PPAR-SPARING THIAZOLIDINEDIONES AND COMBINATIONS FOR THE TREATMENT OF DIABETES MELLITUS AND OTHER METABOLIC DISEASES
The present invention relates to thiazolidinedione analogues and pharmaceutical compositions that are useful for treating and/or preventing diabetes mellitis, optionally in combination with a second treatment. Furthermore, the present invention also provides methods of inducing remission of the symptoms of diabetes mellitis in a patient comprising administering a thiazolidinedione analogue and a GLP-1 agonist.
1 . A method of treating or delaying the onset of diabetes mellitus comprising administering to a patient a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
R′ 2 is H;
R 2 is H, halo, hydroxy, or optionally substituted aliphatic, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO 2 )NH 2 , —O—CH(R m )OC(O)R n , —O—CH(R m )OP(O)(OR n ) 2 , —O—P(O)(OR n ) 2 , or
wherein each R m is independently an optionally substituted C 1-6 alkyl, each R n is independently C 1-12 alkyl, C 3-8 cycloalkyl, or phenyl, each of which is optionally substituted, or
R 2 and R′ 2 together form oxo;
R 3 is H; and
Ring A is a phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with an R 1 group and an R 4 group; and
a GLP analogue or a DPP4 inhibitor.
2 . The method of claim 1 , wherein R 4 is H, methyl, methoxy, ethyl, ethoxy, —O-isopropyl, —CF 3 , —OCHF 2 or —OCF 3 .
3 . (canceled)
4 . The method of claim 1 , wherein R 1 is H, alkyl, halo or alkoxy.
5 . (canceled)
6 . (canceled)
7 . The method of claim 4 , wherein R 1 is C 1-3 alkyl.
8 . The method of claim 1 , wherein ring A is phenyl that is substituted with R 1 and R 4 groups at any chemically feasible position on ring A.
9 . The method of claim 1 , wherein ring A is pyridin-2-yl or pyridin-3-yl, either of which is substituted with R 1 and R 4 groups at any chemically feasible position on ring A.
10 . The method of claim 8 , wherein ring A is phenyl, and one of R 1 or R 4 is attached to the para or meta position of ring A.
11 . (canceled)
12 . The method of claim 9 , wherein ring A is pyridin-2-yl, and one of R 1 or R 4 is attached to the 5 position of the ring.
13 . The method of claim 9 , wherein ring A is pyridin-3-yl, and one of R 1 or R 4 is attached to the 6 position of the ring.
14 . The method of claim 10 , wherein R 1 is attached to the para or meta position of ring A.
15 . The method of claim 14 , wherein R 1 is F, Cl, or alkoxy.
16 . (canceled)
17 . The method of claim 15 , wherein R 1 is methoxy, ethoxy, propoxy, —O-isopropyl, butoxy, or —O-tertbutyl.
18 . The method of claim 8 , wherein ring A is phenyl, and R 1 is attached to the meta or ortho position of the phenyl ring.
19 . The method of claim 18 , wherein ring A is phenyl, and R 1 is attached to the ortho position of the phenyl ring.
20 . The method of claim 19 , wherein ring A is phenyl, and R 1 is methoxy, ethoxy, or —O-isopropyl.
21 . The method of claim 19 , wherein ring A is phenyl, and R 1 is —CF 3 , —OCHF 2 or —OCF 3 .
22 . The method of claim 12 , wherein ring A is pyridin-2-yl, and R 1 is attached to the 5 position of the ring.
23 . The method of claim 22 , wherein R 1 is alkyl or alkoxy.
24 . The method of claim 23 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tertbutyl.
25 . The method of claim 1 , wherein R′ 2 is H.
26 . The method of claim 25 , wherein R 2 is hydroxy.
27 . (canceled)
28 . The method of claim 1 , wherein R 2 and R′ 2 together form oxo.
29 . The method of claim 1 , wherein the compound of Formula I is selected from:
30 . (canceled)
31 . (canceled)
32 . (canceled)
33 . (canceled)
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . (canceled)
41 . The method of claim 1 , wherein the compound of Formula I is selected from:
42 . The method of claim 1 , comprising administering to a patient a GLP analogue.
43 . The method of claim 42 , wherein the GLP analogue comprises Exenatide, Exendin-4, Liraglutide, Taspoglatide, GLP-1, or any combination thereof.
44 . The method of claim 1 , comprising administering to a patient a DPP4 inhibitor.
45 . The method of claim 44 , wherein the DPP4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
46 . The method of claim 1 , further comprising administering to the patient a pharmaceutical agent having an activity that increases cAMP in the patient.
