CZ141095A3 - Enantioselective ligands for chemotherapy and neutron therapy of tumorous diseases - Google Patents

Abstract

This invention involves enantioselective ligands of the general formula I whereA, M are hydrogen or tert.-butyl,D is hydrogen or - CH2-Ar,Ar is aryl with 6 carbons which may be mono- or disubstituted with alkyl with 1-9 carbon atoms, or 2-thienyl,X has the structure of OCH2(CH2OCH2)nCH2-O-Z, wheren are the numbers 0, 1, 2,Z is hydrogen, alkyl C<1> to C<6>, benzyl or the group B(OH)2, where B is the atom of boron.Enantioselective ligands are racemic or chiral compounds.The method of their production is based on the known fact that alcohols of the benzyl type in an acid medium easily ionise and the originated cation reacts with a nucleophilic agent. Our case starts from easily accessible alcohols (diols) of the general formula II where A, M have the above-mentioned meanings,T is hydrogen or the group -CH2OH.Derivatives of the general formula II react easily with aromatic and heteroaromatic substances rich in electrons and under acid conditions they provide products of the general formula III,where A, M, D, Ar have the above-mentioned meanings.These compounds are interesting ligands, moreover, it is possible to convert them by known methods to demanded compounds of the general formula I.<IMAGE>

Description

Enantioselective ligands for chemotherapy and neutron therapy of cancer.

Technical field

The present invention relates to novel ligands for enantioselective recognition, reaction, catalysis and use in cancer chemotherapy and in neutron capture cancer therapy, and a method for their production.

BACKGROUND OF THE INVENTION

Since Pedersen discovered the ability of some crown ethers to form complexes with both alkali and alkaline earth cations, much research has been done in the field of macrocyclic ligands. The result is Lehn's cryptands, Gram spheres and Gutsche's calixarenes. These macrocyclic compounds have become well-known terms and only the generally high cost and complex preparation associated with these macrocycles hinder the wider use of many derivatives of these macrocycles. For this reason, we find considerably more practical applications for acyclic ligands, which are usually easier to manufacture.

Chiral recognition in synthetic molecular complexes has recently been a frequently studied phenomenon which forms the basis of separation of enantiomers by crystallization, transport or even by chromatography. Neither is the possibility of creating a chiral (micro) environment in the broadest sense leading to new enantioselective reactions, reagents and catalysts. A very special field of chiral recognition is the recognition of chirality of biomacromolecules at the level of drug-protein, enzyme- or drug-nucleic acid interaction. A very special case of molecular chiral recognition is the resolution of the helicity of individual parts and forms of nucleic acids.

Each ligand applicable to chiral recognition must contain an active complex formation site and a spatially close chiral element.

SUMMARY OF THE INVENTION

The present invention provides enantioselective ligands of formula (J),

I ...... 1 ^

JAlOfNISVTA οη3λο5λΜ3ϊη avyo i

- 9-6 | ιΙΛ 9 1 ··

I ‘0150a κ η β e 0

T‘3. Λ wherein A, M are hydrogen or tert-butyl D is hydrogen or -CHi-Ar

Ar is aryl of 6 carbons, optionally mono- or disubstituted with alkyl of 1-6 carbon

1-9 carbon atoms or 2-thienyl; i

X has the structure -OCH ₂ [CH ₂ OCH ₂ ] _n CH ₂ -OZ, where n are the numbers 0, 1,2,

Z is hydrogen, alkyl Cl to C _6, benzyl group or a B (OH) ₂ wherein B is a boron atom.

The enantiomeric ligands are racemic or chiral-compounds.

The method of their preparation is based on the known fact that benzylic alcohols readily ionize under acidic conditions and the cation thus formed reacts with a nucleophilic agent. In our case, starting from readily accessible alcohols (diols) of the general formula (I)

wherein A, M are as defined above.

T is hydrogen or -CH ₂ -OH;

which are accessible using known synthetic methods {Cram D.J. et. al. J.Org.Chem. 1977, 42, 4173, J. Org. 1978, 43, 1930, Hovorka et al. Tetrahedron 1992, 48, 9503 and 9517}. Phenolic groups in the ortho position to the cation formed increase its stability (salicyl type) so that reactions proceed easily and with high yields.

