Claims for Patent: 8,188,065

Summary for Patent: 8,188,065

Title:	Boldine compounds for promoting bone growth
Abstract:	The present invention provides a method of promoting bone growth in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound of Formula I. The present invention also provides methods for the treatment of renal disease and cancer.
Inventor(s):	Ellies; Debra (Parkville, MO), Rosenberg; William (Overland Park, MO)
Assignee:	OsteoGeneX Inc. (Kansas City, KS)
Application Number:	12/571,623
Patent Claims:	1. A method of promoting bone growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I: ##STR00017## wherein each R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 hydroxyalkyl, --OR.sup.8, --C.sub.0-6 alkyl-NR.sup.8R.sup.9, --SR.sup.8, --C(O)R.sup.8, --C.sub.0-6 alkyl-C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.8)C(O)R.sup.9, --N(R.sup.8)C(O)OR.sup.9, --N(R.sup.8)C(O)NR.sup.8R.sup.9, --OP(O)(OR.sup.8).sub.2, --S(O).sub.2OR.sup.8, --S(O).sub.2NR.sup.8R.sup.9, --CN, C.sub.0-6 alkyl-cycloalkyl, heterocycloalkyl, C.sub.0-6 alkyl-aryl and heteroaryl, wherein R.sup.2 or R.sup.4 combines with R.sup.3 to form a bond; alternatively, R.sup.4 and R.sup.6 combine to form .dbd.O; R.sup.8 and R.sup.9 are each independently a member selected from the group consisting of H and C.sub.1-6 alkyl; and salts, hydrates, prodrugs, and isomers thereof, thereby promoting bone growth in the subject. 2. The method of claim 1, wherein the compound is of the following formula: ##STR00018## wherein each of R.sup.7a, R.sup.7b, R.sup.7c and R.sup.7d are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 hydroxyalkyl, --OR.sup.8, --C.sub.0-6 alkyl-NR.sup.8R.sup.9, --SR.sup.8, --C(O)R.sup.8, --C.sub.0-6 alkyl-C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.8)C(O)R.sup.9, --N(R.sup.8)C(O)OR.sup.9, --N(R.sup.8)C(O)NR.sup.8R.sup.9, --OP(O)(OR.sup.8).sub.2, --S(O).sub.2OR.sup.8, --S(O).sub.2NR.sup.8R.sup.9, --CN, C.sub.0-6 alkyl-cycloalkyl, heterocycloalkyl, C.sub.0-6 alkyl-aryl and heteroaryl. 3. The method of claim 2, wherein R.sup.1 and R.sup.2 are each selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkyl-cycloalkyl, and C.sub.1-6 alkyl-aryl; each R.sup.4, R.sup.5, R.sup.6, R.sup.7a, R.sup.7b, R.sup.7c and R.sup.7d is independently selected from the group consisting of H, halogen, C.sub.1-6 alkoxy, and OH, wherein R.sup.2 or R.sup.4 combines with R.sup.3 to form a bond; and alternatively, R.sup.4 and R.sup.6 combine to form .dbd.O. 4. The method of claim 2, wherein the compound is of formula Ia: ##STR00019## 5. The method of claim 4, wherein the compound is of the formula: ##STR00020## 6. The method of claim 5, wherein R.sup.1 is C.sub.1-6 alkyl; and each R.sup.7a and R.sup.7b is independently selected from the group consisting of H, OMe, and OH. 7. The method of claim 6, wherein the compound is: ##STR00021## 8. The method of claim 7, wherein the compound is: ##STR00022## 9. The method of claim 2, wherein the compound is of formula Ib: ##STR00023## 10. The method of claim 9, wherein the compound is of the formula: ##STR00024## 11. The method of claim 10, wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of H and C.sub.1-6 alkyl; and each R.sup.7a and R.sup.7b is independently selected from the group consisting of H, OMe, and OH. 12. The method of claim 11, wherein the compound is selected from the group consisting of: ##STR00025## 13. The method of claim 2, wherein the bone growth is promoted at a site of injury or localized condition. 14. The method of claim 13, wherein the bone growth is promoted at a site selected from the group consisting of a bone fracture and weakened bone. 15. The method of claim 13, wherein the subject requires a spinal fusion, arthrodesis or an orthopedic or periodontal synthetic bone graft or implant. 16. The method of claim 13, further comprising the step of administering to the subject an osteoconductive matrix. 17. The method of claim 16, wherein the osteoconductive matrix comprises an osteoinductive agent selected from the group consisting of bone allograft, bone autograft, demineralized bone and periodontal ligament cells. 18. The method of claim 16, wherein the osteoconductive matrix comprises a calcium salt, calcium sulfate, calcium phosphate, a calcium phosphate cement, hydroxyapatite, corallin based hydroyxapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP) , calcium carbonate, collagen, plaster of Paris, phosphophoryn, a borosilicate, a biocompatible ceramic, a calcium phosphate ceramic and polytetrafluoroethylene. 