WO2003051795A2

WO2003051795A2 - Resin-bonded isonitriles

Info

Publication number: WO2003051795A2
Application number: PCT/EP2002/014386
Authority: WO
Inventors: Bernd Henkel
Original assignee: Morphochem Ag
Priority date: 2001-12-18
Filing date: 2002-12-17
Publication date: 2003-06-26
Also published as: DE10162134A1; WO2003051795A3; AU2002358734A8; AU2002358734A1

Abstract

The invention relates to novel polymer-bonded isocyanide derivatives of general formula (I), to methods for preparing them, and to their use for synthesizing heterocycles and substance libraries.

Description

Resin-bound isonitriles

The present invention relates to new polymer-bound isocyanide derivatives, processes for their preparation and their use for the synthesis of heterocycles and of substance libraries.

Isocyanides are important starting materials for the synthesis of biologically active products. Since they serve as starting materials in multicomponent reactions (MCR), they are suitable for the rapid and efficient synthesis of large substance libraries (A. Dömling, I. Ugi, Angewandte Chemie, 2000, (112), 3300-3344). When generating various substance libraries, synthesis on polymer-bound supports (solid-phase synthesis) has proven to be particularly advantageous, since excess reagents can be used and the product can be cleaved from the resin in good yields at the end of the synthesis sequence. Solid-phase bound amines (AM Strocker et al., Tetrahedron Lett., 1996 (37), 1149; AMM Mjalli et al., Tetrahedron Lett., 1996 (37) 2943; RW Armstrong et al., J. Org. Chem., 1996 (61), 8350) and isocyanides (R. Ashady, I. Ugi, Polymer, 1990 (31), 1165; AMM Mjalli et al., Tetrahedron Lett., 1996 (37) 7489; C. Hulme et al. Tetrahedron Lett., 1998 (39), 7227; BA Kulkarni et al., Tetrahedron Lett., 1999 (40), 5633; JJ Chen et al., Synlett 2001, 1263, WO0137983) already described in the literature.

However, the polymer-bound isocyanides known to date are not of general and wide breadth and are comparatively cumbersome and sequential to synthesize over many steps. The object of the present invention was therefore to provide new polymer-bound derivatives of an isonitrile described by Schöllkopf (U. Schöllkopf et al. Liebigs Ann. Chem. 1979, 1444-1446), which are particularly suitable for the synthesis of heterocycles.

The present invention relates to new polymer-bound isonitriles of the general formula (I):

wherein:

Pol is a carrier;

L is a linker or a direct bond;

R is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or a heteroaralkyl radical, and

X a leaving group such as B. F, Cl, Br, I, NR ³ ^ ² , OR ³ or SO _n R ⁴ , where R ¹ , R ² , R ³ and R ^{4 are} independently a hydrogen atom, an alkyl, alkenyl, alkynyl , Heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or a heteroaralkyl radical or R ¹ and R ² together are part of an optionally substituted heterocycloalkyl ring system and n = 0, 1, 2 or 3 is. The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, Isobutyl, tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.

The terms alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.

The term heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom (preferably oxygen or nitrogen), e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, nitrile, methylcarboxyalkyl ester, carboxyalkyl ester or 2,3-dioxyethyl group. The term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkyl amide, alkoxycarbonyl or alkoxycarbonyloxy.

The term cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic group which has one or more rings which form a skeleton which has 3 to 14 carbon atoms, preferably 3 contains up to 10 carbon atoms, for example the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.

The term heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom and can be used, for example, for piperidine -, Morpholine, N-methylpiperazine or N-phenyl-piperazine group.

The terms alkylcycloalkyl or heteroalkylcycloalkyl refer to groups which, in accordance with the above definitions, contain both cycloalkyl or heterocycloalkyl and also alkyl, alkenyl, alkynyl and / or heteroalkyl groups.

The term aryl or Ar refers to an aromatic group which has one or more rings and is formed by a skeleton which contains 5 or 6 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, e.g. a phenyl, naphthyl, biphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxy-p enyl group.

The term heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom, e.g. the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.

The terms aralkyl or heteroaralkyl refer to Groups which contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups, for example the tetrahydroisoquinolinyl, benzyl, in accordance with the above definitions -, 2- or 3-ethylindolyl or 4-methylpyridino group.

