WO2009129385A1 - Lipides cationiques et utilisations de ceux-ci - Google Patents

Lipides cationiques et utilisations de ceux-ci Download PDF

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Publication number
WO2009129385A1
WO2009129385A1 PCT/US2009/040798 US2009040798W WO2009129385A1 WO 2009129385 A1 WO2009129385 A1 WO 2009129385A1 US 2009040798 W US2009040798 W US 2009040798W WO 2009129385 A1 WO2009129385 A1 WO 2009129385A1
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octadeca
dienyloxy
methyl
ethyl
lipid
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PCT/US2009/040798
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English (en)
Inventor
Prasad A. Dande
Todd M. Hansen
Robert D. Hubbard
Carol K. Wada
Lu Tian
Xiaobin Zhao
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle

Definitions

  • novel delivery formulations research is now able to focus more on improving efficacy on the therapeutic and clinical efficacious of therapeutic agents such as nucleic acids, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), and small nuclear RNA (snRNA).
  • therapeutic agents such as nucleic acids, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), and small nuclear RNA (snRNA).
  • rRNA ribosomal RNA
  • miRNA micro RNA
  • tRNA transfer RNA
  • siRNA small inhibitory RNA
  • snRNA small nuclear RNA
  • Y is a bond or C(O);
  • R 1 and R 2 are heterocycloalkyl or heteroaryl;
  • R 3 and R 4 together are CR 20 R 21 , wherein R 20 is H and R 21 is C 14 -C 2 o-alkyl, Ci 4 -C 20 - alkenyl or (CH 2 O)-Ci 4 -C 20 -alkenyl; or R 20 and R 21 are independently selected C 14 -C 20 -alkyl, Ci 4 -C 20 -alkenyl or (CH 2 0)-C 14 -C 2 o-alkenyl; or
  • R 6 is R 7 , R 8 , R 9 , or R 10 ;
  • R 7 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 8A is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 9A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three or four or five of independently selected R 11 , OR 11 , SR 11 , S(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R ⁇ ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , N R 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR 11 , NHC(O)N(R 1 %, NR 11 C(O)NHR 11 , NR ⁇ C(0)N(R ⁇ ) 2 , C(O)NH 2 , C(O)NHR 11 , C(0)
  • a further embodiment pertains to a method of making Lipid-Based Particles, comprising: (a) mixing the cationic lipid(s), the non-cationic lipid(s) and the PEG-lipid conjugate(s); (b) adding the mixture of step (a) to one or more therapeutic agents; and (c) separating and purifying resulting suspension of step (b). DESCRIPTION OF THE DRAWINGS
  • FIGS 1-19 In vitro trans fection activity of selected cationic lipids that were formulated as disclosed herein.
  • This invention pertains to in vitro and in vivo delivery of therapeutic agents.
  • the invention pertains to compositions that allow for delivery of nucleic acids, including but not limited to RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA
  • nucleic acids including but not limited to RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA
  • Variable moieties of compounds herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.
  • alkenyl means monovalent, straight or branched chain hydrocarbon moieties having one or more than one carbon-carbon double bonds, such as C 2 - alkenyl, C 3 -alkenyl, C 4 -alkenyl, Cs-alkenyl, C ⁇ -alkenyl and the like.
  • heteroarenes include, but are not limited to furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiadiazole thiophene, tetrazine, tetrazole, triazine, triazole and the like.
  • Choi as used herein, means cholesterol.
  • SPC soybean phosphatidylcholine
  • MALDI matrix assisted laser desorption ionization
  • nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated.
  • degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Cassol et al. (1992); Rossolini et al., MoI. Cell.
  • Nucleotides contain a sugar deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are linked together through the phosphate groups. Nucleotides include chemically modified nucleotides as described in, e.g., WO 03/74654.
  • Bases include purines and pyrimidines, which further include natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs, and synthetic derivatives of purines and pyrimidines, which include, but are not limited to, modifications which place new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates, and alkylhalides.
  • small molecule means antibiotics, antineoplastics, antiinflammatories, anitivirals, immunomodulators and agents that act upon the respiratory system, the cardiovascular system, the central nervous system or a metabolic pathway involved with dyslipidemia, diabetes or Syndrome X.
  • Compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon- carbon or carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules.
  • the compounds of this invention may also exist as a mixture of "E” and "Z" isomers.
  • One embodiment of this invention therefore pertains to a cationic lipid or mixtures thereof, having Formula (I)
  • Y 2 is a bond, C 1 -C 8 alkylene, C(O), C(O)O(Ci-C 8 -alkylene), (C 1 -C 8 - alkylene)NHC(O)O(Ci-C 8 -alkylene), (Ci-C 8 -alkylene)O, (Ci-C 8 -alkylene)OC(O)N(Ci-C 8 - alkylene), or (Ci-C 8 -alkylene)O(Ci-C 8 -alkylene);
  • Y is a bond or C(O);
  • R 1 and R 2 are heterocycloalkyl or heteroaryl;
  • Y 3 -R 3 and Y 4 -R 4 together are CR 20 R 21 ;
  • R , 10 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or more R 6A , 0R 6A , SR 6A , S(O)R 6A , SO 2 R 6A , C(0)R 6A , C0(0)R 6A , 0C(0)R 6A , 0C(0)0R 6A , NH 2 , NHR 6A , N(R 6A ) 2 , NHC(O)R 6A , NR 6A C(O)R 6A , NHS(O) 2 R 6A , N R 6A S(O) 2 R 6A , NHC(O)OR 6A , NR 6A C(O)OR 6A , NHC(O)NH 2 , NHC(O)NHR 6A , NHC(O)N(R 6A ) 2 , NR 6A C(O)NHR 6A , NR 6A C(O)N
  • R 7A is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 9A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 10A is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or more NH 2 , NHC(O)NH 2 , C(O)NH 2 , C(O)NHOH, SO 2 NH 2 , C(O)H, C(O)OH,
  • R 12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 15 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 16 , OR 16 , SR 16 , S(O) 2 R 16 , C(O)OH, NH 2 , NHR 16 N(R 16 ) 2 , C(O)R 16 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , NHC(O)R 16 , NR 16 C(O)R 16 , NHC(O)OR 16 , NR 16 C(O)OR 16 , NR 16 C(O)OR 16 , OH, F, Cl, Br or I;
  • R , 16 is alkyl, alkenyl, alkynyl, or R iv.
  • R 17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R 18 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl.
  • R and R are heterocycloalkyl
  • R and R is H, and the other is C 14 -C 2 o-alkenyl; or
  • R 6 is R 7 , R , R , or R
  • R is heterocycloalkyl which is unfused
  • R is alkyl, which is unsubstituted or substituted with NHR ;
  • R is R ;
  • R is alkyl, which is substituted with NH 2 ;
  • R is R or R ;
  • R 14 is heterocycloalkylwhich is unfused
  • R is alkyl, which is unsubstituted or substituted with R , or N(R ) 2 ;
  • R is unsubstituted or substituted with R ; and R 18 is alkyl.
  • Y 2 , Y 3 , and Y 4 are each a bond.
  • Y 2 is Ci-Cs alkylene, and Y 3 and Y 4 are each a bond.
  • Y 2 is a bond and Y 3 and Y 4 are each C(O).
  • Y 2 is Ci-Cg alkylene, and Y 3 and Y 4 are each C(O).
  • Y 2 is C(O)O(C i-Cs-alkylene), and Y 3 and Y 4 are each a bond. In another embodiment of Formula (I), Y 2 is C(O)O(Ci-Cg-alkylene), and Y 3 and Y 4 are each C(O).
  • R 1 and R 2 are H. In another embodiment of Formula (I), one of R 1 and R 2 is H, and the other is R 5 . In another embodiment of Formula (I), R 1 and R 2 are each independently R 5 . In another embodiment of Formula (I), R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl. In another embodiment of Formula (I), R 1 and R 2 , with the nitrogen to which they are attached, are pyrrolidinyl, piperazinyl, morpholinyl, piperidinyl, azetidinyl, or aziridinyl.
