably in acetonitrile and / or toluene with substituted and / or unsubstituted 1- and / or 2-naphthol compounds the general formula V

wherein the radicals R ¹ = H and R ² = OH or R ¹ = OH and R ² = H
and in each case the radicals
R ³ to R ⁸ , the same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , SO ₂ NH ₂ , SO ₂ NHR ¹³ , NHR ¹³ , SR ¹⁵ , OR ¹⁶ CO (OR ²⁰ ) , CH ₂ CO (OR ²¹ ), CO (R ²² ), a C _1-10 alkyl, an aryl, a heteroaryl or a bonded via a C _1-6 alkylene aryl or heteroaryl radical , preferably = H, Cl, Br, a C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ¹³ = H, COR ¹⁴ , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably = H, a C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ¹⁴ = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ¹⁵ = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ¹⁵ = H, CO (R ^17), C _1-10 alkyl, an aryl, a heteroaryl, or a bonded via a C _1-6 alkylene aryl or heteroaryl radical, preferably a C _{1- 6} denotes an alkyl or an aryl radical bonded via a C _1-2 -alkylene group,
R ¹⁷ = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ¹⁸ = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ^{20 is} H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ²¹ = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a means an aryl radical attached via a C _1-2 alkylene group,
R ²² = H, NHNH ₂ , NHR ¹⁸ , a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably = H, a C _1-6 alkyl radical or bonded via a C _1-2 alkylene group aryl radical
and / or with substituted and / or unsubstituted pyrrole compounds of the general formula VI,

wherein
R ^{1 '} = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene-bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl Radical, a substituted or unsubstituted phenyl, furoyl, thiophene or pyridine radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{2 '} = H,
R ^{3 '} , R ^4' , R ^{5 '} , same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , SO ₂ NH ₂ , NHR ^7' , SR ^{8 '} , OR ^9' , CO (OR ^{10 '} ), CH ₂ CO (OR ^11' ), COR ^{15 '} , a C _1-10 alkyl, an aryl, a heteroaryl or an aryl bound via a C _1-6 alkylene group H or a heteroaryl radical, preferably H, a C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{7 '} = H, COR ^12' , a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene-bonded aryl or heteroaryl radical, preferably a C ₁ Is _-6- alkyl or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{8 '} = H, a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or denotes an aryl radical bonded via a C _1-2 -alkylene group,
R ^{9 '} = H, COR ^13' , a C _1-10 alkyl, an aryl, a heteroaryl or a bonded via a C _1-6 alkylene aryl or heteroaryl radical, preferably a C ₁ Is _-6- alkyl or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{10 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl or denotes an aryl radical bonded via a C _1-2 -alkylene group,
R ^{11 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl or denotes an aryl radical bonded via a C _1-2 -alkylene group,
R ^{12 '} = a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a bonded via a C _1-2 alkylene group aryl radical,
R ^{13 '} = a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene-bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or a bonded via a C _1-2 alkylene group aryl radical,
R ^{14 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl or denotes an aryl radical bonded via a C _1-2 -alkylene group,
R ^{15 '} = NHNH ₂ , NHR ^14' , a C _1-10 alkyl, an aryl, a heteroaryl or a C _1-6 alkylene bonded aryl or heteroaryl radical, preferably a C _1-6 alkyl or bonded via a C _1-2 alkylene group aryl radical
and / or with substituted and / or unsubstituted indole compounds of the general formula VII,

wherein
R ^{1 ''} = H, a C _1-10 -alkyl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl radical or a radical which is attached via a C _1-2 alkylene group bonded aryl radical means
R ^{2 "} = H, F, Cl, Br, CF ₃ , CN, NO ₂ , NHR ^8" , SR ^{9 "} , OR ^10" , SO ₂ NH ₂ , SO ₂ NHR ^{21 "} , CO ( OR ^{11 ''} ), CH ₂ CO (OR ^{12 ''} ), COR ^{19 '} , a C _1-10 alkyl, an aryl, a heteroaryl or an aryl bound via a C _1-6 alkylene group or heteroaryl radical, preferably H, Cl, F, NO ₂ , OR ^{10 ''} , CO (OR ^{11 ''} ), a C _1-6 -alkyl radical or a C _1-2 -alkylene radical Means group-bound aryl radical,
R ^{3 ''} = H,
R ^{4 "} , R ^5" , R ^{6 "} , R ^7" , the same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , NHR ^{8 "} , SR ^9" , OR ^{10 "} , SO ₂ NH ₂ , SO ₂ NHR ^21" , CO (OR ^{11 "} ), CH ₂ CO (OR ^12" ), COR ^{19 "} , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably = H, Cl, F, NO ₂ , OR ^{10 ''} , CO (OR ^{11 ''} ) , a C _1-6 -alkyl or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{8 "} = H, COR ^16" , a C _1-10 -alkyl or an aryl radical, preferably a C _1-6 -alkyl radical,
R ^{9 ''} = H, a C _1-10 -alkyl or an aryl radical, preferably a C _1-6 -alkyl or a phenyl radical,
R ^{10 ''} = H, COR ^{17 ''} , a C _1-10 alkyl, an aryl radical or an aryl or heteroaryl radical bonded via a C _1-6 alkylene group, preferably = H C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{11 ''} = H, a C _1-10 -alkyl or an aryl radical, preferably = H or a C _1-6 -alkyl radical,
R ^{12 ''} = H, a C _1-10 -alkyl radical or an aryl radical, preferably a C _1-6 -alkyl radical,
R ^{16 ''} = a C _1-10 -alkyl, an aryl or a heteroaryl radical, preferably a C _1-6 -alkyl radical,
R ^{17 ''} = a C _1-10 -alkyl radical, preferably a C _1-6 -alkyl radical,
R ^{18 ''} = a C _1-10 -alkyl, an aryl, a heteroaryl or a naphthyl radical, preferably a C _1-6 -alkyl radical,
R ^{19 "} = H, NHNH ₂ , NHR ^20" , a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical, preferably a C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{20 "} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical, preferably a C _1-6 -alkyl- Means radical or an aryl radical bonded via a C _1-2 -alkylene group,
R ^{21 "} = H, COR ^17" , a C _1-10 -alkyl, an aryl radical or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably = H C _1-6 -alkyl radical or an aryl radical bonded via a C _1-2 -alkylene group,
and optionally reacting the resulting naphthol compounds of general formula V in which the radicals R ¹ = CH (R ⁹ ) N (R ¹⁰ ) (R ¹¹ ) and R ² = OH or R ¹ = OH and R ² = CH (R ⁹ ) N (R ¹⁰ ) N (R ¹¹ ) and in each case the radicals R ³ to R ¹¹ , R ¹³ to R ¹⁸ and R ²⁰ to R ^{22 have} the abovementioned meaning, in solution,
preferably in acetonitrile and / or dimethyl sulfoxide, in the presence of a base, preferably potassium tert-butylate or triethylamine, with compounds of the general formula

