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US 7,071,219 B2Granted
Mono-acylated o-phenylendiamines derivatives
AssigneeHoffmann-La Roche Inc.
InventorsGeorg Fertig, Frank Herting, Manfred Kubbies, Anja Limberg, Ulrike Reiff, Michael Weidner
Life of this patent
Estimating the term…
Abstract
Mono-acylated o-phenylendiamines derivatives of formula A wherein Ar, R1, and R2 are as described herein, have been found useful for the treatment of diseases mediated by the inhibition of histone deacetylase, such as cancer.
Claims39
A compound of formula A
- wherein
- Ar is pyridine-2,5-diyl, pyridine-5,2-diyl, pyridine-2,6-diyl, or pyridine-2,4-diyl,
- R1, R2 are each independently selected from hydrogen, substituted or unsubstituted C1-12-alkyl, substituted or unsubstituted C2-12-alkenyl, substituted or unsubstituted C2-12-alkynyl, and substituted or unsubstituted C3-12-cycloalkyl, wherein the substituent is selected from hydroxy, halogen, C3-12-cycloalkyl, alkoxy, alkylsulfanyl, acyloxy, alkoxycarbonyl, acyl, C1-6-alkyl-NH—C(O)—, C1-6-alkyl-C(O)NH— and —NR3R4, or alternatively
- R1 is hydrogen, and
- R2 is hydroxy, alkoxy, C2–C12-alkenyloxy, phenoxy, or phenoxy substituted with methyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ethenyl or —C(O)—O—CH3;
- and
- R3 and R4 are each independently selected from hydrogen or C1-6-alkyl, or alternatively
- R3 and R4 together with the nitrogen-atom to which they are attached form a ring, which ring is monosubstituted by oxo and which ring optionally contains a further heteroatom,
- or a pharmaceutically acceptable salt thereof.
6 more elements
A process for the preparation of a compound of formula I
- wherein
- Ar is pyridine-2,5-diyl, pyridine-5,2-diyl, pyridine-2,6-diyl, or pyridine-2,4-diyl,
- R1, R2 are each independently selected from hydrogen, substituted or unsubstituted C1-12-alkyl, substituted or unsubstituted C2-12-alkenyl, substituted or unsubstituted C2-12-alkynyl, and substituted or unsubstituted C3-12-cycloalkyl, wherein the substituent is selected from hydroxy, halogen, C3-12-cycloalklyl, alkoxy, alkylsulfanyl, acyloxy, alkoxycarbonyl, acyl, C1-6-alkyl-NH—C(O)—, C1-6-alkyl-C(O)NH— and —NR3R4, or alternatively
- R1 is hydrogen, and
- R2 is hydroxy, alkoxy, C2–C12-alkenyloxy, phenoxy, or phenoxy substituted with methyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ethenyl or —C(O)—O—CH3;
- and
- R3 and R4 are each independently selected from hydrogen or C1-6-alkyl, or alternatively
- R3 and R4 together with the nitrogen-atom to which they are attached form a ring, which ring is monosubstituted by oxo and which ring optionally contains a further heteroatom,
- or a pharmaceutically acceptable salt thereof, comprising:
- activating a compound of the formula II
- wherein when R2 is hydroxy, R2 the hydroxyl is optionally protected by a protecting group,
- in the presence of an activating agent;
- adding a compound of formula III
- wherein Y represents hydrogen or a suitable amino protecting group;
- and cleaving off any protecting groups to give a compound of formula I.
12 more elements
A process for the preparation of a compound of formula I
- wherein
- Ar is pyridine-2,5-diyl, pyridine-5,2-diyl, pyridine-2,6-diyl, or pyridine-2,4-diyl,
- R1, R2 are each independently selected from hydrogen, substituted or unsubstituted C1-12-alkyl, substituted or unsubstituted C2-12-alkenyl, substituted or unsubstituted C2-12-alkynyl, and substituted or unsubstituted C3-12-cycloalkyl, wherein the substituent is selected from hydroxy, halogen, C3-12-cycloalkyl, alkoxy, alkylsulfanyl, acyloxy, alkoxycarbonyl, acyl, C1-6-alkyl-NH—C(O)—, C1-6-alkyl-C(O)NH— and —NR3R4, or alternatively
- R1 is hydrogen, and
- R2 is hydroxy, alkoxy, C2–C12-alkenyloxy, phenoxy, or phenoxy substituted with methyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ethenyl or —C(O)—O—CH3;
- and
- R3 and R4 are each independently selected from hydrogen or C1-6-alkyl, or alternatively
- R3 and R4 together with the nitrogen-atom to which they are attached form a ring, which ring is monosubstituted by oxo and which ring optionally contains a further heteroatom,
- or a pharmaceutically acceptable salt thereof, comprising:
- reacting a compound of the formula VI
- wherein Y is suitable protecting group,
- with an an amine of the formula HNR1R2, and wherein when R2 is hydroxy, the hydroxyl optionally is protected wth a protecting group;
- and
- cleaving off any protecting groups to give a compound of formula I.
11 more elements
Dependencies are inferred from the claim text.