PHOSPHORYLATED POLYOLS, PYROPHOSPHATES, AND DERIVATIVES THEREOF HAVING BIOLOGICAL ACTIVITY

• US 20140142052A1
• Filed: 05/17/2013
• Published: 05/22/2014
• Est. Priority Date: 05/17/2012
• Status: Abandoned Application

• Current Assignee: Universite De Strasbourg (Financière Meeschaert SA), NormOxys, Inc.
• Original Assignee: NormOxys, Inc.
• Inventors: Lehn, Jean-Marie, Nicolau, Yves Claude, Pothukanuri, Srinivasu, Hey, John, Brockman, Adam, Yu, Jeremy
• Application Number:
  US13/897,113
• Publication Number:
  US 20140142052A1
• Time in Patent Office: Days
• US Class Current: 514/25
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/665 having oxygen as a ring hetero atom, e.g. fosfomycin
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07F 9/093 Polyol derivatives esterified at least twice by phosphoric acid groups
• CPC Class Codes: C07F 9/65746 the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: C07H 11/04 Phosphates; Phosphites; Polyphosphates

Abstract

The present invention provides phosphorylated and pyrophosphate derivatives of polyols, and structural derivatives of these compounds, and provides pharmaceutical compositions comprising the same. The compounds and compositions disclosed herein have various biological activities, including for example, as allosteric effectors of hemoglobin and/or as kinase inhibitors. The present invention further provides methods for therapy in human or mammalian patients, and methods for synthesis of biologically active compounds and their intermediates.

Claims

1. A method for treating a patient having a condition associated with PI3 kinase activity, comprising administering to the patient an effective amount of a PI3K inhibitor having a pyrophosphoryl ring, or structural mimetic thereof.

2. The method of claim 1, wherein the patient'"'"'s condition is associated with, or characterized by, an amplification, somatic mutation, chromosomal rearrangement, overexpression, or overactivity of a PI3K.

3. The method of claim 2, wherein the PI3K is one or more of a class I PI3K, class II PI3K, class III, and class IV PI3K.

4. The method of any one of claim 1, wherein the patient has a mutation or alteration in a PI3K pathway gene.

5. The method of claim 4, wherein the condition is associated with an inactivation of the tumor suppressor PTEN.

6. The method of claim 1, wherein the condition is an allergic disease, inflammation, heart disease, autoimmunity, diabetes mellitus, or cancer.

7. The method of claim 6, wherein the condition is cancer, and the cancer is one or more of ovarian, cervical, endometrial, colorectal, breast, pancreatic, gastric, glioblastoma, melanoma, liver, prostate, leukemia, lymphoma, head and neck, gastric, kidney, or lung.

8. The method of claim 7, wherein the patient is tested prior to therapy for an alteration, hyperactivity, or overexpression of a PI3K, or mutation or inactivation of PTEN.

9. The method of claim 1, wherein the method comprises administering a compound that is a polyphosphorylated inositol having at least one internal pyrophosphate ring.

10. The compound of claim 9, wherein the compound is myo-inositol 1,6;

2,3;

4,5 tripyrophosphate, or a pharmaceutically acceptable prodrug or salt thereof.

11. The method of claim 1, wherein the compound is a compound of Formula (II):

12. The method of claim 1, wherein the patient is treated with one or more additional agents that act synergistically with PI3K inhibition.

13. The method of claim 12, wherein an additional agent is a receptor kinase inhibitor, a PI3K pathway inhibitor, or targets the apoptotic machinery.

14. The method of claim 13, wherein the PI3K inhibitor further acts as an allosteric effector of hemoglobin.

15. A compound of the formula (II)

16. A method for treating a disease associated with PI3K activity or hypoxia, comprising, administering a compound or pharmaceutical composition of claim 15.

17. The method of claim 16, wherein the disease is cancer, heart failure, anemia, or Alzheimer'"'"'s disease.

18. The method of claim 17, wherein the condition is a cancer selected from ovarian, cervical, endometrial, colorectal, breast, pancreatic, gastric, glioblastoma, melanoma, liver, prostate, leukemia, lymphoma, head and neck, gastric, kidney, and lung cancer.