Polyamide chains of precise length
AssigneeGryphon Therapeutics, Inc.
InventorKeith Rose
Life of this patent
Estimating the term…
Abstract
Provided are chains of precise length and methods for their preparation. These chains are formed by the reaction of a derivative of a diacid and a diamine in a stepwise manner on a support. One of the reactants contains a water soluble oligomer, preferably polyethylene glycol. These chains are then used to chemically modify target macromolecules such as biologically important polypeptides.
Claims68
A branched water-soluble polyamide composition comprising two or more water-soluble organic polyamide-based chains having a precise number of repeating units, said polyamide-based chains covalently attached through a multivalent linker to a moiety selected from the group consisting of a target molecule, a terminal group, a protecting group, and a reactive group, said water-soluble organic polyamide-based chains having a repeat unit of the formula:
- —{NH—Y—NH—CO—X—CO}n—
- wherein X and Y are divalent organic radicals lacking reactive functional groups or are absent, and can be the same or different, and can vary independently with each of said repeating units;
- n is an integer from 2 to 100;
- and wherein said water-soluble organic polyamide-based chains contain a sufficient number of water-soluble repeat units to render said composition water-soluble.
A branched water-soluble polyamide comprising the formula:
- {H-Ser-(‘PEG’-succ)2}2Lys-NH2
- wherein ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A branched water-soluble polyamide comprising the formula:
- {O═CH—CO—(‘PEG’-succ)2}2Lys-NH2
- wherein ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A branched water-soluble polyamide comprising the formula:
- {peptide(oxime)-(‘PEG’-succ)2}2Lys-NH2
- wherein said peptide comprises the sequence -GGLYACHMGPMTWVCQPLRG-(SEQ ID NO:1);
- oxime is —COCH2ON═CHC(O)—;
- ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A branched water-soluble polyamide comprising the formula:
- ({H-Ser-(‘PEG’-succ)4}4Lys)2Lys-NHCH2CH2SH
- wherein ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A branched water-soluble polyamide comprising the formula:
- ({H-Ser-(‘PEG’-succ)4)}4Lys)2Lys-NHCH2CH2S—CH2C(O)NH-fluorescein
- wherein ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A branched water-soluble polyamide comprising the formula:
- ({peptide-(‘PEG’-succ)8-Lys(oxime)amide}4Lys)2Lys-NHCH2CH2S—CH2C(O)NH-fluorescein
- wherein said peptide comprises the sequence -ADGACRNPWC-(SEQ ID NO:6);
- oxime is —COCH2ON═CHC(O)—;
- ‘PEG’ represents the formula —NH—(CH2)3—(OCH2CH2)3—CH2—NH—;
- and succ represents the formula —CO—(CH2)2—CO—.
A modified target molecule covalently attached through a multivalent linker to a homogenous branched water-soluble polyamide comprising two or more water-soluble polyamide chains of precise length, said chains having a polyethylene glycol-based repeating monomer unit and a terminal end group comprising a residue of a moiety selected from the group consisting of a target molecule, a multivalent linker, a terminal group, a reporter group, a protecting group, and a reactive group.
A branched water-soluble polyamide comprising two or more water-soluble polyamide chains of precise length covalently attached through a multivalent linker to a residue of a moiety selected from the group consisting of a target molecule, a terminal group attached to a support, a protecting group, and a reactive group, wherein said water-soluble polyamide chains of precise length are homogenous and comprise a polyethylene glycol-based repeating monomer unit and a terminal end group comprising a residue of a moiety selected from the group consisting of a target molecule, a linker, a terminal group, a reporter group, a protecting group and a reactive group.
A method of producing a composition comprising a branched water-soluble organic polyamide-based chain having a precise number of repeating units, said method comprising:
- (a) forming a conjugate by reacting a multivalent linker with a homogenous water-soluble organic polyamide-based chain having a precise number of repeating units, wherein said multivalent linker comprises as components:
- (i) two or more first reactive groups capable of conjugation to a complementary reactive group;
- and (ii) a moiety selected from the group consisting of a target molecule, a terminal group attached to a support, a protecting group, and a second reactive group that is non-reactive with said complementary reactive group;
- and wherein said polyamide-based chain comprises as components:
- (i) a single complementary reactive group capable of conjugation to said two or more first reactive groups of said multivalent linker;
- and (ii) a repeat unit of the formula:
- —{NH—Y—NH—CO—X—CO}n—
- wherein X and Y are divalent organic radicals lacking reactive functional groups or are absent and are the same or different, and can vary independently with each of said repeating units;
- n is an integer from 2 to 100;
- and wherein a sufficient number of said repeating units comprise a water-soluble repeat unit to render said polyamide-based chain water soluble;
- and
- (b) isolating said conjugate, whereby said branched water-soluble polyamide composition is produced.