XR ²³ ,

wherein
X = Cl, Br or I, preferably Cl
and
the radical R ^{23 is} COR ²² , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group, preferably a C _1-6 -alkyl -Rest or a bonded via a C _1-2 alkylene group aryl radical, where the radical R ^{22 has} the meaning above, or
if appropriate, reaction of the compounds of general formula VII thus obtained, in which the radicals R ^{1 '} = H and R ^3' = CH (R ⁹ ) N (R ¹⁰ ) (R ¹¹ ) and the other radicals R ⁹ to R ¹¹ , R ^{2 '} , R ^4' to R ^{12 '} and R ^16' to R ^{21 'have} the abovementioned meaning, in solution, preferably in acetonitrile and / or dimethyl sulfoxide, in the presence of a base, preferably potassium hydroxide with compounds of the general formula

XR ²⁴ ,

wherein
X = Cl, Br or I, preferably Cl
and
the radical R ²⁴ represents a C _1-10 alkyl or a bonded via a C _1-6 -alkylene group aryl or heteroaryl radical, preferably a C _1-6 alkyl residue or via a C _{1- 2-} alkylene group bonded aryl radical,
at a temperature of preferably from 10 to 190 ° C. and, if appropriate, purification of the 1- and 2-naphthol compounds and / or indole compounds thus obtained by filtration, preferably by filtration through a scavenger resin, more preferably by filtration over polymer-bound tris (2-aminoethyl) amine and / or 3- (3-mercaptophenyl) propanamidomethylpolystyrene and isolation of the 1- and 2-naphthol compounds and / or indole compounds by conventional methods.

Alkyl radicals are also at least simple, preferably with halogen and / or an OH radical, particularly preferably with F and / or an OH radical, substituted hydrocarbons understood. Include these more than one Substituents, these substituents may be the same or different. The Hydrocarbons may be branched, unbranched or cyclic.

Preferably, the alkyl radicals are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, heptyl, nonyl or decanyl.

An aryl radical is also at least one of an OH, a halogen, preferably F, Br or Cl, a CF ₃ , a C _1-6 alkyl, a C _1-6 alkoxy or a Phenyl radical substituted phenyl or naphthyl radicals understood. The unsubstituted or substituted phenyl radicals may also be condensed with further rings. Preferably, the aryl radicals are 2-, 3-, 4-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 4-tert-butylphenyl, 2-chloro 4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-cyanophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethoxyphenyl, 3,4 -Dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-, 3-, 4-fluorophenyl, 2-methoxyphenyl, 2-, 3-, 4-methylphenyl, 3-phenoxyphenyl, 2-, 4-trifluoromethylphenyl or 3,4,5-trimethoxyphenyl.

By a heteroaryl radical is meant aromatic compounds which at least one heteroatom, preferably nitrogen, oxygen and / or sulfur, particularly preferably have nitrogen and / or oxygen. Most notably the heteroaryl radical is preferably a substituted or unsubstituted thiophene radical or furfuryl residue.

The preparation of the substance library according to the invention is preferably carried out on an automatic system from Zymark according to FIG. 1 and FIG. 2 as described below in the examples.

The substance library according to the invention is used in various test methods for Screening of drugs screened.

In particular, test methods for finding active substances which are known as Pharmaceutical and / or pesticides can be used.

Very particular preference is given to a test method for finding active substances which to treat / combat pain, inflammatory and allergic reactions, drug and / or alcohol abuse, diarrhea, gastritis Ulcers, cardiovascular diseases, urinary incontinence, depression, Shock, migraine, narcolepsy, obesity, asthma, glaucoma and / or hyperkinetic syndrome.

The appropriate screening tests for testing the compounds of The substance library according to the invention on their effectiveness are as carried out in the examples described below.

Examples

The following examples serve to illustrate the invention, but limit the general idea of the invention is not a.

General Synthetic Instructions for the Preparation of Aminal Compounds of general formula III General Method of Synthesis 1

To 2.7 equivalents of a 40% solution of the respective secondary amine with of general formula II were slowly stirred at 20 ° C 1.0 equivalents the respective aromatic, heteroaromatic and / or aliphatic Dropped aldehyde compound of general formula I. Then the solution became stirred for a further 30 minutes at a temperature of 80 ° C, then auf Cooled room temperature and treated with 0.57 equivalents of potassium carbonate. This formed two phases that were separated from each other, the aqueous phase was extracted three times with 100 ml of ethyl acetate. The combined, organic phases were dried over potassium carbonate and from Solvent freed. The aminal compounds of the general Formula III was then used without further purification in subsequent reactions used.

General Synthesis 2

To a solution of 1.0 equivalent of the respective aromatic, heteroaromatic and / or aliphatic aldehyde compound of the general Formula I in 80 ml of absolute toluene was 1.6 equivalents of boric anhydride given. Subsequently, a solution of 2.4 equivalents of a secondary Amines of general formula II in 85 ml of absolute toluene with vigorous stirring added. The start of the reaction was evident Recognize temperature increase. Then the reaction solution became another two Stirred at a temperature of 45 to 50 ° C hours. After cooling  At room temperature, the excess boric anhydride was separated and the filtrate is freed from the solvent. The aminal compounds of the general formula III were without further purification in the following Reactions used.