The terms alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups are represented by fluorine, chlorine or bromine or iodine atoms or OH, SH, NH ₂ or N0 ₂ groups are replaced. These terms also refer to groups substituted with unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.

Compounds of formula (I) may contain one or more centers of chirality due to their substitution. The present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio. Furthermore, the present invention also encompasses all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof.

The term linker refers to a chemical group that is suitable for connecting molecules to the carrier. The linker is a chemical structural unit that is covalently bound to the solid support on the one hand and covalently to the U group on the other. Due to the linker, the target molecule can be completed synthesis under gentle conditions again cleaved from the carrier. Depending on the synthesis strategy, it is possible that part of the linker becomes part of the target compound during the cleavage. A linker can be an alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aralkylene or a heteroaralkylene group. Examples of linkers are found in P. Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John Wiley & Sons, New York, 2000; D. Obrecht and JM Villalgordo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular- Weight Compound Libraries, Tetrahedron Organic-Chemistry Series Volume 17, Elsevier Science Ltd, Oxford, 1998 and in FZ Dörwald, Organic Synthesis on Solid Phase, Wiley - VCH, Weinheim, 2000. Examples include the trityl linker (optionally substituted in the 2-position by a chlorine atom or in the 4-position by a methyl or methoxy group), the Wang linker, the SASRIN ™ linker, the Rink acid linker, the benzhydryl alcohol -Linker, the HMBA linker and polymeric benzyl halide (linker of the Merrifield resin) and the P7ΛM linker. The Wang Linker, the Trityllinker, the Merrifield Linker and the HMBA Linker are preferred.

The term carrier refers to a polymer (preferably a chemically inert polymer) that has been modified for organic solid phase synthesis so that chemical substances can be covalently bound to it. Examples of polymeric supports are described in P. Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John Wiley & Sons, New York, 2000; D. Obrecht and JM Villalgordo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Tetrahedron Organic-Chemistry Series Volume 17, Elsevier Science Ltd, Oxford, 1998 and in F. Z. Dörwald, Organic Synthesis on Solid Phase, Wiley-VCH, Weinheim, 2000. A distinction is made between soluble and insoluble polymeric carriers. Examples of soluble polymeric carriers are the polyethylene glycols (PEG). Examples of insoluble polymeric supports are polymers based on polystyrene (crosslinked with divinylbenzene) such as B. the Merrifield resin, bromo- (4-methoxyphenyl) methyl polystyrene, 4- (bromomethyl) phenoxyethyl polystyrene, the 2-chlorotrityl resin, tentacle polymers such as Tentagel®, silica gel, controlled pore glass (CPG), cellulose, copolymers and gold. Polymeric carriers are available from a number of companies such as B. Calbiochem-Novabiochem AG, Laufelfingen, Switzerland, Bachern AG, Bubendorf, Switzerland, Rapp Polymer GmbH, Tübingen, Germany, Advanced ChemTech, Louisville, KY, USA and Shearwater Corporation, Huntsville, Alabama, USA. Preferred carriers are polystyrene (crosslinked with up to 3% divinylbenzene (preferably 1-2% DVB), polyethylene glycol derivatives and tentacle polymers (in particular Tentagel®).

Preferred compounds of the general formula (I) are those in which X is a group of the formula -NR -'- R ² or -0R ³ , where R ¹ , R ² and R ^{3 are} preferably Ci-C _δ -alkyl groups or R ¹ and R ² together are part of a heterocycloalkyl ring system with 5 to 7 ring atoms; X is particularly preferably a group of the formula -NMe ₂

Further preferred are compounds of the general formula (I) in which R is a hydrogen atom.

Pol-L- preferably have one of the following structures:

where PS is a cross-linked polystyrene with up to 3% DVB (preferably 1-2%).

Also preferred is PS polyethylene glycol (with different chain lengths) or a tentacle polymer (in particular Tentagel®).

Compounds of the general formula (I) in which Pol-L- together are 4-methylenephenoxymethyl-polystyrene (Wang resin) or 4-methylene-benzamidomethyl-polystyrene (HMBA resin) are particularly preferred.

