Compounds and compositions for intracellular delivery of agents

Patent metadata

Field	Value
Publication number	US-2018369419-A1
Application number	US-201616065067-A
Country	US
Kind code	A1
Filing date	Dec 22, 2016
Priority date	Dec 22, 2015
Publication date	Dec 27, 2018
Grant date	—

Abstract

The disclosure features amino lipids and compositions involving the same. Nanoparticle compositions include an amino lipid as well as additional lipids such as phospholipids, structural lipids, PEG lipids, or a combination thereof. Nanoparticle compositions further including therapeutic and/or prophylactic agents such as RNA are useful in the delivery of therapeutic and/or prophylactic agents to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

First claim

What is claimed is:

1 . A compound having one of the formulae (I), (Ib), or (III):

or a salt or isomer thereof, wherein
ring A is

t is 1 or 2;
A 1 and A 2 are each independently selected from CH or N;
A 3 is CH or N;
A 4 is CH 2 or NH; and at least one of A 3 and A 4 is N or NH;
A 6 and A 7 are each independently selected from CH or N, wherein at least one of A 6 and A 7 is N;
Z is CH 2 or absent wherein when Z is CH 2 , the dashed lines (1) and (2) each represent a single bond; and when Z is absent, the dashed lines (1) and (2) are both absent;
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of C 5-20 alkyl, C 5-20 alkenyl, —R″MR′, —R*YR″, —YR″, and —R*OR″;
each M is independently selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O) 2 —, an aryl group, and a heteroaryl group;
X 1 , X 2 , and X 3 are independently selected from the group consisting of a bond, —CH 2 —, —(CH 2 ) 2 —, —CHR—, —CHY—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—CH 2 —, —CH 2 —C(O)—, —C(O)O—CH 2 —, —OC(O)—CH 2 —, —CH 2 —C(O)O—, —CH 2 —OC(O)—, —CH(OH)—, —C(S)—, and —CH(SH)—;
X 4 and X 5 are independently selected from the group consisting of —CH 2 —, —(CH 2 ) 2 —, —CHR—, —CHY—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—CH 2 —, —CH 2 —C(O)—, —C(O)O—CH 2 —, —OC(O)—CH 2 —, —CH 2 —C(O)O—, —CH 2 —OC(O)—, —CH(OH)—, —C(S)—, and —CH(SH)—;
each Y is independently a C 3-6 carbocycle;
each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;
each R is independently selected from the group consisting of C 1-3 alkyl and a C 3-6 carbocycle;
each R′ is independently selected from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, and H; and
each R″ is independently selected from the group consisting of C 3-12 alkyl and C 3-12 alkenyl,
wherein when the compound is of Formula (I), and
ring A is

then
i) at least one of X 1 , X 2 , and X 3 is not —CH 2 —; and/or
ii) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is —R″MR′; or
wherein when the compound is of Formula (I) and ring A is

and X 1 ,
X 2 , and X 3 are each —CH 2 —, then
R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of C 6-20 alkyl and C 6-20 alkenyl and
when ring A is

then
i) R 1 , R 2 , R 3 , R 4 , and R 5 are the same, wherein R 1 is not C 12 alkyl, C 18 alkyl, or C 18 alkenyl;
ii) only one of R 1 , R 2 , R 3 , R 4 , and R 5 is selected from C 6-20 alkenyl;
iii) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 have a different number of carbon atoms than at least one other of R 1 , R 2 , R 3 , R 4 , and R 5 ;
iv) R 1 , R 2 , and R 3 are selected from C 6-20 alkenyl, and R 4 and R 5 are selected from C 6-20 alkyl; or
v) R 1 , R 2 , and R 3 are selected from C 6-20 alkyl, and R 4 and R 5 are selected from C 6-20 alkenyl.

