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US 9,889,202 B2Granted
Compounds and methods for trans-membrane delivery of molecules
AssigneeAposense Ltd.
InventorIlan Ziv
Life of this patent
Estimating the term…
Abstract
A novel delivery system for drugs, and especially macromolecules such as proteins or oligonucleotides through biological membranes is provided, and specifically delivery of siRNA The delivery system comprises conjugation of the macromolecule drug to a moiety that enables effective passage through the membranes. Respectively, novel compounds and pharmaceutical compositions are provided, utilizing said delivery system. In one aspect of the invention, the compounds may be utilized in medical practice, for example, in delivery of siRNA or antisense oligonucleotides across biological membranes for the treatment of medical disorders.
Claims30
A method for delivery of a drug across biological membranes, the method comprising utilization of a Conjugate, having the structure as set forth in Formula (I):
- wherein:
- D is a drug to be delivered across biological membranes, selected from a group consisting of a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO;
- y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5, 6;
- wherein at least one of y, z or w is different from 0;
- E, E′, or E″ can be the same or different, each having the structure as set forth in general Formula (II):
- (A)a-B-L1-Q1-L2-Q2-L3 Formula (II)
- wherein B is a steroid moiety selected from the group consisting of cholesterol, bile acid, estradiol, estriol;
- and any combination thereof;
- wherein B is optionally further substituted by one or more groups selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, C12, C13, C14alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 aryl or heteroaryl;
- wherein B is optionally substituted by a hydroxyl, amine, or thiol;
- Q1 and Q2 are each independently an optionally cleavable group, selected from null, ester, thio-ester, amide [—C(═O)—NH— or —NH—C(═O)—], carbamate [—O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, analogs of BAPTA and EGTA;
- and any combinations thereof;
- L1and L2 are each independently selected from null or L1, L2 and L3 are each independently selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl;
- —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5;
- nucleoside, nucleotide;
- imidazole, azide, acetylene;
- and any combinations thereof;
- wherein each group is optionally substituted by one or more hydroxyl, amine, or thiol;
- wherein each of Q1, Q2, L1, L2 and L3 is optionally an initiator group, selected from C4, C5,C6-1,2-dithiocycloalkyl(1,2-dithiocyclo-butane;
- 1,2-dithiocyclo-pentane;
- 1,2-dithiocyclohexane;
- 1,2-dithiocycloheptane);
- γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ε-Lactam (7 atoms amide ring);
- γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring);
- an amine group or both an initiator group and an amine group;
- A is selected from the group consisting of Formulae (III), Formula (IV), Formula (V) and Formula (VI):
- M is selected from —O— or —CH2—;
- and g, h and k are each individually an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- * is —H, or a point of linkage to B;
- a is an integer, selected from 1, 2, 3 or 4.
33 more elements
A method for delivery of a drug across biological membranes, the method comprising utilization of a Conjugate, having the structure as set forth in Formula (I):
- wherein:
- D is a drug to be delivered across biological membranes, selected from a group consisting of a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO;
- y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5, 6;
- wherein at least one of y, z or w is different from 0;
- E, E′ or E″ has the structure as set forth in Formula (VII):
- wherein k is an integer, selected from 0, 1, 2, 3, and 4;
- U is selected from null, O, N and NH;
- and
- wherein B is a steroid moiety selected from the group consisting of cholesterol, bile acid, estradiol, estriol;
- and any combination thereof;
- wherein B is optionally further substituted by one or more groups selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, C12, C13, C14alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 aryl or heteroaryl;
- wherein B is optionally substituted by a hydroxyl, amine, or thiol;
- Q1 and Q2 are each independently an optionally cleavable group, selected from null, ester, thio-ester, amide [—C(═O)—NH— or —NH—C(═O)—], carbamate [—O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, analogs of BAPTA and EGTA;
- and any combinations thereof;
- L1and L2 are each independently selected from null or L1, L2 and L3 are each independently selected from the group consisting of:
- linear, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl;
- —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5;
- nucleoside, nucleotide;
- imidazole, azide, acetylene;
- and any combinations thereof;
- wherein each group is optionally substituted by one or more hydroxyl, amine, or thiol;
- wherein each of Q1, Q2, L1, L2 and L3 is optionally an initiator group, selected from C4, C5,C6-1,2-dithiocycloalkyl(1,2-dithiocyclo-butane;
- 1,2-dithiocyclo-pentane;
- 1,2-dithiocyclohexane;
- 1,2-dithiocycloheptane);
- γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ε-Lactam (7 atoms amide ring);
- γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring);
- an amine group;
- or both an initiator group and an amine group.
