US2024009169A9PendingUtilityA9
PPARG Modulators for the Treatment of Osteoporosis
Est. expiryApr 16, 2034(~7.8 yrs left)· nominal 20-yr term from priority
A61K 31/404A61K 31/4045C07D 209/08A61K 31/41A61K 31/4245A61K 31/4439A61K 31/454A61K 31/4709A61K 31/5377C07D 209/18
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Claims
Abstract
The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for treatment of a patient afflicted by a progressive bone disease, comprising administering to the patient an effective dose of a compound of formula (I)
wherein:
R is H, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl, or (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl;
Y 1 or Y 2 are each independently C or N, provided that when Y 1 or Y 2 is N, R 1 or R 2 , respectively, is absent;
R 1 and R 2 are independently H, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl, or (C 1 -C 6 )haloalkyl; or R 1 and R 2 together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SO q wherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, halo, oxo, (C 1 -C 6 )haloalkyl, nitro, cyano-(C 0 -C 6 )alkyl, R′O 2 C—(C 0 -C 6 )alkyl, methylenedioxy, R′O—(C 0 -C 6 )alkyl, (R′) 2 N—(C 0 -C 6 )alkyl, (R′) 2 NC(═O)—(C 0 -C 6 )alkyl, R′C(═O)N(R′)—(C 0 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, aryl, aroyl, or SO 2 NR′ 2 ;
R 3 is optionally mono- or multi-substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C 1 -C 6 )alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C 1 -C 6 )alkyl; wherein if present each substituent on R 3 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO 2 R′, methylenedioxy, OR′, N(R′) 2 , C(O)N(R′) 2 , (C 1 -C 6 )alkyl-S(O) q , SO 2 NR′ 2 , and (C 1 -C 6 )alkoxyl; and provided that group R 3 N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N 1 or Y 1 ;
wherein each R′ is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 9 )cycloalkyl, (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 ) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O) q ;
wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl of R′ is optionally mono- or independently multi-substituted with (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halo, oxo, aryl, or aroyl;
each of X 1 -X 5 is independently N or CH, or is C substituted with an independently selected R 4 or is C substituted with Z, provided that no more than two of X 1 -X 5 are N, and provided that there is no more than one Z group bonded to the ring comprising X 1 -X 5 ;
each R 4 is independently halo, nitro, (C 1 -C 6 )fluoroalkyl, R′—(C 0 -C 6 )alkyl, R′O 2 C—(C 0 -C 6 )alkyl, NC—(C 0 -C 6 )alkyl, R′O—(C 0 -C 6 )alkyl, (R′) 2 N—(C 0 -C 6 )alkyl, (R′) 2 NC(═O)—(C 0 -C 6 )alkyl, R′C(═O)N(R′)—(C 0 -C 6 )alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4-oxadiazol-5(4H)-on)-3-yl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, R'S(O) 2 NHC(O), R′C(O)NHS(O) 2 , an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C 1 -C 6 )alkyl or (C 3 -C 9 )cycloalkyl-(C 0 -C 6 )alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′) 2 , C-bonded tetrazolyl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R 4 is —(C(R″) 2 ) m CO 2 R′, —(C(R″) 2 ) m CON(R′) 2 , —(C(R″) 2 ) m CN, —O(C(R″) 2 ) m CO 2 R′, —O(C(R″) 2 ) m CON(R′) 2 , or —O(C(R″) 2 ) m CN, wherein m is 1, 2, or 3;
R″ is H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 9 )cycloalkyl, (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 ) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring;
Z is a group of formula
wherein a wavy line indicates a point of bonding, each of Z 1 -Z 5 is independently N or is C substituted with an independently selected H or R 4 ; provided that no more than two of Z 1 -Z 5 are N;
Y is (C 1 -C 2 )alkyl, or sulfur;
when Y is (C 1 -C 2 )alkyl, R 5 and R 6 are independently H or (C 1 -C 4 )alkyl or independently each R 5 and R 6 together with the carbon atom to which they are bonded form a carbonyl, or, one R 5 group can further be bonded to X 5 to form a 4- to 8-membered ring; and,
when Y is sulfur, R 5 and R 6 are both oxygen;
or a pharmaceutically acceptable salt thereof;
wherein the effective dose of the compound acts to inhibit bone resorption, improve bone formation, or both, in the patient.
2 . The method of claim 1 , wherein Y 1 or Y 2 are each C and R 1 and R 2 are independently H or methyl.
3 . The method of claim 1 , wherein Y 1 is N and Y 2 is C, or wherein Y 1 is C and Y 2 is N.
4 . The method of claim 1 , wherein R 3 is benzyl, α-phenethyl, α-phenpropyl, cycloalkyl or cycloalkylalkyl, any of which is unsubstituted or substituted.
5 . The method of claim 1 , wherein R 3 is heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is unsubstituted or substituted.
6 . The method of claim 1 , wherein R 3 is any one of:
wherein a wavy line indicates a point of attachment.
7 . The method of claim 1 , wherein YR 5 R 6 is SO 2 .
8 . The method of claim 1 , wherein Y is C 1 -alkyl; and R 5 and R 6 are H, or wherein Y is C 2 -alkyl, and R 5 and R 6 are H.
