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US 8,168,826 B2Granted
Method of producing highly functionalized 1,3-diamino-propan-2-ols from solid support
AssigneeJanssen Pharamcuetica N.V.
InventorsSteve J. Coats, Dennis J. Hlasta, Mark J. Schulz
Life of this patent
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Abstract
The invention is directed to compounds and methods of synthesizing hydroxyethylamino amides and their use in treatment of aspartyl protease mediated diseases and conditions.
Claims12
A method of synthesizing a hydroxyethylamino amide of Formula (I):
- wherein:
- R1 is selected from the group consisting of C1-8alkanyl, cyclicC1-8alkanyl, C6-14aryl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, and C1-8alkoxy(C2-8)alkynyl, wherein C1-8alkanyl, cyclicC1-8alkanyl, C6-14aryl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, and C1-8alkoxy(C2-8)alkynyl-are optionally substituted with one to two substituents independently selected from the group consisting of C6-14aryloxy, diC1-8alkanylamino, C1-8alkanylamino, C1-8alkanyl, C6-14aryl, C1-8alkanyloxy, C1-8alkanylcarbonyl, perhaloC1-6alkanyl, halo, C1-8alkanyl, C1-8alkanylthio, C6-14arylalkynyl, C1-8alkanylsulfonyl, C6-14arylC1-8alkanyl, C1-8alkanyloxy, C6-14arylC1-8alkanyloxy, C6-14arylC1-8alkanyloxycarbonylamino, and C1-8alkanylcarbonylamino;
- R2 is selected from the group consisting of C1-8alkanyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, and C1-8alkanyloxy(C2-8)alkynyl, wherein C1-8alkanyl, C1-8alkenyl C2-8alkynyl are optionally substituted with one or two substituents independently selected from the group consisting of C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, and C6-14aryl;
- R3 is selected from the group consisting of C1-8alkanyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkoxy(C2-8)alkynyl, C1-8alkanyl, cyclicC1-8alkanyl, andC6-14aryl, wherein C1-8alkanyl, cyclicC1-8alkanyl, and C6-14aryl, are optionally substituted with one or two substituents independently selected from the group consisting of (C1-8alkanylthio)(aminocarbonyl), C1-8alkanylaminocarbonyl, (C6-14aryl)(C1-8alkanylaminocarbonyl), amino, aminosulfonylC6-14aryl, C1-8alkanyloxycarbonylamino, C1-8alkanylC6-14arylamino, C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C6-14aryl, C6-14arylC1-8alkanyloxycarbonylamino, C6-14aryloxy, C6-14aryloxyC6-14aryl, diC1-8alkanyloxyC6-14aryl, dihaloC6-14aryl, and haloC6-14aryl, wherein said aryl is optionally substituted with a substituent independently selected from the group consisting of C1-8alkanyl, and C6-14aryloxy;
- and
- an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, the method comprising:
- (a) preparing a epoxymethylated support of formula (Ia)
- wherein (support) is an amine based polystyrene resin;
- (b) reacting the support of formula (Ia) with an R1 carboxylic acid or a compound of the formula R1 COY wherein Y is selected from the group consisting of OH, Cl, Br, OC1-3alkanyl and OOCR1 to generate an epoxymethylated amido support of formula (Ib)
- (c) reacting the epoxymethylated amido support of formula (Ib) with an R2 amine of the formula R2NH2 to generate a hydroxyethylamino amido support of formula (Ic)
- (d) reacting the hydroxyethylamino amido support of formula (Ic) with an R3 aldehyde of the formula R3CHO to generate a hydroxyethylamino amido support of formula (Id)
- (e) cleaving the hydroxyethylamino amide of formula (I) from the hydroxyethylamino amido support of formula (Id) with a suitable cleaving agent.
9 more elements
A method of synthesizing a hydroxyethylamino amide of Formula (I):
- wherein:
- R1 is selected from the group consisting of C1-8alkanyl, cyclicC1-8alkanyl, and C6-14aryl, wherein C1-8alkanyl, cyclicC1-8alkanyl, and C6-14aryl-are optionally substituted with one to two substituents independently selected from the group consisting of C6-14aryloxy, diC1-8 alkanylamino, C1-8 alkanylamino, C1-8 alkanyl, C6-14aryl, C1-8alkanyloxy, C1-8alkanylcarbonyl, perhaloC1-6alkanyl, halo, C1-8alkanyl, C1-8alkanylthio, C6-14arylalkynyl, C1-8alkanylsulfonyl, C6-14arylC1-8alkanyl, C1-8 alkanyloxy, C6-14arylC1-8alkanyloxy, C6-14arylC1-8 alkanyloxycarbonylamino, and C1-8 alkanylcarbonylamino;
- R2 is selected from the group consisting of C1-8alkanyl, C1-8alkenyl, and hydrogen, wherein C1-8alkanyl and C1-8alkenyl are optionally substituted with one or two substituents independently selected from the group consisting of C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C6-14aryl, and C6-14aryl;
- R3 is C1-8alkanyl and is optionally substituted with one or two substituents independently selected from the group consisting of (C1-8alkanylthio)(aminocarbonyl), C1-8alkanylaminocarbonyl, (C6-14aryl)(C1-8alkanylaminocarbonyl), amino, aminosulfonylC6-14aryl, C1-galkanylC3-8cyclicheteroalkanyl, C1-8alkanyloxycarbonylamino, C1-galkanylC6-14arylamino, C1-galkanylC6-14aryl, C1-galkanyloxyC6-14aryl, C6-14arY1, C6-14arylC1-8alkanyloxycarbonylamino, C6-14aryloxy, C6-14aryloxyC6-14aryl, diC1-8alkanyloxyC6-14aryl, dihaloC6-14aryl, and haloC6-14aryl,-wherein aryl is optionally substituted with a substituent independently selected from C1-salkanyl or C6-14aryloxy,
- and an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, the method comprising:
- (a) preparing an epoxymethylated support of formula (Ia)
- wherein (support) is an amine based polystyrene resins;
- (b) reacting the epoxymethylated support of formula (Ia) with an R1 carboxylic acid or a compound of the formula R1COY wherein Y is selected from the group consisting of OH, Cl, Br, OC1-3alkanyl and OOCR1 to generate an epoxymethylated amido support of formula (Ib)
- (c) reacting the epoxymethylated amido support of formula (Ib) with an R2 amine of the formula R2NH2 to generate a hydroxyethylamino amido support of formula (Ic)
- (d) reacting the hydroxyethylamino amido support of formula (Ic) with an R3 aldehyde of the formula R3CHO to generate a hydroxyethylamino amido support of formula (Id)
- (e) cleaving the hydroxyethylamino amide of formula (I) from the hydroxyethylamino amido support of formula (Id) with a suitable cleaving agent.
8 more elements
Dependencies are inferred from the claim text.