# US 2014/0194389 A1 · Bisphosphonate compounds

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- Number: US 2014/0194389 A1
- Document ID: US20140194389A1
- Status: Published application
- Kind: A1
- Application number: 14/205,937
- Filed: 2014-03-12
- Published: 2014-07-10
- Earliest claimed: 2009-10-26
- Assignees: Warner Chilcott Company, LLC
- Applicants: Warner Chilcott Company, LLC
- Inventors: Frank Hallock Ebetino; Adam Wieslaw Mazur; Roy Lee Martin Dobson
- Web page: https://patentgrep.com/patent/US20140194389A1

## CPC

- C07F 9/65746: {the molecule containing more than one cyclic phosphorus atom}
- A61P 3/12: for electrolyte homeostasis
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07F 9/657181: {the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim at position 1

-67. (canceled)

### Claim 68

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 R1, R2, R3, R4 and R5 are each independently
a) hydrogen;
b) halogen, —CN, —CF3, or —NO2;
c) C1-C8 alkyl or C1-C8 haloalkyl;
d) C2-C8 alkenyl or C2-C8 haloalkenyl;
e) C2-C8 alkynyl or C2-C8 haloalkynyl;
f) optionally substituted aryl or optionally substituted heteroaryl;
g) —C(O)R6;
h) —C(O)OR6, or —CO2R6;
i) —OR6, —O-L-OC(O)R6, or —O-L-OC(O)OR6;
j) —OC(O)R6, or —OC(O)-L-OC(O)R6;
k) —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)O-L-C(O)OR7, or -L-OC(O)R6;
l) —C(O)NR6R7, or —CNR6R7;
m) —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)O-L-(R6)-L-C(O)R7, —OC(O)—C(R6)(R7)-L-OC(O)R8, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8);
n) —SR6, or —NR6R7;
o) —NR6C(O)R7;
p) —NR6C(O)OR7;
q) —NR6C(O)NR7;
r) —OSO2R6;
s) —SO2OR6;
t) —SO2R6;
u) —NR6SO2R7;
v) —SO2NR6R7;
or
bb) R1 and R2, R2 and R3, R3 and R4, or R4 and R5 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 —CH2—, —O—, —NR7—, or —S—;
p is an integer from 1 to 3;
R14 is hydrogen, halogen, C1-C8 alkyl, or C1-C8 alkoxyl;
Z is
each R6 is independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 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;
R7 and R8 are each independently hydrogen or C1-C8 alkyl; and L is C1-C8 alkyl; or
R6 and R7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

### Claim 69 (depends on 68)

The method of claim 68, wherein R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, —CF3, C1-C8 alkyl, optionally substituted phenyl, —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
wherein Y is —CH2—, —O—, —NR7—, or —S—;
p is an integer from 1 to 3;
R14 is hydrogen, halogen, C1-C8 alkyl, or C1-C8 alkoxyl; and
Z is

### Claim 70 (depends on 68)

The method of claim 68, wherein one of R1, R2, R3, R4, and R5 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
any two of the remaining R1, R2, R3, R4, and R5 are halogen; and each of the remaining R-groups of R1, R2, R3, R4, and R5 are hydrogen.

### Claim 71 (depends on 68)

The method of claim 68, wherein one of R1, R2, R3, R4, and R5 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
one of the remaining R-groups of R1, R2, R3, R4, and R5 is halogen, —CF3, C1-C8 alkyl, phenyl, —OR6, or —C(O)OR6; and each remaining R-group of R1, R2, R3, R4, and R5 is hydrogen.

### Claim 72 (depends on 68)

The method of claim 68, wherein one of R1, R2, R3, R4, and R5 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and the remaining R-groups of R1, R2, R3, R4, and R5 are each hydrogen.

### Claim 73 (depends on 68)

The method of claim 68, wherein R1 and R5 are each independently halogen; and
R3 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and the remaining R-groups of R1, R2, R3, R4, and R5 are each hydrogen.