General synthesis instructions for the synthesis of iminium salts of general formula IV General Method of Synthesis 3

A solution of 1.0 equivalents of acetyl chloride in absolute diethyl ether was added slowly with stirring to 1.0 equivalent of an ice-cooled solution or Suspension prepared according to general synthesis instructions 1 or 2 Dropped Aminalverbindung the general formula III. Subsequently, the Reaction mixture overnight at about 20 ° C stirred. This resulted in a Precipitate which is sucked off under nitrogen and then in an oil pump vacuum was dried. The iminium salts of general formula IV thus obtained were used without further purification in the subsequent reactions.

General Synthesis Protocol for the Synthesis of the Compounds of substance library General Synthesis 4

The synthesis of the substance library according to the invention was carried out on an automatic system of the company Zymark according to FIG. 1 or FIG. 2:
1 comprises a capper station ( Fig. 1) for closing the reaction tubes, a robot 1 ( Fig. 2 ) and a robot 2 (Fig. 3 ), wherein the robot 1 moves the reaction tubes or the corresponding racks and the robot 2 pipettes the reagents into the reaction tubes, a temperature-controllable reactor block (point 4 ), stirring blocks (point 5 ) and a filtration station (point 6), in which the reaction solution is filtered off.

Fig. 2 also comprises a robot 1 (no. 1) and a robot 2 (no. 2) which both move the glass tubes with the synthetic products onto the various stations. The stations are in detail a vortexer (Item 3 ) for mixing the samples and for adding solutions or solvents, a spin reactor (Item 4 ) for the mixing of samples, a phase detection station (Item 5 ) Detection of the phase boundary and the phase separation and a station (point 6 ) for drying the synthesis products via salt cartridges.

To synthesize the naphthol compounds of the substance library according to the invention, a round-bottomed tube made of glass (diameter 16 mm, length 125 mm) was manually provided with a stirrer and on the capper station (item 1 ) according to Figure 1 with a screw cap with septum locked. The tube was then placed by robot 1 (point 2 ) in the reactor block heated to 25 ° C (point 4 ). Robot 2 (Point 3 ) then pipetted the following reagents in succession:

• 1. 1 ml of a 0.1 M solution of a 1- or 2-naphthol compound of the general Formula V in acetonitrile and 14 ul of triethylamine.
• 2. 1.2 ml of a 0.1 M solution of an iminium salt of the general formula IV in Acetonitrile.

The iminium salts were previously prepared as indicated in the examples below. The reaction mixture was subsequently stirred at 90 ° C. in one of the stirring blocks (section 5 ) for 960 minutes. Thereafter, the reaction solution was filtered off at the filtration station (Item 6 ). The tube was rinsed twice with 1 ml of dichloromethane and 200 ul of water.

The rack with the tubes was then placed manually on the automatic processing plant of FIG . There, the reaction mixture was added to a vortexer (point 3 ) with 2 ml of water and 2 ml of ethyl acetate.

The mixture was then adjusted to pH = 1 with 1 ml of aqueous 5% hydrochloric acid solution, then thoroughly mixed in the spin reactor (Item 4 ) for 10 minutes, and a clear phase boundary was formed by the slow decrease in the rotary motion. This phase boundary was optically detected on the phase detection station (point 5 ) and the aqueous phase was pipetted off. In the next step, this was mixed with 2 ml of ethyl acetate and adjusted to a pH of 11 with 1 ml of saturated aqueous sodium bicarbonate solution. In the spin-reactor (Fig. 4 ) was again thoroughly mixed for 10 minutes and then the organic phase was pipetted off. In the next step, the aqueous phase was treated again with 1.5 ml of ethyl acetate. The solution was shaken, centrifuged and the organic phase was pipetted off. The combined organic phases were dried over 2.4 g of MgSO ₄ (granulated) and the solvent was removed using a vacuum centrifuge.

To synthesize the pyrrole compounds of the substance library according to the invention, a round-bottomed tube made of glass (diameter 16 mm, length 125 mm) with a thread was manually provided with a stirrer and on the capper station (item 1 ) according to Figure 1 with a screw cap with septum locked. The tube was then placed by robot 1 (point 2 ) in the reactor block heated at 0 ° C (point 4 ). Robot 2 (Item 3 ) pipetted the following reagents in succession:

• 1. 1 ml of a 0.1 M solution of a pyrrole compound of the general formula VI in Acetonitrile.
• 2. 1.2 ml of a 0.1 M solution of an iminium salt of the general formula IV in Acetonitrile.

The iminium salts were previously prepared as indicated in the examples below. The reaction mixture was subsequently stirred at 18 ° C. in one of the stirring blocks (section 5 ) for 960 minutes. Thereafter, the reaction solution was filtered off at the filtration station (Item 6 ).

Then the solvent was first removed in a vacuum centrifuge.  

The rack with the tubes was then placed manually on the automatic processing plant of FIG . There, the reaction mixture was then added to a vortexer (point 3 ) with 2 ml of acetone.

The spin reactor (Fig. 4 ) was then thoroughly mixed for 10 minutes and finally the acetone was decanted off. This step was repeated a further three times and then the solvent was removed in a vacuum centrifuge.

For the synthesis of the indole compounds of the substance library according to the invention, a glass round-bottomed tube (diameter 16 mm, length 125 mm) was manually provided with a stirrer and on the capper station (item 1 ) according to Fig. 1 with a screw cap with septum locked. The tube was then placed by robot 1 (point 2 ) in the reactor block heated at 0 ° C (point 4 ). Robot 2 (Item 3 ) pipetted the following reagents in succession:

• 1. 1 ml of a 0.1 M solution of an indole compound of the general formula VII in Acetonitrile.
• 2. 1.2 ml of a 0.1 M solution of an iminium salt of the general formula IV in Acetonitrile.

