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US 2015/0031108 A1Published application
Processes for preparing peptide conjugates and linkers
AssigneePfizer Inc.
InventorsJavier Magano, Mark Thomas Maloney, Olivier J. Marcq, Durgesh Vasant Nadkarni, Mark John Pozzo, John Joseph Teixeira, JR.
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Abstract
The present invention provides a process for preparing a compound of Formula 5b, as well as intermediates thereof, and novel classes of compounds useful in process for preparing these and similar compounds.
Claims31
A process for preparing a compound according to formula 5a
- comprising
- (i) reacting 9a and 11 together in the presence of 1-propanephosphonic acid anhydride (T3P) to create compound 13a
- (ii) catalytic hydrogenation with Pd/C of compound 13a in a THF:H2O solution of at least about 50% THF to produce a compound of formula 14a
- (iii) combining a solution of 14a in THF with a compound according to formula 15 in a reaction substantially free of base to produce compound 6a
- (iv) reacting a compound according to the formula 6a with a compound according to formula 19a in THF in the presence of DCC to produce compound 20a
- (v) combining 20a with a ε-amino containing peptide 2 dissolved in an aprotic polar 15th solvent to produce compound 3a
- (vi) dissolving compound 3a in DMSO;
- (vii) adding histidine buffer at pH between about 5.5 to about 7.5 to the solution of DMSO and 3a of step (vi);
- (viii) Adding an antibody comprising a variable light region comprising SEQ ID NO:5 and a variable heavy region comprising SEQ ID NO:6 to the solution of step (vii), so as to have a peptide:antibody molar ratio of between about 1.8:1 to about 3:1;
- (ix) Agitating the mixture formed in step (viii) at a medium speed so as to avoid foaming the reaction mixture for at least about 1 hr at between about pH 5.5 and about pH7.5 and at a temperature of between about 5° C. and 35° C.;
- and
- (x) Filtration of the solution from (ix) to extract the resultant peptide-linker antibody conjugate 5a
- wherein q=1, 2, 3, 4, or 5, X=F or Cl, and m=3, 4, or 5.
10 more elements
A process for conjugating a peptide of formula 3b to an antibody comprising the steps:
- (i) dissolving compound 3b in DMSO:
- (ii) adding histidine buffer at pH between about 5.5 to about 7.5 to the solution of DMSO and 3b of step (i);
- (iii) Adding an antibody comprising comprises a variable light region comprising SEQ ID NO:5 and a variable heavy region comprising SEQ ID NO:6 to the solution of step (ii), wherein the antibody is in a solution of about 10 mM histidine and about 10 mM glycine buffer containing about 2% (w/w) sucrose so as to have a peptide:antibody molar ratio of between about 1.8:1 to about 3:1;
- (iv) Agitating the mixture formed in step (vi) at a medium speed so as to avoid foaming the reaction mixture for at least about 1 hr at between about pH 5.5 and about pH7.5 and at a temperature of between about 5° C. and 35° C.;
- (v) Filtration of the solution from (iv) to extract the resultant peptide-linker antibody conjugate 5b,
- wherein n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, q=1, 2, 3, 4, or 5.
3 more elements
The process as claimed in claimed 1, wherein q=2, n when present=1, m when present=5, and x when present =F.
A compound comprising a structure selected from the group consisting of:
- wherein q is 1, 2, 3, 4, or 5, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and X is any halogen, and m=3, 4 or 5
Dependencies are inferred from the claim text.