  • one of R 3 and R 4 is H, and the other is C 14 -C 20 - alkenyl.
  • R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • R 5 is unsubstituted. In another embodiment of Formula (I), R 5 is substituted with one or more R 6 . In another embodiment of Formula (I), R 5 is substituted with NHR 6 or N(R 6 ) 2 .
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl wherein the heterocycloalkyl is substituted with alkyl which is unsubstituted.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 is H; R 2 is R 5 ; R 5 is alkyl and is substituted with R 6 ; R 6 is R 9 ; R 9 is heterocycloalkyl which is unfused; and R 3 and R 4 are independently C 14 -C 20 -alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond;
  • R 1 is H;
  • R 2 is R 5 ;
  • R 5 is alkyl and is substituted with N(R 6 ) 2 ;
  • R 6 is R 10 ;
  • R 10 is alkyl which is unsubstituted; and
  • R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 is H; R 2 is R 5 ; R 5 is alkyl and is substituted with R 6 ; R 6 is R 9 ; R 9 is heterocycloalkyl which is unfused; and R 3 and R 4 are independently C 14 -C 20 -alkenyl; wherein the heterocycloalkyl is substituted with alkyl which is unsubstituted.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl; wherein the heterocycloalkyl is substituted R 15 ; R 15 is alkyl which is substituted with N(R 16 ) 2 ; and R 16 is alkyl.
  • R 1 and R 2 are H; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond;
  • R 1 is H;
  • R 2 is R 5 ;
  • R 5 is alkyl and is substituted with R 6 ;
  • R 6 is R 7 ;
  • R 7 is phenyl which is unfused; wherein the phenyl is substituted with R 11 ;
  • R 11 is R 15 ;
  • R 15 is alkyl which is substituted with R 16 ;
  • R 16 is R 17 ; and R 17 is heterocycloalkyl.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 are R 5 ; R 5 is alkyl wherein one alkyl is unsubstituted and the other is substituted with R 6 ; R 6 is R 9 ; R 9 is heterocycloalkyl which is unfused; and R 3 and R 4 are independently C 14 -C 20 -alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond;
  • R 1 is H;
  • R 2 is R 5 ;
  • R 5 is alkyl and is substituted with R 6 ;
  • R 6 is R 7 ;
  • R 7 is phenyl which is unfused; wherein the phenyl is substituted with R 11 ;
  • R 11 is R 15 ;
  • R 15 is alkyl which is substituted with R 16 ;
  • R 16 is R 17 ;
  • R 17 is heterocycloalkyl which is unfused; wherein the heterocycloalkyl is substituted with R 18 ;
  • R 18 is alkyl and
  • R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 are R 5 ; R 5 is alkyl wherein one alkyl is unsubstituted and the other is substituted with N(R 6 )2; R 6 is R 10 , R 10 is alkyl which is unsubstituted; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl; wherein the heterocycloalkyl is substituted with R 11 , R 11 is R 15 ; R 15 is alkyl which is substituted with R 16 ; R 16 is R 17 ; and R 17 is heteroaryl which is unfused.
  • Y 2 , Y 3 , and Y 4 are each a bond;
  • R 1 is H;
  • R 2 is R 5 ;
  • R 5 is alkyl and is substituted with R 6 ;
  • R 6 is R 8 ;
  • R 8 is heteroaryl which is unfused; wherein the heteroaryl is substituted with R 11 ;
  • R 11 is R 14 ;
  • R 14 is heterocycloalkyl which is unfused;
  • R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 is Ci-Cs alkylene, Y 3 and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl wherein the heterocycloalkyl is substituted with alkyl which is unsubstituted.
  • Y 2 is Ci-Cs alkylene, Y 3 and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 is Ci-Cs alkylene, Y 3 and Y 4 are each a bond; R 1 is H; R 2 is R 5 ; R 5 is alkyl and is substituted with R 6 ; R 6 is R 9 ; R 9 is heterocycloalkyl; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 is Ci-Cs alkylene, Y 3 and Y 4 are each a bond; R 1 and R 2 are R 5 ; R 5 is alkyl which is unsubstituted; and R 3 and R 4 are independently Ci 4 -C 2 o-alkenyl.
  • Y 2 is C(O)O(Ci-C 8 -alkylene), Y 3 and Y 4 are each a bond; R 1 is H; R 2 is R 5 ; R 5 is alkyl and is substituted with N(R 6 ) 2 ; R 6 is R 10 ; R 10 is alkyl which is unsubstituted; and R 3 and R 4 are independently Ci4-C2o-alkenyl.
  • Y 2 , Y 3 , and Y 4 are each a bond; R 1 and R 2 , with the nitrogen to which they are attached, are heterocycloalkyl; and R 3 and R 4 are independently C 14 -C 20 -alkenyl; wherein the heterocycloalkyl is substituted with R 11 , R 11 is R 15 ; R 15 is alkyl which is substituted with R 16 ; R 16 is R 17 ; and R 17 is heterocycloalkyl which is unfused.
  • Still another embodiment pertains to compounds of Formula I which are l-(2- ((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)pyrrolidine; N,N-dimethyl-N-(2-((9Z, 12Z)-octadeca-9, 12- dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)amine; N-(3-( 1 H-imidazol- 1 - yl)propyl)-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9 ,12- dienyloxy)methyl)ethyl)amine; 1 -methyl
  • Still another embodiment pertains to compounds of Formula I which are chosen from 1 -methyl-4-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)piperazine, N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)- octadeca-9,12-dienyloxy)methyl)ethyl)-N-(3-pyrrolidin-l-ylpropyl)amine, N,N-dimethyl-N'- (2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)ethane- 1 ,2-
  • a further embodiment pertains to particles comprising one or more cationic lipid(s) having Formula I.
  • a further embodiment pertains to particles comprising one or more cationic lipid(s) having Formula I and one or more therapeutic agents.
  • said therapeutic agent is a nucleic acid encoded with a product of interest, including but not limited to, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), small nuclear RNA (snRNA), antigens, fragments thereof, proteins, peptides, and small-molecules.
  • RNA nucleic acid encoded with a product of interest, including but not limited to, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), small nuclear RNA (snRNA
  • a further embodiment pertains to nanoparticles comprising one or more cationic lipid(s) having Formula I.
  • a further embodiment pertains to nanoparticles comprising one or more cationic lipid(s) having Formula I and one or more therapeutic agents.
  • said therapeutic agent is a nucleic acid encoded with a product of interest, including but not limited to, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), small nuclear RNA (snRNA), antigens, fragments thereof, proteins, peptides, and small-molecules.
  • RNA nucleic acid encoded with a product of interest, including but not limited to, RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), small nuclear RNA (
  • a still further embodiment pertains to Cationic-Based Lipid Encapsulation Systems (CaBLES) comprising non-cationic lipid(s), polyethylene glycol (PEG)-lipid conjugate(s) and cationic lipid(s) having Formula I.
