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US 9,309,230 B2Granted
Oligooxopiperazines and methods of making and using them
AssigneeNew York University
InventorsParamjit S. Arora, Petra To{hacek over (s)}ovská, Danielle Guarracino, Brooke Bullock Lao
Life of this patent
Estimating the term…
Abstract
The present invention relates to oligooxopiperazines and their use. Methods for preparing oligooxopiperazines are also disclosed.
Claims41
A pharmaceutical formulation comprising:
- (i) an oligooxopiperazine of Formula I:
- wherein:
- each of R1, R2, R3, and R4 is independently an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- each R6 is independently H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- A is X1 or C, wherein:
- X1 is H, COR′, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag;
- wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- C is a moiety of the formula
- wherein:
- each X′ is independently H, COR′, CO2R′, CONHR′, N(R″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- R0 is an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- and
- R6 is H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- and
- B is Y or D, wherein:
- Y is OR′, COR′, N(R′″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R′″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- D is a moiety of the formula
- wherein:
- R5 is an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- R6 is H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- and
- E is X2 or F, wherein:
- X2 is H, COR′, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag;
- wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- F is a moiety of the formula
- wherein:
- R6 is H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- R7 is an amino acid side chain;
- and
- Y is OR′, COR′, N(R′″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R′″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- with the proviso that A and B are not both, respectively, C and D, and
- (ii) a pharmaceutically acceptable vehicle.
51 more elements
A method of making an oligooxopiperazine of Formula IA:
- wherein:
- each of R1, R2, R3, R4, and R5 is independently an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- each R6 is independently H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- X1 is H, COR′, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag;
- wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- E is X2 or F, wherein:
- X2 is H, COR′, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag;
- wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- F is a moiety of the formula
- wherein:
- R6 is H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- R7 is an amino acid side chain;
- and
- Y is OR′, COR′, N(R′″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R′″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- (i) wherein said method comprises:
- providing a compound of Formula III:
- wherein:
- PG is a protecting group for the protection of an amine;
- R8 is an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- and
- R9 is —O-Res or —NH-Res, wherein Res is a solid phase peptide synthesis resin;
- providing a compound of Formula IV1:
- wherein R10 is —OH or a halide;
- and
- reacting the compound of Formula III with a first alkylating agent and the compound of Formula IV1 under conditions effective to produce a compound of Formula V:
- wherein:
- if E is not —CR6R7—CO—Y, where R7 is the same as R8 and Y is the same as R9, said method further comprises converting —CR6R8—CO—R9 in the compound of Formula V to E;
- and
- if X1 is not hydrogen, said method further comprises converting the N-terminal hydrogen in the compound of Formula V to X1;
- or (ii) wherein said method comprises:
- providing a compound of Formula X:
- wherein:
- PG1 is a protecting group for the protection of an amine, and
- R10 is —OH or a halide;
- providing a compound of Formula XI5/8:
- wherein:
- PG2 is a protecting group for the protection of a carboxylic acid;
- and
- R8 is an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- and
- reacting the compound of Formula X with the compound of Formula XI5/8 under conditions effective to produce a compound of Formula XII:
- wherein:
- if E is not —CR6R7—CO—Y, where R7 is the same as R8 and Y is the same as PG2, said method further comprises converting —CR6R8—CO—PG2 in the compound of Formula XII to E;
- and
- wherein if X1 is not PG1, said method further comprises converting PG1 in the compound of Formula XII to X1.
53 more elements
A method of making an oligooxopiperazine of Formula IB:
- wherein:
- each of R1, R2, R3, and R4 is independently an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- each R6 is independently H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- X1 is H, COR′, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag;
- wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- Y is OR′, COR′, N(R′″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R′″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- (i) wherein said method comprises:
- providing a compound of Formula VII′:
- wherein:
- PG is a protecting group for the protection of an amine;
- and
- R9 is —O-Res or —NH-Res, wherein Res is a solid phase peptide synthesis resin;
- providing a compound of Formula IV1:
- wherein R10 is —OH or a halide;
- reacting the compound of Formula VII′ with a first alkylating agent and the compound of Formula IV1 under conditions effective to produce a compound of Formula VI′:
- and
- converting —R9 in the compound of Formula VI′ to Y;
- wherein if X1 is not hydrogen, said method further comprises converting the N-terminal hydrogen in the compound of Formula VI′ to X1;
- or (ii) wherein said method comprises:
- providing a compound of Formula XIII:
- wherein:
- PG1 is a protecting group for the protection of an amine, and
- R10 is —OH or a halide;
- providing a compound of Formula XI3/4:
- wherein PG2 is a protecting group for the protection of a carboxylic acid;
- and
- reacting the compound of Formula XIII with the compound of Formula XI3/4 under conditions effective to produce a compound of Formula X′:
- and
- converting —PG2 in the compound of Formula X′ to Y;
- wherein if X1 is not PG1, said method further comprises converting PG1 in the compound of Formula X′ to X1.
34 more elements
A method of making an oligooxopiperazine of Formula IC:
- wherein:
- each of R0, R1, R2, R3, and R4 is independently an amino acid side chain, H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- each R6 is independently H, N(R)2, OR, halogen, an alkyl, or an aryl;
- wherein each R is independently H, an alkyl, or an aryl;
- X′ is H, COR′, CO2R′, CONHR′, N(R″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- Y is OR′, COR′, N(R′″)2, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
- wherein:
- R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- and
- each R′″ is independently H, CO2R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
- (i) wherein said method comprises:
- providing a compound of Formula VII′:
- wherein:
- PG is a protecting group for the protection of an amine;
- and
- R9 is —O-Res or —NH-Res, wherein Res is a solid phase peptide synthesis resin;
- providing a compound of Formula IV1:
- wherein R10 is —OH or a halide;
- reacting the compound of Formula VII′ with a first alkylating agent and the compound of Formula IV1 under conditions effective to produce a compound of Formula VI′:
- converting —R9 in the compound of Formula VI′ to Y;
- and
- converting the N-terminal hydrogen in the compound of Formula VI′ to a moiety of formula
- or (ii) wherein said method comprises:
- providing a compound of Formula XIII:
- wherein:
- PG1 is a protecting group for the protection of an amine, and
- R10 is —OH or a halide;
- providing a compound of Formula XI3/4:
- wherein PG2 is a protecting group for the protection of a carboxylic acid;
- and
- reacting the compound of Formula XIII with the compound of Formula XI3/4 under conditions effective to produce a compound of Formula X′:
- converting —PG2 in the compound of Formula X′ to Y;
- and
- converting PG1 in the compound of Formula X′ to a moiety of formula
37 more elements
Dependencies are inferred from the claim text.