A method of producing a composition comprising a water-soluble organic polyamide-based chain of precise length having a precise number of repeating units, said method comprising:
- (a) acylating amino groups of a compound of the formula:
- (H—{NH—Y—NH—CO—X—CO}n—{NH—Y′—NH}n′)q—V
- wherein X, Y and Y′ are divalent organic radicals lacking reactive functional groups or are absent and are the same or different, and can vary independently with each repeating unit;
- n is an integer from 1 to 49;
- n′ is 0 or 1;
- q is an integer from 1 to 10;
- V is a terminal group having a multivalent linker of the formula —Z—Q-support, wherein Z is a divalent linker or spacer or may be absent, Q is a linker or target molecule, and the support is a solid phase, matrix or surface, said acylating being performed with a molar excess of an activated form of a diacid derivative having the formula HOOC—X—COOH;
- (b) activating carboxylate groups of the product of step (a);
- (c) aminolysing the product of step (b) with a molar excess of a diamine having the formula NH2—Y—NH2;
- (d) optionally, repeating steps (a)-(c) n more times, wherein any of the X and Y substituents of steps (a)-(d) may be the same or different from the X and Y substituents used in any previous said acylating and aminolysing steps, and wherein a sufficient number of said repeating units comprise a water-soluble repeat unit to render said polyamide-based chain water soluble;
- and
- (e) optionally, performing one or more additional coupling steps to extend the polyamide-based chain of the product of step (c) or (d) to generate a compound comprising the formula:
- (U—{NH—Y—NH—CO—X—CO}n—{NH—Y′—NH}n′)q—V
- wherein U is selected from the group consisting of a target molecule, a terminal group, a protecting group, and a reactive group.
The method of claim 63, said method further comprising isolating said compound comprising said water-soluble organic polyamide-based chain of precise length.
A branched water-soluble polyamide composition comprising two or more water-soluble organic polyamide-based chains having a precise number of repeating units, wherein:
- said repeating units are polyethylene glycol-based monomer units that comprise a divalent organic radical of the formula —a—(OCH2CH2)p—b—, where a and b are divalent organic radicals lacking reactive functional groups that may be the same or different, and present or absent, and where p is an integer selected from the group consisting of 1-5;
- and
- said water-soluble organic polyamide-based chains have a repeat unit of the formula:
- —{NH—Y—NH—CO—X—CO}n—
- wherein X and Y are divalent organic radicals lacking reactive functional groups or are absent, and can be the same or different, and can vary independently with each of said repeating units;
- n is an integer from 2 to 100;
- and wherein said water-soluble organic polyamide-based chains contain a sufficient number of water-soluble repeat units to render said composition water-soluble;
- and
- said polyamide-based chains are covalently attached through a multivalent linker to a moiety selected from the group consisting of a target molecule, a terminal group, a protecting group, and a reactive group.
A branched water-soluble polyamide composition comprising two or more water-soluble organic polyamide-based chains having a precise number of repeating units, wherein:
- said repeating units are polyethylene glycol-based monomer units that comprise a divalent organic radical of the formula —a—(OCH2CH2)p—b—, where a and b are divalent organic radicals lacking reactive functional groups that may be the same or different, and present or absent, and where p is an integer that is small enough for the monomer unit to have a discrete value of p rather than a range;
- said water-soluble organic polyamide-based chains have a repeat unit of the formula;
- —{NH—Y—NH—CO—X—CO}n—
- wherein X and Y are divalent organic radicals selected from the group consisting of —((CH2)3—(OCH2CH2)3—CH2)— and —((CH2)3—O—(CH2)2—(CH2)2—O—(CH2)3)— or are absent, and can be the same or different, and can vary independently with each of said repeating units;
- n is an integer from 2 to 100;
- and wherein said water-soluble organic polyamide-based chains contain a sufficient number of water-soluble repeat units to render said composition water-soluble;
- and
- said polyamide-based chains are covalently attached through a multivalent linker to a moiety selected from the group consisting of a target molecule, a terminal group, a protecting group, and a reactive group.
Dependencies are inferred from the claim text.