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US 5,684,131 AGranted
Substituted benzhydrylamines as handles for solid phase peptide synthesis
OwnerMichal Lebl, Marcel Patekinventors
Life of this patent
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Abstract
The present invention is directed to a novel "handle" for solid phase peptide synthesis. The handles can be converted from a stable form to a labile form, allowing for cleavage of a peptide amide from the support after synthesis under mild conditions, and after deprotection of the amino acid side chains. The handles are based on a substituted benzhydrylamine skeleton.
Claims12
A solid phase support comprising a handle for use in peptide synthesis of the general formula (I) ##STR4## wherein the phenyl group bearing (X.sup.1).sub.a, Z and optionally (Y).sub.c is referred to as a first phenyl group, and the phenyl group bearing (X.sup.2).sub.b and optionally (Y).sub.d is referred to as a second phenyl group;
- X.sup.1 is selected from the group consisting of --SR.sup.1, --S(O)R.sup.1, and --S(O).sub.2 R.sup.1, each X.sup.1 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Z is --OR.sup.3, being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.3 is a C.sub.1 -C.sub.10 hydrocarbon group substituted with a carboxyl group for coupling to a solid phase support;
- X.sup.2 is selected from the group consisting of --SR.sup.2, --S(O)R.sup.2, and --S(O).sub.2 R.sup.2, each X.sup.2 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the second phenyl group;
- R.sup.2 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Y is --OR.sup.4 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.1).sub.a or Z on the first phenyl group and in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.2).sub.b on the second phenyl group;
- R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group;
- a=1-2;
- b=1-3;
- c=0-1
- d=0-1;
- and
- D is selected from the group consisting of --H, a protecting group and an N.sup..alpha. -protected aminoacyl, wherein when X.sup.1 is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, and X.sub.2 is --S(O)R.sup.2 or --S(O).sub.2 R.sup.2, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine.
11 more elements
A solid phase support comprising a handle for use in peptide synthesis of the general formula:
- ##STR5## in which Z is --OR.sup.4, R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group comprising a carboxyl group for coupling to a solid phase support;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group and in which each G is independently selected from the group consisting of --S--, --SO--, and --SO.sub.2 --;
- and in which D is H, a protecting group or an N.sup..alpha. -protected aminoacyl, wherein when each GR.sup.1 group is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine.
A method for preparing a handle for use in peptide synthesis comprising the steps of:
- (a) treating a benzoic acid with thionyl chloride to obtain a benzoyl chloride, said benzoic acid having the formula:
- ##STR6## in which a=1 and (X.sup.1).sub.a is in an ortho or para position with respect to the carboxyl group of the benzoic acid, or a=2 and (X.sup.1).sub.a is in the ortho and para positions with respect to the carboxyl group of the benzoic acid, X.sup.1 is --SR.sup.1, and R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group;
- (b) mixing the benzoyl chloride prepared in step (a) with a substituted benzene to obtain a mixture, said substituted benzene having the formula:
- ##STR7## in which b=1 to 3, X.sup.2 is --SR.sup.2, and R.sup.2 is a C.sub.1 -C.sub.10 hydrocarbon group;
- (c) treating the mixture of step (b) with two molar equivalents of AlCl.sub.3 to obtain an ortho-hydroxybenzophenone;
- (d) alkylating the --OH group of the ortho-hydroxybenzophenone of step (c) to obtain an ortho-alkoxybenzophenone;
- (e) reacting the ortho-alkoxybenzophenone of step (d) with hydroxylamine to yield an oxime derivative of the ortho-alkoxybenzophenone;
- and
- (f) reducing the oxime to yield a benzhydrylamine.
6 more elements
A method for preparing a resin for peptide synthesis comprising conjugating a handle to a resin to form a resin-handle conjugate, said handle having the general formula (I) ##STR8## wherein the phenyl group bearing (X.sup.1).sub.a, Z and optionally (Y).sub.c is referred to as a first phenyl group, and the phenyl group bearing (X.sup.2).sub.b and optionally (Y).sub.d is referred to as a second phenyl group;
- X.sup.1 is selected from the group consisting of --SR.sup.1, --S(O)R.sup.1, and --S(O).sub.2 R.sup.1, each X.sup.1 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Z is --OR.sup.3, being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.3 is a C.sub.1 -C.sub.10 hydrocarbon group substituted with a carboxyl group for coupling to a solid phase support;
- X.sup.2 is selected from the group consisting of --SR.sup.2, --S(O)R.sup.2, and --S(O).sub.2 R.sup.2, each X.sup.2 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the second phenyl group;
- R.sup.2 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Y is --OR.sup.4, being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.1).sub.a or Z on the first phenyl group and in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.2).sub.b on the second phenyl group;
- R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group;
- a=1-2;
- b=1-3;
- c=0-1
- d=0-1;
- and
- D is selected from the group consisting of --H, a protecting group and an N.sup..alpha. -protected aminoacyl, wherein when X.sup.1 is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, and X.sub.2 is --S(O)R.sup.2 or --S(O).sub.2 R.sup.2, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine.