It is the derivatives of formula (2) that react readily with aromatic- and heteroaromatic electron-rich substances and, under acidic conditions, give products of

He knows

wherein A, M, D, Ar are as defined above.

These compounds are in themselves interesting ligands, and moreover, they can be easily converted by the known methods into the desired compounds of formula J

In the ligand molecule of the invention, the site for interaction with the biomolecule (one or two) forms an aromatic or heteroaromatic system interacting, for example, by intercalation with nucleotides. The chirality of the binaphthol skeleton responsible for recognizing nucleotide helicity. The process according to the invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dissolve 5g of 3,5-di-tert-butylphenol in 150 ml of dichloroethane, cool to 0 ° C and slowly add dropwise 9.54g of commercial boron trifluoride etherate at the same temperature. The reaction mixture is then added dropwise under the same conditions to 5 g of binaphthol triol (3-hydroxymethyl-2,2'-dihydroxy-1,1'-binaphthalene) and the mixture is stirred at the same temperature for 2 hours. Isolation is performed by quenching the mixture with 150 ml of water and extraction with dichloroethane (3x). The combined extracts were washed with water, sodium bicarbonate solution, dried and evaporated. The crude product was purified by filtration through a short column of silica gel in petroleum ether-20% toluene. Evaporation gave 6g of analytically pure product (82%) of Formula 3 (A, B, D = H, Ar = 2-hydroxy-4,6-di-tert-butylphenyl). Calcd: C, 83.30; 7.19% H found: 83.25% C 7.15% H 1 H-NMR spectrum (CDCl 3, ppm.):

1.40 (s, 9H, t Bu); 1.43 (s, 9H, tBu); 4.45 (s, 2H, Ar-CH ₂ Ar); 4.63 (s, 1H, Ar-OH); 5.10 (s, 1H, ArOH); 5.29 (s, 1H, Ar-OH); 6.87 (d, J = 1.7Hz, 1H, aroma); 7.10-7.44 (m, m, 9H, arom.); 7.71 (d, J = 7.7 Hz, 1H, arom.); 7.92 (d, 10.6Hz, 1H, arom.); 8.02 (d, J = 8.8 Hz, 1H, arom.).

Starting from optically pure S-binaphthol triol, the optically active compound was obtained in identical yield and with specific physicochemical characteristics only specific rotation was determined α = 32.188 (MeOH, c = 0.786%)

Example 2

Using benzene instead of 3,5-di-tert-butylphenyl and 6'-tert-butyl-2-hydroxymethyl; 3 _with 3'-dihydroxy-1,1'-binaphthalene instead of the "binaphthol triol" of Example 1 and the reaction proceeds under the same conditions. hour, isolated 72% pure product (Formula 3, A, D = H, B = tBu, Ar = phenyl).

For C 31 H 28 O 2 calculated: 86.14% C; H, 6.48; Found: C, 86.20; 6.53% H ¹ H-NMR spectrum (CDCl 3, ppm):

1.43 (s, 9H, tBu); 4.28 (s, 2H, Ar-CH ₂ -Ar); 5.13 (s, 1H, Ar-OH); 5.28 (s, 1H, Ar-OH); 7.13-7.17 (m, 2H, arom.); 7.25-7.45 (m, 9H, aromatic); 7.17 (s, 1H, arom.); 7.81 (d, J = 7, 6Hz, 1H, arom.); -7- $ (d, J = 1.0Hz, 1H, arom.); 7.95 (d, J = 8.9 Hz, 1H, arom.).

Example 3

Using p-cresol instead of 3,5-di-tert-butylphenol in Example 1 and reacting under the same conditions for 45 minutes, 67% of pure product is isolated (Formula 3, A, B, D = H, Ar = 2-hydroxy-5- methylphenyl).

