2,2′-biphenazine compounds and methods useful for treating disease

• US 8,987,271 B2
• Filed: 12/22/2011
• Issued: 03/24/2015
• Est. Priority Date: 12/22/2010
• Status: Active Grant

• Current Assignee: Eutropics Pharmaceuticals, Inc.
• Original Assignee: Eutropics Pharmaceuticals, Inc.
• Inventors: Cardone, Michael H., Yu, Xiang Y., Kolodziej, Andrew F.
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US13/335,287
• Publication Number:
  US 20120225851A1
• Time in Patent Office: 1,188 Days
• Field of Search: 514/250, 544/347
• US Class Current: 514/250
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07C 217/92 the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 229/18 the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 229/34 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 229/48 with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
• CPC Class Codes: C07C 229/58 having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 229/64 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/36 with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/34 : in position 2
• CPC Class Codes: C07D 211/46 : having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/79 : Acids; Esters
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 235/26 : Oxygen atoms
• CPC Class Codes: C07D 239/28 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/46 : Phenazines
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/48 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical

Abstract

The invention relates to a chemotherapeutic cancer treatment in which compounds (BH3Is) are administered to a mammal to treat B-cell Lymphoma or other hematopoietic cancers, including diseases associated with MCL-1. The invention also provides a method for treating types of hematopoietic cancers, such as B-cell lymphoma, using a combination of one or more disclosed compounds in combination with other therapies, for example, 26S proteosome inhibitors, such as, for example, Bortezomib. The invention also relates to autoimmune treatment with pharmaceutical compositions comprising one or more disclosed compounds. The invention also relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have unique in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease. Illustrative compounds are those of Formula II:

Claims

1. A compound selected from dimethyl 4,4′

-diformyl-1,1′

,3,3′

,6,6′

-hexahydroxy-[2,2′

-biphenazine]-9,9′

-dicarboxylate and dimethyl 1,1′

,3,3′

,6,6′

-hexahydroxy-4,4′

-bis(hydroxymethyl)-[2,2′

-biphenazine]-9,9′

-dicarboxylate.

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. A compound, wherein the compound is dimethyl 4,4′

-diformyl-1,1′

,3,3′

,6,6′

-hexahydroxy-[2,2′

-biphenazine]-9,9′

-dicarboxylate.

4. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.

5. A compound, wherein the compound is dimethyl 1,1′

,3,3′

,6,6′

-hexahydroxy-4,4′

-bis(hydroxymethyl)-[2,2′

-biphenazine]-9,9′

-dicarboxylate.

6. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.