US 20120231 01 0A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0231010 A1 Ellies et al. (43) Pub. Date: Sep. 13, 2012 (54) VINPOCETINE AND EBURNAMONINE A6IP35/00 (2006.01) DERVATIVES FOR PROMOTING BONE A6IP 9/10 (2006.01) GROWTH A6IF 2/28 (2006.01) A6II 3/663 (2006.01) (75) Inventors: Debra Ellies, Parksville, MO (US); A638/23 (2006.01) William Rosenberg, Overland A 6LX 3/59 (2006.01) Park, KS (US) A6II 35/12 (2006.01) A6II 35/32 (2006.01) (73) Assignee: OsteoGeneX Inc., Kansas City, KS A6IP 9/00 (2006.01) (US) A 6LX 39/395 (2006.01) (21) Appl. No.: 13/474,544 (22) Filed: May 17, 2012 (52) U.S. Cl. ...................... 424/142.1: 514/283: 514/108; 514f11.9514f167: 424/93.7 424/549; 623/23.61 Related U.S. Application Data s s s s (63) Continuation of application No. 12/494.670, filed on Jun. 30, 2009, now Pat. No. 8,198,292. (60) Provisional application No. 61/078,163, filed on Jul. 3, (57) ABSTRACT 2008. The present invention provides a method of promoting bone Publication Classificati growth in a Subject in need thereof, by administering to the ublication Classification Subject a therapeutically effective amount of a compound of (51) Int. Cl. Formula I. The compounds include the salts, hydrates and A6 IK 3/4375 (2006.01) isomers thereof. The present invention also provides methods A6IPI3/2 (2006.01) for the treatment of renal disease and cancer. Patent Application Publication Sep. 13, 2012 Sheet 1 of 2 US 2012/023101.0 A1 D D 1 8% 5 2 16%14% 2 1 2% 3 1 1 to 8% g 4%6% F 9 2%O% 1 11 1-1, B C F.G. 1 O.40 O.35 O.30 O.25 O.20 O.15 O. 10 O.05 O.OO FIG. 2 Patent Application Publication Sep. 13, 2012 Sheet 2 of 2 US 2012/0231010 A1 Osteocalcin Levels 62% Vinpocetine 70% 60% 39% 50% EburnamOnline 40% 30% 20% 10% O% US 2012/0231 0 1 0 A1 Sep. 13, 2012 VNPOCETINE AND EBURNAMONNE composition is intended to be administered easily into the DERVATIVES FOR PROMOTING BONE missing part of injured bone without diffusing to Surrounding GROWTH Organs. 0008. In U.S. Pat. No. 5,939,039, issued in 1999 teaches CROSS-REFERENCES TO RELATED the processes to yield unique calcium phosphate precursor APPLICATIONS minerals that can be used to form a self-setting cement or 0001. This application is a Continuation of U.S. applica paste. Once placed in the body, these calcium phosphate tion Ser. No. 12/494,670, filed Jun. 30, 2009, which claims cements (CPC) will be resorbed and remodeled (converted) to priority to U.S. Provisional Application No. 61/078,163, filed bone. Jul. 3, 2008, the contents of which are incorporated in their 0009 For example, calcium phosphate particles prepared entirety herein for all purposes. in accordance with the 039 patent can be used in any of the orthopedic or dental procedures known for the use of calcium BACKGROUND OF THE INVENTION phosphate; the procedures of bone filling defect repair, onco logical defect filling, craniomaxillofacial Void filling and 0002. It is well-understood that bone formation is indi reconstruction, dental extraction site filling. cated for treatment of a wide variety of disparate disorders in O010 U.S. Publication No. 2006/0198863 to Carl Alex mammals including simple aging, bone degeneration and ander DePaula, published Sep. 7, 2006, relates to a formable osteoporosis, fracture healing, fusion or arthrodesis, osteo ceramic composition for filling bone defects. The composi genesis imperfecta, etc., as well as for Successful installation tion comprises ceramic beta tricalcium phosphate particles of various medical orthopedic and periodontal implants such having a particle size from about 40 microns to 500 microns as screws, rods, titanium cage for spinal fusion, hip joints, admixed with a hydrogel carrier containing citric acid buffer. knee joint, ankle joints, shoulder joints, dental plates and The composition has a pH between 7.0 to 7.8 and the hydrogel rods, etc. component of the carrierranges from about 1.0 to 5.0% of the 0003 Increasing bone mineralization to treat conditions composition. characterized at least in part by increased bone resorption, (0011 Wise and SOST are understood to be closely related Such as osteopenia, bone fractures, osteoporosis, arthritis, family members (Ellies et al., JBMR 2006 November; tumor metastases, Paget’s disease and other metabolic bone 21 (11):1738-49.). Those of ordinary skill are aware that the disorders, using cathepsin Kinhibitors and TGF-beta binding Wise null mutant mouse exhibits a bone phenotype (Keynote proteins, etc., are well-known as shown by U.S. Publication presentation at the 2005 American Society of Bone Mineral No. 2004/0235728 to Selwyn Aubrey Stoch, published Nov. Research meeting in Nashville,Tenn. State of the Art lectures, 25, 2004, and Mary E. Brunkow et