EP-4735450-A1 - DIANHYDROHEXITOL BASED IONIZABLE LIPIDS FOR NUCLEIC ACID DELIVERY

EP4735450A1EP 4735450 A1EP4735450 A1EP 4735450A1EP-4735450-A1

Abstract

The present invention provides, in part, dianhydrohexitol-based cationic lipids of Formula (I), and sub-formulas thereof: (I), or a pharmaceutically acceptable salt thereof. The present invention also provides, in part, dianhydrohexitol-based cationic lipids of Formula (II), and sub-formulas thereof: (II), or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.

Inventors

DASARI, RAMESH
DENG, HONGFENG
KARMAKAR, Saswata
KARVE, Shrirang
VAIDYA, Amita
NYAMKONDIWA, Kudzai

Assignees

Sanofi Pasteur, Inc.

Dates

Publication Date: 20260506
Application Date: 20240628

Claims (1)

CLAIMS WHAT IS CLAIMED IS: 1. A compound having a structure according to Formula (I): or a pharmaceutically acceptable salt thereof wherein: A 1 is selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O)O-, - SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the left hand side of each recited structure is bound to the -(CH 2 ) a -; Z 1 is selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, - NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the right hand side of each recited structure is bound to the -(CH 2 ) a -; each R is independently selected from: (i) , wherein each R 1 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; (ii) , wherein each R 2 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and AAf-X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, - (*C=O)-O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and - (*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; (iii) , wherein each R 3 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (iv) , wherein each R 4 is independently selected from optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; wherein at least three R are independently selected from ( each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10; and each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10. 2. The compound of claim 1, wherein the compound has a structure according to Formula (IBla): or a pharmaceutically acceptable salt thereof, wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is independently selected from 3 or 4. 3. The compound of claim 1, wherein the compound has a structure according to Formula (IBlb): or a pharmaceutically acceptable salt thereof, wherein each R 1A , R 1B , R 1C and R 1D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein i) each a is 2, and/or ii) each b is independently selected from 5 or 7. 4. The compound of claim 1, wherein the compound has a structure according to Formula (IBlc): or a pharmaceutically acceptable salt thereof, wherein each R 3A , R 3B , R 3C and R 3D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein i) each a is 3, and/or ii) each c is 6. 5. The compound of claim 1, wherein the compound has a structure according to Formula (IB2a): or a pharmaceutically acceptable salt thereof, wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is independently selected from 3 or 4. 6. The compound of claim 1, wherein the compound has a structure according to Formula (ICla): or a pharmaceutically acceptable salt thereof, wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is independently selected from 3 or 4. 7. The compound of claim 1, wherein the compound has a structure according to Formula (IClb): or a pharmaceutically acceptable salt thereof, wherein each R 1A , R 1B , R 1C and R 1D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein each a is 2, and/or ii) each b is independently selected from 5 or 7. 8. The compound of claim 1, wherein the compound has a structure according to Formula (IC2a): or a pharmaceutically acceptable salt thereof, wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is 3. 65. The compound of claim 1, wherein the compound of Formula (I) has a structure according or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from: , wherein each R 1 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; wherein each R 2 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; , wherein each R 3 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein (i) each a is 3 or 4 and/or (ii) each b is 5, 6, or 7. (b) Formula (ID2): or a pharmaceutically acceptable salt thereof, wherein each R 1A , R 1B , R 1C and R 1D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein (i) each a is 4, and/or (ii) each b is independently selected from 5 or 7. (c) Formula (IE1): or a pharmaceutically acceptable salt thereof, wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is 3 or 4. (d) Formula (IE2): or a pharmaceutically acceptable salt thereof, wherein d is 0 or 1, and wherein each R 2A , R 2B , R 2C and R 2D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X 1 , wherein each W 1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 ; optionally wherein each a is 3 or 4. 10. A compound having a structure according to Formula (II): CD or a pharmaceutically acceptable salt thereof wherein: each R is independently selected from: (i) , wherein each R 1 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (ii) 0 , wherein each R 3 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and each c is independently selected from 2, 3, 4, 5, 6, and 7. 11. The compound of claim 10, wherein the compound has a structure according to Formula or a pharmaceutically acceptable salt thereof, wherein each R 3A , R 3B , R 3C and R 3D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl. 12. The compound of claim 10, wherein the compound has a structure according to Formula or a pharmaceutically acceptable salt thereof, wherein each R 1A , R 1B , R 1C and R 1D is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl. 13. A composition comprising the cationic lipid of any one of claims 1-12, and further comprising: (i) one or more non-cationic lipids, (ii) one or more cholesterol-based lipids, and (iii) one or more PEG-modified lipids, optionally wherein the composition is a lipid nanoparticle, for example, a liposome. 14. The composition of claim 13, wherein the lipid nanoparticle encapsulates an mRNA encoding a peptide or protein, optionally for use in a vaccine. 15. The composition of claim 14 for use in therapy. 16. The composition of claim 14 for use in a method of treating or preventing a disease amenable to treatment or prevention by the peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen and/or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer, further optionally wherein the composition is administered intravenously, intrathecally, intramuscularly, intranasally, sublingually, or by pulmonary delivery, optionally through nebulization.