Again preferred are linker systems, the one Have leaving group which can form a salt with alkali or alkaline earth anions of isocyanoacetic acid (e.g. chloride, bromide or tosylate).

The compounds of the general formula (I) can be prepared in a two-stage process. In the first step, an isocyanoacetic acid salt (III) is coupled to a resin (II).

(") (Hl) (IV)

The resin-bound isocyanoacetic acid (IV) is then reacted with a compound of the general formula (V) to give compound (I).

Shark is a halogen atom (preferably chlorine or bromine), M an alkali metal ion, an ammonium ion or an alkaline earth metal ion (preferably potassium) and R ^{5 is} an alkyl group (preferably methyl or ethyl).

The compounds of the general formula according to the invention

(I) can be used for solid phase synthesis of heterocycles. The in the literature for syntheses in

Solution described method (Bienayme, - K. Bouzid,

Tetrahedron Lett. 1998, 39, 2735-2738; S. Heck, A. Dömling, Synlett 2000, 424-426; EP0248414; U. Schöllkopf et al. Liebigs Ann. Chem. 1979, 1444-1446; Bossio et al. J. Chem. Research (S) 1993, 1, 1; J. Kolb et al. Tetrahedron Letters, 2002, 43, 6897-6901) can be applied to solid-phase synthesis. Furthermore, these compounds are of great interest for the synthesis of substance libraries (especially in drug discovery).

In particular, the compounds of the general formula (I) according to the invention can be used for the synthesis of oxazole, thiazole, imidazole, tetrazole and piperazine derivatives.

It is particularly preferred to use the compounds of the general formula (I) according to the invention for the solid phase synthesis of heterocycles of the formulas (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XIII ), the radicals R ^a , R ^b , R ^c , R ^d , R ^Θ , R ^f , R ^s and R ^h independently of one another an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl -, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl radicals, or two of the radicals R, R ^b , R °, R ^d , R ^e , R ^f , R ^g and R ^h optionally part of an aryl , Heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or a heteroaralkyl ring system.

(VI) (VII) _{v „|)

Compounds of formula (VI) can by reacting a

Compound of formula (I) with compounds of the formulas

R ^b C0R ^c , R ^a NH ₂ and TMS-N ₃ are produced.

Compounds of formula (VII) can be obtained by reacting a compound of formula (I) with compounds of the formulas

R ^b COR ^c and R ^a NH ₂ are produced.

Compounds of formula (VIII) can by reacting a compound of formula (I) with compounds of

Formulas R ^b COR ^c and TMS-N ₃ can be produced. Compounds of formula (IX) can by reacting a

Compound of formula (I) with compounds of the formulas

R ^b COR ^c and R ^d COSH are produced.

Compounds of formula (X) can by reacting a

Compound of formula (I) can be prepared with H ₂ S. Compounds of formula (XI) can by reacting a

Compound of formula (I) with a compound of formula

R ^a NH ₂ are prepared.

Compounds of formula (XII) can by reacting a

Compound of formula (I) with compounds of the formulas R ^b COR ^c , R ^d COSH and R ^a NH ₂ are prepared. Compounds of the formula (XIII) can be prepared by reacting a compound of the formula (I) with compounds of the formulas R ^b COR ^c and H ₂ NCR ^Θ R ^f CR ^g R ^h COSH.

Examples

The potassium salt of isocyanoacetic acid was prepared according to the method described in I. Hoppe, U. Schöllkopf, Chem. Ber. 1976, 109, 482-487.

Coupling of the potassium salt of isocyanoacetic acid

4- (bromomethyl) phenoxypolystyrene

5 g of 4- (bromomethyl) phenoxypolystyrene (4mmol) are abs in 30 ml of DMF. swollen and 985 mg of isocyanoacetic acid potassium salt (8 mmol) added. This mixture is now shaken at room temperature for 16 h. Then the polymer is filtered off and five times with 50 ml of DMF abs. and five times with 50 ml of abs. washed. The resin is then dried in vacuo. To determine the loading, 100 mg of the resin are mixed with 181.2 mg of the preformed imine from benzaldehyde and aniline (1 mmol) and 297.3 mg of Fmoc-glycine (1 mmol) and 1 ml of abs. Dichloromethane and 1 ml abs. Added methanol. This mixture is now shaken at room temperature for 16 h. It is then suctioned off, three times with 5 ml of abs. Dichloromethane and five times with 5 ml abs. Washed methanol and then dried the sample in vacuo. The Fmoc determination is then carried out according to a method by Meienhofer (J. Meienhofer et al., Int. J. Peptide Protein Res. 13, (1979), 35-42). This resulted in a loading of 0.31 mmol / g.