The iminium salts were previously prepared as indicated in the examples below. The reaction mixture was subsequently stirred at 15 ° C. in one of the stirring blocks (section 5 ) for 665 minutes. Thereafter, the reaction solution was filtered off at the filtration station (Item 6 ).

Then the solvent was first removed in a vacuum centrifuge. The rack with the tubes was then placed manually on the automatic processing plant of FIG . There, the reaction mixture was then added to a vortexer (point 3 ) with 2 ml of acetone.

The spin reactor (Fig. 4 ) was then thoroughly mixed for 10 minutes and finally the acetone was decanted off. This step was repeated a further three times and then the solvent was removed in a vacuum centrifuge.

General Method of Synthesis 5

A solution of 1.0 equivalents of indole or naphthol Mannich Base the general formulas V and VII in absolute dimethylsulfoxide was 15 minutes with 1.0 equivalents of potassium hydroxide treated, followed by 1.0 equivalents Alkylating added and stirred for a further 24 hours at about 20 ° C. Thereafter, 3.0 equivalents of 3- (3-mercaptophenyl) - propanamidomethylpolystyrene, allowed to react with each other for another three hours, filtered from the PS resin and concentrated the filtrate in vacuo. That way The residue obtained was taken up in a 1: 1 dichloromethane / water mixture, Stirred for 30 minutes, the phases separated, with the aqueous phase thrice with each 20 ml of dichloromethane was extracted. The combined, organic phases were dried over magnesium sulfate and freed from the solvent.

General Method of Synthesis 6

A solution of 1.0 equivalents of indole or naphthol Mannich Base the general formulas V or VII in absolute dimethyl sulfoxide was 15 minutes with 1.0 equivalents of potassium hydroxide treated, followed by 1.0 equivalents Acylation added and stirred for a further 24 hours at about 20 ° C. Thereafter, 3.0 equivalents of polymer-bound tris (2 aminoethyl) amine, allowed to react with each other for an additional three hours, filtered from PS resin and concentrated the filtrate in vacuo. The residue thus obtained Was taken up in a 1: 1 dichloromethane / water mixture, stirred for 30 minutes, separated the phases, with the aqueous phase thrice with 20 ml each Dichloromethane was extracted. The combined, organic phases were over Dried magnesium sulfate and freed from the solvent.  

example 1

[(1H-indol-3-yl) -phenyl-methyl] -dimethyl-amine

1st stage Benzylidene-dimethyl-ammonium chloride

The reaction of 32.0 ml (0.213 mol) of dimethylamine solution and 8.0 ml (0.079 mol) Benzaldehyde according to general synthesis instructions 1 for aminal compounds and subsequent reaction with 4.7 ml (0079 mol) of acetyl chloride according to General Synthesis Method 3 for iminium salts gave 9.5 g (corresponding to 70.7%). the theoretically calculated yield) of benzylidene-dimethyl-ammonium chloride.

2nd stage [(1H-indol-3-yl) -phenyl-methyl] -dimethyl-amine

The preparation was carried out according to general synthesis instructions 4 from 1H-indole and benzylidene-dimethyl-ammonium chloride.

The structure was detected by means of ¹³ C-NMR: δ = 144.35; 136.73; 128.30; 127.89; 126.55; 126.28; 123.32; 121.20; 119.96; 118.75; 111.72; 69.67; 44.49 ppm.

Example 2

Dimethyl - [(1-methyl-1H-indol-3-yl) -phenyl] -amine

The preparation was carried out according to general synthesis instructions 4 from 1-methyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1.
The structure was detected by means of ¹³ C-NMR: δ = 136.89; 135.85; 129.37; 129.17; 128.92; 128.34; 128.11; 127.77; 127.68; 126.73; 121.87; 119.66, 118.23, 109.99; 108.81; 66.23; 41.59; 41.37; 32.78 ppm.

Example 3

3- (phenylpyrrolidine-1-yl-methyl) -1H-indole

1st stage 1-benzylidene-pyrrolidinium chloride

The reaction of 16.4 ml (0.200 mol) of pyrrolidine and 10.1 ml (0.100 mol) Benzaldehyde according to general synthesis instructions 2 for aminal compounds and subsequent reaction with 6.0 ml (0.100 mol) of acetyl chloride according to  General Synthesis Method 3 for iminium salts gave 14.1 g (corresponding to 12%). the theoretical calculated yield) of 1-benzylidene-pyrrolidinium chloride.

2nd stage 3- (phenylpyrrolidine-1-yl-methyl) -1H-indole

The preparation was carried out according to general synthesis instructions 4 from 1H-indole and 1-benzylidene-pyrrolidinium chloride.
The structure was detected by means of CSI-MS: calculated mass 276.38 g / mol,
found mass M + H = 276.9 g / mol.

Example 4

1-methyl-3- (morpholin-4-yl-phenylmethyl) -1H-indole

1st stage 4-benzylidene-morpholin-4-ium chloride

The reaction of 17.9 ml (0.200 mol) of morpholine and 10.1 ml (0.100 mol) Benzaldehyde according to general synthesis instructions 2 for aminal compounds and subsequent reaction with 6.0 ml (0.100 mol) of acetyl chloride according to General Synthesis Procedure 3 for iminium salts gave 10.1 g (corresponding to 48%). the theoretical calculated yield) of 4-benzylidene-morpholine-4-ium chloride.

2nd stage

The preparation was carried out according to general synthesis instructions 4 from 1-methyl-1H-indole and 4-benzylidene-morpholine-4-ium chloride.
The structure was detected by means of ¹³ C-NMR: δ = 142.83; 137.05; 28.29; 27.96; 27.47; 127.04; 126.68; 121.55; 120.25; 119.02; 115.57; 109.17; 68.74; 67.36; 52.49; 32.68 ppm.

