PPAR-SPARING THIAZOLIDINEDIONES AND COMBINATIONS FOR THE TREATMENT OF OBESITY AND OTHER METABOLIC DISEASES
The present invention relates to thiazolidinedione analogues and pharmaceutical compositions that are useful for treating and/or preventing obesity or diabetes, optionally in combination with a second treatment therapy such a diet restriction or an increase in duration or exertion in physical activity.
1 . A method of treating or delaying the onset of obesity 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 at any chemically feasible position on ring A.
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 . The method of claim 2 , wherein R 4 is H.
4 . The method of claim 3 , wherein R 1 is H, alkyl, halo or alkoxy.
5 . (canceled)
6 . (canceled)
7 . (canceled)
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 . The method of claim 10 , wherein ring A is phenyl, and one of R 1 or R 4 is attached to the meta position of ring A.
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 16 , 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, —O-isopropyl —CF 3 —OCHF 2 or —OCF 3 .
21 . (canceled)
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 hydroxyl, —O-acyl, —O-aroyl, or —O-heteroaroyl.
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 . A method of treating or delaying the onset of obesity 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.
43 . The method of claim 42 , wherein the alkali earth metal comprises sodium or potassium.
44 . (canceled)
45 . The method of claim 43 , wherein R 4 is H, methyl, methoxy, ethyl, ethoxy, —O-isopropyl, —CF 3 , —OCHF 2 or —OCF 3 .
46 . (canceled)
47 . The method of claim 43 , wherein R 1 is H, alkyl, halo or alkoxy.
48 . (canceled)
49 . (canceled)
50 . (canceled)
51 . The method of claim 43 , wherein ring A is phenyl that is substituted with R 1 and R 4 groups at any chemically feasible position on ring A.
52 . The method of claim 43 , 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.
53 . The method of claim 51 , wherein ring A is phenyl, and one of R 1 or R 4 is attached to the para or meta position of ring A.
54 . The method of claim 53 , wherein ring A is phenyl, and one of R 1 or R 4 is attached to the meta position of ring A.
55 . The method of claim 52 , wherein ring A is pyridin-2-yl, and one of R 1 or R 4 is attached to the 5 position of the ring.
56 . The method of claim 52 , wherein ring A is pyridin-3-yl, and one of R 1 or R 4 is attached to the 6 position of the ring.
57 . The method of claim 53 , wherein R 1 is attached to the para or meta position of ring A.
58 . The method of claim 57 , wherein R 1 is F, Cl, or alkoxy.
59 . (canceled)
60 . The method of claim 58 , wherein R 1 is methoxy, ethoxy, propoxy, —O-isopropyl, butoxy, or —O-tertbutyl.
61 . The method of claim 51 , wherein ring A is phenyl, and R 1 is attached to the meta or ortho position of the phenyl ring.
62 . The method of claim 61 , wherein ring A is phenyl, and R 1 is attached to the ortho position of the phenyl ring.
63 . The method of claim 62 , wherein ring A is phenyl, and R 1 is methoxy, ethoxy, —O-isopropyl —CF 3 —OCH 3 —OCHF 2 or —OCF 3 .
64 . (canceled)
65 . The method of claim 55 , wherein ring A is pyridin-2-yl, and R 1 is attached to the 5 position of the ring.
66 . The method of claim 65 , wherein R 1 is alkyl or alkoxy.
67 . The method of claim 66 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tertbutyl.
68 . The method of claim 43 , wherein R′ 2 is H.
69 . The method of claim 68 , wherein R 2 is hydroxyl, —O-acyl, —O-aroyl, or —O-heteroaroyl.
70 . (canceled)
71 . The method of claim 43 , wherein R 2 and R′ 2 together form oxo.
72 . The method of claim 43 , wherein the compound of Formula I is selected from:
73 . A method for reducing the bodyweight of a patient 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 at an chemically feasible position on ring A.
74 . The method of claim 73 , further comprising administering to a patient a second pharmaceutical agent having an activity that increases cAMP in the patient.
75 . The method of claim 74 , wherein the second pharmaceutical agent further comprises a beta-adrenergic agonist.
76 . The method of claim 75 , wherein the beta-adrenergic agonist comprises a beta-1-adrenergic agonist, a beta-2-adrenergic agonist, a beta-3-adrenergic agonist, or any combination thereof.
77 . The method of claim 75 , 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.
78 . The method of claim 1 , wherein the obesity being treated or delayed is central obesity.
79 . The method of claim 1 , further comprising restricting the diet of the patient.
80 . The method of claim 79 , further comprising increasing the duration or exertion of the patient's physical activity.
81 . 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 ) 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′ 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 or an alkali earth metal salt thereof, a second pharmaceutical agent having an activity that increases cAMP in a patient, and a pharmaceutically acceptable carrier.
82 . The pharmaceutical composition of claim 81 , wherein the second pharmaceutical agent comprises a beta-adrenergic agonist.
83 . (canceled)
84 . The pharmaceutical composition of claim 82 , 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.
85 . A pharmaceutical composition comprising a compound selected from:
a second pharmaceutical agent having an activity that increases cAMP in a patient, and a pharmaceutically acceptable carrier.
86 . A pharmaceutical composition comprising an alkali earth metal salt of a compound selected from:
a second pharmaceutical agent having an activity that increases cAMP in a patient, and a pharmaceutically acceptable carrier.
87 . The composition of claim 86 , wherein the alkali earth metal is sodium or potassium.
88 . (canceled)
89 . A method of treating or delaying the onset of obesity comprising administering to a patient an alkali earth metal salt of a compound selected from:
90 . The method of claim 89 , wherein the alkali earth metal is sodium or potassium.
91 . The method of claim 90 , further comprising administering to the patient a second pharmaceutical agent having an activity that increases cAMP in a patient.