COMPOSITIONS AND METHODS USEFUL FOR TREATING DISEASES

• US 20120225851A1
• Filed: 12/22/2011
• Published: 09/06/2012
• 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.
• Granted Patent: US 8,987,271 B2
• Time in Patent Office: Days
• US Class Current: 514/171
• 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 present invention relates to a chemotherapeutic cancer treatment in which compounds of Formula Ia′, Ib′, Ic′, or II′ (referred to as a group as BH3Is) are administered to a mammal for the treatment of B-cell Lymphoma or other hematopoietic cancers, including diseases associated with MCL-1. In another aspect, the invention provides a method for treating particular types of hematopoietic cancers, such as B-cell lymphoma, using a combination of one or more compounds selected from the group consisting of compounds or Formula Ia, Ib, Ic, or II in combination with other therapies, for example, a class of therapeutics known as 26S proteosome inhibitors, such as, for example, Bortezomib. In another aspect the present invention relates to autoimmune treatment with pharmaceutical compositions comprising one or more compounds of Formula Ia′, Ib′, Ic′, or II′. In another aspect, this invention 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.

Claims

1-2. -2. (canceled)

3. A compound of Formula Ic:

7. The composition of claim 3, wherein said composition is a pharmaceutical composition comprising a compound of Formula Ic′

;

4. A compound of Formula II:

8. The composition of claim 4, wherein said composition is a compound of Formula II′

;

22. A composition of claim 4, wherein the composition is a pharmaceutical composition.

23. A composition of claim 8, wherein the composition is a pharmaceutical composition.

5-6. -6. (canceled)

9. A method for treating a patient having cancer, said method comprising administering to said patient a pharmaceutical composition comprising one or more compounds of Formula II in amounts sufficient to inhibit growth of said cancer in said patient.

10. The method of claim 9, wherein the cancer is a hematopoietic cancer.

11. The method of claim 10, wherein the hematopoietic cancer is multiple myeloma, B cell lymphoma, T cell lymphomas, chronic lymphocytic leukemia, multiple myeloma, acute myelogenous leukemia, Acute lymphoblastic leukemia, Chronic myelogenous leukemia, Acute monocytic leukemia, Burkitt'"'"'s lymphoma, Hodgkin'"'"'s lymphomas, Non-Hodgkin'"'"'s lymphomas including;

Diffuse large B-cell lymphoma, Follicular lymphoma, Follicular lymphoma, Mantle cell lymphoma, and Marginal zone lymphoma.

12. The method of claim 9 wherein the patient is also administered a 26S proteosome inhibitor.

13. The method of claim 12 wherein the 26S proteosome inhibitor is bortezomib.

14. The method of claim 13 wherein the patient is also administered any combination of dexamethasone derivative and/or thalidomide derivative compound.

15. The method of claim 14 wherein the thalidomide derivative is revlamid.

16. The method of claim 9, wherein the patient is also administered a chemotherapeutic agent that increases the level of Mcl-1 in the cancer cell.

17-21. -21. (canceled)