2 .- 88 . (canceled)

89 . The compound of claim 1 , being of formula (IIa):

90 .- 125 . (canceled)

126 . The compound of claim 1 being of formula (IIIa):

127 .- 140 . (canceled)

141 . A compound of claim 1 , wherein the compound is a compound having the formula (Ib) and wherein
each M is independently selected from the group consisting of —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O) 2 —, an aryl group, and a heteroaryl group.

142 .- 150 . (canceled)

151 . A compound having the formula (17-I) or (19-I):

or salt or isomer thereof, wherein
R 1a is —(CH 2 ) n a Q a , where Q a is selected from a heterocycle, —OR a , —O(CH 2 ) n a N(R a ) 2 , —C(O)OR a , —OC(O)R a , —CX a 3 , —CX a 2 H, —CX a H 2 , —CN, —N(R a ) 2 , —C(O)N(R a ) 2 , —N(R a )C(O)R a , and —N(R a )S(O) 2 R a and each n a is independently selected from 1, 2, 3, 4, and 5;
R 2a and R 3a are each independently selected from the group consisting of C 3-24 alkyl, C 3-24 alkenyl, —R a *Y a R a ″, —Y a R a ″, and —R a *OR a ″;
each Y a is independently a C 3-6 carbocycle;
each R a * is independently selected from the group consisting of C 1-12 alkyl and C 1-12 alkenyl;
each X a is independently selected from the group consisting of F, Cl, Br, and I;
each R a is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H; and
each R a ″ is selected from the group consisting of C 3-12 alkyl and C 3-12 alkenyl;
wherein R 2a includes 7 or fewer carbon atoms;
R 1b is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl, —R b ″M b R b ′, a C 3-6 carbocycle, —(CH 2 ) n Q b , and —(CH 2 ) n CHQ b R b , where Q b is selected from a heterocycle, —OR b , —O(CH 2 ) n N(R b ) 2 , —C(O)OR b , —OC(O)R b , —CX b 3 , —CX b 2 H, —CX b H 2 , —CN, —N(R b ) 2 , —C(O)N(R b ) 2 , —N(R b )C(O)R b , and —N(R b )S(O) 2 R b and each n is independently selected from 1, 2, 3, 4, and 5;
R 2b and R 3b are independently selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, —R b ″M b R b ′, —R b *Y b R b ′, —Y b R b ″ and —R b *OR b ″;
each M b is independently selected from the group consisting of —C(O)O—, —OC(O)—, —C(O)N(R b ′)—, —N(R b ′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR b ′)O—, —S(O) 2 —, an aryl group, and a heteroaryl group;
W is selected from the group consisting of —CH 2 —, —CHR b —, —C(O)—, —CH(OH)—, —C(S)—, and —CH(SH)—;
each X b is independently selected from the group consisting of F, Cl, Br, and I;
each Y b is independently a C 3-6 carbocycle;
each R b * is independently selected from the group consisting of C 1-12 alkyl and C 1-12 alkenyl;
each R b is independently selected from the group consisting of C 1-3 alkyl, a C 3-6 carbocycle, C 2-3 alkenyl, and H;
each R b ′ is independently selected from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, and H; and
each R b ″ is independently selected from the group consisting of C 3-12 alkyl and C 3-12 alkenyl.

152 .- 153 . (canceled)

154 . A compound of claim 151 , wherein the compound is a compound having the formula (17-I), and wherein
R 2a is selected from the group consisting of C 8-24 alkenyl; and R 3a is selected from the group consisting of C 8-24 alkyl.

155 .- 161 . (canceled)

162 . A compound of claim 151 , wherein the compound is a compound having the formula (17-I), and wherein
R 2a is selected from the group consisting of C 13-20 alkyl; and R 3a is selected from the group consisting of C 8-20 alkyl.

163 .- 166 . (canceled)

167 . A compound of

Assignees

• Modernatx Inc
• Moderna Tx Inc

Inventors

• Benenato Kerry E
• Butcher William

Classifications

• A61P37/06

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title