Example 5

1-methyl-3- (phenylpiperidin-1-yl-methyl) -1H-indole

1st stage 1-benzylidene-piperidinium chloride

The reaction of 19.8 ml (0.200 mol) piperidine and 10.1 ml (0.100 mol) Benzaldehyde according to general synthesis instructions 2 for aminal compounds and subsequent reaction with 6.0 ml (0.100 mol) of acetyl chloride according to General Synthesis Method 3 for iminium salts gave 11.7 g (corresponding to 56%). the theoretically calculated yield) of 1-benzylidene-piperidinium chloride.

2nd stage 1-methyl-3- (phenylpiperidin-1-yl-methyl) -1H-indole

The preparation was carried out according to general synthesis instructions 4 from 1-methyl-1H-indole and 1-benzylidene-piperidinium chloride.
The structure was detected by means of ESI-MS: calculated mass 304.44 g / mol,
found mass M + H = 304.8 g / mol.

Example 6

3- (phenylpiperidin-1-yl-methyl) -1H-indole

The preparation was carried out according to general synthesis instructions 4 from 1H-indole and 1-benzylidene-piperidinium chloride, which was prepared according to Example 5.
The structure was detected by ESI-MS: calculated mass 290.41 g / mol,
found mass M + H = 290.9 g / mol.

Example 7

1-methyl-2- (phenylpyrrolidin-1-yl-methyl) -1H-pyrrole

The preparation was carried out according to general synthesis instructions 4 from 1-methyl-1H-pyrrole and 1-benzylidene-pyrrolidinium chloride, which was prepared according to Example 3.
The structure was detected by means of ESI-MS: calculated mass 240.35 g / mol,
found mass M + H = 241.5.

Example 8

Dimethyl - [(1-methyl-1H-pyrrol-2-yl) phenylmethyl] amine

The preparation was carried out according to general synthesis instructions 4 from 1-methyl-1H-pyrrole and benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1.
The structure was detected by means of ¹³ C-NMR: δ = 141.26; 133.74; 128.91; 128.65; 127.42; 127.34; 122.39; 108.15; 107.02; 69.39; 44.48; 34.79 ppm.

Example 9

{[1- (4-methoxy-benzyloxy) -naphthalene-2-yl] -phenyl-methyl} -dimethyl-amine

The preparation was carried out according to general synthesis instructions 4 and 5 from 1-naphthol, benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1, and 4-methoxybenzyl chloride.
The structure was detected by means of ¹³ C-NMR: δ = 159.58; 151.92; 143.29; 134.03; 132.03; 129.76; 129.21; 128.38; 128.07; 127.99; 126.86; 125.84; 125.74; 122.40; 114.10; 75.85; 69.45; 55.37; 44.82 ppm.

Example 10

{[2- (4-methoxy-benzyloxy) -naphthalene-1-yl] -phenyl-methyl} -dimethyl-amine

The preparation was carried out according to general synthesis instructions 4 and 5 from 2-naphthol, benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1, and 4-methoxybenzyl chloride.
The structure was detected by means of ESI-MS: calculated mass 397.52 g / mol,
found mass M + H = 398.0 g / mol.

Example 11

1- (morpholin-4-yl-phenylmethyl) -naphthalen-2-ol

The preparation was carried out in accordance with general synthesis instructions 4 from 2-naphthol and 4-benzylidene-morpholine-4-ium chloride, which was prepared according to Example 4.
The structure was detected by means of ESI-MS: calculated mass 319.41 g / mol,
found mass M + H = 320.1 g / mol.

Example 12

1- (phenylpiperidin-1-yl-methyl) naphthalene-2-ol

The preparation was carried out according to general synthesis instructions 4 from 2-naphthol and 1-benzylidene-piperidinium chloride, which was prepared according to Example 5.
The structure was detected by means of ESI-MS: calculated mass 317.43 g / mol,
found mass M + H = 318.3 g / mol.

Example 13

4-Methoxy-benzoic acid 1- (dimethylamino-phenyl-methyl) -naphthalen-2-yl-ester

The preparation was carried out according to general synthesis instructions 4 and 6 from 2-naphthol, benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1 and 4-methoxybenzoyl chloride.
The structure was detected by means of ESI-MS: calculated mass 411.51 g / mol,
found mass M + H = 412.0 g / mol.

Example 14

2-Chloro-benzoic acid 1- (dimethylamino-phenyl-methyl) -naphthalen-2-yl-ester

The preparation was carried out according to general synthesis instructions 4 and 6 from 2-naphthol, benzylidene-dimethyl-ammonium chloride, which was prepared according to Example 1, and 2-chlorobenzoyl chloride.
The structure was detected by means of ESI-MS: calculated mass 415.92 g / mol,
found mass M + H = 416.0 g / mol.

Pharmacological investigations 1. in vitro tests

The broad testing of the compounds of the substance library according to the invention their effectiveness was assessed according to the usual high throughput screening Methods, as described in John P. Devlin, High Throughput Screening, 1997. Marcel Dekker Inc. are described. They are hereby incorporated by reference and apply thus as part of the revelation.

The effect of the compounds of the substance library according to the invention is in particular by its affinity for the N-methyl-D-aspartate (NMDA) receptor family, to α-adrenergic receptors and opioid receptors.

2. Analgesia test in writhing test on the mouse

The in-depth study on analgesic efficacy was conducted in phenylquinone induced writhing in the mouse (modified according to I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959)). These were male NMRI mice used in the weight of 25-30 g. Groups of 10 animals per Substance dose was given 10 minutes after intravenous administration of the test substances 0.3 ml / mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Fa. Sigma, Deisenhofen; Preparation of the solution with the addition of 5% ethanol and Storage in a water bath at 45 ° G) intraperitoneally. The animals were individually placed in observation cages. By means of a push button counter was the Number of pain-induced stretching movements (so-called Writhing reactions = pushing the body off with the Hind limbs) 5-20 minutes after phenylquinone administration. When Control animals were carried, received only physiological saline.

All substances were tested in the standard dose of 10 mg / kg. The inhibition of writhing reactions by a substance was calculated according to the following formula:

The investigated compounds of the invention showed an analgesic Effect.

The results of selected writhing examinations are in the following Table 1 summarized.