Examination of the polymer sample by FT-IR spectroscopy showed an isonitrile band at 2145 cm ^-1 . The following polymeric supports were reacted in DMF with the potassium salt of isocyanoacetic acid analogously to the process described (loads in brackets).

- Merrifield resin (0.33 mmol / g) - Brominated Wang resin (0.44 mmol / g)

- Bromo (4-methoxyphenyl) methyl polystyrene (0.53 mmol / g)

- Trityl resin (1-chloro-l, 1-diphenyl-l- (p-carboxyphenyl) - methane from aminomethyl polystyrene) (0.44 mmol / g)

Coupling of 4-bromomethylbenzoic acid on aminomethyl polystyrene

8,387 g of 4-bromomethylbenzoic acid (39 mmol) is dissolved in 10 ml of DMSO and 6,106 ml of diisopropylcarbodiimide (39 mmol) are added. This mixture is stirred for 30 minutes at room temperature and then added to a suspension of 15 g of aminomethylpolystyrene (19.5 mmol) in 90 ml of DMSO. This mixture is now shaken overnight. It is then suctioned off and five times with 100 ml of DMSO and five times with 100 ml of abs. DMF washed. The resin is processed directly in the next step. The completeness of the coupling is checked with the Kaiser test (E. Kaiser et al., Anal. Biochem. 34, (1970), 595).

Coupling of the potassium salt of isocyanoacetic acid on 4-bromomethylbenzamidomethylethyl polystyrene

4-Bromomethylbenzamidomethylpolystyrene (19.5 mmol) is abs in 100 ml DMF. swollen and 4.8 g of isocyanoacetic acid potassium salt (39 mmol) added. This mixture is now shaken at room temperature for 16 h. Then the polymer is filtered off and five times with 100 ml of DMF abs. and five times with 100 ml of abs. washed. The resin is then dried in vacuo. The load determination was the same as for the clutch described on 4- (bromomethyl) phenoxypolystyrene and was 0.35 mmol / g.

In addition, this polymer sample was measured using FT-IR spectroscopy. It showed an isonitrile band at 2147 cm ^"1 .

General instructions for the preparation of resin-bound ß-dimethylamino-α-isocyanacrylic acid

1 g of polymer-bound isocyanoacetic acid (0.31 or 0.35 mmol) is abs in 1.5 ml of THF. and 1.5 ml of abs. swollen and then 4.8 ml of dimethylformamide diethyl acetal (28 mmol) are added. This mixture is shaken overnight and then washed three times with THF, EtOH and MeOH and dried.

Solid phase synthesis of heterocycles

1. Synthesis of tetrazoles:

7- (4-chloro-phenyl) -8-isopropyl-7, 8-dihydro-tetrazolo [1,5-a] pyrazine-5-carboxylic acid

0.092 ml isobutyraldehyde (mmole) and 128 mg 4-chloroaniline (mmole) are each in 1 ml THF abs. and MeOH abs. dissolved and stirred for 1 hour at room temperature. Then 500 mg of HMBA resin bound ß-dimethylamino-α-isocyanacrylic acid

(0.25mmol), 0.183ml trimethylsilyl azide (1.4mmol) and 1ml each of the solvents are added. This

Mixture is then shaken at room temperature for 16 hours. It is suctioned off and the resin is washed three times with THF, MeOH and again with THF. The resin is then shaken with a 1: 1 mixture of THF and IM HCl for 2 h. Then resin is washed three times with THF and methanol and then dried in vacuo. For splitting off, 24 mg of LiOH (mmol) are dissolved in 2 ml of water and 2 ml of THF are added. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is suctioned off and washed several times with MeOH. The organic solvents are stripped off and the water phase is neutralized with 2M HC1. To separate the LiCl formed, the product is purified by RP-HPLC. Yield: 40mg = 50%; MS data: calculated m / z = 319.75, found (M + H) ⁺ = 320.2.