  • CaBLES Cationic-Based Lipid Encapsulation Systems
  • Y 2 is a bond, C 1 -C 8 alkylene, C(O), C(O)O(d-C 8 -alkylene), (C 1 -C 8 - alkylene)NHC(O)O(Ci-C 8 -alkylene), (Ci-C 8 -alkylene)O, (Ci-C 8 -alkylene)OC(O)N(Ci-C 8 - alkylene), or (Ci-C 8 -alkylene)O(Ci-C 8 -alkylene);
  • Y 3 is a bond or C(O);
  • Y 4 is a bond or C(O);
  • R 1 and R 2 are each independently H, cycloalkyl, cycloalkenyl or R 5 ; or
  • R 1 and R 2 are heterocycloalkyl or heteroaryl;
  • R 3 and R 4 together are CR 20 R 21 , wherein R 20 is H and R 21 is C 14 -C 2 o-alkyl, Ci 4 -C 20 - alkenyl or (CH 2 0)-Ci 4 -C 2 o-alkenyl; or R 20 and R 21 are independently selected C 14 -C 20 -alkyl, Ci4-C 20 -alkenyl or (CH 2 0)-C 14 -C 2 o-alkenyl; or
  • Y 3 -R 3 and Y 4 -R 4 together are CR 20 R 21
  • R 5 is alkyl, which is unsubstituted or substituted with one or more R 6 , OR 6 , SR 6 , S(O)R 6 , SO 2 R 6 , C(O)R 6 , CO(O)R 6 , OC(O)R 6 , OC(O)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(O)R 6 , NR 6 C(O)R 6 , NHS(O) 2 R 6 , N R 6 S(O) 2 R 6 , NHC(O)OR 6 , NR 6 C(O)OR 6 , NHC(O)NH 2 , NHC(O)NHR 6 , NHC(O)N(R 6 ) 2 , NR 6 C(O)NHR 6 , NR 6 C(O)N(R 6 ) 2 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 ,
  • R 6 is R 7 , R 8 , R 9 , or R 10 ;
  • R 8 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 10 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or more R 6A , 0R 6A , SR 6A , S(O)R 6A , SO 2 R 6A , C(0)R 6A , C0(0)R 6A , 0C(0)R 6A , 0C(0)0R 6A , NH 2 , NHR 6A , N(R 6A ) 2 , NHC(0)R 6A , NR 6A C(O)R 6A , NHS(O) 2 R 6A , N R 6A S(O) 2 R 6A , NHC(0)0R 6A , NR 6A C(O)OR 6A , NHC(O)NH 2 , NHC(0)NHR 6A , NHC(O)N(R 6A ) 2 , NR 6A C(O)NHR 6A , NR 6A C(O)N(R 6A ) 2
  • R 6A is R 7A , R 8A , R 9A , or R 10A ;
  • R 8A is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 10A is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or more NH 2 , NHC(O)NH 2 , C(O)NH 2 , C(O)NHOH, SO 2 NH 2 , C(O)H, C(O)OH, C(N)NH 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
  • each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three or four or five of independently selected R 11 , OR 11 , SR 11 , S(O)R 11 , SO 2 R 11 , C(O)R 11 , CO(O)R 11 , OC(O)R 11 , OC(O)OR 11 , NH 2 , NHR 11 , N(R ⁇ ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHS(O) 2 R 11 , N R 11 S(O) 2 R 11 , NHC(O)OR 11 , NR 11 C(O)OR 11 , NHC(O)NH 2 , NHC(O)NHR 11 , NHC(O)N(R 1 %, NR 11 C(O)NHR 11 , NR ⁇ C(0)N(R ⁇ ) 2 , C(O)NH 2 , C(O)NHR 11 , C(0)
  • R 11 is R 12 , R 13 , R 14 or R 15 ;
  • R 12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 15 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 16 , OR 16 , SR 16 , S(O) 2 R 16 , C(O)OH, NH 2 , NHR 16 N(R 16 ) 2 , C(O)R 16 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , NHC(O)R 16 , NR 16 C(O)R 16 , NHC(O)OR 16 , NR 16 C(O)OR 16 , NR 16 C(O)OR 16 , OH, F, Cl, Br or I;
  • R 16 is alkyl, alkenyl, alkynyl, or R 17 ;
  • R . 17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
  • R 12 , R 13 , R 14 , and R 17 are independently unsubstituted or substituted with one or more R 18 , OR 18 , SR 18 , S(O)R 18 , SO 2 R 18 , C(O)R 18 , CO(O)R 18 , OC(O)R 18 , OC(O)OR 18 , NH 2 , NHR 18 , N(R 18 ) 2 , NHC(O)R 18 , NR 18 C(O)R 18 , NHS(O) 2 R 18 , NR 18 S(O) 2 R 18 , NHC(O)OR 18 , NR 18 C(O)OR 18 , NHC(O)NH 2 , NHC(O)NHR 18 , NHC(O)N(R 18 ) 2 , NR 18 C(O)NHR 18 , NR 18 C(O)N(R 18 ) 2 , C(O)NH 2 , C(O)NHR 18 , C(O)N
  • R 18 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
  • Lipid-Based Particles of the present invention are defined as CaBLES which further comprise one or more therapeutic agent(s).
  • Therapeutic agents that can be delivered with CaBLES include RNA, antisense oligonucleotide, a DNA, a plasmid, a ribosomal RNA (rRNA), a micro RNA (miRNA), transfer RNA (tRNA), a small inhibitory RNA (siRNA), small nuclear RNA (snRNA), chimeric nucleic acids, an antigen, fragments thereof, a protein, a peptide, small-molecules, or mixtures thereof.
  • the CaBLES and/or the Lipid-Based Particle formulation can have a ligand attached, such as a targeting ligand or a chelating moiety for complexing calcium.
  • a ligand attached such as a targeting ligand or a chelating moiety for complexing calcium.
  • the cationic lipids of Formula I maintains a positive charge.
  • the ligand that is attached has a positive charge.
  • Suitable ligands include, but are not limited to, a compound or device with a reactive functional group and include lipids, amphipathic lipids, carrier compounds, bioaffinity compounds, biomaterials, biopolymers, biomedical devices, analytically detectable compounds, therapeutically active compounds, enzymes, peptides, proteins, antibodies, immune stimulators, radiolabels, fluorogens, biotin, drugs, haptens, DNA, RNA, polysaccharides, liposomes, virosomes, micelles, immunoglobulins, functional groups, other targeting moieties, or toxins.
  • a further embodiment pertains to CaBLES or Lipid-Base Particles wherein the PEG lipid conjugate is about 0.1-20 weight/weight % of total lipid in particle, the non-cationic lipid is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and the cationic lipid is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to CaBLES or Lipid-Base Particles wherein the PEG lipid conjugate is about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and the cationic lipid is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to Lipid-Base Particles wherein the Lipid-Based Particle comprises, cholesterol, DSPC, N-(3-(lH-imidazol-l-yl)propyl)-N-(2-((9Z,12Z)- octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy)methyl)ethyl)amine, one or more PEG-lipid conjugates and one or more nucleic acids.
  • a further embodiment pertains to a pharmaceutical composition wherein the (PEG)- lipid conjugates are about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and N-(3-(lH-imidazol-l-yl)propyl)-N-(2-((9Z,12Z)-octadeca-9,12- dienyloxy)-l -(((9Z, 12Z)-octadeca-9,l 2-dienyloxy )methyl)ethyl)amine is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to Lipid-Base Particles wherein the non-cationic lipids are cholesterol and DSPC, the cationic lipid is N-(3-(lH-imidazol-l-yl)propyl)-N-(2- ((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)amine, the PEG-lipid conjugate is N-(2,3- dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether, and the therapeutic agent is siRNA.
  • the non-cationic lipids are cholesterol and DSPC
  • the cationic lipid is N-(3-(lH-imidazol-l-yl)propyl)-N-(2- ((9Z, 12Z)-octadeca-9, 12-dienyloxy)-
  • a further embodiment pertains to Lipid-Base Particles, wherein the N-(2,3- dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether is about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and the N-(3 -( 1 H-imidazol- 1 -yl)propyl)-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)- octadeca-9,12-dienyloxy)methyl)ethyl)amine is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to a pharmaceutical composition wherein the Lipid- Based Particle comprises, cholesterol, DSPC, N,N-dimethyl-N'-(2-((9Z,12Z)-octadeca-9,12- dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)ethane- 1 ,2-diamine, one or more PEG-lipid conjugates and one or more nucleic acids.
  • the Lipid- Based Particle comprises, cholesterol, DSPC, N,N-dimethyl-N'-(2-((9Z,12Z)-octadeca-9,12- dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)ethane- 1 ,2-diamine, one or more PEG-lipid conjugates and one or more nucleic acids.