Table 1 Analgesia test in writhing test on the mouse

Example no. Inhibition of writhing reaction in% 1 41 2 39 3 57 4 75 5 6 6 82 7 87 8th 17 9 40 10 81 11 30 12 92 13 21 14 48

Claims (54)

1. Substance library available through the reaction of aromatic Aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic aldehyde compounds without acidic proton in α-position, in solution, in the presence of a base with secondary amines Aminal compounds, implementation of these aminal compounds without further Purification with acid chlorides in absolute solvent to iminium salts and their implementation without further purification in an organic Solvents with unsubstituted or substituted naphthol, pyrrole and / or indole compounds, purification and isolation of the thus obtained Compounds according to the usual methods and, if appropriate, implementation of so obtained naphthol and / or indole compounds in solution with organic halogen compounds, in the presence of a base and optionally purification by filtration and isolation of the thus obtained Naphthol and / or indole compounds by the usual methods. 2. substance library according to claim 1, obtainable by the reaction of aromatic aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic aldehyde compounds of the general formula I,
in which the radical R ⁹ denotes an aryl radical, a heteroaryl radical or an alkyl radical without an acidic proton in the α-position,
in solution, in the presence of a base, preferably at a temperature of -10 to + 110 ° C with secondary amines of general formula II,
wherein
the radicals R ¹⁰ and R ¹¹ , which may be identical or different, denote a C _1-10 -alkyl, an aryl or an aryl radical bonded via a C _1-6 -alkylene group
or the radicals R ¹⁰ and R ¹¹ together with (CH ₂ ) ₂ O (CH ₂ ) ₂ or (CH ₂ ) _n with
n = an integer from 3 to 6,
to aminal compounds of general formula II,
Reaction of these aminal compounds of the general formula III without further purification with an acid chloride in absolute solvent to give iminium salts of the general formula IV
and reaction of these iminium salts of the general formula IV without further purification in solution with substituted and / or unsubstituted 1- and / or 2-naphthol compounds of the general formula V
wherein the radicals R ¹ = H and R ² = OH or R ¹ = OH and R ² = H
and in each case the radicals
R ³ to R ⁸ , the same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , SO ₂ NH ₂ , SO ₂ NHR ¹³ , NHR ¹³ , SR ¹⁵ , OR ¹⁶ , CO (OR ²⁰ ), CH ₂ CO (OR ²¹ ), CO (R ²² ), a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl group bonded via a C _1-6 -alkylene group. Mean rest,
R ¹³ denotes H, COR ¹⁴ , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ¹⁴ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ¹⁵ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ¹⁶ denotes H, CO (R ¹⁷ ), a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ¹⁷ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ¹⁸ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ²⁰ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ²¹ denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{22 is} H, NHNH ₂ , NHR ¹⁸ , a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical,
and / or with substituted and / or unsubstituted pyrrole compounds of the general formula VI,
wherein
R ^{1 'is} H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{2 '} = H,
R ^{3 '} , R ^4' , R ^{5 '} , same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , SO ₂ NH ₂ , NHR ^7' , SR ^{8 '} , OR ^9' , CO (OR ^{10 '} ), CH ₂ CO (OR ^11' ), COR ^{15 '} , a C _1-10 alkyl, an aryl, a heteroaryl or an aryl bound via a C _1-6 alkylene group - or heteroaryl radical means
R ^{7 '} = H, COR ^12' , a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical,
R ^{8 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical,
R ^{9 '} = H, COR ^13' , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{10 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical,
R ^{11 '} = H, a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 -alkylene group bonded aryl or heteroaryl radical,
R ^{12 '} = a C _1-10 -alkyl, an aryl, a heteroaryl or a C _1-6 alkylene-bonded aryl or heteroaryl radical,
R ^{13 '} = a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{14 '} denotes H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{15 '} = NHNH ₂ , NHR ^14' , a C _1-10 alkyl, an aryl, a heteroaryl or a bonded via a C _1-6 alkylene group aryl or heteroaryl radical
and / or with substituted and / or unsubstituted indole compounds of the general formula VII,
wherein
R ^{1 "} = H, a C _1-10 -alkyl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{2 "} = H, F, Cl, Br, CF ₃ , CN, NO ₂ , NHR ^8" , SR ^{9 "} , OR ^10" , SO ₂ NH ₂ , SO ₂ NHR ^{21 "} , CO ( OR ^{11 ''} ), CH ₂ CO (OR ^{12 ''} ), COR ^{19 '} , a C _1-10 alkyl, an aryl, a heteroaryl or an aryl bound via a C _1-6 alkylene group - or heteroaryl radical means
R ^{3 ''} = H,
R ^{4 "} , R ^5" , R ^{6 "} , R ^7" , the same or different, = H, F, Cl, Br, CF ₃ , CN, NO ₂ , NHR ^{8 "} , SR ^9" , OR ^{10 "} , SO ₂ NH ₂ , SO ₂ NHR ^21" , CO (OR ^{11 "} ), CH ₂ CO (OR ^12" ), COR ^{19 "} , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{8 "} = H, COR ^16" , a C _1-10 -alkyl or an aryl radical,
R ^{9 ''} = H, a C _1-10 -alkyl or an aryl radical,
R ^{10 ''} = H, COR ^{17 ''} , a C _1-10 -alkyl, an aryl radical or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{11 ''} = H, a C _1-10 -alkyl or an aryl radical,
R ^{12 ''} = H, a C _1-10 -alkyl radical or an aryl radical,
R ^{16 ''} = a C _1-10 -alkyl, an aryl or a heteroaryl radical,
R ^{17 ''} = a C _1-10 -alkyl radical,
R ^{18 ''} = a C _1-10 -alkyl, an aryl, a heteroaryl or a naphthyl radical,
R ^{19 "} = H, NHNH ₂ , NHR ^20" , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{20 '' is} H, a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
R ^{21 ''} = H, COR ^{17 ''} , a C _1-10 -alkyl, an aryl radical or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
and optionally reacting the resulting naphthol compounds of general formula V in which the radicals R ¹ = CH (R ⁹ ) N (R ¹⁰ ) (R ¹¹ ) and R ² = OH or R ¹ = OH and R ² = CH (R ⁹ ) N (R ¹⁰ ) (R ¹¹ ) and in each case the radicals R ³ to R ¹¹ , R ¹³ to R ¹⁸ and R ²⁰ to R ^{22 have} the abovementioned meaning, in solution, in the presence of a base with organic halogen compounds the general formula
XR ²³ ,
wherein
X = Cl, Br or I means
and
the radical R ^{23 is} COR ²² , a C _1-10 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group and the radical R ^{22 is} the has the above meaning
or
if appropriate, reaction of the compounds of general formula VII thus obtained, in which the radicals R ^{1 ''} = H and R ^{3 ''} = CH (R ⁹ ) N (R ¹⁰ ) (R ¹¹ ) and the other radicals R ⁹ to R ¹¹ , R ^{2 "} , R ^4" to R ^{12 "} and R ^16" to R ^{21 "have} the abovementioned meaning, in solution, in the presence of a base with organic halogen compounds of the general formula