7-benzyl-8-isopropyl-7, 8-dihydro-tetrazolo [1, 5-a] pyrazine-5-carboxylic acid

0.092ml isobutyraldehyde (1mmol) and 0.11ml benzylamine (1mmol) are each in 1ml THF abs. and MeOH abs. dissolved and stirred in at room temperature. Then 500 mg of HMBA resin bound ß-dimethylamino-α-isocyanacrylic acid

Mixture is then shaken at room temperature for 16 hours. It is suctioned off and the resin is washed three times with THF, MeOH and again with THF. The resin is then shaken with a 1: 1 mixture of THF and IM HCl for 2 h. The resin is then washed three times with THF and methanol and dried in vacuo. For splitting off, 24 mg of LiOH (mmol) are dissolved in 2 ml of water and 2 ml of THF are added. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is suctioned off and washed several times with MeOH. The organic solvents are stripped off and the water phase is neutralized with 2M HCl. To separate the LiCl formed, the product is purified by RP-HPLC. Yield: 42.5mg = 57%; MS data: calculated m / z = 299.34, found (M + H) ⁺ = 300.2.

7-butyl-8-isopropyl-7, 8-dihydro-tetrazolo [1, 5-a] pyrazine-5- carboxylic acid

0.092ml isobutyraldehyde (mmol) and 0.1ml n-butylamine

(lmmol) in 1ml THF abs. and MeOH abs. dissolved and stirred lh at room temperature. Then 500 mg of HMBA resin bound ß-dimethylamino-α-isocyanacrylic acid (0.25mmol), 0.183ml trimethylsilyl azide (1.4mmol) and 1ml each of the solvents are added. This mixture is then shaken for 16 hours at room temperature. It is suctioned off and the resin is washed three times with THF, MeOH and again with THF. The resin is then shaken with a 1: 1 mixture of THF and IM HCl for 2 h. Then resin is washed three times with THF and methanol and then dried in vacuo. For splitting off, 24 mg of LiOH (mmol) are dissolved in 2 ml of water and 2 ml of THF are added. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is then suctioned off and washed several times with MeOH. The organic solvents are stripped off and the water phase is neutralized with 2M HCl. To separate the LiCl formed, the product is purified by RP-HPLC. Yield: 47.5mg = 72%; MS data: calculated m / z = 265.32, found (M + H) ⁺ = 266.2.

2. Synthesis of thiazoles:

2- {l- [Acetyl- (4-chlorophenyl) amino] -2-methyl-propyl} -thiazole-4-carboxylic acid

128mg 4-chloroaniline (lmmol) and 0.092ml isobutyraldehyde

(lmmol) in a mixture of MeOH / DCM abs. (2ml) precondensed for 1 hour. Then 500 mg of HMBA resin bound β-dimethylamino-α-isocyanacrylic acid (0.25mmol), 0.072ml thioacetic acid (1mmol) and 2ml of the above solvent mixture are added and shaken for 16 hours at room temperature. The resin is suctioned off and several times with DCM and washed with MeOH. The resin is then dried in vacuo. 24mg of LiOH (lmmol) in 2ml

Dissolved water and added 2ml THF. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is suctioned off and washed several times with MeOH. The combined filtrates are with

Neutralized 2N HCl and evaporated to dryness. The

The residue is taken up in ethyl acetate. The

The ethyl acetate phase is shaken out with water and dried over sodium sulfate. The desiccant is filtered off and the solvent is removed. Yield:

25mg = 28%; MS data: calculated m / z = 352.84, found

(M + H) ⁺ = 353.2.