ProC28C2 ₂ O ₃ Calculated: C 82.74%; H, 5.46. Found: C, 82.81; 5.41% H

Starting from optically pure S-binaphthol triol, the optically active compound was obtained in identical yield and with specific physicochemical characteristics, only the specific rotation was determined .alpha. = -23.443 (MeOH, c = 0.883%). ):

2.31 (s, 3H, Ar-Me); 4.16 (dd, J = 21,5Hz, J = 6.5Hz, 2H, Ar-CH _{2 &apos;}Ar); 5.03 (bs, 1H, Ar-OH); 5.79 (bs, 1H, Ar-OH); 6.17 (bs, 1H, Ar-OH); 6.73 (d, J = 8.2 Hz, 1H, arom.); 6.95 (d, J = 7.9 Hz, 1H,

Example 4

Using 2,4-di-tert-butylphenol instead of 3,5-di-tert-butylphenol in Example 1 and the reaction proceeding under the same conditions for 40 minutes, 70% of the pure product is isolated (Formula 3, A, B, D = H, Ar = 2-hydroxy-3,5-di-tert-butylphenyl).

C 8 H 8 O 10 requires: 83.30% C; 7.19% H found; 83.33% C; 7.28% H r

Example 5

If thiophene is used instead of 3,5-di-tert-butylphenol in Example 1 and the reaction proceeds under the same conditions for 5 minutes, 82% of the pure product is isolated (Formula 3, A, B, D = H, Ar = 2-thienyl).

Example 6

Using 4-n-nonylphenol instead of 3,5-di-tert-butylphenol in Example 1 and reacting under the same conditions for 45 minutes, 81% of pure product is isolated (Formula 3, A, B, D = H, Ar = 2- hydroxy-5-n-nonylphenyl).

For C 18 H 17 O 5 calculated: 83.36% C; 7.38% H found :. 83.41% C; 7.45% H H H-NMR spectrum (CDCl 3, ppm.):

0.62-1.54 (m, 19H, n-nonyl); 4.20 (bs, 2H, Ar-CH ₂ -Ar); 6.79 (d, J = 8.2 Hz, 1H, arom.); 7.12 (t, J = 8.2 Hz, 3H, arom.); 7.24-7.41 (m, 4H, arom.); 7.81-8.01 (m, 6H, arom.),

Example 7

If toluene is used instead of 3,5-di-tert-butylphenol and 3,3'-bis-hydroxy-methyl-2,2'-dihydroxy-ina-binaphthalene instead of the "binaphthol triol" of Example 1, the reaction is isolated for 2 hours. % Pure product (Formula 3, A, B = H, D = CH ₂ Ar, Ar = 4-methylphenyl).

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Industrial applicability

The invention is applicable in the chemical industry and medicine.

AND

Claims (5)

Patent claims CLAIMS 1. Enantioselective ligands for chemotherapy and neutron therapy for cancer of the formula X wherein A, M are hydrogen or tert-butyl D is hydrogen or -CH 2-Ar Ar is aryl of 6 carbons, or aryl of 6 carbons mono- or disubstituted with C 1 -C 9 alkyl or 2-thienyl, X has the structure -OCH 2 [CH 2 OCH 2] _n CH 2 -OZ, where n are the numbers 0,1,2, Z is hydrogen, C 1 -C 6 alkyl, benzyl, or a B (OH) 2 group wherein B is boron atom. . 4). . A process for the preparation of enantioselective ligands according to claim 1, characterized in that the benzyl alcohols of the general formula (I): wherein A, M are as defined above, T is hydrogen or a -CH 2 -OH group, by reaction with an appropriate aromatic or heteroaromatic system under acidic catalysis conditions to give intermediates of the formula wherein A, M, D, Ar are as defined above, followed by alkylation of phenolic hydroxy groups in a known manner. A process for producing enantioselective ligands according to claim 1 3, characterized in that substances selected from the group consisting of protic and Lewis acids, preferably of heterogeneous nature, are used as the acid catalyst. A process for producing enantioselective ligands according to claim 4, characterized in that boron trifluoride etherate in an amount of 0.01 to 2 equivalents is used as the catalyst Based on the starting alcohol. Process for preparing enantioselective ligands according to claims 3 and 4, characterized in that the process is carried out in a chlorinated hydrocarbon medium, preferably 1,2-dichloroethane.