31 more elements
A conjugate according to Formula (I):
- wherein:
- D is a drug to be delivered across biological membranes, selected from a group consisting of a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO;
- y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5, 6;
- wherein at least one of y, z or w is different from 0;
- E, E′, or E″ can be the same or different, each having the structure as set forth in general Formula (II):
- (A)a-B-L1-Q1-L2-Q2-L3 Formula (II)
- wherein B is a steroid moiety selected from the group consisting of cholesterol, bile acid, estradiol, estriol;
- and any combination thereof;
- wherein B is optionally further substituted by one or more groups selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, C12, C13, C14alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 aryl or heteroaryl;
- wherein B is optionally substituted by a hydroxyl, amine, or thiol;
- Q1 and Q2 are each independently an optionally cleavable group, selected from null, ester, thio-ester, amide [—C(═O)—NH— or —NH—C(═O)—], carbamate [—O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, analogs of BAPTA and EGTA;
- and any combinations thereof;
- L1and L2 are each independently selected from null or L1, L2 and L3 are each independently selected from the group consisting of:
- linear, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14, alkyl or hetero-alkyl;
- linear C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 aryl or heteroaryl;
- —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5;
- nucleoside, nucleotide;
- imidazole, azide, acetylene;
- and any combinations thereof;
- wherein each group is optionally substituted by one or more hydroxyl, amine, or thiol;
- wherein each of Q1, Q2, L1, L2 and L3 is optionally an initiator group, selected from C4, C5,C6-1,2-dithiocycloalkyl(1,2-dithiocyclo-butane;
- 1,2-dithiocyclo-pentane;
- 1,2-dithiocyclohexane;
- 1,2-dithiocycloheptane);
- γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ε-Lactam (7 atoms amide ring);
- γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring);
- an amine group;
- or both an initiator group and an amine group;
- A is selected from the group consisting of Formulae (III), Formula (IV), Formula (V) and Formula (VI):
- M is selected from —O—or -CH2-;
- and g, h and k are each individually an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- * is —H, or a point of linkage to B;
- a is an integer, selected from 1, 2, 3 or 4.
34 more elements
A precursor, having the structure as set forth in Formula (XVII):
- wherein W is a moiety, selected from E, E′ or E″as described in any of Formula II, VII, VIIa, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI;
- wherein Formula (II) is defined as:
- (A)a-B-L1-Q1-L2-Q2-L3 Formula (II)
- wherein B is a steroid moiety selected from the group consisting of cholesterol, bile acid, estradiol, estriol;
- and any combination thereof;
- wherein B is optionally further substituted by one or more groups selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, C12, C13, C14alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 aryl or heteroaryl;
- wherein B is optionally substituted by a hydroxyl, amine, or thiol;
- Q1 and Q2 are each independently an optionally cleavable group, selected from null, ester, thio-ester, amide [—C(═O)—NH— or —NH—C(═O)—], carbamate [—O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, analogs of BAPTA and EGTA;
- and any combinations thereof;
- L1and L2 are each independently selected from null or L1, L2 and L3 are each independently selected from the group consisting of:
- linear, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 aryl or heteroaryl;
- —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5;
- nucleoside, nucleotide;
- imidazole, azide, acetylene;
- and any combinations thereof;
- wherein each group is optionally substituted by one or more hydroxyl, amine, or thiol;
- wherein each of Q1, Q2, L1, L2 and L3 is optionally an initiator group, selected from C4, C5,C6-1,2-dithiocycloalkyl(1,2-dithiocyclo-butane;
- 1,2-dithiocyclo-pentane;
- 1,2-dithiocyclohexane;
- 1,2-dithiocycloheptane);
- γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ε-Lactam (7 atoms amide ring);
- γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring);
- an amine group;
- or both an initiator group and an amine group;
- A is selected from the group consisting of Formulae (III), Formula (IV), Formula (V) and Formula (VI):
- M is selected from —O—or —CH2-;
- and g, h and k are each individually an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- * is —H, or a point of linkage to B;
- a is an integer, selected from 1, 2, 3 or 4
- and wherein Formula VII is defined as:
- wherein k is an integer, selected from 0, 1, 2, 3, and 4;
- U is selected from null, O, N and NH;
- D is a drug to be delivered across biological membranes, selected from a group consisting of a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO;
- Formulae (VIIa) is defined as:
- wherein g stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Formula (VIII) is defined as:
- where k stands for an integer, selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- h stands for an integer, selected from the group consisting of 0, 1, 2, 3 and 4;
- U is selected from null, O, N or NH;
- Z is selected from hydrogen, hydroxyl and amine groups;
- Y is selected from —CH— and a nitrogen atom
- Formula (IX) is defined as:
- Formula (X) is defined as:
- wherein w stands for an integer of 0, 1, 2 or 3;
- t stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14;
- p stands for an integer of 0, 1, 2 or 3;
- R1 stands for hydrogen, or an alkyl group of 1, 2 or 3 carbon atoms;
- Formula (XI) is defined as:
- Formula (XII) is defined as:
- wherein b stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- J is selected from null, nitrogen or an oxygen atom;
- Formula (XIII) is defined as:
- Formula (XIV) is defined as:
- Formula (XV) is defined as:
- where y stands for an integer, selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;
- Formula (XVI) is defined as:
- or has a structure as set forth in Formula (XVIII):
- wherein G is a moiety, selected from E, E′ or E″ as described in any of Formula II, VII, VIIa, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI and where DMT (dimethoxytrityl) is a protecting group for a hydroxyl;
- and CPG is Controlled Pore Glass.