47 . The method of claim 46 , wherein the pharmaceutical agent comprises a beta-adrenergic agonist.
48 . (canceled)
49 . The method of claim 47 , wherein the beta-adrenergic agonist comprises noradrenaline, isoprenaline, dobutamine, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol, L-796568, amibegron, solabegron, isoproterenol, albuterol, metaproterenol, arbutamine, befunolol, bromoacetylalprenololmenthane, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, epinephrine, etilefrine, hexoprenaline, higenamine, isoetharine, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractopamine, reproterol, rimiterol, ritodrine, tretoquinol, tulobuterol, xamoterol, zilpaterol, zinterol, or any combination thereof.
50 . A method of treating or delaying the onset of diabetes mellitus comprising administering to a patient an alkali earth metal salt of a compound of Formula I:
wherein:
Each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
R′ 2 is H;
R 2 is H, halo, hydroxy, or optionally substituted aliphatic, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO 2 )NH 2 , —O—CH(R m )OC(O)R n , —O—CH(R m )OP(O)(OR n ) 2 , —O—P(O)(OR n ) 2 , or
wherein each R m is independently an optionally substituted C 1-6 alkyl, each R n is independently C 1-12 alkyl, C 3-8 cycloalkyl, or phenyl, each of which is optionally substituted, or
R 2 and R′ 2 together form oxo;
R 3 is H; and
Ring A is a phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with an R 1 group and an R 4 group; and a GLP analogue or a DPP4 inhibitor.
51 . The method of claim 50 , wherein the alkali earth metal is sodium or potassium.
52 . (canceled)
53 . The method of claim 50 , wherein R 4 is H, methyl, methoxy, ethyl, ethoxy, —O-isopropyl, —CF 3 , —OCHF 2 or —OCF 3 .
54 . (canceled)
55 . The method of claim 50 , wherein R 1 is H, alkyl, halo or alkoxy.
56 . (canceled)
57 . (canceled)
58 . The method of claim 55 , wherein R 1 is C 1-3 alkyl.
59 . The method of claim 50 , wherein ring A is phenyl that is substituted with R 1 and R 4 groups at any chemically feasible position on ring A.
60 . The method of claim 50 , wherein ring A is pyridin-2-yl or pyridin-3-yl, either of which is substituted with R 1 and R 4 groups at any chemically feasible position on ring A.
61 . The method of claim 59 , wherein ring A is phenyl, and one of R 1 or R 4 is attached to the para or meta position of ring A.
62 . (canceled)
63 . The method of claim 60 , wherein ring A is pyridin-2-yl, and one of R 1 or R 4 is attached to the 5 position of the ring.
64 . The method of claim 60 , wherein ring A is pyridin-3-yl, and one of R 1 or R 4 is attached to the 6 position of the ring.
65 . The method of claim 61 , wherein ring A is phenyl, and R 1 is attached to the para or meta position of ring A.
66 . The method of claim 65 , wherein R 1 is F, or Cl, or alkoxy.
67 . (canceled)
68 . The method of claim 66 , wherein R 1 is methoxy, ethoxy, propoxy, —O-isopropyl, butoxy, or —O-tertbutyl.
69 . The method of claim 59 , wherein ring A is phenyl, and R 1 is attached to the meta or ortho position of the phenyl ring.
70 . (canceled)
71 . The method of claim 69 , wherein R 1 is methoxy, ethoxy, or —O-isopropyl.
72 . The method of claim 69 , wherein R 1 is —CF 3 , —OCHF 2 or —OCF 3 .
73 . The method of claim 63 , wherein ring A is pyridin-2-yl, and R 1 is attached to the 5 position of the ring.
74 . The method of claim 73 , wherein R 1 is alkyl or alkoxy.
75 . The method of claim 74 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tertbutyl.
76 . The method of claim 50 , wherein R′ 2 is H.
77 . The method of claim 76 , wherein R 2 is hydroxy.
78 . (canceled)
79 . The method of claim 50 , wherein R 2 and R′ 2 together form oxo.
80 . The method of claim 50 , wherein the compound of Formula I is selected from:
81 . (canceled)
82 . (canceled)
83 . (canceled)
84 . (canceled)
85 . (canceled)
86 . (canceled)
87 . (canceled)
88 . (canceled)
89 . (canceled)
90 . (canceled)
91 . (canceled)
92 . The method of claim 50 , wherein the compound of Formula I is selected from:
93 . The method of claim 50 , comprising administering to the patient a GLP analogue.
