Triazole macrocycle systems

Patent metadata

Field	Value
Publication number	US-2016304564-A1
Application number	US-201615093869-A
Country	US
Kind code	A1
Filing date	Apr 8, 2016
Priority date	Feb 23, 2007
Publication date	Oct 20, 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 peptidomimetic macrocycle that incorporates:
(a) a crosslink between two amino acids; (b) an alkyne moiety; and (c) 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; and
n is an integer from 1 to 5.

79 . The peptidomimetic macrocycle of claim 78 , wherein R 2 is hydrogen.

80 . The peptidomimetic macrocycle of claim 78 , wherein R 2 is methyl.

81 . The peptidomimetic macrocycle of claim 78 , wherein a secondary structure of the peptidomimetic macrocycle is more stable than a corresponding secondary structure of a corresponding non-macrocyclic polypeptide.

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

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

84 . The peptidomimetic macrocycle of claim 82 , wherein the α-helix is more stable than an α-helix of a corresponding non-macrocyclic polypeptide.

85 . The peptidomimetic macrocycle of claim 82 , wherein the α-helix comprises about 2 turns.

86 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle has an α-helical secondary structure, and the peptidomimetic macrocycle is more stable than a corresponding α-helical secondary structure of a corresponding non-macrocyclic polypeptide.

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

88 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle comprises an α-helix in aqueous solution.

89 . The peptidomimetic macrocycle of claim 88 , wherein the peptidomimetic macrocycle exhibits increased α-helical structure in aqueous solution compared to a corresponding non-macrocyclic polypeptide.

90 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle exhibits increased thermal stability compared to a corresponding non-macrocyclic polypeptide.

91 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle exhibits increased biological activity compared to a corresponding non-macrocyclic polypeptide.

92 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle exhibits increased resistance to proteolytic degradation compared to a corresponding non-macrocyclic polypeptide.

93 . The peptidomimetic macrocycle of claim 78 , wherein the peptidomimetic macrocycle exhibits increased ability to penetrate living cells compared to a corresponding non-macrocyclic polypeptide.

94 . The peptidomimetic macrocycle of claim 82 , wherein the crosslink spans from 1 turn to 5 turns of the α-helix.

95 . The peptidomimetic macrocycle of claim 82 , wherein the crosslink spans approximately 1, 2, 3, 4, or 5 turns of the α-helix.

96 . The peptidomimetic macrocycle of claim 82 , wherein the length of the crosslink is about 5 Å to about 9 Å per turn of the α-helix.

97 . The peptidomimetic macrocycle of claim 78 , wherein the length of the crosslink spans approximately 1 turn of a secondary structure of the peptidomimetic macrocycle.

98 . The peptidomimetic macrocycle of claim 97 , wherein the length of the crosslink is about equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.

99 . The peptidomimetic macrocycle of claim 97 , wherein the length of the crosslink is about equal to the length of from about 8 carbon-carbon bonds to about 12 carbon-carbon bonds.

100 . The peptidomimetic macrocycle of claim 97 , wherein the macrocycle comprises a ring of about 18 atoms to 26 atoms.

Assignees

• Aileron Therapeutics Inc

Inventors

• Nash Huw M

Classifications

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K1/1075

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

• C07K14/4748

  Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE · CPC title

• C07K7/56

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