2- [1- (acetylbenzylamino) -2-methylpropyl] thiazole-4-carboxylic acid

0.11ml benzylamine (1mmol) and 0.092ml isobutyraldehyde (1mmol) are in a mixture of MeOH / DCM abs. (2ml) precondensed for 1 hour. Then 500 mg of HMBA resin-bound β-dimethylamino-α-isocyanacrylic acid (0.25 mmol), 0.072 ml of thioacetic acid (1 mmol) and 2 ml of the above solvent mixture are added and shaken for 16 hours at room temperature. The resin is suctioned off and washed several times with DCM and MeOH. The resin is then dried in vacuo. For splitting off, 24 mg of LiOH (mmol) are dissolved in 2 ml of water and 2 ml of THF are added. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is suctioned off and washed several times with MeOH. The combined filtrates are neutralized with 2N HCl and evaporated to dryness. The residue is taken up in ethyl acetate. The ethyl acetate phase is shaken out with water and dried over sodium sulfate. The desiccant is filtered off and the solvent is removed. Yield: 35mg = 36%; MS data: calculated m / z = 394.50, found (M + H) ⁺ = 395.3.

2- [1- (acetylbutylamino) -2-methylpropyl] thiazole-4-carboxylic acid

0.1ml n-butylamine (1mmol) and 0.092ml isobutyraldehyde (1mmol) are in a mixture of MeOH / DCM abs. (2ml) precondensed for 1 hour. Then 500 mg of HMBA resin-bound β-dimethylamino-α-isocyanacrylic acid (0.25 mmol), 0.072 ml of thioacetic acid (1 mmol) and 2 ml of the above solvent mixture are added and shaken for 16 hours at room temperature. The resin is suctioned off and washed several times with DCM and MeOH. The resin is then dried in vacuo. For splitting off, 24 mg of LiOH (mmol) are dissolved in 2 ml of water and 2 ml of THF are added. The dried resin is added to this mixture and the mixture is shaken for 16 hours. The resin is suctioned off and washed several times with MeOH. The combined filtrates are neutralized with 2N HCl and evaporated to dryness. The residue is taken up in ethyl acetate. The ethyl acetate phase is shaken out with water and dried over sodium sulfate. The desiccant is filtered off and the solvent is removed. Yield: 35mg = 47%; MS data: calculated m / z = 298.41, found (M + H) ⁺ = 299.2.

The following compounds were prepared according to the rules described above using the appropriate starting materials:

2- {l- [Benzoyl- (3, 4-dimethoxybenzyl) amino] butyl} thiazole-4-carboxylic acid

Yield: 69mg = 61%. MS data: calculated m / z = 454.55, found (M + H) ⁺ = 455.5. 2- {l- [Benzoyl- (2, 2-dimethylpropyl) amino] butyl} thiazole-4-carboxylic acid

Yield: 60mg = 64%. MS data: calculated m / z = 374.51, found (M + H) ⁺ = 375.4.

2- [1- (benzoylcyclobutylamino) butyl] thiazole-4-carboxylic acid

Yield: 76mg = 85%. MS data: calculated m / z = 358.46, found (M + H) ⁺ = 359.4.

2- {[Benzoyl- (4-chlorophenyl) amino] cyclopropylmethyl} thiazole-4-carboxylic acid

Yield: 39mg = 37%. MS data: calculated m / z = 412.90, found (M + H) ⁺ = 413.4.

2- {[Benzoyl- (3, 4-dimethoxybenzyl) amino] cyclopropylmethyl} thiazole-4-carboxylic acid

Yield: 94mg = 83%. MS data: calculated m / z = 452.53, found (M + H) ⁺ = 453.4.

2- [(Benzoyl-cyclobutyl-amino) -cyclopropyl-methyl] -thiazole-4-carboxylic acid

Yield: 64mg = 72%. MS data: calculated m / z = 356.45, found (M + H) ⁺ = 357.4.

2- {[Benzoyl- (2, 2-dimethylpropyl) amino] methyl} thiazole-4-carboxylic acid

Yield: 30mg = 36%. MS data: calculated m / z = 332.42, found (M + H) ⁺ = 333.3.

2- {[Benzoyl- (4-chlorophenyl) amino] cyclohexylmethyl} thiazole-4-carboxylic acid

Yield: 58mg = 51%. MS data: calculated m / z = 454.98, found (M + H) ⁺ = 545. 5.

2- {[Benzoyl- (3, 4-dimethoxybenzyl) amino] cyclohexylmethyl} thiazole-4-carboxylic acid Yield: 57mg = 46%. MS data: calculated m / z = 494.61, found (M + H) ⁺ = 495.5.

