Chiral compounds of varying conformational rigidity and methods of synthesis

Patent metadata

Field	Value
Publication number	US-2018371014-A1
Application number	US-201815972619-A
Country	US
Kind code	A1
Filing date	May 7, 2018
Priority date	Sep 7, 2011
Publication date	Dec 27, 2018
Grant date	—

Abstract

Synthesis of compounds having varying degrees of conformational rigidity is obtained via a low cost, high yield and efficient synthetic reactions. The library of compounds is structurally diverse, having at least one or more chiral centers and providing large numbers of compounds having building block diversity and substantial scaffold diversity. The compounds further provide a novel method for obtaining candidate therapeutic agents for prevention, treatment or diagnosis of diseases.

First claim

What is claimed:

1 . A method of synthesizing a chiral monomer comprising:
obtaining a stereodefined allylic alcohol via a stereoselective aldol reaction or a related transformation reaction and proceeding via stereoselective allylic transposition of the resulting allylic alcohol; and converting the resulting rearranged product to a chiral acid having a general structure of Formula I′:

2 . The method of claim 1 , wherein R 1 and R 2 comprise a molecular architecture compatible with the synthesis of Formula I′ or introduced after synthesis of a central pentenoic acid of Formula I′.

3 . The method of claim 1 , wherein two or more monomers of Formula I′ are optionally oligomerized, the oligomerization of Formula I′ proceeding via a 1- or 2-directional homologation or functionalization of Formula I′.

4 . The method of claim 3 , wherein X and Y comprise any molecule compatible with the oligomerization of Formula I′.

5 . The method of claim 2 , wherein an oligomer or polymer of Formula I′ comprises homogeneous monomers, heterogeneous monomers or combinations thereof.

6 . A compound comprising a monomer set forth in Formula I:

wherein, X and Y comprise any molecular motifs or functional groups compatible with oligomerization of two or more monomers of Formula I.

7 . The compound of claim 6 , wherein an oligomeric compound comprises at least two or more monomers represented by Formula I comprising a chiral center in an R configuration, an S configuration or multiple combinations thereof.

8 . The compound of claim 6 , wherein the monomer of Formula I is a pentenoic amide.

9 . The compound of claim 8 , wherein the pentenoic amide is a central N-substituted 5-amino-2, 4-dialkyl-3-pentenoic amide.

10 . The compound of claim 6 , wherein a monomer of Formula I comprises substitutions which maintain conformational control about a β, γ-unsaturated carbonyl and minimize allylic strain.

11 . The compound of claim 6 , wherein monomers or oligomers of Formula I comprise substitutions having varying degrees of flexibility imparted by monomers comprising the backbone.

12 . The compound of claim 6 , wherein uni- or bidirectional functionalization of Formula I produces a higher molecular weight compound comprising Formula I having a structure whereby conformation is controlled by minimization of A-1,3 strain inherent to a substituted β,γ-unsaturated carbonyl.

13 . The compound of claim 12 , wherein the higher molecular weight compound of Formula I comprises oligomers having repeating units of Formula I and/or repeating monomers of Formula I having different substitutions R 1 and R 2 , wherein R 1 and R 2 comprise any molecular architecture capable of forming a bond with the monomers or oligomers of Formula I.

14 . The compound of claim 13 , wherein R 1 and R 2 independently comprise OR 3 , NHR 4 , NR 4 R 5 , halide, alkyl, linear alkyl, branched alkyl, heteroatom-substituted alkyl, unsaturated and polyunsaturated linear and branched hydrocarbons, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl, heteroatom-substituted unsaturated and polyunsaturated linear and branched hydrocarbons, cycloalkyl, heteroatom-substituted cycloalkyl, saturated and unsaturated heterocycles, substituted cycloalkyl, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic; R 3 independently comprises H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; and, R 4 independently comprises H, OR 3 , alkyl, aryl, or heteroaryl.

15 . The compound of claim 6 , wherein X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3 independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4 independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1 independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2 independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X.

16 . A method of identifying a candidate therapeutic agent, comprising:
screening a library comprising one or more monomers, oligomers, or polymers of Formula I:

contacting a biological sample, cell, tissue, or molecule in solution or attached to a solid or semi-solid support, with a compound of Formula I;
assaying for any desired therapeutic effects; and,
identifying a candidate therapeutic agent.

17 . The method of claim 16 , wherein for Formula I: X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl; R 3 independently comprises amide, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; R 4 independently comprises H, OR 4 , alkyl, aryl, heteroaryl; *C is a chiral center [(R) or (S)]; R 1 independently comprises alkyl, aryl, heteroaryl, alkenyl, OR 4 ; R 2 independently comprising alkyl, cycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, heterocycloalkyl; Y independently comprises a halide, NHR 4 , NR 4 R 5 , OH, OR 3 , or C(O)X.

18 . The method of claim 16 , wherein desired therapeutic effects comprise: tumor cell death, inhibition of viral replication, cytolysis of virally infected cells, modulation of receptors, modulation of growth factors, modulation of cytokines, modulation of cellular factors, modulation of immune cells, anti-bacterial effects, anti-parasitic effects or combinations thereof.

19 . A pharmaceutical composition comprising a compound having a structure of Formula I:

20 . The pharmaceutical composition of claim 19 , wherein X and Y comprise any molecular motif or functional group compatible with oligomerization of two or more monomers of Formula I.

21 . The pharmaceutical composition of claim 19 , wherein R 1 and R 2 comprise any molecular architecture capable of forming a bond with monomers or oligomers of Formula I.

22 . The pharmaceutical composition of claim 21 , wherein R 1 and R 2 independently comprise OR 3 , NHR 4 , NR 4 R 5 , halide, alkyl, linear alkyl, branched alkyl, heteroatom-substituted alkyl, unsaturated and polyunsaturated linear and branched hydrocarbons, alkenyl, cycloalkyl, aryl, heteroaryl, heteroaryl, heterocycloalkyl, heteroatom-substituted unsaturated and polyunsaturated linear and branched hydrocarbons, cycloalkyl, heteroatom-substituted cycloalkyl, saturated and unsaturated heterocycles, substituted cycloalkyl, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic; R 3 independently comprises H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, NR 4 R 5 , carboxyl, heterocycloalkyl; and, R 4 independently comprises H, OR 3 , alkyl, aryl, or heteroaryl.

23 . The pharmaceutical composition of claim 19 , wherein X independently comprises OR 3 , NHR 4 , NR 4 R 5 , H, halide, alkyl, alkenyl, cycloalky

Assignees

• Scripps Research Inst

Inventors

• Micalizio Glenn C
• Kodadek Thomas
• Sarkar Mohosin

Classifications

• A61K31/19 Primary

  Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C57/52

  containing halogen · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07K5/08 Primary

  Tripeptides · CPC title