IP Library › Granted Patent US 8,822,435
Granted Patent B2
US 8,822,435 · App. 14/205,937 · Granted Sep 2, 2014

Bisphosphonate compounds

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Quick Facts
Patent No.
US 8,822,435
App. No.
14/205,937
Granted
Sep 2, 2014
Kind
B2
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 (94)

1. A method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, Paget's disease, or alveolar bone loss comprising administering an effective amount of a compound of Formula I,

or a pharmaceutically acceptable salt thereof to a patient in need of such treatment,

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

or

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 method 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

or

3. The method 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.

4. The method 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.

5. The method 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.

6. The method 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)NR—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.

7. The method 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 ),

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.

8. The method 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 ),

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.

9. The method 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.

10. The method 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.

11. The method of claim 1 , wherein the compound is:

12. A method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, Paget's disease, or alveolar bone loss comprising administering an effective amount of a compound of Formula II,

or a pharmaceutically acceptable salt thereof to a patient in need of such treatment,

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

or

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;

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.

13. A method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, Paget's disease, or alveolar bone loss comprising administering an effective amount of a compound of Formula IV,

or a pharmaceutically acceptable salt thereof to a patient in need of such treatment,

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; and

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 u 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

or

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;

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.

14. The method of claim 13 , wherein the compound is a compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IVa, IVb, IVc, IVd, or IVe:

15. The method of claim 14 , 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

16. The method of claim 15 , 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 →