  • a further embodiment pertains to a pharmaceutical composition wherein the (PEG)- lipid conjugates are about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and N,N-dimethyl-N'-(2-((9Z,12Z)-octadeca-9,l 2-dienyloxy)- 1 - (((9Z,12Z)-octadeca-9,12-dienyloxy)methyl)ethyl)ethane-l,2-diamine is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to Lipid-Base Particles, wherein the non-cationic lipids are cholesterol and DSPC, the cationic lipid is N,N-dimethyl-N'-(2-((9Z,12Z)- octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)ethane- 1 ,2- diamine, the PEG-lipid conjugate is N-(2,3-dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether, and the therapeutic agent is siRNA.
  • the non-cationic lipids are cholesterol and DSPC
  • the cationic lipid is N,N-dimethyl-N'-(2-((9Z,12Z)- octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-oct
  • Based Particle comprises, cholesterol, DSPC, N-(2-(lH-imidazol-4-yl)ethyl)-N-(2-((9Z,12Z)- octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy)methyl)ethyl)amine, one or more PEG-lipid conjugates and one or more nucleic acids.
  • a further embodiment pertains to a pharmaceutical composition wherein the (PEG)- lipid conjugates are about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and N-(2-(lH-imidazol-4-yl)ethyl)-N-(2-((9Z,12Z)-octadeca-9,12- dienyloxy)-l -(((9Z, 12Z)-octadeca-9,l 2-dienyloxy )methyl)ethyl)amine is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to Lipid-Base Particles, wherein the non-cationic lipids are cholesterol and DSPC, the cationic lipid is N-(2-(lH-imidazol-4-yl)ethyl)-N-(2- ((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)amine, the PEG-lipid conjugate is N-(2,3- dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether, and the therapeutic agent is siRNA.
  • the non-cationic lipids are cholesterol and DSPC
  • the cationic lipid is N-(2-(lH-imidazol-4-yl)ethyl)-N-(2- ((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1
  • a further embodiment pertains to Lipid-Base Particles, wherein the N-(2,3- dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether is about 0.1-20 weight/weight % of total lipid in particle, the DSPC is about 1-30 weight/weight % of total lipid in particle, the cholesterol is about 5-45 weight/weight % of total lipid in particle, and the N-(2-( 1 H-imidazol-4-yl)ethyl)-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)- octadeca-9,12-dienyloxy )methyl)ethyl)amine is about 5-60 weight/weight % of total lipid in particle.
  • a further embodiment pertains to Lipid-Based Particles, wherein the ratio of one or more (PEG)-lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids of Formula (I), to one or more therapeutic agents is between about 50:1 to about 5:1.
  • a further embodiment pertains to Lipid-Based Particles, wherein the ratio of one or more (PEG)-lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids of Formula (I), to one or more therapeutic agents is between about 30:1 to about 10:1.
  • functional CaBLES comprising one or more (PEG)- lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids of Formula 1 effectively encapsulate nucleic acids, such as siRNA, with efficiencies from about 50- 100%.
  • functional CaBLES comprising one or more (PEG)- lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids of Formula 1 effectively encapsulate nucleic acids, such as siRNA, with efficiencies from about 80- 100%.
  • functional CaBLES comprising one or more (PEG)- lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids chosen from 1 -(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)pyrrolidine; N,N-dimethyl-N-(2-((9Z, 12Z)-octadeca-9, 12- dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)amine; N-(3-( 1 H-imidazol- 1 - yl)propyl)-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9)
  • functional CaBLES comprising one or more (PEG)- lipid conjugates, one or more non-cationic lipids, and one or more cationic lipids chosen from 1 -(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)pyrrolidine; N,N-dimethyl-N-(2-((9Z, 12Z)-octadeca-9, 12- dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12-dienyloxy )methyl)ethyl)amine; N-(3-( 1 H-imidazol- 1 - yl)propyl)-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9)
  • a further embodiment pertains to examples of non-cationic lipids that are useful for the practice of this invention which include, but are not limited to, cholesterol, cholesterol sulfate, ceramide, sphingomyelin, lecithin, sphingomyelin, egg sphingomyelin, milk sphingomyelin; egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, hydrogenated soybean phosphatidylethanolamine, egg phosphatidylethanolamine, hydrogenated soybean phosphatidylcholine, soybean phosphatidylcholine, 1 ,2-dilauroyl-sn- glycerol, 1 ,2-dimyristoyl-sn-glycerol, 1 ,2-dipalmitoyl-sn-glycerol, 1 ,2-distearoyl-sn-glycerol, 1 ,2-dilauroyl-sn-glycero-3-phosphatidic acid
  • a further embodiment pertains to examples of PEG-lipid conjugates that are useful for the practice of this invention which include, but are not limited to, 2-(tetradecyloxy)-l- ((tetradecyloxy)methyl)ethyl 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93, 96,99,102,105,108,111,114,117,120,123,126,129,132,135,138- hexatetracontaoxanonatriacontahect- 1 -ylcarbamate, 2-(hexadecyloxy)- 1 -
  • PEG-lipid conjugates are described in, e.g., US App. No. 61/095,748, which was filed on September 10, 2008 and is incorporated herein by reference.
  • PEG-lipid conjugates are described in, e.g., US App. No. 61/095,769, which was filed on September 10, 2008 and is incorporated herein by reference.
  • a still further embodiment pertains to combinations of polyethylene glycol (PEG)- lipid conjugates which are useful for the practice of this invention, wherein two PEG-lipid conjugates are chosen from N-(carbonyl-methoxypolyethyleneglycol-2000)-l,2-dimyristoyl- sn-glycero-3-phosphoethanolamine , N-(carbonyl-methoxypolyethyleneglycol-2000)- 1 ,2- dipalmitoyl-sn-glycero-3 -phosphoethanolamine, N-(carbonyl-methoxypolyethyleneglycol- 200O)-1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1 ,2-distearoyl-sn-glycerol- methoxypolyethyleneglycol-
  • a still further embodiment pertains to combinations of polyethylene glycol (PEG)- lipid conjugates which are useful for the practice of this invention and include 1,2- dimyristoyl-sn-glycerol-methoxypolyethyleneglycol-2000 and N-(carbonyl- methoxypolyethyleneglycol-2000)- 1 ,2-distearoyl-sn-glycero-3 -phosphoethanolamine, 1 ,2-distearoyl-sn-glycerol-methoxypolyethyleneglycol-2000 and N-(carbonyl- methoxypolyethyleneglycol-2000)- 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, N- [3 ,4-bis(hexadecyloxy)butyl]- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,
  • the cationic lipids of the CaBLES and Lipid-Based Particles comprises about 2 to about 60 weight/weight percent of total lipid in the particle.
  • the non-cationic lipids of the CaBLES and Lipid-Based Particles comprises about 5 to about 90 weight/weight percent of total lipid in the particle.
  • Based Particles comprises from 0.1 to about 20 weight/weight percent of total lipid in the particle.
  • R 8A is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene;
  • R 15 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 16 , OR 16 , SR 16 , S(O) 2 R 16 , C(O)OH, NH 2 , NHR 16 N(R 16 ) 2 , C(O)R 16 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , NHC(O)R 16 , NR 16 C(O)R 16 , NHC(O)OR 16 , NR 16 C(O)OR 16 , NR 16 C(O)OR 16 , OH, F, Cl, Br or I;
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.
  • compositions and the method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions.
  • Lipid-Based Particles are expected to be useful when used with: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and BfI-I) inhibitors, Bcr-Abl kinase inhibitors, BiTE (Bi-Specif ⁇ c T cell Engager) antibodies, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVD's, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAP's) intercalating antibiotics, kinase inhibitors, mammalian target of
  • a BiTE antibody is a bi-specific antibody that directs T-cells to attach cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
  • Exemplary BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like.
  • Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE ® (laromustine, VNP 4010 IM), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA (bendamustine), treosulfan, rofosfamide and the like.
  • BCNU carmustine
  • CLORETAZINE ® laromustine, VNP 4010 IM
  • cyclophosphamide dec
  • ALKERAN (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-I, tiazofurin, tegafur, TS-I, vidarabine, UFT and the like.