11 more elements
A method of peptide synthesis comprising:
- (a) oxidizing a handle of the general formula (I) ##STR9## wherein the phenyl group bearing (X.sup.1).sub.a, Z and optionally (Y).sub.c is referred to as a first phenyl group, and the phenyl group bearing (X.sup.2).sub.b and optionally (Y).sub.d is referred to as a second phenyl group;
- X.sup.1 is selected from the group consisting of --SR.sup.1, --S(O)R.sup.1, and --S(O).sub.2 R.sup.1, each X.sup.1 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Z is --OR.sup.3, being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the first phenyl group;
- R.sup.3 is a C.sub.1 -C.sub.10 hydrocarbon group substituted with a carboxyl group for coupling to a solid phase support;
- X.sup.2 is selected from the group consisting of --SR.sup.2, --S(O)R.sup.2, and --S(O).sub.2 R.sup.2, each X.sup.2 being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, on the second phenyl group;
- R.sup.2 is a C.sub.1 -C.sub.10 hydrocarbon group;
- Y is --OR.sup.4, being in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.1).sub.a or Z on the first phenyl group and in an ortho or para position, with respect to the carbon atom of the handle bearing NHD, not occupied by (X.sup.2).sub.b on the second phenyl group;
- R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group;
- a=1-2;
- b=1-3;
- c=0-1
- d=0-1;
- and
- D is selected from the group consisting of --H, a protecting group and an N.sup..alpha. -protected aminoacyl, wherein when X.sup.1 is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, and X.sub.2 is --S(O)R.sup.2 or --S(O).sub.2 R.sup.2, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine,
- said handle having a protecting group and --SR.sup.1 and --SR.sup.2 group(s) to afford a handle having a protecting group and --S(O)R.sup.1 and --S(O)R.sup.2 groups or --S(O).sub.2 R.sup.1 and --S(O).sub.2 R.sup.2 groups;
- (b) removing the protecting group from the handle of step (a) to afford a deprotected handle;
- (c) coupling an activated amino group to the deprotected handle to afford a handle-amino acid conjugate;
- (d) successfully coupling at least one activated amino acid to the handle-amino acid conjugate to afford a handle-peptide conjugate;
- (e) reducing the --S(O)R.sup.1 and --S(O)R.sup.2 group(s) or the --S(O).sub.2 R.sup.1 and --S(O).sub.2 R.sup.2 group(s) of the handle-peptide conjugate;
- and
- (f) deprotecting the peptide and cleaving it from the handle.
19 more elements
A method for preparing a resin for peptide synthesis comprising conjugating a handle to a resin to form a resin-handle conjugate, said handle having the general formula:
- ##STR10## in which Z is --OR.sup.4, R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group comprising a carboxyl group for coupling to a solid phase support;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group and in which each G is independently selected from the group consisting of --S--, --SO--, and --SO.sub.2 --;
- and in which D is H, a protecting group or an N.sup..alpha. -protected aminoacyl, wherein when each GR.sup.1 group is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine.
A method of peptide synthesis comprising:
- (a) oxidizing a handle of the general formula:
- ##STR11## in which Z is --OR.sup.4, R.sup.4 is a C.sub.1 -C.sub.10 hydrocarbon group comprising a carboxyl group for coupling to a solid phase support;
- R.sup.1 is a C.sub.1 -C.sub.10 hydrocarbon group and in which each G is independently selected from the group consisting of --S--, --SO--, and --SO.sub.2 --;
- and in which D is H, a protecting group or an N.sup..alpha. -protected aminoacyl wherein when each GR.sup.1 group is --S(O)R.sup.1 or --S(O).sub.2 R.sup.1, the handle is stable to conditions sufficiently acidic to hydrolyze an Fmoc or a tBoc group from an amine,
- said handle having a protecting group and --SR.sup.1 and --SR.sup.2 group(s) to afford a handle having a protecting group and --S(O)R.sup.1 and --S(O)R.sup.2 groups or --S(O).sub.2 R.sup.1 and --S(O).sub.2 R.sup.2 groups;
- (b) removing the protecting group from the handle of step (a) to afford a deprotected handle;
- (c) coupling an activated amino group to the deprotected handle to afford a handle-amino acid conjugate;
- (d) successfully coupling at least one activated amino acid to the handle-amino acid conjugate to afford a handle-peptide conjugate;
- (e) reducing the --S(O)R.sup.1 and --S(O)R.sup.2 group(s) or the --S(O).sub.2 R.sup.1 and --S(O).sub.2 R.sup.2 group(s) of the handle-peptide conjugate;
- and
- (f) deprotecting the peptide and cleaving it from the handle.
8 more elements
Dependencies are inferred from the claim text.