Aminobenzenedicarboxylic acid-based combinatorial libraries

• US 6,127,191 A
• Filed: 11/26/1997
• Issued: 10/03/2000
• Est. Priority Date: 12/03/1996
• Status: Expired due to Term

• Current Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Subasinghe, Nalin, Wu, Zhengdong, Graybill, Todd L., Salvino, Joseph M., Fedde, Cynthia L.
• Primary Examiner(s): Celsa, Bennett
• Assistant Examiner(s): Ricigliano, Joseph W.
• Application Number:
  US08/980,062
• Time in Patent Office: 1,042 Days
• Field of Search: 562/493, 560/8, 564/305, 435/DIG. 34, 435/DIG. 40, 436/518
• US Class Current: 506/30
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 279/14 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/44 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 335/22 being further substituted by carboxyl groups
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/15 to an acyclic saturated chain
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• CPC Class Codes: C40B 40/04 Libraries containing only organic compounds
• CPC Class Codes: C40B 50/14 Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support

Abstract

The present invention provides a library of compounds, each comprised of a common aminobenzenedicarboxylic acid core structure (scaffold) that serves as a template for synthesizing approximately 10¹ -10⁶ compounds which are analogs of the scaffold. The library is employed to study ligand binding by biological receptors, such as enzymes, G-protein coupled receptors and membrane channels. For example, certain individual compounds within the library selectively bind and inhibit the action of trypsin-like serine proteases. The present invention also relates to combinatorial synthetic methods for making such libraries of compounds. Additionally, the present invention relates to novel scaffold-modified solid supports, particularly scaffold-modified polymer resins and methods for preparing said resins. Further, the present invention is directed to methods for screening a compound or plurality of compounds made according to the synthetic methods disclosed herein, which comprise using the compounds in suitable assays developed for detecting the compounds'"'"' utility as pharmaceutical agents.

Claims

1. A composition of matter, comprising

a solid support material having a plurality of pendant scaffold moieties covalently attached thereto, wherein said scaffold moieties have the formula:

##STR122## where Y'"'"' is nitro;

Z'"'"' is hydrogen or a suitable carboxylic acid protecting group; and

represents the attachment point of the scaffold moiety to the solid support material, wherein said attachment is either directly to the solid support material or via a cleavable linker.

2. The composition of claim 1, wherein;

and Z'"'"' is trialkylsilyl, alkyl, alkenyl, aryl or aralkyl, any of which is optionally substituted.

3. The composition of claim 1, wherein Z'"'"' is methyl.

4. In a solid phase support material useful for the synthesis of organic compounds, wherein said solid phase support originally has a plurality of protected or free pendant amino or hydroxy groups, the improvement comprising one or more scaffold moieties having the formula:

##STR123## where Y is nitro and Z is hydrogen or a suitable carboxylic acid protecting group; and

wherein said scaffold moieties are covalently attached to one or more of said amino or hydroxy groups via an amide or ester linkage.

5. A method for preparing one or more solid support-bound compounds said method comprising the steps of:

(a) attaching a plurality of scaffold structures of the formula;

##STR124## where Y is nitro and Z is a suitable carboxylic acid protecting group to one or more polymeric resin supports by reacting the carboxylic acid functional group of said scaffold with pendant amino or hydroxy groups on said polymeric resin supports to form a plurality of resin-bound scaffolds;

(b) reducing said one or more nitro groups to one or more amino groups;

(c) optionally converting the one or more amino groups at position Y of said resin bound scaffolds to functional groups selected from isocyanato and isothiocyanato;

(d) reacting one or more appropriate organic compounds selected from the group consisting of acid chlorides, sulfonyl chlorides, primary and secondary amines and alcohols, with the amino, isocyanato or isothiocyanato group at position Y on the scaffold molecules whereby the functional group of said one or more organic compounds chemically reacts with the amino, isocyanato or isothiocyanato groups on said scaffold molecules; and

(e) hydrolyzing the carboxylic acid ester attached to said one or more resin-bound intermediates and reacting the resulting de-esterified intermediates with at least one primary or secondary amine to form said one or more resin-bound compounds.

6. The method of claim 5, further comprising the step of cleaving said one or more resin bound compounds from said one or more polymeric resins.