### Claim 74 (depends on 68)

The method of claim 68, wherein R1 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
one of the remaining R-groups of R1, R2, R3, R4, and R5 is halogen, —CF3, C1-C8 alkyl, phenyl, —OR6, or —C(O)OR6; and each remaining R-group of R1, R2, R3, R4, and R5 is hydrogen.

### Claim 75 (depends on 68)

The method of claim 68, wherein R3 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
one of the remaining R-groups of R1, R2, R3, R4, and R5 is halogen, —CF3, C1-C8 alkyl, phenyl, —OR6, or —C(O)OR6; and each remaining R-group of R1, R2, R3, R4, and R5 is hydrogen.

### Claim 76 (depends on 68)

The method of claim 68, wherein R1 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and R2, R3, R4, and R5 are each hydrogen.

### Claim 77 (depends on 68)

The method of claim 68, wherein R3 is —OR6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and R1, R2, R4, and R5 are each hydrogen.

### Claim 78 (depends on 68)

The method of claim 68, wherein the compound is:

### Claim 79

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 —OR6, —CO2R6, -L-OC(O)R6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)O-L-C(O)OR7, —C(O)NR6R7, —CNR6R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and
B and C are each independently hydrogen, halogen, —CF3, —CN, C1-C8 alkyl, phenyl, —OR6, or —C(O)OR6, 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 —CH2—, —O—, —NR7—, or —S—;
p is an integer from 1 to 3;
Z is
each R6 is independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 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 C1-C8 alkyl;
R14 is hydrogen, halogen, C1-C8 alkyl, or C1-C8 alkoxyl;
R7 and R8 are each independently hydrogen or C1-C8 alkyl; or
R6 and R7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

### Claim 80

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 —OR6, —CO2R6, -L-OC(O)R6, —O-L-OC(O)R6, —O-L-OC(O)OR6, —OC(O)R6, —OC(O)-L-OC(O)R6, —OC(O)OR6, —OC(O)O-L-C(O)R7, —OC(O)O-L-C(O)OR7, —C(O)NR6R7, —CNR6R7, —OC(O)NR6R7, —OC(O)N(R6)-L-OC(O)R7, —OC(O)N(-L-OC(O)R7)(-L-OC(O)R8),
and
B and C are each independently hydrogen, halogen, —CF3, —CN, C1-C8 alkyl, phenyl, —OR6, or —C(O)OR6, 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
R9 and R10 are each independently hydrogen, halogen, oxygen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, —OR6, —SR6, —NR6R7, —(C1-C8 alkyl)-NR6R7, —(C1-C8 haloalkyl)-NR6R7, —(C2-C8 alkenyl)-NR6R7, —(C2-C8 haloalkenyl)-NR6R7, —(C2-C8 alkynyl)-NR6R7, —(C2-C8 haloalkyl)-NR6R7, -L-R11; or R9 and R10 taken together form a monocyclic or bicyclic optionally substituted carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;
wherein R11 is optionally substituted aryl or optionally substituted heteroaryl;
m and n are each independently an integer from 0 to 2;
Y is —CH2—, —O—, —NR7—, or —S—;
p is an integer from 1 to 3;
Z is
each R6 is independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 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 C1-C8 alkyl;
R14 is hydrogen, halogen, C1-C8 alkyl, or C1-C8 alkoxyl;
R7 and R8 are each independently hydrogen or C1-C8 alkyl; or
R6 and R7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic.

### Claim 81 (depends on 80)

The method of claim 80, wherein the compound is a compound or a pharmaceutically acceptable salt or hydrate of a compound of Formula IVa, IVb, IVc, IVd, or IVe:

### Claim 82 (depends on 81)

The method of claim 81, 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 R9 is H, OH, or F; R10 is
and Rx is C1-C8 alkyl, C1-C8 alkoxyl or

### Claim 83 (depends on 82)

The method of claim 82, wherein the compound is