2- {[Benzoyl- (2, 2-dimethyl-propyl) -amino] -cyclohexyl-methyl} -thiazole-4-carboxylic acid. Yield: 56 mg = 54%. MS data: calculated m / z = 414.57, found (M + H) ⁺ = 415.4.

2- [(Benzoyl-cyclobutyl-amino) -cyclohexyl-methyl] -thiazole-4-carboxylic acid Yield: 52 mg = 52%. MS data: calculated m / z = 398.53, found (M + H) ⁺ = 399.3.

2- [1- (Benzoylphenethylamino) -3-methylbutyl] thiazole-4-carboxylic acid Yield: 27mg = 26%. MS data: calculated m / z = 422.55, found (M + H) ⁺ = 423.4.

2- (1- {Benzoyl- [2- (1H-indol-3-yl) ethyl] amino} -3-methylbutyl) thiazole-4-carboxylic acid. Yield: 57 mg = 49%. MS data: calculated m / z = 461.59, found (M + H) ⁺ = 462.5.

2- (l- {benzoyl- [2- (lH-indol-3-yl) ethyl] amino} -2-phenylethyl) thiazole-4-carboxylic acid. Yield: 51 mg = 41%. MS data: calculated m / z = 495.60, found (M + H) ⁺ = 496.5.

2- {l- [Benzoyl- (3-methylbutyl) amino] -3-methylbutyl} thiazole-4-carboxylic acid Yield: 57mg = 59%. MS data: calculated m / z = 388.53, found (M + H) ⁺ = 389.4.

2- {l- [Benzoyl- (3-methylbutyl) amino] -2-phenylethyl} thiazole-4-carboxylic acid

Yield: 42mg = 40%. MS data: calculated m / z = 422.55, found (M + H) ⁺ = 423.4.

2- [1- (benzoylphenethylamino) -3-methylbutyl] thiazole-4-carboxylic acid

Yield: 63mg = 70%. MS data: calculated m / z = 360.48, found (M + H) ⁺ = 361.3.

2- [1- (acetylphenethylamino) -2-phenylethyl] thiazole-4-carboxylic acid

Yield: 36mg = 37%. MS data: calculated m / z = 394.50, found (M + H) ⁺ = 395.4.

2- (l- {acetyl- [2- (1H-indol-3-yl) ethyl] amino} -3-methylbutyl) thiazole-4-carboxylic acid

Yield: 51mg = 51%. MS data: calculated m / z = 399.52, found (M + H) ⁺ = 400.4.

2- (l- {acetyl- [2- (1H-indol-3-yl) ethyl] amino} -2-phenylethyl) thiazole-4-carboxylic acid

Yield: 51mg = 47%. MS data: calculated m / z = 433.53, found (M + H) ⁺ = 434.4.

2- {l- [Acetyl- (3-methylbutyl) amino] -3-methylbutyl} thiazole-4-carboxylic acid

Yield: 39mg = 48%. MS data: calculated m / z = 326.46, found (M + H) ⁺ = 327.3.

2- {l- [acetyl- (3-methylbutyl) amino] -2-phenyl-ethyl} - thiazole-4-carboxylic acid

Yield: 48mg = 53%. MS data: calculated m / z = 360.48, found (M + H) ⁺ = 361.3.

3. Synthesis of Imidazoles:

1- (4-pentylphenyl) -lH-imidazole-4-carboxylic acid:

500 mg of ß-dimethylamino-α-isocyanacrylic acid (O.lβmmol) bound with Wang resin are added to 5ml Smith Process Glass Vial and 4ml of dimethoxyethane and 0.228ml of 4-n-pentylaniline (1.28mmol) are added and the tube is closed. Then the sample is heated in the 300W Smith Creator microwave at 220 ° C for 15 minutes. After cooling, the tube is opened, the resin is removed and washed three times with dimethoxyethane and with methanol and dried in a high vacuum.

The dried resin is then treated for 1 hour with trifluoroacetic acid / dichloromethane = 1: 1. The resin is then filtered off and washed three times with 5 ml of dichloromethane each. The combined filtrates are spun in to dryness. The crude product is purified via RP-HPLC. Yield: 14mg = 34%. MS data: calculated m / z = 258.32, found (M + H) ⁺ = 259.4.

