Back to results
US 6,528,631 B1Granted
Oligonucleotide-folate conjugates
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Muthiah Manoharan, Balkrishen Bhat
Life of this patent
Estimating the term…
Abstract
Oligonucleotide-folate conjugates are described wherein folates are conjugated to one or more sites on an oligonucleotide including the 2′-, 3′-, 5′-, nucleobase and internucleotide linkage sites. The folate can be attached via the α- or γ-carboxylate, optionally through a linking group. Methods for the regiospecific synthesis of the conjugates are disclosed.
Claims42
A compound having the Formula XIIIA, XIIIB, XIIIC or XIIID:
- wherein:
- W13 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XIIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is —O—(CH2)n—NH— where n is from 1 to about 10;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is a hydroxyl group, or a protected hydroxyl group.
28 more elements
A compound having the Formula XIIIA, XIIIB, XIIIC or XIIID:
- wherein:
- W13 has the Formula:
- R1 is dimethoxytrityl;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XIIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is trifluoroacetoyl;
- R6is —C(═O)—CH(CH3)2;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is t-butoxy.
28 more elements
A compound having the Formula XIIIA, XIIIB, XIIIC or XIIID:
- wherein:
- W13 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23);
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XIIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is a group of Formula:
- where R3 is β-cyanoethyl, and R2 is diisopropylamino;
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is a hydroxyl group, or a protected hydroxyl group.
29 more elements
A compound having the Formula XIIIA, XIIIB, XIIIC or XIIID:
- wherein:
- W13 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XIIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- X3 is a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is a hydroxyl group, or a protected hydroxyl group.
28 more elements
A compound having the Formula XIIIA, XIIIB, XIIIC or XIIID:
- wherein:
- W13 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XIIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is OH;
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is a hydroxyl group, or a protected hydroxyl group.
28 more elements
A synthetic method comprising the steps of:
- (a) providing a compound of Formula IA, IB, IC or ID:
- wherein:
- W1a is W1b—H, OH, NH2 or SH where W1b is a linking group;
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- R20 is a group of Formula:
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH, or N—R22—(R23)v
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- v is from 0 to about 10;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- q is 0 to about 50, provided that when said compound has formula ID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- (b) reacting said compound of Formula I with a compound of Formula II:
- wherein:
- R30 is an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- R4 is a hydroxyl group, or a protected hydroxyl group;
- p is 1 or 2;
- to form a compound of Formula IVA, IVB, IVC, or IVD:
- wherein:
- W4 has the formula:
- where W1 is a linking group, O, NH, or S;
- and
- treating said compound of Formula IVA, IVB, IVC or IVD with a deprotecting reagent to form a compound of Formula VA, VB, VC or VD:
- where W5 has the Formula:
32 more elements
A compound having the Formula XVIA, XVIB, XVIC or XVID:
- wherein:
- W16 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 akoxy, C2-C20 alkenyloxy, or C2-C20 alkynyloxy;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkyene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50 provided that when said compound has formula XVID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- and
- p is 1 or 2.
25 more elements
A compound having the Formula XVIIA, XVIIB, XVIIC or XVIID:
- wherein:
- W17 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0 to about 50, provided that when said compound has formula XVIID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R5 is H or an amino protecting group.
26 more elements
A synthetic method comprising the steps of:
- (a) providing a compound of Formula IA, IB, IC or ID:
- wherein:
- W1a is W1b—H, OH, NH2 or SH, where W1b is a linking group;
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- R20 is a group of Formula:
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH, or N—R22—(R23)v
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- v is from 0 to about 10;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- q is 0 to about 50, provided that when said compound has formula ID, q is at least 1;
- M is an optionally protected internucleoside linkage;
- (b) reacting said compound of Formula I with a compound of Formula II:
- wherein:
- R30 is an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- to form a compound of Formula IVA, IVB, IVC, or IVD:
- wherein:
- W4 has the formula:
- wherein W1 is a linking group, O, NH or S;
- and
- treating said compound of Formula IVA, IVB, IVC or IVD with a deprotecting reagent to form a compound of Formula VA, VB, VC or VD:
- where W5 has the Formula:
- (c) condensing said compound of Formula V with a compound of Formula VI:
- wherein:
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- to form a compound of Formula VIIA, VIIB, VIIC, or VIID:
- wherein W7 has the Formula:
37 more elements
A compound having the Formula XIIIA, XIIIB, or XIIIC:
- wherein:
- W13 has the Formula:
- R1 is H or a hydroxyl protecting group;
- B is a nucleobase;
- each R21 is H, OH, F, or a group of formula Z—R22—(R23)v;
- Z is O, S, NH or N—R22—(R23)v;
- R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
- R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
- or R21 has one of the formulas:
- wherein:
- y1 is 0 or 1;
- y2 is 0 to 10;
- y3 is 1 to 10;
- E is N(R41)(R42) or N═C(R41)(R42);
- each R41 and each R42 is independently H, C1-C10 alkyl, a nitrogen protecting group, or R41 and R42 taken together form a nitrogen protecting group;
- or R41 and R42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;
- v is from 0 to about 10;
- q is 0;
- M is an optionally protected internucleoside linkage;
- W1 is a linking group, O, NH or S;
- R20 is OH or a group of Formula:
- R2 is —N(R7)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
- R7 is straight or branched chain alkyl having from 1 to 10 carbons;
- R3 is a phosphorus protecting group;
- R5 is H or an amino protecting group;
- R6 is H or an amino protecting group;
- X3 is —CH(Z1)— or a group of Formula XI:
- Z1 is the sidechain of a naturally occurring amino acid, or a protected sidechain of a naturally occurring amino acid;
- p is 1 or 2;
- and
- R4 is a hydroxyl group, or a protected hydroxyl group.
28 more elements
Dependencies are inferred from the claim text.