19. The method of claim 2, wherein the bone growth is systemic. 20. The method of claim 19, wherein the subject suffers from a low bone mass phenotype disease. 21. The method of claim 20, wherein the low bone mass phenotype disease is selected from the group consisting of osteoporosis, osteopenia, and osteoporosis-pseudoglioma syndrome (OPPG). 22. The method of claim 2, wherein the compound is administered in combination with an antiresorptive drug. 23. The method of claim 22, wherein the antiresorptive drug is selected from the group consisting of denosumab, a RankL inhibitor, a bisphosphonate, a selective estrogen receptor modulator (SERM), calcitonin, a calcitonin analog, Vitamin D and a Vitamin D analog. 24. The method of claim 22, wherein the bone growth is systemic. 25. The method of claim 22, wherein the bone growth is promoted by a local application of the compound and the antiresorptive drug. 26. A method of treating renal damage, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I: ##STR00026## wherein each R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 hydroxyalkyl, --OR.sup.8, --C.sub.0-6 alkyl-NR.sup.8R.sup.9, --SR.sup.8, --C(O)R.sup.8, --C.sub.1-6 alkyl-C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.8)C(O)R.sup.9, --N(R.sup.8)C(O)OR.sup.9, --N(R.sup.8)C(O)NR.sup.8R.sup.9, --OP(O)(OR.sup.8).sub.2, --S(O).sub.2OR.sup.8, --S(O).sub.2NR.sup.8R.sup.9, --CN, C.sub.0-6 alkyl-cycloalkyl, heterocycloalkyl, C.sub.0-6 alkyl-aryl and heteroaryl, wherein R.sup.2 or R.sup.4 combines with R.sup.3 to form a bond; alternatively, R.sup.4 and R.sup.6 combine to form .dbd.O; R.sup.8 and R.sup.9 are each independently a member selected from the group consisting of H and C.sub.1-6 alkyl; and salts, hydrates, prodrugs and isomers thereof, thereby treating renal damage in the subject. 27. An orthopedic or periodontal medical device comprising a structural support, wherein an implantable portion of the structural support is adapted to be permanently implanted within a subject, wherein the implantable portion is attached to a bone, the structural support bearing at least a partial external coating comprising a compound of Formula I: ##STR00027## wherein each R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 hydroxyalkyl, --OR.sup.8, --C.sub.0-6 alkyl-NR.sup.8R.sup.9, --SR.sup.8, --C(O)R.sup.8, --C.sub.0-6 alkyl-C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.8)C(O)R.sup.9, --N(R.sup.8)C(O)OR.sup.9, --N(R.sup.8)C(O)NR.sup.8R.sup.9, --OP(O)(OR.sup.8).sub.2, --S(O).sub.2OR.sup.8, --S(O).sub.2NR.sup.8R.sup.9, --CN, C.sub.0-6 alkyl-cycloalkyl, heterocycloalkyl, C.sub.0-6 alkyl-aryl and heteroaryl, wherein R.sup.2 or R.sup.4 combines with R.sup.3 to form a bond; alternatively, R.sup.4 and R.sup.6 combine to form .dbd.O; R.sup.8 and R.sup.9 are each independently a member selected from the group consisting of H and C.sub.1-6 alkyl; and salts, hydrates, prodrugs and isomers thereof. 28. A method of treating cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I: ##STR00028## wherein each R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 hydroxyalkyl, --OR.sup.8, --C.sub.0-6 alkyl-NR.sup.8R.sup.9, --SR.sup.8, --C(O)R.sup.8, --C.sub.0-6 alkyl-C(O)OR.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.8)C(O)R.sup.9, --N(R.sup.8)C(O)OR.sup.9, --N(R.sup.8)C(O)NR.sup.8R.sup.9, --OP(O)(OR.sup.8).sub.2, --S(O).sub.2OR.sup.8, --S(O).sub.2NR.sup.8R.sup.9, --CN, C.sub.0-6 alkyl-cycloalkyl, heterocycloalkyl, C.sub.0-6 alkyl-aryl and heteroaryl, wherein R.sup.2 or R.sup.4 combines with R.sup.3 to form a bond; alternatively, R.sup.4 and R.sup.6 combine to form .dbd.O; R.sup.8 and R.sup.9 are each independently a member selected from the group consisting of H and C.sub.1-6 alkyl; and salts, hydrates, prodrugs and isomers thereof, wherein the cancer is selected from the group consisting of bone cancer, colon cancer, multiple myeloma, gastric cancer, colorectal cancer, prostate cancer, cervical cancer, lung cancer, pancreatic cancer, medulloblastoma, liver cancer, parathyroid cancer, endometrial cancer, and breast cancer, thereby treating cancer in the subject.

Details for Patent 8,188,065

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	PROLIA	denosumab	Injection	125320	06/01/2010		2028-10-02
Amgen, Inc.	XGEVA	denosumab	Injection	125320	11/18/2010		2028-10-02