  • Bcl-2 proteins inhibitors include AT-IOl ((-)gossypol), GENASENSE ® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro( 1 , 1 '-biphenyl)-2-yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 -(dimethylamino)- 1 - ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2- (4-chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4- ((( 1
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-
  • COX-2 inhibitors include ABT-963, ARCOXIA ® (etoricoxib), BEXTRA ® (valdecoxib), BMS347070, CELEBREX ® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX ® (deracoxib), JTE-522, 4-methyl-2-(3 ,4-dimethylphenyl)- 1 -(4- sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX ® (rofecoxib) and the like.
  • EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX ® (cetuximab), HR3, IgA antibodies, IRESSA ® (gefitinib),
  • TARCEVA ® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB ® (lapatinib) and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
  • Inhibitors of apoptosis proteins include ApoMab (a fully human affinity-matured IgGl monoclonal antibody), antibodies that target TRAIL or death receptors (e.g., pro- apoptotic receptor agonists DR4 and DR5), conatumumab, ETR2-ST01, GDCO 145, (lexatumumab), HGS-1029, LBY-135, PRO-1762 and tratuzumab.
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-OOl, rapamycin, temsirolimus and the like.
  • FELDENE piroxicam
  • ibuprofen cream ALEVE
  • NAPROSYN naproxen
  • VOLTAREN ® diclofenac
  • INDOCIN ® indomethacin
  • CLINORIL ® sinalindac
  • TOLECTIN ® tolmetin
  • LODINE ® etodolac
  • TORADOL ® ketorolac
  • DAYPRO ® oxaprozin
  • Platinum chemotherapeutics include cisplatin, ELOXATIN (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN (carboplatin), satraplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, TSP- 1 and the like.
  • MYOCET liposomal doxorubicin
  • elsamitrucin epirbucin
  • glarbuicin glarbuicin
  • ZAVEDOS idarubicin
  • mitomycin C nemorubicin
  • neocarzinostatin peplomycin
  • pirarubicin rebeccamycin
  • stimalamer streptozocin
  • VALSTAR valrubicin
  • Antibodies include AVASTIN (bevacizumab), CD40-specif ⁇ c antibodies, chTNT- 1/B, denosumab, ERBITUX ® (cetuximab), HUMAX-CD4 ® (zanolimumab), IGFlR-specif ⁇ c antibodies, lintuzumab, PANOREX ® (edrecolomab), RENCAREX ® (WX G250),
  • Hormonal therapies include ARIMIDEX (anastrozole), AROMASIN (exemestane), arzoxifene, CASODEX (bicalutamide), CETROTIDE (cetrorelix), degarelix, deslorelin, DESOPAN (trilostane), dexamethasone, DROGENIL , (flutamide), EVISTA ® (raloxifene), AFEMATM (fadrozole), FARESTON ® (toremifene), FASLODEX ®
  • NOLVADEX ® tamoxifen citrate
  • PLENAXISTM abarelix
  • prednisone PROPECIA ®
  • Proteasome inhibitors include VELC ADE ® (bortezomib), MG 132, NPI-0052, PR-171 and the like.
  • agents include ALF AFERONE ,(IFN- ⁇ ), BAM- 002 (oxidized glutathione), BEROMUN ® (tasonermin), BEXXAR ® (tositumomab),
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include include krestin, lentinan, sizof ⁇ ran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
  • Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3 -yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE ® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
  • compounds having Formula I may be combined with other chemptherapeutic agents such as ABRAXANETM (ABI-007), ABT- 100 (farnesyl transferase inhibitor), ADVEXIN ® (Ad5CMV-p53 vaccine), ALTOCOR ® or MEVACOR ® (lovastatin), AMPLIGEN ® (poly Lpoly C12U, a synthetic RNA), APTOS YN ® (exisulind), AREDIA ® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3,17-dione-androsta-l,4- diene), AVAGE (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC (cancer vaccine), CELEUK ® (celmoleukin), CEPLENE
  • CR CR
  • NIPENT pentostatin
  • ONCONASE a ribonuclease enzyme
  • ONCOPHAGE ® melanoma vaccine treatment
  • ONCOVAX ® IL-2 Vaccine
  • ORATHECINTM rubitecan
  • OSIDEM antibody-based cell drug
  • OVAREX ® MAb murine monoclonal antibody
  • paditaxel PAND IMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
  • PANVAC -VF investment cancer vaccine
  • pegaspargase pegaspargase
  • PEG Interferon A PEG Interferon A
  • CR CR
  • phenoxodiol procarbazine, rebimastat, REMOVAB (catumaxomab), REVLIMID (lenalidomide), RSRl 3 (efaproxiral), SOMATULINE ® LA (lanreotide), SORIAT ANE ® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PTlOO), TARGRETIN (bexarotene), TAXOPREXIN ® (DHA-paclitaxel), TELCYTA ® (canfosfamide, TLK286), temilifene, TEMOD AR ® (temozolomide), tesmilifene, thalidomide, THERATOPE ® (STn- KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quin
  • vitaxin anti-alphavbeta3 antibody
  • XCYTRIN motexafm gadolinium
  • XINLAYTM atrasentan
  • XYOTAXTM paclitaxel poliglumex
  • CaBLES comprise one or more non-cationic lipids, one or more cationic lipids having Formula I and one or more polyethylene glycol (PEG)-lipid conjugate.
  • PEG polyethylene glycol
  • Lipid-Based Particles of the present invention are defined as CaBLES which further comprise one or more therapeutic agent(s). These particles have mean diameter sizes of 50- 300 nm, of which 50-250 nm is preferred and 50-200 nm is most preferred.
  • Functional CaBLES effectively encapsulate nucleic acids, (e.g., single stranded or double stranded DNA, single stranded or double stranced RNA, RNAi, siRNA, and the like). Suitable nucleic acids include, but are not limited to, plasmids, antisense oligonucleotides, ribozymes as well as other poly- and oligonucleotides.
  • the nucleic acid encodes a product, e.g., a therapeutic product, of interest.
  • the CaBLES of the present invention can be used to deliver the nucleic acid to a cell (e.g., a cell in a mammal) for, e.g., expression of the nucleic acid or for silencing of a target sequence expressed by the cell.
  • the siRNA can have varying lengths (10-200 bps) and structures (hairpins, single/double strands, bulges, nicks/gaps, mismatches) and processed in the cell to provide active gene silencing.
  • a double- stranded siRNA can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3 '-ends of a given strand.
  • Non-cationic lipids have a neutral charge or an anionic charge at physiological pH.
  • a neutral lipid also known as a "helper lipid,” has no net charge at physiological pH.
  • helper lipid has no net charge at physiological pH.
  • These lipids can also be zwitterionic.
  • Polyethylene glycol (PEG)-lipid conjugates are used to minimize particle aggregation in solution, provide increased in vivo serum circulation, and enhance distribution of nanoparticles to organs, tissues, cell types, and tumors of interest.
  • These shielding lipids consist of a lipid portion linked to a "PEG” portion via carbamate, ester, amide, ether, amine, thioether, or dithiol linkages.
  • PEG is a polyethylene glycol consisting of repeating C2H4O units with an average molecular weight between 500 to 10,000 daltons and may be substituted by alkoxy, acyl, alkyl, or aryl.
  • the CaBLES and/or Lipid Based Particles may target using targeting moieties that are specific to a cell type or tissue.
  • targeting moieties such as ligands, cell surface receptors, glycoproteins, vitamins, (e.g., ribolflavin) and moncoleonal antibodies, has been previously described (see, e.g., U.S. Pat. Nos. 4,957,773 and 4,603,044).
  • the targeting moeities can comprise the entire entire protein or fragments thereof.
  • the targeting moiety is a small protein, or peptide.
  • the targeting moiety is a small-molecule.
