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US 8,710,215 B2Granted
Bisphosphonate compounds
AssigneeWarner Chilcott Company, LLC
InventorsFrank Hallock Ebetino, Adam Wieslaw Mazur, Roy Lee Martin Dobson
Life of this patent
Estimating the term…
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.
Claims51
A compound of Formula I,
- or a pharmaceutically acceptable salt or hydrate thereof,
- 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;
- 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-C8haloalkyl, 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.
32 more elements
A compound of Formula II,
- or a pharmaceutically acceptable salt or hydrate thereof,
- 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),
- 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.
10 more elements
A compound of Formula IV,
- or a pharmaceutically acceptable salt or hydrate thereof,
- 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),
- 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-C8haloalkyl)-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 R5 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.
14 more elements
Dependencies are inferred from the claim text.