Benzylated PDE4 inhibitors
AssigneeInflazyme Pharmaceuticals Ltd.
InventorsRonald W. Lauener, David L. Burgoyne, Patrick J. Rebstein, Lloyd F. Mackenzie, Yuanlin Zhou, Yaping Shen
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Abstract
The present invention is directed to a method for reducing the emetogenic effects of PDE inhibitors, and more particularly is directed to compounds having PDE4 inhibition activity with little or no emetogenic side-effects, and chemical methods including benzylation for preparing such compounds. A benzyl group may be attached to either a carbon or nitrogen atom of a PDE4 inhibitor. Suitable benzylation chemistry is to extract a hydrogen from a PDE4 inhibitor, preferably with a base, and then react the resulting nucleophilic PDE4 inhibitor with a benzylating agent, e.g., benzyl bromide or a derivative thereof.
Claims11
A compound of the formula
- and isolated stereoisomers, salts and solvates thereof, wherein
- Bzl is a benzyl group of the formula
- wherein each of the numerals 1, 2, 3, 4 and 5 is carbon, with the proviso that the ring is aromatic;
- n is 5 and R1 at each occurrence is independently selected from halogen, nitro, R2, NR2(m), and OR2 wherein m=0, 1, 2, or 3 and R2 at each occurrence is independently selected from H, C1-C8alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C3-C7cycloalkyl, C6-C9polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C1-C4alkyl and indanyl;
- wherein the alkyl portion of an R2 group may be optionally substituted with one or more fluorine atoms, hydroxyl or C1-C8alkoxy;
- and the aryl portion of an R2 group may be optionally substituted with C1-C8alkyl, C1-C8alkoxy or halogen;
- A is selected from a direct bond, optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenyl and optionally substituted phenylene;
- p is 5 and R3 at each occurrence is independently selected from halogen, nitro, R4, NR4(q), and OR4 wherein q=0, 1, 2, or 3 and R4 at each occurrence is independently selected from H, C1-C8alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C3-C7cycloalkyl, C6-C9polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C1-C4alkyl and indanyl;
- wherein the alkyl portion of an R4 group may be optionally substituted with one or more fluorine atoms, hydroxyl or C1-C8alkoxy;
- and the aryl portion of an R4 group may be optionally substituted with C1-C8alkyl, C1-C8alkoxy or halogen;
- with the proviso that R3 at the para position relative to A is alkoxy, and R3 at one meta position is selected from alkyl having at least 3 carbons and alkoxy having at least 3 carbons.
Dependencies are inferred from the claim text.