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US 6,660,832 B1Granted
Macrocyclic compounds and preparation methods thereof
AssigneeIsis Pharmaceuticals, Inc.
InventorsElizabeth Jefferson, Eric Edward Swayze
Life of this patent
Estimating the term…
Abstract
The present invention is directed to macrocyclic compounds of the formula (I) wherein Q, X, R1 and R5 are as defined herein. Compounds of the invention are useful for therapeutic and prophylactic treatment of bacterial infection in mammals. Solid phase synthetic procedures are provided effecting synthesis of the macrocyclic rings attached to a solid support.
Claims31
A macrocyclic compound of formula (I),
- wherein:
- X is O, NH or S;
- Q is a bivalent linker comprising at least two amino acid residues wherein one of said amino acids is a β-amino acid;
- R1 is an amino acid side chain;
- R5 is H, OH, COOH, halogen, SH, cyano, amino, diazo, iminium, nitroso, nitro, sulfonate ester, trialkylamino, trifluoromethyl, sulfate, alkoxy, —C(O)NH2, —C(O)NHR6, —C(O)-(amino acid residue)1-4, —C(O)OR6, —CH2OH, —CH2OR6, —NHC(O)R7 or —NH-(amino acid residue)1-4;
- R6 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido, or a nucleobase;
- or R6 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- and
- R7 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido or a nucleobase;
- or R7 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, C1-4 alkyl, COOH, oxo, cyano, amino, amidino, guanidino, or ureido.
7 more elements
A macrocyclic compound of formula II,
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, amino or an amino acid side chain;
- R5 is H, OH, COOH, halogen, SH, cyano, amino, diazo, iminium, nitroso, nitro, sulfonate ester, trialkylamino, trifluoromethyl, sulfate, alkoxy, —C(O)NH2, —C(O)NHR6, —C(O)-(amino acid residue)1-4, —C(O)OR6, —CH2OH, —CH2OR6, —NHC(O)R7 or —NH-(amino acid residue)1-4;
- R6 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido, or a nucleobase;
- or R6 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- and
- R7 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido or a nucleobase;
- or R7 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, C1-4 alkyl, COOH, oxo, cyano, amino, amidino, guanidino, or ureido.
6 more elements
A compound of formula II,
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, OH, amino, carboxyl, halogen, cycloalkyl, aryl, a heterocycle, a nucleobase or alkyl optionally substituted with OH, COOH, halogen, oxo, SH, alkylthio, amino, amido, guanidino, amidino, cycloalkyl, aryl, a heterocycle or a nucleobase wherein said cycloalkyl, aryl and heteroaryl groups are optionally substituted with OH, amino, oxo, COOH or halogen;
- R5 is H, OH, COOH, halogen, SH, cyano, amino, diazo, iminium, nitroso, nitro, sulfonate ester, trialkylamino, trifluoromethyl, sulfate, alkoxy, —C(O)NH2, —C(O)NHR6, —C(O)-(amino acid residue)1-4, —C(O)OR6, —CH2OH, —CH2OR6, —NHC(O)R7 or —NH-(amino acid residue)1-4;
- R6 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido, or a nucleobase;
- or R6 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- and
- R7 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido or a nucleobase;
- or R7 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, C1-4 alkyl, COOH, oxo, cyano, amino, amidino, guanidino, or ureido.
6 more elements
A compound having the formula:
A macrocyclic compound of the formula (I),
- wherein:
- X is O, NH or S;
- Q is a bivalent linker comprising at least two amino acid residuals wherein one of said amino acids is a β-amino acid;
- R1 is an amino acid side chain;
- and
- R5 is an electron withdrawing group.
3 more elements
A macrocyclic compound of formula II,
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 arc each independently H, amino or an amino acid side chain;
- and
- R5 is an electron withdrawing group.