60 more elements
A precursor, having the structure as set forth in any of Formula II, VII, VIIa, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI, wherein D is selected from phosphoroamidate, an activated ester, azide or acetylene and wherein Formula (II) is defined as:
- (A)a-B-L1-Q1-L2-Q2-L3 Formula (II)
- wherein B is a steroid moiety selected from the group consisting of cholesterol, bile acid, estradiol, estriol;
- and any combination thereof;
- wherein B is optionally further substituted by one or more groups selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, C12, C13, C14alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl;
- linear, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14 aryl or heteroaryl;
- wherein B is optionally substituted by a hydroxyl, amine, or thiol;
- Q1 and Q2 are each independently an optionally cleavable group, selected from null, ester, thio-ester, amide [—C(═O)—NH— or —NH—C(═O)—], carbamate [—O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, analogs of BAPTA and EGTA;
- and any combinations thereof;
- L1and L2 are each independently selected from null or L1, L2 and L3 are each independently selected from the group consisting of:
- linear C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14, alkyl or hetero-alkyl;
- linear C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl, cyclic or branched C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 alkylene or heteroalkylene;
- C5, C6, C7, C8, C9, C10, C11, C12, C13or C14 aryl or heteroaryl;
- —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5;
- nucleoside, nucleotide;
- imidazole, azide, acetylene;
- and any combinations thereof;
- wherein each group is optionally substituted by one or more hydroxyl, amine, or thiol;
- wherein each of Q1, Q2, L1, L2 and L3 is optionally an initiator group, selected from C4, C5,C6-1,2-dithiocycloalkyl(1,2-dithiocyclo-butane;
- 1,2-dithiocyclo-pentane;
- 1,2-dithiocyclohexane;
- 1,2-dithiocycloheptane);
- γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ε-Lactam (7 atoms amide ring);
- γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring);
- an amine group;
- or both an initiator group and an amine group;
- A is selected from the group consisting of Formulae (III), Formula (IV), Formula (V) and Formula (VI):
- M is selected from —O—or —CH2-;
- and g, h and k are each individually an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- * is —H, or a point of linkage to B;
- a is an integer, selected from 1, 2, 3 or 4
- and wherein Formula VII is defined as:
- wherein k is an integer, selected from 0, 1, 2, 3, and 4;
- U is selected from null, O, N and NH
- Formulae (VIIa) is defined as:
- wherein g stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
- Formula (VIII) is defined as:
- where k stands for an integer, selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
- h stands for an integer, selected from the group consisting of 0, 1, 2, 3 and 4;
- U is selected from null, O, N or NH;
- Z is selected from hydrogen, hydroxyl and amine groups;
- Y is selected from —CH—and a nitrogen atom Formula (IX) is defined as:
- Formula (X) is defined as:
- wherein w stands for an integer of 0, 1, 2 or 3;
- t stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14;
- p stands for an integer of 0, 1, 2 or 3;
- R1 stands for hydrogen, or an alkyl group of 1, 2 or 3 carbon atoms;
- Formula (XI) is defined as:
- Formula (XII) is defined as:
- wherein b stands for an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- J is selected from null, nitrogen or an oxygen atom;
- Formula (XIII) is defined as:
- Formula (XIV) is defined as:
- Formula (XV) is defined as:
- where y stands for an integer, selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;
- Formula (XVI) is defined as:
- and wherein Formula (XVIII):
- wherein G is a moiety, selected from E, E′ or E″ as described in any of Formula II, VII, VIIa, VIII, IX, X, XI, XII, XIII, XIV, XV or XVI and where DMT (dimethoxytrityl) is a protecting group for a hydroxyl;
- and CPG is Controlled Pore Glass.
57 more elements
A method of delivering a drug across a biological membrane, the method comprising:
- conjugating at least one asymmetrically polar chemical moiety to a drug, wherein the moiety is capable of moving within the hydrophobic membrane milieu towards the membrane core, directed by the internal membrane electrical field;
- and
- contacting the biological membrane with the conjugated-drug.
A method of delivering a drug across a biological membrane, the method comprising:
- providing a conjugate of a drug and at least one asymmetrically polar chemical moiety, wherein the moiety is capable of moving within the hydrophobic membrane milieu towards the membrane core, directed by the internal membrane electrical field;
- and contacting the biological membrane with the conjugated-drug.
A conjugate of a drug and at least one asymmetrically polar chemical moiety, wherein the moiety is capable of moving within the hydrophobic membrane milieu towards the membrane core, directed by the internal membrane electrical field, for use in delivering a drug across a biological membrane.
Dependencies are inferred from the claim text.