Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1996-09-11
1998-05-26
Davis, Zinna Northington
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 23, C07C20501
Patent
active
057568103
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/US95/03223 filed Mar. 10, 1995
BACKGROUND OF THE INVENTION
There is interest in methods for the synthesis of large numbers of diverse compounds which can be screened for various possible physiological or other activities. Techniques have been developed in which one adds individual units sequentially as part of the chemical synthesis to produce all or a substantial number of the possible compounds which can result from all the different choices possible at each sequential stage of the synthesis. For these techniques to be successful, it is necessary for the compounds to be amenable to methods by which one can determine the structure of the compounds so made. Brenner and Lerner (PNAS USA 81: 5381-83 (1992)) and WO 93/20242, for example, describe a synthesis wherein oligonucleotides are produced in parallel with and are chemically linked as genetic tags to oligopeptides as the compounds of interest. WO 93/06121 teaches methods for particles-based synthesis of random oligomers wherein identification tags on the particles are used to facilitate identification of the oligomer sequence synthesized. A detachable tagging system is described in Ohlmeyer et al., Proc. Natl. Acad Sci. USA, 90p10922-10926, December 1993.
SUMMARY OF THE INVENTION
The present invention relates to combinatorial chemical libraries of compounds encoded with tags and to the use of these libraries in assays to discover biologically active compounds. The present invention also relates to libraries containing aryl sulfonamides, N-acyl derivatives, and N-substituted pyrrolidines and piperidines and using these libraries to identify biologically active members by screening for inhibition of serine proteases such as thrombin and Factor X.sub.a ; metallo proteases such as angiotensin converting enzyme (ACE); and carbonic anhydrase isozymes. The present invention also relates to members of the library which are inhibitors of carbonic anhydrase and thrombin. The invention also relates to methods for their preparation, intermediates, and to methods and pharmaceutical formulations for using these aryl sulfonamides, N-acyl derivatives, and N-substituted pyrrolidines and piperidines in the treatment of mammals, especially humans.
Because of their activity as inhibitors of serine proteases and carbonic anhydrase isozymes, the compounds of the present invention are useful in the treatment of hypercoagulation disease, post-myocardial infarction treatment, post-angioplasty treatment, and ocular diseases such as glaucoma.
DETAILED DESCRIPTION OF THE INVENTION
The combinatorial libraries of the present invention are represented by Formula I:
Preferred compounds of Formula I are those wherein: T'--L-- is of the Formula: ##STR1## wherein n=3-12 when Ar is pentachlorophenyl and n=4-6 when Ar is 2,4,6-trichlorophenyl; ##STR2## wherein the left-hand bond as shown is the point of attachment to the solid support and the right hand bond is the point of attachment to the ligand, and B is O or NH, with the proviso that in (b) B is NH when attached to a carbonyl group in the ligand.
Depending on the choice of L' (see Table 1), the ligands of Formula II may be detached by photolytic, oxidative, or other cleavage techniques. For example, when --L'-- is (a) and B is O, photolytic detachment may be represented by: ##STR3## wherein L" is the residue from L' and II'BH is II.
Therefore, compounds of the present invention are also represented by Formula II --R.sup.9, --NH(CH.sub.2).sub.2-5 --R.sup.9, ##STR4## R.sup.2 is the residue on the .alpha. carbon of methionine, O-t-butyl-serine, serine, S-trityl-cysteine, cysteine, aspartic acid-.beta.-t-butyl ester, aspartic acid, glutamic acid-.gamma.-t-butyl ester, glutamic acid, N.sup.im -trityl-histidine, histidine, N.sup..epsilon. -Boc-lysine, lysine, N.sup.g -Mtr-arginine, arginine, N-.beta.-trityl-asparagine, asparagine, N-.gamma.-trityl-glutamine, glutamine, N.sup.in -Boc-tryptophan, tryptophan, isoleucine, phenylalanine, glycine, alanine, valine, or leucine; --R.sup.10, with the proviso tha
REFERENCES:
patent: 5281585 (1994-01-01), Duggan et al.
Barany et al, JACS, vol. 107, No. 17, 1985, pp. 4936-4942.
Angelastro et al., Inhibition of Human Neutrophil Elastase with Peptidyl Electrophilic Ketones. 2. Orally Active P.sub.G -Val-Pro-Val Pentafluoroethyl Ketones, J. Med. Chem., 37(26) 4538-53, 1994.
Gubert, S. et al., Synthesis and Pharmacological Screening of New Angiotensin Converting Enzyme Inhibitors, Farmaco, 45(1), 59-79, 1990.
Ponticello et al., J. Med. Chem., 3.0, 591-597, 1987.
Brenner and Lerner, Proc. Natl. Acad. Sci., 8 9, 5381-5383, Jun. 1992.
Ohlmeyer et al., Proc. Nat'l. Acad. Sci. 9 0, 10922-10926, Dec. 1993.
Chen et al., J. Chem. Soc., 116, 2261-2262, 1994.
Baldwin John J.
Henderson Ian
Ohlmeyer Michael H. J.
Davis Zinna Northington
Pharmacopeia Inc.
LandOfFree
Process of preparing 3-nitro benzoate compounds in lower alkanol does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process of preparing 3-nitro benzoate compounds in lower alkanol, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process of preparing 3-nitro benzoate compounds in lower alkanol will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1962579