XR ²⁴ ,
wherein
X = Cl, Br or I means
and
the radical R ^{24 is} a C _1-10 -alkyl or an aryl or heteroaryl radical bonded via a C _1-6 -alkylene group,
at a temperature of preferably 10 to 190 ° C and optionally purification of the thus obtained 1- and 2-naphthol compounds and / or indole compounds by filtration and isolation of the 1- and 2-naphthol compounds and / or indole compounds the usual methods. 3. substance library according to claim 2, characterized in that the radical R ^{9 is} an unsubstituted or substituted phenyl, thiophene, pyrrolyl or Furturyl radical or a C _1-6 alkyl radical without acidic proton in α-position and the remaining radicals R ³ to R ⁸ , R ¹⁰ , R ¹¹ , R ¹³ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 4. substance library according to claim 2 or 3, characterized in that at least one of R ¹⁰ or R ^{11 is} a substituted or unsubstituted phenyl radical, a C _1-6 alkyl radical or a via a C _1-2 alkylene Group bonded aryl radical and the other radical R ¹⁰ or R ¹¹ and the other radicals R ³ to R ⁸ , R ¹³ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^{15 '} , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 5. Substance library according to one of claims 2 to 4, characterized in that at least one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ^{8 is} H, Cl, Br, a C _1-6 alkyl Radical or an aryl radical bonded via a C _1-2 -alkylene group and the respectively remaining radicals R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ as well as the radicals R ¹³ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ²⁴ are as defined Claim 2 have. 6. Substance library according to one of claims 2 to 5, characterized in that the radical R ^{13 is} H, a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the other radicals R ¹⁴ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 7. Substance library according to one of claims 2 to 6, characterized in that the radical R ^{14 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the rest Radicals R ¹⁵ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 8. Substance library according to one of claims 2 to 7, characterized in that the radical R ^{15 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the remaining radicals R ¹⁶ to R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 9. substance library according to one of claims 2 to 8, characterized in that the radical R ^{16 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the other radicals R ¹⁷ , R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 10. substance library according to one of claims 2 to 9, characterized in that the radical R ^{17 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the remaining radicals R ¹⁸ , R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ²⁴ have the meaning according to claim 2. 11. Substance library according to one of claims 2 to 10, characterized in that the residue Riß stands for a C _1-6 -alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the remaining radicals R ²⁰ to R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ²⁴ are as defined in claim 2 have. 12. substance library according to one of claims 2 to 11, characterized in that the radical R ^{20 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the remaining radicals R ²¹ , R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ²⁴ are as defined Claim 2 have. 13. substance library according to one of claims 2 to 12, characterized in that the radical R ^{22 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the remaining radicals R ²² , R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2 , 14. substance library according to one of claims 2 to 13, characterized in that the radical R ^{22 is} H, a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the other radicals R ^{1 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 15. Substance library according to one of claims 2 to 14, characterized in that the radical R ^{1 'is} a C _1-6 alkyl radical, an unsubstituted or substituted phenyl, furoyl, thiophene or pyridine radical or an over a C _1-2 -alkylene group bonded aryl radical and the radicals R ^{2 '} to R ^5' , R ^{7 '} to R ^15' , R ^{1 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 16. substance library according to one of claims 2 to 15, characterized in that at least one of the radicals R ^{3 '} , R ^4' or R ^{5 'is} H, a C _1-6 alkyl radical or a via a C _{1- 2-} alkylene group bonded aryl radical and the other radicals R ^{3 '} , R ^4' or R ^{5 '} and R ^7' to R ^{15 '} , R ^1'' to R ^12'' , R ^16'' to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 17. substance library according to one of claims 2 to 16, characterized in that the radical R ^{7 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the Radicals R ^{8 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meanings according to Claim 2. 18. substance library according to one of claims 2 to 17, characterized in that the radical R ^{8 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the radicals R ^{9 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 19. substance library according to one of claims 2 to 18, characterized in that the radical R ^{9 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the radicals the radicals R ^{10 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 20. substance library according to one of claims 2 to 19, characterized in that the radical R ^{10 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the radicals R ^{11 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 21. Substance library according to one of claims 2 to 20, characterized in that the radical R ^{11 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the Radicals R ^{12 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to claim 2. 22. Substance library according to one of claims 2 to 21, characterized in that the radical R ^{12 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the Radicals R ^{13 '} to R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meanings according to Claim 2. 23. substance library according to one of claims 2 to 22, characterized in that the radical R ^{13 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the R ^{14 '} , R ^15' , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ²⁴ are each as defined in claim 2. 24. Substance library according to one of claims 2 to 23, characterized in that the radical R ^{14 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the R ^{15 '} , R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ²⁴ are each as defined in claim 2. 