  • Cationic lipids are those having one or more moieties that are positively charged at a physiologically relevant pH, typically between 4-8. Particular cationic lipids are as shown in Formula I. Examples of cationic lipids that are useful for the practice of this invention include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride, DC-Choi, l,3-dioleoyloxy-2-(6-carboxyspermyl)-propyl amide, dioctadecylamidoglycyl spermine, N,N-distearyl-N,N-dimethylammonium bromide, N-(2,3-dioleyloxy)propyl)-N,N- dimethylammonium chloride, l,2-dioleoyl-3-trimethylammonium-propane chloride, l,2-dilineoyl-3-dimethylammonium-propane, N
  • Lipid-Based Particles are a mixture of one or more cationic lipids of Formula (I), one or more non-cationic lipids, one or more PEG-lipid conjugates, and one or more therapeutic agents.
  • Specific Lipid-Based Particles comprise the following lipid mixtures: cationic lipid(s) (about 2-60% by weight), non-cationic lipid(s) (about 5-90% by weight), and PEG-lipid conjugate(s) (about 0.1-20%).
  • Non-cationic 10 0.5 lipid
  • the mixing solution of cationic lipids, cholesterol, non-cationic lipids and PEG-lipids was prepared in ethanol (total concentration at 10 mg/mL).
  • siSTABLE purchased from ThermoFisher
  • antisense-5'-AAU CUU GCC AGC UUU CCC CUU-3' SEQ ID NO: 2
  • % stock solution was prepared in 10 mg/mL of solution by dissolving 10 mg siRNA in 1 mL of RNAse-free UltraPure Water.
  • the calculated amount of siRNA solution was added to 1 mL of citrate buffer (pH 4.0, 20 mM), to provide an siRNA concentration of 0.2 mg/mL, and warmed to 6OC.
  • the calculated amount of lipid solution was warmed to 6OC, transferred to a 0.5 mL syringe with 28/4 gauge needle, and injected into the citrate buffer with stirring at 6OC.
  • 3 mL of PBS solution at room temperature (pH 7.4) was added into the lipid mixture with stirring.
  • the Lipid-Based Particle solution was cooled to room temperature.
  • siRNA concentrations were measured using Quanti-iT RiboGreen RNA reagent (Molecular Probes, (Rl 1490)). Vesicle sizes were characterized by dynamic light scattering with a DynaProTM Plate Reader (Wyatt Technology) in 96-well half-area UV plate (Coring) after diluting the formulation sample (20 ⁇ L) in phosphate buffered saline (80 ⁇ L) at a pH of about 7-8. A 1% agarose gel-based assay was used for analyzing nuclease degradation and protection. Encapsulation efficiency (EE) was calculated using data obtained from a RiboGreen assay.
  • EE Encapsulation efficiency
  • RNA concentration and encapsulation efficiency were determined using a Quant-iT ® Ribogreen RNA reagent and kit available from Invitrogen.
  • the siRNA was released from the Lipid-Based Particle using one of the following reagents: ethanol, Triton X-100, or phenol/chloroform.
  • the siRNA concentration is quantified using fluorescent reading at 480 nm/520 nm.
  • Particle sizes and size distributions were characterized by using dynamic light scattering (DLS).
  • DLS plate reader (DynaproTM, Wyatt Technology) was used for the DLS measurement. This DLS plate reader uses an 830 nm laser and the scattering angle is 158°. It also can control temperature from 4°C to 70 0 C. A 96-well format was employed for the samples.
  • Samples for DLS analysis were prepared by mixing 20 ⁇ L of each sample stock solution with 80 ⁇ L PBS directly in the 96-well plate (#3697, Corning). Sample mixing was accomplished using a microplate shaker (Orbis, Mikura Ltd.). Plates were read at 20 0 C with an acquisition time of 50 seconds for each sample, and data was analyzed with Wyatt Technology's Dynamics V6 software. To rule out potential multiple scattering artifacts, a second plate at 4-fold reduced sample concentrations was independently prepared by mixing 5 ⁇ L stock solutions with 95 ⁇ L PBS. Under our experimental conditions the results at the two concentrations were very similar, and the final reported result for each sample represents the average of values obtained from the two plates.
  • MDA435-TetR-Luc cells (The positive readout reporter cell line MDA435-TetR-Luc contained a stably integrated copy of the luciferase gene expressed from a CMV promoter containing the tetR operator site. In addition, gene coding for a destabilized TetR protein was expressed in this cell line.) were plated in 96 well plate at a density of 1OK cells per well in 100 ul of DMEM (Dulbecco's Modified Eagles Medium, Invitrogen Corp.) containing 10% fetal bovine serum (Invitrogen Corp.).
  • DMEM Dulbecco's Modified Eagles Medium, Invitrogen Corp.
  • 10% fetal bovine serum Invitrogen Corp.
  • l,3-dihydroxypropan-2-one can be reacted with a compound of Formula (7) to provide a compound of Formula (8).
  • the reaction typically requires the use of coupling reagents such as but not limited to 4-(dimethylamino)pyridine and l-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride in a solvent such as but not limited to methylene chloride.
  • a compound of Formula (8) can be reacted with an amine of Formula (4), as described in Scheme 2, to provide a compound of Formula (9), which is representative of a compound of Formula I wherein Y 3 and Y 4 are carbonyl and Y 2 is a bond.
  • 2-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)propane-l,3-diol which can be prepared as described in EXAMPLE 26 A, can be reacted with a compound of Formula (10) and a reducing agent in the presence of acetic acid to provide a compound of Formula (11).
  • Typical reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride, and typical solvents for the reaction include 1 ,2-dichloroethane, methanol, dichloromethane, or mixtures thereof.
  • the silica was loaded into an Analogix DASI module, and the product was isolated by flash chromatography (Analogix, SF65 ⁇ 200g with 2-4% ethyl aceate/hexanes). MS (ESI) m/z 587.6 (M-OC 2 H 6 +1), 655.5 (M+23) + .
  • EXAMPLE 11 l,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propan-2-amine Prepared as described in EXAMPLE 6 by substituting ammonium acetate for 3- (pyrrolidin-l-yl)propan-l -amine.
  • N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dieny loxy)methyl)ethyl)-N-(3 -(pyrrolidin- 1 -ylmethyl)benzyl)amine Prepared as described in EXAMPLE 6 by substituting (3 -(pyrrolidin- 1- ylmethyl)phenyl)methanamine for 3 -(pyrrolidin- 1 -yl)propan- 1 -amine.
  • EXAMPLE 14 N-methyl-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)ethyl)-N-(3 -pyrrolidin- 1 -ylpropyl)amine Prepared as described in EXAMPLE 6 by substituting N-methyl-3 -(pyrrolidin- 1- yl)propan-l -amine for 3 -(pyrrolidin- l-yl)propan-l -amine.
  • EXAMPLE 18 N-methyl-N-(2-((9Z, 12Z)-octadeca-9, 12-dienyloxy)- 1 -(((9Z, 12Z)-octadeca-9, 12- dieny loxy)methyl)ethyl)-N-(3 -(pyrrolidin- 1 -ylmethyl)benzyl)amine
  • N -methyl- 1 -(3 -(pyrrolidin- 1- ylmethyl)phenyl)methanamine for 3 -(pyrrolidin- 1 -yl)propan- 1 -amine.
  • EXAMPLE 2 IB (9Z,9'Z, 12Z, 12'Z)-2-(4-methylpiperazin- 1 -yl)propane- 1 ,3-diyl dioctadeca-9, 12-dienoate Prepared as described in EXAMPLE 6D by substituting 1-methylpiperazine for 3-(pyrrolidin-l-yl)propan-l -amine and EXAMPLE 21A for l,3-bis((9Z,12Z)-octadeca-9,12- dienyloxy)propan-2-one (EXAMPLE 6C).