Description

DIANHYDROHEXITOL BASED IONIZABLE LIPIDS FOR NUCLEIC ACID DELIVERY RELATED APPLICATIONS [001] This application claims priority to European application no. EP23306049.0 filed on 28th June 2023, the entire disclosure of which is hereby incorporated by reference. BACKGROUND [002] Delivery of nucleic acids has been explored extensively as a potential therapeutic option for certain disease states. In particular, messenger RNA (mRNA) therapy has become an increasingly important option for the prevention and treatment of various diseases (e.g. in the use of vaccines). [003] Efficient delivery of liposome-encapsulated nucleic acids remains an active area of research. Liposome-encapsulated nucleic acids can be administered intramuscularly (IM). [004] The cationic lipid component of a liposome plays an important role in facilitating effective encapsulation of the nucleic acid during the loading of liposomes. In addition, cationic lipids may play an important role in the efficient release of the nucleic acid cargo from the liposome into the cytoplasm of a target cell. Various cationic lipids suitable for in vivo use have been discovered. However, there remains a need to identify cationic lipids that are effective for intramuscular delivery of mRNA (e.g., in vaccines, such as for Flu or Respiratory Syncytial virus (RSV)). There also remains a need to identify cationic lipids that can be synthesized efficiently and cheaply without the formation of potentially toxic by-products. SUMMARY OF THE INVENTION [005] The present invention provides, among other things, a novel class of cationic lipid compounds for in vivo delivery of therapeutic agents, such as nucleic acids. The inventors of the present invention have surprisingly found that lipid nanoparticles comprising cationic lipids with Dianhydrohexitol based cores (e.g. isosorbide, isomannide and isoidide based cores) are very effective for the intramuscular delivery of mRNA encapsulated in said lipid nanoparticles. Indeed, lipid nanoparticles comprising the cationic lipids of the present invention have demonstrated high levels of peptide or protein expression when delivering mRNA encoding for said peptide or protein by intramuscular delivery. For example, lipid nanoparticles comprising cationic lipids of the present invention and encapsulating human erythropoietin (hEPO) mRNA achieved improved expression of hEPO mRNA when administered to mice by intramuscular delivery to lipid nanoparticles comprising MC3, which is the current gold standard for in vivo delivery of e.g. siRNA (see W02010/144740). [006] The cationic lipids of the present invention are also more straightforward to synthesize than other cationic lipids, such as MC3. Indeed, the synthesis of MC3 involves a six-step process and requires handling of a Grignard reagent. In contrast, the present invention provides cationic lipids that can be prepared from readily available and inexpensive starting reagents, such as isosorbide (l,4:3,6-dianhydro-D-glucidol), isomannide (l,4:3,6-dianhydro-D-mannitol) and isoidide (1, 4:3,6- dianhydro-L-iditol). [007] The cationic lipids of the present invention also comprise cleavable groups (e.g., esters, thioesters, disulphides, carbonates, carbamates and thiocarbamates) that are contemplated to improve biodegradability and thus contribute to their favorable safety profile. [008] It is contemplated that these compounds are capable of highly effective in vivo intramuscular delivery of the therapeutic agents and vaccines (e.g., for Flu or Respiratory Syncytial virus (RSV)). It is also contemplated that lipid nanoparticles comprising these cationic lipid compounds are capable of highly effective in vivo delivery while maintaining a favorable safety profile. It is also contemplated that lipid nanoparticles comprising these cationic lipid compounds may exhibit improved degradation in vivo. [009] In an aspect, provided herein are cationic lipids having a structure according to Formula (I): or a pharmaceutically acceptable salt thereof wherein: A1 is selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O)O-, - SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the left hand side of each recited structure is bound to the -(CH2)a-; Z1 is selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, - NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the right hand side of each recited structure is bound to the -(CH2)a-; each R is independently selected from: , wherein each R1 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; , wherein each R2 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X1, wherein each W1 is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1 is independently select