94 . The method of claim 93 , wherein the GLP analogue comprises Exenatide, Exendin-4, Liraglutide, Taspoglatide, GLP-1, or any combination thereof.
95 . The method of claim 50 , comprising administering to a patient a DPP4 inhibitor.
96 . The method of claim 95 , wherein the DPP4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
97 . The method of claim 50 , further comprising administering to the patient a pharmaceutical agent having an activity that increases cAMP in the patient.
98 . The method of claim 97 , wherein the pharmaceutical agent comprises a beta-adrenergic agonist.
99 . (canceled)
100 . The method of claim 98 , wherein the beta-adrenergic agonist comprises noradrenaline, isoprenaline, dobutamine, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol, L-796568, amibegron, solabegron, isoproterenol, albuterol, metaproterenol, arbutamine, befunolol, bromoacetylalprenololmenthane, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, epinephrine, etilefrine, hexoprenaline, higenamine, isoetharine, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractopamine, reproterol, rimiterol, ritodrine, tretoquinol, tulobuterol, xamoterol, zilpaterol, zinterol, or any combination thereof.
101 . A pharmaceutical composition comprising a compound of Formula I,
wherein:
Each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
R′ 2 is H;
R 2 is H, halo, hydroxy, or optionally substituted aliphatic, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO 2 )NH 2 , —O—CH(R m )OC(O)R n , —O—CH(R m )OP(O)(OR n ) 2 , —O—P(O)(OR n ) n , or
wherein each R m is independently an optionally substituted C 1-6 alkyl, each R n is independently C 1-12 alkyl, C 3-8 cycloalkyl, or phenyl, each of which is optionally substituted, or
R 2 and R′ 2 together form oxo;
R 3 is H; and
Ring A is a phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with an R 1 group and an R 4 group; and a GLP analogue.
102 . The pharmaceutical composition of claim 101 , wherein the GLP analogue comprises Exenatide, Exendin-4, Liraglutide, Taspoglatide, GLP-1, or any combination thereof.
103 . A pharmaceutical composition comprising a compound of Formula I,
wherein:
Each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
R′ 2 is H;
R 2 is H, halo, hydroxy, or optionally substituted aliphatic, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO 2 )NH 2 , —O—CH(R m )OC(O)R n , —O—CH(R m )OP(O)(OR n ) 2 , —O—P(O)(OR n ) n , or
wherein each R m is independently an optionally substituted C 1-6 alkyl, each R n is independently C 1-12 alkyl, C 3-8 cycloalkyl, or phenyl, each of which is optionally substituted, or
R 2 and R′ 2 together form oxo;
R 3 is H; and
Ring A is a phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with an R 1 group and an R 4 group; and a DPP4 inhibitor.
104 . The pharmaceutical composition of claim 103 , wherein the DPP4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
105 . (canceled)
106 . (canceled)
107 . (canceled)
108 . A pharmaceutical composition comprising an alkali earth metal salt of a compound of Formula I,
wherein:
Each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
R′ 2 is H;
R 2 is H, halo, hydroxy, or optionally substituted aliphatic, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO 2 )NH 2 , —O—CH(R m )OC(O)R n , —O—CH(R m )OP(O)(OR n ) 2 , —O—P(O)(OR n ) n , or
wherein each R m is independently an optionally substituted C 1-6 alkyl, each R n is independently C 1-12 alkyl, C 3-8 cycloalkyl, or phenyl, each of which is optionally substituted, or
R 2 and R′ 2 together form oxo;
R 3 is H; and
Ring A is a phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with an R 1 group and an R 4 group; and a GLP analogue or a DDP4 inhibitor.
109 . The pharmaceutical composition of claim 108 , further comprising a GLP analogue selected from Exenatide, Exendin-4, Liraglutide, Taspoglatide, GLP-1, or any combination thereof.
110 . (canceled)
111 . The pharmaceutical composition of claim 108 , further comprising a DPP4 inhibitor selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
112 . (canceled)
113 . The pharmaceutical composition of claim 108 , further comprising a beta-adrenergic agonist selected from noradrenaline, isoprenaline, dobutamine, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol, L-796568, amibegron, solabegron, isoproterenol, albuterol, metaproterenol, arbutamine, befunolol, bromoacetylalprenololmenthane, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, epinephrine, etilefrine, hexoprenaline, higenamine, isoetharine, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractopamine, reproterol, rimiterol, ritodrine, tretoquinol, tulobuterol, xamoterol, zilpaterol, zinterol, or any combination thereof.
114 - 168 . (canceled)