9 . The method of claim 1 , wherein R 4 is —CO 2 H, —(CH 2 ) m CO 2 H, —O(CH 2 ) m CO 2 H, —CN, —(CH 2 ) m CN, —O(CH 2 ) m CN, —C(CH 3 ) 2 CO 2 H, —C(CH 3 ) 2 CN, —OC(CH 3 ) 2 CO 2 H, —OC(CH 3 ) 2 CN, —CH(CH 3 )CO 2 H, —CH(CH 3 )CN, —OCH(CH 3 )CO 2 H, —OCH(CH 3 )CN; —CH(CH 2 CH 3 )CO 2 H, —CH(CH 2 CH 3 )CN, —OCH(CH 2 CH 3 )CO 2 H, —OCH(CH 2 CH 3 )CN; —CH(i-Pr)CO 2 H, —CH(i-Pr)CN, —OCH(i-Pr)CO 2 H, —OCH(i-Pr)CN, wherein iPr indicates isopropyl; —CH(t-Bu)CO 2 H, —CH(t-Bu)CN, —OCH(t-Bu)CO 2 H, —OCH(t-Bu)CN, wherein t-Bu indicates t-butyl; —(CHR″) m C(═O)N(R″) 2 , —O(CHR″) m C(═O)N(R″) 2 ,
wherein a wavy line indicates a point of attachment.
10 . The method of claim 1 , wherein for the compound of formula (I), no Z group is present on the ring comprising X 1 -X 5 , providing a compound of formula (IA).
11 . The method of claim 10 , wherein the compound of formula (IA) is any one of:
or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein for the compound of formula (I), Z is present, providing a compound of formula (IB).
13 . The method of claim 12 , wherein Z 1 -Z 5 are all carbon.
14 . The method of claim 12 , wherein the compound of formula (IB) is any one of:
or a pharmaceutically acceptable salt thereof.
15 . The method of claim 1 , wherein the progressive bone disease is osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism.
16 . The method of claim 1 , wherein administration of the compound of formula (I) acts to increase FGF21 while increasing bone health.
17 . Use of a compound of formula (I) for treatment of a progressive bone disease, wherein the compound of formula (I) is:
wherein:
R is H, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl, or (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl;
Y 1 or Y 2 are each independently C or N, provided that when Y 1 or Y 2 is N, R 1 or R 2 , respectively, is absent;
R 1 and R 2 are independently H, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl, or (C 1 -C 6 )haloalkyl; or R 1 and R 2 together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SO q wherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, halo, oxo, (C 1 -C 6 )haloalkyl, nitro, cyano-(C 0 -C 6 )alkyl, R′O 2 C—(C 0 -C 6 )alkyl, methylenedioxy, R′O—(C 0 -C 6 )alkyl, (R′) 2 N—(C 0 -C 6 )alkyl, (R′) 2 NC(═O)—(C 0 -C 6 )alkyl, R′C(═O)N(R′)—(C 0 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, aryl, aroyl, or SO 2 NR′ 2 ;
R 3 is optionally mono- or multi-substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C 1 -C 6 )alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C 1 -C 6 )alkyl; wherein if present each substituent on R 3 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO 2 R′, methylenedioxy, OR′, N(R′) 2 , C(O)N(R′) 2 , (C 1 -C 6 )alkyl-S(O) q , SO 2 NR′ 2 , and (C 1 -C 6 )alkoxyl; and provided that group R 3 N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N 1 or Y 1 ;
wherein each R′ is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 9 )cycloalkyl, (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 ) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O) q ;
wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl is optionally mono- or independently multi-substituted with (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halo, oxo, aryl, or aroyl;
each of X 1 -X 5 is independently N or CH, or is C substituted with an independently selected R 4 or is C substituted with Z, provided that no more than two of X 1 -X 5 are N, and provided that there is no more than one Z group bonded to the ring comprising X 1 -X 5 ;
each R 4 is independently halo, nitro, (C 1 -C 6 )fluoroalkyl, R′—(C 0 -C 6 )alkyl, R′O 2 C—(C 0 -C 6 )alkyl, NC—(C 0 -C 6 )alkyl, R′O—(C 0 -C 6 )alkyl, (R′) 2 N—(C 0 -C 6 )alkyl, (R′) 2 NC(═O)—(C 0 -C 6 )alkyl, R′C(═O)N(R′)—(C 0 -C 6 )alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4-oxadiazol-5(4H)-on)-3-yl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, R'S(O) 2 NHC(O), R′C(O)NHS(O) 2 , an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C 1 -C 6 )alkyl or (C 3 -C 9 )cycloalkyl-(C 0 -C 6 )alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′) 2 , C-bonded tetrazolyl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R 4 is —(C(R″) 2 ) m CO 2 R′, —(C(R″) 2 ) m CON(R′) 2 , —(C(R″) 2 ) m CN, —O(C(R″) 2 ) m CO 2 R′, —O(C(R″) 2 ) m CON(R′) 2 , or —O(C(R″) 2 ) m CN, wherein m is 1, 2, or 3;
R″ is H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 9 )cycloalkyl, (C 3 -C 9 )cycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl(C 1 -C 6 ) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring;
Z is a group of formula
wherein a wavy line indicates a point of bonding, each of Z 1 -Z 5 is independently N or is C substituted with an independently selected H or R 4 ; provided that no more than two of Z 1 -Z 5 are N;
Y is (C 1 -C 2 )alkyl, or sulfur;
when Y is (C 1 -C 2 )alkyl, R 5 and R 6 are independently H or (C 1 -C 4 )alkyl or independently each R 5 and R 6 together with the carbon atom to which they are bonded form a carbonyl, or, one R 5 group can further be bonded to X 5 to form a 4- to 8-membered ring; and,
when Y is sulfur, R 5 and R 6 are both oxygen;
or a pharmaceutically acceptable salt thereof;
wherein the effective dose of the compound acts to inhibit bone resorption, improve bone formation, or both, in the patient.
18 . The use of claim 17 , wherein the progressive bone disease is osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism.
19 . The use of claim 17 , wherein administration of the compound of formula (I) acts to increase FGF21 while increasing bone health.
20 . A compound of formula
or a pharmaceutically acceptable salt thereof.Cited by (0)
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