Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-2017165290-A1
Application number	US-201615340082-A
Country	US
Kind code	A1
Filing date	Nov 1, 2016
Priority date	Oct 27, 2011
Publication date	Jun 15, 2017
Grant date	—

Abstract

Described herein are compounds and compositions characterized, in certain embodiments, by conjugation of various groups, such as lipophilic groups, to an amino or amide group of an amino acid, a linear or cyclic peptide, a linear or cyclic polypeptide, or structural isomer thereof, to provide compounds of the present invention, collectively referred to herein as “APPLs”. Such APPLs are deemed useful for a variety of applications, such as, for example, improved nucleotide delivery. Exemplary APPLs include, but are not limited to, compounds of Formula (I), (II), (III), (IV), (V), and (VI), and salts thereof, as described herein:

wherein m, n, p, R′, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , Z, W, Y, and Z are as defined herein.

First claim

1 . A method of delivering a polynucleotide to a cell, the method comprising contacting a composition comprising a polynucleotide and a compound of Formula (III):

or salt thereof, with the cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the cell;
wherein:
p is an integer of between 1 and 9, inclusive;
each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), (iii);
each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, —OR A1 , —N(R A1 ) 2 , —SR A1 , or a group of formula (iv); wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring,
provided at least one instance of R 1 is a group of formula:

L is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
R 6 and R 7 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
each instance of R 2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
Formulae (i), (ii), and (iii) are:

wherein each instance of formula (i) is independently formula (i-a) or formula (i-b):

each instance of R′ is independently hydrogen or optionally substituted alkyl;
X is O, S, or NR X , wherein Rx is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
Y is O, S, or NR Y , wherein R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
R P is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
R L is optionally substituted C 6-50 alkyl, optionally substituted C 6-50 alkenyl, optionally substituted C 6-50 alkynyl, optionally substituted heteroC 6-50 alkyl, optionally substituted heteroC 6-50 alkenyl, optionally substituted heteroC 6-50 alkynyl, or a polymer;
provided that at least one instance of R Q , R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii).

2 . (canceled)

3 . The method of claim 1 , wherein each instance of Q is O.

4 . The method of claim 1 , wherein at least one instance of R 2 is hydrogen.

5 . The method of claim 1 , wherein each instance of R 1 is a group of formula (iv).

6 . The method of claim 1 , wherein L is an optionally substituted alkylene.

7 . The method of claim 1 , wherein the group of formula (iv) is of formula:

wherein q is an integer between 1 and 50, inclusive.

8 - 10 . (canceled)

11 . The method of claim 1 , wherein the compound is selected from the group consisting of:

and salts thereof,
wherein:
R 1 is selected from the group consisting of —H, —CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH(CH 3 ) 2 ,

provided at least one R 1 is a group of formula:

and
R 6 and R 7 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, and a group of formula (i), (ii), or (iii).

12 . The method of claim 1 , wherein the compound is selected from the group consisting of:

Assignees

• Massachusetts Inst Technology

Inventors

• Dong Yizhou
• Love Kevin Thomas
• Langer Robert S
• Anderson Daniel Griffith
• Chen Delai
• Chen Yi
• Vegas Arturo Jose
• Alabi Akinleye C
• Zhang Yunlong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title