2 more elements
A compound of formula II,
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, OH, amino, carboxyl, halogen, cycloalkyl, aryl, a heterocycle, a nucleobase or alkyl optionally substituted with OH, COOH, halogen, oxo, SH, alkylthio, amino, amido, guanidino, amidino, cycloalkyl, aryl, a heterocycle or a nucleobase wherein said cycloalkyl, aryl and heteroaryl groups are optionally substituted with OH, amino, oxo, COOH or halogen;
- and
- R5 is an electron withdrawing group.
2 more elements
A process for preparing macrocyclic compounds or solid support-bound compound of formula (IIa),
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, amino or an amino acid side chain;
- R5 is H, OH, COOH, halogen, SH, cyano, amino, diazo, iminium, nitroso, nitro, sulfonate ester, trialkylamino, trifluoromethyl, sulfate, alkoxy, —C(O)NH2, —C(O)NHR6, —C(O)-(amino acid residue)1-4, —C(O)OR6, —CH2OH, —CH2OR6, —NHC(O)R7 or —NH-(amino acid residue)1-4;
- R6 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido, or a nucleobase;
- or R6 is aryl, aralkyl a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- R7 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido or a nucleobase;
- or R7 is aryl, aralkyl, a heterocycle or a heterocycle-alkyl group each optionally substituted with OH, halogen, C1-4 alkyl, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- and
- R8 is H or a solid support, provided that no more than one R8 is a solid support;
- comprising cyclizing a compound or solid support-bound compound of formula (III)
- wherein L is a leaving group;
- for a time and under conditions effective to achieve aromatic nucleophilic substitution.
10 more elements
A process for preparing macrocyclic compounds or solid support-bound compound of formula (IIa),
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, amino or an amino acid side chain;
- R5 is an electron withdrawing group;
- and
- R8 is H or a solid support, provided that no more than one R8 is a solid support;
- comprising cyclizing a compound or solid support-bound compound of formula (III)
- wherein L is a leaving group, for a time and under conditions to achieve aromatic nucleophilic substitution.
5 more elements
A process for preparing macrocyclic compounds of formula II
- wherein:
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, amino or an amino acid side chain;
- R5 is H, OH, COOH, halogen, SH, cyano, amino, diazo, iminium, nitroso, nitro, sulfonate ester, trialkylamino, trifluoromethyl, sulfare, alkoxy, —C(O)NH2, —C(O)NHR6, —C(O)-(amino acid residue)1-4, —C(O)OR6, —CH2OH, —CH2OR6, 13 NHC(O)R7 or —NH-(amino acid residue)1-4;
- R6 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido, or a nucleobase;
- or R6 is aryl, aralkyl a heterocycle or a heterocycle-akyl group each optionally substituted with OH, halogen, COOH, oxo, cyano, amino, amidino, guanidino, or ureido;
- and
- R7 is alkyl optionally substituted with OH, halogen, COOH, cyano, amino, amidino, guanidino, ureido or a nucleobase;
- or R7 is aryl, aralkyl, a heterocycle or a heterocycle-akyl group each optionally substituted with OH, halogen, C1-4 alkyl, COOH, oxo, cyano amino, amidino, guanidino, or ureido;
- said process comprising,
- cyclizing a compound or solid support-bound compound of formula (III)
- wherein:
- L is a leaving group;
- and
- R8 is H or a solid support, provided that no more than one R8 is a solid support;
- for a time and under conditions effective to achieve aromatic nucleophilic substitution.
13 more elements
A process for preparing macrocyclic compounds of formula II,
- wherein;
- X is O, NH or S;
- R1, R2, R3, and R4 are each independently H, amino or an amino acid side chain;
- and
- R5 is an electron withdrawing group;
- said process comprising,
- cyclizing a compound or solid support-bound compound of formula (III)
- wherein:
- L is a leaving group;
- and
- R8 is H or a solid support, provided that no more than one R8 is a solid support;
- for a time and under conditions to achieve aromatic nucleophilic substitution.
9 more elements
Dependencies are inferred from the claim text.