IP Library › Granted Patent US 8,710,215

Granted Patent B2

US 8,710,215 · App. 13/650,785 · Granted Apr 29, 2014

Bisphosphonate compounds

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Quick Facts

Patent No.: US 8,710,215
App. No.: 13/650,785
Granted: Apr 29, 2014
Kind: B2

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Abstract

Novel bisphosphonate cyclic acetal compounds are disclosed, as well as methods of preparing the compounds, pharmaceutical compositions including the compounds, and administration of the compounds in methods of treating bone metabolism disorders, such as abnormal calcium and phosphate metabolism.

Claims (140)

1. A compound of Formula I,

or a pharmaceutically acceptable salt or hydrate thereof,

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently

a) hydrogen;

b) halogen, —CN, —CF 3 , or —NO 2 ;

c) C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

d) C 2 -C 8 alkenyl or C 2 -C 8 haloalkenyl;

e) C 2 -C 8 alkynyl or C 2 -C 8 haloalkynyl;

f) optionally substituted aryl or optionally substituted heteroaryl;

g) —C(O)R 6 ;

h) —C(O)OR 6 , or —CO 2 R 6 ;

i) —OR 6 , —O-L-OC(O)R 6 , or —O-L-OC(O)OR 6 ;

j) —OC(O)R 6 , or —OC(O)-L-OC(O)R 6 ;

k) —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)O-L-C(O)OR 7 , or -L-OC(O)R 6 ;

l) —C(O)NR 6 R 7 , or —CNR 6 R 7 ;

m) —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)O-L-(R 6 )-L-C(O)R 7 , —OC(O)—C(R 6 )(R 7 )-L-OC(O)R 8 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 );

n) —SR 6 , or —NR 6 R 7 ;

o) —NR 6 C(O)R 7 ;

p) —NR 6 C(O)OR 7 ;

q) —NR 6 C(O)NR 7 ;

r) —OSO 2 R 6 ;

s) —SO 2 OR 6 ;

t) —SO 2 R 6 ;

u) —NR 6 SO 2 R 7 ;

v) —SO 2 NR 6 R 7 ;

bb) R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

wherein m and n are each independently an integer from 0 to 2;

Y is —CH 2 —, —O—, —NR 7 —, or —S—;

p is an integer from 1 to 3;

R 14 is hydrogen, halogen, C 1 -C 8 alkyl, or C 1 -C 8 alkoxyl;

Z is

each R 6 is independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, an optionally substituted 4-8 membered saturated carbocyclic or heterocyclic ring, optionally substituted aryl, optionally substituted heteroaryl, -L-optionally substituted aryl or -L-optionally substituted heteroaryl;

R 7 and R 8 are each independently hydrogen or C 1 -C 8 alkyl; and L is C 1 -C 8 alkyl; or

R 6 and R 7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, —CF 3 , C 1 -C 8 alkyl, optionally substituted phenyl, —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —C(O)OR 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

wherein Y is —CH 2 —, —O—, —NR 7 —, or —S—;

p is an integer from 1 to 3;

R 14 is hydrogen, halogen, C 1 -C 8 alkyl, or C 1 -C 8 alkoxyl; and

Z is

3. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently —OR 6 , —O—(CH 2 ) p —OC(O)R 6 , —O—(CH 2 ) p —OC(O)OR 6 , —OC(O)R 6 , —OC(O)—C(R 6 )(R 7 )—(CH 2 ) p —OC(O)R 8 , —C(O)OR 6 , —OC(O)OR 6 , —OC(O)O—CH(R 6 )(CH 2 ) p C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )(CH 2 ) p —OC(O)R 7 , —OC(O)N(—(CH 2 ) p —OC(O)R 7 )(—(CH 2 ) p —OC(O)R 8 ),

4. The compound of claim 1 , wherein R 6 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, benzyl;

R 7 and R 8 are each independently hydrogen, methyl, or ethyl;

Y is —O—;

L is C 1 -C 3 alkyl;

m is 0; and

n is 0 or 1.

5. The compound of claim 3 , wherein R 6 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, benzyl;

R 7 and R 8 are each independently hydrogen, methyl, or ethyl; and

Y is —O—.