25. substance library according to one of claims 2 to 24, characterized in that the radical R ^{15 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the Radicals R ^{1 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meanings according to Claim 2. 26. Substance library according to one of claims 2 to 25, characterized in that the radical R ^{1 'is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the Radicals R ^{2 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meanings according to Claim 2. 27. substance library according to one of claims 2 to 26, characterized in that the radical R ^{2 ''} for H, Cl, F, NO ₂ , OR ^{10 ''} , CO (OR ^{11 ''} ), a C _1-6 - Alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the radicals R ^{3 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 is} the Meaning according to claim 2 have. 28. substance library according to one of claims 2 to 27, characterized in that at least one of the radicals R ^{4 ''} , R ^{5 ''} , R ^{6 ''} or R ^{7 ''} for H, Cl, F, NO ₂ , OR ^{10 ''} , CO (OR ^{11 ''} ), a C _1-6 -alkyl or an aryl radical bonded via a C _1-2 -alkylene group and the respective remaining radicals R ^{4 ''} , R ^{5 ''} , R ^{6 "} or R ^7" and the radicals R ^{8 "} to R ^12" , R ^{16 "} to R ^21" , R ²³ and R ^{24 have} the meaning according to Claim 2. 29. substance library according to one of claims 2 to 28, characterized in that the radical R ^{8 'is} a C _1-6 alkyl radical and the radicals R ^9'' to R ^12'' , R ^16'' to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 30. substance library according to one of claims 2 to 29, characterized in that the radical R ^{9 '' is} a C _1-6 alkyl radical or an unsubstituted or substituted phenyl radical and the radicals R ^{10 ''} to R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 31. substance library according to one of claims 2 to 30, characterized in that the radical R ^{10 '' is} H, a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and the radicals R ^{11 ''} , R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 32. substance library according to one of claims 2 to 31, characterized in that the radical R ^{11 '' is} H or a C _1-6 alkyl radical and the radicals R ^{12 ''} , R ^{16 ''} to R ^{21 ''} , R ²³ and R ^{24 have} the meaning according to claim 2. 33. substance library according to one of claims 2 to 32, characterized in that the radical R ^{12 'is} a C _1-6 alkyl radical and the radicals R ^16'' to R ^21'' , R ²³ and R ^{24 is} the Meaning according to claim 2 have. 34. substance library according to one of claims 2 to 33, characterized in that the radical R ^{16 '' is} a C _1-6 alkyl radical and the radicals R ^{17 ''} to R ^{21 ''} , R ²³ and R ²⁴ have the meaning according to claim 2. 35. substance library according to one of claims 2 to 34, characterized in that the radical R ^{17 '' is} a C _1-6 alkyl radical is the radicals R ^{18 ''} to R ^{21 ''} , R ²³ and R ^{24 is} the Meaning according to claim 2 have. 36. substance library according to one of claims 2 to 35, characterized in that the radical R ^{18 '' is} a C _1-6 alkyl radical and the radicals R ^{19 ''} to R ^{21 ''} , R ²³ and R ²⁴ have the meaning according to claim 2. 37. Substance library according to one of claims 2 to 36, characterized in that the radical R ^{19 '' is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical and; the radicals R ^{20 "} , R ^21" , R ²³ and R ^{24 have} the meanings according to claim 2. 38. substance library according to one of claims 2 to 37, characterized in that the radical R ^{20 '' is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the Radicals R ^{21 "} , R ²³ and R ^{24 have} the meanings according to claim 2. 39. Compound library according to one of claims 2 to 38, characterized in that the radical R ^{21 "stands} for H, a C _1-6 -alkyl radical or an aryl radical attached via a C _1-2 -alkylene group and the radicals R ²³ and R ^{24 have} the meaning according to claim 2. 40. substance library according to one of claims 2 to 39, characterized in that the radical R ^{23 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene group aryl radical and the radical R ^{24 has} the meaning according to claim 2. 41. substance library according to one of claims 2 to 40, characterized in that the radical R ^{24 is} a C _1-6 alkyl radical or a bonded via a C _1-2 alkylene aryl radical. 42. substance library according to one of claims 1 to 41, characterized characterized in that the reaction of the aromatic aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic Aldehyde compounds without acidic proton in α-position in an organic Solvent, preferably in toluene. 43. substance library according to one of claims 1 to 42, characterized characterized in that the reaction of the aromatic aldehyde compounds and / or heteroaromatic aldehyde compounds and / or aliphatic Aldehyde compounds without acidic proton in α-position in the presence of Potassium carbonate or boric anhydride is carried out as a base. 44. substance library according to one of claims 1 to 43, characterized characterized in that acetyl chloride is used as the acid chloride. 45. Compound library according to one of claims 1 to 44, characterized characterized in that the aminal compounds in absolute diethyl ether be implemented. 46. Compound library according to one of claims 1 to 45, characterized in that the reaction of the iminium salts in acetonitrile and / or Dimethyl sulfoxide and / or toluene, preferably in acetonitrile and / or toluene he follows. 47. substance library according to one of claims 1 to 46, characterized characterized in that the reaction with organic halogen compounds in Dimethylformamide and / or dimethyl sulfoxide takes place.   48. Compound library according to one of claims 1 to 47, characterized in that the reaction with compounds of the general formula XR ²³ in the presence of potassium tert-butylate or triethylamine takes place as a base. 49. substance library according to one of claims 1 to 47, characterized in that the reaction with compounds of the general formula XR ²⁴ in the presence of potassium hydroxide takes place as a base. 50. substance library according to one of claims 1 to 49, characterized characterized in that the purification of the naphthol and / or indole Compounds by filtration through a scavenger resin, preferably by Filtration over polymer-bound tris- (2-aminoethyl) -amine and / or 3- (3 Mercaptophenyl) -propanamidomethylpolystyrene. 51. substance library according to one of claims 2 to 50, characterized characterized in that X = Cl means. 52. Use of a substance library according to one of claims 1 to 51 in a test method for finding active ingredients. 53. Use of a substance library according to one of claims 1 to 51 in a test method for finding pharmaceutical agents. 54. Use of a substance library according to one of claims 1 to 51 in a test method for finding analgesic substances.