Process for intermediates for the synthesis of LHRH antagonists
AssigneeAbbott Laboratories
InventorsKenneth W. Funk, Edwin O. Lundell, Robert B. Miller, Jane L. Chang, Vimal Kishore, James J. Napier, Michael A. Staeger
Life of this patent
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Abstract
A method is provided for preparing decapeptide and undecapeptide derivatives of LHRH by solution phase peptide chemistry as well as intermediate peptides useful in the same method.
Claims20
A process for preparing an LHRH antagonist having the structure Q-D2Nal.sup.1 -D4ClPhe.sup.2 -D3Pal.sup.3 -Ser.sup.4 -NMeTyr.sup.5 -DLys(Nic).sup.6 -Leu.sup.7 -Lys(iPr).sup.8 -Pro.sup.9 DAla.sup.10 NH.sub.2 wherein Q is selected from the group consisting of N-acetyl and THF-Gly, comprising the steps of
- a) coupling a first protected oligopeptide compound having the formula
- P.sup.1 -Ser(P.sup.2)-NMeTyr(P.sup.3)-D-Lys(Nic)-Leu-Lys(iPr)-Pro-DAlaNH.sub.2(IV)
- wherein P.sup.1 is an amino protecting group, and P.sup.2 and P.sup.3 are independently selected --OH protecting groups
- with a second oligopeptide compound having the formula
- Q-D-2Nal-D-4ClPhe-D-3PalOH (III)
- to produce a third oligopeptide compound having the formula
- Q-D-2Nal-D-4ClPhe-D-3Pal-Ser(R.sup.1)-NMeTyr(R.sup.2)-D-Lys(Nic)-Leu-Lys(iP r)-Pro-D-AlaNH.sub.2 (V)
- wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen and --OH protecting group with the proviso that at least one of R.sup.1 or R.sup.2 is an --OH protecting group and
- b) when either or both of R.sup.1 and R.sup.2 is an --OH protecting group, deprotecting the compound of formula III to produce the LHRH antagonist.
The process of claim 9 further comprising the step of preparing compound II from a compound B.sub.3 having the formula P.sup.1 -Ser(P.sup.2)-NMeTyr(P.sup.3)-D-Lys(Nic)-aa.sub.1 -O-P.sup.4 wherein P.sup.4 is a carboxyl protecting group.
An intermediate oligopeptide selected from the group consisting of:
- (a) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-Leu-OH;
- (b) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-OH;
- (c) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-OH;
- (d) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-OH;
- (e) Boc-Lys(iPr)-Pro-D-AlaNH.sub.2 ;
- (f) Boc-Leu-Lys(iPr)-Pro-D-AlaNH.sub.2 ;
- (g) THF-Gly-D-2Nal-D-4ClPhe-D-3Pal-OH;
- and
- (h) THF-Gly-OH.
A pre-intermediate oligopeptide selected from the group consisting of:
- (a) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-All;
- (b) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-Bzl;
- (c) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-Me;
- (d) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-O-All;
- (e) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-O-Bzl;
- (f) Boc-Ser(Bzl)-NMeTyr(Bzl)-D-Lys(Nic)-O-Me;
- (g) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-All;
- (h) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-Bzl;
- (i) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-Me;
- (j) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-O-AH;
- (k) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-O-Bzl;
- (l) Boc-Ser(Bzl)-NMeTyr(Cl.sub.2 Bzl)-D-Lys(Nic)-O-Me;
- (m) H-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-AH;
- (n) H-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-Bzl;
- (o) H-NMeTyr(Bzl)-D-Lys(Nic)-Leu-O-Me;
- (p) H-NMeTyr(2Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-All;
- (q) H-NMeTyr(2Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-Bzl;
- (r) H-NMeTyr(2Cl.sub.2 Bzl)-D-Lys(Nic)-Leu-O-Me;
- (s) Boc-D-Lys(Nic)-Leu-O-All;
- (t) Boc-D-Lys(Nic)-Leu-O-Bzl;
- (u) Boc-D-Lys(Nic)-Leu-O-Me;
- (v) Boc-D-2Nal-D-4ClPhe-D-3Pal-O-All;
- (w) Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Bzl;
- (x) Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Me;
- (y) THF-Gly-D-2Nal-D-4ClPhe-D-3Pal-O-All;
- (z) THF-Gly-D-2Nal-D-4ClPhe-D-3Pal-O-Bzl;
- (aa) THF-Gly-D-2Nal-D-4ClPhe-D-3Pal-O-Me;
- (bb) THF-Gly-O-All;
- (cc) THF-Gly-O-Bzl;
- (dd) THF-Gly-O-Me;
- (ee) Cbz-Pro-D-AlaNH.sub.2 ;
- and
- (ff) Boc-Lys(Cbz)-Pro-D-AlaNH.sub.2.
Dependencies are inferred from the claim text.