The following compounds were prepared according to the procedure described above using the appropriate starting materials:

1-phenylamino-1H-imidazole-4-carboxylic acid. Yield: 5 mg = 10%. MS data: calculated m / z = 203.23, found (M + H) ⁺ = 204.2.

1- (3-Chloro-4-fluorophenyl) -lH-imidazole-4-carboxylic acid Yield: 11mg = 29%. MS data: calculated m / z = 240.62, found (M + H) ⁺ = 241. 1 .

l-quinolin-6-yl-lH-imidazole-4-carboxylic acid

Yield: 8mg = 21%. MS data: calculated m / z = 239.24, found (M + H) ⁺ = 240.2.

l-pyridin-3-ylmethyl-1H-imidazole-4-carboxylic acid. Yield: 24 mg = 74%. MS data: calculated m / z = 202.20, found (M + H) ⁺ = 203.1.

1- [2- (4-Hydroxyphenyl) ethyl] -IH-imidazole-4-carboxylic acid Yield: 8 mg = 22%. MS data: calculated m / z = 232.24, found (M + H) ⁺ = 233.2.

l-butyl-lH-imidazole-4-carboxylic acid

Yield: 10mg = 37%. MS data: calculated m / z = 168.20, found (M + H) ⁺ = 169.2.

1- (1, 2-Diphenylethyl) -lH-imidazole-4-carboxylic acid Yield: 25mg = 54%. MS data: calculated m / z = 292.34, found (M + H) ⁺ = 293.2.

1- (5-Methylfuran-3-ylmethyl) -lH-imidazole-4-carboxylic acid Yield: 9mg = 27%. MS data: calculated m / z = 206.20, found (M + H) ⁺ = 207.1.

1- (2-Hydroxyethyl) -lH-imidazole-4-carboxylic acid Yield: 20mg = 80%. MS data: calculated m / z = 156.14, found (M + H) ⁺ = 157.1.

Claims

claims

1. Compounds of the general formula (I)

wherein:

Pol is a carrier;

L is a linker or a direct bond;

X is a leaving group.

2. Compounds according to claim 1, wherein R is a hydrogen atom.

3. Compounds according to claim 1 or 2, wherein X is a group of the formula -NR ^ -R ² or -OR ³ , wherein R ¹ , R ² , and R ³ independently of one another are a hydrogen atom, an optionally substituted alkyl, heteroalkyl, Aryl, aralkyl, cycloalkyl, cycloaralkyl, heterocycloalkyl, heteroaralkyl, or a heteroaryl radical or R ¹ and R ² together form part of an optionally substituted heterocycloalkyl ring system.

4. Compounds according to claim 3, wherein R ¹ , R ² and R ³

Ci-C _δ alkyl groups or R ¹ and R ² together part of one

Heterocycloalkyl ring system with 5 to 7 ring atoms

5. Compounds according to any one of claims 1 to 4, wherein X is a dimethylamino group.

6. Compounds according to any one of claims 1 to 5, wherein Pol-L- together have one of the following structures

where PS is a cross-linked polystyrene with up to 3% DVB (preferably 1-2%).

7. Compounds according to any one of claims 1 to 5, wherein Pol-L- together are 4-methylenephenoxymethylpolystyrene or 4-methylenebenzamidomethylpolystyrene.

A process for the preparation of compounds of the general formula (I) which comprises the following steps: i) coupling of an isocyanoacetic acid salt (III) to a resin (II).

(II) (IM) (IV)

ii) reaction of the resin-bound isocyanoacetic acid (IV) with a compound of the general formula (V) to give compound (I).

Here, shark is a halogen atom, M is an alkali metal ion, an ammonium ion or an alkaline earth metal ion and R ^{5 is} an alkyl group.

9. The method according to claim 8, wherein shark is a chlorine or a bromine atom, MM is a potassium atom and R ^{5 is} a methyl or an ethyl group.

10. Use of a compound according to any one of claims 1 to 7 for the synthesis of heterocycles.

11. Use of a compound according to any one of claims 1 to 7 for the synthesis of substance libraries.