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US 2026/0294826 A1Published application
Spleen-targeted lipid nanoparticles
AssigneesBeijing Jitai Pharmaceutical Technology Co., Ltd., Hangzhou Jitai Pharmaceutical Technology Co., Ltd.
InventorsZhuorui SUN, Shaoli LIU, Andong LIU, Lin ZHANG, Feng SHI, Shuaibo SHAO, Jeffrey Michael WARRINGTON
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Abstract
The present application relates to lipid nanoparticles comprising steroid compound, as well as the preparation and uses of such lipid nanoparticles. Such lipid nanoparticles are useful in the delivery of payloads, such as nucleic acids, in vivo to non-hepatic organs (e.g., spleen) for the treatment or prevention of certain diseases or disorders, particularly spleen diseases.
Claims63
A lipid nanoparticle comprising an ionizable lipid and a steroid compound, wherein the steroid compound is a compound of formula (I):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- is a single bond or double bond;
- Y is —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2—, —C(O)NR2—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2—, —NR2aC(O)NR2—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2—, —C(O)NR2—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
- m is an integer from 1 to 12;
- m1 is an integer from 0 to 12;
- V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- L2b is absent or optionally substituted C1-10 alkylene;
- each instance of R2b, R′2b and R″2b are independently H or C1-8 alkyl;
- Rz1 is C1-14 alkyl or C1-14 alkenyl, wherein the alkyl and alkenyl are optionally substituted;
- and
- provided that when Y is —NHC(O)—, at least one of the following conditions are met:
- (i) m is an integer from 5 to 12;
- or
- (ii) V1 is not N(CH3)2.
16 more elements
A lipid nanoparticle comprising an ionizable lipid and a steroid compound, wherein the steroid compound is a compound of formula (I-P):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- is a single bond or double bond;
- Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, —S(O)0-2—, or —OPO3—, and wherein the attachment to the left is to the direction of V1;
- each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
- R205 is absent, a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein the alkyl, the haloalkyl, the alkenyl, and the alkynyl are optionally substituted;
- m is an integer from 1 to 12;
- m1 is an integer from 0 to 12;
- V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- L2b is absent or optionally substituted C1-10 alkylene;
- each instance of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- and
- Rz1 is C1-4 alkyl or C1-4 alkenyl, wherein the alkyl and alkenyl are optionally substituted.
12 more elements
A lipid nanoparticle comprising an ionizable lipid and a steroid compound, wherein the steroid compound is:
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
A steroid compound of formula (II-A):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- each is independently a single bond or double bond;
- Y is —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, or -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
- m is an integer from 3 to 12;
- m1 is integer from 0 to 12;
- V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- L2b is absent or optionally substituted C1-10 alkylene;
- each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- and
- Rz1 is C1-14 alkyl or C1-14 alkenyl, wherein the alkyl and alkenyl are optionally substituted;
- and provided that the compound is not:
13 more elements
A steroid compound of formula (II-B):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- Y is —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, or —S(O)0-2—, and wherein the attachment to the left is to the direction of V1;
- each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, or -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
- m is an integer from 5 to 12;
- m1 is integer from 0 to 12;
- V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- L2b is absent or optionally substituted C1-10 alkylene;
- and
- each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- preferably, Y1 is —C(O)O—, —OC(O)—, —O—, —S—, —NR2a—, —OC(O)NR2a—, or —NR2aC(O)—.
11 more elements
A steroid compound of formula (I-P):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- is a single bond or double bond;
- Y1 is absent, —C(O)O—, —O—, —NH—, —SC(O)O—, —OC(O)NR2a—, —NR2aC(O)NR2a—, —OC(O)S—, —OC(O)O—, —NR2aC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR2a—, —C(O)NR2a—, —NR2aC(O)—, —NR2aC(O)S—, —SC(O)NR2a—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR2a—, —NR2aC(S)O—, —S(O)0-2—, or —OPO3—, and wherein the attachment to the left is to the direction of V1;
- each instance of R2a is independently H, C1-10 alkyl, C3-14 cycloalkyl, or 3 to 14-membered heterocyclyl, and wherein the alkyl, cycloalkyl, and heterocyclyl are independently optionally substituted with C1-10 alkyl, L2b-OR2b, Lb-SR2b, L2b-NR2bR′2b, L2bN+R2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- each instance of R201, R202, R203, R204 are independently H, OH, alkyl, alkoxy, -L2b-NR21R22, -L2b-N+R21R22R23, L2b-OC(O)R21, or L2b-C(O)OR21;
- R205 is absent, a cation, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein the alkyl, haloalkyl, alkenyl, and alkynyl are optionally substituted;
- m is an integer from 1 to 12;
- m1 is an integer from 0 to 12;
- V1 is NR21R22, N+R21R22R23, imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, (iso)thiazole, (iso)oxazole, oxadiazine, oxazoline, dithiourazole, (iso)triazole, tetrazole, pentazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinolinone, (iso)quinoline, amidine, guanidine, or urea;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR′2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- L2b is absent or optionally substituted C1-10 alkylene;
- each instance of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- and
- Rz1 is C1-14 alkyl or C1-14 alkenyl, wherein the alkyl and alkenyl are optionally substituted.
12 more elements
A steroid compound of formula (II-C1):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- Rz1 is
- R2a is H, optionally substituted C1-8 alkyl, -L2b-OR2b, L2b-OC(O)R2b, or L2b-C(O)OR2b, preferably H, —CH3, —CH2C(O)OCH3, or —CH2C(O)OH;
- V1 is NR21R22 or N+R21R22R23, wherein each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- provided that R21 and R22 are not both hydrogen;
- L2b is absent or optionally substituted C1-10 alkylene;
- each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- and
- m is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
7 more elements
A steroid compound of formula (II-C2):
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
- Rz1 is
- V1 is NR21R22 or N+R21R22R23, wherein each instance of R21, R22, R23 are independently H, optionally substituted C1-8 alkyl, -L2b-OR2b, -L2b-SR2b, -L2b-NR2bR′2bR″2b, L2b-OC(O)R2b, or L2b-C(O)OR2b;
- provided that R21 and R22 are not both hydrogen.
- L2b is absent or optionally substituted C1-10 alkylene;
- each of R2b, R′2b and R″2b are independently H or C1-10 alkyl;
- and
- M is absent or one or more anions independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, triflate, trifluoroacetate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoates, oxalate, malonate, succinate, fumarates, maleate, benzoates, phthalates, phenylacetate, lactate, glycolate, tartrate, mandelate, mesylate, gluconate, aspartate, or glutamate;
- and
- m is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
7 more elements
A steroid compound, which is:
- or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.