Back to results
US 6,284,784 B1Granted
Substituted 2-pyrrolidinone activators of PKC
AssigneeGeorgetown University
InventorsAlan P. Kozikowski, Shaomeng Wang, Lixin Qiao
Life of this patent
Estimating the term…
Abstract
Compounds of formula I: wherein R1 and R2 have any of the values defined in the specification, and their pharmaceutically acceptable salts, are PKC activators and are useful for treating diseases, such as, for example, cancer. Also disclosed are pharmaceutical compositions comprising compounds of formula I, processes for preparing compounds of formula I, and intermediates useful for preparing compounds of formula I.
Claims37
A therapeutic method for treating a condition characterized by the pathological proliferation of mammalian cells sensitive to a compound of Formula I comprising administering to a mammal afflicted with such a condition, an effective amount of a compound of Formula I:
- wherein
- R1 and R2 are each independently (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, (C3-C8)cycloalkyl(C1-C15)alkenyl, (C3-C8)cycloalkyl(C1-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C2-C15)alkenyl, heteroaryl(C2-CC15)alkenyl, aryl(C2-C15)alkynyl, heteroaryl(C2-C15)alkynyl, aryl(C1-C15)alkoxy, C1-C15)alkoxyl, aryl(C1-C15)alkynyl, heteroaryl(C1-C15)alkanoyl, aryl(C1-C15)alkanoyloxy, or heteroaryl(C1-C15)alkanoyloxy;
- wherein any R1 or 2 is optionally substituted with one or more substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifuoromethoxy, (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl, (C1-C15)alkyl, (C3-C8)cycloalkyl-(C2-C15)alkenyl, (C3-C8)cycloalkyl(C2-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, C(═O)ORa, C(═O)NRbRc, OC(═)ORa, OC(═O)NRbRc, and NReRf;
- and wherein any aryl or heteroaryl of R1 or R2 is optionally substituted on a non-aromatic carbon by a divalcnt (C2-C7)alkylene chain to form a (C3-C8)spirocycloalkyl;
- each Ra is independently hydrogen or (C1-C6)alkyl;
- each Rb and Rc is independently, hydrogen or (C1-C10)alkyl;
- or Rb, and Re together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- and
- each Re and Rf is independently hydrogen, (C1-C10)alkyl, (C1-C10)alkanoyl, phenyl, benzyl, or phenethyl;
- or Rc and Rf together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- or a pharmaceutically acceptable salt thereof.
8 more elements
A method modulating protein kinase C in a mammalian cells comprising administering an effective dose of a compound of Formula I:
- wherein
- R1 and R2 art each independently (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, (C3-C8)cycloalkyl(C1-C15)alkenyl, (C3-C8)cycloalkyl(C1-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C2-C15)alkenyl, heteroaryl(C2-C15)alkenyl, aryl(C2-C15)alkynyl, heteroaryl(C2-C15)alkynyl, aryl(C1-C15)alkoxy, heteroaryl(C1-C15)alkoxy, aryl(C1-C15)alkanoyl, heteroaryl(C1-C15)alkanoyl, aryl (C1-C15)alkanoyloxy, or heteroaryl(C1-C15)alkanoyloxy;
- wherein any R1 or R2 is optionally substituted with one or more substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl,(C1-C15)alkyl, (C3-C8)cycloalkyl-(C2-C15)alkenyl, (C3-C8)cycloalkyl(C2-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, C(═O)ORa, C(═O)NRb, Rc, OC(═O)ORa, OC(═O)NRbRc, and NReRf;
- and wherein any aryl or heteroaryl of R1 or R2 is optionally substituted on a non-aromatic carbon by a divalent (C2-C7)alkylene chain to form a (C3-C8)spirocycloalkyl;
- each Ra is independently hydrogen or (C1-C6)alkyl;
- each Rb and Rc is independently, hydrogen or (C1-C10)alkyl;
- or Rb, and Rc together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- and
- each Re and Rf is independently hydrogen, (C1-C10)alkyl, (C1-C10)alkanoyl, phenyl, benzyl, or phenethyl;
- or Re and Rf together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- or a pharmaceutically acceptable salt thereof.
8 more elements
A method for reducing pathological proliferation of mammalian cells sensitive to the compound of Formula I, comprising administering to the cells an effective amount of a compound of Formula I,
- wherein
- R1 and R2 are each independently (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, (C3-C8)cycloalkyl(C1-C15)alkenyl, (C314 C8)cycloalkyl(C1-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C2-C15)alkenyl, heteroaryl(C2-C15)alkenyl, aryl(C2-C15)alkynyl, heteroaryl(C2-C15)alkynyl, aryl(C1-C15)alkoxy, heteroaryl(C1-C15)alkoxy, aryl(C1-C15)alkanoyl, heteroaryl(C1-C15)alkanoyl, aryl (C1-C15)alkanoyloxy, or heteroaryl(C1-C15)alkanoyloxy;
- wherein my R1 or R2 is optionally substituted with one or more substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C15)alkyl, (C2-C15)alkenyl, (C2-C15)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl,(C1-C15)alkyl, (C3-C8)cycloalkyl-(C2-C15)alkenyl, (C3-C8)cycloalkyl(C2-C15)alkynyl, (C1-C15)alkoxy, (C1-C15)alkanoyl, (C1-C15)alkanoyloxy, C(═O)ORa, C(═O)NRbRc, OC(═O)ORa, OC(═O)NRbRc, and NReRf;
- and wherein any aryl or heteroaryl of R1 or R2 is optionally substituted on a non-aromatic carbon by a divalent (C2-C7)alkylene chain to form a (C3-C8)spirocycloalkyl;
- each Ra is independently hydrogen or (C1-C6)alkyl;
- each Rb and Rc is independently, hydrogen or (C1-C10)alkyl;
- or Rb, and Rc together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- and
- each Re and Rf is independently hydrogen, (C1-C10)alkyl, (C1-C10)alkanoyl, phenyl, benzyl, or phenethyl;
- or Re and Rf together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
- or a pharmaceutically acceptable salt thereof.
8 more elements
Dependencies are inferred from the claim text.