Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-12
1999-01-05
McKane, Joseph K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546113, 548469, 548492, 548508, 548511, C07D20908, C07D47104
Patent
active
058564969
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the generation of a plurality (library) of different indole derivatives, and to the use of said library to search for novel classes of compounds and individual compounds possessing selected properties for pharmaceutical applications.
Recently there has been an ever-increasing demand for chemical compounds that selectively act at specific biological recognition sites. These compounds can be used, inter alia, as inhibitors, activators or modulators of enzymes, as receptor ligands (agonists, antagonists or modulators), or for marking. To this purpose, methods have been developed to simultaneously synthesize a multiplicity (library) of different compounds and to assay them. These libraries (combinatorial compound libraries) usually consist of natural or modified aminoacids or nucleotides, and the like. The individual different ligands of these libraries are normally synthesized in parallel, either as mixtures or as physically separated individuals. These parallel syntheses make it possible to produce libraries containing a very large number of different ligands over a short period of time.
Also some libraries of small organic compounds have been synthesized, but the nature of the basic molecular backbone (scaffold) is mainly limited to aromatic and alicyclic compounds. Only some heterocyclic scaffolds have been synthesized. On the other hand, a large number of pharmacologically active compounds include heterocycles, and namely benzofused heterocyclic compounds. Therefore, there is still the need for new heterocyclic scaffolds to be synthesized and tested by means of combinatorial chemistry.
These libraries of small organic compounds are often synthesized on solid phase by using suitable resins and linkers. However, for this purpose a limited number of reactions is available, if compared with the number of organic reactions known in literature. Particularly, the use of organometallic catalysts in solid phase syntheses (SPS) is very limited, since many difficulties are encountered. For instance, the metal often separates at the reaction end contaminating the final products. Moreover, additives are usually added to the reaction medium which remain in suspension and contaminate the final products.
We have now surprisingly found that it is possible to synthesize in solid phase arrays of indole derivatives of formula (I) as reported hereinbelow, by using organometallic catalysts. The use of solid phase synthesis allows purification of the final product from excess reagents and catalysts by simple washing. Moreover, it is possible to employ mild reaction conditions during the whole reaction, obtaining high yields and high purity degrees. It is to be noted that purity is very important in combinatorial chemistry, since the obtained arrays are usually tested as such, without any purification. Therefore, a low purity degree of the final products can be very harfmul for biological testing. We have surprisingly found that the compound libraries generated by the instantly claimed process have a very high purity degree (typically, 85-95% by HPLC assay), which allows biological testing on the crude products with a high confidence degree, without any cross contaminations.
Therefore, a first object of the present invention is a process for preparing a plurality (library) of indole derivatives of formula: ##STR1## wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are, each independently, hydrogen or a structural diversity element, with the proviso that at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is different from hydrogen;
R.sub.0 is --NR.sub.6 R.sub.7 or --OR.sub.8, wherein R.sub.6, R.sub.7, and R.sub.8 are, each independently, hydrogen or a structural diversity element;
A is CH or N, and may be in any of the unsubstituted positions of the phenyl ring; and
n is zero or an integer from 1 to 4;
said process comprising the steps of: ##STR2## wherein:
R.sub.4 and R.sub.5 are, each independently, hydrogen or a structural diversity element;
A is CH or N, and m
REFERENCES:
patent: 5096724 (1992-03-01), Zenner et al.
Tetrahedron Letters, vol. 35, No. 48, pp. 8919-8922, Heck Reactions In Solid Phase Synthesis, Yu et al., 1994.
J. Am. Chem. Soc., vol. 113, pp. 6689-6690, Synthesis of Indoles . . . Alkynes. Larock et al., 1991.
Chem. Pharm. Bulletin, vol. 36(4), pp. 1305-1308, Condensed Heteroaromatic . . . methanesulfonamides. Sakamoto et al., 1988.
Tetrahedron Letters, vol. 33, No. 27, pp. 3915-3918, A Versatile Approach to . . . Halides. Arcadi et al., 1992.
Tetrahedron Letters, vol. 38 No. 13, pp. 2307-2310, Solid-Phase Synthesis . . . Derivatives. Fagnola et al., 1997.
Bedeschi Angelo
Candiani Ilaria
Fagnola Maria Chiara
Mongelli Nicola
Visentin Giuseppina
McKane Joseph K.
Pharmacia & Upjohn S.p.A.
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