  • EXAMPLE 24A Prepared as described in EXAMPLE 23 C by substituting pyrrolidine for
  • EXAMPLE 25A tert-butyl butane- 1 ,4-diylbis(3-(2,2,2-trifluoroacetamido)propylcarbamate)
  • N ⁇ N 1 -(butane- l,4-diyl)dipropane-l,3-diamine 100 ml
  • dicholormethane 100 ml
  • ethyl 2,2,2-trifluoroacetate 6.17 ml, 51.9 mmol
  • dicholormethane 50 ml
  • the reaction mixture was cooled in an ice bath, treated with sodium triacetoxyborohydride (0.087 g, 0.409 mmol),, stirred at room temperature for 2 hours, cooled to 0 0 C, quenched with saturated NaHCO 3 and extracted with dichloromethane. The extract was washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated. The concentrate was purified by flash chromatography (Analogix 1 :4 methanol/ethyl acetate/5% NH 4 OH). MS (ESI) m/z 973.8 (M+l) + .
  • EXAMPLE 26B 4,4'-((3-((9Z,12Z)-octadeca-9,12-dienyloxy)-2-(((9Z,12Z)-octadeca-9,12- dienyloxy)methyl)propoxy)(phenyl)methylene)bis(methoxybenzene)
  • the title compound was prepared as described in EXAMPLE 6D by substituting EXAMPLE 26A 2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)propane-l,3-diol for 2, 2-dimethoxypropane-l, 3-diol (EXAMPLE 6A).
  • the crude material was purified by flash silica gel chromatography (hexanes). MS (ESI) m/z 927.2 (M+Na) + , 620.4 (M-DMT+18) + .
  • EXAMPLE 26E N-(3-[(9Z, 12Z)-octadeca-9, 12-dienyloxy]-2- ⁇ [(9Z, 12Z)-octadeca-9, 12- dienyloxy]methyl ⁇ propyl)-N-(3-pyrrolidin- 1 -ylpropyl)amine
  • the title compound was prepared as described in EXAMPLE 6D by substituting EXAMPLE 26D (3-((9Z, 12Z)-octadeca-9, 12-dienyloxy)-2-(((9Z, 12Z)-octadeca-9, 12- dienyloxy)methyl)propanal) for EXAMPLE 6C.
  • EXAMPLE 32B was prepared using the procedure described for EXAMPLE 3 IE, substituting EXAMPLE 32A for EXAMPLE 3 ID.
  • MS (ESI) m/z 498.5 (M+H) + ; 1 U NMR (300 MHz, CDCl 3 ) ⁇ ppm 8.24 (s, 2H) 3.53-3.70 (m, IH) 3.34-3.53 (m, 6H) 3.07-3.34 (m, 2H) 1.87-2.13 (m, 2H) 1.48-1.67 (m, 4H) 1.16-1.39 (m, 44H) 0.82-0.94 (m, 6H).
  • EXAMPLE 32C was prepared using the procedure described for EXAMPLE 3 IF, substituting EXAMPLE 32B for EXAMPLE 3 IE.
  • MS (MALDI) m/z 2617.6; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 3.95-4.02 (m, 2H) 3.83-3.92 (m, IH) 3.68-3.72 (m, IH) 3.65 (m, 180H) 3.35- 3.60 (m, 10H) 1.59-1.73 (m, 2H) 1.49-1.60 (m, 4H) 1.18-1.36 (m, 44H) 0.82-0.94 (m, 6H).
  • EXAMPLE 33B was prepared using the procedure described for EXAMPLE 32B, substituting EXAMPLE 33A for EXAMPLE 32A.
  • MS (ESI) m/z 554.6 (M+H) + ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ ppm 8.12-8.38 (m, 2H) 3.54-3.70 (m, IH) 3.33-3.53 (m, 6H) 3.06-3.33 (m, 2H) 1.84-2.14 (m, 2H) 1.46-1.71 (m, 4H) 1.14-1.37 (m, 52H) 0.81-0.94 (m, 6H).
  • EXAMPLE 33C was prepared using the procedure described for EXAMPLE 3 IF, substituting EXAMPLE 33B for EXAMPLE 3 IE.
  • MS (MALDI) m/z 2866.7; 1 U NMR (300 MHz, CDCl 3 ) ⁇ ppm 3.98 (s, 2H) 3.84-3.91 (m, IH) 3.60-3.68 (m, 180H) 3.36-3.60 (m, HH) 1.50-1.72 (m, 6H) 1.26 (s, 52H) 0.84-0.92 (m, 6H).
  • EXAMPLE 34A was prepared using the same procedure described for EXAMPLE 32A, substituting octadecyl methanesulfonate for tetradecyl methanesulfonate.
  • LCMS APCI
  • EXAMPLE 34B was prepared using the same procedure described for EXAMPLE 3 IE, substituting EXAMPLE 34A for EXAMPLE 3 ID.
  • LCMS m/z 610.9; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 3.08-3.70 (m, 9H) 1.85-2.15 (m, 2H) 1.55 (s, 4H) 1.15-1.37 (m, 60H) 0.84-0.92 (m, 6H).
  • EXAMPLE 34C was prepared using the same procedure described for EXAMPLE 3 IF, substituting EXAMPLE 34B for EXAMPLE 3 IE.
  • MS (MALDI) m/z 2773.6; 1 U NMR (300 MHz, CDCl 3 ) ⁇ ppm 3.95-4.01 (m, 2H) 3.84-3.91 (m, IH) 3.59-3.70 (m, 180H) 3.27-
  • EXAMPLE 32B (100 mg) was dissolved in dichloromethane (1-2 niL) and mPEG- NPC (26.0 mg) was added. Hunig's base (26 mg) was added, and the mixture was stirred overnight at room temperature. The mixture was loaded directly onto a silica gel column (4 g Analogix) and chromatographed (Analogix 280, dichloromethane/methanol, 0-20%) to give EXAMPLE 35.
  • EXAMPLE 38 was prepared using the same procedure described for EXAMPLE 3 IF, substituting RAPP 12 2000-35 (Rapp Polymere) for mPEG2000-SCM.
  • MS (MALDI) m/z 2584.3; 1 H NMR (300 MHz, CDCl 3 ) ⁇ ppm 6.43-6.61 (m, 2H) 3.60-3.68 (m, 200H) 3.36-3.58 (m, 16H) 2.42-2.57 (m, 4H) 1.49-1.85 (m, 6H) 1.19-1.35 (m, 52H) 0.82-0.92 (m, 6H).
  • EXAMPLE 39 was prepared using the same procedure described for EXAMPLE 3 IF, substituting mPEG-NPC (Creative PEGWorks) for mPEG2000-SCM (Laysan Bio, Inc.). MS (MALDI) m/z 2588.5; 1 U NMR (300 MHz, CDCl 3 ) ⁇ ppm 5.14 (m, IH) 4.17-4.26 (m, 3H) 4.01-4.11 (m, IH) 3.83-3.91 (m, IH) 3.60-3.71 (m, 180H) 3.48-3.60 (m, 4H) 3.35-3.44 (m, 5H) 2.23-2.37 (m, 4H) 1.62-1.86 (m, 6H) 1.21-1.37 (m, 40H) 0.83-0.93 (m, 6H).
  • EXAMPLE 4OB was prepared using the same procedure described for EXAMPLE 3 IE, substituting EXAMPLE 4OA for 3 ID. MS (ESI) m/z 482.6 (M+H) + .
  • EXAMPLE 4OC was prepared using the same procedure described for EXAMPLE 3 IF, substituting EXAMPLE 4OB for EXAMPLE 3 IE.
  • MS (MALDI) m/z 2689.0; 1 U NMR (300 MHz, CDCl 3 ) ⁇ ppm 5.09-5.19 (m, IH) 4.17-4.26 (m, 3H) 4.01-4.11 (m, IH) 3.73-3.91 (m, IH) 3.61-3.70 (m, 180H) 3.48-3.60 (m, 4H) 3.35-3.44 (m, 5H) 2.23-2.36 (m, 4H) 1.54- 1.84 (m, 6H) 1.21-1.36 (m, 48H) 0.82-0.93 (m, 6H).
