Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-07
2003-12-23
Baker, Maurie Garcia (Department: 1639)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C435S007100, C435S091500, C436S531000, C548S472000, C548S491000, C564S189000, C564S204000
Reexamination Certificate
active
06667406
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to methods of synthesizing libraries of diverse complex isoindole and isoquinoline compounds through the use of a facile intramolecular Diels Alder reaction. The invention is further directed to methods for synthesizing the libraries on solid supports. The invention is further directed to methods for identifying and isolating isoindole and isoquinoline compounds with useful and diverse activities from such libraries.
2. Background
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through molecular biology techniques or synthetic chemical techniques. Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels. Correlation of the labeled receptor bound to the substrate with its location on the substrate identifies the binding compound. Using these techniques, the development of efficient high throughput screening has greatly enhanced the pharmaceutical industry's ability to screen large numbers of compounds for biological activity.
Central to these methods is the screening of a multiplicity of compounds in the library and the ability to identify the structures of the compounds which have a requisite biological activity. Preferably, in order to facilitate synthesis and identification, the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm. In this regard, libraries of diverse compounds are prepared and then screened to identify “lead compounds” having good binding affinity to the receptor.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of the alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity. Thus libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e. those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.
Thus, the generation of chemical libraries on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.
Two particular classes of compounds which would be useful for inclusion in screening libraries are hexahydroisoindole and octahydroisoquinoline derivatives. These classes of compounds are known to possess diverse pharmacological and chemical properties and certain members of these classes of compounds are well known to possess biological activity. The following references, hereby incorporated by reference, report the biological activity of such chemical compounds:
Dondio, Giulio; Clarke, Geoffrey D.; Giardina, Giuseppe; Petrillo, Paola; Petrone, Giuseppe; Ronzoni, Silvano; Visentin, Luciano; Vecchietti, Vittorio. The role of the “spacer” in the octahydroisoquinoline series: Discovery of SB 213698, a non-peptidic, potent and selective delta opioid agonist. Analgesia (Elmsford, N. Y.) (1995), 1(4-6), 394-9. CODEN: AALGEB; ISSN: 1071-569X. CAN 124:134781
Clarke, Dondio G.; Giardina, G. D.; Petrillo, P.; Rapalli, L.; Ronzoni, S.; Vecchietti, V. Potent and selective non-peptidic delta opioid ligands based on the novel heterocycle-condensed octahydroisoquinoline structure. Regul. Pept. (1 994), (Suppl. 1), S43-S44. CODEN: REPPDY; ISSN: 0167-0115. CAN 120:260570
Judd, Duncan B.; Brown, Dearg S.; Lloyd, Jane E.; McElroy, Andrew B.; Scopes, David I. C.; Birch, Phillip J.; Hayes, Ann G.; Sheehan, Michael J. Synthesis, antinociceptive activity and opioid receptor profiles of substituted trans-3-(decahydro- and octahydro-4a-isoquinolinyl)phenols. J. Med. Chem. (1992), 35(1), 48-56. CODEN: JMCMAR; ISSN: 0022-2623. CAN 116:41268
Yamaguchi, Toshiaki; Yanagi, Takashi; Hokari, Hiroshi; Mukaiyama, Yuko; Kamijo, Tetsuhide; Yamamoto, Iwao. Preparation and optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229. Chem. Pharm. Bull. (1998), 46(2), 337-340. CODEN: CPBTAL; ISSN: 0009-2363. CAN 128:217248
Commercon, Alain; Lebrun, Alain; Mailliet, Patrick; Peyronel, Jean Francois; Sounigo, Fabienne; Truchon, Alain; Zucco, Martine; Cheve, Michel. New benzisoindole derivatives as inhibitors of farnesyl transferase, their preparation, and pharmaceutical compositions containing them. Fr. Demande, 96 pp. CODEN: FRXXBL. FR2736641 A1 19970117. CAN 127:95194
Hecker, Scott J.; Jefson, Martin R.; McFarland, James W. Preparation of derivatives of rosaramicin, repromicin, 5-mycaminosyltylonide, desmycosin, lactenocin, O-demethyllactenocin, cirramycin A1, and 23-deoxymycaminosyltylonide as antibacterials and antimycoplasmics. U.S., 22 pp. Cont.-in-part of U.S. Ser. No. 996,243, abandoned. CODEN: USXXAM. U.S. Pat. No. 5,545,624A 19960813. CAN 125:248316
Steiner, Gerd; Munschauer, Rainer; Unger, Liliane; Teschendorf, Hans-Juergen; Hoeger, Thomas. Preparation of N-substituted bridged 4,7,8,9-tetrahydroisoindoline derivatives as drugs. Ger. Offen., 6 pp. CODEN: GWXXBX. DE4341400 A1 19950608. CAN 123:285768
Kamijo, Tetsukyo; Yanagi, Takashi; Hokari, Hiroshi; Oda, Juko. Preparation of hexahydroisoindoline derivative as antidiabetic agent. Jpn. Kokai Tokkyo Koho, 6 pp. CODEN: JKXXAF. JP 06340622 A2 19941213 Heisei. CAN 122:213925
Kamijo, Tetsukyo; Yanagi, Takashi; Hokari, Hiroshi; Oda, Juko. Preparation of hexahydroisoindoline derivative as antidiabetic agent. Jpn. Kokai Tokkyo Koho, 6 pp. CODEN: JKXXAF. JP 06340623 A2 19941213 Heisei. CAN 122:187390
Ohnota, Hideki; Kobayashi, Miho; Koizumi, Takashi; Katsuno, Kenji; Sato, Fumiyasu; Aizawa, Toru. In vitro insulinotropic action of a new non-sulfonylurea hypoglycemic agent, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229), in rat pancreatic B-cells. Biochem. Pharmacol. (1995), 49(2), 165-71. CODEN: BCPCA6; ISSN: 0006-2952. CAN 122:96220
Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate libraries of diverse hexahydroisoindole and octahydroisoquinoline derivatives optionally attached to a solid support. There is thus a need for a facile in situ method for the generation of a multiplicity of reduced isoindole and isoquinoline compounds.
SUMMARY OF THE INVENTION
This invention is directed to general synthetic methods for preparing hexahydroisoindole, hexahydroisooxyindole and octahydroisooxyquinoline compounds on or off a solid support by employing a mild Diels Alder reaction for the in situ generation of the final compounds. The invention is further directed to the use of these methods to incorporate such reduced isoindole and isooxyquinoline groups in synthetic compound libraries and to libraries containing such compounds.
Hexahydroisoindole, hexahydroisooxyindole, and octahydroisooxyquinoline derivative libraries provided by this invention are synthesized by the Diels Alder cycloaddition reaction of amino acid derived novel triene precursors in accordance with the following general schemes:
wherein R
1
is a st
Murray William V.
Sun Sengen
Baker Maurie Garcia
Ortho-McNeil Pharmaceutical , Inc.
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