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US 2006/0041011 A1Published application
Prodrugs of propofol, compositions and uses thereof
AssigneeXenoPort, Inc.
InventorsFeng Xu, Mark Gallop
Life of this patent
Estimating the term…
Abstract
The present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting.
Claims47
A compound according to structural Formula (I):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- each R1 and R2 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally, R1 and R2 together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
- A is hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally, A, Y and one of R1 and R2 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
- Y is —O— or —NR3—;
- R3 is hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl;
- n is an integer from 1 to 5;
- X is —NR4—, O, —CH2— or —S—;
- and
- R4 is hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl.
6 more elements
A compound according to structural Formula (II):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
A compound according to structural Formula (III):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen, [H2NCHR5C(O)]— or —C(O)OR6;
- R5 is hydrogen, C1-6 alkyl, substituted C-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring;
- and
- R6 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-8 arylalkyl or substituted C6-8 arylalkyl.
2 more elements
A compound of structural Formula (IV):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
A compound according to structural Formula (V):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
The compound of claim 327, wherein A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2NH2, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —H2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl 3-indolylmethyl or R5 and the alpha amino group together with the atoms to which they are bonded form a pyrrolidine ring.
A compound of structural Formula (XII):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted CS-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
A compound according to structural Formula (XIII):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
A compound according to structural Formula (XIV):
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, wherein:
- A is hydrogen or [H2NCHR5C(O)]— and R5 is hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C5-7 aryl, substituted C5-7 aryl, C6-11 arylalkyl, substituted C6-11 arylalkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C5-7 heteroaryl, substituted C5-7 heteroaryl, C6-11 heteroarylalkyl, substituted C6-11 heteroarylalkyl or optionally, R5 and the alpha amino group together with the atoms to which they are bonded form a C5-7 cycloheteroalkyl or substituted C5-7 cycloheteroalkyl ring.
A compound selected from:
- 2,6-(Diisopropyl)phenyl 1-[((2S)-2-amino-3-methylbutyryl)aminomethyl]-1-cyclohexane acetate;
- 2,6-(Diisopropyl)phenyl 1-[((2S)-2-amino-3-hydroxypropionyl)aminomethyl]-1-cyclohexane acetate;
- 2,6-(Diisopropyl)phenyl 1-[((2S)-2-amino-(3R)-3-hydroxybutyryl)aminomethyl]-1-cyclohexane acetate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-carbamoylpropionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-carboxypropionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2,3-diaminopropionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-hydroxypropionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-aminopropionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-(3R)-3-hydroxybutyryl]amino-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-(4-hydroxyphenyl)propionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-(indol-3-yl)propionylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[aminomethylcarbonylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-4-carboxybutyrylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2,6-diaminohexanoylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-pyrrolidin-2-ylcarbonylamino]-3,3-dimethylbutanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-methylbutyrylamino]-3,3-dimethylbutanoate;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-carbamoylpropionate;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethanol;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-hydroxypropionate;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-carbamoylpropionamide;
- 1-Amino-2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethane;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl glycinamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2,6-diaminohexanoylamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-hydroxypropionamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-(4-hydroxyphenyl)propionamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonylamino]ethyl (2S)-2-amino-3-carboxypropionamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonylamino]ethyl (2S)-2-amino-3-hydroxypropionamide;
- 2-[2,6-(Diisopropyl)phenoxycarbonylamino]ethyl (2S)-2-amino-3-methylbutanoylamide;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-methylbutyrylamino]butanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-carbamoylpropionylamino]butanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-4-carboxylbutyrylamino]butanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-(3R)-3-hydroxylbutyryl]aminobutanoate;
- and
- 2,6-(Diisopropyl)phenyl 4-[(2S)-pyrrolidin-2-ylcarbonylamino]butanoate;
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-hydroxypropionylamino]butanoate;
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
33 more elements
A compound selected from:
- 2,6-(Diisopropyl)phenyl 1-[((2S)-2-amino-(3R)-3-hydroxybutyryl)aminomethyl]-1-cyclohexane acetate;
- 1-Amino-2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethane;
- 2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-hydroxypropionamide;
- and
- 2,6-(Diisopropyl)phenyl 4-[(2S)-2-amino-3-methylbutyrylamino]butanoate;
- or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
3 more elements
Dependencies are inferred from the claim text.