  • EXAMPLE 33B (100 mg) and mPEG-COOH (278 mg, PSA-288, Creative PEGWorks) were combined in dichloromethane (2 mL). N 1 -((ethylimino)methylene)-N 3 ,N 3 - dimethylpropane- 1,3 -diamine hydrochloride (346 mg) was added followed by 4- (dimethylamino)pyridine (2 mg). The mixture was stirred overnight at room temperature then loaded directly onto a 4 g silica gel column (Analogix) and purified (Analogix 280, dichloromethane:methanol 0-20%).
  • the silica was loaded into an Analogix DASI module, and the product was isolated by flash chromatography (Analogix, SF65 ⁇ 200g, 2% ethyl acetate/hexanes for six column volumes, then 4% ethyl acetate/hexanes until major product eluted).
  • MS (ESI) m/z 512 (M-CH 3 +l).
  • the silica gel was loaded into an Analogix DASI module, and the product was isolated by flash chromatography (Analogix, SF65 ⁇ 200g, 2% ethyl acetate/hexanes for six column volumes, then 4% ethyl acetate/hexanes until the product eluted.
  • MS (ESI) m/z 500.4 (M+18) + .
  • This EXAMPLE was prepared as described in EXAMPLE 43, substituting hexadecyl methanesulfonate for 1-bromotetradecane in EXAMPLE 43 A.
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ ppm 3.54-3.66 (m, 180H), 3.32-3.49 (m, 9H), 3.38 (s, 3H), 1.51-1.59 (m, 4H), 1.21-1.36 (m, 48H), 0.86-0.90 (m, 6H); MS (MALDI) m/z 2614.
  • This EXAMPLE was prepared as described in EXAMPLE 43 substituting octadecyl methanesulfonate for 1-bromotetradecane in EXAMPLE 43 A.
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ ppm 3.52-3.66 (m, 180H), 3.32-3.49 (m, 9H), 3.38 (s, 3H), 1.51-1.59 (m, 4H), 1.21-1.36 (m, 52H), 0.86-0.90 (m, 6H); MS (MALDI) m/z 2557.
  • N-Boc-serinol (1,1-dimethylethyl (2- hydroxy-l-(hydroxymethyl)ethyl)carbamate) (2.0 g) and sodium hydride (1.255 g) in N 5 N- dimethylformamide (50 mL).
  • the mixture was cooled using an ice/water bath, and 1- bromohexadecane (7.98 g) was added to it.
  • the mixture was heated at 70 0 C overnight, then cooled to room temperature.
  • the mixture was cooled to 0 0 C and quenched with a few drops of cold water.
  • the mixture was diluted with saturated ammonium chloride (50 mL).
  • the aqueous layer was extracted with ethyl acetate, and the extract was washed with brine, dried over Na 2 SO 4 , and concentrated.
  • the concentrate was added to a silica gel column and was eluted with ethyl acetate/hexane (1 :9).
  • This EXAMPLE was prepared as described in EXAMPLE 49, substituting 1- bromooctadecane hexadecane for 1-bromotetradecane in EXAMPLE 49A.
  • 1 H NMR 300 MHz CDCl 3 ) ⁇ ppm 4.14- 4.20 (m, IH), 4.08 (s, 2H), 3.86 -3.89 (t, 4H), 3.71-3.75 (m, 4H), 3.61-3.70 (m, 180H), 3.38 (s, 3H), 1.50-1.56 (m, 4H), 1.20-1.30 (m, 64H), 0.86-0.90 (m, 6H); MS (MALDI) m/z 2900.
  • N-(2,3-dimyristyloxypropyl)carbamate polyethyleneglycol-2000 methyl ether EXAMPLE 56 was prepared using the known synthetic route; see: Heyes, J.; Hall, K.; Tailor, V.; Lenz, R.; MacLachlan, I. J. Controlled Release 2006, 112, 280-290.

Abstract

L'invention concerne des lipides cationiques, des systèmes d'administration de médicaments à base de lipides cationiques, des façons de les fabriquer et des procédés de traitement de maladies avec ceux-ci.
PCT/US2009/040798 2008-04-16 2009-04-16 Lipides cationiques et utilisations de ceux-ci WO2009129385A1 (fr)

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Cited By (24)

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US10323076B2 (en) 2013-10-03 2019-06-18 Modernatx, Inc. Polynucleotides encoding low density lipoprotein receptor
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EP3736261A1 (fr) * 2015-09-17 2020-11-11 ModernaTX, Inc. Composés et compositions pour l'administration intracellulaire d'agents thérapeutiques
US10266485B2 (en) 2015-09-17 2019-04-23 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
WO2017049245A3 (fr) * 2015-09-17 2017-05-18 Modernatx, Inc. Composés et compositions pour l'administration intracellulaire d'agents thérapeutiques
JP6948313B6 (ja) 2015-09-17 2022-02-08 モデルナティエックス インコーポレイテッド 治療剤の細胞内送達のための化合物および組成物
JP7326395B2 (ja) 2015-09-17 2023-08-15 モデルナティエックス インコーポレイテッド 治療剤の細胞内送達のための化合物および組成物
US11220476B2 (en) 2015-09-17 2022-01-11 Modernatx, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
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US10799463B2 (en) 2015-12-22 2020-10-13 Modernatx, Inc. Compounds and compositions for intracellular delivery of agents
US11471533B2 (en) 2016-09-27 2022-10-18 Kyowa Kirin Co., Ltd. Compound usable as cationic lipid
EP3521270A4 (fr) * 2016-09-27 2020-06-24 Kyowa Kirin Co., Ltd. Composé lipidique cationique
US11583504B2 (en) 2016-11-08 2023-02-21 Modernatx, Inc. Stabilized formulations of lipid nanoparticles
US10857105B2 (en) 2017-03-15 2020-12-08 MordernaTX, Inc. Compounds and compositions for intracellular delivery of therapeutic agents
US11203569B2 (en) 2017-03-15 2021-12-21 Modernatx, Inc. Crystal forms of amino lipids
WO2018177383A1 (fr) * 2017-03-29 2018-10-04 中国医学科学院基础医学研究所 Application d'un composé ou d'un extrait de médecine chinoise traditionnelle dans la préparation d'un agent d'administration d'acide nucléique et produits apparentés correspondants
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CN110520408A (zh) * 2017-03-29 2019-11-29 中国医学科学院基础医学研究所 化合物或中药提取物在制备核酸递送试剂中的应用及其相关产品
WO2019027055A1 (fr) 2017-08-04 2019-02-07 協和発酵キリン株式会社 Nanoparticules lipidiques contenant un acide nucléique
US11969506B2 (en) 2018-03-15 2024-04-30 Modernatx, Inc. Lipid nanoparticle formulation
CN111918858A (zh) * 2018-03-29 2020-11-10 中国医学科学院基础医学研究所 化合物或中药提取物在制备核酸递送试剂中的应用及其相关产品
CN111918858B (zh) * 2018-03-29 2023-03-21 中国医学科学院基础医学研究所 化合物或中药提取物在制备核酸递送试剂中的应用及其相关产品
WO2019184991A1 (fr) * 2018-03-29 2019-10-03 中国医学科学院基础医学研究所 Utilisation d'un composé ou d'un extrait de médecine chinoise traditionnelle dans la préparation d'un agent d'administration d'acide nucléique, et produits associés
US11318232B2 (en) 2018-05-22 2022-05-03 Interface Biologics, Inc. Compositions and methods for delivering drugs to a vessel wall
US11597698B2 (en) 2019-09-19 2023-03-07 Modernatx, Inc. Branched tail lipid compounds and compositions for intracellular delivery of therapeutic agents
US11066355B2 (en) 2019-09-19 2021-07-20 Modernatx, Inc. Branched tail lipid compounds and compositions for intracellular delivery of therapeutic agents
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CN113527081B (zh) * 2021-08-30 2022-11-08 上海日异生物科技有限公司 一种3-氧代环丁烷基羧酸的制备方法
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CN114230521B (zh) * 2022-02-22 2022-05-31 中国科学院基础医学与肿瘤研究所(筹) 一种可电离的阳离子化合物及其复合物的应用
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