6. The compound of claim 1 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

7. The compound of claim 6 , wherein the 5- to 7-membered carbocyclic or heterocyclic ring is unsubstituted.

8. The compound of claim 6 , wherein the 5- to 7-membered carbocyclic or heterocyclic ring is saturated or aromatic.

9. The compound of claim 6 , wherein the 5- to 7-membered heterocyclic ring includes 1 or 2 heteroatoms.

10. The compound of claim 6 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together form

11. The compound of claim 10 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together are

12. The compound of claim 10 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together are

and the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 are each hydrogen.

13. The compound of claim 6 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together are

wherein R 15 is hydrogen, halogen, or —OR 6 .

14. The compound of claim 13 , wherein R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together are

and the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 are each independently —H or —OC(O)OR 6 .

15. The compound of claim 1 , wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is —OR 6 ,

—O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

any two of the remaining R 1 , R 2 , R 3 , R 4 , and R 5 are halogen; and each of the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen.

16. The compound of claim 1 , wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is —OR 6 ,

—O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

one of the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen, —CF 3 , C 1 -C 8 alkyl, phenyl, —OR 6 , or —C(O)OR 6 ; and each remaining R-group of R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen.

17. The compound of claim 1 , wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is —OR 6 ,

—O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

and the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 are each hydrogen.

18. The compound of claim 1 , wherein R 1 and R 5 are each independently halogen; and

R 3 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

and the remaining R-groups of R 1 , R 2 , R 3 , R 4 , and R 5 are each hydrogen.

19. The compound of claim 18 , wherein R 1 and R 5 are each independently —F or —Cl.

20. The compound of claim 1 , wherein R 1 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

21. The compound of claim 1 , wherein R 3 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

22. The compound of claim 1 , wherein R 1 is —OR 6 , —O-L-OC(O)R 6 ,

—O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

and R 2 , R 3 , R 4 , and R 5 are each hydrogen.

23. The compound of claim 1 , wherein R 3 is —OR 6 , —O-L-OC(O)R 6 ,

—O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

and R 1 , R 2 , R 4 , and R 5 are each hydrogen.

24. The compound of claim 22 , wherein R 1 is —OC(O)OR 16 , —OC(O)R 16 or —OC(O)NR 16 R 17 and R 16 and R 17 are each independently C 1 -C 4 alkyl.

25. The compound of claim 23 , wherein R 3 is —OC(O)OR 16 , —OC(O)R 16 or —OC(O)NR 16 R 17 and R 16 and R 17 are each independently C 1 -C 4 alkyl.

26. The compound of claim 1 , wherein R 1 is —OC(O)OCH 3 , —OC(O)OCH 2 CH 3 or —OC(O)OCH(CH 3 ) 2 ; and

R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, —CF 3 , C 1 -C 8 alkyl, optionally substituted phenyl, —OR 6 , or —C(O)OR 6 .

27. The compound of claim 1 , wherein R 3 is —OC(O)OCH 3 or —OC(O)OCH(CH 3 ) 2 ; and

R 1 , R 2 , R 4 and R 5 are each independently hydrogen, halogen, or —CF 3 .

28. A compound of Formula II,

or a pharmaceutically acceptable salt or hydrate thereof,

wherein A is —OR 6 , —CO 2 R 6 , -L-OC(O)R 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)O-L-C(O)OR 7 , —C(O)NR 6 R 7 , —CNR 6 R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

B and C are each independently hydrogen, halogen, —CF 3 , —CN, C 1 -C 8 alkyl, phenyl, —OR 6 , or —C(O)OR 6 , or B and C when taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

wherein m and n are each independently an integer from 0 to 2;

Y is —CH 2 —, —O—, —NR 7 —, or —S—;

p is an integer from 1 to 3;

Z is

L is C 1 -C 8 alkyl;

R 14 is hydrogen, halogen, C 1 -C 8 alkyl, or C 1 -C 8 alkoxyl;

R 7 and R 8 are each independently hydrogen or C 1 -C 8 alkyl; or

R 6 and R 7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

29. The compound of claim 28 , wherein A is in the ortho or para position relative to C*.

30. The compound of claim 28 , wherein A is in the meta position relative to C*.

31. The compound of claim 28 , wherein the compound is a compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IIa, IIb, IIc, IId, or IIe:

32. The compound of claim 28 , wherein A is —OC(O)NR 6 R 7 , —OC(O)R 6 , or —OC(O)OR 6 .

33. The compound of claim 32 , wherein R 6 and R 7 are each independently hydrogen or C 1 -C 8 alkyl.

34. The compound of claim 33 , wherein B and C are each independently hydrogen, cyano, halogen, or —OC(O)R 6 .

35. The compound of claim 34 , wherein B and C are each independently halogen.

36. The compound of claim 35 , wherein B and C are each fluoro.

37. The compound of claim 4 , wherein R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, —CH 2 CH(CH 3 ) 2 , pentyl, —CH 2 C(CH 3 ) 3 , heptyl, —CH(CH 3 )(CH 2 ) 5 CH 3 , —CH═C(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl or tetrahydro-2H-pyranyl.

38. The compound of claim 1 , wherein R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, —CH 2 CH(CH 3 ) 2 , pentyl, —CH 2 C(CH 3 ) 3 , heptyl, —CH(CH 3 )(CH 2 ) 5 CH 3 , —CH═C(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or tetrahydro-2H-pyranyl; and R 7 and R 8 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl.

39. The compound of claim 1 , wherein L is C 1 -C 3 alkyl.

40. The compound of claim 1 , wherein R 2 , R 3 , R 4 and R 5 are each hydrogen and R 1 is —OC(O)OR 6 or —OC(O)OR 6 .

41. The compound of claim 40 , wherein R 1 is —OC(O)OR 6 and R 6 is C 1 -C 8 alkyl.

42. The compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 1 , wherein the compound is:

43. The compound or a pharmaceutically acceptable salt or hydrate of the compound of claim 1 , wherein the compound is:

44. The compound of claim 43 , wherein the compound is a trans-isomer.

45. The compound of claim 44 , wherein the compound is a monosodium salt monohydrate.

46. A compound of Formula IV,

or a pharmaceutically acceptable salt or hydrate thereof,

R 9 and R 10 are each independently hydrogen, halogen, oxygen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 6 , —SR 6 , —NR 6 R 7 , —(C 1 -C 8 alkyl)—NR 6 R 7 , —(C 1 -C 8 haloalkyl)-NR 6 R 7 , —(C 2 -C 8 alkenyl)-NR 6 R 7 , —(C 2 -C 8 haloalkenyl)-NR 6 R 7 , —(C 2 -C 8 alkynyl)-NR 6 R 7 , —(C 2 -C 8 haloalkyl)-NR 6 R 7 , -L-R 11 ; or R 9 and R 10 taken together form a monocyclic or bicyclic optionally substituted carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

wherein R 11 is optionally substituted aryl or optionally substituted heteroaryl;

m and n are each independently an integer from 0 to 2;

Y is —CH 2 —, —O—, —NR 7 —, or —S—;

p is an integer from 1 to 3;

Z is

R 7 and R 5 are each independently hydrogen or C 1 -C 8 alkyl; or

R 6 and R 7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

47. The compound of claim 46 , wherein A is in the ortho or para position relative to C*.

48. The compound of claim 46 , wherein A is in the meta position relative to C*.

49. The compound of claim 46 , wherein the compound is a compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IVa, IVb, IVc, IVd, or IVe:

50. The compound or a pharmaceutically acceptable salt or hydrate of a compound of claim 49 , wherein the compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IVa is a compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IVf,

wherein R 9 is H, OH, or F; R 10 is

and R x is C 1 -C 8 alkyl, C 1 -C 8 alkoxyl or

51. The compound or a pharmaceutically acceptable salt or hydrate of a compound of claim 50 , wherein the compound is

Assignments (2)

CORRECTIVE ASSIGNMENT TO CORRECT THE US PATENT NO. 8,050,873 PREVIOUSLY RECORDED ON REEL 040183 FRAME 0129. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Feb 22, 2018

From: WARNER CHILCOTT COMPANY, LLC

To: ALLERGAN PHARMACEUTICALS INTERNATIONAL LIMITED

Reel/Frame 045417/0593 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 29, 2016

From: WARNER CHILCOTT COMPANY, LLC

To: ALLERGAN PHARMACEUTICALS INTERNATIONAL LIMITED

Reel/Frame 040183/0129 →