Triazole macrocycle systems

Patent metadata

Field	Value
Publication number	US-2016289274-A1
Application number	US-201615093426-A
Country	US
Kind code	A1
Filing date	Apr 7, 2016
Priority date	Feb 23, 2007
Publication date	Oct 6, 2016
Grant date	—

Abstract

The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production.

First claim

1 - 77 . (canceled)

78 . A method of synthesizing a peptidomimetic macrocycle, the method comprising:
(a) synthesizing a peptide that incorporates:
(i) an alkyne moiety; and
(ii) an amino acid moiety of the formula:

wherein:
R 2 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
each Q and T is independently selected from the group consisting of alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene and [—R 4 —K—R 4 —] n , each of which is unsubstituted or substituted with R 5 ;
each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroalkylalkyl, or heterocycloalkyl;
R 10 and R 11 are independently —H or any protecting group suitable for peptide synthesis;
g and h are each independently an integer from 0 to 5;
n is an integer from 1 to 5; and
(b) macrocyclizing the peptide.

79 . The method of claim 78 , wherein the peptidomimetic macrocycle comprises an additional macrocycle.

80 . The method of claim 78 , wherein R 2 is hydrogen.

81 . The method of claim 78 , wherein R 2 is methyl.

82 . The method of claim 78 , wherein the peptidomimetic macrocycle comprises an α-helix.

83 . The method of claim 82 , wherein the α-helix comprises from 1 turn to 5 turns.

84 . The method of claim 78 , wherein the peptidomimetic macrocycle comprises a ring of about 29 atoms to about 37 atoms.

85 . The method of claim 78 , wherein the method is performed in solution.

86 . The method of claim 78 , wherein the method is performed on a solid support.

87 . The method of claim 78 , wherein the peptidomimetic macrocycle comprises two macrocycle-forming linkers.

88 . The method of claim 87 , wherein the length of one of the macrocycle-forming linkers spans about 1 turn of a secondary structure of the peptidomimetic macrocycle.

89 . The method of claim 87 , wherein the length of one of the macrocycle-forming linkers is about equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.

90 . The method of claim 87 , wherein the length of one of the macrocycle-forming linkers is about equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.

91 . The method of claim 87 , wherein the peptidomimetic macrocycle comprises a ring of about 18 atoms to 26 atoms.

Assignees

• Aileron Therapeutics Inc

Inventors

• Nash Huw M

Classifications

• C07K4/00

  Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof · CPC title

• C07K1/006 Primary

  of peptides containing derivatised side chain amino acids · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• C07K1/1075

  by covalent attachment of amino acids or peptide residues · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title