Cycloalkyl derivatives and the solid-phase synthesis of such...

Details Cycloalkyl derivatives and the solid-phase synthesis of such... Cycloalkyl derivatives and the solid-phase synthesis of such...

1998-09-14

2003-02-18

Celsa, Bennett (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S128000, C560S129000, C560S170000, C562S579000, C564S001000, C568S700000, C436S518000, C436S536000

Reexamination Certificate

active

06521780

ABSTRACT:

The invention relates to cycloalkyl derivatives, to a process for preparing them and to their use.
TECHNICAL FIELD
In classical research looking for active substances, the biological effect of novel compounds has been tested in random screening on the whole organism, for example the plant or the microorganism. In this case the biological testing was the limiting factor with respect to the synthetic chemistry. The provision of molecular test systems by molecular and cell biology has lead to a drastic change in the situation.
A large number of molecular test systems have been and are being developed for modern research looking for active substances, such as receptor binding assays, enzyme assays and cell-cell interaction assays. Automation and miniaturization of these test systems permits the sample throughput to be high. This development makes it possible to test in ever shorter times a continually increasing number of chemicals for their biological effect in random screening and thus for possible use as lead structure for an active substance in medicine, veterinary medicine or crop protection.
A modern automated test system allows 100,000 or more chemicals to be tested for their biological effect each year in a mass screening.
This development has made classical synthetic chemistry the limiting factor in research looking for active substances.
If the capacity of these test systems is to be fully exploited, there must be a considerable increase in the efficiency of the chemical synthesis of active substance lead structures.
BACKGROUND ART
Combinatorial chemistry can contribute to this necessary increase in efficiency, especially when it makes use of automated solid-phase synthetic methods (see, for example, review on articles J. Med. Chem. 37 (1994) 1233 and 1385). Combinatorial chemistry makes it possible to synthesize a wide variety of different chemical compounds, called substance libraries. Solid-phase synthesis has the advantage that by-products and excess reactants can easily be removed, so that elaborate purification of the products is unnecessary. The finished synthetic products can be passed directly, i.e. carrier-bound, or after elimination from the solid phase, to mass screening. Intermediates can also be tested in the mass screening.
Applications described to date have been mainly confined to the peptide and nucleotide areas (Lebl et al., Int. J. Pept. Prot. Res. 41, 1993: 203 and WO 92/00091) or their derivatives (WO 96/00391). Since peptides and nucleotides have only limited possible uses as drugs because of their unfavorable pharmacological properties, it is desirable to utilize the solid-phase synthetic methods known and established in peptide and nucleotide chemistry for synthetic organic chemistry.
U.S. Pat. No. 5,288,514 reports one of the first combinatorial solid-phase syntheses in organic chemistry outside peptide and nucleotide chemistry. U.S. Pat. No. 5,288,514 describes the sequential solid-phase synthesis of 1,4-benzodiazepines.
WO 95/16712, WO 95/30642 and WO 96/00148 describe other solid-phase syntheses of potential active substances in combinatorial chemistry.
However, in order to be able fully to exploit the possibilities of modern test systems in mass screening, it is necessary continuously to feed novel compounds of maximum structural diversity into the mass screening. This procedure makes it possible considerably to reduce the time for identification and optimization of a novel active substance lead structure.
It is therefore necessary continually to develop novel diverse combinatorial solid-phase syntheses. It is moreover worthwhile to aim at biologically active compounds.
In view of the significance of cycloalkyl derivatives, specifically of cycloalkylmalonic ester derivatives, as potential active substances in the drugs and crop protection sectors, it is of great importance to provide efficient methods for their solid-phase preparation and, in particular, for the subsequent testing in mass screening.
DISCLOSURE OF INVENTION
It is an object of the present invention to provide a rapid and efficient solid-phase process for preparing cycloalkyl derivatives which meets the requirements of combinatorial chemistry.
We have found that this object is achieved by a process for preparing cycloalkyl derivatives of the formula I
in which the variables and substituents have the following meanings:
(P) a solid phase,
(L) a linker with 2 to 12 carbon atoms or the structure —CH
2
—CH
2
—(—O—CH
2
—CH
2
—)
1-100
—,
R
1
hydrogen or a low molecular weight organic radical,
R
2
hydrogen or unsubstituted or substituted alkyl, alkenyl, alkynyl or cycloalkyl or
R
1
and R
2
together an unsubstituted or substituted 4- to 8-membered ring
R
3
unsubstituted or substituted C
1
-C
10
-alkyl, C
3
-C
8
-cycloalkyl or aryl,
R a low molecular weight organic radical or two adjacent R radicals together form an unsubstituted or substituted carbo- or hetero-cyclic ring
n=0 to 4
m=0 to n+2,
which comprises reacting a compound of the formula II
with aldehydes of the formula III
in the presence of a base to give compounds of the formula IV
and cyclizing the resulting product IV in the presence of a Lewis acid.
The invention additionally relates to novel cycloalkyl derivatives and to their use.
MODE(S) FOR CARRYING OUT THE INVENTION
It is possible to use as solid phase (P) in the process according to the invention supports known from solid-phase peptide synthesis. Usable supports can, as long as they are compatible with the synthetic chemistry used, consist of a large number of materials. The size of the supports may be varied within wide limits depending on the material. Particles in the range from 1 &mgr;m to 1.5 cm are preferably used as supports, and particles in the range from 1 &mgr;m to 100 &mgr;m are particularly preferred for polymeric supports.
The shape of the supports is immaterial, but spherical particles are preferred. The supports may have a homogeneous or heterogeneous size distribution, but homogeneous particle sizes are preferred.
Examples of suitable solid phases (P) are ceramic, glass, latex, crosslinked polystyrenes, polyacrylamides, silica gels, cellulose particles, resins, gold or colloidal metal particles.
In order to make it possible to attach the reactant and eliminate the product after the synthesis, the support must be suitably functionalized or provided with a linker which has an appropriate functional group. Examples of suitable and preferred supports and support-linker conjugates are chlorobenzyl-resin (Merrifield resin), Rink resin (Novabiochem), Sieber resin (Novabiochem), Wang resin (Bachem), Tentagel resins (Rapp-Polymere), Pega resin (Polymer Laboratories) or polyacrylamides. Particularly preferred supports are chlorobenzyl-resins, Tentagel resins or polyacrylamides. For attachment of the preferred linker
HO—{circle around (L)}—OH
with 2 to 12 carbon atoms to the solid phase, the latter must where appropriate be modified in a manner to the skilled worker. The linker can be branched or unbranched, chiral or achiral.
Examples of diols which may be mentioned are ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,4-pentanediol, 2-methyl-1,4-butanediol, 1,2-hexanediol, 1,3-hexanediol, 1,4-hexanediol, 1,5-hexanediol, 1,6-hexanediol, 2,3-hexanediol, 2,4-hexanediol, 2,5-hexanediol, 2-methyl-1,5-pentanediol or 3-methyl-1,5-pentanediol.
To determine the concentration of hydroxyl groups on the linker-coupled resin, the latter was reacted with 3,5-dinitrobenzoyl chloride in pyridine, and nitrogen determination on the resulting ester is a measure of the hydroxyl group concentration. This is in the range from 0.5 to 0.85 mmol of hydroxyl groups per gram of resin.
Polyacrylamides [(P)—NH
2
] can be derivatized, for example, with 4-chloromethylbenzoic acid in such a way that the doubly deprotonated linker can be attached (Scheme I).
The amide linkage (1) between the support and the 4-chloromethyl

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