al., U.S. Pat. No. 6,489, an embryonic source of skeletal tissue. Patterning Craniofa 445 and U.S. Publication No. 2004/0009535, published Jan. cial Development; by Robb Krumlauf, Ph.D., Stowers Insti 15, 2004. In the Brunkow 535 publication and 445 patent, tute for Medical Research, Kansas City, Mo., USA). the TGF-beta binding proteins include Sost polypeptide (full (0012 U.S. Publication No. 2005/025604 to Vignery pub length and short peptide) antibodies that interfere with the lished Nov. 17, 2005 shows induction of bone formation by interaction between the TGF-beta binding protein sclerostin mechanically inducing an increase in osteoblast activity and and a TGF-beta Superfamily member, particularly a bone elevating systemic blood concentration of a bone anabolic morphogenic protein. All of the diseases named above are due agent, including optionally elevating systemic blood concen to a systemic loss of bone mineral and thus the administration of the antibody therapeutic is for systemic (whole body) tration of an antiresorptive agent. increase in bone mineral density. 0013 Finally, Yanagita, Modulator of bone morphogenic 0004. In the Brunkow 535 publication and 445 patent, protein activity in the progression of kidney diseases, Kidney the binding proteins preferably bind specifically to at least Int., Vol. 70, No. 6 (2006) 989-93 shows Usag-1 (also known one human bone morphogenic protein (BMP) among BMP-5 as “Wise') protects the kidney from cisplatin insult due to and BMP-6. BMP inhibition. See also Yanagita, Uterine sensitization 0005 U.S. Pat. No. 6,395,511 to Brunkow, et al. teaches a associated gene-1 (USAG-1), a novel antagonist expressed in novel family of human TGF-beta binding proteins and the kidney, accelerates tubular injury, J. Clin. Invest., Vol. nucleic acids encoding them. The protein binds to at least 116, No. 1 (2005) 70-9, Yanagita, BMP antagonists: their human bone morphogenic protein-5 and human bone mor roles in development and involvement in pathophysiology, phogenic protein-6. Cytokine Growth Factor Rev. Vol 16, No. 3 (2005) 309-17, 0006 Sclerosteosis is a progressive sclerosing bone dys and Yanagita, USAG-1. a bone morphogenic protein antago plasia. Sclerostin (the Sost gene) was originally identified as inist abundantly expressed in the kidney, Biochem. Biophys. the Sclerosteosis-causing gene. Sclerostin was intensely Res. Commun., Vol. 316, No. 2 (2004) 490-500. expressed in developing bones of mouse embryos. Punctu 0014 What is needed in the art is a new method for treat ated expression of Sclerostin was localized on the Surfaces of ing the bone disorders described above, as well as others. both intramembranously forming skull bones and endochon Surprisingly, the present invention meets these and other drally forming long bones. The physiological role of Scleros needs. tin remains to be elucidated. However, it is known that loss of function mutations in Sost cause a rare bone dysplasia char BRIEF SUMMARY OF THE INVENTION acterized by skeletal overgrowth. 0007. In U.S. Publication No. 2006/0165799, published 0015. In one embodiment, the present invention provides a Jul. 27, 2006, teaches a bone-filling composition for stimu method of promoting bone growth in a Subject in need lating bone-forming and bone-consolidation comprising bio thereof, comprising administering to the Subject a therapeu compatible calcium sulfate and Viscous biopolymers. The tically effective amount of a compound of Formula I: US 2012/0231 0 1 0 A1 Sep. 13, 2012 0022 FIG. 3 shows the increase in tibia long bone bone volume/total volume when compared to baseline controls: (I) 9% at 5 mg/kg (D) and 17% at 0.33 mg/kg (E) of eburnamo nine phosphate in mice. 0023 FIG. 4 shows the increase in osteocalcin serum lev els, of 62% and 39%, for vinpocetine citrate at 10 mg/kg and eburnamonine phosphate at 0.33 mg/kg, respectively. DETAILED DESCRIPTION OF THE INVENTION I. General 0024. The present invention encompasses compounds, compositions and methods for promoting bone growth in a wherein each of R', R. R. R7 or R are independently H, subject. The compounds of the present invention are SOST halogen, C-alkyl, Calkoxy, Chaloalkyl, C2-alkenyl, (Sclerostin) and Wise antagonists that modulate the Wnt path C2-alkynyl, C. haloalkoxy, C. alkyl-hydroxy, —OR". way. By modulating the Wnt pathway, the compounds and C(O)R, C(O)OR1, C(O)NR'R'', NR'R'', compositions of the present invention promote bone growth. N(R')C(O)R', N(R')C(O)OR, N(R')C(O) The bone growth can be systemic or local bone growth. The NR'R'', OP(O)(OR), S(O),OR', S(O) compounds and compositions of the present invention can be NR'R'', CN, -CH=N-OH, C alkyl-OC(O)-aryl, administered locally or systemically.