US2004063717A1PendingUtilityA1
Method of treating diabetes
Priority: May 21, 2002Filed: May 21, 2003Published: Apr 1, 2004
Est. expiryMay 21, 2022(expired)· nominal 20-yr term from priority
A61P 3/06A61P 3/10A61P 43/00A61K 9/4866A61K 9/2027A61P 27/02A61K 9/0095A61K 45/06A61K 9/0014A61K 9/0075A61K 31/495A61K 9/0019A61K 9/02A61K 9/2054A61K 31/496
48
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Claims
Abstract
Methods are provided for treating diabetes, lowering plasma level of HbA1c, glucose plasma levels, total cholesterol plasma level, and/or triglyceride plasma level while increasing HDL cholesterol levels and delaying onset of diabetic retinopathy in a diabetic, pre-diabetic, or non-diabetic mammal while minimizing undesirable side effects.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating diabetes in a mammal, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
2 . The method of claim 1 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
3 . The method of claim 2 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 1 and R 4 , R 1 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
5 . The method of claim 4 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
6 . A method of lowering plasma level of HbA1c in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
7 . The method of claim 6 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
8 . The method of claim 7 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
9 . The method of claim 6 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 1 and R 7 , R 3 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
10 . The method of claim 9 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
11 . A method of lowering triglyceride plasma level in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
12 . The method of claim 11 wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
13 . The method of claim 12 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
14 . The method of claim 11 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
15 . The method of claim 14 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
16 . A method of lowering glucose plasma level in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
17 . The method of claim 16 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
18 . The method of claim 17 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
19 . The method of claim 16 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
20 . The method of claim 19 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
21 . A method of lowering total cholesterol plasma level in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
22 . The method of claim 21 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
23 . The method of claim 22 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
24 . The method of claim 21 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
25 . The method of claim 24 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
26 . A method for delaying onset of diabetic retinopathy in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
27 . The method of claim 26 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
28 . The method of claim 27 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
29 . The method of claim 26 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 11 and R 12 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
30 . The method of claim 29 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
31 . A method of raising HDL cholesterol plasma level in a mammal, wherein the mammal is diabetic, non-diabetic, or pre-diabetic, comprising administration of a therapeutically effective amount of a partial fatty acid oxidation inhibitor to a mammal in need thereof.
32 . The method of claim 31 , wherein the partial fatty acid oxidation inhibitor is a compound Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof.
33 . The method of claim 32 , wherein the partial fatty acid oxidation inhibitor is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable salt thereof.
34 . The method of claim 31 , wherein the partial fatty acid oxidation inhibitor is a compound of Formula II:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, lower alkyl, or —C(O)R;
in which R is —OR 9 or —NR 9 R 10 , where R 9 and R 10 are hydrogen or lower alkyl; or
R 1 and R 2 , R 1 and R 4 , R 5 and R 6 , R 7 and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or
R 1 and R 5 , or R 1 and R 7 , or R 3 and R 5 , or R 3 and R 7 , when taken together form a bridging group —(CR 12 R 13 ) n —, in which n is 1, 2 or 3, and R 12 and R 13 are independently hydrogen or lower alkyl; with the proviso that the maximum number of carbonyl groups is 2; the maximum number of —C(O)NR 9 R 10 groups is 1; and the maximum number of bridging groups is 1;
T is oxygen, sulfur, or NR 11 , in which R 11 is hydrogen or lower alkyl;
V is —N<, —CH<, or —N—CH<;
X 1 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
X 2 is optionally substituted aryl or optionally substituted heteroaryl;
Y is optionally substituted monocyclic heteroaryl; and
Z 1 and Z 2 are independently optionally substituted alkylene of 1-4 carbon atoms.
35 . The method of claim 34 , wherein the partial fatty acid oxidation inhibitor of Formula II is 1-{4-[5-(4-trifluoromethylphenyl))-[1,2,4]-oxadiazol-3-ylmethyl]-piperazin-1-yl}-3-(2-methylbenzothiazol-1,5-yloxy)-propan-2-ol; as a racemic mixture, or an isomer thereof.
36 . The method of claim 1 , wherein the partial fatty acid oxidation inhibitor is administered as an immediate release formulation.
37 The method of claim 1 , wherein the partial fatty acid oxidation inhibitor is administered as a sustained release formulation.
38 . The method of claim 1 , wherein the partial fatty acid oxidation inhibitor is administered in a formulation that has both immediate release and sustained release aspects.
39 . The method of claim 37 , wherein the partial fatty acid oxidation inhibitor is ranolazine.
40 . The method of claim 39 , wherein the sustained release formulation provides a plasma level of ranolazine between 550 and 7500 ng base/ml over a 24 hour period.
41 . The method of claim 40 , wherein the sustained release formulation comprises
Weight
Ingredient
Range (%)
Ranolazine
75
Microcrystalline cellulose (filler)
10.6
Methacrylic acid copolymer
10.0
Sodium hydroxide
0.4
Hydroxypropyl methylcellulose
2.0
Magnesium stearate
2.0
42 . The method of claim 41 , wherein the sustained release formulation comprises:
Ingredient
Ranolazine Form'n (mg)
Ranolazine
500
Microcrystalline cellulose (filler)
70.7
Methacrylic acid copolymer
66.7
Sodium hydroxide
2.7
Hydroxypropyl methylcellulose
13.3
Magnesium stearate
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